Compounds for controlling the activity of microRNA-124

Abstract

The present invention discloses a compound for controlling the activity of microRNA-124. The compound has a structure represented by formula (I) and can be used for the prevention or treatment of inflammatory diseases, including, but not limited to, inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjögren's syndrome, bronchitis, asthma, and colorectal cancer. TIFF2026530085000160.tif39165

Description

[Technical Field]

[0001] This invention belongs to the field of medicinal chemistry and relates to compounds for controlling the activity of microRNA-124, methods for preparing the same, and their medical applications for the treatment of inflammatory diseases. [Background technology]

[0002] RNA interference (RNAi) is a process that effectively silences or represses target gene expression, referring to intracellular mRNA-specific degradation mediated by endogenous or exogenous double-stranded RNA (dsRNA), thereby silencing target gene expression and resulting in the loss of the corresponding functional phenotype. One silencing mechanism involves the inhibition of specific mRNA translation induced by microRNAs.

[0003] MicroRNAs, also known as "mature microRNAs," are small (approximately 18-24 nucleotides long) non-coding RNA molecules encoded within the genomes of plants and animals. In some cases, highly conserved, endogenously expressed microRNAs regulate gene expression by binding to the 3' untranslated region (3'-UTR) of specific mRNAs. To date, 700 different miRNAs have been identified in the human genome, and these are widely involved in various physiological and pathological processes, such as growth, development, and apoptosis through different expression patterns. In recent years, changes in human miRNA levels have been found to be critically associated with various diseases, particularly inflammatory responses, sepsis, ischemia / reperfusion injury, and cancer.

[0004] Current research has found that overexpression of miRNA (i.e., miR-124) initiates an anti-inflammatory cascade. miR-124 targets signaling molecules and activator 3 (STAT3) to regulate cytokine production in macrophages, reducing the secretion of IL-1β, IL-6, and TNF-α, thereby inhibiting Th17 proliferation. Upregulation of miR-124 in macrophages also reduces MCP1 production, thereby limiting neutrophil recruitment, activating macrophage differentiation from M1 to M2, inactivating inflammatory macrophages, and converting them into microglia-like cells. Featuring a novel anti-inflammatory mechanism, Abivax's microRNA therapy ABX464 is under development for multiple inflammatory diseases.

[0005] Overexpression of microRNA-124 in inflammatory responses and its anti-inflammatory cascade demonstrate that microRNA-124-targeted therapies can effectively treat and / or prevent inflammatory diseases. [Overview of the Initiative]

[0006] The present invention provides compounds, pharmaceutical compositions, and methods for preparing the same that control the activity of microRNA-124, which are used medically for the treatment of inflammatory diseases.

[0007] A first aspect of the present invention provides a compound of the following formula (I), or a pharmaceutically acceptable salt thereof, [ka] In the formula, X and Y are selected independently from CH or N. A is selected from cyano, hydroxyl, carboxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, and optionally substituted aromatic rings, wherein the substituents of the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl and aromatic rings are hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr 1 Selected independently from, HetAr 1 This is an optionally substituted 4-10 membered heterocycle, or a 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, HetAr 1 The substituents can be selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl. R1 and R2 are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, and optionally substituted C1-C6 alkylamino, and the substituents of C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkylamino are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino. Alternatively, R¹ and R², together with the carbon atom to which they are bonded, further form an optionally substituted saturated 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring optionally contains a heteroatom selected from N and O, and the substituents of the optionally substituted saturated 5- to 6-membered heterocyclic ring are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C₁~C₆ alkyl, C₁~C₆ haloalkyl, C₁~C₆ alkoxy, C₁~C₆ haloalkoxy, C₁~C₆ alkylamino, and C₁~C₆ haloalkylamino, Alternatively, R¹ and R², together with the carbon atom to which they are bonded, further form an optionally substituted 5- to 6-membered aromatic ring, and the substituents are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C₁~C₆ alkyl, C₁~C₆ haloalkyl, C₁~C₆ alkoxy, C₁~C₆ haloalkoxy, C₁~C₆ alkylamino, and C₁~C₆ haloalkylamino.

