miR-124 inducer, preparation method thereof and use thereof

Abstract

The present invention relates to a compound as represented by formula (1) and a method for preparing the same, as well as a composition comprising the compound as represented by formula (1) and / or a pharmaceutically acceptable salt thereof, a method for preparing the same and its use as a miR-124 inducer in the preparation of a medicament for the treatment of miR-124-mediated diseases. [63] TIFF2026506166000177.tif36170

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and more particularly to miR-124 inducers having the structure as shown in formula (1), as well as methods for their preparation and the use of compounds of this type in the preparation of pharmaceutical compositions for treating, regulating and / or preventing diseases associated with miR-124 mediation. [Background technology]

[0002] MicroRNAs (miRNAs) are a type of small RNA molecule approximately 20–24 nucleotides long that exert various important regulatory effects within cells. Each miRNA can have multiple target genes, and several miRNAs can regulate the same gene, forming a complex regulatory network. Such complex regulatory networks can regulate the expression of multiple genes via a single miRNA or precisely control the expression of a gene via a combination of several miRNAs. It is estimated that miRNAs regulate one-third of human genes. Although miRNAs account for only 2% of the total number of human genes, they regulate more than 30% of the genes in the human genome, making them a core component of the gene regulatory network [Stem Cells, 2013, 31:2205–2217]. miRNAs regulate processes such as cell proliferation, differentiation, and apoptosis in living organisms, and have important regulatory effects on individual growth and development, as well as the occurrence and progression of various diseases, including inflammation and tumors. Increasing research suggests that miRNAs are involved in the regulation of virtually all biological processes in living organisms [Trends Mol Med, 2014, 331:1-10].

[0003] MiR-124 is a highly conserved miRNA expressed in organisms ranging from Caenorhabditis elegans to humans. Current research suggests that the three human miR-124-encoding genes are located on 8p23.1, 8q12.3, and 20q13.33, respectively. The promoters of these genes all contain CpG islands, which, when methylated, can repress the miR-124-encoding genes [Oncogene, 2012, 31:1609-1622]. MiR-124 is the most abundant miRNA in the central nervous system, suggesting its close association with CNS injury and repair. Niina Vuokila et al. found that miR-124 long-term regulates the hippocampal gene expression network after brain injury, acting as a chronic regulator of gene expression after brain injury [Cell Mol Life Sci, 2018, 75:4557-4581]. MiR-124 may have great therapeutic potential in Alzheimer's disease. It is specifically overexpressed in the brain, and its expression levels were significantly reduced in the brains of Alzheimer's disease patients. MiR-124 influences synaptic plasticity, neuroinflammation, Aβ production, and tau phosphorylation by regulating the expression of various genes (e.g., BACE1, Caveolin-1, GSK-3β, PTPN1, DACT1, etc.). Furthermore, miR-124 has been found to be underexpressed in tumors such as brain tumors, gastric cancer, breast cancer, cervical cancer, and prostate cancer, suggesting that miR-124 has the potential to treat a variety of tumors.

[0004] In recent years, miR-124 has attracted considerable attention for its anti-inflammatory activity. ABX464 is a small molecule drug. Its effects, mediated by RNA splicing regulation, constitute potent anti-inflammatory and antiviral effects, and it also has the potential to reduce the AIDS virus reservoir. ABX464's anti-inflammatory activity is mediated by its binding to the target-point cap-binding complex, which is located at the 5' end of non-coding RNA molecules within cells. This binding triggers splicing of long non-coding RNAs, thereby inducing overexpression of the single microRNA product miR-124. miR-124 then initiates a cascade reaction, thereby producing potent anti-inflammatory effects [Retrovirology, 2015, 12:1-15]. ABX464 is currently being developed as a treatment for various inflammatory and viral diseases, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, AIDS, and novel coronavirus pneumonia. [ka] However, ABX464 still has drawbacks such as poor physicochemical properties and poor oral absorption, leaving significant room for improvement. Therefore, the development of novel miR-124 inducers with high activity, metabolic stability, and / or high safety is an urgent issue in the art. Summary of the Invention [Problem to be solved by the invention]

[0005] The object of the present invention is to provide a novel miR-124 inducer having high activity, metabolic stability and / or high safety, and a preparation method and application thereof. [Means for solving the problem]

[0006] A first aspect of the present invention provides a compound having a structure as shown in general formula (1), or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, [ka] In the formula: n is 0, 1, 2 or 3; Each R is a halogen, CN, nitro group, C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group or C 1-3 independently selected from the group consisting of halogenated alkoxy groups; R 1 are H, CN, and C 1-3 Alkyl group, C 1-3 selected from the group consisting of an alkoxy group or a halogen; A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, a 5- to 7-membered benzocycloalkyl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, benzocycloalkyl group, and benzoheterocyclic group are not halogen, CN, C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Halogenated alkoxy groups, C 1-3 may be further substituted with 0 to 4 groups selected from the group consisting of halogenated alkylthio groups or SF5; X is O and Y is C 1-3 Alkyl group, C 1-3 Halogenated alkyl group or C 3-6 a cycloalkyl group, or X and Y together with the atoms to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclic group, and the heteroaryl and heterocyclic groups are C 1-3 Alkyl group or C 1-3 It may be further substituted with 0 to 2 groups of halogenated alkyl groups.

[0007] In another preferred embodiment, R or R 1 contains at least one halogen atom.

[0008] In another preferred example, each R is independently selected from the group consisting of F, Cl, Br, Me, Et, OMe, OEt, CF3, CN, OCF3, or NO2.

[0009] In another preferred embodiment, R 1 is selected from the group consisting of H, CN, Me, Et, OMe, OEt, F, Cl or Br.

[0010] In another preferred embodiment, A is [ka] is selected from the group consisting of:

[0011] In another preferred embodiment, the compound has the structure shown in formula (1A): [ka] In the formula: n is 0, 1 or 2; R is a halogen, CN, nitro group, C 1-3 Alkyl group, C 1-3 Halogenated alkyl group or C 1-3 alkoxy groups; R 1 is a halogen, A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, and benzoheterocyclic group are not halogen, CN, C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Halogenated alkoxy groups, C 1-3 may be further substituted by 0 to 4 halogenated alkylthio groups or SF5 groups; X is O and Y is C 1-3Alkyl group, C 1-3 Halogenated alkyl group or C 3-6 a cycloalkyl group, or X and Y together with the atoms to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclic group, and the heteroaryl and heterocyclic groups are C 1-3 Alkyl group or C 1-3 It may be further substituted with 0 to 2 groups of halogenated alkyl groups.

[0012] In another preferred embodiment, [ka] wherein "*" indicates the position of attachment to the benzene ring.

[0013] In another preferred embodiment, the compound has a structure selected from the group consisting of: [ka] where n, Y, R, and R 1 and A are defined as in claim 1.

[0014] In another preferred embodiment, the compound has the structure shown in formula (1B): [ka] In the formula: [ka] represents a single or double bond, n is 1, 2 or 3; Each R is independently halogen, CN, or C 1-3 Alkyl group, C 1-3 Halogenated alkyl groups, C 1-3 Alkoxy group or C 1-3 halogenated alkoxy groups; R 1are H, CN, and C 1-3 Alkyl group or C 1-3 alkoxy groups; A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, a 5- to 7-membered benzocycloalkyl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, benzocycloalkyl group, and benzoheterocyclic group are not halogen, CN, C 1-3 Alkyl group, C 3-6 Cycloalkyl groups, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Halogenated alkoxy groups, C 1-3 It may be further substituted with 0 to 4 groups selected from the group consisting of halogenated alkylthio groups or SF5.

[0015] In another preferred embodiment, the compound has a structure shown in formula (2): [ka] where: [ka] represents a single or double bond, n is 0, 1 or 2; R 1 is selected from the group consisting of H, F, Cl or Br; Each R is independently selected from the group consisting of F, Cl, or Br.

[0016] In another preferred embodiment, A is [ka] is selected from the group consisting of:

[0017] In another preferred embodiment, R 1 When is H, n is 1 or 2.

[0018] In another preferred embodiment, the compound has a structure selected from the group consisting of: [ka] TIFF2026506166000014.tif231168TIFF2026506166000015.tif228168TIFF2026506166 000016.tif228168TIFF2026506166000017.tif230168TIFF2026506166000018.tif23216 8TIFF2026506166000019.tif223168TIFF2026506166000020.tif232168TIFF2026506166 000021.tif228169TIFF2026506166000022.tif223169TIFF2026506166000023.tif79169

[0019] A second aspect of the present invention provides a pharmaceutical composition for treating, regulating and / or preventing a disease associated with miR-124 mediation, said pharmaceutical composition comprising: (1) a compound according to the first aspect of the present invention as an active ingredient, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and and optionally (2) a pharmaceutically acceptable excipient or carrier.

[0020] A third aspect of the present invention provides a use of a compound according to the first aspect of the present invention, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used in the preparation of a pharmaceutical composition for treating, regulating and / or preventing a disease associated with miR-124 mediation.

[0021] In another preferred example, the miR-124-mediated disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, brain tumor, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, AIDS, Crohn's disease, ulcerative colitis, rheumatoid arthritis, allergic rhinitis, osteoarthritis, fibrotic diseases, AIDS, and / or novel coronavirus pneumonia.

[0022] A fourth aspect of the present invention provides a method for preparing a compound of formula (1), comprising the steps of: (1) reacting a compound of formula (A) and its tautomer in an inert solvent to obtain a compound of formula (B); [ka] (2) reacting a compound of formula (B) with a compound of formula (d) in an inert solvent to obtain a compound of formula (1); [ka] where Z is halogen or OTf, and X, Y, R, R 1 , A and n are as defined in claim 1.

