Isoxazole-heterocyclic derivatives, pharmaceutical compositions and uses

Abstract

The present invention relates to isoxazole-heterocyclic derivatives, pharmaceutical compositions and uses, in particular to a compound represented by formula (I) or its pharma- ceutical acceptable salts, stereoisomers, tautomers, prodrugs, amorphous forms, isotopically substituted forms, polymorphs or solvates, pharmaceutical compositions comprising said compounds, and α5-GABA A Use of such compounds as receptor modulators is provided.

Description

[Technical field]

[0001] cross reference This application claims priority to Chinese Patent Application No. 202210312824.7, entitled "Isoxazole-heterocyclic derivative, pharmaceutical composition and use", filed with the State Intellectual Property Office of China on March 28, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention is directed to α5-GABA A The present invention relates to isoxazole-heterocyclic derivatives having receptor modulating functions, pharmaceutical compositions containing the same and uses thereof. [Background technology]

[0003] γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the mammalian central nervous system, and two classes of GABA receptors exist naturally. The first is the GABA receptor, which is a member of the ligand-gated ion channel superfamily. A receptor, and the other is a member of the G protein-coupled receptor superfamily, GABA B Mammalian GABA receptors A The receptor subunits include subunits α1 to α6, β1 to β4, γ1 to γ3, δ, ε, θ, and ρ1 to ρ3, of which the α, β, and γ subunits are fully functional GABA receptors. A The α subunit is essential for the formation of the GABA receptor. A It has been found to be crucial for the binding of benzodiazepines to the receptor.

[0004] GABA including α5 A Receptor (α5-GABA A GABA receptors in mammalian brains AIt accounts for less than 5% of GABA receptors and is expressed at very low levels in the cerebral cortex, but in the hippocampal tissue of the brain A It accounts for more than 20% of the receptors and is rarely expressed in other brain regions. α5-GABA in the hippocampal tissue of the brain A In light of the research into the specific distribution and function of the receptor, many pharmaceutical companies, including Roche, MSD, etc., have started to develop α5-GABA receptor antagonists. A He worked on the study of receptor ligands, and later discovered a number of compounds, especially α5-GABA receptor ligands, in the hippocampal tissue of the brain. A Receptor counter-regulators (or negative regulators, inverse agonists) have been synthesized, and among them, α5IA and MRK-016 have shown good cognitive improvement effects in animal disease models. A It is generally recognized that counter-regulators of the α5-GABA receptor may be useful in the treatment of cognitive disorders, particularly in the treatment of Alzheimer's disease. A It has been disclosed that receptor counterregulators may be used in the treatment of multi-infarct dementia and stroke-related disorders.

[0005] Depression is a serious mental illness that may be life-threatening (such as suicide). The current standard of care for antidepressant treatment is selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), but these drugs generally reach maximum efficacy after 6 to 8 weeks of medication. Furthermore, their effectiveness is limited, with only about half of patients showing therapeutic effects. Other commercially available antidepressants and antidepressants under clinical development also have varying degrees of side effects, limiting their use. Therefore, there is an urgent need in clinical practice for antidepressants with fast-acting functions and fewer side effects to reduce the burden on patients with depression and on society.

[0006] Fishell et al. A The antidepressant effects of receptor counter-regulators have been reported (J. Fischell et al., Neuropsychopharmacology, 2015, 40(11), 2499-2509), and selective α5-GABA AWe believe that the receptor counter-regulator can achieve a rapid effect different from that of conventional antidepressants, and its safety is superior to that of existing ketamine therapy with the same rapid effect. A Receptor countermodulators may represent a novel mechanism of action antidepressant therapy with rapid efficacy, fulfilling a significant unmet need in the current clinical treatment of depression.

[0007] Compounds containing the α5 subunit of GABA A Many studies have been conducted to determine whether a compound is a counter-regulator or antagonist of the GABA receptor. For example, in WO 1992022652 and WO 1994013799, GABA receptor binding assays were performed to determine whether a compound is a counter-regulator or antagonist of the GABA receptor. A A combination of α5, β3 and γ2 receptors is used. In the process of drug screening, the method described by Goeders et al. (Goeders, NE and Kuhar, MJ Life Sci. 1985, 37(4), 345-355) is commonly used. GABA A Many studies have also been conducted to determine whether ligands capable of binding to the receptor α5 subunit are antagonists, agonists or inverse regulators, and reference can be made to the methods described in Wafford et al. (Wafford, KA, Mol. Pharmacol. 1993, 43, 240-244).

[0008] Recent discoveries suggest that GABA A It has been shown that GABA receptors mediate at least two modes of inhibition: transient and tonic inhibition. A The receptors trigger an action potential to synchronously release vesicles containing GABA within the synapse, resulting in a rapid increase in millimolar GABA concentration in the synaptic cleft and a rise in postsynaptic GABA. A This results in synchronous activation of the receptor and rapid desensitization, resulting in transient inhibition. A The receptors respond to sustained low concentrations of GABA, typically in the range of tens of nanomolar to several millimolar. AGABA A The receptors are activated asynchronously and sequentially, resulting in tonic inhibition. Transient and tonic inhibition jointly regulate neuronal excitability and signal transduction (Farrant, M. et al., Nat Rev Neurosci, 2005, 6, 215-229). Yeung JY et al. reported that low concentrations of GABA inhibit α5-GABA. A (Yeung JY et al., Mol Pharmacol, 2003, 63, 2-8) KY Lee reported that in isolated DRG cells cultured for 24 hours, sustained high affinity GABA receptors were activated by low concentrations of GABA. A (Lee, KY et al., Neuroscience, 2012, 208, 133-142). I. Lecker et al. reported in 2013 that α5-GABA A It has been disclosed that the receptor counter-modulator L-655,708 dose-dependently inhibits the current induced by low concentrations (5nM, 50nM and 500nM) of GABA, and that at the highest concentration of L-655,708, even when the GABA concentration was increased to 1μM, it could only inhibit 15% of the current, and that as the GABA concentration continued to increase, it no longer had an inhibitory effect on the current induced by GABA (Lecker, I. et al., British Journal of Anaestheia, 2013, 110(S1), i73-i81).

[0009] α5-GABA A Target subtype selectivity is also important in the development of receptor countermodulators. A Since benzodiazepines, which are positive modulators of the receptor, are used clinically for anxiolytic and antiepileptic treatment, inverse modulators of this target may have anxiolytic and antiepileptic effects (HJ Little, et al., Br J Pharmacol, 1984, 951-958). AIn developing a receptor counterregulator, α5-GABA A Improves receptor binding and functional selectivity, reducing potential side effects that promote anxiety and epilepsy (mainly α2-GABA A It is necessary to avoid side effects caused by the activation of the α5-GABA receptor (Theresa M. Ballard et al., Psychopharmacography, 2009, 207-223). A Receptor counter-regulators have insufficient stability in gastric fluid and poor solubility in intestinal fluid, and therefore poor druggability when developed as oral drugs, making their widespread use difficult. Summary of the Invention

[0010] In one aspect, the present invention provides a compound represented by formula (I): [ka] (In the formula, R 1 is selected from phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2 or 3 halogens; R 2 is selected from H, linear or branched C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl; Ring A is selected from 5- to 10-membered heterocyclic groups containing 1, 2 or 3 ring heteroatoms selected from N, P, O or S; R 4is selected from a fused group formed by a heterocycle and a heterocycle, the heterocycle forming the fused group being selected from a 5- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, P, O or S, the fused group being unsubstituted or substituted with one or more substituents, the substituents being optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted sulfonyl, or an optionally substituted heterocycle containing 1, 2 or 3 heteroatoms, the heteroatoms being selected from N, P, O or S; R 3 is selected from halogen, linear or branched C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl; m is 0, 1 or 2. This is due to the stability in gastric juice and the α5-GABA A It has good solubility in DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Unless otherwise stated, the following definitions are set forth to illustrate and define the meaning and scope of various terms used herein to describe the invention.

[0012] The following definitions of general terms apply whether they occur alone or in combination.

[0013] The nomenclature used in this invention is based on AutoNom™ 2000, a computerized system from the Beilstein Laboratory used to generate the IUPAC systematic nomenclature. When an open valency appears on a carbon, oxygen, sulfur, or nitrogen atom in the structures depicted herein, it indicates the presence of a hydrogen atom.

[0014] Unless otherwise specified, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent. Substituents may include deuterium and hydrogen variants so long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" refers to substituted or unsubstituted, and unless otherwise specified, the type and number of substituents may be any that are chemically available.

[0015] The term "unsubstituted" refers to the absence of substituents on a specified group.

[0016] The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from among possible substituents.

[0017] When specifying the number of substituents, the term "one or more" refers to one to the maximum possible number of substitutions, i.e., one to all hydrogens are replaced with a substituent. Unless otherwise specified, one, two, three, four or five substituents are preferred. When a group can have multiple substituents and multiple possible substituents are indicated, the substituents are independently selected and do not necessarily have to be the same.

[0018] When any variable substituent occurs more than once in a composition or structure of a compound, each definition is independent. Thus, for example, if a group is substituted with 0-2 substituents, the group may be optionally substituted with up to 2 substituents, each of which has an independent option. In addition, combinations of substituents and / or their variants are only permissible if such combinations result in stable compounds.

[0019] The term "optional" or "optionally" refers to the event or condition subsequently recited may, but need not, occur, and includes situations in which the event or condition occurs as well as situations in which the event or condition does not occur.

[0020] If the linking group described does not specify the direction of the link, the linking direction can be any direction. For example, [ka] In the above, the linking group L is [ka] In this case, [ka] is linked to the phenyl and cyclopentyl groups in the same left-to-right reading order, [ka] or can be linked in the opposite direction to the left-to-right reading order to the phenyl and cyclopentyl groups to form: [ka] Combinations of linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0021] Unless otherwise specified, the number of atoms on a ring is generally defined as the number of members in the ring, e.g., a "4- to 14-membered ring" refers to a "ring" having 4 to 14 atoms arranged in a ring.

[0022] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any particular case of n to n+m carbons, such as C1-C6 including C1, C2, C3, C4, C5, C6, as well as any range of n to n+m, such as C1-C6 including C1-C3, C1-C6, C3-C6, etc. Similarly, a ring with n to n+m members includes any number of atoms from n to n+m on the ring, such as a 4-membered to 14-membered ring, including 4-membered, 6-membered, 8-membered, 10-membered and 14-membered rings, as well as any range of n to n+m, such as a 4-membered to 14-membered ring, including a 4-membered to 6-membered ring, a 4-membered to 7-membered ring, a 5-membered to 10-membered ring, a 5-membered to 7-membered ring, etc.

[0023] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine. The term "oxy" refers to the -O- group. The term "acyloxy" refers to the -C(=O)O- group. The term "carbonyl" or "acyl" refers to the -C(=O)- group. The term "nitro" refers to the -NO 2 The term "cyano" refers to the -CN group. The term "amino" refers to the -NH 2 The term "sulfonyl" refers to -S(=O) 2 - refers to the group.

[0024] The term "alkyl" refers to a linear or branched saturated hydrocarbon group having, for example, 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms. The term "optionally substituted alkyl" includes unsubstituted alkyl and substituted alkyl, where unsubstituted alkyl refers to an alkyl that is not substituted with a substituent. Examples of "unsubstituted alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like. Substituted alkyl refers to an alkyl substituted with one to four substituents, for example, halo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, alkylsulfonyl, substituted alkylsulfonyl, and the like.

[0025] The term "cycloalkyl" refers to a non-aromatic, saturated or unsaturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, and may include fused, bridged, or spiro ring systems, for example, having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms. The term "optionally substituted cycloalkyl" includes unsubstituted cycloalkyl and substituted cycloalkyl, where unsubstituted cycloalkyl refers to cycloalkyl that is not substituted with a substituent. Examples of "unsubstituted cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, adamantine, and the like. Substituted cycloalkyl refers to cycloalkyl substituted with 1 to 4 substituents such as halo, nitro, cyano, hydroxy, alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two substituents on amino are selected from alkyl, aryl, or arylalkyl).

[0026] The term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic group containing a heteroatom, preferably a saturated or partially unsaturated monocyclic or polycyclic group containing 1, 2, 3, 4, 5 or 6 ring heteroatoms selected from N, P, O or S. For example, it may be a non-aromatic or aromatic ring having 3 to 20 carbon atoms, such as a 3- to 8-membered monocyclic ring, a 7- to 14-membered bicyclic ring (also referred to as a "bicyclic heterocycle") or an 11- to 20-membered tricyclic ring (also referred to as a "tricyclic heterocycle"), or it may be a 3- to 8-membered cyclic lactam having at least one nitrogen atom in a ring containing at least one carbon atom. Examples include, but are not limited to, a pyridine ring, pyrimidinonyl, pyridonyl, imidazolyl, triazolyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, oxiranyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, N-pyridyl urea, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, and the like.

[0027] The term "ring heteroatom" refers to a heteroatom that constitutes a ring in a heterocycle.

[0028] In the term "fused group formed by a heterocycle and a heterocycle", the heterocycle is as defined above, and the fused group may be formed by condensing two or more (e.g., three or four) single heterocycles. Two single heterocycles are condensed to form a biheterocycle. The fused group may be an unsubstituted fused group or a substituted fused group. The unsubstituted fused group is, for example, thieno[3,2-c]pyridine, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, or pyrimidoimidazooxazine, but is not limited thereto. The substituted fused group refers to a fused group substituted with one or more substituents, such as alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, formyl, substituted formyl, sulfonyl, substituted sulfonyl, a heterocycle containing 1 to 3 heteroatoms, a substituted heterocycle containing 1 to 3 heteroatoms, etc., where the heteroatom is selected from N, O, P, or S.

[0029] The formula: [ka] and * Both represent linkage sites.

[0030] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0031] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and sterically hindered isomers, as well as mixtures thereof, such as racemic mixtures, are part of the present invention. In this context, if the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated. In addition, the present invention relates to all geometric and positional isomers. The compounds of the present invention may exist in different tautomeric forms, and all of these forms are included within the scope of the present invention. All stereoisomers of the compounds of the present invention are expected to include mixtures or pure or essentially pure forms. Separation can be achieved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.

[0032] The term "prodrug" refers to a functional derivative of a compound of formula (I) that is readily converted in vivo into a compound of formula (I). Suitable derivatives can be selected and prepared by conventional techniques known to those skilled in the art, see, for example, Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0033] The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate, salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, methanesulfonate, and pamoate. A "pharmaceutically acceptable salt" may contain another molecule, such as maleate or other counterion. The counterion acts to stabilize the charge(s) of the parent compound. A "pharmaceutically acceptable salt" may have more than one charged atom, and multiple charged atoms may have multiple counterions.

[0034] When the compound of the present invention is a base, the desired "pharmaceutically acceptable salt" can be prepared in a suitable manner, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, a pyranosidyl acid such as glucuronic acid or galacturonic acid, an α-hydroxy acid such as citric acid or tartaric acid, an amino acid such as glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, or a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid.

[0035] If the compound of the invention is an acid, the desired "pharmaceutically acceptable salt" can be prepared in a suitable manner, for example, by treating the free acid with an inorganic or organic base, such as an amine, an alkali metal hydroxide or an alkaline earth metal hydroxide. Examples of suitable salts include, but are not limited to, organic salts derived from amino acids, primary, secondary and tertiary amine salts, and salts of cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0036] The compounds of the present invention can exist on a continuum of solid states ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials do not show distinct X-ray diffraction patterns and are more formally referred to as liquids while exhibiting solid properties. Such materials change from solid to liquid properties when heated, usually characterized by a second order ("glass transition") state change. The term "crystalline" refers to a solid phase in which the material has an ordered internal structure at the molecular level and exhibits a unique X-ray diffraction pattern with defined peaks. Such materials also exhibit liquid properties when heated sufficiently, but the change from solid to liquid is usually characterized by a first order ("melting point") phase change.

