Novel substituted pyrazine-carboxamide derivatives

Abstract

This invention relates to formula I: This relates to the compounds of JPEG2026512972000438.jpg4271, methods for their manufacture, pharmaceutical compositions containing them, and their use in the treatment of conditions related to the function of metabotropic glutamate receptor subtype 4 (mGluR4), in particular, and / or in the prevention of such conditions. A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 The terms have the meanings provided herein.

Description

[Technical Field]

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

[0002] L-glutamate (hereinafter referred to as glutamate) is one of the most abundant excitatory neurotransmitters in the vertebrate brain. Dysfunction of the brain's glutamatergic system often leads to neurological or psychiatric disorders. Therefore, modulation of the glutamatergic system is considered an attractive therapeutic approach. Glutamate acts through different types of glutamate receptors located on the cell surface. These include AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) exert their effects through coupling to G proteins and activation of a second messenger system. mGluR subtypes are classified into three groups (based on sequence homology, pharmacology, and a second messenger system), with Group III being the largest group (mGluR4, mGluR6, mGluR7, mGluR8) [Conn and Pin, Annu Rev Pharmacol Toxicol, 1997, 37: 205-237]. Group III mGlu receptors primarily share presynaptic expression (Schoepp, Pharmacol Exp Ther, 2001, 299: 12-20), where they regulate glutamic and GABAic transmission. Activation of Group III receptors (including mGluR4) reduces neurotransmitter release due to its activation of Gαi / o, which leads to attenuated adenylyl cyclase activity.

[0003] mGluR4 receptors are primarily located in the presynaptic terminals of nerve endings. mGluR4 expression is evident in multiple brain regions, with particularly high expression rates in the basal ganglia and cerebellum. Due to its role in regulating mGluR4 expression and neurotransmitter release within related brain circuits, mGluR4 modulators are thought to influence the regulation of excitation / inhibition balance, which is crucial for behavioral control (including Parkinson's disease), impulse control, learning and memory, cognition, anxiety, pain, cerebellar function, epilepsy, and information processing (Marino et al. Ann NY Acad Sci, 2003, 1003: 435-437; Isherwood et al. Neuropharmacology 2017, 123: 249-260; Makoff et al. Mol Brain Res, 1996, 37: 239-248; Davis et al. Neuropharmacology 2013, 66: 365-372; Iscru et al. Genes Brain Behav. 2013, 12: 615-625; Szczurowska and Mares, (Physiol Res, 2012, 61: 619-628) are not the only effects of this drug. Since mGluR4 has been reported to be expressed in peripheral tissues, including but not limited to the islets of Langerhans, it is thought that mGluR4 antagonists may also have therapeutic effects in metabolic disorders, gastrointestinal disorders, and cancer, but not limited to these (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). Since mGluR4 has been reported to be expressed in vagal afferent pathways, as well as in the central satiety pathway and brain circuits, it is thought that antagonists of mGluR4 function may also have therapeutic effects in disorders including, but not limited to, overweight and obesity (Blackshow et al. Front Neurosci 2011, 5: 40; 1-7; Page et al. Br J Pharmacol. 2012, 166: 1537-1558).

[0004] WO21028512 describes aryl sulfonamides as mGluR4 NAM. However, the activity of these compounds appears to be too low to be applicable as pharmaceuticals, and in particular, the activity of acidic aryl sulfonamides appears to be too low because they may be further exposed to the blood-brain barrier, which limits brain exposure for CNS applications. [Overview of the project]

[0005] Detailed description of the invention The present invention provides novel substituted pyrazine-carboxamide derivatives, which are unexpectedly potent mGluR4 negative modulators, namely compounds of formula I (Embodiment 1), or physiologically acceptable salts thereof.

[0006] [ka] (In the formula, A represents C1-C6-alkyl, C3-C6-cycloalkyl, C3-C5-cycloalkyl-C1-C2-alkyl-, C1-C3-alkyl-O-C1-C3-alkyl-, 4- to 6-membered heterocycloalkyl-, 4- to 6-membered heterocycloalkyl-C1-C3-alkyl-, and the latter groups may be substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, and fluoro. R 1 represents C1-C7-alkyl, C1-C3-alkyl-O-C1-C3-alkyl-, C3-C7-cycloalkyl, 4- to 6-membered heterocycloalkyl, C3-C7-cycloalkyl-C1-C3-alkyl-, 4- to 6-membered heterocycloalkylmethyl-, C5-C6-heterocycloalkyl ethyl-, and the latter groups may be substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, C3-C7-cycloalkoxy, hydroxy, and fluoro. R 2 R 3 R 4 and R 5 are, independently of each other, hydrogen, halogen, cyano, C1-C4-alkyl, C1-C3-alkyl-O-C1-C3-alkyl-, C3-C6-cycloalkyl, 4- to 6-membered C4-C6-heterocycloalkyl, C1-C4-alkoxy-, C3-C6-cycloalkoxy-, and the latter six groups may be substituted with 1 to 4 substituents selected from C1-C4-alkyl, C1-C4-alkoxy, hydroxy, and fluoro. Provided that as a condition, at least one of the R 2 R 3 R 4 and R 5 groups is not hydrogen. R 6 represents halogen, C1-C3-alkyl optionally substituted with 2 to 3 fluorine atoms).

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

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

[0009] In a further embodiment according to any one of the above embodiments, in general formula I, R 2 , R 3 , R 4 and R 5 These independently represent hydrogen, fluoro, chloro, bromo, cyano, methyl, cyclopropyl, and methoxy, and the latter three groups may be substituted with two or three fluoro substituents. However, the condition is R 2 , R 3 , R 4 and R 5 At least one of the groups is not hydrogen.

[0010] In a further embodiment according to any one of the above embodiments, in general formula I, R 6 This represents a C1-C3 alkyl group that may be substituted with 2-3 fluorine atoms. In another embodiment according to one of the above embodiments, in general formula I, A is

[0011] [ka] This represents a group selected from the group that includes it. In another embodiment according to one of the above embodiments, in general formula I, R 1 teeth,

[0012] [ka] This represents a substituent selected from the group consisting of the following.

[0013] In another embodiment according to one of the above embodiments, in general formula I, R 2 This represents hydrogen. In another embodiment according to one of the above embodiments, in general formula I, R 3 The characters represent hydrogen, fluoro, bromo, and trifluromethyl. In another embodiment according to one of the above embodiments, in general formula I, R 4 These represent hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluromethyl, CF3O-, and CHF2O-. In another embodiment according to one of the above embodiments, in general formula I, R 5 These represent hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl, and methoxy. In another embodiment according to one of the above embodiments, in general formula I, R 6 This represents methyl, trifluromethyl, and -CF2H.

[0014] The compounds of the present invention are effective mGluR4 negative modulators that inhibit the function of mGluR4, thereby blocking glutamate-induced intracellular cAMP reduction. Thus, the present invention provides compounds for use in the treatment of mGluR4-mediated disorders. The present invention further provides a method for treating mGluR4-mediated disorders in human subjects, comprising administering to a subject a compound, a composition of the compound, or a pharmaceutically acceptable salt thereof of the present invention.

[0015] In one embodiment, the present invention relates to a method for treating a condition in which the severity of the condition can be reduced by administering a compound described herein that inhibits mGluR4 function by reducing mGluR4 activity, for example, a compound that inhibits glutamate-induced intracellular cAMP reduction. Described herein are measured IC50 for mGluR4 inhibition at 100 nanometers, preferably 50 nM or less. 50 It is a compound that possesses mGluR4 function and is an antagonist. In another embodiment, compounds described herein that are mGluR4 function antagonists may be used to inhibit mGluR4 function, for example, mGluR4-mediated glutamate-induced intracellular cAMP reduction. In some embodiments, compounds described herein may be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction in vitro, for example, in cells in culture medium. In other embodiments, compounds described herein may be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP reduction in vivo.

[0016] definition Terms not specifically defined herein should be given the meanings that a person skilled in the art would assign to them in light of this disclosure and context. The terms “negative modulator,” “antagonist,” and “inhibitor” are interchangeable and refer to agents that reduce or suppress biological activity, such as reducing receptor activity, and include negative allosteric modulators (NAMs). The mGluR4 receptor described herein includes homomultimeric and heteromultimeric structures (e.g., homomultimeric mGluR4 and heterologous mGluR4-mGluR2). Inhibitors of mGluR4 function include inhibitors having any combination of the structural and / or functional properties disclosed herein.

[0017] In terms of methods of inhibition or treatment of the subject matter, the “effective dose” of an (mGluR4) antagonist refers to the amount of antagonist in a preparation that, when applied as part of a desired dosage regimen, produces the desired clinical or functional outcome. While not wishing to be bound by theory, an effective dose of an mGluR4 antagonist for use in the methods of the present invention would be the amount of mGluR4 antagonist effective in reducing the in vitro or in vivo function of one or more mGluR4 receptors. Illustrative functions include, but are not limited to, changes in intracellular cAMP, or the release of synaptic neurotransmitters, or changes in neuronal activity or modulation of impulsive behavior. Compounds that antagonize mGluR4 function include compounds that antagonize the in vitro or in vivo functional activity of mGluR4. When a particular functional activity can be immediately observed only in an in vitro assay, the ability of a compound to inhibit mGluR4 function in that in vitro assay acts as a reasonable substitute for the activity of that compound. In certain embodiments, the effective dose is sufficient to inhibit mGluR4-mediated cellular function.

[0018] mGluR4 antagonists for use in the methods of the present invention may be characterized according to their action or lack of action on one or more receptors. When other receptors are referred to, inhibition of the function of such other receptors is similarly defined. For example, receptor inhibition or receptor activation means that the antagonist inhibits the functional activity of one or more of the other receptors. Such functions include, for example, transmembrane signaling, and / or changes in the intracellular concentration of intracellular substances such as cAMP mediated by a particular receptor, and subsequent functions such as neurotransmitter release. The terms "compound" and "agent" are interchangeable and used to refer to the negative modulator of the present invention.

[0019] In the groups, radicals, or subgroups defined below, the number of carbon atoms is often specified before the group; for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups containing two or more subgroups, the last designated subgroup is the chemical bond site of the group; for example, the substituent "aryl-C1-3-alkyl-" means an aryl group bonded to a C1-3-alkyl- group, the latter of which is bonded to the core or the group to which the substituent is chemically bonded. If the compounds of the present invention are described in terms of their chemical names and formulas, in the event of any discrepancy, the formula shall prevail. An asterisk can be used in a sub-formula to indicate a bond connected to the defined core molecule.

[0020] Stereochemistry / solvates / hydrates The compounds described herein may be chiral (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by the resolution of racemic mixtures or by stereoselective synthesis.

[0021] The separation of racemic mixtures of compounds can be carried out by any of the many methods known in the art. An example of such a method is fractional crystallization using a “chiral resolving agent” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional crystallization are, for example, optically active acids, such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or a variety of optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R- forms, or diastereomerically pure forms), 2-phenylglycinol, norefedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane. The separation of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art. The compounds of the present invention also include tautomers, such as keto-enol tautomers.

[0022] Unless otherwise indicated, throughout this specification and the accompanying "Claims," ​​a given chemical formula or name will encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers) and racemic compounds thereof, as well as mixtures of different enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the aforementioned forms in which such isomers and enantiomers exist. The compounds of the present invention may also include all isotopes of atoms generated in the intermediate or final compound. For example, the compounds of the present invention may include radioactive isotopes, such as tritium. 3 H) or carbon-14 ( 14 C) may be radiolabeled. All variations of the isotope, whether radioactive or not, are intended to be included within the scope of this invention.

[0023] salt The phrase “medically acceptable” is used herein to mean a compound, material, composition and / or dosage form that is suitable for use without excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit / risk ratio, within the bounds of sound medical judgment. As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound, wherein the parent compound forms a salt with an acid or a base. Examples of acids that form pharmaceutically acceptable salts with parent compounds containing a basic moiety include mineral acids 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-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid and galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0024] The neutralized form of the compound of the present invention is preferably regenerated by contacting the salt with a base or acid in a conventional method to isolate the parent compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; otherwise, the salt is equivalent to the parent form of the compound for the purposes of the present invention.

[0025] halogen The term "halogen" generally refers to fluorine, chlorine, bromine, and iodine. Alkyl The term "C1-n-alkyl" (wherein n is an integer from 2 to n) refers to an acyclic, saturated, branched, or linear hydrocarbon group having 1 to n carbon atoms, either alone or in combination with another group. For example, the term C1-C5-alkyl includes the following groups: 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)-.

[0026] Cycloalkyl The term "C3-n-cycloalkyl" (wherein n is an integer from 4 to n) refers to a cyclic, saturated, unbranched hydrocarbon group having 3 to n carbon atoms, either alone or in combination with another group. For example, the term C3-7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Heterocycloalkyl The term "heterocycloalkyl" refers to a saturated or unsaturated, mono- or polycyclic ring system containing an aromatic ring system consisting of 3 to 14 ring atoms, with one or more heteroatoms selected from N, O, or S(O)r (where r=0, 1, or 2), where none of the heteroatoms are part of the aromatic ring. Many of the terms assigned above may be used repeatedly in the definitions of formulas or bases, and in each instance, independently of each other, have one of the meanings assigned above.

[0027] According to the present invention, compounds of general formula (I) can be obtained by methods that are known in themselves, for example, by the following methods. (a) General formula (I): [ka] (In the formula, A and R 1 ~R 6 It is defined as described in Embodiment 1, Furthermore, this may be protected at any amino, hydroxy, carboxy, or thiol group through common protecting groups, such as those described in, for example, TW Greene, PGM Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and protecting groups that can be cleaved by methods known from the literature. The preparation of the compound may be described in the examples, or it may be carried out by a combination of reaction steps in the formula in Scheme 1 below, for example.

[0028] Scheme 1 [ka]

[0029] [ka] During the ceremony, Q is a leaving group, or for example, a halogen atom, hydroxyl, C 1-4 - Indicates a group that can be converted in situ to a leaving group such as alkyloxy, alkyloxycarbonyloxy, 4-pentafluorophenyloxy, nitrophenyloxy, trichloromethyl, or acyloxy, or together with a carbonyl group, indicates an alkali carboxylate group. and R11 represents a protecting group for carboxylate functional groups known from the literature, such as tert.-butyl, methyl, ethyl, allyl, or benzyl groups. R12 represents a protecting group for an amino functional group known from the literature, such as tert.-butoxycarbonyl, benzyloxycarbonyl, or trifluoroacetyl. R13 represents a leaving group for the alkylation reaction, such as an iodine atom or a bromine atom, or a tosylate group or a mesylate group. R14 represents a leaving group for nucleophilic aromatic substitution reactions, such as a fluorine atom or a chlorine atom.

[0030] [ka] The reaction step i (substitution) shown in Scheme 1 may be carried out in the manner described in the examples or under conditions known from the literature, for example: The compound of general formula II is mixed with the compound of general formula XIII in a solution such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution, or sulfolane, optionally in the presence of an inorganic or organic base such as potassium carbonate, sodium hydrate, triethylamine, or a Huenig base, at a temperature between -20°C and 200°C, preferably between -10°C and 100°C.

[0031] [ka] The reaction step ix (substitution, followed by nitro reduction) shown in Scheme 1 may be carried out in the manner described in the examples or under conditions known from the literature, for example: The substitution of substituent IX with amine XII, as described above, leads to a nitro reduction as described below: Nitro reduction to an amine group can be achieved in an aqueous solvent, such as water, isopropanol / water, tetrahydrofuran / water, or 1,4-dioxane / water, or in a solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, or 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 allanate, at a temperature between -40 and 100°C, preferably between -10°C and 50°C. Alternatively, reduction can be achieved with hydrogen 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, in the presence of a catalyst such as palladium / activated carbon, Raney nickel, or platinum, at a temperature between -20°C and 50°C, preferably 0°C to ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably 1 to 5 bar.

[0032] [ka]

[0033] Reaction steps ii and iv (acylation) may be carried out in the manner described in the examples or under conditions known from the literature, for example: This is achieved by acylation of an amine (III or IV) with an optionally activated carboxylic acid (XI).

[0034] The acylation is preferably carried out at a temperature between -20°C and 200°C, but more preferably between -10°C and 100°C, in a solvent such as dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, sodium hydroxide solution, or sulfolane, with the corresponding halide or anhydride, and optionally in the presence of an inorganic or organic base such as potassium carbonate, sodium hydrate, triethylamine, or a Hünig base.

[0035] However, acylation may also be carried out with a free acid in the presence of an acid activator or dehydrating agent, for example, ethyl-1-ethoxy-1,2-dihydroquinoline-1-carboxylate, isobutylchloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, cycloanhydride propane phosphate, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide / camphorsulfonic acid, N,N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxybenzotriazole, N,N'-carbonyldiimidazole, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate / N-methylmorpholine, O-(benzotriazole-1- The experiment may be carried out at a temperature between -20°C and 200°C, preferably between -10°C and 160°C, in the presence of (yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N-ethyldiisopropylamine, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate / N-methylmorpholine, O-pentafluorophenyl-N,N,N',N'-tetramethyluronium-hexafluorophosphate / triethylamine, N,N'-thionyldiimidazole, or triphenylphosphine / carbon tetrachloride, optionally with the addition of a sodium hydroxide solution, cesium, potassium carbonate, sodium carbonate, or bicarbonate, or an amine base such as pyridine, triethylamine, N-methylmorpholine, or diisopropylethylamine.