[0023] In another preferred embodiment, the compound of formula (1) is a compound of formula (1a) or (1b), The method also includes the steps of: (s1) reacting a compound of formula (A1) and / or a tautomer thereof in an inert solvent to obtain a compound of formula (B1); [ka]

[0024] (s2) reacting the compound of formula (B1) with the compound of formula (d) in an inert solvent to obtain the target compound of formula (1a); [ka] In each formula, Z is halogen or OTf, and R, R1 , A and n are as defined in claim 1.

[0025] In another preferred embodiment, the method comprises the steps of: (t1) subjecting a compound of formula (C) to a cyclization reaction in an inert solvent to obtain a compound of formula (d); [ka] (t2) reacting a compound of formula (d) with a compound of formula (d) in an inert solvent to obtain the target compound of formula (1b); [ka] In each formula, Z is halogen or OTf, and R, R 1 , A and n are as defined in claim 1.

[0026] A fifth aspect of the present invention provides a method for treating, modulating and / or preventing a disease associated with miR-124 mediation, comprising administering to an individual in need thereof a compound according to the first aspect of the invention, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention.

[0027] In another preferred embodiment, the individual includes human and non-human mammals. [Effects of the Invention]

[0028] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief explanation of the drawings]

[0029] [Figure 1] FIG. 1 shows the changes in mouse body weight over time after administration of the drug to each test group. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present inventors have conducted extensive and thorough research, and through extensive screening and testing, have for the first time discovered a compound of formula (1), which has significant therapeutic effects on miR-124-mediated diseases. The compound of the present invention has a strong ability to induce miR-124 expression in PMA / IO-stimulated PBMC cells, and also has good pharmacokinetic properties. At the same time, the compound has significant in vivo activity and good drug discovery potential. Based on this, the present invention has been completed.

[0031] Compounds of the Invention and Their Synthesis The present invention provides an inducer of miR-124, i.e., a compound of formula (1), or an isomer, crystalline form, pharmaceutically acceptable salt (inorganic or organic salt), hydrate, or solvate thereof. Preferably, the compound of the present invention is as described in the first aspect.

[0032] The present invention further provides a method for preparing the compound of the present invention represented by formula (1). Hereinafter, the method for preparing the compound of the present invention represented by formula (1) will be specifically explained, but these specific methods do not limit the present invention in any way.

[0033] Meanwhile, the compounds described herein are prepared according to methods known in the art. However, the process conditions, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the following explanation. The compounds of the present invention can be easily prepared by arbitrarily combining various synthetic methods described herein or known in the art, and such combinations can be easily performed by those skilled in the art. Meanwhile, the present invention further provides a method for preparing the compounds represented by the general formula (1A) or general formula (1B), which are prepared using the following general reaction schemes 1 to 9.

[0034] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 1, where Z is halogen or OTf, and R, R 1 , Y, A and n are as defined above.

[0035] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 2, where L is halogen, Z is halogen or OTf, and R, R 1 , Y, A and n are as defined above.

[0036] [ka] Embodiments of compounds of general formula (1A) or general formula (1B) can be prepared according to Reaction Scheme 3, where L is halogen, X is N or CH, Z is halogen or OTf, and R 2 and R 3 is H, C 1-3 Alkyl group or C 1-3 R, R are independently selected from halogenated alkyl groups; 1 , A and n are as defined above.

[0037] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 4, where R 2 is H, C 1-3 Alkyl group or C 1-3 A halogenated alkyl group, R, R 1 , A and n are as defined above.

[0038] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 5, where R 2 and R 3 is H, C 1-3 Alkyl group or C 1-3 R, R are independently selected from halogenated alkyl groups; 1 , A and n are as defined above.

[0039] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 6, where L is halogen, Z is halogen or OTf, and R, R 1 , A and n are as defined above.

[0040] [ka] Embodiments of compounds of general formula (1) can be prepared according to Reaction Scheme 7, where L is halogen, Z is halogen or OTf, and R 2 is C 1-3 Alkyl group or C 1-3 A halogenated alkyl group, R, R 1 , A and n are as defined above.

[0041] [ka] Embodiments of compounds of general formula (1B) can be prepared according to Reaction Scheme 8, where L is halogen, Z is halogen or OTf, and R, R 1 , A and n are as defined above.

[0042] [ka] Embodiments of compounds of general formula (1B) can be prepared according to Reaction Scheme 9, where L is a halogen, Z is Cl or Br, PG is an amino protecting group such as Boc, Cbz, Bn, PMB, etc., and R, R 1 , A and n are as defined above.

[0043] Related Definitions Unless otherwise specified, the following terms and phrases used herein shall have the following meanings: A particular term or phrase should not be construed as unclear or ambiguous unless specifically defined, and should be understood according to its ordinary meaning. When a trade name is used herein, it refers to the corresponding product or its active ingredient.

[0044] As used herein, the term "pharmaceutically acceptable" refers to those 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, hypersensitivity reaction, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0045] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared by a compound having certain substituents discovered in this invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, trans-butenedioic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, as well as salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups, which allow them to be converted into either base or acid addition salts.

[0046] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a chemical amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0047] The compounds of the present invention can exist in particular geometric or stereoisomeric forms. The present invention includes all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemates and other mixtures thereof (e.g., enantiomerically and diastereomerically enriched mixtures), and all such mixtures are within the scope of the present invention. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present invention.

[0048] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0049] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" derive from the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0050] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer whose molecules have two or more centers of chirality and which do not have a mirror-image relationship between them.

[0051] Unless otherwise specified, "(D)" or "(+)" denotes dextrorotatory, "(L)" or "(-)" denotes levorotatory, and "(DL)" or "(±)" denotes racemic.

[0052] Unless otherwise specified, [ka]

[0053] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the difference in relative proportions of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0054] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, and the diastereomers can then be resolved and recovered by conventional methods known in the art to yield the pure enantiomers. Furthermore, separation of enantiomers and diastereomers is typically achieved using chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (e.g., forming carbamates from amines).

[0055] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14Compounds can be labeled with radioactive isotopes such as CI, ...

[0056] "Optional" or "optionally" means that the described event or circumstance may occur, but need not occur, and the description includes circumstances in which the event or circumstance occurs as well as circumstances in which the event or circumstance does not occur.

[0057] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, and the substituent can include both deuterium and hydrogen, as long as the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is oxygen (i.e., =O), it refers to the replacement of two hydrogen atoms. Oxygen substitution does not occur in aromatic groups. The term "optionally substituted" refers to either substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any based on chemical feasibility.

[0058] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0 to 2 R, that group may be optionally substituted with up to two R, and each occurrence of R is independently selected. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0059] When the number of one linking group is 0, such as -(CH2)0-, the linking group is a single bond.

[0060] When one of the variables is selected from a chemical bond, it indicates that the two linked groups are directly linked, for example, in XLY, when L represents a chemical bond, it indicates that the structure is actually XY.

[0061] Unless otherwise specified, C n-n+m or C n -C n+m includes any specific situation of n to n+m carbon atoms, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 and any range from n to n+m, e.g., C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 Similarly, n- to n+m-membered rings means that the number of atoms on the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered ring, and also includes any range of n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring.

[0062] Unless otherwise specified, "C 1-3 The term "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 The alkyl group is C 1-2 Alkyl groups and C 2-3 alkyl groups, which may be monovalent (e.g., methyl groups), divalent (e.g., methylene groups), or polyvalent (e.g., methine groups). 1-3Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, etc. In this application, the term "alkyl group" is intended to include substituted alkyl groups, i.e., alkyl groups substituted at one or more positions, particularly with 1 to 4 substituents at any position. A "halogenated alkyl group" refers to an alkyl group, as defined herein, in which one or more hydrogen atoms have been replaced with the same or different halogen atoms. Examples of halogenated alkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl groups (e.g., -CF3), etc.

[0063] Unless otherwise specified, "C 3-6 "Cycloalkyl group" refers to a saturated cyclic aliphatic hydrocarbon group of 3 to 6 carbon atoms, including monocyclic and bicyclic systems. 3-6 The cycloalkyl group is C 3-5 , C 4-5 and C 5-6 cycloalkyl groups, which may be monovalent, divalent or polyvalent. 3-6 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Cycloalkyl groups are optionally substituted with one or more substituents, where each substituent is independently a hydroxy group, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, an amino group, a monoalkylamino group, or a dinoalkylamino group.

[0064] Unless otherwise specified, "C 1-3 The term "alkoxy group" refers to any alkyl group containing 1 to 3 carbon atoms connected to the remainder of the molecule through an oxygen atom. 1-3 The alkoxy group is C 1-2 , C2 and C3 alkoxy groups, etc., 1-3 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.

[0065] Unless otherwise specified, "C 1-3The term "alkylthio group" includes those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. 1-3 The alkylthio group is C 1-2 , C2 and C3 alkylthio groups, etc., 1-3 Non-limiting examples of alkylthio groups include methylthio groups, ethylthio groups, propylthio groups, n-propylthio groups, isopropylthio groups, and the like.

[0066] Unless otherwise specified, the term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings are rings which share adjacent pairs of carbon atoms) group having a conjugated l-electron system, preferably 6- to 10-membered groups such as phenyl and naphthyl groups.

[0067] Unless otherwise specified, a "5-7 membered benzoheterocyclic group" refers to a benzoheterocyclic group having a phenyl group structure fused to a heterocycloalkyl ring, where the "heterocyclic group" in the "benzoheterocyclic group" refers to a saturated cyclic group consisting of 5 to 7 ring atoms, one or two of which are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. Non-limiting examples of benzoheterocyclic groups include: [ka] etc.