[0008] In some other embodiments, the present invention further provides a compound of the following formula (I-1), or a pharmaceutically acceptable salt thereof,

Chemical Formula

[0009] The compounds described in the present invention, the following compounds a to x: [ka] [ka] [ka] The aforementioned compound is excluded.

[0010] Furthermore, in some embodiments of the present invention, in the compound of formula (I), X is CH, Y is N, A is a C2-C6 alkenyl, R1 and R2, together with the carbon atoms to which they are bonded, further form an optionally substituted 5-6 membered aromatic ring, bond to an adjacent benzene ring to form a condensed ring, the substituent is a halogen, and further, R1 and R2, together with the carbon atoms to which they are bonded, form a benzene ring, bond to an adjacent benzene ring to form a condensed ring, the substituent is a halogen.

[0011] The present invention further provides compounds of the following formula (II) or pharmaceutically acceptable salts thereof, [ka] R3 is hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr 2 Selected from, where R is a C1-C6 alkyl, HetAr 2 It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, which bond to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl. R4 is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, where R is C1-C6 alkyl. The following compounds A-U: [ka] [ka] It will be excluded.

[0012] Furthermore, in some embodiments of the present invention, in the compound of formula (II), R3 is HetAr 2 Selected from, HetAr 2R4 is a substituted or unsubstituted 4-6 membered monocyclic aromatic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, bonded to an adjacent benzene ring to form a fused ring, wherein the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl, and further substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, and C1-C3 hydroxyalkyl, where R4 is a halogen.

[0013] Furthermore, in some other embodiments of the present invention, in the compound of formula (II), R3 is HetAr 2 Selected from, HetAr 2 R4 is a substituted or unsubstituted 4- to 6-membered monocyclic saturated heterocycle containing one oxygen atom, bonded to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, cyano, hydroxyl, and carboxyl, where R4 is a halogen.

[0014] The present invention further provides compounds of the following formula (III) or pharmaceutically acceptable salts thereof, [ka] R6 is hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr 3 Selected from, where R is a C1-C6 alkyl group, HetAr 3It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, which bond to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, hydroxyl, and carboxyl. R7 and R8 are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, where R is C1-C6 alkyl.

[0015] Furthermore, in the present invention, the compound of formula (III) is, In some embodiments, R6 is selected from C1-C6 haloalkoxy or C1-C6 haloalkylthio, and R7 and R8 are independently selected from hydrogen, halogen, C1-C6 haloalkyl, and C1-C6 alkoxy. In some more specific embodiments, R6 is selected from C1-C3 haloalkoxy or C1-C3 haloalkylthio, and R7 and R8 are independently selected from hydrogen, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy. In some embodiments, neither R7 nor R8 is hydrogen.

[0016] Furthermore, in the present invention, in the compound of formula (III), in some other embodiments, R6 is HetAr 1 Selected from, this is a substituted or unsubstituted 4-6 member monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, bonded to an adjacent benzene ring to form a fused ring, the substituents are selected from hydrogen and halogens, and R7 and R8 are independently selected from hydrogen and halogens, and in some embodiments, R7 and R8 are both not hydrogen.

[0017] The present invention further provides a compound of the following formula (III-1) or a pharmaceutically acceptable salt thereof, [ka] R6 is hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr 3 Selected from, where R is a C1-C6 alkyl group, HetAr 3 It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, which bond to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, hydroxyl, and carboxyl. R0 is H or [ka] R7 and R8 are halogens, C1-C6 haloalkylaminos, and HetAr 4 , and [ka] Selected independently from, HetAr 4 R is an optionally substituted 4-10 membered heterocycle or 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S, a R is selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl, b and R c is independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl or R b and R cThese, together with the nitrogen atoms to which they are bonded, further form optionally substituted saturated 5-6 membered heterocycles, the 5-6 membered heterocycles optionally containing heteroatoms selected from N and O, and the substituents of the optionally substituted saturated 5-6 membered heterocycles are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino.