[0036] Other methods of amide coupling are described, for example, in "Comprehensive Functional Group Interconversions", Vol. 5, page 257ff., Pergamon 1995 by PD Bailey, ID Collier, and KM Morgan, or in Houben-Weyl Supplementary Volume 22, published by Thieme, 2003, and in the references cited therein.

[0037] [ka] Reaction step viiii (acylation followed by deprotection) may be carried out in the manner described in the examples or under conditions known from the literature, for example: The acylation of the amine-retaining substrate VII, as described above, with reagent XI, is followed by the cleavage of the protecting group, as described below: Any protecting group used may be subsequently cleaved by hydrolysis in an aqueous solvent, such as water, isopropanol / water, tetrahydrofuran / water, or 1,4-dioxane / water, at a temperature between 0°C and 100°C, preferably between 10°C and 50°C, by ether splitting in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or an alkali metal base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, or in the presence of iodotrimethylsilane, for example.

[0038] However, each of the benzyl, methoxybenzyl, or benzyloxycarbonyl groups is hydrocracking by hydrogen 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 between 0°C and 50°C, preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably 1 to 5 bar, in the presence of a catalyst such as palladium / activated carbon. However, the protecting group may also be cleaved by the method described by TW Greene and PGM Wuts in "Protective Groups in Organic Synthesis," Wiley, 1991 and 1999.

[0039] [ka]

[0040] Reaction steps iii and v (acylation, followed by cyclization) may be carried out in the manner described in the examples or under conditions known from the literature, for example: The acylation of amine-retaining substrate VI or VII with free carboxylic acid V, as described above, proceeds to the cyclization described below: Cyclization is preferably carried out in a solvent or solvent mixture, such as ethanol, isopropanol, acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, or tetralin, dimethyl sulfoxide, dichloromethane, chloroform, or tetrachloromethane, at a temperature between 0°C and 250°C, but preferably between 20°C and 100°C, optionally in the presence of a coupling agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphate, acetic acid, acetic anhydride, or N,N'-dicyclohexylcarbodiimide, or optionally in the presence of a base such as potassium methoxide or potassium tert.-butoxide, or in the presence of a metal salt such as lithium bromide, aluminum bromide, zinc bromide, or aluminum-doped montmorillonite clay. However, cyclization can also be carried out without a solvent and / or coupling agent.

[0041] [ka]

[0042] Reaction steps vi and vii (acylation, followed by deprotection and cyclization) may be carried out in the manner described in the examples or under conditions known from the literature, for example: The acylation of the amine-retaining substrate VI, as described above, with reagent X, proceeds to the cleavage of the protecting group as described above, followed by the cyclization as described above.

[0043] [ka]

[0044] The reaction step x (acylation followed by deprotection) shown in Scheme 1 may be carried out in the manner described in the examples or under conditions known from the literature, for example: The acylation of substrate VI with a carboxylic acid or carboxylic acid derivative X, as described above, is followed by the deprotection described above.

[0045] [ka]

[0046] The reaction step xi (acylation followed by cyclization) shown in Scheme 1 may be carried out in the manner described in the examples or under conditions known from the literature, for example: The acylation of substrate XIV with a carboxylic acid or carboxylic acid derivative XI, as described above, proceeds to the cycloaddition described above.

[0047] The terms “mGluR4,” “mGluR4 protein,” and “mGluR4 receptor” are used interchangeably throughout this application. Unless expressly stated otherwise, the term “mGluR4” includes homomultimeric structures (e.g., homomultimeric mGluR4) and heteromultimeric structures (e.g., heteromultimeric mGluR4-mGluR2).

[0048] Biological assays The biological activity of the compound is determined by the following method: In vitro study of the efficacy of A. mGluR4 The in vitro activity of the compounds according to the present invention can be studied as follows: HEK293 cells overexpressing human metabolic glutamate receptor 4 are thawed at 37°C and immediately diluted in cell culture medium. After centrifugation, the cell pellet is resuspended in culture medium and then distributed from a stirred spinner flask into the wells of an assay plate. The plate is incubated at room temperature for 1 hour, and then incubated at 37°C / 5% CO2 for 24 hours. The cells are washed three times in the plate with 80 μL of HBSS / HEPES buffer (10 μL of buffer remaining in the wells after washing), and then 5 μL of the compound per well, diluted in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%), and 1 mM IBMX (final concentration: 0.5 mM) are added to the wells of the assay plate. Subsequently, 1 mM IBMX (final concentration: 0.5 mM) dissolved in HBSS / HEPES buffer containing 5 μL of L-glutamic acid (final concentration: 10 μM), forskolin (final concentration: 1 μM), and 0.2% BSA (final concentration: 0.1%) per well is added to the assay plate (final DMSO concentration: 1%). Several wells of the assay plate are used for either a positive or negative control, or for the cAMP standard curve. The assay plate is incubated at room temperature for 30 minutes. Then, 5 μL of anti-cAMP-antibody-d2 solution and 5 μL of cAMP-europium cryptochloride dilution per well are added to all wells of the plate, and the plate is photoprotected at room temperature and incubated for a further 60 minutes. Emissions at 615 nm and 665 nm (excitation wavelength: 320 nm) are measured using an EnVision® reader (PerkinElmer). The ratio between emissions at 665 nm and emissions at 615 nm is calculated using a reader. The entire assay is performed in a dark room or under green light.

[0049] cAMP standards are prepared by diluting the cAMP stock solution with HBSS / Hepes buffer: 5 μl / well of cAMP dilution (in HBSS / Hepes buffer containing 1 mM IBMX and 0.2% BSA - final concentration: 0.5 mM IBMX and 0.1% BSA) is added to the wells of the assay plate, along with 10 μl / well of HBSS / Hepes buffer containing 0.2% BSA + 5 μl / well of 4% DMSO (final DMSO concentration: 1% - as in the well containing the compound). The final cAMP concentrations in the assay plate are 0, 0.17, 0.69, 2.78, 11.1, 44.5, 178, and 712 nM (two wells / cAMP concentration).

[0050] The microtiter plates for each assay also contained a well with a vehicle control (negative control; 100% CTL; 10 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO) instead of the compound as a control for L-glutamate-induced signaling, and a well with a vehicle control without L-glutamate (positive control; 0% CTL; 0 μM L-glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO) as a control for non-specific changes in the signal. The data analysis is performed by calculating the ratio of emissions at 665 nm to emissions at 615 nm (Em665 / Em615 ratio). Then, the compound signal is normalized using positive and negative controls according to the following formula: PoC = 100 × ((Signal sample - Positive control) / (Negative control - Positive control))

[0051] B. Evaluation of metabolic stability in human liver microsomes (human MSTs) The metabolic stability of the compounds according to the present invention can be studied as follows: The metabolic degeneration of the test compound is assayed at 37°C using stored human liver microsomes. Each time point contains a final incubation volume of 100 μL, consisting of TRIS buffer (0.1 M), MgCl2 (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM at pH 7.6 at room temperature. Following a short preliminary incubation period at 37°C, the reaction is initiated by adding beta-nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH, 1 mM) and terminated by transferring aliquots to the solvent after different time points. After centrifugation (10000 g, 5 min), aliquots of the supernatant are assayed by LC-MS / MS for the amount of the parent compound. Half-life (t 1 / 2 This is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

[0052] Evaluation of efflux in Madin Darby canine kidney (MDCK) cells into which the human MDR1 gene has been introduced. The apparent permeability coefficient (PE) of compounds across the MDCK-MDR1 cell monolayer is measured in the apical-to-basal (AB) and basal-to-apical (BA) transport directions (pH 7.4, 37°C). AB permeability (PEAB) represents drug absorption from the blood into the brain, while BA permeability (PEBA) represents drug efflux from the brain back into the bloodstream via both passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed on MDCK-MDR1 cells, mostly by overexpressed human MDR1P-gp. Compounds are assigned permeability / absorption classes by comparison with the AB permeability of a reference compound with known in vitro permeability and oral absorption in humans. Identical or similar permeability in both transport directions suggests passive permeability and a point of permeability in the vector to further active transport mechanisms. Higher PEBA than PEAB suggests the involvement of active efflux mediated by MDR1 P-gp. Active transport is concentration-dependently saturable.

[0053] MDCK-MDR1 cells (1~2×10e5 cells / 1cm 2Cells were seeded on a filter insert (Costar transwell polycarbonate or PET filter, pore size 0.4 μm) and cultured for 7 days (DMEM). Subsequently, MDR1 expression was increased by culturing the cells in complete medium with 5 mM sodium butyrate for 2 days. The compound was dissolved in a suitable solvent (such as DMSO, a 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 × 7H2O, 0.41 mM NaH2PO4 × H2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to prepare a transport solution (0.1-300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) is applied to the apical or basolateral donor side to measure AB permeability or BA permeability (3 filter repeats), respectively. The receiver side contains the same buffer as the donor side. Samples are collected from the donor at the start and end of the experiment, and also from the receiver side at various time intervals up to 2 hours for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiver volume is replaced with unused receiver solution.

[0054] Evaluation of efficacy against impulsive behavior in rats using the 5-choice reaction time task and the 5-CSRTT. The efficacy of the treatment for motor impulse behavior can be studied as follows: 5-CSRTT task training was performed according to the standard protocol (Isherwood et al. Neuropharmacology 2017, 123: 249-260). In short, rats were trained to stick their noses into one of five positions on the curved wall of an operant chamber where a light cue was presented (Med Associates Inc, St. Albans, Vermont). If a rat stuck its nose into the lit position for 1 second or up to 1 second after stimulus presentation, a sugar pellet was delivered into a reward container located across the chamber. Infrared beams at each selection opening and reward container allowed for precise detection of the rat's response to this task related to the operant. Any response at any nose-poking opening that occurred before the start of the light cue (premature response) was defined as motor impulse behavior.

[0055] After achieving stable performance, a new analytical approach was applied, which revealed characteristic (long-term) stability in the number of premature responses made by individual animals over several months. In general, this analysis allowed for reliable stratification of animals into high-impulse and low-impulse groups based on a long-term assessment of the number of premature responses they made during training.

[0056] All subjects received both the vehicle and the compound on separate days, with each dose separated by approximately two weeks, in a crossover experiment. The order of vehicle and compound administration was randomized within the subjects, while a third group received atomoxetine on both experimental days as a technical control. As a standardized numerical threshold for impulse levels, animals with >40 premature responses in the vehicle (out of 200 initiated trials) were labeled as high impulse, and animals with <40 premature responses were labeled as low impulse. Importantly, this numerical threshold-based labeling overlapped >80% with long-term analysis of the training data (as described above). The high convergence of these two approaches to stratification allowed us to reliably compare the compound effects in consistently high-impulse rats with those in consistently low-impulse rats in the 5-CSRTT. Biological data

[0057] [Table 1]

[0058] The compound of the present invention is structurally different from the structurally closest compound in the prior art (i.e., Examples 8, 12, 125 and Intermediate-250 in WO2019 / 138017) in that the heterocyclic linkage as a carboxamide is a pyrazine (6-membered heteroaryl) group rather than a pyrazole or isoxazole moiety (5-membered heteroaryl). While the structurally closest compound disclosed in WO2019 / 138017 is the immunomodulator (IL-17 modulator) disclosed therein, the compound of the present invention is unexpectedly a highly potent mGluR4 negative modulator (see Table 2). The structurally closest compound disclosed in WO2019 / 138017 was tested in Assay A and found to lack therapeutic activity as an mGluR4 modulator (Table 1). Unexpectedly, the compound of the present invention is >100-fold potent in Assay A (compare the data in Table 1 with the data in Table 2).

[0059] [Table 2] TIFF2026512972000018.tif207153 TIFF2026512972000019.tif216153 TIFF2026512972000020.tif216153 TIFF2026512972000021.tif226153 TIFF2026512972000022.tif221153 TIFF2026512972000023.tif229153 TIFF2026512972000024.tif220153 TIFF2026512972000025.tif212153 TIFF2026512972000026.tif201153 TIFF2026512972000027.tif195153 TIFF2026512972000028.tif208153 TIFF2026512972000029.tif218153 TIFF2026512972000030.tif197153 TIFF2026512972000031.tif218153 TIFF2026512972000032.tif231153 TIFF2026512972000033.tif231153 TIFF2026512972000034.tif199153 TIFF2026512972000035.tif216153 TIFF2026512972000036.tif230153 TIFF2026512972000037.tif218153 TIFF2026512972000038.tif218153 TIFF2026512972000039.tif227153 TIFF2026512972000040.tif201153 TIFF2026512972000041.tif211153 TIFF2026512972000042.tif202153 TIFF2026512972000043.tif235153 TIFF2026512972000044.tif213153 TIFF2026512972000045.tif202153 TIFF2026512972000046.tif232153 TIFF2026512972000047.tif229153 TIFF2026512972000048.tif224153 TIFF2026512972000049.tif235153 TIFF2026512972000050.tif237153 TIFF2026512972000051.tif223153 TIFF2026512972000052.tif220153 TIFF2026512972000053.tif96153

[0060] Use / Method of Use in Treatment The present invention relates to compounds useful in the treatment and / or prevention of diseases, disorders and conditions in which inhibition of mGluR4 activity has therapeutic utility, including but not limited to the treatment of psychiatric and neurological conditions associated with lack of impulse control or maladaptive impulses. Such lack of impulse control is seen in addiction, including substance use disorders; personality disorders, e.g., borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders, e.g., binge eating disorder; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, e.g., post-traumatic stress disorder; tic disorders such as Tourette syndrome; and other behavioral disorders, e.g., restless legs syndrome. According to further aspects of the present invention, the compounds of the present invention are useful in the treatment of mGluR4-related pathophysiological disturbances, cognition, motivational behavior / reward, mood and stress, and aggression. In addition, there is therapeutic benefit in cancer and related disorders associated with maladaptive tumor formation such as osteosarcoma. According to a further aspect of the present invention, the compounds of the present invention are useful in treating metabolic disorders by mGluR4-related modulation of satiety pathways and / or signaling, for the treatment of disorders including but not limited to obesity.

[0061] In terms of their pharmacological effects, the compounds of the present invention are suitable for use in the treatment and / or prevention of diseases or conditions selected from the following enumeration: (1) Disorders related to dysfunction in impulse control, e.g., gambling addiction, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, shopping addiction, internet addiction, obsessive-compulsive disorder, sexual disorders, sexual dysfunction, psychosexual disorders, eating disorders, e.g., binge eating, bulimia nervosa, anorexia nervosa, other specific feeding or eating disorders, obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi syndrome, bulimia nervosa, appetite / taste disorders, bipolar disorder, post-traumatic stress disorder; (2) Drug abuse / dependence / craving, or addiction (including, but not limited to, drugs such as cocaine, opiates, morphine, barbiturates, benzozeadipines, amphetamines, nicotine / tobacco, and other psychostimulants) and prevention of relapse, alcohol dependence and alcohol-related disorders, drug abuse or addiction or relapse, tolerance to or withdrawal from drugs; (3) Psychiatric and neurological conditions, such as attention deficit hyperactivity disorder, conduct disorder, inattention 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 limb syndrome, dementia, motor disorders, severe intellectual disability, neurodegenerative disorders, including those relating to disease classifications, such as disinhibition-dementia-Parkinson's disease-muscle atrophy complex, palpidopont-nigral degeneration, mood disorders, bipolar disorder, attachment, depression, attachment depression, borderline personality disorder, antisocial disorder - Sonality disorders, aggression, e.g., impulsive aggression, suicidal tendencies, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neurosis / disorder, depressive neurosis / disorder, anxiety neurosis, dysthymia, neurological disorders, e.g., cerebral edema and angioedema, Parkinson's disease and Alzheimer's disease, brain dementia such as senile dementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, convulsive disorders, stroke, myasthenia gravis, encephalomyelitis, meningitis and other infections of the brain and meninges, HIV and schizophrenia, delusional disorder, autism, affective disorder, and Tourette syndrome, tic disorders, and other behavioral disorders, epilepsy, chronic pain; (4) Cognitive impairment in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease, and other neurological and psychiatric disorders; (5) Personality disorders, such as borderline personality disorder, antisocial personality disorder, paranoid personality disorder, schizophrenia and schizotypal personality disorder, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, and other specific and nonspecific personality disorders; (6) Sleep disorders, such as narcolepsy, jet lag, sleep apnea, insomnia, parasomnias, disturbances of biological and circadian rhythms, and sleep disturbances associated with psychiatric and neurological disorders; (7) Non-neurological conditions, including metabolic conditions such as diabetes mellitus, insulin resistance, metabolic syndrome, overweight, obesity, and use for weight loss, cosmetic weight loss, prevention of relapse during or after obesity treatment, weight maintenance, vomiting, cardiovascular disorders, and disorders related to maladaptive blood pressure control such as hypertension or hypotension; (8) Cancer and related disorders, including maladaptive tumor formation such as osteosarcoma, breast cancer, ependymoma, bladder cancer, and colorectal cancer.