[0068] Unless otherwise specified, "5-7 membered benzocycloalkyl group" refers to a benzocycloalkyl group having a phenyl group structure fused to a cycloalkyl ring, where the "cycloalkyl group" in the "benzocycloalkyl group" refers to a saturated cyclic group consisting of 5 to 7 carbon atoms. Non-limiting examples of benzocycloalkyl groups include: [ka] etc.

[0069] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, or nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, and examples thereof include furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. [ka] etc.

[0070] Unless otherwise specified, the term "heterocyclic group," alone or in combination with other terms, refers to a saturated or partially saturated cyclic group, each consisting of 4 to 14 ring atoms, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur atoms are optionally oxidized (i.e., C(═O), NO, SO, and SO). It includes monocyclic, bicyclic, and tricyclic systems, in which bicyclic and tricyclic systems include spirocyclic, fused, and bridged rings. Furthermore, a heteroatom can occupy the position of attachment of the heterocyclic group to the remainder of the molecule, and heterocyclic groups include saturated and partially unsaturated heterocyclic groups. Non-limiting examples of heterocyclic groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl group and 3-piperidinyl group etc.), piperazinyl group (including 1-piperazinyl group and 2-piperazinyl group etc.), morpholinyl group (including 3-morpholinyl group and 4-morpholinyl group etc.), dioxanyl group, dithianyl group, isoxazolidinyl group, isothiazolidinyl group, 1,2-oxazinyl group, 1,2-thiazinyl group, hexahydropyridazinyl group, homopiperazinyl group, homopiperidinyl group, [ka] etc.

[0071] "Halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0072] A "cyano group" refers to -CN.

[0073] Certain pharmaceutical and medical terms The term "acceptable" as used herein means that the formulation or active ingredient does not have excessive adverse effects on health for general therapeutic purposes.

[0074] The terms "treatment," "treatment," or "therapy," as used herein, include alleviating, inhibiting, or ameliorating a disease symptom or condition, inhibiting the development of complications, ameliorating or preventing underlying metabolic syndrome, inhibiting the development of a disease or condition, such as controlling a disease or progression of a condition, alleviating a disease or condition, regressing a disease or condition, reducing complications of a disease or condition, or preventing or treating symptoms of a disease or condition. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, condition, or condition, particularly, improve its severity, delay the onset, delay the progression of the condition, or reduce the duration of the condition. These conditions can result from or be associated with administration, whether the administration is fixed or episodic, continuous or intermittent.

[0075] "Active ingredient" refers to compounds represented by general formula (1) and pharmaceutically acceptable inorganic or organic salts of compounds of formula (1). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and occur in the form of racemates, racemic compounds, single enantiomers, diastereomeric compounds, and single diastereomers. The presence of asymmetric centers may depend on the nature of the various substituents on the molecule. Each such asymmetric center independently gives rise to two optical isomers, and all possible optical and diastereomeric mixtures, as well as pure or partially pure compounds, are within the scope of the present invention. The present invention is intended to encompass all such isomeric forms of these compounds.

[0076] The terms "compound," "composition," "agent," or "medicine or medicament," etc., are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), elicits a desired pharmaceutical and / or physiological response via local and / or systemic action.

[0077] The terms "administered," "administering," or "administration," as used herein, refer to the direct administration of a compound or composition, or the administration of a prodrug, derivative, analog, or the like of an active compound.

[0078] The numerical ranges and parameters used to define the broad scope of the present invention are approximations, and the relevant numerical values ​​in the specific examples are presented herein as precisely as possible. However, any numerical values ​​inherently contain standard deviations resulting from individual testing methods. Herein, the term "about" typically indicates that the actual numerical value is within ±10%, 5%, 1%, or 0.5% of the specified numerical value or range. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean as determined by one of ordinary skill in the art. Unless experimental examples are included or otherwise expressly stated, all ranges, numbers, values, and percentages used herein (e.g., amounts of ingredients, lengths of time, temperatures, operating conditions, numerical ratios, and other similar terms) are understood to be modified by the term "about." Accordingly, unless otherwise specified, all numerical parameters disclosed in this specification and the appended claims are approximations and can be modified as necessary. At the very least, these numerical parameters should be understood as values ​​obtained using the indicated number of significant digits and ordinary rounding rules.

[0079] Unless otherwise defined herein, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Furthermore, unless otherwise indicated, singular terms used herein include the plural of that noun, and plural nouns used herein include the singular of that noun.

[0080] Medication route The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts in a safe and effective amount and pharmacologically acceptable excipients or carriers. Here, the term "safe and effective amount" refers to the amount of the compound sufficient to clearly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined based on the specific circumstances of the subject, such as the age, condition, and duration of treatment.

[0081] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatibility" refers to the ability of the components of the composition to be blended with each other without significantly reducing the efficacy of the compounds of the present invention. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0082] The compounds of the present invention can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0083] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as, for example, sodium citrate or dicalcium phosphate, or with ingredients such as (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarders, such as paraffin; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0084] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a specific part of the digestive tract. Examples of embedding materials that can be used include polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0085] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form can contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0086] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0087] In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar, or mixtures of these substances.

[0088] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0089] Dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers, or propellants that may be required.

[0090] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0091] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the considered effective dose. For a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0092] The main advantages of the present invention are:

[0093] (a) Unexpectedly, compared to ABX464, the compounds of the present invention exhibit superior in vitro activity while also exhibiting superior in vivo pharmacokinetic properties, making them more suitable for drug development.

[0094] (b) The compounds of the present invention have excellent drug discovery potential.

[0095] (c) Compared to ABX464, the compounds of the present invention have significantly superior efficacy in treating a DSS-induced mouse inflammatory bowel disease model.

[0096] The above features mentioned in the present invention or the features mentioned in the examples can be arbitrarily combined. All features disclosed herein can be used in any compositional form, and each feature disclosed herein can be replaced with any alternative feature serving the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely generic examples of equivalent or similar features.

[0097] The following description will explain in detail various specific aspects, characteristics and advantages of the above compounds, methods and pharmaceutical compositions, so as to better understand the contents of the present invention. Please note that the following detailed description and examples are for describing specific examples and are for reference only. After reading the description of the present invention, those skilled in the art can make various modifications or changes to the present invention, and their equivalents are still within the scope of the present application.

[0098] The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer, with a CuKα light source and a φ / ω scanning mode. After collecting the relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0099] The solvents used in the present invention are commercially available. Compounds are named according to conventional nomenclature in the art or according to ChemDraw software, and commercially available compounds are named according to the supplier's catalog name.

[0100] In all examples, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer. Chemical shifts are expressed in δ (ppm). The silica gel used for separation was 200-300 mesh unless otherwise specified. All eluent ratios are by volume.

[0101] The present invention uses the following abbreviations: CHCl3 represents chloroform, Cu represents copper, Cs2CO3 represents cesium carbonate, EA (EtOAc) represents ethyl acetate, DCM represents dichloromethane, dioxane represents 1,4-dioxane, DMF represents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, EtOH represents ethanol, Fe represents iron, h represents hour, K2 CO3 represents potassium carbonate, LC-MS represents liquid chromatography mass spectrometry, MeI (CHI) represents iodomethane, MeOH represents methanol, MS represents mass spectrometry, Na2CO3 represents sodium carbonate, NaH represents sodium hydride, NaOH represents sodium hydroxide, NMR represents nuclear magnetic resonance, Pd / C represents palladium on carbon, Pd (OAc)2 represents palladium acetate, PE represents petroleum ether, POCl3 represents phosphorus oxychloride, PtO2 represents platinum dioxide, rt represents room temperature, SOCl2 represents dichlorothionyl group, TEA (Et3N) represents triethylamine, TLC represents thin layer chromatography, THF represents tetrahydrofuran, Tf2O represents trifluoromethanesulfonic anhydride, Tol represents toluene, TsCl represents p-toluenesulfonyl chloride, Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, AcOH (HOAc) represents acetic acid, CDI represents carbonyldiimidazole, DIEA (DIEPA) represents diisopropylethylamine, and NHCl represents ammonium chloride.

[0102] Hereinafter, the present invention will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight.

[0103] Preparation Example 1: Synthesis of 3,5-dichloro-1-methylquinoxalin-2(1H)-one (Intermediate 1) [ka]

[0104] Step 1: Synthesis of 1-1 3-Chloro-2-nitroaniline (3 g, 17.38 mmol) was dissolved in THF (50 mL), NaH (765 mg, 19.12 mmol) was slowly added under ice bath conditions, and the mixture was stirred for 30 min. Then, a THF solution of MeI (2.47 g, 17.38 mmol) was slowly added, and the mixture was allowed to warm to room temperature. The reaction was monitored for completion by LC-MS. The mixture was quenched by adding water under ice bath conditions, extracted with EA (50 mL × 3), and the combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give a red solid 1-1 (1.2 g, 37% yield). ESI-MS m / z: 186.9 [M+H]. + .

[0105] Step 2: Synthesis of 1-2 1-1 (1.2 g, 6.45 mmol) was dissolved in EtOH (30 mL) and water (10 mL), iron powder (1.81 g, 32.25 mmol) and NHCl (3.45 g, 64.5 mmol) were added, and the mixture was stirred at 70 °C. The reaction was monitored for completion by LC-MS. After suction filtration and extraction with EA (30 mL × 3), the combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 2 / 1) to give 1-2 (500 mg, 50% yield) as a yellow oil. ESI-MS m / z: 156.9 [M+H] + .

[0106] Step 3: Synthesis of 1-3 Dissolve 1-2 (500 mg, 3.21 mmol) in ethyl oxalyl chloride (10 mL) and react with stirring at room temperature. Monitor the reaction completion by LC-MS. Directly spin-dry the solvent with an oil pump and subject it to column chromatography (PE / EA = 30 / 1 to 10 / 1) to obtain a yellow solid 1-3 (320 mg, 47% yield). ESI-MS m / z: 210.8 [M+H] + .