[0018] In some embodiments, R6 is selected from C1-C6 haloalkoxy or C1-C6 haloalkylthio, preferably R6 is selected from C1-C3 haloalkoxy or C1-C3 haloalkylthio, and more preferably R6 is trifluoromethyloxy.

[0019] In some embodiments, R7 is selected from F, Cl, or Br.

[0020] In some embodiments, R0 is H.

[0021] In some embodiments, R7 is a halogen, and R8 is HetAr 4 or [ka] Selected from, preferably HetAr 4 HetAr is an arbitrarily substituted 4-10 membered heterocycle having 1-3 heteroatoms independently selected from N, O, or S. 4 Preferred substituents are selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, butyl, and C1-C3 haloalkyl.

[0022] In some embodiments, R a R is selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, and butyl. b and R cThis is independently selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, and butyl, or R b and R c These, together with the nitrogen atoms to which they are bonded, further form an optionally substituted saturated 5-6 membered heterocycle containing N and O, wherein the substituents of the 5-6 membered heterocycle are independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino, preferably R b and R c is independently selected from methyl, ethyl, propyl, and butyl, or R b and R c These, together with the nitrogen atoms to which they are bonded, further form a saturated 5-6 membered heterocycle containing N and O.

[0023] The present invention also relates to the following compounds 1-7 and 9-51, or pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka] To provide.

[0024] Another aspect of the present invention relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] Includes.

[0025] The compound of formula (Ia) or a pharmaceutically acceptable salt thereof and the compound of formula (Ib) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (I) or a pharmaceutically acceptable salt thereof. In the formula, B is a halogen, preferably a chlorine atom, and X, Y, R1 and R2 are as defined in formula (I).

[0026] Another aspect of the present invention relates to a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, the method being as follows: [ka] Includes.

[0027] The compound of formula (IIa) or a pharmaceutically acceptable salt thereof and the compound of formula (IIb) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (II) or a pharmaceutically acceptable salt thereof. In the formula, B is a halogen, preferably a chlorine atom, and R3 and R4 are as defined in formula (II).

[0028] Another aspect of the present invention relates to a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method being described below: [ka] Includes.

[0029] The compound of formula (IIIa) or a pharmaceutically acceptable salt thereof and the compound of formula (IIIb) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (III) or a pharmaceutically acceptable salt thereof. In the formula, B is a halogen, preferably a chlorine atom, and R6, R7, and R8 are as defined in formula (III).

[0030] The present invention further provides pharmaceutical compositions comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0031] The present invention also provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof as microRNA-124 regulators.

[0032] The present invention also provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in the prevention or treatment of inflammatory diseases.

[0033] The inflammatory diseases described in the present invention include, but are not limited to, inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjögren's syndrome, bronchitis, asthma, and colorectal cancer, and in particular, inflammation associated with inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, bronchitis, and colorectal cancer.

[0034] The present invention also includes methods for synthesizing the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0035] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0036] The term "alkyl," used alone or as part of a larger group such as "alkoxy" or "alkylamino" and similar terms, means a saturated aliphatic linear or branched monovalent hydrocarbon radical. Unless otherwise specified, alkyl groups generally have 1 to 6 carbon atoms, i.e., (C1-C6) alkyl. As used herein, (C1-C6) alkyl means a radical having 1 to 6 carbon atoms arranged linearly or branchedly. Examples include methyl, ethyl, n-propyl, and isopropyl.

[0037] "Alkenyl" refers to a branched or linear monovalent hydrocarbon radical containing at least one double bond. Alkenyl groups can be monounsaturated or polyunsaturated and can exist in E or Z configurations. Unless otherwise specified, alkenyl groups generally have 2 to 6 carbon atoms, i.e., (C2-C6) alkenyls. For example, "(C2-C6) alkenyl" refers to a radical having 2 to 6 carbon atoms arranged linearly or branchedly. "Alkynyl" refers to a branched or linear monovalent hydrocarbon radical containing at least one triple bond. Unless otherwise specified, alkynyl groups usually have 2 to 6 carbon atoms, i.e., (C2-C6) alkynyls. For example, "(C2-C6) alkynyl" refers to a radical having 2 to 6 carbon atoms arranged linearly or branchedly.