[0062] The applicable daily dose of the compound of the present invention may vary between 0.1 and 2000 mg. The actual effective or therapeutic dose will depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In all cases, the drug substance will be administered in a dose and manner that enables the effective dose to be delivered, which is appropriate for the patient's condition.

[0063] Pharmaceutical composition Suitable compositions for administering the compounds of the present invention will be apparent to those skilled in the art, and such compositions 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 generally vary within the range of 0.1 to 95% by mass, preferably 5.0 to 90% by mass, of the composition. Suitable tablets can be obtained, for example, by mixing the compound of the present invention with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants, and compressing the resulting mixture into tablets.

[0064] Combination therapy The compounds according to the present invention may be used in conjunction with other treatment options known to be used in the art in connection with any of the treatment instructions that are the focus of the present invention. Such active pharmaceutical ingredients or treatment options that are considered suitable for use in combination with compounds and for treatments according to the present invention include antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptics, antiparkinsonian drugs, hypnotics, nootropics, stimulants, drugs for attention-deficit hyperactivity disorder, further psychotropic drugs, anti-inflammatory drugs, analgesics, chemotherapeutic agents, and treatment options used for metabolic disorders, liver diseases and kidney diseases.

[0065] Experiment Section List of abbreviations: %Sol: Percentage of solvent μL (microliter) ACN Acetonitrile Acetic acid (ACOH) aq. Water-based Boc tert.-butyloxycarbonyl Boc2O di-tert-butyl dicarbonate chir. (Chiral) CIP 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate conc. concentration d day DA diode array DAD Diode Array Detector DCM Dichloromethane DMF (N,N-dimethylformamide) ELSD Evaporative Light Scattering Detector HCl ethyl acetate ETOH Ethanol g grams h time half-conc. HPLC (High-Performance Liquid Chromatography) i.vac. in a vacuum IPA Isopropyl Alcohol M moles MeOH methanol MEOH methanol mg milligrams min ml (milliliter) mL (milliliter) MS mass spectrometer N Normal NBS N-bromo-succinimide NMM (N-methylmorpholine) NMP (N-methylpyrrolidone) PE (Petroleum Ether) PPA 1-Propanephosphonic Acid Cyclic Anhydride prep. PSI (pounds per square inch) quant. quantitative RF Delay Front RT retention time sat. saturation scCO2 Supercritical carbon dioxide SFC Supercritical Fluid Chromatography TBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium-tetrafluoroborate TEA (Triethylamine) Temp. Temperature tert. tertiary TFA (Trifluoroacetic Acid) THF (Tetrohydrofuran) wt mass X-Phos G1 Chloro-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)-phenyl)]-palladium(II)

[0066] method: HPLC-MS method: Method A

[0067] [Table 3] Method B

[0068] [Table 4] Method C

[0069] [Table 5] Chiral SFC analysis method: Method 1:

[0070] [Table 6] Method 2:

[0071] [Table 7] Method 3:

[0072] [Table 8] Method 4:

[0073] [Table 9] Method 5:

[0074] [Table 10] Method 6:

[0075] [Table 11] Method 7:

[0076] [Table 12] Method 8:

[0077] Table 13 Method 9:

[0078] Table 14 Method 10:

[0079] Table 15 Method 11:

[0080] Table 16 Method 12:

[0081] Table 17 Method 13:

[0082] Table 18 Method 14:

[0083] Table 19 Method 15:

[0084] Table 20 Method 16:

[0085] Table 21 Method 17:

[0086] Table 22 Method 18:

[0087] Table 23 Method 19:

[0088] Table 24 Method 20:

[0089] Table 25 Method 21:

[0090] Table 26 Method 22:

[0091] Table 27 Method 23:

[0092] Table 28 Method 24:

[0093] Table 29 Method 25:

[0094] Table 30 Method 26:

[0095] Table 31 Method 27:

[0096] Table 32 Method 28:

[0097] Table 33 Method 29:

[0098] Table 34 Method 30:

[0099] Table 35 Method 31:

[0100] Table 36 Method 32:

[0101] Table 37 Method 33:

[0102] Table 38 Method 34:

[0103] Table 39 Method 35:

[0104] Table 40 Method 36:

[0105] Table 41 Method 37:

[0106] Table 42 Method 38:

[0107] Table 43 Method 39:

[0108] Table 44 Method 40:

[0109] Table 45 Method 41:

[0110] Table 46 Method 42:

[0111] Table 47 Method 43:

[0112] Table 48 Method 44:

[0113] Table 49 Method 45:

[0114] Table 50 Method 46:

[0115] Table 51 Method 47:

[0116] Table 52 Method 48:

[0117] Table 53 Method 49:

[0118] Table 54 Method 50:

[0119] Table 55 Method 51:

[0120] Table 56 Method 52:

[0121] Table 57 Method 53:

[0122] Table 58 Method 54:

[0123] Table 59 Method 55:

[0124] Table 60 Method 56:

[0125] Table 61 Method 57:

[0126] Table 62 Method 58:

[0127] Table 63 Method 59:

[0128] Table 64 Method 60:

[0129] Table 65 Method 61:

[0130] Table 66 Method 62:

[0131] Table 67 Method 63:

[0132] Table 68 Method 64:

[0133] Table 69 Method 65:

[0134] Table 70 Method 63:

[0135] Table 71 Method 64:

[0136] Table 72 Method 65:

[0137] Table 73 Method 66:

[0138] Table 74 Method 67:

[0139] Table 75 Method 68:

[0140] Table 76 Method 69:

[0141] Table 77 Method 70:

[0142] Table 78 Method 71:

[0143] Table 79 Method 72:

[0144] Table 80 Method 73:

[0145] Table 81 Method 74:

[0146] Table 82 Method 75:

[0147] Table 83 Method 76:

[0148] Table 84 Method 77:

[0149] Table 85 Method 78:

[0150] Table 86 Method 79:

[0151] Table 87 Method 80:

[0152] Table 88 Method 81:

[0153] Table 89 Method 82:

[0154] Table 90 Method 83:

[0155] [Table 91] Method 84:

[0156] [Table 92] Method 85:

[0157] [Table 93] Method 86:

[0158] [Table 94] Method 87:

[0159] [Table 95] Method 88:

[0160] [Table 96]

[0161] NMR method: NMR spectra were recorded on a Bruker AVANCE IIIHD 400MHz instrument using TopSpin3.2pl6 software. Chemical shifts were assigned in δ units, downfield from an internal reference such as trimethylsilane and / or water and / or solvent (e.g., d6-DMSO) to parts per million (ppm). Selected data were reported in the following manner: chemical shift (multiplicity, coupling coefficient (J), number of hydrogens). Abbreviations are as follows: s (singularity), d (doubleity), t (triplicity), q (quadripleity), spt (septuplicity), m (multiplicity), br (broadly multiplicity). [Examples]

[0162] (Example 1) [ka]

[0163] Step 1: Mix 1,4-difluoro-2-nitrobenzene (1 g, 6.3 mmol) with a 2N ethylamine solution in THF (15 mL, 30 mmol) and stir at ambient temperature for 16 hours. Filter the mixture and concentrate the filtrate under vacuum. Wash the residue with water, filter again, wash with water, and dry at ambient temperature. Yield: 1.13 g (6.1 mmol; 98%) Intermediate-1a MS(ESI + ):(M+H) + 185;HPLC:RT=1.05min, Method:Z018_S04

[0164] Step 2: Intermediate-1a (100 mg, 0.54 mmol) is mixed with 50 mg of Raney nickel in 10 mL of THF and hydrogenated at 50 psi for 2 hours. The mixture is filtered and the filtrate is concentrated under vacuum. Yield: 80 mg (0.52 mmol; 96%) Intermediate-1b MS(ESI + ):(M+H) + 155;HPLC:RT=0.55min, Method:Z018_S04

[0165] Step 3: (2S)-2-amino-2-cyclopropyl ethyl acetate hydrochloride (2.9 g, 18 mmol) is mixed with 5-methyl-pyrazine-2-carboxylic acid (3.0 g, 22 mmol) and TEA (10 mL, 72 mmol) in 100 mL of THF at 0°C, and CIP (5.2 g, 19 mmol) is added. After stirring at 0°C for 30 minutes, the mixture is filtered and the filtrate is concentrated under vacuum. The residue is washed with Na2CO3 aqueous solution (0.5 N), extracted with DCM, dehydrated with magnesium sulfate, and concentrated under vacuum. The residue is taken out with 40 mL of MeOH and mixed with NaOH aqueous solution (4 N, 6.0 mL, 24 mmol), and stirred at ambient temperature for 1 hour. The mixture is then acidified by adding AcOH, filtered, and the filtrate is purified by preparative HPLC (gradient (H2O + 0.15% TFA) / ACN 9:1~>7:3, C-18 Sunfire, 50°C). The fractions containing the product are combined and freeze-dried. Yield: 3.0g (13 mmol; 73%) Intermediate-1c MS(ESI + ):(M+H) + 236;HPLC:RT=0.73min, Method:Z018_S04

[0166] Step 4: At 0°C, PPA (50%, 280 μL, 0.48 mmol) is added to a 5 mL mixture of intermediate-1b (80 mg, 0.52 mmol) and intermediate-1c (100 mg, 0.43 mmol) with NMM (160 μL, 1.5 mmol) in DCM. Cooling is removed and the mixture is stirred for 45 minutes. 100 μL of water is added and the mixture is stirred at ambient temperature for 30 minutes. Then, 5 mL of AcOH is added and the mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated under vacuum, and the residue is purified by preparative HPLC (gradient (H2O + 0.15% TFA) / ACN 88:12~>68:32, C-18 Sunfire, 50°C). The fractions containing the product are combined and freeze-dried. The residue is taken out in MeOH and passed through a cartridge equipped with ion exchange resin (Agilent PL-HCO3 MP SPE) and concentrated under vacuum. Yield: 110 mg (0.31 mmol; 73%) Example 1

[0167] [Table 97] Similar to Example 1, the following product is obtained:

[0168] [Table 98]

[0169] [Table 99]

[0170] [Table 100]

[0171] [Table 101]

[0172] [Table 102]

[0173] [Table 103]

[0174] [Table 104]

[0175] [Table 105]

[0176] Similar to Example 1, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: Examples 19, 19-1, 19-2, 19-3

[0177] [Table 106]

[0178] [Table 107]

[0179] [Table 108]

[0180] [Table 109] Similar to Example 1, the following product is obtained:

[0181] [Table 110]

[0182] [Table 111]

[0183] [Table 112]

[0184] [Table 113]

[0185] [Table 114]

[0186] [Table 115]

[0187] [Table 116]

[0188] [Table 117]

[0189] [Table 118]

[0190] [Table 119] Similar to Example 1, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: Examples 48, 48-1, 48-2, 48-3

[0191] [Table 120]

[0192] [Table 121]

[0193] [Table 122]

[0194] [Table 123] The following compounds were obtained in a manner similar to that of Example 1.

[0195] [Table 124]

[0196] [Table 125]

[0197] [Table 126]

[0198] [Table 127]

[0199] [Table 128]

[0200] Similar to Example 1, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: Examples 70, 70-1, 70-2, 70-3

[0201] [Table 129]

[0202] [Table 130]

[0203] [Table 131]

[0204] [Table 132] The following compounds were obtained in a manner similar to that of Example 1.

[0205] [Table 133]

[0206] [Table 134]

[0207] [Table 135] Similar to Example 1, the following compound is obtained. The product is a mixture of four stereoisomers. Two stereoisomers are obtained by chiral SFC separation: Examples 84, 84-1

[0208] [Table 136]

[0209] [Table 137] Similar to Example 1, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 91, 91-1, 91-2, 91-3

[0210] [Table 138]

[0211] [Table 139]

[0212] [Table 140]

[0213] [Table 141] The following compounds are obtained with similarity to those in Example 1:

[0214] [Table 142]

[0215] [Table 143]

[0216] [Table 144]

[0217] Similar to Example 1, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 97, 97-1, 97-2, 97-3

[0218] [Table 145]

[0219] [Table 146]

[0220] [Table 147]

[0221] [Table 148] The following compounds were obtained in a manner similar to that of Example 1.

[0222] Table 149

[0223] Table 150

[0224] Table 151

[0225] Table 152

[0226] Table 153

[0227] Table 154

[0228] Table 155

[0229] Table 156

[0230] Table 157

[0231] Table 158

[0232] [Table 159]

[0233] [Table 160]

[0234] (Example 4) [ka]

[0235] Step 1: Mix 1,4-difluoro-2-nitrobenzene (100 g; 0.63 mol) and 2,2-difluoroethylamine (266 mL; 3.8 mol) with K2CO3 (400 g; 1.3 mol) in 800 mL of ACN, and stir at 80°C for 2 days. Filter the mixture and concentrate the filtrate under vacuum. Use the residue without further purification. R f :0.4(PE / Â 85:15) Yield: 105g (0.48mol; 76%) Intermediate-4a MS(ESI + ):(M+H) + 221;HPLC:RT=1.00min, method:Z018_S04

[0236] Step 2: A mixture of intermediate-4a (50 g, 0.23 mol) and 10 g of Raney nickel in 500 mL of MeOH is hydrogenated at ambient temperature for 4 hours at 50 psi (hydrogen gas). The mixture is then filtered, washed with siRNA, and concentrated under vacuum. The residue is used without further purification. R f :0.4(PE / Â 85:15) Yield: 45g (0.22mol; 98%) Intermediate-4b MS(ESI + ):(M+H) + 191;HPLC:RT=0.71 min, method:Z018_S04

[0237] Step 3: To a mixture of intermediate-4b (91 g, 0.48 mol) and (S)-Boc-amino-cyclopropyl-acetic acid (103 g, 0.48 mol) in 300 mL of pyridine, PPA (50% by mass in HCl, 609 g, 0.96 mol) is added at 0°C. The mixture is then stirred at ambient temperature for 16 hours. 600 mL of water is added, and the mixture is extracted with HCl. The combined organic layer is dehydrated with Na2SO4, filtered, and concentrated. The residue is used without further purification. Yield: 125g (0.32mol; 67%) Intermediate-4c MS(ESI + ):(M+H) + 388;HPLC:RT=1.02 min, method:Z011_S03

[0238] Step 4: Intermediate-4c (100g, 0.26mol) is stirred in 300mL of acetic acid at 40°C for 2 days. The mixture is then concentrated, 600mL of water is added, and extraction is performed with siRNA. The combined organic layer is washed with aqueous NaHCO3 solution, dehydrated with Na2SO4, filtered, and the filtrate is concentrated. The residue is purified by column chromatography (100-200 mesh silica gel, PE / siRNA 7:3), the product containing the fractions is combined, and all solvent is removed under vacuum. The residue is taken out in diethyl ether and the solvent is evaporated. Yield: 70g (0.19mol; 73%) Intermediate-4d MS(ESI + ):(M+H) + 370;HPLC:RT=1.17min, Method:Z003_S05

[0239] Step 5: To 50 mL of dioxane, HCl from 100 mL of dioxane (4 M) is added to intermediate-4d (80 g, 0.22 mol), and the mixture is stirred at ambient temperature for 4 hours. The mixture is then filtered, the solid is washed with diethyl ether, and dried. Yield: 67 g (0.22 mol; quantitative) intermediate-4e MS(ESI+ ):(M+H) + 270;HPLC:RT=0.83min, Method:Z011_S03 Step 6: To 70 mL of HCl, 5-(difluoromethyl)-pyrazine-carboxylic acid (4.4 g, 25 mmol) is mixed with intermediate-4e (7.0 g, 23 mmol) and 12.7 mL of TEA (92 mmol). To avoid heating above 5°C, PPA solution (50% by mass in HCl, 17.7 mL, 30 mmol) is added over 4 minutes at 0°C. After a further 15 minutes, the cooling is removed and the mixture is stirred at ambient temperature for 1.5 hours. 70 mL of HCl is added, followed by the addition of NH3 aqueous solution to adjust the pH to basic, and the organic phase is collected. The organic phase is washed with semi-concentrated NaCl (aqueous solution), dehydrated with MgSO4, and concentrated under vacuum. The residue is purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 61:39~>41:59). The products containing the fractions are combined and concentrated under vacuum. The suspension is filtered, the solid is washed with water, and dried at 50°C. Yield: 5.8g (13.7 mmol; 60%)

[0240] [Table 161] Similar to Example 4, the following product is obtained:

[0241] [Table 162]

[0242] [Table 163]

[0243] [Table 164]

[0244] [Table 165]

[0245] [Table 166]

[0246] [Table 167]

[0247] [Table 168]

[0248] [Table 169]

[0249] [Table 170]

[0250] [Table 171]

[0251] [Table 172]

[0252] [Table 173] Similar to Example 4, the following compounds were obtained as a mixture of four stereoisomers, which were then separated by chiral SFC: Examples 40, 40-1, 40-2, 53.

[0253] [Table 174]

[0254] [Table 175]

[0255] [Table 176]

[0256] [Table 177] Similar to Example 4, the following compounds were obtained.