[0107] Step 4: Synthesis of Intermediate 1 1-3 (320 mg, 1.52 mmol) was dissolved in POCl3 (10 mL) and stirred at 110 °C. The reaction was monitored for completion by LC-MS. The solvent was directly spun dry, water (50 mL) was added, neutralized with saturated sodium bicarbonate, and extracted with EA (30 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give intermediate 1 (220 mg, 63% yield) as a yellow solid. ESI-MS m / z: 228.8 [M+H] + .

[0108] Preparation Example 2: Synthesis of 3,7-dichloro-5-fluoro-1-methylquinoxalin-2(1H)-one (Intermediate 2) [ka]

[0109] Step 1: Synthesis of 2-1 4-Chloro-2,6-difluoronitrobenzene (2 g, 10.33 mmol) was dissolved in EtOH (50 mL), and aqueous methylamine solution (1.07 g, 10.33 mmol, 30%) was added. The mixture was stirred at room temperature and monitored for reaction completion by LC-MS. The EtOH solution was directly spun dry, and water (100 mL) was added. Extraction was performed with EA (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give a yellow solid 2-1 (1.5 g, 71% yield). ESI-MS m / z: 204.8 [M+H]. + .

[0110] Using 2-1 as a raw material, intermediate 2 can be synthesized according to the similar method to the synthesis of intermediate 1 of 1-1, and ESI-MS m / z: 247.0 [M+H] + .

[0111] Preparation Example 3: Synthesis of 6-chloromidazo[1,2-a]quinoxalin-4-yl trifluoromethanesulfonate (Intermediate 3) [ka]

[0112] Step 1: Synthesis of 3-1 2,6-Dichloronitrobenzene (2 g, 10.42 mmol) was dissolved in DMF (50 mL), and ethyl imidazole-2-carboxylate (1.46 g, 10.42 mmol) and CsCO (5.08 g, 15.63 mmol) were added. The mixture was stirred at 80 °C and monitored for reaction completion by LC-MS. Water (200 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give a white solid 3-1 (2.7 g, 88% yield). ESI-MS m / z: 295.9 [M+H]. + .

[0113] Step 2: Synthesis of 3-2 3-1 (2.7 g, 9.15 mmol) was dissolved in HOAc (30 mL), iron powder (2.56 g, 45.76 mmol) was added, and the mixture was stirred at 100 °C. The reaction was monitored for completion by LC-MS. The mixture was suction filtered, HOAc was removed by spin drying, neutralized with saturated sodium bicarbonate solution, and extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 2 / 1) to give yellow solid 3-2 (1.1 g, 55% yield). ESI-MS m / z: 219.8 [M+H]. + .

[0114] Step 3: Synthesis of Intermediate 3 3-2 (1.1 g, 5.02 mmol) and TEA (1.01 g, 10.04 mmol) were dissolved in DCM (30 mL). Under argon gas protection, TfO (2.12 g, 7.53 mmol) was added with stirring at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature and monitored for reaction completion by LC-MS. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 50 / 1 to 20 / 1) to give intermediate 3 (1.3 g, 74% yield) as a white solid. ESI-MS m / z: 351.8 [M+H] + .

[0115] Using ethyl imidazole-2-carboxylate and the corresponding substituted nitrobenzene as starting materials, intermediates 4-54 can be synthesized according to a method similar to that of intermediate 3.

[0116] [Table A] TIFF2026506166000048.tif255168TIFF2026506166000049.tif247168TIFF202 6506166000050.tif228169TIFF2026506166000051.tif240169TIFF20265061660 00052.tif240169TIFF2026506166000053.tif240169TIFF2026506166000054.t if240169TIFF2026506166000055.tif241169TIFF2026506166000056.tif241169

[0117] Preparation Example 4: Synthesis of 4,6-dichloro-[1,2,4]triazolo[4,3-a]quinoxaline (Intermediate 55) [ka]

[0118] Step 1: Synthesis of 55-1 3-Chloro-o-phenylenediamine (2 g, 14.03 mmol) was dissolved in diethyl oxalate (20 mL) and heated to 120 °C. The reaction was monitored by LC-MS for completion of the reaction. The solvent was directly spun dry using an oil pump, and the mixture was subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain intermediate 55-1 (2.2 g, 80% yield) as a pale yellow solid. ESI-MS m / z: 196.9 [M+H] + .

[0119] Step 2: Synthesis of 55-2 Intermediate 55-1 (2.2 g, 11.22 mmol) was dissolved in POCl3 (20 mL) and heated to 100 °C. The reaction was monitored by LC-MS for completion of the raw material. Directly concentrated, water (50 mL) was added, neutralized with saturated sodium bicarbonate solution, extracted with EA (30 mL × 3), the organic phases were combined, dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 3 / 1) to give intermediate 55-2 (1.6 g, 62% yield) as a yellow solid, with ESI-MS m / z: 232.8 [M+H]. + .

[0120] Step 3: Synthesis of 55-3 Intermediate 55-2 (1.6 g, 6.87 mmol) was dissolved in EtOH (20 mL), hydrazine hydrate (808 mg, 13.74 mmol, 85%) was added, and the reaction was allowed to proceed at room temperature. The reaction was monitored for completion by LC-MS. Direct concentration was performed to remove the bulk of the ethanol, and water (50 mL) was added. Extraction was performed with EA (30 mL x 3). The combined organic phases were dried and concentrated to give Intermediate 55-3 (1.8 g, crude product) as a pale yellow solid. ESI-MS m / z: 228.9 [M+H] + .

[0121] Step 4: Synthesis of intermediate 55 Intermediate 55-3 (1.8 g, crude product) was dissolved in triethyl orthoformate (20 mL) and heated to 100 °C. The reaction was monitored by LC-MS for completion of the raw material reaction. Directly concentrated, water (50 mL) was added, and extracted with EA (30 mL × 3). The combined organic phase was dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give intermediate 55 (1.1 g, 67% yield) as a yellow solid. ESI-MS m / z: 238.8 [M+H] + .

[0122] 55-3 is used as a common raw material and reacted with triethyl orthoacetate and trifluoroacetic acid to give intermediate 56 and intermediate 57, respectively.

[0123] [Table B]

[0124] Preparation Example 5: Synthesis of 4,6-dichloro-1,2-dihydroimidazo[1,2-a]quinoxaline (Intermediate 58) [ka]

[0125] Step 1: Synthesis of 58-1 55-2 (1 g, 4.31 mmol) was dissolved in EtOH (20 mL), ethanolamine (526 mg, 8.62 mmol) was added, and the temperature was raised to 70 °C with stirring. The reaction was monitored for completion by LC-MS. A large amount of EtOH was directly spin-dried, added to water (50 mL), and extracted with EA (30 mL × 3). The organic phases were combined, dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give red solid 58-1 (950 mg, 86% yield). ESI-MS m / z: 257.9 [M+H]. + .

[0126] Step 2: Synthesis of intermediate 58 58-1 (950 mg, 3.70 mmol) was dissolved in CHCl3 (20 mL) and SOCl2 (10 mL) and stirred at 80 °C. The reaction mixture was monitored for completion by LC-MS. The mixture was poured into water (50 mL), neutralized with saturated sodium bicarbonate solution, and extracted with CHCl3 (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 5 / 1 to 0 / 1) to give intermediate 58 (500 mg, 57% yield) as a yellow solid. ESI-MS m / z: 239.9 [M+H] + .

[0127] Intermediates 59-61 are synthesized following a similar method to intermediate 58 using various substituted o-phenylenediamines as starting materials.

[0128] [Table C]

[0129] Preparation Example 6: Synthesis of 6-bromo-1,2-dihydroimidazo[1,2-a]quinoxalin-4-yl trifluoromethanesulfonate (Intermediate 62) [ka]

[0130] Using 3-bromo-o-phenylenediamine as starting material, 62-1 is synthesized following a method similar to that of intermediate 58.

[0131] Step 1: Synthesis of 62-2 62-1 (1 g, 3.51 mmol) was dissolved in THF / HO (20 mL / 4 mL), LiOH (281 mg, 7.02 mmol) was added, and the reaction was heated to 60 °C with stirring. The reaction was monitored for completion by LC-MS. A large amount of THF was directly spun dry, added to water (50 mL), neutralized with 1 M HCl until slightly acidic, and extracted with EA (30 mL × 3). The organic phases were combined, dried, and concentrated to give yellow solid 62-2 (910 mg, 97% yield). ESI-MS m / z: 266.0 [M+H]. + .

[0132] Step 2: Synthesis of intermediate 62 62-2 (910 mg, 3.42 mmol) and TEA (691 mg, 6.84 mmol) were dissolved in DCM (20 mL). TfO (1.45 g, 5.13 mmol) was added under argon gas protection with stirring at 0 °C. After the addition was complete, the reaction was stirred at room temperature and monitored for completion of the reaction by LC-MS. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 3 / 1) to give intermediate 62 (830 mg, 61% yield) as a white solid. ESI-MS m / z: 397.9 [M+H] + .

[0133] Preparation Example 7: Synthesis of 6-chloro-[1,2,4]triazolo[1,5-a]quinoxalin-4-yl trifluoromethanesulfonate (Intermediate 63) [ka]

[0134] Step 1: Synthesis of 63-1 2-Chloro-6-fluoronitrobenzene (2 g, 11.40 mmol) was dissolved in DMF (50 mL), followed by the addition of hydrazine hydrate (1.34 g, 22.80 mmol) and Na2CO3 (2.42 g, 22.80 mmol). The reaction was stirred at room temperature and monitored for completion of the reaction by LC-MS. Water (50 mL) was added, and the mixture was extracted with EA (30 mL x 3). The combined organic phases were dried and concentrated to give brick-colored solid 63-1 (1.7 g, 80% yield). ESI-MS m / z: 187.9 [M+H]. + .