[0037] As used herein, the term "polymorphism" refers to a distinct solid crystalline phase of a certain compound of the invention in the solid state resulting from the existence of two or more different molecular configurations. Certain compounds of the invention may exist in more than one crystalline form, and the invention is intended to include various crystalline forms and mixtures thereof.

[0038] The term "solvate" as used herein refers to a combination or complex of one or more solvent molecules and the compound of the present invention. Examples of solvents for forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid and ethanolamine. The compound of the present invention may exist in unsolvated or solvated form with pharma-ceutically acceptable solvents such as water, ethanol, etc. Therefore, the present invention includes both solvated and unsolvated forms.

[0039] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. The term "isotopically modified" refers to a substance having the same number of atoms but an atomic mass or mass number different from those predominant in nature. For example, a compound may contain deuterium ( 2 H), tritium (3 H), iodine-125( 125 I) or C-14( 14 The compounds of the present invention may be labeled with a radioisotope such as 1,2-dihydro-1,3-trimethyl-1,4-trimethyl-1,5-triphenylphosphine (C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. Isotopic variations may enhance certain therapeutic effects, for example, deuterium enrichment may extend half-life or reduce required dosage in vivo, or may provide a standard compound that can be used for characterization of biological samples. Isotopically enriched compounds within formula (I) can be prepared without undue experimentation by conventional techniques known to those skilled in the art using appropriate isotopically enriched reagents and / or intermediates, or by methods similar to those described in the schemes and examples herein.

[0040] Unless otherwise specified, the term "stereoisomer" can mean "diastereomer" or "enantiomer" or "cis-trans isomer".

[0041] The terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another. The term "diastereomers" refers to stereoisomers whose molecules have two or more centers of chirality and that are not mirror images of one another.

[0042] Unless otherwise specified, the term "cis-trans isomers" or "geometric isomers" refers to stereoisomers resulting from the inability to freely rotate about double or single bonds of ring carbon atoms.

[0043] Unless otherwise specified, "(D)" or "(+)" refers to dextrorotatory, "(L)" or "(-)" refers to levorotatory, and "(DL)" or "(±)" refers to racemization.

[0044] Solid wedge connections unless otherwise specified [ka] and the connection of the dashed wedge lines [ka] is used to represent the absolute configuration of a stereocenter, and the straight solid line [ka] and the connection of straight dashed lines [ka] is used to indicate the relative configuration of stereocenters. [ka] is a solid wedge connection [ka] Or a connection of dashed wedge lines [ka] or a wavy line [ka] is a connection of solid straight lines [ka] and the connection of straight dashed lines [ka] is used to represent

[0045] Star * or [ka] represents the linking site.

[0046] The compounds of the present invention may exhibit specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional isomers that are in dynamic equilibrium and can rapidly interconvert at room temperature. If tautomers are available (e.g., in solution), chemical equilibrium between tautomers can be achieved. For example, proton tautomers, also known as prototropic tautomers, involve interconversion by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion by recombination of certain bond monads. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxy-3-en-2-one.

[0047] Furthermore, ring A is selected from 5- or 6-membered heterocyclic groups containing 1, 2 or 3 nitrogen atoms as ring heteroatoms.

[0048] In preferred embodiments, Ring A is selected from pyridine, pyridazine, pyrazine, pyrimidine, piperidine, or piperazine.

[0049] In a more preferred embodiment, Ring A is selected from pyridine, pyridazine or pyrazine.

[0050] In addition, R 3 is selected from methyl or methoxy.

[0051] Furthermore, m is 0 or 1, and in a preferred embodiment, m is 0.

[0052] In addition, R 4 has a structure represented by formula (II) or formula (III). [ka] (In the formula, Ring B, ring C, and ring D are each independently selected from 5- to 10-membered heterocyclic groups containing 1, 2, or 3 heteroatoms, the heteroatoms being selected from N, P, O, and S; R 5 , R 6 or R 7 are each independently selected from oxo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted sulfonyl, or an optionally substituted heterocycle containing 1, 2 or 3 heteroatoms, the heteroatoms being selected from N, O, S; n, j, or q are each independently selected from 1 or 2; (R 5 )q is a hydrogen atom on ring D of q number of R 5 means that it is replaced by R 5 may be the same or different, (R 6 )n is R with n hydrogen atoms on ring B 5 means that it is replaced by R 6 may be the same or different, (R 7 )j is R with j hydrogen atoms on ring C 5 means that it is replaced by R 7 may be the same or different.)

[0053] In a preferred embodiment, R 5 , R 6 or R 7 are each independently selected from oxo, C1-C6 alkyl, C3-C8 cycloalkyl, formyl, sulfonyl, or a C3-C8 heterocycle containing 1, 2 or 3 heteroatoms, the heteroatoms being selected from N, O, S, where the alkyl, cycloalkyl, formyl, sulfonyl, or heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl.

[0054] Furthermore, ring B is selected from 5- to 7-membered heterocycles containing 1, 2 or 3 nitrogen atoms as heteroatoms constituting the ring.

[0055] In certain preferred embodiments, Ring B is selected from triazole, pyrazole, imidazole, a 6-membered cyclic lactam, or a diazacyclopentane, where the 6-membered cyclic lactam contains two nitrogen atoms as ring heteroatoms.

[0056] In certain more preferred embodiments, Ring B is:

[0057] [ka]

[0058] Furthermore, ring C is selected from 5- to 7-membered heterocycles containing, as heteroatoms constituting the ring, 1 or 2 heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0059] In certain preferred embodiments, ring C is selected from the heterocycles described in any one of 1) and 2) below. 1) Pyrrole, imidazole, triazole or a 6-membered cyclic lactam, provided that the 6-membered cyclic lactam contains two nitrogen atoms as heteroatoms constituting the ring. 2) A 5- to 7-membered heterocycloalkane or heterocycloalkene containing, as heteroatoms constituting the ring, one or two heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0060] In certain more preferred embodiments, Ring C is selected from: [ka]

[0061] During the ceremony, [ka] represents a bonding site between ring C and ring B, * represents the linking site between ring C and ring D.

[0062] Furthermore, ring D is selected from 5- to 7-membered heterocycles containing, as heteroatoms constituting the ring, 1 or 2 heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom.

[0063] In certain preferred embodiments, Ring D is selected from a 5- to 7-membered bridged ring containing one nitrogen atom and one oxygen atom, or a 5- or 6-membered bridged ring containing one nitrogen atom.

[0064] In certain more preferred embodiments, Ring D is selected from: [ka]

[0065] In addition, R 7 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, formyl substituted with C1-C3 alkyl, sulfonyl substituted with C1-C3 alkyl, C3-C6 heterocyclic group containing one O atom or one S atom, where the alkyl, cycloalkyl or heterocyclic group is unsubstituted or substituted with one, two or three halogens.

[0066] In certain preferred embodiments, R 7 is methyl, ethyl, -CF 3 , -COCH 3 , [ka] is selected from.

[0067] In certain preferred embodiments, R 4 has the structure of formula (II), n is 0 or 1, and R 4 has the structure of formula (III), n is 0 or 1 and q is 0.

[0068] In a preferred embodiment, R 1is selected from phenyl substituted with 1, 2 or 3 halogens.

[0069] In a preferred embodiment, R 2 is selected from H, straight chain or branched C1-C4 alkyl.

[0070] In a more preferred embodiment, R 1 teeth, [ka] Selected from R 2 is selected from methyl.

[0071] Additionally, the compound has a structure represented by formula (VI), formula (V), formula (IV) or formula (IIV): [ka]

[0072] R 3 is as defined above, and R 4 is as defined above.

[0073] In a more preferred embodiment, the compound is selected from any one of the following compounds:

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] The present invention also provides a pharmaceutical composition comprising at least one compound according to any item of the present invention, or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, isotopic substitution, polymorph or solvate thereof, and a pharma- ceutically acceptable carrier and / or adjuvant.

[0079] The present invention also relates to α5-GABA A There is provided the use of a compound according to any item of the invention, or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, polymorph or solvate thereof, or a pharmaceutical composition in the preparation of a medicament for treating or preventing a disease associated with a receptor.

[0080] In addition, α5-GABA A The disease associated with the receptor is at least one selected from depression, pain, Alzheimer's disease, multi-infarct dementia, stroke, anxiety disorder, generalized anxiety disorder, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder, fibromyalgia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, social anxiety disorder, autism, autistic disorder, schizophrenia, obesity, bulimia nervosa or anorexia nervosa, Tourette's syndrome, vasomotor flushing, sexual dysfunction, borderline personality disorder, chronic fatigue syndrome, Raynaud's syndrome, Parkinson's disease, epilepsy, and mood disorder after head trauma.

[0081] Further, the depression is bipolar depression, postpartum depression, major depression, psychotic deprementia, atypical depression, melancholia, treatment-resistant depression, depression associated with Huntington's disease, depression associated with multiple sclerosis, or depression associated with an anxiety disorder.

[0082] The present invention also provides the use of a compound or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, polymorph or solvate thereof, pharmaceutical mixture, or pharmaceutical composition according to any item of the present invention in the preparation of a medicament for treating or preventing the following diseases: Depression, pain, Alzheimer's disease, multi-infarct dementia, stroke, anxiety disorders, generalized anxiety disorder, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder, fibromyalgia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, social anxiety disorder, autism, autistic disorder, schizophrenia, obesity, bulimia nervosa or anorexia nervosa, Tourette's syndrome, vasomotor flushing, sexual dysfunction, borderline personality disorder, chronic fatigue syndrome, Raynaud's syndrome, Parkinson's disease, epilepsy, and mood disorders following head trauma.

[0083] The present invention also relates to a method for the treatment of α5-GABAergic syndrome by administering to a patient an effective dose of a compound according to any of the items of the present invention or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, polymorph or solvate thereof, pharmaceutical mixture, or pharmaceutical composition. A Methods for treating or preventing receptor-related diseases are provided.

[0084] The present invention also provides a method for treating or preventing the following diseases by administering to a patient an effective dose of a compound according to any item of the present invention or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, polymorph or solvate thereof, pharmaceutical mixture, or pharmaceutical composition. Depression, pain, Alzheimer's disease, multi-infarct dementia, stroke, anxiety disorder, generalized anxiety disorder, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder, fibromyalgia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, social phobia, autism, autistic disorder, schizophrenia, obesity, bulimia nervosa or anorexia nervosa, Tourette's syndrome, vasomotor flushing, sexual dysfunction, borderline personality disorder, chronic fatigue syndrome, Raynaud's syndrome, Parkinson's disease and epilepsy, or mood disorders following head trauma

[0085] Technical and scientific terms used herein that are not specifically defined have the meanings that are commonly understood by one of ordinary skill in the art to which this invention belongs.

[0086] The term "treat / treatment" as used herein means administering one or more medicinal substances, particularly compounds of formula (I) according to the present invention and / or pharmaceutically acceptable salts thereof, to an individual suffering from a disease or having symptoms of a disease with the intent to cure, alleviate, relieve, alter, treat, ameliorate, improve or affect the disease or symptoms of the disease. The term "prevent" as used herein means administering one or more medicinal substances, particularly compounds of formula (I) according to the present invention and / or pharmaceutically acceptable salts thereof, to an individual having a predisposition to a disease to prevent the individual from developing the disease. When referring to chemical reactions, "treat", "contact" and "react" mean adding or mixing two or more reagents under suitable conditions to produce a specified and / or desired product. It is to be understood that the reaction that produces a specified and / or desired product does not necessarily result directly from the combination of two reagents that are initially added, i.e., there may be one or more intermediates that are produced in the mixture that ultimately result in the formation of the specified and / or desired product.

[0087] The term "patient" as used herein is defined as any warm-blooded animal, such as, but not limited to, a mouse, guinea pig, dog, horse or human, preferably, the patient is a human.

[0088] The present invention provides a therapeutically effective amount of α5-GABA A The present invention provides a method for treating α5-GABA receptors comprising administering to a subject a subject in need thereof a therapeutically effective amount of the α5-GABA receptor. A The receptor counter-modulators may be administered as starting compounds, but it is preferred that the active ingredient, optionally in the form of a physiologically acceptable salt, be mixed with one or more additives, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical adjuvants to form a pharmaceutical composition.

[0089] The term "effective amount" as used herein means an amount generally sufficient to produce a beneficial effect in an individual. The effective amount of the compound according to the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, individual medical history, individual health status, degree of individual responsiveness to the drug, etc.).

[0090] In a preferred embodiment, the present invention provides α5-GABA A The present invention provides a pharmaceutical composition comprising an α5-GABA receptor counterregulator, A The receptor counterregulators are mixed with one or more pharma- ceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients known or used in the art. A carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation and not deleterious to the recipient thereof.

[0091] For this reason, the compounds used in the present invention can be formulated with conventional additives or diluents into pharmaceutical compositions and their unit dosage forms. Such forms include solids (especially in the form of tablets, filled capsules, powders and pills), and liquids (especially aqueous or non-aqueous solutions, suspensions, emulsions, elixirs), and capsules filled in the above forms, all forms for oral administration, suppositories for rectal administration, and sterile injection solutions for parenteral administration. Such pharmaceutical compositions and their unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and such unit dosage forms can contain any suitable effective amount of active ingredients corresponding to the required daily dosage range.

[0092] The compounds used in the present invention can be administered in a variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain the compound according to the present invention or a pharma- ceutically acceptable salt thereof as an active ingredient.

[0093] For compounding the compound used in the present invention into pharmaceutical composition, pharma-ceutically acceptable carrier can be either solid or liquid.Solid formulations include powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more substances that also function as diluent, flavoring, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrating agent or encapsulating material.

[0094] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active ingredient.

[0095] In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0096] Powders and tablets preferably contain 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, saccharides, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "formulation" includes active compounds formulated with an encapsulating material as a carrier, which provides a capsule in which the active ingredient is surrounded by the carrier and bound thereto, with or without a carrier. Similarly, formulations include cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0097] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is then dispersed homogeneously therein by stirring The molten homogeneous mixture is then poured into suitable sized molds and allowed to cool and solidify.

[0098] Compositions suitable for vaginal administration may be in the form of pessaries, tampons, creams, gels, pastes, foams or sprays. In addition to the active ingredient, the composition will also contain suitable carriers known in the art.

[0099] Liquid formulations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.For example, parenteral injection liquid preparations can be formulated as water-polyethylene glycol solutions.

[0100] For this reason, the compound used in the present invention can be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion), and can be in unit dosage form with the addition of preservatives in ampoules, prefilled syringes, small volume infusion bags or multi-dose containers.The composition can take the form of a suspension, solution or emulsion in an oily or aqueous carrier, and can contain formulation components such as suspending agents, stabilizing agents and / or dispersing agents.Alternatively, the active ingredient can be in powder form, which can be obtained by sterilizing isolation of a sterile solid or lyophilizing a solution, and is reconstituted with a suitable carrier such as sterile pyrogen-free water before use.

[0101] Aqueous solutions suitable for oral administration can be prepared by dissolving the active component in water and adding the desired colorants, flavors, stabilizing, and thickening agents.

[0102] Aqueous suspensions suitable for oral administration can be made by dispersing finely divided active ingredient in water containing viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other known suspending agents.

[0103] Also included are solid formulations designed to be converted immediately prior to use into liquid formulations for oral administration. Such liquid formulations include solutions, suspensions, and emulsions. Such formulations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0104] For topical application to epidermis, the compound of the present invention can be formulated into ointment, cream, lotion or transdermal patch.For example, ointment and cream can be formulated with aqueous or oily base and add suitable thickening agent and / or gelling agent.Lotion is formulated with aqueous or oily base and generally also contains one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents or coloring agents.