[0257] [Table 178]

[0258] [Table 179]

[0259] [Table 180]

[0260] [Table 181]

[0261] [Table 182]

[0262] [Table 183]

[0263] [Table 184] Similar to Example 4, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: Examples 58, 58-1, 58-2, 89

[0264] [Table 185]

[0265] [Table 186]

[0266] [Table 187]

[0267] [Table 188] Similar to Example 4, the following compound is obtained:

[0268] [Table 189]

[0269] [Table 190]

[0270] Similar to Example 4, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 71, 71-1, 71-2, 71-3

[0271] [Table 191]

[0272] [Table 192]

[0273] [Table 193]

[0274] [Table 194]

[0275] [Table 195] Two of the four stereoisomers were isolated after separation by chiral SFC: Examples 76, 76-1

[0276] [Table 196]

[0277] [Table 197] Similar to Example 4, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 78, 78-1, 78-2, 78-3

[0278] [Table 198]

[0279] [Table 199]

[0280] [Table 200]

[0281] [Table 201] Similar to Example 4, the following compounds were obtained.

[0282] [Table 202]

[0283] [Table 203]

[0284] [Table 204]

[0285] [Table 205]

[0286] [Table 206]

[0287] [Table 207]

[0288] [Table 208]

[0289] [Table 209]

[0290] [Table 210]

[0291] [Table 211]

[0292] [Table 212]

[0293] [Table 213]

[0294] [Table 214]

[0295] [Table 215]

[0296] [Table 216]

[0297] [Table 217]

[0298] [Table 218]

[0299] [Table 219]

[0300] (Example 14) [ka]

[0301] Step 1: Sodium (0.95 g, 41.2 mmol) was added to 80 mL of EtOH, and the mixture was cooled to no more than 35°C and stirred for 45 minutes. N1-methyl-4-(trifluoromethyl)-benzene-1,2-diamine (2.50 g, 12.9 mmol) and ethyl diethoxyacetate (4.15 mL, 23.2 mmol) were added to 20 mL of EtOH, and the mixture was heated and refluxed for 20 hours. Then, 200 mL of saturated aqueous NH4Cl was added, and the mixture was concentrated under vacuum. The residue was diluted with 250 mL of water and extracted with ethyl acetate. The combined organic layer was dehydrated with MgSO4 and concentrated under vacuum. The residue was taken out in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.15% NH3): ACN 56:44~>36:64). The products containing the fractions were combined and freeze-dried. The solid was removed in DCM and concentrated under vacuum. Yield: 1.78 g (5.89 mmol; 46%) Intermediate-14a MS(ESI + ):(M+H) + 303;HPLC:RT=1.05min, method:Z011_S03

[0302] Step 2: The mixture of intermediate-14a (12.8 g, 42.3 mmol) and hydrochloric acid in dioxane (4N; 128 mL, 512 mmol) was stirred and heated under reflux for 1.5 hours. The heat was removed and the mixture was poured into a mixture of 800 mL of water and 500 mL of saturated NaHCO3 aqueous solution. The mixture was stirred for 5 minutes and filtered. The solid was washed with water, dried under vacuum, and the residue was taken out in n-butyl acetate and concentrated under vacuum. Yield: 9.33 g (40.1 mmol; 95%) intermediate-14b MS(ESI + ):(M+H) + 229;HPLC:RT=0.88 min, method:Z011_S03

[0303] Step 3: Intermediate-14b (23.2 g, 99.6 mmol), (S)-(-)-2-methyl-2-propane-sulfinamide (13.3 g, 105 mmol), and Cs2CO3 (42.2 g, 130 mmol) in 370 mL of DCM are stirred under heating and refluxed for 1.25 hours. Then, the heating is removed, MgSO4 is added, the mixture is filtered, and the filtrate is concentrated under vacuum. The residue is taken out in DCM and di-isopropyl ether and concentrated under vacuum. The formed solid is filtered and recovered. The filtrate is further concentrated under vacuum, and the residue is purified by column chromatography (silica gel; eluent gradient petroleum ether: siRNA 80:20~>45:55). The products containing the fractions are combined and concentrated under vacuum. The residue is combined with the recovered solid. Yield: 31.6 g (95.4 mmol; 96%) Intermediate-14c MS(ESI + ):(M+H) + 332;HPLC:RT=1.07min, Method:Z018_S04 Chiral SFC Rt 4.27 minutes (Method: I_SA_10_IPA_NH3_003)

[0304] Step 4: Under an argon atmosphere and in an additionally dried glass container, 1-4 dioxene (17.18 mL, 211.25 mmol) is added to 150 mL of THF at -35°C, while keeping the temperature below -30°C, and n-hexyl lithium (2.45 N in hexane; 76.98 mL, 188.52 mmol) is added. Then, the cooling is removed and the mixture is warmed to 20°C. The mixture is immediately cooled to 0°C and stirred at this temperature for 30 minutes. The mixture is then cooled to -65°C and added to the mixture of intermediate-14c (50 g, 150.89 mmol) in 500 mL of THF at -75°C under argon, in an additionally dried glass container, while keeping the temperature of the mixture below -70°C. The mixture is then stirred at -70°C for 20 minutes. The mixture is then poured into 650 mL of saturated NH4Cl aqueous solution. Add tert-butyl methyl ether (650 ml) and warm the mixture to room temperature with stirring. Extract the aqueous layer with tert-butyl methyl ether, wash the combined organic layers with brine, dehydrate with MgSO4, and concentrate under vacuum. Add SiO2 (70 ml) to the residue. Filter the mixture, wash with SiO2, and collect the solid. The resulting product contained only one stereoisomer. Yield: 38.5 g (92 mmol; 61%) Intermediate-14d Chiral SFC Rt 5.38 minutes (Method: I_IH_15_IPA_NH3_003)

[0305] Step 5: To intermediate-14d (15.4 g, approximately 90%, 33.2 mmol) in 47 mL of MeOH3 at 10°C, hydrogen chloride in dioxane (4N, 18.3 mL, 73.0 mmol) is added. After 5 minutes, the coolant is removed and the mixture is stirred at ambient temperature for 22 hours. Then, concentrated NH3 aqueous solution is added to adjust the pH to 7.5, and the mixture is concentrated under vacuum. The residue is adjusted to pH 8 by adding concentrated NH3 aqueous solution, 300 mL of water is added, and the mixture is extracted with DCM. The aqueous layer is adjusted to pH 10 by adding Na2CO2 solution (aqueous, 2N) and extracted with siRNA. The organic layers are washed with water, combined, dehydrated with MgSO4, and concentrated under vacuum. Yield: 12.4g (content about 75%; 29.8mmol; 90%) Intermediate-14e MS(ESI + ):(M+H) + 314;HPLC:RT=0.87min, Method:Z011_S03 Chiral SFC Rt 3.51 minutes (Method: I_IG_20_IPA_NH3_003)

[0306] Step 6: To 250 mL of DCM containing intermediate-14e (12.4 g, approximately 75%, 29.8 mmol) and TEA (8.8 mL, 63.3 mmol), Boc2O (8.3 g, 38.0 mmol) is added, and the mixture is stirred at ambient temperature for 15.5 hours. The organic layer is washed with water, dehydrated with MgSO4, and concentrated under vacuum. It is then purified by chromatography (silica gel, eluent gradient petroleum ether: siRNA 75:25~>45:55). The products containing the fractions are combined and concentrated under vacuum. Yield: 9.82 g (23.7 mmol; 75%) Intermediate-14f MS(ESI + ):(M+H) + 414 Chiral SFC Rt 4.64 minutes (Method: I_IG_10_IPA_NH3_003)

[0307] Step 7: Intermediate -14f (8.8 g, 21.3 mmol) in 300 mL of THF is mixed with activated carbon-supported palladium (10%, 1.3 g). The mixture is hydrogenated under a hydrogen atmosphere at 60 psi for 22 hours, then further activated carbon-supported palladium (10%, 1 g) is added and hydrogenation is continued for 5 hours, then further activated carbon-supported palladium (10%, 0.5 g) is added and hydrogenation is continued for 3 hours. The mixture is allowed to stand overnight, then filtered and concentrated under vacuum. The product is obtained as a mixture of stereoisomers and is used without further separation. In the synthesis scheme, only the major isomers are shown. Yield: 8.76g (21.1 mmol; 99%) Intermediate - 14g MS(ESI + ):(M+H) +416;HPLC:RT=1.04 min, method:Z011_S03 Stereoisomer 1: Chiral SFC Rt 2.69 min (Method: I_IG_10_IPA_NH3_003) Stereoisomer 2: Chiral SFC Rt 3.33 min (Method: I_IG_10_IPA_NH3_003)

[0308] Step 8: Add TFA (14.3 mL, 186 mmol) to 14 g (7.7 g, 18.7 mmol) of intermediate in 65 mL of DCM at 5°C. Remove the cooler and stir the mixture at ambient temperature for 3.8 hours. Add 150 g of ice and adjust the pH of the mixture to approximately 10 by adding concentrated NH3 aqueous solution. Extract the aqueous layer with DCM, dehydrate the combined organic layer with MgSO4, and concentrate under vacuum. Yield: 5.92 g (18.7 mmol; quantitative) intermediate - 14h Chiral SFC Rt 2.57 minutes (Method: I_SA_10_MEOH_NH3_003)

[0309] Step 9: To a 59 mL mixture of intermediate-14h (5.9 g, 18.7 mmol) and NMM (5.1 mL, 46.8 mmol) in toluene, methylpyraine-2-carboxylic acid (3.2 g, 22.6 mmol) is added, and the mixture is cooled to 0°C while stirring. Then, while maintaining the temperature below 10°C, PPA (50% in toluene; 14.5 mL, 24.3 mmol) is added dropwise. After 5 minutes, the cooling is removed, and the mixture is stirred at ambient temperature for 75 minutes. Water is added, and the mixture is adjusted to pH 9 by adding NMM. The aqueous layer is extracted with toluene, and the combined organic layers are washed with semi-concentrated brine, activated carbon is added, and the mixture is stirred and dehydrated with MgSO4. After filtration, the mixture is concentrated under vacuum, and the residue is taken out in toluene and purified by chromatography (silica gel, eluent toluene:EtOH 97:3). The products containing the fractions are combined and concentrated under vacuum. The product is obtained as a mixture of two stereoisomers, which is then purified by chiral SFC. Yield: 4.05 g (9.30 mmol) Example 14, and 0.71 g (1.63 mmol) Example 14-1

[0310] [Table 220]

[0311] [Table 221]

[0312] (Examples 18 and 54) [ka]

[0313] Step 1: To a mixture of 1,2-diamino-4-bromo-3-methylbenzene (110 mg, 0.55 mmol), intermediate-1c (120 mg, 0.51 mmol), and NMM (190 μL, 1.7 mmol) in 5 mL of DCM, PPA (50% in Â; 330 μL, 0.56 mmol) is added at 0°C. After stirring at 0°C for 45 minutes, 200 μL of water is added, and the mixture is stirred at ambient temperature for 30 minutes. Next, 5 mL of acetic acid is added, and the mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated under vacuum and purified by preparative HPLC (C-18 Sunfire, 50°C, eluent gradient (water + 0.15% TFA): ACN 83:17~>63:37). The products containing the fractions are combined, set to basic with aqueous NH3 solution, and concentrated under vacuum. The aqueous phase is extracted with DCM, the combined organic layer is dehydrated with MgSO4, and concentrated under vacuum. Yield: 200 mg (0.50 mol; 98%) Intermediate-18a MS(ESI + ):(M+H) + 400;HPLC:RT=0.79min, method:Z018_S04

[0314] Step 2: Intermediate-18a (200 mg, 0.5 mmol) is mixed with 1-bromo-2-methoxyethane (50 μL, 0.53 mmol) and Cs2CO3 (300 mg, 0.92 mmol) in 3 mL of DMF and stirred at ambient temperature for 16 hours. Then, the mixture is stirred at 50 °C for 30 minutes, followed by the addition of Cs2CO3 (300 mg, 0.92 mmol) and 1-bromo-2-methoxyethane (50 μL, 0.53 mmol), and the mixture is stirred at ambient temperature for 20 hours. DCM and water are added, and the aqueous phase is extracted with DCM. The organic layers are combined, dehydrated with MgSO4, and concentrated under vacuum. The residue is purified by preparative HPLC (C-18 X-Bridge, 50 °C, eluent gradient (water + 0.15% NH3): ACN 54:46~>34:66). The products containing the fractions are combined and freeze-dried. Yield: 170 mg (0.37 mol; 74%) Example 54

[0315] [Table 222]

[0316] Step 3: Example 54 (155 mg, 0.34 mmol) was stirred with Zn(CN)2 (80 mg, 0.68 mmol) and X-Phos G1 (15 mg, 0.02 mmol) in 750 μL of NMP at 100°C under argon for 30 minutes. Then, water was added and the mixture was sonicated. 10 mL of ACN / THF 1:1 mixture was added, the mixture was filtered, and the filtrate was purified by preparative HPLC (C-18 X-Bridge, 50°C, eluent gradient (water + 0.15% NH3): ACN 65:35~>45:55). The products containing the fractions were combined and lyophilized. The residue was further purified by chiral SFC. Yield: 90 mg (0.27 mmol; 66%) Example 18

[0317] [Table 223]

[0318] (Example 20) [ka]

[0319] Step 1: To the intermediate-60b (1.30 g, 4.4 mmol) in 30 mL of ACN and 10 mL of water, add cer(IV)-ammonium nitrate (3.62 g, 6.6 mmol) and stir the mixture at ambient temperature for 3 hours. Then, concentrate the mixture under vacuum, remove the residue with water, and extract with SiO2. Dehydrate the combined organic layer with Na2SO4 and concentrate under vacuum. Remove the residue in 3 mL of THF and 10 mL of TEA, add Boc2O (3.48 g, 6.4 mmol), and stir the mixture at ambient temperature for 3 hours. After that, concentrate the mixture under vacuum. Yield: 0.80 g (2.8 mmol; 63%) Intermediate-20a MS(ESI + ):(M+H) + 290

[0320] Step 2: LiOH (0.10 g, 4.2 mmol) is added to intermediate-20a (0.80 g, 2.8 mmol) in 10 mL of MeOH and 3 mL of water, and the mixture is stirred at ambient temperature for 3 hours. The mixture is then concentrated under vacuum and purified by preparative HPLC. Yield: 0.60 g (2.3 mmol, 82%) Intermediate-20b as a mixture of stereoisomers MS(ESI + ):(M+H) + 262

[0321] Step 3: To a mixture of intermediate-4b (280 mg, 1.4 mmol), intermediate-20b (380 mg, 1.4 mmol), and NMM (0.95 mL, 8.7 mmol) in 3 mL of DCM, PPA (50% in siRNA; 1.3 mL, 2.2 mmol) is added at 0°C. After stirring at 0°C for 2 hours, the mixture is concentrated under vacuum. Then, 2.1 g of acetic acid is added, and the mixture is stirred at 50°C for 8 days. The mixture is concentrated under vacuum. The mixture contains four stereoisomers, which can be separated into two pairs of enantiomers via preparative HPLC (C-18 Sunfire 10 μm, eluent gradient (water + 0.15% TFA): ACN 64:36~>44:56). The products containing the fractions are combined and lyophilized. Only one pair of enantiomers (intermediate-20c) is used in step 4, and this is depicted in the reaction scheme.