[0135] Step 2: Synthesis of 63-2 63-1 (900 mg, 4.80 mmol) and ethyl 2-ethoxy-2-imidate (835 mg, 5.76 mmol) were dissolved in EtOH (20 mL), HOAc (1 mL) was added, and the mixture was stirred at room temperature after the addition. After the completion of the addition, the reaction mixture was monitored by LC-MS for the completion of the reaction. The mixture was directly spun dry, added to water (50 mL), and extracted with EA (30 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 20 / 1 to 5 / 1) to give brick-colored solid 63-2 (1.2 g, 88% yield). ESI-MS m / z: 286.9 [M+H]. + .

[0136] Step 3: Synthesis of 63-3 63-2 (1.2 g, 4.2 mmol) and TEA (1.27 g, 12.6 mmol) were dissolved in toluene (30 mL) and ethyl oxalyl chloride (1.15 g, 8.4 mmol) was added at room temperature. After the addition was complete, the mixture was heated to 110 °C and stirred. The reaction was monitored for completion by LC-MS. The mixture was directly spun dry, added to water (50 mL), and extracted with EA (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 20 / 1 to 3 / 1) to give yellow solid 63-3 (1.2 g, 77% yield). ESI-MS m / z: 368.9 [M+H]. + .

[0137] Step 4: Synthesis of 63-4 63-3 (1.2 g, 3.26 mmol) was dissolved in HOAc (30 mL), iron powder (913 mg, 16.30 mmol) was added, and the mixture was stirred at 100 °C. The reaction was monitored for completion by LC-MS. The mixture was suction filtered, HOAc was removed by spin drying, neutralized with saturated sodium bicarbonate, and extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 2 / 1) to give yellow solid 64-4 (510 mg, 54% yield). ESI-MS m / z: 292.9 [M+H]. + .

[0138] Step 5: Synthesis of 63-5 Dissolve 63-4 (510 mg, 1.75 mmol) in MeOH (10 mL) and water (2 mL), add NaOH (140 mg, 3.50 mmol), and stir at room temperature. Monitor the reaction completion by LC-MS. Remove methanol by spin drying, neutralize with 1 M HCl to pH 6-7, and extract with EA (50 mL x 3). Combine the organic phases, dry, and concentrate to give yellow solid 63-5 (500 mg, crude product). ESI-MS m / z: 264.8 [M+H]. + .

[0139] Step 6: Synthesis of 63-6 63-5 (500 mg, crude product) was dissolved in EtOH (10 mL), concentrated HCl (2 mL) was added, and the mixture was stirred at 80 °C. The reaction was monitored for completion by LC-MS. The EtOH was removed by spin drying, neutralized with saturated sodium bicarbonate solution, and extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give yellow solid 63-6 (300 mg, 78% yield). ESI-MS m / z: 220.8 [M+H]. + .

[0140] Step 7: Synthesis of intermediate 63 63-6 (300 mg, 1.36 mmol) and TEA (275 mg, 2.72 mmol) were dissolved in DCM (10 mL). TfO (575 mg, 2.04 mmol) was added under argon gas protection with stirring at 0 °C. After the addition was complete, the reaction was stirred at room temperature and monitored for reaction completion by LC-MS. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 3 / 1) to give intermediate 63 (330 mg, 69% yield) as a white solid. ESI-MS m / z: 352.8 [M+H] + .

[0141] Preparation Example 8: Synthesis of 6-chloro-[1,2,4]triazolo[1,5-a]quinoxalin-4-yl trifluoromethanesulfonate (Intermediate 64) [ka]

[0142] Step 1: Synthesis of 64-1 63-1 (1.5 g, 8.02 mmol) and ethyl acetimidate hydrochloride (990 mg, 8.02 mmol) were dissolved in Py (20 mL) and reacted with stirring at room temperature. The reaction completion was monitored by LC-MS. Direct spin-drying was performed, followed by addition of water (50 mL), and extraction with EA (30 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 20 / 1 to 5 / 1) to give brick-colored solid 64-1 (800 mg, 44% yield). ESI-MS m / z: 228.9 [M+H]. + .

[0143] Step 2: Synthesis of 64-2 64-1 (800 mg, 3.51 mmol) was dissolved in toluene (20 mL) and ethyl oxalyl chloride (958 mg, 7.02 mmol) was added at room temperature. After the addition was complete, the mixture was heated to 110 °C and stirred. The reaction was monitored for completion by LC-MS. The mixture was directly spun dry, added to water (50 mL), and extracted with EA (30 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 2 / 1) to give yellow solid 64-2 (680 mg, 63% yield). ESI-MS m / z: 310.8 [M+H]. + .

[0144] Step 3: Synthesis of 64-3 64-2 (680 mg, 2.19 mmol) was dissolved in acetic acid (10 mL), iron powder (614 mg, 10.97 mmol) was added, and the mixture was stirred at 100 °C. The reaction was monitored for completion by LC-MS. The mixture was suction filtered, the acetic acid was removed by spin drying, neutralized with saturated sodium bicarbonate, and extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give yellow solid 64-3 (210 mg, 41% yield). ESI-MS m / z: 234.9 [M+H]. + .

[0145] Step 4: Synthesis of intermediate 64 64-3 (210 mg, 0.90 mmol) and TEA (182 mg, 1.80 mmol) were dissolved in DCM (10 mL). Under argon gas protection, TfO (381 mg, 1.35 mmol) was added with stirring at 0 °C. After the addition was complete, the reaction was stirred at room temperature and monitored for reaction completion by LC-MS. The mixture was poured into water (50 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 3 / 1) to give intermediate 64 (170 mg, 52% yield) as a white solid. ESI-MS m / z: 366.8 [M+H] + .

[0146] Preparation Example 9: Synthesis of 7,9-dichloromidazo[1,2-a]quinoxalin-4-yl trifluoromethanesulfonate (Intermediate 65) [ka]

[0147] Step 1: Synthesis of 65-1 2,3,5-Trichloronitrobenzene (2.00 g, 8.83 mmol) was dissolved in DMSO (50 mL), imidazole (0.6 g, 8.83 mmol) and NaOH (706 mg, 17.66 mmol) were added, and the mixture was stirred at room temperature. The reaction was monitored for completion by LC-MS. Water (100 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give white solid 65-1 (1.86 g, 82% yield). ESI-MS m / z: 257.8 [M+H]. + .

[0148] Step 2: Synthesis of 65-2 65-1 (1.86 g, 7.24 mmol) was dissolved in EtOH / HO (10 / 1, 33 mL), iron powder (2.03 g, 36.2 mmol) and NHCl (1.94 g, 36.2 mmol) were added, and the mixture was stirred at 80 °C. The reaction was monitored for completion by LC-MS. After suction filtration, EtOH was removed by spin drying, water (100 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give yellow solid 65-2 (1.4 g, 85% yield). ESI-MS m / z: 227.8 [M+H]. + .

[0149] Step 3: Synthesis of 65-3 65-2 (1.4 g, 6.17 mmol) was dissolved in toluene (30 mL), CDI (1.5 g, 9.26 mmol) was added, and the mixture was stirred at 120 °C. The reaction was monitored for completion by LC-MS. The toluene was removed by spin drying, water (100 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give yellow solid 65-3 (1.17 g, 75% yield). ESI-MS m / z: 253.8 [M+H]. + .

[0150] Step 3: Synthesis of intermediate 65 65-3 (1.17 g, 4.62 mmol) and TEA (934 mg, 9.25 mmol) were dissolved in DCM (30 mL). TfO (1.56 g, 5.54 mmol) was added under argon gas protection with stirring at 0 °C. After the addition was complete, the reaction was stirred at room temperature and monitored for reaction completion by LC-MS. The mixture was poured into water (100 mL) and extracted with DCM (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 20 / 1 to 10 / 1) to give intermediate 65 (1.46 g, 82% yield) as a white solid. ESI-MS m / z: 385.7 [M+H] + .

[0151] Using imidazole and the corresponding substituted nitrobenzene as starting materials, intermediates 66-67 are synthesized following a similar method to intermediate 65.

[0152] [Table D]

[0153] Preparation Example 10: Synthesis of 4-chloro-9-fluoro-1,2-dihydroimidazo[1,2-a]quinoxaline (Intermediate 68) [ka]

[0154] Step 1: Synthesis of 68-1 2,3-Difluoronitrobenzene (5.00 g, 31.45 mmol) was dissolved in DMF (100 mL), p-methoxybenzylamine (4.31 g, 31.45 mmol) and DIEA (8.11 g, 62.9 mmol) were added, and the mixture was stirred at 80 °C. The reaction was monitored for completion by LC-MS. Water (200 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give yellow solid 68-1 (5.9 g, 68% yield). ESI-MS m / z: 276.9 [M+H]. + .

[0155] Step 2: Synthesis of 68-2 68-1 (5.9 g, 21.38 mmol) was dissolved in EtOH / HO (10 / 1, 110 mL), iron powder (5.99 g, 106.9 mmol) and NH4Cl (5.72 g, 106.9 mmol) were added, and the mixture was stirred at 80 °C. The reaction was monitored for completion by LC-MS. After suction filtration, ethanol was removed by spin drying, water (200 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give yellow solid 68-2 (7.62 g, 88% yield). ESI-MS m / z: 276.9 [M+H]. + .