[0038] "Alkoxy" refers to alkyl radicals, represented as -O-alkyl, that are bonded via an oxygen-bonding atom. For example, "(C1-C6) alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0039] "Alkylthio" refers to alkyl radicals, represented as -S-alkyl, that are bonded via a sulfur-bonding atom. For example, "(C1~C6) alkylthio" includes methylthio, ethylthio, propylthio, and butylthio.

[0040] "Cycloalkyl" refers to saturated aliphatic cyclic hydrocarbon radicals, i.e., (C3-C6) cycloalkyls, which generally contain 3 to 6 ring carbon atoms. Examples of (C3-C6) cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0041] The term "alkylamino" refers to an alkyl or alkoxy group to which one or more amino groups are optionally attached. It is represented by -N-alkyl, -NH-alkyl, or NH2-alkyl. For example, "(C1-C6) alkylamino" includes methoxy, ethoxy, propoxy, and butoxy.

[0042] A "monocyclic heterocycle" means a saturated or unsaturated 4-7 membered ring radical that, when used alone or as part of a larger group, generally contains one or more double bonds and typically has a carbon atom and 4-7 ring atoms selected from at least one (generally 1-4, more commonly 1 or 2) heteroatoms (e.g., oxygen, nitrogen). A "substituted monocyclic heterocycle" is one which is substituted with any one or more substituteable ring atoms (ring carbon atoms bonded to hydrogen). A "monocyclic saturated heterocycle" means a saturated 4-7 membered ring radical that does not contain double bonds and generally has a carbon atom and 4-7 ring atoms selected from at least one (generally 1-4, more commonly 1 or 2) heteroatoms (e.g., oxygen, nitrogen). The term "monocyclic heterocyclil" is intended to include all possible isomer forms.

[0043] When used alone or as part of a larger group, "monocyclic aromatic heterocyclic" refers to an unsaturated 4-6 membered ring radical, and generally refers to an aromatic ring group having carbon and 4-6 ring atoms selected from at least one (generally 1-4, more commonly 1 or 2) heteroatoms (e.g., oxygen, nitrogen). Examples of monocyclic 4- to 6-membered heteroaryls include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), and pyrrolyl. Examples include (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (e.g., 2-pyridinyl, 4-pyridinyl, 5-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl).

[0044] A "condensed ring" refers to a bicyclic system consisting of two adjacent rings that share two common atoms.

[0045] Certain compounds described herein may exist in various stereoisomers or tautomers. Stereoisomers are compounds that differ only in their spatial arrangement. Where compounds in this disclosure are named or shown structurally without indicating their stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, geometric isomers, including substantially pure stereoisomers or geometric isomers, and combinations thereof. [Modes for carrying out the invention]

[0046] Detailed description of the embodiment The present invention will be further described below in conjunction with specific embodiments based on general technical knowledge and prior art. The following embodiments are merely some preferred examples of the present invention and should not be construed as limiting the invention. Those skilled in the art can make several modifications without departing from the scope of the invention, and these modifications should also be considered to fall within the scope of protection of the present invention. [Examples]

[0047] Example 1: Synthesis of Compound 1 [ka] A 25 mL round-bottom flask was filled with nitrogen, and compound 1a (198 mg, 1.0 mmol, Bide Pharmatech), compound 1b (189 mg, 1.0 mmol, Bide Pharmatech), xanthophos (29 mg, 0.05 mmol), Pd(OAc)2 (8.5 mg, 0.05 mmol), cesium carbonate (978 mg, 3.0 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 20 hours. The reaction was stopped, and the mixture was evaporated under reduced pressure. Water (40 mL) was added, the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined, concentrated, and purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 1 (200 mg).