[0105] Compositions suitable for oral topical administration include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerol or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0106] The solutions or suspensions may be applied directly to the nasal cavity by conventional means such as a dropper, pipette or nebulizer. The compositions may be in single or multidose form.

[0107] Administration to the respiratory tract can also be achieved by an aerosol in which the active ingredient is packaged in a pressurized pack with a suitable propellant, including a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metering valve.

[0108] Alternatively, the active ingredient may be in the form of a dry powder, for example a powder mixture of the compound and a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier conveniently can form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, such as gelatin capsules or cartridges, or blister packs from which the powder may be administered by means of an inhaler.

[0109] In compositions to be administered to the respiratory tract, including intranasal compositions, the compound will typically have a small particle size, for example less than about 5 microns. Such a particle size can be obtained by means known in the art, for example by micronization.

[0110] Where appropriate, compositions adapted for sustained release of the active ingredient may be employed.

[0111] The pharmaceutical formulation is preferably in unit dosage form. In such form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be an enclosed formulation in which a large number of individual formulations, such as tablets, capsules, and powders, are enclosed in vials or ampoules, are contained in a sealed package. Furthermore, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or an appropriate amount of the above-mentioned capsules, tablets, etc., in any enclosed form.

[0112] Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

[0113] Further information on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

[0114] The amount of active ingredient in a unit dose formulation can vary depending on the particular application and the potency of the active ingredient, and can be adjusted from 0.01 mg to about 0.1 g. For example, in pharmaceutical applications, the drug can be administered in capsules of 0.01 mg to about 100 mg three times a day, and the composition may contain other compatible therapeutic agents as necessary.

[0115] Treatment method In therapeutic use, the compounds used in the present invention are administered at an initial dose of 0.001 mg / kg (body weight) to 10 mg / kg (body weight) per day. However, the dose may vary depending on the needs of the patient, the severity of the condition being treated, and the compound being used. Generally, treatment is started with a dose that is less than the optimal dose of the compound, and then this dose is increased by small increments to achieve the best effect. For convenience, the total daily dose can be divided into multiple doses within a day, if necessary.

[0116] The pharmaceutical composition of the present invention can also be used simultaneously with other drugs for the treatment of pain, epilepsy, anxiety and depression, including but not limited to morphine, gabapentin, etc. Thus, the present invention provides a drug for the treatment of pain, epilepsy, anxiety and depression that is not only effective but also has no significant side effects. Another object of the present invention is to provide a drug that is extremely safe for special patient groups, such as the elderly, patients with impaired liver or kidney function, or patients with cardiovascular disease.

[0117] The present invention also provides a method of treating or preventing a disease by administering to a patient an effective dose of a compound or composition as described above.

[0118] The present invention also provides a method for treating α5-GABAergic disorders by administering to a patient an effective dose of the compound or the composition described above. A Methods for treating or preventing receptor-related diseases are provided.

[0119] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below. All preferred embodiments, including but not limited to the examples of the present invention, obtained by combining with other chemical synthetic methods and equivalents known to those skilled in the art, are within the scope of the present invention.

[0120] Beneficial Effects: The isoxazole-heterocyclic derivatives of the present invention (i.e., the compounds of formula (I) above, or pharma- ceutically acceptable salts, stereoisomers, tautomers, prodrugs, amorphous forms, isotopically substituted forms, polymorphs or solvates thereof) have important pharmacological properties and are capable of inhibiting the α5-GABA A The compounds of the present invention are α5-GABA receptor counter-modulators. A Not only does it have excellent affinity activity and counterregulatory activity for the α5-GABA receptor, but more importantly, it also has good gastric stability and solubility, making it more suitable for oral drug development and oral absorption. Therefore, the compound according to the present invention, or a pharma- ceutically acceptable salt or prodrug thereof, is capable of inhibiting α5-GABA receptor agonist activity. A It can be used alone or in combination with other drugs to treat or prevent diseases associated with the receptor. EXAMPLES

[0121] A clear and complete description of the technical solutions of the present invention is presented below. Obviously, the described embodiments are only a part, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts are within the scope of protection of the present invention. Here, the solvent ratios used in the purification steps (such as preparative thin layer chromatography, column chromatography, etc.) of the following examples are volume ratios.

[0122] Intermediate 1: 3-(6-fluoropyridin-3-yl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine

[0123] First step: 3-(2-azidoethoxy)propyl-1-yne [ka]

[0124] 60% sodium hydride (0.22 g, 5.5 mmol) was added to anhydrous tetrahydrofuran (30 mL), the reaction mixture was cooled to 0° C., and a solution of 2-azidoethanol (0.4 g, 4.6 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise to it. The reaction mixture was stirred at 0° C. for 30 minutes, and 3-bromopropyl-1-yne (0.82 g, 5.5 mmol, 80% purity) was slowly added dropwise to it. After complete addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL), and the reaction solution was extracted three times with ethyl acetate (10 mL), and then the organic phase was concentrated to give the title compound as a pale yellow oil (0.86 g crude product). LC-MS: m / z[M+H] + =126.

[0125] Second step: 3-(6-fluoropyridin-3-yl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine [ka]

[0126] 2-Fluoro-5-iodopyridine (268 mg, 1.2 mmol), cuprous iodide (23 mg, 0.12 mmol) and tetra(triphenylphosphine)palladium (69 mg, 0.06 mmol) were added to triethylamine (15 mL), the reaction mixture was stirred at room temperature under argon protection for 1 hour, to which was added 3-(2-azidoethoxy)propyl-1-yne (150 mg of crude product). The reaction mixture was stirred at 60° C. for 16 hours under argon protection. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution (50 mL), extracted three times with ethyl acetate (30 mL), and then the organic phase was concentrated and separated by preparative thin layer chromatography (dichloromethane / methanol=100 / 1) to obtain the title compound as a pale yellow solid (40 mg). 1 H NMR (400 MHz, CDCl 3) δ 8.32(s,1H), 8.29~8.21(m,1H), 7.07(dd,J=2.9,8.3Hz,1H), 5.12(s,2H), 4.54(t,J=5.1Hz,2H), 4.18(t,J=5.1Hz,2H);LC-MS: m / z[M+H] + =221.

[0127] Intermediate 2 and Intermediate 3 were prepared according to the preparation method of Intermediate 1, except that the starting material in the "Starting Material" column was used in place of the corresponding starting material (2-fluoro-5-iodopyridine) in the same molar amount as shown in the table below.

[0128] [Table 1]

[0129] Intermediate 4: 4-(((5-bromopyridin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole [ka]

[0130] (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (0.2 g, 0.97 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) was dissolved in anhydrous tetrahydrofuran (3 mL), to which 60% sodium hydride (0.07 g, 2.91 mmol) was added at 0° C., and after stirring for 15 minutes, a solution of 5-bromo-2-fluoropyridine (0.19 g, 1.07 mmol) in tetrahydrofuran (3 mL) was slowly added dropwise. After complete addition, the mixture was reacted at room temperature for 2 hours. The reaction was quenched with water (25 mL) and extracted twice with ethyl acetate (25 mL), after which the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by preparative thin layer chromatography (dichloromethane / methanol=100 / 1) to give the title compound as an oil (150 mg, 43% yield). LC-MS: m / z[M+H] + =363.

[0131] Intermediate 5 and Intermediate 6 were prepared according to the preparation method of Intermediate 4, except that the starting material in the "Starting Material" column was used in place of the corresponding starting material (5-bromo-2-fluoropyridine) in the same molar amount as shown in the table below.

[0132] [Table 2]

[0133] Intermediate 7: 3-(4-fluorophenyl)-5-methyl-4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)pyridin-2-yl)oxy)methyl)isoxazole [ka]

[0134] 4-(((5-bromopyridin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (0.270 g, 0.74 mmol), bis(pinacolato)diboron (0.2 g, 0.777 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.061 g, 0.074 mmol), potassium acetate (0.15 g, 1.48 mmol) were dissolved in 1,4-dioxane (6 mL) and reacted at 100° C. for 5 hours under nitrogen protection. After filtering the reaction mixture through diatomaceous earth, the filtrate was concentrated and separated by preparative thin layer chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound as a yellow solid (140 mg, 52% yield). LC-MS: m / z[M+H] + =329.

[0135] Intermediate 8: 3-Bromo-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one

[0136] First step: tert-Butyl 3-bromo-8-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate [ka]

[0137] tert-Butyl 3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (250 mg, 0.82 mmol, CAS: 723286-80-4) was dissolved in chloroform (3 mL) and acetonitrile (3 mL), to which was added an aqueous solution (6 ml) of sodium periodate (807 mg, 3.77 mmol), followed by the addition of ruthenium dioxide hydrate (31 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (6 mL), extracted three times with chloroform (5 mL), and the organic phases were combined, dried, and filtered through diatomaceous earth. The filtrate was concentrated and separated and purified by column chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a white solid (140 mg, 54% yield). LC-MS: m / z[M+H] + =317.

[0138] Second step: 3-bromo-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one [ka]

[0139] tert-Butyl 3-bromo-8-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (140 mg, 0.44 mmol) was dissolved in dichloromethane (3 mL), to which trifluoroacetic acid (150.51 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was directly concentrated to give the title compound as a light green solid (100 mg crude product), which was used directly in the next step without further purification. LC-MS: m / z[M+H]+ =217.

[0140] Intermediate 9: 3-Bromo-7-methyl-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one [ka]

[0141] 3-Bromo-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one (100 mg, 0.46 mmol) was dissolved in tetrahydrofuran (1 ml), to which 60% sodium hydride (22 mg, 0.92 mmol) was added under ice bath conditions, stirred for 15 minutes, then iodomethane (131 mg, 0.92 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and extracted three times with ethyl acetate (15 mL), after which the organic phases were combined, concentrated, and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a white solid (42 mg, yield over two steps: 29%). LC-MS: m / z[M+H] + =231.

[0142] Intermediate 10 was prepared according to the preparation method of Intermediate 9, except that the starting material in the "Starting material" column was used in place of the corresponding starting material (iodomethane) in the same molar amount as shown in the table below.

[0143] [Table 3]

[0144] Intermediate 11: Methyl 5-chloro-3-methylpyrazine-2-carboxylate First step: 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide [ka]

[0145] Methyl 3-methylpyrazine-2-carboxylate (2.0 g, 13.1 mmol) was dissolved in chloroform (20 mL), m-chloroperbenzoic acid (2.49 g, 14.5 mmol) was added thereto, and the mixture was reacted at 70° C. for 5 hours. The reaction solution was diluted with water (50 mL) and extracted twice with dichloromethane (50 mL), and then the organic phases were combined, concentrated, and purified by column chromatography (dichloromethane / methanol=10 / 1) to obtain the title compound product as a white solid (1.5 g). LC-MS: m / z[M+1] + =169.

[0146] Second step: methyl 5-chloro-3-methylpyrazine-2-carboxylate [ka]

[0147] 3-(Methoxycarbonyl)-2-methylpyrazine 1-oxide (1.5g, 9.28mmol) was dissolved in N,N-dimethylformamide (15mL), and phosphorus oxychloride (2.54mL) was slowly added dropwise thereto, and the reaction mixture was stirred at 100°C for 1 hour. Saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution until it became weakly alkaline, and then extracted twice with dichloromethane (50mL). The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain the title compound product as a pale yellow liquid (1.0g). LC-MS: m / z[M+1] + =187.

[0148] Intermediate 12: Methyl 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-2-methoxynicotinate First step: methyl 6-fluoro-2-methoxynicotinate [ka]

[0149] Methyl 2,6-difluoronicotinate (2.0 g, 11.6 mmol) was dissolved in tetrahydrofuran (35 mL), to which sodium methoxide (660 mg, 12.1 mmol) was added, and the reaction mixture was reacted at 5° C. for 30 minutes. The reaction solution was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL), and then the organic phases were combined, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain the title compound product as a white solid (1.58 g). LC-MS: m / z[M+1] + =186.

[0150] Second step: methyl 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-2-methoxynicotinate [ka]

[0151] Methyl 6-fluoro-2-methoxynicotinate (1.5 g, 9.28 mmol) was dissolved in N,N-dimethylformamide (20 mL), to which potassium carbonate (2.24 g, 16.2 mmol) and (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (1.68 g, 10.25 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) were added, and the reaction mixture was reacted at 80° C. for 12 hours. The reaction solution was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL), and then the organic phases were combined, concentrated, and purified by column chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound product as a pale yellow liquid (1.5 g). LC-MS: m / z[M+1] + =373.

[0152] Intermediate 13: 4-(bromomethyl)-3-(4-fluorophenyl)-5-methylisoxazole [ka]

[0153] (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (2.4 g, 11.59 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) was added to anhydrous dichloromethane (30 mL) and cooled to 0° C., to which phosphorus tribromide (1.5 mL) was slowly added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was slowly added dropwise to saturated sodium bicarbonate solution, and the mixture was stirred for another 15 minutes, after which the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (2 g crude product). LC-MS: m / z[M+H] + =270.

[0154] Intermediate 14: Methyl 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-5-methoxynicotinate First step: 6-hydroxy-5-methoxynicotinic acid [ka]

[0155] Methyl 6-chloro-5-methoxynicotinate (0.9 g, 4.46 mmol), potassium hydroxide (0.3 g, 5.35 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.19 g, 0.45 mmol) and tris(dibenzylideneacetone)dipalladium (0.41 g, 0.45 mmol) were added to a mixed solvent of 1,4-dioxane (10 mL) and water (10 mL) in sequence, and the reaction mixture was reacted at 90 °C for 12 hours under argon protection. The reaction solution was added to water (50 mL), extracted twice with ethyl acetate (50 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH = 5-6 with 1 M HCl, extracted three times with ethyl acetate (50 mL), and the combined organic phase was directly concentrated to obtain the title compound as a yellow solid (0.9 g crude product). LC-MS: m / z[M+H] + =170.

[0156] Second step: methyl 6-hydroxy-5-methoxynicotinate [ka]

[0157] 6-Chloro-5-methoxynicotinic acid (0.8 g crude product) was dissolved in methanol (20 mL), and sulfonyl chloride (0.84 g, 7.05 mmol) was added thereto at 0° C., and the reaction mixture was stirred at 68° C. for 12 hours. The reaction solution was directly concentrated, the residue was diluted with water (50 mL), and extracted three times with dichloromethane (50 mL), and the organic phases were combined, concentrated, and separated and purified by column chromatography (dichloromethane / methanol=20 / 1) to obtain the title compound as a white solid (0.8 g). LC-MS: m / z[M+H] + =184.

[0158] Third step: methyl 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-5-methoxynicotinate [ka]

[0159] Methyl 6-hydroxy-5-methoxynicotinate (0.7 g, 2.59 mmol) was dissolved in 1,2-dichloroethane (20 mL), to which silver oxide (0.9 g, 3.89 mmol) and 4-(bromomethyl)-3-(4-fluorophenyl)-5-methylisoxazole (617 mg, 3.37 mmol) were added, and the reaction mixture was stirred at 80° C. for 12 hours. The reaction solution was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL), and the organic phases were combined, concentrated, and separated and purified by column chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound as a yellow solid (46 mg, 5% yield). LC-MS: m / z[M+H] + =373.

[0160] Intermediate 15: 6-Chloronicotinohydrazine [ka]

[0161] Methyl 6-chloronicotinate (5 g, 3.4 mmol) was added to ethanol (30 mL) to which hydrazine hydrate (222 mg, 10.2 mmol) was added and the reaction mixture was stirred at room temperature overnight. A white solid precipitated and the reaction mixture was filtered to give the title compound as a white solid (5 g crude). LC-MS: m / z[M+H] + =172.