[0156] Step 3: Synthesis of 68-3 68-2 (7.62 g, 27.61 mmol) was dissolved in diethyl oxalate (50 mL) and stirred at 120 °C. The reaction mixture was monitored by LC-MS for the completion of the reaction. After cooling and suction filtration, a gray solid 68-3 (5.72 g, 69% yield) was obtained. ESI-MS m / z: 300.9 [M+H] + .

[0157] Step 4: Synthesis of 68-4 68-3 (5.72 g, 19.07 mmol) was dissolved in DMF (50 mL), DIEA (4.92 g, 38.14 mmol) and POCl3 (8.77 g, 57.21 mmol) were added, and the mixture was stirred at 80 °C after the addition was complete. After the addition, the reaction mixture was monitored for completion by LC-MS. Water (200 mL) was added, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to give yellow solid 68-4 (3.27 g, 54% yield). ESI-MS m / z: 318.9 [M+H]. + .

[0158] Step 5: Synthesis of 68-5 68-4 (3.27 g, 10.28 mmol) was dissolved in sulfuric acid (10 mL) and stirred at room temperature. The reaction was monitored by LC-MS for completion. The raw material was slowly added to ice water and extracted with EA (50 mL × 3). The combined organic phase was dried, concentrated, and subjected to column chromatography (PE / EA = 5 / 1 to 1 / 1) to give yellow solid 68-5 (1.32 g, 65% yield). ESI-MS m / z: 198.8 [M+H]. + .

[0159] Step 6: Synthesis of 68-6 68-5 (1.32 g, 6.67 mmol) and TEA (1.35 g, 13.33 mmol) were dissolved in DCM (30 mL). TfO (2.26 g, 8.00 mmol) was added under argon gas protection with stirring at 0 °C. After the addition was complete, the reaction was stirred at room temperature and monitored for reaction completion by LC-MS. The mixture was poured into water (50 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 3 / 1) to give yellow solid 68-6 (1.94 g, 88% yield). ESI-MS m / z: 330.8 [M+H]. + .

[0160] Step 7: Synthesis of 68-7 68-6 (1.94 g, 5.88 mmol) and ethanolamine (717 mg, 11.76 mmol) were dissolved in EtOH (30 mL) and stirred at room temperature. The reaction was monitored for completion by LC-MS. EtOH was removed by spin drying, water (200 mL) was added, and the mixture was extracted with EA (50 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 3 / 1 to 1 / 1) to give yellow solid 68-7 (1.08 g, 76% yield). ESI-MS m / z: 241.8 [M+H]. + .

[0161] Step 8: Synthesis of intermediate 68 68-7 (1.08 g, 4.48 mmol) was dissolved in POCl3 (20 mL) and stirred at 70 °C. The reaction was monitored for completion by LC-MS. POCl3 was removed by spin drying, and the mixture was added to water (100 mL). Extraction was performed with EA (30 mL × 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 5 / 1 to 0 / 1) to give intermediate 68 (759 mg, 76% yield) as a yellow solid. ESI-MS m / z: 223.8 [M+H] + .

[0162] Using various substituted nitrobenzenes as starting materials, intermediates 69-74 are synthesized following a similar method to intermediate 68.

[0163] [Table E] TIFF2026506166000068.tif41169

[0164] Example 1: Synthesis of 5-chloro-1-methyl-3-((4-(trifluoromethoxy)phenyl)amino)quinoxalin-2(1H)-one (Compound 1) [ka]

[0165] Intermediate 1 (50 mg, 0.22 mmol), 4-(trifluoromethoxy)aniline (39 mg, 0.22 mmol), Pd(OAc) (5 mg, 0.022 mmol), Xantphos (26 mg, 0.044 mmol), and CsCO (143 mg, 0.44 mmol) were dissolved in dioxane (3 mL) and heated to 90 °C under argon gas protection. The reaction was monitored for completion by LC-MS. The raw material was poured into water (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 10 / 1 to 1 / 1) to give compound 1 (51 mg, 64% yield) as a yellow solid.

[0166] 1 H NMR(400MHz,DMSO-d6):δ9.99(s,1H),8.48(d,J=9.2Hz,2H),7.50-7.45(m,2H),7.39(d,J=8.7Hz,2H),7.37-7.32(m,1H),3.71(s,3H);ESI-MS m / z:369.9[M+H] + .

[0167] Examples 2 to 94: Synthesis of Compounds 2-38, 41 to 96 Using intermediates 1-9, 55-64 and the corresponding amines as starting materials, the target compounds 2-38, 41-96 are obtained according to a method similar to that of Example 1.

[0168] [Table F] TIFF2026506166000071.tif239169TIFF2026506166000072.tif239170TIFF2026506166000073.tif250169TIFF2026506166000074.tif225170TIFF2026506166000075.tif199170TIFF2026506166000076.tif194170TIFF2026506166000077.tif212170TIFF2026506166000078.tif198170TIFF2026506166000079.tif172170TIFF2026506166000080.tif194170TIFF2026506166000081.tif212170TIFF2026506166000082.tif250170TIFF2026506166000083.tif183170TIFF2026506166000084.tif247170TIFF2026506166000085.tif232170TIFF2026506166000086.tif185170TIFF2026506166000087.tif171170TIFF2026506166000088.tif171170TIFF2026506166000089.tif246170TIFF2026506166000090.tif226170TIFF2026506166000091.tif225170TIFF2026506166000092.tif225170TIFF2026506166000093.tif210170TIFF2026506166000094.tif246170TIFF2026506166000095.tif245170TIFF2026506166000096.tif157170TIFF2026506166000097.tif179170TIFF2026506166000098.tif239170TIFF2026506166000099.tif233170TIFF2026506166000100.tif218170TIFF2026506166000101.tif205170TIFF2026506166000102.tif219170TIFF2026506166000103.tif144170

[0169] Example 95: Synthesis of 6-chloro-N-(2,2-difluoro-2,3-dihydrobenzofuran-5-yl)imidazo[1,2-a]quinoxalin-4-amine (Compound 39) [ka]

[0170] Step 1: Synthesis of intermediate 39-1 DMF (30 mL) was added to the reaction bottle, and under argon gas protection, 2-hydroxy-5-nitrobenzaldehyde (500 mg, 2.99 mmol) and sodium difluorochloroacetate (2.28 g, 14.96 mmol) in DMF (10 mL) were slowly added with stirring at 95 °C for 30 min. The reaction mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give yellow solid 37-1 (409 mg, 63% yield). ESI-MS m / z: 217.9 [M+H]. + .

[0171] Step 2: Synthesis of intermediate 39-2 39-1 (409 mg, 1.88 mmol) was dissolved in THF (30 mL), and under argon gas protection, NaH (113 mg, 2.82 mmol) was added with stirring at 0 °C for 30 min. TsCl (430 mg, 2.25 mmol) was then added and the mixture was stirred at room temperature overnight. The reaction was monitored for completion by LC-MS. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 30 / 1 to 10 / 1) to give yellow solid 39-2 (520 mg, 74% yield). ESI-MS m / z: 372.1 [M+H]. + .

[0172] Step 3: Synthesis of intermediate 39-3 Dissolve 39-2 (520 mg, 1.4 mmol) in THF (30 mL), add Pd / C (50 mg, 10%), purge with hydrogen gas, and react at room temperature. Monitor the reaction completion by LC-MS. Filter, concentrate, and subject the mixture to column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain a white solid 39-3 (195 mg, 60% yield). ESI-MS m / z: 172.2 [M+H]. + .

[0173] Step 4: Synthesis of compound 39 Using intermediates 3 and 39-3 as raw materials, the target compound 39 is obtained according to a method similar to that of Example 1.

[0174] 1 H NMR(400MHz,DMSO-d6)δ:10.13(s,1H),8.71(d,J=2.2Hz,1H),8.64(d,J=1.1Hz,1H),8.15(m,1H) ),8.01(m,1H),7.57(d,J=1.1Hz,1H),7.55(m,1H),7.31(m,2H),3.63(t,J=13.2Hz,2H);ESI-MS m / z:373.1[M+H] + .

[0175] Example 96: Synthesis of 6-chloro-N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-5-yl)imidazo[1,2-a]quinoxalin-4-amine (Compound 40) [ka]

[0176] Step 1: Synthesis of intermediate 40-1 2-Chloro-4-nitrophenol (500 mg, 2.88 mmol), K2CO3 (476 mg, 3.45 mmol), propanethiol (110 mg, 1.44 mmol), and 1,2-dibromotetrafluoroethane (1.12 g, 4.32 mmol) were dissolved in DMF (30 mL) and stirred at 50 °C for 48 h. The reaction was monitored for completion by LC-MS. The raw material was poured into 2N aqueous NaOH (50 mL) and extracted with EA (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 100 / 1 to 20 / 1) to give yellow oil 40-1 (426 mg, 42% yield). ESI-MS m / z: 351.8 [M+H]. + .

[0177] Step 2: Synthesis of intermediate 40-2 40-1 (426 mg, 1.21 mmol) was dissolved in DMSO (30 mL), followed by the addition of copper powder (387 mg, 6.05 mmol). The mixture was then heated at 190 °C in a sealed tube for 6 h. The reaction was monitored for completion by LC-MS. The mixture was poured into water (50 mL) and extracted with EA (30 mL x 3). The combined organic phases were dried, concentrated, and subjected to column chromatography (PE / EA = 50 / 1 to 10 / 1) to give yellow solid 40-2 (236 mg, 82% yield). ESI-MS m / z: 237.9 [M+H]. + .