[0322] Stereoisomers: Intermediate as a mixture of enantiomers - 20c: Yield: 119 mg (0.29 mmol; 20%). MS (ESI + ):(M+H) + 416;HPLC:RT=0.98 min, method:Z018_S04 Stereoisomers to 2: As a mixture of enantiomers; Yield: 104 mg (0.25 mmol; 17%) MS(ESI + ):(M+H) + 416;HPLC:RT=0.97min, Method:Z018_S04

[0323] Step 4: Intermediate-20c (119 mg, 0.29 mmol) is stirred in HCl in dioxane (4N; 3.0 mL, 12 mmol) at ambient temperature for 2 hours. The mixture is concentrated under vacuum. Yield: 111 mg (0.29 mmol; quantitative) Intermediate as a mixture of enantiomers - 20d MS(ESI + ):(M+H) + 316

[0324] Step 5: A mixture of intermediate-20d (111 mg, 0.29 mmol), 5-methylpyrazine-2-carboxylic acid (39 mg, 0.29 mmol), and NMM (189 μL, 1.7 mmol) in 3.5 mL of DCM was stirred at 0°C. PPA (50% in Â; 0.3 mL, 0.5 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum, removed in ACN, filtered, and the filtrate was purified by preparative HPLC (C-18 X-Bridge 10 μm, eluent gradient (water + 0.15% NH3): ACN 71:29~>51:49). The products containing the fractions were combined and lyophilized. Subsequently, chiral SFC was performed to obtain the desired enantiomer (Examples 20 and 20-1). Yield: 28 mg (64 μmol; 45%) Example 20

[0325] [Table 224]

[0326] [Table 225]

[0327] (Examples 23 and 77) [ka]

[0328] Step 1: 1-Fluoro-2-nitro-4-(trifluoromethoxy)benzene (50 g, 0.22 mol) is mixed with 2-methoxyethylamine (33.4 g, 0.44 mol) in 250 mL of THF, and TEA (31 mL, 0.22 mol) is added. The mixture is stirred at 50°C for 2 hours. Then, HCl and water are added, the organic layer is washed with brine, and the mixture is concentrated. Yield: 62g (0.22mol; quantitative) Intermediate-23a MS(ESI + ):(M+H) +281;HPLC:RT=1.07min, Method:Z011_S03

[0329] Step 2: Intermediate-23a (62 g, 0.22 mol) and 7.5 g of Raney nickel in 600 mL of THF are hydrogenated with 50 psi hydrogen gas at ambient temperature for 16 hours. The mixture is filtered, and the filtrate is concentrated under vacuum. The residue is used without further purification. Yield: 55.8 g (0.22 mol; quantitative) Intermediate-23b MS(ESI + ):(M+H) + 251;HPLC:RT=0.96min, Method:Z011_S03

[0330] Step 3: PPA (50% in siRNA, 14.4 mL, 24 mmol) is added at 0°C to a mixture in 60 mL of DCM containing intermediate-23b (3.7 g, 15 mmol), 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid (3.0 g, 12.2 mmol), and NMM (8.1 mL, 73 mmol). The mixture is then stirred at ambient temperature for 2 hours. The mixture is concentrated under vacuum, siRNA and water are added, the organic layer is washed with aqueous NaHCO3 solution, dehydrated with Na2SO4, and concentrated under vacuum. The residue is purified by preparative HPLC. Yield: 5.1g (11 mmol; 87%) Intermediate-23c MS(ESI + ):(M+H) + 478;HPLC:RT=1.05 min, method:Z011_S03

[0331] Step 4: Intermediate-23c (5.1 g, 11 mmol) is stirred with HCl in dioxane (4 N, 20 mL, 80 mmol) at ambient temperature for 2 hours. The mixture is then concentrated under vacuum. The residue is used without further purification. Yield: 4.5g (11 mmol; quantitative) Intermediate-23d MS(ESI + ):(M+H) +378;HPLC:RT=0.90min, method:Z011_S03 Step 5: Intermediate-23d (2.3 g, 5.6 mmol) is added to a 20 mL mixture of 5-(difluoromethyl)-pyrazine-2-carboxylic acid (0.97 g, 5.6 mmol), TBTU (1.96 g, 6.1 mmol), and TEA (3.9 mL, 28 mmol) in DMF, and the mixture is stirred at ambient temperature for 3 hours. Water is then added, and the mixture is purified by preparative HPLC. Yield: 1.4g (2.6 mmol; 47%) Intermediate-23e MS(ESI + ):(M+H) + 534;HPLC:RT=1.02 min, method:Z011_S03

[0332] Step 6: Intermediate-23e (1.4 g, 2.6 mmol) is mixed with 10 mL of acetic acid and stirred at 95°C for 2 hours. The mixture is concentrated under vacuum, and the residue is separated in THF and water. The mixture is made basic with an aqueous NH3 solution and purified by preparative HPLC. The mixture of the four stereoisomers is separated by chiral SFC. The biological efficacy is described for Examples 23 and 77. Yield: 107 mg (0.21 mmol; 35%) Example 23 The following compounds were obtained: Examples 23, 77, 23-1, 23-2

[0333] [Table 226]

[0334] [Table 227]

[0335] [Table 228]

[0336] [Table 229] Similar to Example 23, the following product is obtained:

[0337] [Table 230]

[0338] Similar to Example 23, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 56, 56-1, 56-2, 75

[0339] [Table 231]

[0340] [Table 232]

[0341] [Table 233]

[0342] [Table 234]

[0343] Similar to Example 23, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 62, 62-1, 62-2, 62-3

[0344] [Table 235]

[0345] [Table 236]

[0346] [Table 237]

[0347] [Table 238]

[0348] Similar to Example 23, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 82, 82-1, 82-2, 82-3

[0349] [Table 239]

[0350] [Table 240]

[0351] [Table 241]

[0352] [Table 242]

[0353] Similar to Example 23, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: 87, 87-1, 87-2, 87-3

[0354] [Table 243]

[0355] [Table 244]

[0356] [Table 245]

[0357] [Table 246]

[0358] Similar to Example 23, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 90, 90-1, 90-2, 102.

[0359] [Table 247]

[0360] [Table 248]

[0361] [Table 249]

[0362] [Table 250] Similar to Example 23, the following compound was obtained.

[0363] [Table 251]

[0364] Similar to Example 23, the following compounds were obtained. The product was a mixture of four stereoisomers, which were separated by chiral SFC: Examples 103, 103-1, 103-2, 103-3

[0365] [Table 252]

[0366] [Table 253]

[0367] [Table 254]

[0368] [Table 255]

[0369] Similar to Example 23, the following compound is obtained. The product is a mixture of four stereoisomers, which are separated into two pairs of enantiomers by RP-HPLC (SF, TFA, narrow, ACN / H2O): Examples 113, 113-1. For example, the absolute stereoisomers of 113 are assigned only randomly.

[0370] [Table 256]

[0371] [Table 257] The following compounds were obtained with similarity to those in Example 23.

[0372] [Table 258]

[0373] [Table 259]

[0374]

Table 260

[0375] (Example 33)

Chemical formula

[0376] Step 1: A mixture having 1-fluoro-3-methyl-2-nitro-benzene (5.0 g, 32 mmol) and aqueous NH3 solution (32%, 15 mL, 248 mmol) in 30 mL of ACN is stirred in an autoclave at 100 °C for 4 days. Then, water is added and the mixture is concentrated in vacuo. The formed solid is filtered off, washed with water and dried. The product is used without further purification. Yield: 4.0 g (26 mmol; 81%) Intermediate-33a MS (ESI + ): (M+H) + 153; HPLC: RT = 0.87 min, Method: Z018_S04

[0377] Step 2: Intermediate-33a (4.0 g, 26 mmol) in 40 mL of ACN is mixed with NBS (4.7 g, 26 mmol) and the mixture is stirred at ambient temperature for 30 minutes. Water is added and the mixture is concentrated in vacuo. The formed solid is filtered off, washed with water and dried. The product is used without further purification. Yield: 6.0 g (26 mmol; quantitative) Intermediate-33b MS (ESI + ): (M+H) + 231 / 233 (Br); HPLC: RT = 1.01 min, Method: Z018_S04

[0378] Step 3: A mixture of intermediate-33b (6.0 g, 26 mmol) and Raney nickel (600 mg) in 60 mL of THF is hydrogenated at ambient temperature under a hydrogen pressure of 50 psi. The mixture is filtered, and the filtrate is concentrated under vacuum. The residue is used without further purification. Yield: 5.2g (25.6 mmol; 98%) Intermediate-33c MS(ESI + ):(M+H) + 201 / 203(Br);HPLC:RT=0.79min, Method:Z018_S04

[0379] Step 4: A mixture of intermediate-33c (3.0 g, 14.9 mmol), Zn(CN)2 (2.5 g, 21.3 mmol), and XPhos-G1 (500 mg, 0.68 mmol) in 10 mL of NMP is stirred at 100°C for 1 hour. After cooling, the mixture is poured into 150 mL of water, 10 mL of DCM is added, and the mixture is vigorously stirred and filtered. The aqueous phase is separated and extracted with DCM, the combined organic layers are dehydrated with MgSO4, and concentrated under vacuum. The solid from the filtration is washed with MeOH, and the extract is combined with the residue from the extraction and concentrated under vacuum. The residue is purified by preparative HPLC (X-Bridge C-18, eluent gradient (H2O + 0.15% NH3): ACN 95:5~>75:25). The products containing the fractions are combined and concentrated under vacuum. Yield: 1.74 g (11.8 mmol; 79%) Intermediate-33d MS(ESI + ):(M+H) + 148;HPLC:RT=0.55min, method:Z011_S03

[0380] Step 5: A mixture of Intermediate-33d (500 mg, 3.4 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (750 mg, 3.5 mmol) in 6.0 mL of pyridine is stirred at 0 °C and PPA (50% in EtOAc, 3.0 mL, 5.1 mmol) is added. After 15 minutes at 0 °C, the mixture is stirred at ambient temperature for 30 minutes. Water and DCM are added, the aqueous phase is extracted with DCM, the combined organic layers are dried over MgSO4 and concentrated in vacuo. The residue is taken up in dioxane and lyophilized. The residue is taken up in 10 mL of AcOH and stirred at ambient temperature for 4 days. The mixture is purified via preparative HPLC (Sunfire C-18, 50 °C, eluent gradient (H2O + 0.15% TFA): ACN 80:20 ~> 60:40). The fractions containing the product are combined and lyophilized. Yield: 1.3 g (3.0 mmol, 88%) Intermediate-33e MS (ESI + ): (M+H) + 327; HPLC: RT = 0.83 min, method: Z018_S04 Step 6: Intermediate-33e (1.3 g, 3 mmol) is stirred in HCl in dioxane (4N, 10 mL, 40 mmol) at ambient temperature for 1 hour. The mixture is concentrated in vacuo and the residue is used without further purification. Yield: 900 mg (3 mmol, quantitative) Intermediate-33f. MS (ESI + ): (M+H) + 227; HPLC: RT = 0.66 min, method: Z018_S04

[0381] Step 7: To a mixture of intermediate-33f (225 mg, 0.75 mmol), 5-(difluoromethyl)-pyrazine-2-carboxylic acid (160 mg, 0.92 mmol), and TEA (550 μL, 4.0 mmol) in 3 mL of DMF, TBTU (260 mg, 0.81 mmol) is added, and the mixture is stirred at ambient temperature for 15 minutes. Water is added, and the mixture is purified by preparative HPLC (X-Bridge C-18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 73:27~>53:47). The products containing the fractions are combined and freeze-dried. Yield: 220 mg (0.58 mmol, 77%) intermediate - 33 g MS(ESI + ):(M+H) + 383;HPLC:RT=0.85min, Method:Z018_S04

[0382] Step 8: Intermediate-33f (100 mg, 0.26 mmol) is stirred with ethyl 4-methylbenzene-1-sulfonate (55 mg, 0.28 mmol) and Cs2CO3 (200 mg, 0.61 mmol) in 2 mL of DMF at ambient temperature for 40 hours. Then, ethyl 4-methylbenzene-1-sulfonate (50 mg, 0.25 mmol) is added and the mixture is stirred at ambient temperature for 24 hours. Then, THF is added to the mixture, and the resulting mixture is filtered. The filtrate is purified by preparative HPLC (X-Bridge C-18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 6:4~>4:6). The products containing the fractions are combined and concentrated under vacuum. The residue is further purified by chiral SFC. Yield: 52 mg (0.10 mmol, 42%) Example 33

[0383] [Table 261] Similar to Example 33, the following product is obtained:

[0384] [Table 262]

[0385] (Example 44) [ka]

[0386] Step 1: A mixture containing 1-fluoro-3-methyl-2-nitrobenzene (2.0 g, 13.3 mmol) and difluoroethylamine (4.0 g, 49 mmol) in 10 mL of ACN is stirred in a microwave oven at 140°C for 35 hours. The mixture is then filtered, and the filtrate is concentrated under vacuum. The residue is separated with water and DCM, the aqueous phase is extracted with DCM, the organic layers are combined, dehydrated with MgSO4, and concentrated under vacuum. Yield: 2.8 g (approximately 90%; 12 mmol; 90%) Intermediate-44a MS(ESI + ):(M+H) + 217;HPLC:RT=1.03min, Method:Z018_S04

[0387] Step 2: Intermediate-44a (2.8 g, 12 mmol) in 30 mL of ACN is mixed with NBS (2.1 g, 12 mmol), and the mixture is stirred at ambient temperature for 30 minutes. Water is added, and the mixture is purified by preparative HPLC (X-Bridge C-18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 5:5~>3:7). The products containing the fractions are combined, concentrated under vacuum, decomposed by sonication to form a solid, and filtered. The solid is washed with water and dried under vacuum. Yield: 2.7 g (9.2 mmol; 78%) Intermediate-44b MS(ESI + ):(M+H) + 295 / 297(Br);HPLC:RT=1.12min, Method:Z018_S04

[0388] Step 3: A mixture of intermediate-44b (750 mg, 2.5 mmol) and Raney nickel (100 mg) in 20 mL of THF is hydrogenated at ambient temperature under a hydrogen pressure of 50 psi. The mixture is then filtered, and the filtrate is purified by preparative HPLC (X-Bridge C-18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 62:38~>42:58). The products containing the fractions are combined and freeze-dried. Yield: 540 mg (2.0 mmol; 80%) intermediate-44c MS(ESI + ):(M+H) + 265 / 267(Br);HPLC:RT=0.97min, Method:Z018_S04

[0389] Step 4: A mixture of intermediate-44c (150 mg, 0.57 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (125 mg, 0.58 mmol) in 4.0 mL of pyridine is stirred at 0°C, and PPA (50% in siRNA, 600 μL, 1.0 mmol) is added. After 1 hour at 0°C, water is added, the precipitate is filtered off, washed with water, and collected with 5 mL of AcOH. The mixture is stirred at ambient temperature for 40 hours. Then the mixture is stirred at 60°C for 48 hours. The residue is concentrated under vacuum, collected with THF / MeOH, set to basic conditions with TEA, and purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 46:54~>26:74). The products containing the fractions are combined and freeze-dried. Yield: 141 mg (0.32 mmol, 56%) intermediate-44d MS(ESI + ):(M+H) + 444 / 446(Br);HPLC:RT=1.16min, Method:Z011_S03

[0390] Step 5: Intermediate-44d (141 mg, 0.32 mmol) is stirred in HCl in dioxane (4N, 0.95 mL, 3.8 mmol) at ambient temperature for 16 hours. The mixture is concentrated under vacuum, the residue is removed in ACN, and concentrated again under vacuum. Yield: 128 mg (0.31 mmol, 97%) Intermediate-44e MS(ESI + ):(M+H) + 344 / 346(Br);HPLC:RT=0.98min, Method:Z011_S03 Step 6: To a mixture of intermediate-44e (125 mg, 0.30 mmol), 5-methyl-pyrazine-2-carboxylic acid (46 mg, 0.33 mmol), and TEA (187 μL, 1.3 mmol) in 3.5 mL of DMF, TBTU (101 mg, 0.32 mmol) is added, and the mixture is stirred at ambient temperature for 1 hour. The mixture is poured into water at 0°C, stirred for 10 minutes, the formed solid is filtered, washed with water, picked up in dioxane, and freeze-dried. Yield: 137 mg (0.28 mmol, 94%) Intermediate-44f MS(ESI + ):(M+H) + 464 / 466(Br);HPLC:RT=1.08min, Method:Z011_S03

[0391] Step 7: A mixture of intermediate-44f (125 mg, 0.27 mmol), Zn(CN)2 (65 mg, 0.55 mmol), and XPhos-G1 (20 mg, 27 μmol) in 750 μL of NMP is stirred under argon at 100°C for 1 hour. After cooling, one drop of water is added, followed by the addition of 2 mL of ACN and THF, respectively. The mixture is filtered and purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.15% NH3): ACN 65:35~>45:55). The products containing the fractions are combined and lyophilized. The residue is purified via chiral SCF. Yield: 66 mg (0.16 mmol, 64%) Example 44

[0392] [Table 263]

[0393] (Example 57) [ka]

[0394] Step 1: To a mixture of 1,4,5-trifluoro-2-nitro-benzene (7 mL; 61 mmol) and TEA (21 mL; 153 mmol) in 200 mL of DCM, ethylamine (2 M in THF; 33.6 mL; 67 mmol) is slowly added, and the mixture is stirred at ambient temperature for 22 hours. Ethylamine (2 M in THF; 7 mL; 14 mmol) is added, and the mixture is stirred at ambient temperature for 6 hours. The mixture is washed with water, the organic layer is dehydrated with Na2SO4, filtered, and concentrated under vacuum. The mixture is filtered, and the filtrate is concentrated under vacuum. The residue is purified by chromatography (silica gel; eluent gradient petroleum ether: siRNA = 90:10 to > 80:20). The products containing the fractions are combined and concentrated under vacuum. R f :0.43 (PE / SiO 9:1) Yield: 5.7g (28 mmol; 46%) Intermediate-57a MS(ESI + ):(M+H) + 203;R f :0.43 (PE / SiO 9:1) Step 2: A mixture of intermediate-57a (1.0 g, 4.9 mmol) and 100 mg of 10% activated carbon-supported Pd in ​​20 mL of THF is hydrogenated at ambient temperature for 15 hours at 50 psi (hydrogen gas). The mixture is then filtered and concentrated under vacuum. Yield: 820 mg (approximately 90% content; 4.8 mmol; 96%) Intermediate-57b MS(ESI + ):(M+H) + 173;HPLC:RT=0.65min, Method:Z018_S04

[0395] Step 3: To a mixture of intermediate-57b (approximately 90%, 330 mg, 1.7 mmol) in 5 mL of DCM and (2S)-2-Boc-amino-3-hydroxy-3-methylbutanoic acid (450 mg, 1.9 mmol) and NMM (800 μL, 7.3 mmol), PPA (50% by mass in Â, 1.4 mL, 2.3 mmol) was added at 0°C. The mixture was then stirred at 0°C for 5 hours. Water was added, and the mixture was concentrated under vacuum. The residue was purified by preparative HPLC (XBridge C18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 59:41~>39:61). The products containing the fractions were combined and freeze-dried. Yield: 550 mg (1.4 mmol; 81%) Intermediate-57c MS(ESI + ):(M+H) + 388;HPLC:RT=1.05min, Method:Z018_S04