[0162] Intermediate 16 to Intermediate 21 were synthesized according to the preparation method of Intermediate 15, except that the starting material in the "Starting material" column was used in place of the corresponding starting material (methyl-6-chloronicotinate) in the same molar amount as shown in the table below.

[0163] [Table 4]

[0164] Intermediate 22: tert-Butyl 5-methoxy-3,6-dihydropyrazine-1(2H)-carboxylate [ka]

[0165] tert-Butyl 3-oxopiperazine-1-carboxylate (10 g, 50 mmol) and trimethyloxonium tetrafluoroborate (10.34 mg, 70 mmol) were added to dichloromethane (100 mL) and the reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the reaction solution was stirred for an additional hour, and after multiple extractions with dichloromethane, the organic phases were combined, dried and concentrated to give the title compound as a pale yellow gum (10 g crude product), which was used directly in the next reaction without further purification.

[0166] Intermediate 23: 3-(4-fluorophenyl)-5-methyl-4-(((5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)isoxazole First step: tert-butyl 3-(5-chloropyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate [ka]

[0167] tert-Butyl 5-methoxy-3,6-dihydropyrazine-1(2H)-carboxylate (1.24 g, 5.79 mmol, intermediate 22) and 5-chloropyrazine-2-carbohydrazide (1 g, 5.79 mmol, intermediate 17) were dissolved in ethanol (20 mL), and the mixture was heated to 120° C. and stirred overnight. The reaction solution was directly concentrated and purified by column chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a light yellow solid (1 g, 51% yield). LC-MS: m / z[M+H] + =337.

[0168] Second step: tert-butyl 3-(5-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate [ka]

[0169] (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (500 mg, 2.4 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) was dissolved in tetrahydrofuran (15 mL), to which 60% sodium hydride (193 mg, 4.8 mmol) was added under ice bath conditions, the mixture was stirred for 30 minutes, and then tert-butyl 3-(5-chloropyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (812 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride solution and extracted multiple times with ethyl acetate, after which the organic phases were combined, dried, concentrated, and purified by column chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound as a light yellow oil (600 mg, 49% yield). LC-MS: m / z[M+H] + =508.

[0170] Third step: 3-(4-fluorophenyl)-5-methyl-4-(((5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)isoxazole [ka]

[0171] tert-Butyl 3-(5-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (500 mg, 0.99 mol) was dissolved in methanol (5 mL) and water (5 mL) and the mixture was subjected to microwave reaction in a microwave reactor at 150° C. for 1.5 hours. The mixture was directly concentrated to give the title compound as a pale yellow oil (400 mg, 99% yield). LC-MS: m / z[M+H] + =408.

[0172] Intermediate 24 was synthesized according to the preparation method of Intermediate 23, except that the starting material in the "Starting Material" column was used in place of the corresponding starting material (5-chloropyrazine-2-carbohydrazide) in the same molar amount as shown in the table below.

[0173] [Table 5]

[0174] Intermediate 25: 4-((5-(7-cyclobutyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole [ka]

[0175] 3-(4-Fluorophenyl)-5-methyl-4-(((5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)isoxazole (200 mg, 0.49 mmol, intermediate 23) was dissolved in methanol (12 mL), to which cyclobutanone (84 mg, 0.98 mmol) was added, the mixture was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (185 mg, 2.94 mmol) was added, followed by heating the mixture to 60° C. and stirring overnight. The mixture was purified by column chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a white solid (100 mg, 44% yield). LC-MS: m / z[M+H] + =462.

[0176] Intermediate 26 was synthesized according to the preparation method of Intermediate 25, except that the starting material in the "Starting material" column was used in place of the corresponding starting material (cyclobutanone) in the same molar amount as shown in the table below.

[0177] [Table 6]

[0178] Intermediate 27: 1,4-Oxazepan-3-one First step: 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid [ka]

[0179] tert-Butyl (3-hydroxypropyl)carbamate (4 g, 23 mmol) was added to anhydrous tetrahydrofuran (40 mL) and cooled to 0° C., to which 60% sodium hydride (2.47 g, 68 mmol) was slowly added, and after stirring for 15 minutes, additional methyl bromoacetate (5.24 g, 34 mmol) was added, and the reaction mixture was then stirred at room temperature overnight. The reaction was quenched with water and extracted multiple times with ethyl acetate, after which the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (3 g crude). LC-MS: m / z[M+1] + =234.

[0180] Second step: methyl 2-(3-aminopropoxy)acetate [ka]

[0181] 2-(3-((tert-butoxycarbonyl)amino)propoxy)acetic acid (3 g crude product) was dissolved in methanol (30 mL) and cooled to 0° C., to which sulfonyl chloride (4.6 g, 39 mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated to give the title compound (1 g crude product). LC-MS: m / z[M+1] + =148.

[0182] Third step: 1,4-oxazepan-3-one [ka]

[0183] Methyl 2-(3-aminopropoxy)acetate (1 g crude product) was dissolved in methanol (20 mL), to which potassium carbonate (1.9 g, 13.6 mmol) was added, and the reaction mixture was heated to 60° C. and stirred for 1 h. After the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=2 / 1) to give the title compound (0.16 g, yield over three steps: 5%). LC-MS: m / z[M+H] + =116.

[0184] Intermediate 28: 5-Chloro-3,6-dihydro-2H-1,4-oxazine [ka]

[0185] 3-Morpholon (4 g) was dissolved in a mixed solvent of dichloromethane (5 mL), to which phosphorus oxychloride was added, and the reaction mixture was stirred at 40° C. for 1 hour. The reaction solution was concentrated to give the title compound (4.5 g crude product), which was used directly in the next reaction without further purification.

[0186] Intermediate 29 to Intermediate 33 were synthesized according to the preparation method of Intermediate 28, except that the starting material in the "Starting material" column was used in place of the corresponding starting material (3-morpholone) in the same molar amount as shown in the table below.

[0187] [Table 7]

[0188] Intermediate 34: 3-(6-chloropyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine [ka]

[0189] 5-Chloro-3,6-dihydro-2H-1,4-oxazine (5 g, 29 mmol, intermediate 28) was dissolved in toluene (250 mL), to which 6-chloronicotinohydrazine (4.5 g, 37 mmol, intermediate 15) and N,N-diisopropylethylamine (3.7 g, 28.9 mmol) were added separately, and the reaction mixture was stirred at 130° C. for 4 h and cooled to room temperature. The reaction mixture was adjusted to pH=10-11 with saturated sodium bicarbonate solution, stirred at 100° C. for 16 h, and extracted multiple times with ethyl acetate. The organic phases were combined and concentrated to give the crude title compound (0.36 g, yield over three steps: 38%). LC-MS: m / z[M+H] + =237.

[0190] Intermediate 35 to Intermediate 47 were synthesized according to the preparation method of Intermediate 34, except that the same molar amount of Starting Material 1 and the same molar amount of Starting Material 2 in the "Starting Material" column were used instead of the corresponding starting materials (6-chloronicotinohydrazine and 5-chloro-3,6-dihydro-2H-1,4-oxazine) as shown in the table below.

[0191] [Table 8] TIFF2025510390000065.tif121164

[0192] Intermediate 48: 4-(((5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl)pyridin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole [ka]

[0193] (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (141 mg, 0.68 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) was added to anhydrous tetrahydrofuran (10 mL) and cooled to 0° C., to which was added 60% sodium hydride (82 mg, 2.04 mmol), and after stirring at 0° C. for 30 minutes, 3-(6-chloropyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazine (172 mg, 0.68 mmol, intermediate 36) was added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated and separated by preparative thin layer chromatography (petroleum ether / ethyl acetate=1 / 1) to give the title compound as an orange solid (160 mg, 56% yield). LC-MS: m / z[M+H] + =424.

[0194] Intermediate 49 was synthesized according to the preparation method of Intermediate 48, except that the starting material in the "Starting Material" column was used in place of the corresponding starting material (3-(6-chloropyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazine) in the same molar amount as shown in the table below.

[0195] [Table 9]

[0196] Intermediate 50: 3-(6-chloropyridin-3-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3]oxazine First step: 5-(6-chloropyridin-3-yl)-1,3,4-oxadiazole-2-thiol [ka]

[0197] 6-Chloronicotinohydrazine (0.7 g, 4.06 mmol, intermediate 15) was dissolved in ethanol (16 mL) and water (8 mL), to which carbon disulfide (3.09 g, 40.6 mmol) and potassium hydroxide (0.34 g, 6.09 mmol) were further added, and the mixture was heated to 90° C. and stirred overnight. The reaction solution was concentrated to give the title compound (0.84 g crude product). LC-MS: m / z[M+1] + =214.

[0198] Second step: 2-(6-chloropyridin-3-yl)-5-(methylthio)-1,3,4-oxadiazole [ka]

[0199] 5-(6-chloropyridin-3-yl)-1,3,4-oxadiazole-2-thiol (0.84 g, 3.9 mmol) was dissolved in methanol (20 mL), to which iodomethane (1.12 g, 7.84 mmol) was further added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol=100 / 1) to obtain the title compound (0.7 g, 78% yield). LC-MS: m / z[M+H] + =228.

[0200] Third step: 2-(6-chloropyridin-3-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole [ka]

[0201] 2-(6-chloropyridin-3-yl)-5-(methylthio)-1,3,4-oxadiazole (0.7 g, 3.08 mmol) was dissolved in dichloromethane (10 mL), m-chloroperbenzoic acid (1.59 g, 9.24 mmol) was further added thereto, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound (280 mg, 35% yield). LC-MS: m / z[M+H] + =260.

[0202] Fourth step: 6-chloro-N'-(5,6-dihydro-4H-1,3-oxazin-2-yl)nicotinic acid hydrazide [ka]

[0203] 2-(6-chloropyridin-3-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole (280 mg, 1.05 mmol) was dissolved in tetrahydrofuran (10 mL), to which 3-aminopropanol (94.64 mg, 1.26 mmol) was further added, followed by slow dropwise addition of triethylamine (319 mg, 3.15 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol=10 / 1) to obtain the title compound (120 mg, 37.5% yield). LC-MS: m / z[M+H] + =255.

[0204] Fifth step: 3-(6-chloropyridin-3-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3]oxazine [ka]

[0205] 6-Chloro-N'-(5,6-dihydro-4H-1,3-oxazin-2-yl)nicotinic acid hydrazide (120 mg, 0.47 mmol) was added to dichlorobenzene (8 mL) and subjected to a microwave reaction at 180°C for 4 hours. The reaction solution was separated by preparative thin layer chromatography (dichloromethane / methanol = 20 / 1) to obtain the title compound (50 mg, yield 45%). LC-MS: m / z [M+H] + =237.

[0206] Intermediate 51: 3-(4-fluorophenyl)-5-methyl-4-((5-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrazin-2-yl)oxy)methyl)isoxazole [ka]

[0207] 4-((5-bromopyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (300 mg, 0.82 mmol) was added to 1,4-dioxane (10 mL) and to this was further added 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (158 mg, 0.82 mmol), tris(dibenzylideneacetone)dipalladium (75 mg, 0.082 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51 mg, 0.088 mmol) and cesium carbonate (430 mg, 1.32 mmol) and the reaction mixture was stirred at 100° C. overnight under nitrogen protection. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound (80 mg, yield 20.5%). LC-MS: m / z[M+1] + =476.

[0208] Intermediate 52: 3-(6-fluoropyridin-3-yl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine First step: (6-fluoropyridin-3-yl)(3-(hydroxymethyl)morpholino)methanone [ka]

[0209] 6-Fluoronicotinic acid (1.5 g, 10.6 mmol), morpholin-3-ylmethanol (1.25 g, 10.6 mmol) and N,N-diisopropylethylamine (2.75 g, 21.3 mmol) were added to dichloromethane (20 mL), to which 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.85 g, 12.8 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a yellow liquid (2.1 g, 82% yield). LC-MS: m / z[M+1] + =241.

[0210] Second step: 4-(6-fluoronicotinoyl)morpholine-3-formaldehyde [ka]

[0211] (4-(6-fluoropyridine-3-carbonyl)morpholin-3-yl)methanol (0.5 g, 2.08 mmol) and Dess-Martin reagent (0.88 g, 2.08 mmol) were dissolved in dichloromethane (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated and separated by preparative thin layer chromatography (dichloromethane / methanol=50 / 1) to give the title compound as an oily liquid (90 mg, 18% yield). LC-MS: m / z[M+1] + =239.

[0212] Third step: 3-(6-fluoropyridin-3-yl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine [ka]

[0213] 4-(6-fluoropyridine-3-carbonyl)morpholine-3-formaldehyde (0.09 g, 0.38 mmol) and ammonium acetate (0.059 g, 0.76 mmol) were dissolved in acetic acid (4 mL) and reacted at 80° C. for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and extracted multiple times with ethyl acetate, after which the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by preparative thin layer chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a colorless oil (10 mg, 12% yield). LC-MS: m / z[M+1] + =220.

[0214] Intermediate 53: 3-Bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ka]

[0215] tert-Butyl 3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.2 g, 0.66 mmol) was dissolved in dichloromethane (4 mL), to which trifluoroacetic acid (2 mL) was added, and the reaction mixture was stirred at room temperature overnight. Excess sodium bicarbonate solid was added to the reaction mixture. After filtering the reaction mixture through diatomaceous earth, the filtrate was concentrated to give the title compound as a yellow oil (0.1 g, 77% yield). LC-MS: m / z[M+1] + =203.

[0216] Intermediate 54: 1-(3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethan-1-one [ka]

[0217] 3-Bromo-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.13 g, 0.64 mmol), acetyl chloride (0.098 g, 0.96 mmol) and sodium bicarbonate (0.11 g, 1.28 mmol) were dissolved in dichloromethane (6 mL) and reacted at room temperature for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound (0.12 g crude product). LC-MS: m / z[M+1] + =245.

[0218] Intermediate 55 was synthesized according to the preparation method of Intermediate 54, except that the starting material in the "Starting material" column was used in place of the corresponding starting material (acetyl chloride) in the same molar amount as shown in the table below.

[0219] [Table 10]

[0220] Intermediate 56: (3S,11aR)-7-chloro-3,4-dihydro-1H,9H,11H-3,11a-methanopyrimido[6',1':2,3]imidazo[5,1-C][1,4]oxazin-9-one [ka]

[0221] Intermediate 56 was synthesized according to the method in WO2021089032.

[0222] Intermediate 57: 3-Chloro-7,8-dihydro-1H,6H,9H-7,8a-methanopyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one [ka]

[0223] Intermediate 57 was synthesized according to the method in WO2021089032.

[0224] Intermediate 58: 7-Chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one [ka]

[0225] 7-Chloro-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.02 g, 0.12 mmol), iodomethane (0.026 g, 0.18 mmol) and cesium carbonate (0.078 g, 0.24 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. After adding water (20 mL) to the reaction solution, it was extracted twice with ethyl acetate (20 mL), and then the organic phases were combined, dried and concentrated to give the title compound (160 mg). LC-MS: m / z[M+1] + =186.

[0226] Intermediate 59: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine First step: 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole [ka]

[0227] 4-Bromo-1H-pyrazole (2.0 g, 13.6 mmol) was dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (5.64 g, 40.8 mmol) and tert-butyl(2-chloroethoxy)dimethylsilane (4.88 g, 20.4 mmol) were added thereto, and the reaction solution was reacted at 25° C. for 12 hours. The reaction solution was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL), and then the organic phases were combined, dried, concentrated, and separated and purified by column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain the title compound as a white solid (3.2 g). LC-MS: m / z[M+1] + =305.