[0178] Step 3: Synthesis of intermediate 40-3 40-2 (236 mg, 1 mmol) was dissolved in MeOH (30 mL), PtO (20 mg) was added, and the mixture was purged with hydrogen gas. The mixture was then reacted at room temperature and monitored for completion of the reaction by LC-MS. After suction filtration and concentration, a colorless oil 40-3 (220 mg, crude product) was obtained. ESI-MS m / z: 207.9 [M+H] + .

[0179] Step 4: Synthesis of compound 40 Using intermediates 3 and 40-3 as raw materials, the target compound 40 is obtained according to a method similar to that of Example 1.

[0180] 1 H NMR(400MHz,DMSO-d6)δ:10.23(s,1H),8.75(m,2H),8.35(m,1H),8.21(m,1H),7.77(d,J=1.2Hz,1H),7.56(m,1H),7.35(m,2H);ESI-MS m / z:408.9[M+H] + .

[0181] Examples 97-249: Synthesis of Compounds B1-B153 Using intermediates 10-54, 65-74 and the corresponding amines as raw materials, the target compounds B1-B153 are obtained according to the synthesis method similar to that in Example 1.

[0182] [Table G] TIFF2026506166000107.tif241170TIFF2026506166000108.tif207170TIFF2026506166000109.tif214170TIFF2026506166000110.tif240170TIFF2026506166000111.tif240170TIFF2026506166000112.tif239170TIFF2026506166000113.tif240170TIFF2026506166000114.tif239170TIFF2026506166000115.tif207170TIFF2026506166000116.tif215170TIFF2026506166000117.tif229170TIFF2026506166000118.tif240170TIFF2026506166000119.tif212170TIFF2026506166000120.tif232170TIFF2026506166000121.tif213170TIFF2026506166000122.tif221170TIFF2026506166000123.tif247170TIFF2026506166000124.tif244170TIFF2026506166000125.tif213170TIFF2026506166000126.tif214170TIFF2026506166000127.tif248170TIFF2026506166000128.tif233170TIFF2026506166000129.tif240170TIFF2026506166000130.tif216170TIFF2026506166000131.tif222170TIFF2026506166000132.tif215170TIFF2026506166000133.tif222170TIFF2026506166000134.tif216170TIFF2026506166000135.tif244170TIFF2026506166000136.tif237170TIFF2026506166000137.tif222170TIFF2026506166000138.tif214170TIFF2026506166000139.tif220170TIFF2026506166000140.tif161170.

[0183] Example 250: Induction of miR-124 expression in PBMC cells by compounds In this study, we evaluate the ability of the compounds of the present invention to affect miR-124 transcriptional activity in vitro. In this experiment, we use qPCR method to analyze the expression status of miR-124 in human PBMCs (Sailybio).

[0184] 1 mL of thawed human PBMCs was added to 19 mL of medium (RPMI1640 + 10% hFBS + 1% 2-mercaptoethanol) and cultured in a cell incubator for 30 minutes. PBMCs were collected and cultured at 3.0 × 10 cells / mL in medium containing 10 ng / mL PMA (Invivogen) and 200 ng / mL ionomycin (Invivogen). 6 The cells were resuspended in 3 mL of PBS (cells / well) and incubated in a 6-well plate for 48 hours. The diluted compounds were added to the cells to a final compound concentration of 0.1 μM. After 72 hours, the cells were centrifuged and collected.

[0185] Cellular miRNA was extracted and purified according to the instructions in the MiPure Cell / Tissue miRNA Kit (Vazyme). Genomic DNA removal reaction solution was added to the purified sample, followed by reverse transcription using a PCR amplifier (GeneAmp PCR). The resulting product was subjected to qPCR testing using a real-time fluorescent quantitative PCR instrument (QuantStudio™ 7 Flex). Data analysis was performed using Quant Studio 7 software, which automatically calculated Ct values ​​with default settings and exported the files. The relative expression level of miR-124 was calculated using the following formula: ΔCt = Ct (target gene) - Ct (internal reference gene), ΔΔCt = ΔCt (compound group) - ΔCt (control group), and relative mRNA expression = 2^(-ΔΔCt). In this study, miR-191 was used as the internal reference gene, and the control group was DMSO-treated.

[0186] [Table 1] TIFF2026506166000142.tif242170TIFF2026506166000143.tif244170TIFF2026506166000144.tif80170Note: The test results for compound ABX464 are the results measured from two independent experiments.

[0187] As can be seen from the data in the above table, compared to the positive control ABX464, the compounds of the present invention have a very strong ability to induce miR-124 expression in PBMC cells.

[0188] Example 251: In vivo pharmacokinetic evaluation in mice Compounds were administered orally (po) at a dose of 10 mg / kg, with a final test article concentration of 0.4 mg / mL. The preparation solvent was 5% DMSO + 45% PEG400 + 50% aqueous solution or suspension. Nine male ICR mice were selected from each group, and three non-consecutive time points were collected from each mouse, with three mice per time point. Sample collection times were 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after dosing. Approximately 80 μL of blood was collected from the orbit or heart of each mouse at each time point. All whole blood samples were collected into EDTA K2-containing test tubes and centrifuged (4000 rpm / min) at 4°C for 10 min to separate plasma, which was then stored at -40°C or below for sample analysis. Plasma concentrations of the compounds were measured by liquid chromatography-tandem mass spectrometry, and the corresponding pharmacokinetic parameters were calculated based on the plasma concentration-time curve.

[0189] [Table 2] TIFF2026506166000146.tif116170As can be seen from the above table, all of the compounds of the present invention have good oral absorption properties and reach the maximum plasma drug concentration (C max ), area under the concentration-time curve (AUC0-t The metabolic parameters, such as the mean residence time (MRT) and the absorption rate (Abs) of 100mg / kg ...

[0190] Further experiments have shown that other compounds of the present invention also have good oral absorption properties and peak plasma drug concentrations (C max ), area under the concentration-time curve (AUC 0-t ) and mean residence time (MRT), all demonstrating superiority over the reference drug ABX464.

[0191] Example 252: Preventive and therapeutic effects of compounds on inflammatory bowel disease (IBD) in mice In this study, we evaluated the preventive and therapeutic effects of the compound of the present invention on dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice. C57BL / 6 female mice from Beijing Charles Rivers Laboratory Animal Technology Co., Ltd. were selected to produce a mouse inflammatory bowel disease model by DSS induction.

[0192] 1. Test methods and materials 1.1. Test animals The test mice were female C57BL / 6 mice, 6-8 weeks old, purchased from Beijing Charles Rivers Laboratory Animal Technology Co., Ltd. After purchase, mice were housed in SPF grade IVC cages, 2-6 mice per cage. Food and water were allowed to flow freely. The temperature was maintained at 20-26°C (68-79°F), the relative humidity was 40-70%, and the lighting conditions were fluorescent lights on for 12 hours (8:00-20:00) and off for 12 hours every day. The test began after one week of acclimation.

[0193] 1.2. Main reagents and equipment used in the test Dextran sulfate sodium (DSS, MW = 36,000-50,000): MP Biomedicals, Catalog No. 160110, Batch No. S3045 Dimethyl sulfoxide (DMSO): Sinopharm Chemical Reagent Co., Ltd., Catalog No. 30072418, Batch No. 20230309 Polyethylene glycol-15 hydroxystearate (Solutol HS-15): Sigma, Catalog No. 42966, Batch No. BCCJ5912; Zoletil: Virbac, batch number 8V4RA Xylazine: Tokyo Chemical Industry Co., Ltd., batch number R834H-MB; Balance: METTLER TOLEDO, model AL104, Centrifuge: Thermo Fisher Scientific Co., Ltd., model Thermo Fisher 21R; 1.3. Test design and test method 1.3.1. Drug Preparation The compounds of the present invention and ABX464 solvent: 5% DMSO + 10% Solutol + 85% saline, stored at 4°C.

[0194] DSS-containing drinking water: Dissolve an appropriate amount of DSS powder in autoclaved drinking water to prepare a 2% DSS solution.

[0195] 1.3.2. Test Grouping and Test Method The mice were randomly divided into eight groups based on their body weight, including a normal control group (negative control), a model group (DSS group), an ABX464 group, and five groups treated with the compounds of the present invention (compounds 19, 43, 59, 84, and 89, respectively, at 40 mg / kg orally, once daily).

[0196] [Table H]

[0197] After 7 days of acclimation, the model and compound groups were given 2% DSS-containing aqueous solution for 7 days from day 0, followed by normal water for 3 days. All groups were given the corresponding vehicle and drug by oral gavage for 10 consecutive days starting from the day of the test. During the test, the mice were observed for weight changes every day, and the disease index (DAI) score was evaluated daily. The total score was calculated on the final day. On the final day of the test, all test animals were euthanized, and the mouse colons were collected and their lengths were measured.

[0198] 1.3.3. Statistical analysis of data The test data are expressed as mean ± standard error (mean ± SEM). The data are analyzed by the corresponding statistical method using GraphPad Prism or SPSS. P<0.05 is considered to be statistically significant.

[0199] 2. Test Results 2.1. Effect of the compounds of the present invention on body weight in mice with DSS-induced inflammatory bowel disease According to the weight test results (Figure 1), compared with the normal control group, the model group mice showed significant weight loss from day 5, with the weight loss rate exceeding 10% from day 10. Compared with the model group, the compound group began to regain weight from day 7. On day 10, the weight gain rates of compounds 19, 59, and 84 of the present invention were 0.16%, 2.12%, and 0.38%, respectively, and the weight loss rates of compounds 43 and 89 of the present invention were 2.22% and 1.85%, respectively. Compared with ABX464 (weight loss rate was 5.37%), the compounds of the present invention showed superior efficacy in reducing weight loss in mice.