[0048] [ka]

[0049] Example 2: Synthesis of Compound 2 [ka] Compound 1a (800 mg, 1.0 eq, Bide Pharmatech), Compound 2a (519 mg, 1.2 eq, Energy Chemical), Pd(OAc)2 (91 mg, 0.1 eq), Cesium carbonate (2.6 g, 2.0 eq), and Xanthophos (701 mg, 0.3 eq) were added to a 75 mL sealed tube. Tert-butanol (10 mL) was added and thoroughly mixed. The mixture was then heated and stirred in an oil bath at 110 °C under argon protection for 20 hours. The reaction was stopped, methanol (20 mL) was added, and the mixture was filtered by suction. The filtrate was washed with methanol. The filtrate was concentrated and purified by column chromatography (PE:EA = 100:1~4:1, v / v) to obtain Compound 2 (230 mg).

[0050] [ka]

[0051] Example 3: Synthesis of Compound 3 [ka] The method for preparing compound 3b described above was as follows: Compound 1a (2g, 1.0eq, Bide Pharmatech), Compound 3a (3.67g, 2.0eq, Bide Pharmatech), Pd2(dba)3 (925mg, 0.1eq), BINAP (1.26g, 0.2eq), and Cs2CO3 (9.87g, 3.0eq) were added to a sealed tube, followed by the addition of 1,4-dioxane (20mL). The mixture was heated and stirred at 100°C. After the reaction was complete, water (100mL) was added, and the mixture was extracted with ethyl acetate (3×50mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain crude product 3b (4g).

[0052] The preparation method for compound 3c was as follows: Crude compound 3b (4 g) obtained from Preparation Example 1 was dissolved in tetrahydrofuran (10 mL) in a one-necked flask, concentrated hydrochloric acid was added dropwise, and a white solid precipitate was obtained at the bottom of the flask. The mixture was filtered by aspirate, and the filtered cake was dried to obtain compound 3c (2 g).

[0053] The preparation method for compound 3d was as follows: Compound 3c (1.75 g, 1.0 eq), (Boc)2O (3.72 g, 2.1 eq, Energy Chemical), DIPEA (3.15 g, 3.0 eq), and 4-DMAP (994 mg, 1.0 eq) were added to a sealed tube, followed by the addition of 1,4-dioxane (20 mL). The mixture was heated and stirred overnight at 100°C. After the reaction was complete, (100 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 3d (740 mg).

[0054] The preparation method for compound 3f described above was as follows: Compound 3d (740 mg, 1.0 eq) was added to a one-necked flask, then dissolved in 10 mL of DMF, followed by the addition of NaH (159 mg, 1.5 eq). The mixture was stirred at room temperature for 0.5 hours. Compound 3e (353 mg, 1.1 eq, Energy Chemical) was then added, and the mixture was stirred at room temperature. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3f (400 mg), which was used directly in the next step without purification.

[0055] Synthesis of compound 3 above: Compound 3f was added to a necked flask, followed by the addition of HCl / EA (2 mL, 10 eq), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was evaporated to dryness and purified by column chromatography to obtain compound 3 (220 mg).

[0056] [ka]

[0057] Example 4: Synthesis of Compound 4 [ka] The preparation method for compound 3f described above was as follows: Compound 4a (2 g, 1.0 eq, Bide Pharmatech), reduced iron powder (1.73 g, 3.0 eq), ammonium chloride (498 mg, 0.9 eq), and mixed solvent (10 mL ethanol / water = 3:1, v / v) were added to a one-necked flask. The mixture was heated under reflux at 80°C for approximately 12 hours. After the reaction was complete, methanol was added to dissolve the mixture, and then it was filtered by suction. The filtration cake was washed with methanol, evaporated to dryness, and then separated and purified by column chromatography to obtain compound 4b (1.6 g). Synthesis of compound 4: In a sealed tube, compound 4b (200 mg, 1.0 eq), compound 1a (218 mg, 0.9 eq, Bide Pharmtech), Pd(OAc)2 (28 mg, 0.1 eq), cesium carbonate (799 mg, 2.0 eq), and xanthophos (213 mg, 0.3 eq) were added, followed by the addition of tert-butanol (10 mL). The mixture was thoroughly mixed, argon purging was performed for protection, and the sealed tube was closed. The reaction mixture was heated and stirred in an oil bath at 110°C for 4 hours. After the reaction was complete, 20 mL of methanol was added, and the mixture was filtered by suction. The filtrate was washed with methanol. The filtrate was concentrated and separated and purified by column chromatography (PE:EA = 100:1~4:1, v / v) to obtain compound 4 (80 mg).