[0228] Second step: 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-formaldehyde [ka]

[0229] Under nitrogen protection, 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (3.2 g, 11.7 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium diisopropylamide (11.76 mL, 23.52 mmol, 2 M) was added dropwise thereto at -78°C, and stirred for 30 minutes, followed by N,N-dimethylformamide (1.72 g, 23.5 mmol). After complete addition, the reaction mixture was stirred for 1 hour. Dilute hydrochloric acid was added dropwise to the reaction solution until it became weakly acidic. The reaction solution was then diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL), after which the organic phases were combined, dried, concentrated, and separated and purified by column chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain the title compound as a white solid (2.5 g). LC-MS: m / z[M+1] + =333.

[0230] Third step: 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol [ka]

[0231] 4-Bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-formaldehyde (2.5 g, 7.53 mmol) was added to a mixed solvent of water (5 mL) and 2-methyltetrahydrofuran (5 mL), trifluoroacetic acid (10 mL) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Saturated sodium bicarbonate solution was then added to the reaction solution until it became weakly alkaline. The reaction solution was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL), and the organic phases were combined, dried, concentrated, and separated and purified by column chromatography (cyclomethane / methanol = 20 / 1) to obtain the title compound as a pale yellow solid (1.35 g). LC-MS: m / z[M+H] + =219.

[0232] Fourth step: 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka]

[0233] 3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-4-ol (500mg, 2.28mmol) was added to dichloromethane (15mL), and then trifluoroacetic acid (2.04mL, 27.3mmol) and triethylsilane (1.59g, 13.7mmol) were added thereto, and the reaction solution was stirred at 25°C for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution until it became weakly alkaline. The reaction solution was diluted with water (50mL) and extracted twice with ethyl acetate (50mL), and then the organic phases were combined, dried, concentrated, and separated and purified by column chromatography (chloromethane / methanol=20 / 1) to obtain the title compound as a pale yellow liquid (440mg). LC-MS: m / z[M+H] + =203.

[0234] Fifth step: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine [ka]

[0235] 3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (200 mg, 0.99 mmol) was dissolved in 1,4-dioxane (10 mL), to which potassium carbonate (290 mg, 2.97 mmol), tetrabutylammonium bromide (64 mg, 0.2 mmol), bis(pinacolato)diboron (50 mg, 1.98 mmol) and bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.2 mmol) were added separately, and the reaction mixture was stirred at 105° C. for 2 hours under argon-saturated conditions. The reaction mixture was diluted with water (50 mL) and extracted twice with ethyl acetate (50 mL), after which the organic phases were combined, dried, concentrated, and separated and purified by column chromatography (dichloromethane / ethyl acetate=20 / 1) to give the title compound (200 mg). LC-MS: m / z[M+H] + =251.

[0236] Intermediate 60: 2-Methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine First step: 2-methylimidazo[1,2-a]pyrazine [ka]

[0237] Pyrazin-2-amine (2.0 g, 21.0 mmol) was dissolved in ethanol (25 mL), to which 1-bromopropan-2-one (3.46 g, 25.2 mmol) was added, and the mixture was reacted at 80° C. for 2 hours. The reaction solution was directly concentrated, separated and purified by column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain the title compound as a white solid (1.3 g). LC-MS: m / z[M+1] + =134.

[0238] Second step: 2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine [ka]

[0239] 2-Methylimidazo[1,2-a]pyrazine (0.5 g, 3.76 mmol) was dissolved in methanol (10 mL), Pd / C catalyst (50 mg) was added thereto, and the reaction mixture was stirred in a hydrogen environment at 25° C. for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound as a pale yellow liquid (0.8 g). LC-MS: m / z[M+1] + =138.

[0240] Intermediate 61: 3-(4-fluorophenyl)-5-methyl-4-(((5-(tributylstannyl)pyrazin-2-yl)oxy)methyl)isoxazole [ka]

[0241] 4-(((5-bromopyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (1 g, 2.75 mmol, intermediate 5), tricyclohexylphosphine (77 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (151 mg, 16 mmol) and lithium chloride (525 mg, 12.4 mmol) were added to 1,4-dioxane (40 mL), to which hexabutylditin (2.71 g, 4.67 mmol) was added, and the reaction mixture was heated to 110° C. under an argon atmosphere and stirred overnight. A saturated aqueous solution of potassium fluoride was added to the reaction solution, followed by stirring for 2 hours. A dark precipitate formed and the reaction mixture was filtered through diatomaceous earth, after which the filtrate was dried, concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a pale yellow oil (500 mg, 32% yield). LC-MS: m / z[M+H] + =576.

[0242] Intermediate 62: Methyl 1-(2-aminoethyl)-4-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate First step: 1-tert-butyl 2-methyl 4-[6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl]piperazine-1,2-dicarboxylate [ka]

[0243] Compounds 4-(((6-chloropyridazin-3-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (300 mg, 0.94 mmol, intermediate 6), 1-(tert-butyl) 2-methyl(S)-piperazine-1,2-dicarboxylate (0.34 g, 1.41 mmol, CAS: 129799-15-1), cesium carbonate (0.55 g, 1.69 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (0.079 g, 0.094 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.044 g, 0.094 mmol) were added to 1,4-dioxane (20 mL), and the reaction mixture was stirred at 100° C. for 16 hours. After the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a white solid (450 mg, 91% yield). LC-MS: m / z[M+H] + =528.

[0244] Second step: methyl 4-[6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl]piperazine-2-carboxylate [ka]

[0245] 1-tert-Butyl 2-methyl 4-[6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl]piperazine-1,2-dicarboxylate (450 mg, 0.85 mmol) was dissolved in dichloromethane (10 mL) at room temperature, to which trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was quenched by pouring into saturated sodium bicarbonate solution (50 mL) and extracted twice with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the title compound (360 mg crude product). LC-MS: m / z[M+H] + =428.

[0246] Third step: methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate [ka]

[0247] Methyl 4-[6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl]piperazine-2-carboxylate (310 mg, 0.73 mmol), tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.20 g, 0.88 mmol, CAS: 459817-82-4) and cesium carbonate (0.36 g, 1.09 mmol) were added to acetonitrile (15 mL) under nitrogen protection, and the reaction mixture was stirred at 70° C. for 3 hours. The reaction was filtered through diatomaceous earth, and the filtrate was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were then combined, washed once with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered, after which the filtrate was concentrated to give the title compound (400 mg crude product). LC-MS: m / z[M+H] + =571.

[0248] Fourth step: methyl 1-(2-aminoethyl)-4-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate [ka]

[0249] Under nitrogen protection, methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate (350 mg, 0.61 mmol) was dissolved in hydrogen chloride acetate B ethyl solution (5 mL), and the reaction mixture was stirred at 25° C. for 2 hours. The reaction solution was quenched by pouring into saturated sodium bicarbonate (150 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were then combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered, after which the filtrate was concentrated to give the title compound (200 mg crude product). LC-MS: m / z[M+H] + =471.

[0250] Intermediate 63: (S)-Hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one hydrochloride First step: (S)-1-tert-butyl 3-methyl 4-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1,3-dicarboxylate [ka]

[0251] (S)-1-tert-butylbenzyl 3-methylpiperazine-1,3-dicarboxylate (1.0 g, 4.09 mmol) and (2-bromoethyl)carbamate (1.27 g, 4.91 mmol) were dissolved in anhydrous N,N-dimethylformamide (15.0 mL) at room temperature, potassium carbonate (678 mg, 4.91 mmol) was added thereto, and the reaction mixture was reacted at 100° C. for 16 hours. The reaction solution was diluted with water (40 mL) and extracted with dichloromethane (30 mL×3 times), and then the organic phases were combined, washed with saturated brine (40 mL×2 times), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (methanol:dichloromethane=0:1→1:10) to obtain the title compound as a yellow oil (370 mg). LC-MS: m / z[M+H] + =422.

[0252] Second step: tert-Butyl (S)-9-oxooctahydro-2H-pyrazine[1,2-a]pyrazine-2-carboxylate [ka]

[0253] (S)-1-tert-butyl 3-methyl 4-(2-(((benzyloxy)carbonyl)amino)ethyl)piperazine-1,3-dicarboxylate (370 mg, 0.87 mmol) was dissolved in methanol (6.0 mL) at room temperature, Pd / C (30 mg) was added thereto, and the reaction solution was reacted in a hydrogen (15 psi) atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil (210 mg). LC-MS: m / z[M+H] + =256.

[0254] Third step: (S)-Hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one hydrochloride [ka]

[0255] At room temperature, tert-butyl (S)-9-oxooctahydro-2H-pyrazine[1,2-a]pyrazine-2-carboxylate (60 mg, 0.24 mmol) was dissolved in anhydrous dichloromethane (4 mL), and 4M hydrogen chloride in ethyl acetate (4 mL) was slowly added dropwise thereto, and the reaction solution was reacted for 1 hour with stirring. The reaction solution was concentrated under reduced pressure to give the title product as a yellow solid (50 mg). LC-MS: m / z[M+H] + =156.

[0256] Intermediate 64: 1-(6-fluoropyridin-3-yl)-1,4,6,7-tetrahydropyrano[3,4-d][1,2,3]triazole First step: 5-azido-2-fluoropyridine [ka]

[0257] 6-Fluoro-3-pyridylamine (3 g, 26.7 mmol) was dissolved in acetonitrile (60 mL) and cooled to 0° C., to which tert-butyl nitrite (4.14 g, 40.1 mmol) and azidotrimethylsilane (3.7 g, 32.1 mmol) were added successively at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction solution was added to water (200 mL) and extracted three times with dichloromethane (200 mL). The organic phases were then combined, washed once with saturated brine, dried, and concentrated to give the title compound (3 g, crude), which was used directly in the next reaction. LC-MS: m / z[M+H] + =139.

[0258] Second step: 1-(6-fluoropyridin-3-yl)-1,4,6,7-tetrahydropyrano[3,4-d][1,2,3]triazole [ka]

[0259] Tetrahydro-4H-pyran-4-one (1.23 g, 12.25 mmol) was added to toluene (50 mL), the mixture was heated to 110 ° C, a solution of 5-azido-2-fluoropyridine (2.2 g, 15.93 mmol) in toluene (10 mL) was slowly added dropwise thereto, followed by pyrrolidine (0.96 g, 13.48 mmol), and the reaction solution was stirred at 110 ° C for 3 hours. After cooling to 0 ° C, dichloromethane (100 mL), m-chloroperbenzoic acid (4.97 g, 24.5 mmol), and sodium bicarbonate (2.06 g, 24.5 mmol) were added in sequence, and the reaction mixture was stirred at 0 ° C overnight. The reaction solution was diluted with water (100 mL) and extracted twice with dichloromethane (100 mL). The organic phases were then combined, washed once with saturated brine, dried, concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a pale yellow solid (310 mg). LC-MS: m / z[M+H] + =221.

[0260] Example 1: 3-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine [ka]

[0261] Method A (3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methanol (33 mg, 0.16 mmol, synthesized according to the method disclosed in US Patent Publication No. 20130102778) was dissolved in anhydrous tetrahydrofuran (2 mL), to which was added 60% sodium hydride (7 mg, 0.19 mmol) under ice bath conditions, and the reaction mixture was stirred at 0° C. for 30 minutes, after which 3-(6-fluoropyridin-3-yl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine (35 mg, 0.16 mmol, intermediate 1) was added, and the reaction mixture was subsequently stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL) and extracted three times with ethyl acetate (20 mL), after which the organic phase was concentrated and separated by preparative thin layer chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a white solid (33 mg, 51% yield), which was named compound 1. 1 H NMR (400 MHz, CDCl 3 ) δ 8.30(br.s.,1H), 8.03(d,J=7.3Hz,1H), 7.80(br.s.,2H), 7.15(br.s.,2H), 6.88(d,J=7.8Hz,1H) , 5.27(br.s.,2H), 5.10(br.s.,2H), 4.52(br.s.,2H), 4.17(br.s.,2H), 2.59(br.s.,3H);LC-MS: m / z[M+H] + =408.

[0262] Example 2 3-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)-7-methyl-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one [ka]

[0263] Method B 3-(4-Fluorophenyl)-5-methyl-4-(((5-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)pyridin-2-yl)oxy)methyl)isoxazole (75 mg, 0.18 mmol, intermediate 7), 3-bromo-7-methyl-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one (42 mg, 0.18 mmol, intermediate 9), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (13 mg, 0.018 mmol) and sodium carbonate (38 mg, 0.36 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was heated to 110° C. under argon atmosphere and stirred overnight. After the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated and separated and purified by column chromatography (dichloromethane / methanol=50 / 1) to obtain the title compound as a white solid (23 mg, yield 29%), which was named Compound 2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.49(br.s.,1H), 8.04(d,J=8.3Hz,1H), 7.86~7.69(m,2H), 7.16(t,J=8.3Hz,2H), 6.95(d,J= 8.3Hz,1H), 5.32(s,2H), 4.38(br.s.,2H), 3.81(br.s.,2H), 3.23(s,3H), 2.60(s,3H);LC-MS: m / z[M+H] + =435.

[0264] Example 3 4-((5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole [ka]

[0265] Method C 4-(((5-bromopyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (200 mg, 0.55 mmol, intermediate 5), 3-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole (129 mg, 0.55 mmol, CAS: 1314138-13-0) were dissolved in 1,4-dioxane (6 mL), and 1,1'-bis(diphenylphosphino)ferrocenylpalladium dichloride (40 mg, 0.055 mmol) and sodium carbonate (117 mg, 1.1 mmol) were added thereto. The mixture was heated to 100° C. under argon atmosphere and stirred overnight, then directly purified by column chromatography (dichloromethane / methanol=50 / 1) to give the title compound as a pale yellow solid (15 mg, 7% yield), which was named compound 3. 1 H NMR (400 MHz, CDCl 3 ) δ 8.21(s,2H), 7.97(br.s.,1H), 7.78(t,J=6.6Hz,2H), 7.16(t,J=8.3Hz,2H), 5.24(s, 2H), 4.22(d,J=6.8Hz,2H), 3.16(br.s.,2H), 2.80~2.65(m,2H), 2.59(s,3H);LC-MS: m / z[M+H] + =392.

[0266] Example 4 7-Cyclobutyl-3-(5-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyrazin-2-yl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one [ka]

[0267] Method D 4-((5-(7-Cyclobutyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (100 mg, 0.22 mmol, intermediate 25) was dissolved in a mixture of chloroform (1 mL), acetonitrile (1 mL) and water (2 mL), to which sodium periodate (141 mg, 0.66 mmol) and ruthenium dioxide hydrate (7 mg, 0.044 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. After adding water (4 mL) to the reaction solution, it was extracted three times with dichloromethane (3 mL), and the organic phases were combined and filtered through diatomaceous earth. The filtrate was then dried, concentrated, and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a white solid (19 mg, yield 18%), which was named Compound 4. 1 H NMR (400 MHz, CDCl 3 ) δ 9.22(br.s.,1H), 8.25(br.s.,1H), 7.78(br.s.,2H), 7.18(br.s.,2H), 5.38(br.s.,2H), 5.22(br.s.,1H), 4.8 2(br.s.,2H), 3.82(br.s.,2H), 2.62(br.s.,3H), 2.30(br.s.,2H), 2.18(br.s.,2H), 1.80(br.s.,2H);LC-MS: m / z[M+H] + =476.