[0200] 2.2. Effect of the compounds of the present invention on daily disease index in DSS-induced inflammatory bowel disease mice According to the results of the Daily Illness Index (DAI) total score (Table 3), compared with the normal control group, the DAI score of the model group mice was significantly increased, reaching a total of 14.5 points. However, the total DAI scores of the inventive compound groups 19, 43, 59, 84, and 89 were 8.33, 10.03, 8.57, 8.47, and 10.33, respectively, which significantly lowered the DAI scores compared with the model group. Here, the total DAI scores of compounds 19, 59, and 84 showed significant differences, decreasing by 42.55%, 40.90%, and 41.59%, respectively. Compared with ABX464 (which only decreased by 5.72%), the total DAI scores of the inventive compounds were significantly lower. This indicates that the inventive compounds have a superior effect of improving DAI scores compared with the control drug ABX464.

[0201] [Table 3]

[0202] 2.3. Effect of the compounds of the present invention on colon length in mice with DSS-induced inflammatory bowel disease The colon length measurement results (Table 4) showed that compared with the normal control group, the colon length of the model group mice was significantly shortened, only 77.32% of that of the normal control group, indicating that the inflammatory bowel disease mouse model was successfully established. Compared with the model group, the colon length of the mice in the compound group of the present invention was significantly increased. The colon lengths of compounds 19, 43, 59, 84, and 89 were 96.27%, 99.69%, 100%, 96.89%, and 99.07% of that of the normal control group, respectively, and all were significantly different. This indicates that the compounds of the present invention significantly ameliorate the symptoms of DSS-induced inflammatory bowel disease in mice, essentially restoring them to normal levels. Compared with ABX464, the compounds of the present invention showed comparable improvement in mouse colon length, indicating that they have a slightly superior effect (e.g., compound 59).

[0203] [Table 4]

[0204] 3. Test Conclusion In this study, the preventive and therapeutic effects of the compounds of the present invention on inflammatory bowel disease in DSS-induced mice were evaluated. The test model was successfully established, and significant changes were observed in evaluation indicators such as mouse body weight, disease index, and colon length. The final test results showed that the compounds of the present invention showed good efficacy on mouse body weight, disease index, and colon length, with mouse body weight and disease index significantly higher than those of the control drug ABX464. Therefore, the compounds of the present invention have good preventive and therapeutic effects on inflammatory bowel disease in DSS-induced mice.

[0205] Further experiments showed that other compounds of the present invention (e.g., B7, B83, B97, B108) also showed preventive and therapeutic effects on DSS-induced inflammatory bowel disease in mice, and showed good efficacy on mouse body weight, daily disease index, and colon length, all of which were superior to the control drug ABX464.

[0206] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound having a structure as shown in formula (1), or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, 【Chemistry 46】 In the formula: n is 0, 1, 2 or 3; Each R is a halogen, CN, a nitro group, C １－３ Alkyl group, C １－３ Halogenated alkyl group, C １－３ Alkoxy group or C １－３ independently selected from the group consisting of halogenated alkoxy groups; R １ are H, CN, and C １－３ Alkyl group, C １－３ selected from the group consisting of an alkoxy group or a halogen; A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, a 5- to 7-membered benzocycloalkyl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, benzocycloalkyl group, and benzoheterocyclic group are not halogenated, CN, C １－３ Alkyl group, C ３－６ Cycloalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group, C １－３ Halogenated alkoxy group, C １－３ Halogenated alkylthio group or SF ５ and may be further substituted with 0 to 4 groups selected from the group consisting of: X is O and Y is C １－３ Alkyl group, C １－３ Halogenated alkyl group or C ３－６ a cycloalkyl group, or X and Y together with the atoms to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclic group, and the heteroaryl and heterocyclic groups are C １－３ Alkyl group or C １－３ A compound having a structure as shown in formula (1), which can be further substituted with 0 to 2 halogenated alkyl groups, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

2. R or R １ is characterized in that it contains at least one halogen atom 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

3. Each R is F, Cl, Br, Me, Et, OMe, OEt, CF ３ , CN, OCF ３ Or NO ２ independently selected from the group consisting of 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

4. In the formula (1), R １ is selected from the group consisting of H, CN, Me, Et, OMe, OEt, F, Cl or Br 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

5. A is, 【Chemistry 47】 characterized in that the compound is selected from the group consisting of 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

6. The compound has the structure shown in formula (1A): 【Chemistry 48】 In the formula: n is 0, 1 or 2; R is a halogen, CN, a nitro group, C １－３ Alkyl group, C １－３ Halogenated alkyl group or C １－３ alkoxy groups; R １ is a halogen, A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, and benzoheterocyclic group are not limited to halogen, CN, C １－３ Alkyl group, C ３－６ Cycloalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group, C １－３ Halogenated alkoxy group, C １－３ハ Halogenated alkylthio group or SF ５ and may be further substituted by 0 to 4 groups of X is O and Y is C １－３ Alkyl group, C １－３ Halogenated alkyl group or C ３－６ a cycloalkyl group, or X and Y together with the atoms to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclic group, and the heteroaryl and heterocyclic groups are C １－３ Alkyl group or C １－３ It can be further substituted with 0 to 2 halogenated alkyl groups.

10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof. 【Request Item 7】 【Chemistry 49】 wherein "*" indicates the position at which the compound is connected to the benzene ring.

10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

8. The compound is [Transformation 50] having a structure selected from the group consisting of: where n, Y, R, R １ and A are defined as in claim 1.

10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

9. The compound has a structure shown in formula (1B): 【Chemistry 51】 In the formula: 【Chemistry 52】 represents a single or double bond, n is 1, 2 or 3; Each R is independently a halogen, CN, C １－３ Alkyl group, C １－３ Halogenated alkyl group, C １－３ Alkoxy group or C １－３ halogenated alkoxy groups; R １ are H, CN, and C １－３ Alkyl group or C １－３ alkoxy groups; A is selected from the group consisting of a 6- to 10-membered aryl group, a 5- to 7-membered heteroaryl group, a 5- to 7-membered benzocycloalkyl group, or a 5- to 7-membered benzoheterocyclic group, and the aryl group, heteroaryl group, benzocycloalkyl group, and benzoheterocyclic group are not halogenated, CN, C １－３ Alkyl group, C ３－６ Cycloalkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group, C １－３ Halogenated alkoxy group, C １－３ Halogenated alkylthio group or SF ５ which can be further substituted with 0 to 4 groups selected from the group consisting of 10. The compound of claim 1, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

10. The compound has a structure shown in formula (2): 【Chemistry 53】 where: 【Chemistry 54】 represents a single or double bond, n is 0, 1 or 2; R １ is selected from the group consisting of H, F, Cl or Br; each R is independently selected from the group consisting of F, Cl, or Br; 10. The compound according to any one of claims 1 to 9, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

11. A is, 【Transformation 55】 characterized in that the compound is selected from the group consisting of 11. The compound of claim 10, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

12. R １ is H, n is 1 or 2 11. The compound of claim 10, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

13. The compound is characterized in that it has a structure selected from the group consisting of:

2. The compound according to claim 1, its isomer or a pharmaceutically acceptable salt thereof. 【Transformation 56】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

14. A pharmaceutical composition for treating, regulating and / or preventing a disease associated with miR-124 mediation, comprising: The pharmaceutical composition comprises: (1) a compound according to any one of claims 1 to 13 as an active ingredient, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and A pharmaceutical composition for treating, regulating, and / or preventing a disease mediated by miR-124, characterized by optionally containing (2) a pharmaceutically acceptable excipient or carrier.

15. Use of the compound according to any one of claims 1 to 13, or an isomer, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition according to claim 14, The above use, characterized in that it is used for preparing a pharmaceutical composition for treating, regulating and / or preventing a disease associated with miR-124 mediation.

16. The miR-124-mediated disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, brain tumor, gastric cancer, liver cancer, lung cancer, intestinal cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, prostate cancer, AIDS, Crohn's disease, ulcerative colitis, rheumatoid arthritis, allergic rhinitis, osteoarthritis, fibrotic diseases, AIDS, and / or novel coronavirus pneumonia.

16. The use according to claim 15.

17. A process for preparing a compound of formula (1) comprising: It includes the following steps: (1) reacting a compound of formula (A) with its tautomer in an inert solvent to obtain a compound of formula (B); 【Chemistry 57】 (2) reacting a compound of formula (B) with a compound of formula (d) in an inert solvent to obtain a compound of formula (1); 【Transformation 58】 where Z is halogen or OTf, and X, Y, R, R １ , A and n are as defined in claim 1.

18. The compound of formula (1) is a compound of formula (1a), The method also includes the steps of: (s1) reacting a compound of formula (A1) and / or a tautomer thereof in an inert solvent to obtain a compound of formula (B1); 【Chemistry 59】 (s2) reacting the compound of formula (B1) with the compound of formula (d) in an inert solvent to obtain the target compound of formula (1a); 【Transformation 60】 In each formula, Z is halogen or OTf, and R, R １ , A and n are as defined in claim 1.

18. The method of claim 17.

19. The compound of formula (1) is a compound of formula (1b), The method also includes the steps of: (t1) subjecting a compound of formula (C) to a cyclization reaction in an inert solvent to obtain a compound of formula (d); 【Chemistry 61】 (t2) reacting a compound of formula (d) with a compound of formula (d) in an inert solvent to obtain a target compound of formula (1b); 【Transformation 62】 where Z is halogen or OTf, and R, R １ , A and n are as defined in claim 1.

18. The method of claim 17.

20. 1. A method for treating, modulating and / or preventing a disease associated with miR-124 mediation, comprising: A method for treating, regulating, and / or preventing a disease mediated by miR-124, comprising administering to an individual in need thereof a compound according to any one of claims 1 to 13, or any of its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates, or a pharmaceutical composition according to claim 14.

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