[0396] Step 4: Intermediate-57c (540 mg, 1.4 mmol) is stirred in 10 mL of AcOH at 70°C for 30 hours. The mixture is then purified by preparative HPLC (Sunfire C18, 50°C, eluent gradient (H2O + 0.15% TFA): ACN 72:28~>52:48). The products containing the fractions are combined and freeze-dried. Yield: 510 mg (1.1 mol; 76%) Intermediate - 57d MS(ESI + ):(M+H) + 370;HPLC:RT=0.90min, method:Z018_S04

[0397] Step 5: Intermediate -57d (510 mg, 1.1 mmol) in HCl in dioxane (4N, 5 mL, 20 mmol) is stirred at ambient temperature for 30 minutes. The mixture is then concentrated under vacuum, and the residue is taken out in MeOH, passed through an ion exchange cartridge (Agilent PL-HCO3 MP SPE), and concentrated under vacuum. The residue is purified by preparative HPLC (X-Bridge C18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 79:21~>59:41). The products containing the fractions are combined and freeze-dried. Yield: 190 mg (0.71 mmol; 67%) Intermediate-57e MS(ESI + ):(M+H) + 270;HPLC:RT=0.84 min, method:Z011_S03

[0398] Step 6: To 4 mL of DMF, 5-(difluoromethyl)-pyrazine-carboxylic acid (65 mg, 0.37 mmol) is mixed with intermediate-57e (80 mg, 0.3 mmol) and TEA (250 μL, 1.8 mmol). TBTU (100 mg, 0.31 mmol) is added, and the mixture is stirred at ambient temperature for 20 minutes. Water is added, and the mixture is purified by preparative HPLC (XBridge C18, 50°C, eluent gradient (H2O + 0.1% NH3): ACN 58:42~>38:62). The products containing the fractions are combined and freeze-dried. Yield: 78 mg (0.18 mmol; 62%) Example 57

[0399] [Table 264]

[0400] (Example 60) [ka]

[0401] [ka]

[0402] Step 1: A mixture of 4-methoxyaniline (10 g, 81 mmol), ethyl glyoxylate polymer form (47% in toluene, 17 mL, 81 mmol), and MgSO4 (24 g, 203 mmol) in 125 mL of DCM is stirred at 40°C for 3 hours. The mixture is filtered, and the filtrate is evaporated at 25°C. The residue is used without further purification. Yield: 20.8g (approximately 80% content; 81mol; quantitative) Intermediate-60a MS(ESI + ):(M+H) + 208;HPLC:RT=0.90min, method:Z011_S03

[0403] Step 2: Intermediate-60a (21 g, 80% content, 81 mmol) is degassed from 150 mL of dioxane (unstabilized) and kept under nitrogen. Copper(II) chloride (0.54 g, 4 mmol) and tert.-butyl hydroperoxide (5.5 M in decane; 17.5 mL, 96 mmol) are added, and the mixture is stirred at 50°C for 16 hours. The mixture is concentrated under vacuum and purified by continuous column chromatography (silica gel, PE / siRNA gradient 9:1 to >4:1, then 7:3, then 4:1, combining the products containing the fractions in each step, concentrating under vacuum, and then performing the next purification). Yield: 6.4 g (22 mmol; 27%) Intermediate-60b as a mixture of stereoisomers MS(ESI + ):(M+H) + 296;HPLC:RT=0.90min, method:Z011_S03

[0404] Step 3 Intermediate-60b (300 mg, 1.02 mmol) is mixed with cerium(IV) ammonium nitrate (835 mg, 1.6 mmol) in 10 mL of ACN containing 3 mL of water, and stirred at ambient temperature for 3 hours. The mixture is then filtered and concentrated under vacuum. Yield: 300 mg (Purity: approx. 33%; 0.53 mmol; 52%) Intermediate as a mixture of stereoisomers - 60c MS(ESI + ):(M+H) + 190;TLC:Rf=0.5(Eluent:DCM:MeOH 95:5)

[0405] Step 4: Boc-anhydrous (5.2 g; 24 mmol) was added to a mixture of intermediate-60c (3.0 g; 16 mmol) and TEA (8.0 g; 79 mmol) in 15 mL of THF. The mixture was stirred at ambient temperature for 18 hours, then concentrated under vacuum, and purified by silica gel column chromatography (eluent gradient hexane:siRNA 100:0 to >60:40). Yield: 1.0 g (Purity: approx. 65%; 2.2 mmol; 9%) Intermediate as a mixture of stereoisomers - 60d MS(ESI + ):(M+H) + 234; TLC: Rf = 0.5 (Eluent: Hexane: siRNA 7:3)

[0406] Step 5: LiOH (100 mg; 4.2 mmol) was added to intermediate-60d (0.8 g, 2.8 mmol) in 10 mL of MeOH containing 3 mL of water. The mixture was stirred at ambient temperature for 3 hours, concentrated under vacuum, and purified by preparative HPLC. Yield: 0.5g (1.9 mmol; 68%) Intermediate-60e as a mixture of stereoisomers MS(ESI + ):(M+H) + 262;TLC:Rf=0.5(Eluent:DCM:MeOH 95:5)

[0407] Step 6: To 100 mL of DCM, 1-fluoro-2-nitro-4-trifluoromethylbenzene (2.2 mL; 15.7 mmol) is added, to which ethylamine (2 M in THF; 15.7 mL, 31.4 mmol) is added, and the mixture is stirred at ambient temperature for 20 hours. 100 mL of DCM is added, and the mixture is extracted with 100 mL of water. The organic layer is collected, dehydrated with Na2SO4, filtered, and concentrated under vacuum. Yield: 3.30 g (14.1 mmol; 90%) intermediate - 60 f MS(ESI + ):(M+H) + 235;HPLC:RT=1.10 min, method:Z017_S04

[0408] Step 7: Intermediate -60f (200 mg, 0.85 mmol) is mixed with activated carbon-supported palladium (10%, 50 mg) in 20 mL of MeOH and hydrogenated at a hydrogen pressure of 50 psi for 3.5 hours. The mixture is then filtered and concentrated under vacuum. Yield: 170 mg (0.83 mol; 97%) Intermediate - 60 g MS(ESI + ):(M+H) + 205;HPLC:RT=0.86 min, method:Z018_S04 Step 8: Intermediate-60e (210 mg, 0.80 mmol), intermediate-60 g (170 mg, 0.83 mmol), and NMM 350 μL in 5 mL of DCM are stirred at ambient temperature, and PPA (50% in siRNA; 600 μL, 1.0 mmol) is added. After stirring at ambient temperature for 16 hours, water is added, and the mixture is stirred at ambient temperature for 20 minutes. Then, 5 mL of AcOH is added, and the mixture is stirred at 50°C for 3 hours, at ambient temperature for 16 hours, and at 80°C for 2 hours. The mixture contains four stereoisomers, which can be separated into two pairs of enantiomers by HPLC (C-18 Sunfire, 50°C, eluent gradient (water + 0.15% TFA): ACN 58:42~>38:62). The products containing the fractions are combined and freeze-dried. Only one pair of enantiomers (intermediate-60h) is used in step 9 of the reaction scheme. Stereoisomer vs. 1: Yield: 70 mg (0.13 mmol; 16%) Intermediate as a mixture of enantiomers - 60 h MS(ESI + ):(M+H) + 430;HPLC:RT=1.03 min, method:Z018_S04 Stereoisomer vs. 2: Yield: 120 mg as a mixture of enantiomers MS(ESI + ):(M+H) + 430;HPLC:RT=1.04 min, method:Z018_S04

[0409] Step 9: The intermediate -60h (70 mg, 0.13 mmol) is stirred in 4 mL of hydrochloric acid (4 M in dioxane) at ambient temperature for 1 hour. The mixture is concentrated under vacuum. Yield: 52 mg (0.13 mmol; quantitative) Intermediate-60i as a mixture of enantiomers MS(ESI + ):(M+H) + 330;HPLC:RT=0.77min, Method:Z018_S04

[0410] Step 10: A mixture of intermediate-60i (52 mg, 0.13 mmol), 5-methylpyrazine-2-carboxylic acid (22 mg, 0.16 mmol), TBTU (44 mg, 0.14 mmol), and TEA (100 μL, 0.72 mmol) in 4.0 mL of DMF is stirred at ambient temperature for 15 minutes. Water is added, and the mixture is purified by preparative HPLC (C-18 X-Bridge, 50°C, eluent gradient (water + 0.15% NH3): ACN 61:39~>41:59). The products containing the fractions are combined and lyophilized. Then, chiral SFC is performed to obtain the desired enantiomer. Yield: 15 mg (0.033 mol; 36%) Example 60

[0411] [Table 265]

[0412] (Example 63) [ka]

[0413] Step 1: Methylamine (2N in THF; 36 mL, 72 mmol) is slowly added to a mixture of 3-fluoro-1-trifluoromethyl-4-nitrobenzene (10.1 g, 48 mmol) and K2CO3 (10.0 g, 72 mmol) in 60 mL of DMF, while stirring to maintain the mixture temperature below 35°C. The mixture is then stirred at ambient temperature for 1 hour. The mixture is poured into a saturated aqueous solution of NaHCO3, cooled to 0°C, filtered, and the solid is washed with water. The solid is dried under vacuum and used without further purification. Yield: 10.4 g (47 mmol; 98%) Intermediate-63a MS(ESI + ): M + 220;HPLC:RT=1.03 min, method:Z011_S03

[0414] Step 2: Intermediate -63a (19.9 g, 90.4 mmol) and 2.0 g of 10% Pd / C in 300 mL of MeOH are hydrogenated at ambient temperature for 1 hour under a hydrogen pressure of 60 psi. The mixture is filtered, the filtrate is dehydrated with MgSO4, and concentrated under vacuum. Yield: 15.7g (82.7 mmol; 91%) Intermediate-63b MS(ESI + ):(M+H) + 191;HPLC:RT=0.78 min, method:Z018_S04

[0415] Step 3: A mixture of intermediate 63b (15.7 g, 82.7 mmol) and (2S)-2-Boc-amino-2-cyclopropyl-acetic acid (21.9 g, 102 mmol) in 150 mL of pyridine is stirred at -10°C, and PPA (50% in siRNA, 83 mL, 141 mmol) is slowly added while maintaining the temperature below 0°C. After 2 hours at 0°C, 50 mL of pyridine is added, and the mixture is stirred at ambient temperature for 18 hours. The mixture is poured into 3.5 L of water and 20 mL of concentrated NH3 aqueous solution and stirred vigorously. The formed solid is filtered, washed with water, and dried under vacuum. The solid is removed in 125 mL of AcOH and stirred at ambient temperature for 17 hours. 400 mL of dioxane is added, and the mixture is freeze-dried. The residue is separated in ACN and 2 L of water, the volatile organic solvent is removed under vacuum, the aqueous phase is adjusted to a pH of approximately 9 by adding concentrated NH3 aqueous solution, the mixture is vigorously stirred, and filtered. The solid is washed with 650 mL of water and dried under vacuum. Yield: 18.7g (50.7 mmol, 65%) Intermediate-63c MS(ESI + ):(M+H) + 370;HPLC:RT=0.94 min, method:Z018_S04

[0416] Step 4: To intermediate-63c (18.7 g, 50.6 mmol) in 65 mL of dioxane at 10°C, HCl in dioxane (4N, 130 mL, 520 mmol) is slowly added while cooling, maintaining the temperature below 15°C. The mixture is then stirred at ambient temperature for 2 hours. 600 mL of diethyl ether is added, and the mixture is stirred for 5 minutes. The formed solid is filtered and washed with diethyl ether. The solid is removed in 600 mL of water, concentrated NH3 aqueous solution is added to set the pH to 8.5, and the aqueous phase is extracted with ELISA. The combined organic layers are washed with semi-concentrated brine, dehydrated with MgSO4, and concentrated under vacuum. The residue is used without further purification. Yield: 13.6g (50.5 mmol, 99%) intermediate-63d MS(ESI + ):(M+H) + 270;HPLC:RT=0.90min, method:Z011_S03

[0417] Step 5: A mixture of intermediate 63d (13.6 g, 50.5 mmol) and 5-methyl-pyrazine-2-carboxylic acid (8.6 g, 61 mmol) in 350 mL of toluene is stirred at 0°C, and PPA (50% of toluene, 39 mL, 66 mmol) is added while keeping the mixture below 5°C. After 45 minutes at 0-10°C, 200 mL of toluene and 500 mL of water are added, and the mixture is adjusted to a pH of approximately 8.5 by adding concentrated NH3 aqueous solution. The organic phase is washed with brine, 1.5 g of activated carbon is added, the mixture is dehydrated with MgSO4, filtered, and the filtered solid is washed with 250 mL of toluene. The filtrate is concentrated under vacuum, and the residue is treated with 100 mL of diisopropyl ether. The mixture is filtered, and the solid is washed with 100 mL of diisopropyl ether. The solid is dried under vacuum. Yield: 18.5 g (47.6 mmol, 94%) Example 63

[0418] [Table 266]

[0419] (Example 66) [ka]

[0420] Step 1: 1,2-Diamino-4,5-Difluorobenzene (100 mg, 0.69 mmol) is mixed with intermediate-1c (120 mg, 0.51 mmol) and TEA (425 μL, 3.1 mmol) in 5.0 mL of DCM. PPA (50% in ethyl acetate, 600 μL, 1.0 mmol) is added at 0°C, and the mixture is stirred at 0°C for 1 hour. Then, 100 μL of water is added, and the mixture is stirred at ambient temperature for 1 hour. 5.0 mL of AcOH is added, and the mixture is stirred at ambient temperature for 16 hours. The mixture is concentrated under vacuum, and the residue is purified by preparative HPLC (Sunfire C-18, 50°C, eluent gradient (H2O + 0.15% TFA): ACN 88:12~>68:32). The products containing the fractions are combined and freeze-dried. The residue is collected in MeOH, passed through an ion exchange cartridge (Agilent PL-HCO3 MP SPE), and concentrated under vacuum. Yield: 160 mg (0.47 mmol; 91%) Intermediate-66a MS(ESI + ):(M+H) + 344;HPLC:RT=0.75min, Method:Z018_S04

[0421] Step 2: Methyl methanesulfonate (40 μL, 0.47 mmol) is added to a mixture of intermediate-66a (160 mg, 0.47 mmol) and Cs2CO3 (250 mg, 0.77 mmol) in 5 mL of ACN. The mixture is stirred at ambient temperature for 1 hour. The mixture is then filtered, and the filtrate is purified by preparative HPLC (X-Bridge C-18, 50°C, eluent gradient (H2O + 0.15% NH3): ACN 68:32~>48:52). The products containing the fractions are combined and freeze-dried. Yield: 140 mg (0.39 mmol; 84%) Example 66

[0422] [Table 267] Similar to Example 66, the following product is obtained:

[0423] [Table 268]

[0424] [Table 269]

[0425] [Table 270]

[0426] (Example 69) [ka]

[0427] Step 1: A mixture of N-Boc-threonine (10 g, 46 mmol), benzyl bromide (5.2 mL, 43 mmol), and NaHCO3 (9 g, 107 mmol) in 80 mL of DMF is stirred at ambient temperature for 4 days. The mixture is filtered, and the filtrate is concentrated under vacuum. The residue is taken out in 500 mL of water and extracted with tert-butyl methyl ether. The combined organic layer is dehydrated with MgSO4 and concentrated under vacuum. Yield: 11.8 g (38 mmol; 88%) Intermediate-69a MS(ESI + ):(M+H) + 310;HPLC:RT=0.98 min, method:Z011_S03

[0428] Step 2: To a mixture of intermediate-69a (11.8 g, 38 mmol) and CuI (3.6 g, 19 mmol) in 400 mL of ACN at 50°C, 2,2-difluoro-2-(fluorosulfonyl)-acetic acid is added in 400 mL of ACN over 220 minutes. The mixture is stirred at 50°C for a further 90 minutes, then 30 mL of TEA is added at ambient temperature, and the mixture is concentrated under vacuum. The residue is taken out in 40 mL of THF, and 10 mL of concentrated NH3 aqueous solution is added. Celite is added, the mixture is filtered, and the solid is washed with THF. The filtrate is stored at ambient temperature for 18 hours, filtered, 5 g of PL-thiol resin (Agilent, 2.2 mmol / g, 100A, 45 μm) is added, stirred, and filtered. THF is added to a total volume of 75 mL, and the mixture is purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 52:48~>32:68). The products containing the fractions are combined and freeze-dried. Yield: 4.3g (12 mmol; 31%) Intermediate-69b MS(ESI + ):(M+H) + 360;HPLC:RT=1.10 min, method:Z011_S03

[0429] Step 3: Intermediate -69b (2.2 g, 5.4 mmol) and 300 mg of 10% Pd / C in 100 mL of MeOH are hydrogenated at ambient temperature for 1.5 hours under a hydrogen pressure of 60 psi. The mixture is filtered, the filtrate is dehydrated with MgSO4, and concentrated under vacuum. Yield: 1.6g (5.3 mmol; 99%) Intermediate-69c MS(ESI + ):(M+H) + 270