[0268] Example 5 3-(4-Fluorophenyl)-5-methyl-4-((5-(7-(tetrahydrofuran-3-yl)-5,6,7,8-tetrahydrofuran-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)isoxazole [ka]

[0269] Method E 3-(4-Fluorophenyl)-5-methyl-4-(((5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)isoxazole (100 mg, 0.245 mmol, intermediate 23) was dissolved in methanol (10 mL), to which was added dihydro-3(2H)-furanone (63 mg, 0.73 mmol), and the mixture was stirred at room temperature for 30 minutes, after which sodium cyanoborohydride (46 mg, 0.73 mmol) was added, followed by heating the mixture to 60° C. and stirring overnight. The mixture was then purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a white solid (41 mg, 35% yield), which was named compound 5. 1 H NMR (400 MHz, CDCl 3 ) δ 9.09(s,1H), 8.22(s,1H), 7.78(t,J=6.1Hz,2H), 7.18(t,J=8.1Hz,2H), 5.35(s,2H), 4.49(br.s.,2H), 4.14~4.01(m,2H), 4.01~3.89(m,2H) , 3.89~3.69(m,2H), 3.33(br.s.,1H), 2.99(br.s.,1H), 2.92(br.s.,1H), 2.61(s,3H), 2.19(d,J=6.8Hz,1H), 1.99(d,J=6.8Hz,1H);LC-MS: m / z[M+H] + =478.

[0270] Example 6 (S)-8-(5-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyrazin-2-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one [ka]

[0271] Method F 4-(((5-bromopyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (50 mg, 0.135 mmol, intermediate 5), cesium carbonate (110 mg, 0.34 mmol), (S)-hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one hydrochloride (46 mg, 0.24 mmol, intermediate 63), 2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl (13 mg, 0.027 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) mesylate (23 mg, 0.027 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction mixture was heated to 110° C. under argon atmosphere and stirred overnight. The mixture was filtered through diatomaceous earth, and after adding saturated ammonium chloride solution to the filtrate, the filtrate was extracted three times with ethyl acetate, followed by combining the organic phases, drying, concentrating, and purifying by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a light yellow solid (8 mg, 7% yield), which was named compound 6. 1 H NMR (400 MHz, CDCl 3 ) δ 7.88(s,1H), 7.84~7.76(m,2H), 7.74(s,1H), 7.16(t,J=8.3Hz,2H), 5.84(br.s.,1H), 5.16(s,2H), 4.44(d,J=11.2Hz,1H), 4.16(d, LC-MS: m / z[M+H] + =439.

[0272] Example 7 3-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazine 7,7-dioxide [ka]

[0273] Method G 4-(((5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl)pyridin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole (280 mg, 0.9 mmol, intermediate 48), sodium tungstate (650 mg, 4.5 mmol), and hydrogen peroxide (620 mg, 4.8 mmol) were added to methanol (8 mL) and stirred for 2 hours. After filtering the reaction solution, the filtrate was concentrated and separated by preparative thin layer chromatography (petroleum ether / ethyl acetate=1 / 2) to obtain the title compound (30 mg, 17% yield), which was named Compound 7. 1 H NMR (400 MHz, CDCl 3 ) δ 8.45(s,1H), 7.91(d,J=8.8Hz,1H), 7.86~7.74(m,2H), 7.17(t,J=8.6Hz,2H), 6.95(d,J=8.3H z,1H), 5.32(s,2H), 4.73(s,2H), 4.57(t,J=5.4Hz,2H), 3.51(br.s.,2H), 2.60(s,3H);LC-MS: m / z[M+H] + =456.

[0274] Example 8 Method H 3-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-2-methoxypyridin-3-yl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine [ka]

[0275] 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-2-methoxynicotinohydrazine (500 mg, 1.34 mmol, intermediate 20) was added to toluene (50 mL), to which triethylamine (2 mL, 10.1 mmol) and 5-chloro-3,6-dihydro-2H-1,4-oxazine (240 mg, 2.01 mmol, intermediate 28) were added separately, and the mixture was stirred at 130° C. for 4 hours, followed by addition of saturated sodium bicarbonate solution until pH=10-11. The reaction solution was stirred at 100° C. for 16 hours, diluted with water (100 mL), and extracted twice with ethyl acetate (100 mL). The organic phases were then combined, dried, concentrated, and purified by column chromatography (dichloromethane / ethyl acetate=20 / 1) to obtain the title compound (5.2 mg), which was named compound 8. 1 H NMR (400MHz, CD 3 OD) δ 2.57(s,3H), 3.96(s,3H), 3.99(d,J=4.88Hz,2H), 4.05(d,J=4.88Hz,2H), 4.99(s,2H), 5.40(s,2H) , 6.55(d,J=8.32Hz,1H), 7.23(t,J=8.32Hz,2H), 7.70~7.78(m,2H), 7.80(d,J=8.32Hz,1H);LC-MS: m / z[M+H] + =438.

[0276] Example 9 3-(5-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyrazin-2-yl)-7,8-dihydro-1H,6H,9H-7,8a-methanopyrrolo[1',2':3.4]imidazo[1,2-c]pyrimidin-1-one [ka]

[0277] Method I 3-(4-Fluorophenyl)-5-methyl-4-(((5-(tributylstannyl)pyrazin-2-yl)oxy)methyl)isoxazole (200 mg, 0.35 mmol, Intermediate 61), 3-chloro-7,8-dihydro-1H,6H,9H-7,8a-methanopyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one (78 mg, 0.35 mmol, Intermediate 57) in 1,4-dioxane (4 mL) was added tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) and cuprous iodide (10 mg, 0.053 mmol) and the reaction mixture was refluxed and stirred overnight under argon atmosphere. After the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound as a pale yellow solid (12 mg, 7% yield), which was named Compound 9. 1 H NMR (400 MHz, CDCl 3 ) δ 9.33~9.24(m,1H), 8.27~8.19(m,1H), 7.87~7.74(m,2H), 7.22~7.12(m,2H), 6.64(s,1H), 5.35(br.s.,2H), 4. 22~4.05(m,2H), 3.60~3.43(m,2H), 3.14~3.04(m,1H), 2.60(s,3H), 2.14(br.s.,2H), 1.76(br.s.,2H);LC-MS: m / z[M+H] + =473.

[0278] Example 10 8-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one [ka]

[0279] Method J Under nitrogen protection, methyl 1-(2-aminoethyl)-4-(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridazin-3-yl)piperazine-2-carboxylate (200 mg, 0.43 mmol, intermediate 62) was dissolved in methanol (50 mL), to which triethylamine (0.44 g, 4.3 mmol) was added, and the reaction mixture was stirred at 60° C. for 1 hour. The reaction solution was quenched with water (60 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered, after which the filtrate was concentrated under reduced pressure. The residue was then purified by column chromatography (dichloromethane / methanol=20 / 1) to give the title compound (25 mg), which was named as compound 10. 1 H NMR(400MHz,DMSO-d6) δ 7.78-7.75(m,3H), 7.39-7.34(m,3H), 7.03(d,J=9.6Hz,1H), 5.28(s,2H), 4.47-4.45(m,1H), 4.04-4.01(m,1H), 3.35-3.32 LC-MS: m / z[M+H] + =439.

[0280] The compounds in the following table were prepared according to the method of Example 1 (Method A), except that the starting materials in the "Starting Materials" column were used in place of 3-(6-fluoropyridin-3-yl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine in Example 1 in the same molar amounts.

[0281] [Table 11] TIFF2025510390000111.tif188165TIFF2025510390000112.tif92161

[0282] Compound 11:1 H NMR (400MHz)CDCl 3 : δ 8.35(d,J=8.8Hz,1H), 7.81~7.68(m,2H), 7.22~7.06(m,3H), 5.47(s,2H) , 5.33(s,2H), 4.54(t,J=4.9Hz,2H), 4.18(t,J=4.9Hz,2H), 2.59(s,3H). LC-MS: m / z[M+H] + =409. Compound 12: 1 H NMR (400MHz)CDCl 3 : δ 8.97(s,1H), 8.19(s,1H), 7.87~7.68(m,2H), 7.17(t,J=8.6Hz,2H), 5.31(s, 2H), 5.21(s,2H), 4.51(t,J=4.6Hz,2H), 4.15(t,J=4.9Hz,2H), 2.61(s,3H). LC-MS: m / z[M+H] + =409. Compound 17: 1 H NMR (400MHz)CDCl 3 : δ 8.51(s,1H), 8.01(d,J=8.8Hz,1H), 7.88~7.71(m,2H), 7.17(t,J=8.3Hz,2H), 6.93(d,J=8.8 Hz,1H), 5.32(s,2H), 5.09(s,2H), 4.14(d,J=4.9Hz,2H), 4.09(d,J=4.9Hz,2H), 2.61(s,3H). LC-MS: m / z[M+H] + =408. Compound 18: 1 H NMR (400MHz)CDCl 3 : δ 8.46(d,J=9.3Hz,1H), 7.81~7.65(m,2H), 7.21~7.09(m,3H), 5.50(s,2H) , 5.11(s,2H), 4.69(t,J=4.9Hz,2H), 4.11(t,J=4.9Hz,2H), 2.61(s,3H). LC-MS: m / z[M+H] + =409. Compound 19: 1 H NMR (400MHz)CDCl 3: δ 9.11(s,1H), 8.23(s,1H), 7.85~7.71(m,2H), 7.18(t,J=8.6Hz,2H), 5.35(s,2H), 5.08(s,2H), 4.53(br.s.,2H), 4.08(br.s.,2H), 2.61(s,3H). LC-MS: m / z[M+H] + =409. Compound 20: 1 H NMR (400MHz)CDCl 3 : δ 8.37(s,1H), 7.93~7.72(m,3H), 7.16(t,J=8.3Hz,2H), 6.92(d,J=8.8Hz,1H), 5.31(s, 2H), 4.92(s,2H), 4.27~4.15(m,2H), 4.15~4.06(m,2H), 2.60(s,3H), 2.04(br.s.,2H). LC-MS: m / z[M+H] + =422. Compound 21: 1 H NMR (400MHz)CDCl 3 : δ 8.44(d,J=8.8Hz,1H), 7.80~7.66(m,2H), 7.22~7.08(m,3H), 5.50(s,2H), 5.1 4~4.98(m,2H), 4.94(s,2H), 4.22~4.02(m,2H), 2.60(s,3H), 2.10(br.s.,2H). LC-MS: m / z[M+H] + =423. Compound 22: 1 H NMR (400MHz)CDCl 3 : δ 8.40(d,J=9.3Hz,1H), 7.73(dd,J=5.1,8.6Hz,2H), 7.20~7.05(m,3H), 5.49(s,2H) , 4.50(t,J=7.3Hz,2H), 3.09(t,J=7.6Hz,2H), 2.86(t,J=7.3Hz,2H), 2.60(s,3H). LC-MS: m / z[M+H] + =393. Compound 23: 1 H NMR (400MHz)CDCl 3: δ 9.07(s,1H), 8.21(s,1H), 7.85~7.67(m,2H), 7.17(t,J=8.6Hz,2H), 5.34(s,2H ), 4.36(t,J=7.1Hz,2H), 3.05(t,J=7.1Hz,2H), 2.92~2.73(m,2H), 2.60(s,3H). LC-MS: m / z[M+H] + =393. Compound 24: 1 H NMR(400MHz)DMSO-d6: δ 8.83(s,1H), 8.45(s,1H), 7.78(d,J=5.4Hz,2H), 7.37(t,J=8.1Hz,2H), 5.3 9(s,2H), 4.82(s,2H), 4.64(m,2H), 3.99(s,2H), 2.60(m,3H), 1.89(m,2H). LC-MS: m / z[M+H] + =423. Compound 25: 1 H NMR (400MHz)CDCl 3 : δ 8.45(s,1H), 7.98(d,J=8.6Hz,1H), 7.78(t,J=12Hz,2H), 7.15(t,J=8.3Hz,2H), 6.89(d,J=8.7 Hz,1H), 5.28(s,2H), 4.52~4.49(m,2H), 4.12(t,J=5.9Hz,2H), 2.59(s,3H), 2.27~2.24(m,2H). LC-MS: m / z[M+H] + =408. Compound 28: 1 H NMR (400MHz)CDCl 3 : δ 8.43(br.s.,1H), 7.93(d,J=8.3Hz,1H), 7.84~7.76(m,2H), 7.16(t,J=8.3Hz,2H), 6.94(br.s.,1 H), 6.86(d,J=8.3Hz,1H), 5.28(s,2H), 4.95(s,2H), 4.22~3.91(m,4H), 2.69~2.52(m,3H); LC-MS: m / z[M+1] + =407. Compound 32: 1H NMR(400MHz)DMSO-d6: δ 8.84(s,1H), 8.40(s,1H), 7.84~7.71(m,2H), 7.35(t,J=8.6Hz,2H), 5.43~5.29(m, 2H), 4.26(t,J=5.4Hz,2H), 2.91(t,J=6.1Hz,2H), 2.57(s,3H), 1.98~1.76(m,4H). LC-MS: m / z[M+H] + =407. Compound 33: 1 H NMR(400MHz)DMSO-d6: δ 8.80(s,1H), 8.41(s,1H), 7.81~7.71(m,2H), 7.35(t,J=8.6Hz,2H), 5.36( s,2H), 4.60(br.s.,2H), 3.79(br.s.,4H), 3.19(br.s.,2H), 2.57(s,3H). LC-MS: m / z[M+H] + =423. Compound 42: 1 H NMR (400MHz) CD 3 OD: δ 2.53(s,3H), 2.74(s,3H), 4.02(t,J=4.88Hz,2H), 4.25(t,J=5.12Hz,2H), 5.0 3(s,2H), 5.36(s,2H), 7.19(t,J=8.56Hz,2H), 7.61~7.76(m,2H), 8.27(s,1H). LC-MS: m / z[M+H] + =423. Compound 43: 1 H NMR (400MHz) CD 3 OD: δ 2.39(s,3H), 2.57~2.69(m,3H), 3.91(d,J=4.40Hz,2H), 4.05(d,J=4.40Hz,2H), 5.00(s,2H), 5.33~5.43 (m,2H), 6.79(d,J=8.32Hz,1H), 7.25(t,J=8.32Hz,2H), 7.72(d,J=8.32Hz,1H), 7.83(t,J=6.12Hz,2H). LC-MS: m / z[M+H] + =422. Compound 50: 1H NMR(400MHz)DMSO-d6: δ 8.52(d,J=2.5Hz,1H), 8.08(dd,J=8.9,2.7Hz,1H), 7.86~7.73(m,2H), 7.37(t,J=8.9Hz,2H), 7.08(d ,J=8.8Hz,1H), 5.34(s,2H), 4.78(s,2H), 3.89(t,J=5.5Hz,2H), 2.92(t,J=5.4Hz,2H), 2.59(s,3H). LC-MS: m / z[M+H] + =408.

[0283] The compounds in the following table were prepared according to the method of Example 2 (Method B), except that the starting material in the "Starting Material" column was used in place of 3-bromo-7-methyl-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one in Example 2 in the same molar amounts.