[0058] [ka]

[0059] Example 5: Synthesis of Compound 5 [ka] The preparation method for compound 5b was as follows: A 100 mL round-bottom flask was filled with nitrogen, followed by the sequential addition of sodium hydroxide (12 g, 299 mmol) and DMF (50 mL). The mixture was heated to 95 °C and reacted for 0.5 hours. Next, a solution of compound 5a (5 g, 29.9 mmol, Bide Pharmatech) and compound 2-chloro-2,2-difluoroacetate sodium (23 g, 149 mmol, Bide Pharmatech) in DMF was added dropwise. After the addition was complete, the reaction was continued for 1.5 hours. Once the reaction was complete, water (100 mL) was added, the mixture was extracted with ethyl acetate (3 × 50 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (PE:EA = 100:1 ~ 15:1, v / v) to obtain compound 5b (5.6 g).

[0060] The preparation method for compound 5c was as follows: Compound 5b (3 g, 13.8 mmol), 10% palladium-carbon (300 mg), and methanol (20 mL) were successively added to a 50 mL round-bottom flask. The reaction was carried out overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered by suction, the filtration cake was washed with methanol, and the mixture was concentrated to obtain compound 5c (2.56 g).

[0061] Synthesis of Compound 5 A 25 mL round-bottom flask was packed with nitrogen, and compound 1a (198 mg, 1.0 mmol, Bide Pharmatech), compound 5c (187 mg, 1.0 mmol), xanthophos (29 mg, 0.05 mmol), Pd(OAc)2 (8.5 mg, 0.05 mmol), cesium carbonate (978 mg, 3.0 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 20 hours. The reaction was stopped, and the mixture was evaporated to dryness under reduced pressure. Water (40 mL) was added, the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 5 (156 mg).

[0062] [ka]

[0063] Example 6: Synthesis of Compound 6 [ka] The preparation method for compound 6a was as follows: Compound 5b (1.0 g, 4.61 mmol) and anhydrous THF (15 mL) were added to a 50 mL round-bottom flask and cooled to 0°C. Subsequently, NaH (221 mg, 5.53 mmol) and p-toluenesulfonyl chloride (1.76 g, 9.21 mmol) were added in small increments. After the addition was complete, the reaction was continued at 10°C for 3 hours. Once the reaction was complete, the reaction was stopped with saturated ammonium chloride solution, extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 100:1~25:1, v / v) to obtain compound 6a (1.0 g).

[0064] The preparation method for compound 6b described above was as follows. Compound 6a (1 g, 2.69 mmol), 10% palladium-carbon (300 mg), ethyl acetate (15 mL), and tetrahydrofuran (15 mL) were added sequentially to a 50 mL round-bottom flask. The reaction was carried out overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered under vacuum. The filtered cake was washed with methanol and concentrated to obtain compound 6c (400 mg).

[0065] Synthesis of Compound 6 A 25 mL round-bottom flask was packed with nitrogen, and compound 1a (198 mg, 1.0 mmol, Bide Pharmatech), compound 6b (171 mg, 1.0 mmol), xanthophos (29 mg, 0.05 mmol), Pd(OAc)2 (8.5 mg, 0.05 mmol), cesium carbonate (978 mg, 3.0 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 20 hours. The reaction was stopped, and the mixture was evaporated to dryness under reduced pressure. Water (40 mL) was added, the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 6 (90 mg).