[0430] Step 4: A mixture of intermediate-4b (885 mg, 4.2 mmol) and intermediate-69c (1.4 g, 4.6 mmol) in 10 mL of pyridine is stirred at -10°C, and PPA (50% in Depositphotos, 3.5 mL, 5.9 mmol) is slowly added while maintaining the temperature below 0°C. After 2.5 hours at 0°C, 1 mL of water is added, and the mixture is concentrated under vacuum. The residue is purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 55:45~>35:65). The products containing the fractions are combined and freeze-dried. Yield: 1.6g (3.6 mmol, 86%) Intermediate-69d MS(ESI + ):(M+H) + 442;HPLC:RT=1.07min, Method:Z011_S03

[0431] Step 5: To 9 mL of dioxane at 0°C, intermediate-69d (800 mg, 1.8 mmol) is added, along with HCl in dioxane (4N, 9 mL, 36 mmol) while cooling. The mixture is then stirred at ambient temperature for 2 hours. The mixture is concentrated under vacuum, removed in a DCM, and concentrated under vacuum again. Yield: 710 mg (1.7 mmol, 95%) Intermediate-69e MS(ESI + ):(M+H) + 342;HPLC:RT=0.92min, Method:Z011_S03

[0432] Step 6: A mixture of intermediate-69e (350 mg, 0.76 mmol) and 5-methyl-pyrazine-2-carboxylic acid (126 mg, 0.91 mmol) and TEA (371 μL, 2.7 mmol) in 6.5 mL of ACN is stirred at ambient temperature, and CIP (233 mg, 0.84 mmol) is added. The mixture is stirred at ambient temperature for 1 hour. The mixture is added to 250 mL of semi-concentrated NaCl (aqueous solution), and the pH is set to approximately 9 by adding concentrated NH3 aqueous solution. The mixture is concentrated under vacuum, the solid is filtered, washed with water, and dried under vacuum. The solid is taken out in 5 mL of AcOH and stirred at 55°C for 1 hour and at 65°C for 15 hours. The mixture is concentrated under vacuum, the residue is taken out in THF and MeOH, and the pH is set to basic by adding TEA. It is purified by preparative HPLC. The products containing the fractions are combined and freeze-dried. Yield: 49 mg (0.11 mmol, 15%) Example 69

[0433] [Table 271] Similar to Example 69, the following product is obtained:

[0434] [Table 272]

[0435] [Table 273]

[0436] (Example 85) [ka]

[0437] Step 1: 1,2-Diamino-4,5-Difluorobenzene (500 mg, 3.5 mmol) is mixed with N-Boc-O-methyl-L-threonine (890 mg, 3.8 mmol) and NMM (2.3 mL, 21 mmol) in 50 mL of DCM. PPA (50% in siRNA, 4.1 mL, 6.9 mmol) is added at 0°C, and the mixture is stirred at 0°C for 1.8 hours and then at ambient temperature for 14.5 hours. The mixture is then washed with aqueous Na2CO3 solution (0.5 N) and water, the organic layer is dehydrated with MgSO4, and concentrated under vacuum. The residue is taken out in MeOH / THF and purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 66:34~>46:54). The products containing the fractions are combined and freeze-dried. Yield: 361 mg (1.0 mmol; 27%) Intermediate-85a. MS(ESI + ):(M+H) + 358;HPLC:RT=0.95min, Method:Z011_S03

[0438] Step 2: Intermediate-85a (360 mg, 1.0 mmol) is stirred in AcOH (3.0 mL, 51 mmol) at 95°C for 1.25 hours. The mixture is concentrated under vacuum, and then taken out in HCl solution in dioxane (4N, 3.0 mL, 12 mmol). After stirring at ambient temperature for 45 minutes, the mixture is concentrated under vacuum, taken out in ACN, and concentrated again under vacuum. Yield: 391 mg (Content: approximately 90% 1.0 mmol; quantitative) Intermediate-85b MS(ESI + ):(M+H) + 242;HPLC:RT=0.97min, Method:Z011_S03

[0439] Step 3: CIP (307 mg, 1.1 mmol) is added at ambient temperature to a mixture of intermediate-85b (390 mg, 1.0 mmol), 2-methylpyrazine-5-carboxylic acid (145 mg, 1.1 mmol), and TEA (0.7 mL, 5.0 mmol) in 10 mL of ACN, and then stirred at ambient temperature for 30 minutes. The mixture is concentrated under vacuum. THF is added, and the mixture is purified by preparative HPLC (X-Bridge C-18, 10 μm, eluent gradient (H2O + 0.1% NH3): ACN 74:26~>54:46). Yield: 144 mg (0.38 mmol; 38%) Intermediate-85c MS(ESI + ):(M+H) + 362;HPLC:RT=0.87min, Method:Z011_S03

[0440] Step 4: Methyl methanesulfonate (35 μL, 0.42 mmol) is added to a mixture of intermediate-85c (125 mg, 0.35 mmol) and Cs2CO3 (237 mg, 0.73 mmol) in 6.5 mL of ACN. The mixture is stirred at ambient temperature for 3 hours. The mixture is then concentrated under vacuum, the residue is taken out in DCM, washed with water, the organic layer is dehydrated with MgSO4, mixed with dioxane, and freeze-dried. The residue is taken out in DCM and concentrated under vacuum. Yield: 131 mg (0.35 mmol; quantitative) Example 85

[0441] [Table 274]

[0442] (Example 14) [ka]

[0443] Except for step 7, the following compounds are obtained, which are similar to those in Example 14 (see above):

[0444] (Examples 132 and 133) [ka]

[0445] Step 7: A mixture of intermediate-132f (2.9 g, 6.75 mmol) and Wilkinson catalyst (950 mg, 1.03 mmol) in ethanol (145 ml) is hydrogenated at 40°C for 22 hours under a hydrogen atmosphere at 40 psi. The mixture is filtered and concentrated under vacuum. The residue is dissolved in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.1% NH4OH) 58:42 to >38:62). The fractions containing the product are combined and concentrated under vacuum. The product is isolated as a mixture of stereoisomers and used as is in the following steps. Yield: 2.05 g (4.74 mmol; 70.4%) Intermediate - 132 g MS(ESI + ):(M+H) + 432, HPLC: RT=1.03 min, method: Z011_S03 Chiral SFC Rt stereoisomer 1:0.66 min (Method: I_AC_10_IPA_NH3_002) Chiral SFC Rt stereoisomer 2: 0.86 min (Method: I_AC_10_IPA_NH3_002)

[0446] Step 8: In Example 14, the intermediate was synthesized from 132g in a manner similar to Step 8 to obtain the title compound as a mixture of stereoisomers, which was then used as is in the next step. Yield: 1.18 g (3.56 mmol; 76.8%) intermediate - 132 h MS(ESI + ):(M+H) + 332;HPLC:RT=0.84min, Method:Z011_S03 Chiral SFC Rt diastereomer 1:1.23 min (Method: I_IG_20_MEOH_NH3_002) Chiral SFC Rt diastereomer 2: 1.56 min (Method: I_IG_20_MEOH_NH3_002)

[0447] Step 9: Example 14 was synthesized from intermediate-132h in a manner similar to step 9, yielding Examples 132 and 133 as a mixture of stereoisomers, which were then separated by chiral SFC. Yield: 1.18 g (3.56 mmol; 76.8%) Examples 132 and 133 MS(ESI + ):(M+H) + 332;HPLC:RT=0.84min, Method:Z011_S03

[0448] [Table 275]

[0449] [Table 276]

[0450] Similar to Example 14, the following compound is obtained. The product is a mixture of two stereoisomers. Isolate one stereoisomer: Example 134

[0451] [Table 277]

[0452] The following compounds were obtained in a manner similar to Example 14. The product was a mixture of two stereoisomers, which were separated by chiral SFC: Examples 135, 135-1, 136, 136-1, 137, 137-1.

[0453] [Table 278]

[0454] [Table 279]

[0455] Similar to Example 14, the following compound is obtained. The product is a mixture of two stereoisomers, which are separated by chiral SFC: Examples 136, 136-1

[0456] [Table 280]

[0457] [Table 281]

[0458] Similar to Example 14, the following compound is obtained. The product is a mixture of two stereoisomers, which are separated by chiral SFC: Examples 137, 137-1

[0459] [Table 282]

[0460] [Table 283] Similar to Example 1, the following compounds are obtained:

[0461] [Table 284] The following compound is obtained with similarity to Example 23: (The synthesis is described again.)

[0462] (Example 139) [ka]

[0463] Step 1 A mixture of N-ethyl-2-nitro-4-(trifluoromethyl)aniline (1.4 g, 5.97 mmol), methanol (50 ml), and Pd / C 10% (150 mg) was stirred at room temperature for 5 hours under a hydrogen atmosphere of 50 psi. The mixture was then filtered, concentrated, and purified by HPLC. Yield: 1.22 g (5.97 mmol; 99%) Intermediate-139a HPLC: RT=0.978 min, method: Z011_S03

[0464] Step 2 To a mixture of intermediate-139a (1.19 g, 5.87 mmol), 2-{[(tert-butoxy)carbonyl]amino}-2-(oxolan-3-yl)acetic acid (1.2 g, 4.89 mmol), N-methylmorpholine (3.23 ml, 29.35 mmol), and DCM (30 ml), PPA (50%) (5.76 ml, 9.78 mmol) is added under ice cooling. The resulting mixture is stirred at room temperature for 2 hours. Water is added, and then the mixture is concentrated under vacuum. Water is added to the residue. The mixture is filtered, dissolved in THF / ACN, and purified by chromatography. Yield: 1.3g (3.01 mmol; 61.6%) Intermediate-139b MS(ESI + ):(M+H) + 432, HPLC: RT=1.057 min, Method: Z011_S03 Step 3 Mix intermediate-139b with hydrochloric acid (4M in dioxane, 20 ml) and stir at room temperature for 2 hours. Concentrate the mixture and use without further purification. Yield: 1.1g (2.99 mmol; 99%) Intermediate-139c HPLC: RT=0.786 min, method: Z011_S03

[0465] Step 4 To a mixture of intermediate-139c (1.1 g, 299 mmol), 5-methylpyrazine-2-carboxylic acid (0.496 g, 3.589 mmol), triethylamine (2.084 ml, 14.954 mmol), and DMF (15 ml), TBTU (1.056 g, 3.20 mmol) is added. The mixture is stirred at room temperature for 12 hours. The mixture is diluted with THF and water, concentrated, and purified by HPLC. Yield: 1.1g (3.01 mmol; 81.5%) Intermediate-139d MS(ESI + ):(M+H) + 451, HPLC: RT=0.987 min, Method: Z011_S03

[0466] Step 5 A mixture of intermediate-130d (1.1 g, 2.437 mmol) and acetic acid (20 ml) is stirred at 90°C for 4 hours. The mixture is then concentrated, and THF and MEOH are added. Triethylamine is added until the mixture shows a basic pH. The mixture is then purified by HPLC. The product is isolated as a mixture of four stereoisomers and separated by chiral SFC. Yield: 0.9g (3.01 mmol; 85.2%) MS(ESI + ):(M+H) + 433, HPLC: RT=1.145 min, method: Z011_S03

[0467] [Table 285]

[0468] [Table 286]

[0469] [Table 287]

[0470] [Table 288]

[0471] Similar to Example 139, the following compounds are obtained. The product is a mixture of four stereoisomers, which are separated by chiral SFC: Examples 141, 141-1, 141-2, 142

[0472] [Table 289]

[0473] [Table 290]

[0474] [Table 291]

[0475] [Table 292]

[0476] (Examples 143 and 144) [ka]

[0477] Step 1: PPA (50% in siRNA, 9.72 mL, 15.88 mmol) was added at 0°C to a mixture in 30 mL of DCM containing N1-ethyl l-4-fluorobenzene-1,2-diamine (1.36 g, 7.94 mmol), 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid (2.27 g, 8.34 mmol), and NMM (5.2 mL, 47.66 mmol). The mixture was then stirred at ambient temperature for 2 hours. The mixture was concentrated under vacuum, siRNA and water were added, the organic layer was washed with aqueous NaHCO3 solution, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC. The product was isolated as a mixture of stereoisomers. Yield: 2.6 g (6.81 mmol; 86%) Intermediate-143a MS(ESI + ):(M+H) + 382;HPLC:RT=0.8 min, method:Z011_S03

[0478] Step 2: A mixture of intermediate-143a (2.6 g, 5.45 mmol) and zinc bromide (2.59 g, 11.45 mmol) in 87 ml of butyl acetate was stirred at 110°C for 22 hours. The mixture was cooled and concentrated under vacuum. 50 ml of ice-cooled water was added to the residue and stirred for several minutes. Then, 4 ml of concentrated ammonia solution in aqueous solution was added. The resulting solid was filtered and dried to obtain the product as a mixture of stereoisomers. Yield: 2.05 g (5.45 mmol; 99%) Intermediate-143b MS(ESI + ):(M+H) + 264; HPLC: RT=0.89 min and 0.92 min, Method: Z003_S05

[0479] Step 3: PPA (50% in HCl, 4.21 mL, 7.08 mmol) was added at 0°C to a 20 mL mixture of intermediate-143b (2.05 g, 5.45 mmol), 5-methylpyrazine-2-carboxylic acid (2.27 g, 8.34 mmol), and TEA (3.02 mL, 21.79 mmol) in HCl, and the mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated under vacuum, DCM and water were added, the organic layer was washed with NaHCO3 aqueous solution, dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (XBridge C18, 10 μm, eluent gradient (H2O + 0.1% NH4OH): ACN 73:27~>53:47). Yield: 1.87g (4.88 mmol; 89%) The product was isolated as a mixture of four stereoisomers, which were then separated by chiral SFC to obtain Examples 143, 143-1, 143-2, and 144.

[0480] [Table 293]

[0481] [Table 294]

[0482] [Table 295]

[0483] [Table 296]

[0484] (Examples 145 and 146) [ka]

[0485] Step 1 A mixture of 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (9.65 g, 45.22 mmol), 2,2-difluoroethylamine (4.93 ml, 67.84 mmol), and potassium carbonate (9.38 g, 67.84 mmol) in 110 ml of ACN is stirred at 60°C for 36 hours. The mixture is poured into 500 ml of water and then concentrated under vacuum. The mixture is filtered, and the remaining solid is washed with 500 ml of water. The solid is dried. Yield: 11.98 g (44.34 mmol; 98%) Intermediate-145a MS(ESI + ):(M+H) + 271;HPLC:RT=1.1 min, method:Z018_S04

[0486] Step 2: A mixture of intermediate-145a (1.34 g, 4.95 mmol) and activated carbon-supported palladium (10%) in 27 ml of THF is hydrogenated in a Parr instrument at 60 psi and 25°C for 2 hours. The mixture is then filtered. The filtrate is evaporated under vacuum. The residue is used in the next step without further purification. Yield: 1.19 g (44.34 mmol; 100%) Intermediate-145b HPLC: RT=0.94 min, method: Z011_S03

[0487] Step 3: Example 143 is prepared from intermediate-145b and 2-(Boc-amino)-2-(tetrahydrofuran-3-yl)-acetic acid, similar to Step 1. Yield: 2.55 g (4.92 mmol; 99%) Intermediate-145c MS(ESI + ):(M+H) + 468 Step 4: Example 143 is prepared from intermediate-145c and zinc bromide in a manner similar to Step 2. Yield: 1.78 g (4.08 mmol; 83%) Intermediate-145d MS(ESI + ):(M+H) +350 HPLC: RT = 1.04 min and 1.02 min, Method: Z011_S03

[0488] Step 5: In Example 143, the intermediate -145d and 5-methylpyrazine-2-carboxylic acid are prepared in a manner similar to Step 3. Yield: 0.83g (1.76 mmol; 43%) The product was isolated as a mixture of four stereoisomers, and this was separated by chiral SFC to obtain Examples 145, 145-1, 145-2, and 146.

[0489] [Table 297]

[0490] [Table 298]

[0491] [Table 299]

[0492] [Table 300]

[0493] The following examples were prepared as mixtures of four stereoisomers, similar to Example 1, and separated by chiral SFC to obtain Examples 147, 147-1, 147-2, and 148.

[0494] [Table 301]

[0495] [Table 302]

[0496] [Table 303]

[0497] [Table 304]

[0498] (Example 149) [ka]

[0499] Step 1: To a stirred solution of R-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (5 g, 27 mmol) in THF (50 ml), 2.5 M n-butyllithium in hexane (1.91 g, 30 mmol) was added over 15 minutes at -78°C, and the mixture was stirred at -78°C for 1 hour. Then, dihydropyran-3-one (2.72 g, 27 mmol) was added dropwise to 30 ml of THF, and the mixture was stirred at -25°C for 30 minutes. The mixture was quenched by adding acetic acid (soluble in THF), diluted with water (30 ml), and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine, dehydrated with sodium sulfate, and concentrated. The residue was purified by column chromatography using silica gel (eluent: 30% ethyl acetate in petroleum ether). Yield: 5.5g (19 mmol; 71%) Intermediate-149a

[0500] Step 2: To a mixture of intermediate-149a (15 g, 53 mmol) in THF (50 ml), slowly add 150 ml of 0.2 N hydrochloric acid solution dropwise at 0°C, and stir the mixture at room temperature for 16 hours. Adjust the pH of the reaction mixture to 7.5 with sodium hydroxide solution and freeze-dry. Use the crude product without further purification. Yield: 9.5g (19 mmol; 95%) Intermediate-149b Step 3: To a mixture of intermediate-149b (8 g, 42 mmol) in THF (80 ml), triethylamine (6.42 g, 63 mmol) and di-tert-butyl diacetate (9.23 g, 42 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water and extracted with SiO2 (2 × 50 ml). The combined organic phase was washed with brine, dehydrated with sodium sulfate, and concentrated. The residue was purified by chromatography using silica gel and 50% SiO2 in petroleum ether. Yield: 2.8 g (10 mmol; 23%) intermediate-149c Step 4: To a stirred solution of intermediate-149c (5.2 g, 18 mmol) in THF (50 ml) and water (10 ml), lithium hydroxide monohydrate (1.51 g, 36 mmol) is added. The mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated, diluted with water, and extracted with RINKAN (2 × 30 ml). The aqueous layer is acidified with citric acid (pH 6) and extracted with RINKAN (2 × 60 ml). The combined organic layers are washed with brine, dehydrated with sodium sulfate, and concentrated under vacuum. The residue is purified by chromatography using silica gel and 80% RINKAN in petroleum ether. Yield: 4.2 g (15 mmol; 85%) intermediate-149d.