[0284] [Table 12]

[0285] Compound 13: 1 H NMR(400MHz)CDCl 3 : δ 8.49(br.s.,1H), 8.04(d,J=8.3Hz,1H), 7.79(br.s.,2H), 7.17(t,J=8.1Hz,2H), 6.95(d,J=8.3Hz,1H) , 5.32(s,2H), 4.37(br.s.,2H), 3.80(br.s.,2H), 3.72(d,J=6.8Hz,2H), 2.60(s,3H), 1.34(br.s.,3H). LC-MS: m / z[M+H] + =449. Compound 30: 11H NMR (400 MHz) in DMSO-d6: δ 8.53 (br.s., 1H), 8.07 (br.s., 1H), 7.79 (br.s., 2H), 7.37 (d, J = 5.9 Hz, 2H), 7.01 (br.s., 1H), 5.33 (br.s., 2H), 4.95 (br.s., 1H), 4.83 (br.s., 1H), 4.20 (br.s., 1H), 4.10 (br.s., 1H), 3.86 (br.s., 2H), 2.58 (d, J = 4.4 Hz, 3H), 2.15 (br.s., 3H). LC-MS: m / z [M+H] + = 449. Compound 31: 1 1H NMR (400 MHz) in DMSO-d6: δ 8.56 (br.s., 1H), 8.11 (d, J = 6.8 Hz, 1H), 7.80 (br.s., 2H), 7.42 - 7.30 (m, 2H), 7.02 (d, J = 8.3 Hz, 1H), 5.33 (br.s., 2H), 4.64 (br.s., 2H), 4.26 (br.s., 2H), 3.64 (br.s., 2H), 3.11 (br.s., 3H), 2.59 (br.s., 3H). LC-MS: m / z [M+H] + = 485. Compound 38: 1 1H NMR (400 MHz) in DMSO-d6: δ 8.85 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.79 (t, J = 6.6 Hz, 2H), 7.35 (t, J = 8.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 5.32 (s, 2H), 4.71 (s, 1H), 4.35 (d, J = 12.2 Hz, 1H), 4.01 (d, J = 12.7 Hz, 1H), 3.93 - 3.86 (m, 2H), 3.43 (s, 2H), 2.58 (s, 3H), 1.89 (q, J = 9.9 Hz, 2H). LC-MS: m / z [M+H] + = 488. Compound 39: 1 1H NMR (400 MHz) in CDCl 3: δ 8.81(s,1H), 8.33(d,J=8.3Hz,1H), 7.87~7.76(m,2H), 7.15(t,J=8.6Hz,2H), 6.82(d,J=8.8Hz,1H), 5.98(s,1H) , 5.29(s,2H), 4.11(s,2H), 3.48(s,2H), 3.09(br.s.,1H), 2.60(s,3H), 2.15(br.s.,2H), 1.76(d,J=3.9Hz,2H). LC-MS: m / z[M+H] + =472. Compound 41: 1 H NMR(400MHz)DMSO-d6: δ 8.81(s,1H), 8.28(d,J=8.8Hz,1H), 7.82~7.74(m,2H), 7.35(t,J=8.8Hz,2H), 6.88(d,J=8.3Hz,1 H), 6.22(s,1H), 5.29(s,2H), 3.97(t,J=8.6Hz,2H), 3.68~3.61(m,2H), 2.97(s,3H), 2.56(s,3H). LC-MS: m / z[M+H] + =434.

[0286] The compounds in the following table were prepared according to the method of Example 3 (Method C), except that the starting materials in the "Starting Materials" column were used in place of 3-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazole in Example 3 in the same molar amounts.

[0287] [Table 13]

[0288] Compound 44: 1 H NMR(400MHz)CD 3OD: δ 2.51~2.65(m,3H), 4.13(br.s,2H), 4.19(br.s,2H), 5.12(br.s,2H), 5.33(br.s.,2H), 7 .24(t,J=8.08Hz,2H), 7.80(br.s,2H), 8.00(br.s,1H), 8.19(br.s,1H), 8.43(br.s,1H). LC-MS: m / z[M+H] + =408.

[0289] The compounds in the following table were prepared according to the method of Example 4 (Method D), except that the starting material in the "Starting Material" column was used in place of 4-((5-(7-cyclobutyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole in Example 4 in the same molar amounts.

[0290] [Table 14]

[0291] Compound 14: 1 H NMR(400MHz)CDCl 3 : δ 8.60~8.48(m,1H), 7.73(br.s.,2H), 7.22~7.11(m,3H), 5.53~5.47(m,2H), 5.05~4.95(m,2H), 3.90~3.80(m,2H), 3.29~3.23(m,3H), 2.63~2.58(m,3H). LC-MS: m / z[M+H] + =436. Compound 26: 1 H NMR(400MHz)CDCl 3 : δ 8.95(s,1H), 8.08(s,1H), 7.81~7.73(m,2H), 7.17(t,J=8.4Hz,2H), 5.31(s,2H), 4.59(d,J=7.8Hz,4H), 2.60(s,3H). LC-MS: m / z[M+H] + =490. Compound 36: 1H NMR(400MHz)DMSO-d6: δ 8.00(d,J=9.3Hz,1H), 7.82~7.73(m,2H), 7.40~7.30(m,3H), 5.43(s,2H) , 4.46(d,J=5.4Hz,2H), 4.33(d,J=5.9Hz,2H), 2.58(s,3H), 2.45(s,3H). LC-MS: m / z[M+H] + =436. Compound 37: 1 H NMR(400MHz)DMSO-d6: δ 7.99(d,J=9.8Hz,1H), 7.78(t,J=6.6Hz,2H), 7.51(s,1H), 7.39~7.26(m,3H), 7.22(s,1H), 5.42(s,2H), 4.43(br.s.,4H), 2.58(s,3H). LC-MS: m / z[M+H] + =421.

[0292] The compounds in the following table were prepared according to the method of Example 5 (Method E) except that the dihydro-3(2H)-furanone of Example 5 was replaced by the same molar amounts of the starting material in the "Starting Material" column.

[0293] [Table 15]

[0294] Compound 15: 1 H NMR(400MHz)CDCl 3 : δ 9.08(br.s.,1H), 8.21(br.s.,1H), 7.77(br.s.,2H), 7.22~7.09(m,2H), 5.34(br.s.,2H), 4.78(br .s.,2H), 4.67(br.s.,2H), 4.51(br.s.,2H), 3.84(br.s.,3H), 2.83(br.s.,2H), 2.60(br.s.,3H). LC-MS: m / z[M+H] + =464. Compound 16: 1 H NMR(400MHz)CDCl 3: δ 9.08(s,1H), 8.22(s,1H), 7.78(d,J=6.4Hz,2H), 7.17(t,J=8.3Hz,2H), 5.34(s,2H) ), 4.49(br.s.,2H), 3.89(br.s.,2H), 2.89(br.s.,2H), 2.56(s,3H), 2.60(s,3H). LC-MS: m / z[M+H] + =422.

[0295] The compounds in the following table were prepared according to the method of Example 6 (Method F), except that 4-(((5-bromopyrazin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole and (S)-hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one hydrochloride were replaced with the same molar amounts of starting material 1 and the same molar amounts of starting material 2, respectively, in the "Starting Material" column.

[0296] [Table 16]

[0297] Compound 27: 1 H NMR(400MHz)CDCl 3 : δ 7.90(s,1H), 7.77(dd,J=8.5,5.4Hz,2H), 7.73(s,1H), 7.15(t,J=8.5Hz,2H), 5.17(s, 2H), 4.76(s,2H), 4.07~4.04(m,2H), 4.00(d,J=5.3Hz,2H), 2.56(s,3H), 2.44(s,3H). LC-MS: m / z[M+H] + =422. Compound 34: 1 H NMR(400MHz)DMSO-d6: δ 7.80~7.72(m,2H), 7.62(d,J=9.8Hz,1H), 7.34(t,J=8.6Hz,2H), 7.13(d,J=9 .8Hz,1H), 5.28(s,2H), 4.82(s,2H), 3.98(s,4H), 2.54(s,3H), 2.29(s,3H). LC-MS: m / z[M+H] + =422. Compound 35: 1 H NMR(400MHz)DMSO-d6: δ 7.81~7.69(m,2H), 7.58~7.52(m,1H), 7.34(t,J=8.6Hz,2H), 7.20~7.09(m,2H), 6.94(s, 1H), 5.28(s,2H), 4.74(s,2H), 4.10(d,J=4.4Hz,2H), 4.00(d,J=4.9Hz,2H), 2.54(s,3H). LC-MS: m / z[M+H] + =407. Compound 40: 1 H NMR (400MHz) CD 3 OD: δ 7.89~7.70(m,4H), 7.33~7.12(m,2H), 5.33~5.13(m,2H), 4.05(d,J=12.2Hz,1H), 3.93(d,J=11.7Hz,1H), 3.89~3.75(m,2H ), 3.70(t,J=10.8Hz,1H), 3.23~3.12(m,1H), 3.04~2.85(m,2H), 2.85~2.72(m,1H), 2.63~2.52(m,3H), 2.50~2.32(m,4H). LC-MS: m / z[M+H] + =426. Compound 45: 1 H NMR (400MHz) CD 3 OD: δ 2.60(s,3H), 4.33(br.s,2H), 4.58(br.s,2H), 5.36(s,2H), 6.28(br.s,1H), 6.93~ 7.06(m,2H), 7.25(t,J=8.56Hz,2H), 7.74~7.85(m,2H), 8.10(s,1H), 8.65(s,1H). LC-MS: m / z[M+H] + =420. Compound 46: 1 H NMR (400MHz) CD 3 OD: δ 2.17(s,3H), 2.58(s,3H), 3.96~4.02(m,2H), 4.05~4.12(m,2H), 4.60(s,2H), 5.24(s ,2H), 6.76(s,1H), 7.24(t,J=8.56Hz,2H), 7.77~7.84(m,2H), 7.89(d,J=3.42Hz,2H). LC-MS: m / z[M+H] +=421. Compound 48: 1 H NMR(400MHz)CDCl 3 : δ 7.91(s,1H), 7.83~7.73(m,2H), 7.71(s,1H), 7.16(t,J=8.3Hz,2H), 7.09(s,1H), 6.91(s, 1H), 5.17(s,2H), 4.68(s,2H), 4.14(d,J=4.9Hz,2H), 4.06(d,J=4.9Hz,2H), 2.57(s,3H). LC-MS: m / z[M+H] + =407. Compound 49: 1 H NMR(400MHz)DMSO-d6: δ 7.80~7.72(m,2H), 7.42~7.30(m,3H), 7.04(d,J=9.6Hz,1H), 5.27(s,2H), 4.08~4.05(m,1H), 3.98~3.95(m,1H), 3.76~3.70(m,2H), 3.55~3 .50(m,1H), 3.17~3.13(m,1H), 2.92~2.86(m,1H), 2.81-2.78(m,1H), 2.67~2.65(m,1H), 2.54(s,3H), 2.44~2.38(m,1H), 2.26~2.11(m,3H). LC-MS: m / z[M+H] + =426.

[0298] The compounds in the following table were prepared according to the method of Example 7 (Method G), except that the starting material in the "Starting Material" column was used in place of 4-(((5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]thiazin-3-yl)pyridin-2-yl)oxy)methyl)-3-(4-fluorophenyl)-5-methylisoxazole in Example 7 in the same molar amount.

[0299] [Table 17]

[0300] Compound 29: 1H NMR(400MHz)DMSO-d6: δ 8.30(d,J=9.3Hz,1H), 7.81~7.73(m,2H), 7.45(d,J=9.3Hz,1H), 7.36(t,J=8.8Hz,2 H), 5.52(s,2H), 5.04(s,2H), 4.94(t,J=5.9Hz,2H), 3.94~3.84(m,2H), 2.60(s,3H). LC-MS: m / z[M+H] + =457.

[0301] The compounds in the following table were prepared according to the method of Example 8 (Method H), except that the starting material in the "Starting Material" column was used in place of 6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)-2-methoxynicotinohydrazine in Example 8 in the same molar amounts.

[0302] [Table 18]

[0303] Compound 51: 1 H NMR(400MHz)CD 3 OD: δ 7.56(dd,J=5.4,8.8Hz,2H), 7.19(t,J=8.8Hz,2H), 7.12(d,J=5.9Hz,2H), 5.23(s,2 H), 4.98(s,2H), 4.07~4.02(m,2H), 3.88(t,J=4.9Hz,2H), 3.85(s,3H), 2.59(s,3H). LC-MS: m / z[M+H] + =438.

[0304] The compounds in the following table were prepared according to the method of Example 9 (Method I) except that the starting material in the "Starting Material" column was used in place of 3-chloro-7,8-dihydro-1H,6H,9H-7,8a-methanopyrrolo[1',2':3,4]imidazo[1,2-c]pyrimidin-1-one in Example 9 in the same molar amounts.

[0305] [Table 19]

[0306] Example 47: 1 H NMR(400MHz)CDCl 3 : δ 9.05~8.94(m,1H), 8.35~8.22(m,1H), 7.87~7.70(m,2H), 7.23~7.12(m,2H), 6.85~6.72(m,1 H), 5.32(br.s.,2H), 4.18(br.s.,2H), 3.73(br.s.,2H), 3.12(br.s.,3H), 2.61(br.s.,3H). LC-MS: m / z[M+H] + =435.

[0307] I. Biological Experimental Methods: 1. Construction and subculture of cell lines The α, β, and γ subunits are fully functional GABA receptors. A In this example, human α5-GABA receptor is essential for its formation. A Receptor (containing α5β3γ2 subunits) and α2-GABA A A HEK293 cell line stably expressing the receptor (including α2β3γ2 subunits) was constructed and screened by liposome transfection method, respectively (Felgner, PL, et al., Proceedings of the National Academy of Sciences, 1987, 84: 7413-7417). The specific subunit protein sequences are as follows: α5 subunit (protein sequence can be found in GenBank Accession No.: NM_000810.3), α2 subunit (protein sequence can be found in GenBank Accession No.: NM_000807.4), β3 subunit (protein sequence can be found in GenBank Accession No.: NM_000814.5), γ2 subunit (protein sequence can be found in GenBank Accession No.: NM_000816.3).

[0308] The above cell lines were subcultured. α5β3γ2-HEK293 cells and α2β3γ2-HEK293 cells were amplified to express GABA A The affinity of the compounds for the benzodiazepine site of the receptor (BZD) was tested. During the passage of α5β3γ2-HEK293 cells, a portion of the suspended cells was plated on a poly-D-lysine pretreated glass slide for electrophysiological testing.

[0309] 2. α5-GABA A Receptors and α2-GABA A Affinity activity of the compounds of the present invention for receptors Flunitrazepam is a non-specific agent that binds efficiently to the BZD site. The affinity of compounds for the BZD sites of human α5β3γ2 and α2β3γ2 receptors was compared with that of compounds for binding to these two receptors. 3 H-Flunitrazepam (isotope 3 H-labeled flunitrazepam) can be used to determine the level of

[0310] Membrane preparation: HEK293 cells stably expressing human α5β3γ2 or α2β3γ2 receptors were harvested, suspended in 50 mM Tris-HCl buffer (pH = 7.4), homogenized 10 times for 20 seconds on ice with a homogenizer, and centrifuged at 1,000 g for 10 minutes at 4°C. The supernatant was collected and the above steps were repeated. The supernatant was centrifuged for 60 minutes at 4°C (33,800 g; centrifuge purchased from Thermo, rotor model: A27-8x50), and the precipitate was resuspended in Tris buffer (50 mM Tris-HCl, 10 mM MgCl 2 The cells were resuspended in 0.5 mM EDTA, 10% glycerol (pH 7.0). The precipitate was the cell membrane. The protein content was determined by the BCA (bicinchoninic acid) method (BCA kit from Pierce (Annoron)). The cell membrane was prepared in 1 ml aliquots and stored at -80°C.

[0311] Radioligand competitive binding assay: The assay was performed in a 200 μL system (Agilent 96-well plates) using 100 μL of membranes.3 The concentration of H-flunitrazepam (PerkinElmer, lot: NET567250 UC) was 1 nM, and the concentration of the test compound was 1 × 10 -5 M~1×10 -6 The concentrations ranged from 0.1 to 0.5 M. Flumazenil (Tocris; lot: 1318) was used as a control. 1 μL of 2 mM flumazenil (final concentration 10 μM) was added to low signal control wells (low control, LC) and 1 μL of DMSO (Sigma aldrich, lot: 472301) was added to high signal control wells (high control, HC). The final target membrane protein concentration was 5 μg / well. All test compound sample stocks were in 10 mM DMSO. The working concentrations of the samples were determined by diluting all samples to 0.2 mM in DMSO followed by 4-fold serial gradient dilutions for a total of eight concentration gradients. The 96-well plate was sealed with a plate seal membrane and then incubated at room temperature on a shaker for 1 hour. Meanwhile, the GF / C filter plate was soaked in plate soaking buffer (0.3% PEI, polyethyleneimine, purchased from Sigma aldrich, model: P314, stored at 4°C) for at least 0.5 hours. After completion of the binding incubation, cells were harvested onto GF / C filter plates with a cell collector and washed four times with plate wash buffer (50 mM Tris-HCl, pH 7.4, stored at 4°C). After drying for 1 h in a 50°C oven, the dried GF / C filter plates were bottom sealed with membranes and residual radioactivity on the filter membranes was detected by adding 50 μL of scintillation fluid per well, sealing, and eluting with a Microbeta 2 The GABA was detected by liquid scintillation counting using a microplate counter (purchased from PerkinElmer, model: CNLL0153) for reading. A Receptor membrane proteins 3 The inhibitory activity of the test samples against the binding of H-flunitrazepam was calculated, and the IC 50 was calculated by dose-effect curve fitting (GraphPad Prism 5 software), and the Ki (inhibition constant) of the sample was calculated as IC 50α5-GABA A Receptors and α2-GABA A The binding ability of the compounds to the BZD site of the receptor was evaluated.

[0312] 3. α5-GABA A Functional activity of the compounds of the present invention on receptors α5-GABA A The counterregulatory activity of the test drugs on the receptor was detected by electrophysiological methods. The specific method was as follows:

[0313] Setting of compound concentration: The final concentration of the compounds used in compound screening was 100 nM. The GABA concentration was 0.05 μM to 0.06 μM (approximate EC 7~8 Electrophysiological assays were performed using the whole-cell patch clamp technique and were performed as reported in the literature (Nickolls, SA, et al., British Journal of Pharmacology, 2018, 175: 708-725). The extracellular solution (ECS) components for electrophysiology were: 150 mM NaCl, 5 mM KCl, 2.5 mM CaCl. 2 , 1 mM MgCl 2 , 10 mM HEPES and 10 mM glucose (pH 7.4). The formulation of the electrode internal solution (ICS) for electrophysiology was: 140 mM CsCl, 11 mM EGTA, 10 mM HEPES, 2 mM CaCl 2 , 1 mM MgCl 2 , 4 mM MgATP, 2 mM TEA (pH 7.3). All the above reagents were purchased from Sigma Aldrich. GABA (γ-aminobutyric acid, Sigma Aldrich, Lot: A5385) powder was prepared in pure water to a stock solution and then diluted in ECS. Compounds were first prepared in DMSO to a 4 mM stock solution and then gradually diluted to the corresponding GABA-ECS concentration. All solutions were freshly prepared before electrophysiological testing.

[0314] Acquisition of electrophysiological signals was performed using an EPC 10 amplifier and PatchMaster software (HEKA) or an Axon 700 B amplifier and Clampex software (AXON). Recording electrodes were made by stretching borosilicate glass (purchased from Sutter) and had an electrode resistance of 4 MΩ to 6 MΩ. Extracellular administration was performed using an ALA-VC-8PG (purchased from ALA, USA) system. Single, independently grown cells were selected and lysed after a good seal was formed between the glass electrode and the cell, forming a whole-cell mode. The cell membrane potential was clamped at -60 mV and recordings were performed in gap-free mode. For the test, extracellular solution was first applied extracellularly for approximately 20 seconds. Baseline (I prebaseline After stabilization of the extracellular fluid (ECS), the extracellular fluid was switched to GABA-ECS. At this point, the GABA-induced current (I gaba After stabilization of the currents in about 20 to 40 seconds, the currents induced by both the compound and GABA (I treatment The extracellular solution was switched to a mixed solution of compound and GABA-ECS until a current level (I ) could be detected. Finally, the solution was switched back to the extracellular solution, and the test was terminated after recording for 20 to 40 seconds. The baseline was stabilized and the absolute control current level (I gaba -I prebaseline ) was greater than 40 pA and only cells with relatively stable currents within 10 to 20 seconds were used for compound testing.

[0315] The experimental results were analyzed using PatchMaster v2x90.1 or PatchMaster v2x90.3 software (EPC 10 amplifier) ​​and Clampex 10.6 software (Axon 700B amplifier). The current value of each step was calculated according to the average value of the current stabilized under the corresponding conditions. The control current was I gaba -I prebaseline and the current after compound treatment is defined as I treatment -I prebaseline The counterregulatory activity of a compound was expressed as a percentage and was calculated using the following formula: Counterregulatory Efficiency=[(I treatment -I gaba) / (I gaba -I prebaseline )] × 100%.

[0316] [Table 20] TIFF2025510390000122.tif239153TIFF2025510390000123.tif232150TIFF2025510390000124.tif239155TIFF2025510390000125.tif247156

[0317] The results show that the compounds of the present invention inhibit α5-GABA A It was shown to have good affinity and counter-regulatory activity for the receptor.

[0318] [Table 21] TIFF2025510390000127.tif217159TIFF2025510390000128.tif137163

[0319] Compared to the comparative compounds, the compounds of the present invention have a higher α5-GABA A It has good receptor subunit selectivity and is effective against α2-GABA A It has a good safety profile with fewer potential side effects caused by adverse receptor regulation.

[0320] II. Solubility and Stability of Compounds of the Invention in Simulated Gastric Fluid (SGF) 1. Thermodynamic solubility of compounds in artificial intestinal fluid (1) Experimental materials and equipment: 50 mM phosphate buffer, pH=7.4: 0.39 g NaH 2 PO 4 2H 2 O, 1.4025g Na 2 HPO 4was weighed, placed in an Erlenmeyer flask, dissolved by adding 240 ml of water, mixed homogeneously, adjusted to pH 7.4 with 10 M NaOH solution, transferred to a 250 ml measuring flask, and diluted in a fixed ratio with water.

[0321] Simulated intestinal fluid FaSSIF: 54.76 mg of FaSSIF-V2 (Biorelevant, batch V2FAS-0619-A, lot V2FAS01) was weighed and added to 15 ml of buffer, and after dissolution the solution was made up to 30 ml and allowed to stand at room temperature for 1 hour before use.

[0322] Waters e2695 HPLC high performance liquid chromatography, Mettler XSE105 analytical balance.

[0323] (2) Experimental method: Stock solutions containing 10 mM of each test compound were formulated with DMSO and diluted to standard curve solutions of 1 M to 200 M with diluent (ACN:PB buffer in a 50:50 volume ratio) and tested by HPLC to obtain standard curves of concentration vs. peak area for each test compound.

[0324] Thermodynamic solubility in simulated intestinal fluid (TS in FaSSIF). Approximately 0.3mg of each sample (test compound) was weighed, and two samples were added in parallel to 1.5mL of FaSSIF solution, shaken at 1,000rpm and 37℃ for 4 hours, filtered, discarded 1mL of the first filtrate, and then took 400μL of the subsequent filtrate and tested by high performance liquid chromatography (UV). The test results of the compounds of the present invention are shown in the following table.

[0325] [Table 22] TIFF2025510390000130.tif152153

[0326] Compared with the comparative compounds, the compounds of the present invention have better solubility and are more suitable for oral drug development and oral absorption.

[0327] 2. Compound stability in simulated gastric fluid (SGF) (1) Reagents Simulated Gastric Fluid (SGF), Manufacturer: Dongguan Chuangfeng Automation Technology Co., Ltd.; Product Model: CF-006. (2)Equipment Vibrating constant temperature metal bath, model: Thermo; manufacturer: Digital Skaking Drybath. (3) Test conditions Temperature: 37°C; rotation speed: 1,000 rpm; sampling time: 0, 4 h. (4) Liquid-phase conditions Chromatography column: Welch Xtimate C18 3.0 x 100 mm, 5 μm. Mobile phase: A: 0.04% trifluoroacetic acid (TFA) / H 2 O (v / v), B: acetonitrile (ACN). Gradient elution was performed according to the following table: Flow rate: 1.0 mL / min; Injection volume: 5 μL; Column temperature: 35° C.; Wavelength: 254 nm.

[0328] [Table 23]

[0329] (5) Experimental procedure (a) 0.04% TFA / H 2 Preparation of HO: Measure 400 µL of TFA and add to 1 L of HO. 2 0 and mixed until homogeneous. (b) Sample stock solution: Approximately 3 mg of test sample was weighed out and prepared in DMSO to give a 10 mmol / L stock solution. (c) 50 μL of sample stock solution was taken and placed in a 5 mL volumetric flask, and SGF was added to make a fixed ratio and mixed homogeneously. Four samples were taken in parallel with 400 μL of solution and shaken at 1,000 rpm and 37°C. (d) After 0 and 4 hours respectively, duplicate samples were taken, 400 μL of acetonitrile was added, mixed homogeneously, followed by liquid phase injection, and the % change in the main peak area in the solution after 4 hours relative to 0 hours was calculated, with two average values ​​reported at each time point.

[0330] The test results for the compounds of the present invention are shown in the table below.

[0331] [Table 24] TIFF2025510390000133.tif226166TIFF2025510390000134.tif224166TIFF2025510390000135.tif177167

[0332] Compared with the comparative compounds, the compounds of the present invention have better stability in simulated gastric fluid and are more suitable for oral drug development and oral absorption.

[0333] Obviously, the above examples are only given to clarify the embodiments, rather than to limit them. Those skilled in the art can make other changes or modifications based on the above description. It is not necessary and impossible to list all the embodiments here. Any obvious changes or modifications obtained therefrom are also within the scope of protection of the present invention.

Claims

1. A compound represented by the following formula (I): or a pharma- ceutically acceptable salt, stereoisomer, tautomer, prodrug, amorphous form, isotopically substituted form, polymorph, or solvate thereof: 【Chemistry 1】 (In the formula, R １ is selected from phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with 1, 2 or 3 halogens; R ２ is selected from H, linear or branched C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 cycloalkyl; Ring A is selected from 5- to 10-membered heterocyclic groups containing 1, 2 or 3 ring heteroatoms selected from N, P, O or S; R ４ is selected from a fused group formed by a heterocycle and a heterocycle, the heterocycle forming the fused group being selected from a 5- to 10-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, P, O or S, the fused group being unsubstituted or substituted with one or more substituents, the substituents being optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted sulfonyl, or an optionally substituted heterocycle containing 1, 2 or 3 heteroatoms, the heteroatoms being selected from N, P, O or S; R ３ is selected from hydrogen, halogen, linear or branched C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl; m is selected from 0, 1 or 2.

2. 2. The compound according to claim 1, wherein ring A is selected from a 5- or 6-membered heterocyclic group containing 1, 2 or 3 nitrogen atoms as ring heteroatoms, preferably ring A is selected from pyridine, pyridazine, pyrazine, pyrimidine, piperidine or piperazine, more preferably ring A is selected from pyridine, pyridazine or pyrazine.

3. R ３ The compound of claim 1 , wherein is selected from hydrogen, methyl or methoxy.

4. 2. The compound according to claim 1, wherein m is 0 or 1, preferably 0.

5. R ４ The compound of claim 1 , wherein the compound has a structure represented by formula (II) or formula (III): 【Chemistry 2】 (In the formula, Ring B, ring C, and ring D are each independently selected from a 5- to 10-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, P, O, or S; R ５ , R ６ Or R ７ are each independently selected from oxo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted formyl, optionally substituted sulfonyl, or an optionally substituted heterocycle containing 1, 2 or 3 heteroatoms, said heteroatoms being selected from N, O, S, and preferably R ５ , R ６ Or R ７ are each independently selected from oxo, C1-C6 alkyl, C3-C8 cycloalkyl, formyl, sulfonyl, or a C3-C8 heterocycle containing 1, 2 or 3 heteroatoms, said heteroatoms being selected from N, O, S, wherein said alkyl, said cycloalkyl, said formyl, said sulfonyl, or said heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen or C1-C3 alkyl; n, j, and q are each independently selected from 0, 1, or 2.

6. The compound according to claim 5, wherein ring B is selected from a 5- to 7-membered heterocycle containing one, two or three nitrogen atoms as a heteroatom constituting the ring, preferably ring B is selected from triazole, pyrazole, imidazole, 6-membered cyclic lactam or diazacyclopentane, wherein the 6-membered cyclic lactam contains two nitrogen atoms as a heteroatom constituting the ring, more preferably ring B is selected from the following structures: 【Chemistry 3】

7. Ring C is selected from 5- to 7-membered heterocycles containing, as heteroatoms constituting the ring, 1 or 2 heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom, and preferably, Ring C is selected from the following 1) and 2): 1) pyrrole, imidazole, triazole or a 6-membered cyclic lactam, provided that the 6-membered cyclic lactam contains two nitrogen atoms as heteroatoms constituting the ring; 2) a 5- to 7-membered heterocycloalkane or heterocycloalkene containing, as heteroatoms constituting the ring, one or two heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom; and wherein the heterocycle is selected from the heterocycles described in any one of More preferably, ring C is 【Chemistry 4】 6. The compound of claim 5, selected from:

8. Ring D is selected from 5- to 7-membered heterocycles containing 1 or 2 heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom as heteroatoms constituting the ring, preferably selected from 5- to 7-membered bridged rings containing 1 nitrogen atom and 1 oxygen atom, or 5- or 6-membered bridged rings containing 1 nitrogen atom, more preferably selected from 【Chemistry 5】 6. The compound of claim 5, selected from:

9. R ７ is selected from C1-C6 alkyl, C3-C8 cycloalkyl, formyl substituted with C1-C3 alkyl, sulfonyl substituted with C1-C3 alkyl, C3-C6 heterocyclic group containing one O atom or one S atom, with the proviso that said alkyl, said cycloalkyl or said heterocyclic group is unsubstituted or substituted with one, two or three halogens, preferably R ７ Methyl, ethyl, -CF ３ , -COCH ３ , 【Chemistry 6】 8. The compound according to claim 5 or 7, selected from:

10. R ４ has the structure of formula (II), n is 0 or 1, and R ４ The compound of any one of claims 1 to 9, wherein when has the structure of formula (III), n is 0 or 1, and q is 0.

11. R １ A compound according to any one of claims 1 to 10, wherein is selected from phenyl substituted with one, two or three halogens.

12. R ２ The compound according to any one of claims 1 to 11, wherein is selected from H and linear or branched C1-C4 alkyl.

13. R １ but, 【Chemistry 7】 and R ２ The compound according to any one of claims 1 to 10, wherein is selected from methyl.

14. The compound is represented by the following formula (VI), formula (V), formula (IV) or formula (IIV): 【Chemistry 8】 and having a structure represented by R ３ is as defined in claim 1 or 3, and R ４ is as defined in any one of claims 1, 5, 6, 7, 8, 9.

15. The compound according to claim 1, wherein the compound is any one selected from the following compounds: 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】

16. A pharmaceutical composition comprising at least one of the compounds according to any one of claims 1 to 15, or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, isotopic substitution, polymorph, or solvate thereof, and a pharma- ceutically acceptable carrier and / or adjuvant.

17. α5-GABA Ａ Use of a compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, isotopically substituted form, polymorph or solvate thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for treating or preventing a disease associated with a receptor.

18. The following diseases: Depression, pain, Alzheimer's disease, multi-infarct dementia, stroke, anxiety disorder, generalized anxiety disorder, panic disorder, agoraphobia, post-traumatic stress disorder, premenstrual dysphoric disorder, fibromyalgia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, social anxiety disorder, autism, autistic disorder, schizophrenia, obesity, bulimia nervosa or anorexia nervosa, Tourette's syndrome, vasomotor flushing, sexual dysfunction, borderline personality disorder, chronic fatigue syndrome, Raynaud's syndrome, Parkinson's disease, epilepsy, or mood disorder following head trauma Use of a compound according to any one of claims 1 to 15, or a stereoisomer, tautomer, prodrug, pharma- ceutically acceptable salt, amorphous form, isotopically substituted form, polymorph or solvate thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament for the treatment or prevention of

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