[0501] Step 5: To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (10 ml, 71.45 mmol) in DCM (300 ml), add 2 M ethylamine solution in THF (71.45 ml, 142.9 mmol) dropwise. Stir the mixture overnight. Then add DCM (100 ml) and extract the mixture with water (250 ml). Dehydrate the organic phase with sodium sulfate and concentrate under vacuum. Yield: 16.6g (70.88 mmol; 99%) Intermediate-149e MS(ESI + ):(M+H) + 235;HPLC:RT=1.1 min, method:Z017_S04

[0502] Step 6: A mixture of intermediate-149e (1.4g, 5.97 mmol) and 10% activated carbon-supported palladium (150 mg) in methanol (50 ml) is hydrogenated at 50 psi at room temperature. The mixture is filtered, and the filtrate is concentrated under vacuum. Yield: 1.22 g (5.97 mmol; 99%) intermediate-149f HPLC: RT=0.97 min, method: Z011_S03

[0503] Step 7: To a mixture of intermediate-149f (0.51 g, 2.51 mmol), intermediate-149d (0.6 g, 2.09 mmol), and N-methylmorpholine in DCM (20 ml), 50% PPA (2.47 ml, 4.19 mmol) is added at 0°C. The mixture is then stirred at room temperature for 2 hours. The mixture is concentrated, siRNA is added, and it is extracted with water. The organic layer is washed with saturated sodium bicarbonate solution, dehydrated with sodium sulfate, and concentrated under vacuum. The residue is purified by column chromatography. Yield: 1.22g (5.97 mmol; 99%) intermediate - 149g MS(ESI + ):(M+H) + 462;HPLC:RT=1.06 min, method:Z011_S03

[0504] Step 8 Mix 149 g (0.51 g, 1.11 mmol) of the intermediate with acetic acid (10 ml, 174.5 mmol) and stir at 50°C for 24 hours and then at 90°C for 24 hours. Concentrate the mixture under vacuum. Add THF and methanol to the residue, and add TEA until the mixture becomes basic. Purify this mixture by HPLC. Yield: 1.22 g (5.97 mmol; 99%) intermediate - 149 h MS(ESI + ):(M+H) + 444;HPLC:RT=1.13 min, method:Z011_S03

[0505] Step 9 Mix the intermediate-149h (0.2g, 45 mmol) with 4M hydrochloric acid in 5ml of dioxane and stir at room temperature for 2 hours. Concentrate the mixture and use without further purification. Yield: 1.22 g (5.97 mmol; 99%) Intermediate-149i HPLC: RT=0.91 min, method: Z011_S03

[0506] Step 10 To a mixture of intermediate-149i (0.085 g, 0.22 mmol), 5-methylpyrazine-2-carboxylic acid (0.037 g, 0.27 mmol), and TEA (0.16 ml, 1.12 mmol) in 5 ml of DMF, TBTU (0.079 g, 0.25 mmol) is added. The mixture is stirred at room temperature for 2 hours. Water and acetonitrile are added. The mixture is filtered and concentrated. The residue is purified by HPLC. Yield: 0.081 g (0.17 mmol; 78%) Example 149

[0507] [Table 305] The following examples are obtained in a manner similar to Example 149.

[0508] [Table 306]

[0509] [Table 307]

[0510] [Table 308]

[0511] [Table 309]

[0512] (Example 154) [ka]

[0513] Step 1 To a mixture of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (11.948 ml, 60 mmol) in anhydrous THF (250 ml) cooled to -75°C, n-butyllithium solution (39.375 ml, 63 mmol, 1.6 N in n-hexane) is added dropwise at a temperature below -65°C. The resulting mixture is stirred at this temperature for 1 hour. Next, while maintaining the temperature below -55°C, oxolan-3-one (4.571 ml, 60 mmol) in anhydrous THF (80 ml) is added dropwise. The mixture is stirred at this temperature for 1 hour. Next, glacial acetic acid (3.61 ml, 63 mmol) dissolved in THF (30 ml) is added dropwise. The mixture is diluted with diethyl ether (500 ml) and extracted twice with sodium bicarbonate (2%, 250 ml each time). The combined organic phases are dehydrated with sodium sulfate and concentrated under vacuum. Purification is achieved by column chromatography on silica gel (eluent: cyclohexane / ethyl acetate). Yields: 6.35 g (23.5 mmol; 39%) intermediate-154a and 2.48 g (9.17 mmol, 15.3%) intermediate-154b.

[0514] Step 2 A mixture of intermediate-154a (2g, 7.399 mmol), hydrochloric acid (0.2N, 73.98 ml, 14.797 mmol), and THF (50 ml) is stirred at room temperature for 18 hours. The mixture is concentrated under vacuum, freeze-dried, and used for the next step without further purification. Yield: 3.24 (40% purity) Intermediate-154c

[0515] Step 3 To a mixture of intermediate-154c (3.24 g, 40% purity, 7.3 mmol), THF (75 ml), and triethylamine (6.187 ml, 44.38 mmol), 5-methylpyrazine-2-carboxylic acid (2.146 g, 15.536 mmol) is added, and the mixture is cooled in an ice bath. Then, CIP (4.328 g, 15.536 mmol) is added. The mixture is stirred for 5 minutes under ice cooling and for 1 hour at room temperature. The mixture is concentrated under vacuum. The residue is taken out in methanol (20 ml), filtered, and purified by HPLC (XBridge C18, water / NH4OH / CAN, flow rate 50 ml, T column = 60°C). The products containing the fractions are combined and stirred in a rotovap (bath temperature 45°C) for 2 hours. After concentration under vacuum, the residue is freeze-dried. Yield: 0.8g (2.844 mmol, 38.4%) Intermediate-154d

[0516] Step 4 To a mixture of 1-fluoro-4-methyl-2-nitrobenzene (15 g, 82.885 mmol), potassium carbonate (22.911 g, 165.769 mmol), and THF (150 ml), ethylamine solution in THF (2N, 82.885 ml, 165.769 mmol) is added. The resulting mixture is stirred at room temperature for 16 hours and filtered. The mixture is concentrated under vacuum, diethyl ether is added, and the mixture is concentrated again under vacuum. Yield: 16.75 g (83.49 mmol, 100%) Intermediate-154e

[0517] Step 5 Intermediate-154e, a mixture of THF (30 ml) and Raney nickel (300 mg) is hydrogenated at 60 psi and room temperature for 7 hours. After 1 hour, an additional 300 mg of Raney nickel is added. The mixture is then filtered and concentrated under vacuum. Yield: 2.1 g (12.307 mmol, 98.8%) Intermediate-154f Step 6 To an ice-cooled mixture of intermediate-154f (180 mg, 1.055 mmol), intermediate-154d (370.8 mg, 1.055 mmol), and DMF (12 ml), diisopropylethylamine (0.735 ml, 4.219 mmol) and T3P (1.243 ml, 2.11 mmol) are added. The mixture is stirred under ice cooling for 1 hour. Then, the mixture is allowed to reach room temperature and stirred for 20 hours. After that time, methanol is added, the mixture is filtered, and HPLC (XBridge C18, water / NH4OH / ACN, flow rate 50 ml, T column = 60) is performed. 0 Purify according to C). Combine the products containing the fractions, concentrate them under vacuum, and freeze-dry them. Yield: 43 mg (0.099 mmol, 9.4%) intermediate - 154 g

[0518] Step 7 Mix 154 g (58 mg, 0.134 mmol) of the intermediate with 3 ml of glacial acetic acid and stir at 85°C for 3 hours. At room temperature, add 30 ml of ethyl acetate and potassium carbonate solution. Separate the organic phase and dehydrate with sodium sulfate.

[0519] [Table 310] The following compounds were obtained with similarity to those in Example 154.

[0520] [Table 311]

[0521] [Table 312] The following examples are obtained in similarity to Example 143:

[0522] [Table 313]

[0523] [Table 314]

[0524] The following examples are obtained in similarity to Example 143: Examples 159, 159-1, 159-2, 160

[0525] [Table 315]

[0526] [Table 316]

[0527] [Table 317]

[0528] [Table 318] The following examples were obtained in similarity to Example 143: Examples 161, 161-1, 161-2, 162

[0529] [Table 319]

[0530] [Table 320]

[0531] [Table 321]

[0532] [Table 322]

[0533] The following examples are obtained in similarity to Example 143: Examples 163, 163-1, 163-2, 164

[0534] [Table 323]

[0535] [Table 324]

[0536] [Table 325]

[0537] [Table 326]

[0538] The following compounds are obtained in a manner similar to Example 14, except for step 8. In step 8, the product, which consists of two stereoisomers, is purified by crystallization to obtain a single stereoisomer.

[0539] (Example 14) [ka]

[0540] (Examples 165 and 166) [ka]

[0541] Step 8: Add TFA (5.083 ml, 65.88 mmol) to 165 g (2.5 g, 6.589 mmol) of intermediate in 30 ml of DCM at 5°C. Remove cooling and stir the mixture at ambient temperature for 6.5 hours. Add DCM (50 ml) to the mixture, then add water (150 ml). Extract the organic phase twice with water (100 ml). Adjust the pH of the combined aqueous phase to approximately 10 by adding concentrated NH3 aqueous solution. Extract the aqueous layer with ethyl acetate (250 ml). Dehydrate the combined organic layer with MgSO4 and concentrate under vacuum. Add ethanol (11.75 ml) and water (0.62 ml) to the residue (1.67 g). Heat the mixture to 70°C. Then add 5-methylpyrazine-2-carboxylic acid (0.775 g, 5.612 mmol). To this mixture, add ethanol (5.87 ml) and water (0.31 ml), and heat the mixture at 70°C for 1 hour. Then, slowly cool the mixture to room temperature. Next, cool the mixture to 20°C in less than 1 minute. Filter the mixture, wash with ethanol (3 ml), and dry in a dry spray machine at 50°C. Yield: 1.81 g (4.33 mmol; 73%) Intermediate as a salt containing 5-methylpyrazine-2-carboxylic acid - 165 h

[0542] Step 9: Intermediate as a salt containing 5-methylpyrazine-2-carboxylic acid (0.55 g, 1.32 mmol): A mixture of NMM (0.581 mL, 5.27 mmol) and 5-methylpyrazine-2-carboxylic acid (90.9 mg, 0.66 mmol) in 5.5 ml of ethylacetate is cooled to 0°C with stirring. Then, PPA (50% in ethylacetate; 1.165 mL, 1.97 mmol) is added. After 10 minutes, the cooling is removed and the mixture is stirred at ambient temperature for 45 minutes. Ethyl acetate (20 ml) is added to the mixture, and then it is extracted twice with sodium bicarbonate solution. The combined organic phase is dehydrated with MgSO4. After filtration, the mixture is concentrated under vacuum, and the residue is separated in THF / MeOH and purified by chromatography (XBridge C18, 10, (H2O + 0.1% NH4OH + 28~48% ACN)). The products containing the fractions are combined and concentrated under vacuum. The product is obtained as a single stereoisomer. Yield: 0.461 mg (1.15 mmol; 87%) Example 165.

[0543] [Table 327] Similar to Example 165, the following compounds were obtained.

[0544] [Table 328] Example 167 is prepared in a manner similar to Example 154, starting from intermediate-154b.

[0545] [Table 329]

Claims

1. Compounds of formula I, or physiologically acceptable salts thereof: 【Chemistry 1】 During the ceremony, A is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 5 -cycloalkyl-C 1 -C 2 -alkyl-, C 1 -C 3 -alkyl-O-C 1 -C 3 -alkyl-, 4- to 6-membered heterocycloalkyl-, 4- to 6-membered heterocycloalkyl-C 1 -C 3 -alkyl- and the latter groups may be substituted with 1 to 4 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, fluoro R 1 C 1 -C 7 - Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 7 - Cycloalkyl, 4-6 member heterocycloalkyl, C 3 -C 7 -Cycloalkyl-C 1 -C 3 -Alkyl-, 4-6 member heterocycloalkylmethyl-, C 5 -C 6 -Represents heterocycloalkylethyl-, and the latter group is C 1 -C 4 - Alkyl, C 1 -C 4 - Alkoxy, C 3 -C 7 - May be substituted with 1 to 4 substituents selected from cycloalkoxy, hydroxy, and fluoro. R 2 , R 3 , R 4 and R 5 These are, independently of each other, hydrogen, halogen, cyano, and C 1 -C 4 - Alkyl, C 1 -C 3 -Alkyl-O-C 1 -C 3 -Alkyl-, C 3 -C 6 - Cycloalkyl, 4-6 member carbon 4 -C 6 - Heterocycloalkyl, C 1 -C 4 -alkoxy-, C 3 -C 6 -Represents cycloalkoxy-, and these latter six groups are C 1 -C 4 - Alkyl, C 1 -C 4 - May be substituted with 1 to 4 substituents selected from alkoxy, hydroxy, and fluoro. However, the condition is R 2 , R 3 , R 4 and R 5 At least one of the groups is not hydrogen, R 6 C may be substituted with halogens or 2-3 fluorine atoms. 1 -C 3 - Represents alkyl.

2. The compound according to claim 1, During the ceremony, A is C 1 -C 3 - Alkyl, C 3 -C 6 - Cycloalkyl, C 3 -C 5 -Cycloalkylmethyl-, Tetrahydrofuranyl-, Tetrahydropyranyl-, 1,4-Dioxanyl, Tetrahydrofuranylmethyl-, Tetrahydropyranylmethyl-, 1,4-Dioxanylmethyl-, C 1 -C 2 -Alkyl-O-C 1 -C 2 The latter group represents an alkyl group, and these latter groups may be substituted with one to four substituents selected from methyl, methoxy, hydroxy, and fluoro. The aforementioned compound.

3. A compound according to claim 1 or 2, During the ceremony, R 1 is C 1 -C 3 -alkyl, C 1 -C 2 -alkyl-O-C 1 -C 3 -alkyl-, C 3 -C 4 -cycloalkyl, C 4 -C 5 -heterocycloalkyl, C 3 -C 4 -cycloalkyl-O-C 1 -C 3 -alkyl-, and the latter groups thereof may be substituted with 1 to 4 substituents selected from C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 4 -cycloalkoxy, hydroxy, fluoro The aforementioned compound.

4. A compound according to any one of claims 1 to 3, During the ceremony, R 2 , R 3 , R 4 and R 5 These independently represent hydrogen, fluoro, chloro, bromo, cyano, methyl, cyclopropyl, and methoxy, and the latter three groups may be substituted with two or three fluoro substituents, provided that R 2 , R 3 , R 4 and R 5 At least one of the groups is not hydrogen. The aforementioned compound.

5. A compound according to any one of claims 1 to 4, During the ceremony, R 6 C may be substituted with 2 to 3 fluorine atoms. 1 -C 3 - Represents alkyl, The aforementioned compound.

6. A compound according to any one of claims 1 to 5, During the ceremony, A is, 【Chemistry 2】 Represents a group selected from the group that includes The aforementioned compound.

7. A compound according to any one of claims 1 to 6, During the ceremony, R 1 teeth, 【Transformation 3】 Represents a substituent selected from the group consisting of The aforementioned compound.

8. A compound according to any one of claims 1 to 7, During the ceremony, R 2 This represents hydrogen. The aforementioned compound.

9. A compound according to any one of claims 1 to 8, During the ceremony, R 3 These represent hydrogen, fluoro, bromo, and trifluromethyl. The aforementioned compound.

10. A compound according to any one of claims 1 to 9, During the ceremony, R 4 is hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluromethyl, CF 3 O- and CHF 2 Representing O- The aforementioned compound.

11. A compound according to any one of claims 1 to 10, During the ceremony, R 5 These represent hydrogen, fluoro, chloro, methyl, ethyl, cyclopropyl and methoxy. The aforementioned compound.

12. A compound according to any one of claims 1 to 11, During the ceremony, R 6 These are methyl, trifluromethyl and -CF 2 Representing H, The aforementioned compound.

13. the below described: 【Chemistry 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound according to any one of claims 1 to 12, selected from the group consisting of the following.

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

15. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt according to claim 14, for use as a drug.

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

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt according to claim 14, for use in the treatment and / or prevention of a disease or disorder in which inhibition of the activity of metabomodulatory glutamate receptor subtype 4 (mGluR4) has therapeutic utility.

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

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

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