[0066] [ka]

[0067] Example 7: Synthesis of Compound 7 [ka] The preparation method for compound 7a was as follows: Compound 4a (1 g, 1.0 eq, Bide Pharmatech), TFA (10 mL), and CHCl3 (4 mL) were added sequentially to a one-necked flask. After stirring to dissolve, trimethylsilane (1 g, Energy Chemical) was slowly added dropwise, and the mixture was stirred overnight at room temperature. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with dichloromethane (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated to obtain crude compound 7a (900 mg).

[0068] The preparation method for compound 7b was as follows: Compound 7a (900 mg, 1.0 eq) was added to a one-necked flask, the mixture was dissolved in methanol, then 10% palladium-carbon (50 mg) was added, the system was subjected to hydrogen displacement, and the reaction was carried out by heating at 40°C overnight. After the reaction was complete, the mixture was filtered by suction to remove the palladium-carbon, and the filtrate was concentrated to obtain compound 7b (450 mg). Synthesis of compound 7: Compound 7b (440 mg, 1.0 eq), Compound 1a (292 mg, 0.5 eq, Bide Pharmatech), Pd(OAc)2 (66 mg, 0.1 eq), Cesium carbonate (1.92 g, 2.0 eq), and Xanthophos (512 mg, 0.3 eq) were added to a sealed tube, followed by 3 mL of tert-butanol. The mixture was thoroughly mixed, argon purging was performed for protection, and the sealed tube was closed. The reaction mixture was heated and stirred in an oil bath at 110°C for 4 hours. After the reaction was complete, twice the volume of methanol was added, and the mixture was filtered by suction. The filtered cake was washed with methanol. After spin-drying the organic phase, the residue was purified by column chromatography (PE / EA: 100: 1-3: 1, v / v) to obtain Compound 7 (50 mg).

[0069] [ka]

[0070] Example 8: Synthesis of Compound 8 (disclosed in Example 1 of PCT / CN2022 / 095441) [ka] A 25 mL round-bottom flask was packed with nitrogen, and compound 1a (198 mg, 1.0 mmol, Bide Pharmatech), compound 8a (173 mg, 1.0 mmol, Bide Pharmatech), xanthophos (29 mg, 0.05 mmol), Pd(OAc)2 (8.5 mg, 0.05 mmol), cesium carbonate (978 mg, 3.0 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 100 °C and reacted for 20 hours. The reaction was stopped, and the mixture was evaporated to dryness under reduced pressure. Water (40 mL) was added, the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 8 (89 mg).

[0071] [ka]

[0072] Example 9: Synthesis of Compound 9 [ka] A 25 mL round-bottom flask was packed with nitrogen, and compound 1a (300 mg, 2.1 mmol, Bide Pharmatech), compound 9a (300 mg, 1.5 mmol, Energy Chemical), xanthophos (29 mg, 0.05 mmol), Pd(OAc)2 (8.5 mg, 0.05 mmol), cesium carbonate (978 mg, 3.0 mmol), and tert-butanol (10 mL) were added sequentially. The mixture was heated to 90°C and reacted for 20 hours. The reaction was stopped, and the mixture was evaporated to dryness under reduced pressure. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 9 (210 mg).

[0073] [ka]

[0074] Example 10: Synthesis of Compound 10 [ka] Compound 1a (200 mg, 1 mmol, Bide Pharmatech), Compound 10a (175 mg, 1.2 mmol, Bide Pharmatech), Pd2(dba)3 (92.5 mg, 0.1 mmol), BINAP (188.6 mg, 0.3 mmol), and Cs2CO3 (658 mg, 2 mmol) were added to a sealed tube, followed by the addition of tert-butanol (10 mL) as the solvent. The mixture was subjected to Ar substitution and reacted at 90°C for 3 hours. After the reaction was complete, the reaction was stopped and the mixture was evaporated to dryness under reduced pressure. Water (40 mL) was added, the mixture was extracted with ethyl acetate (3 × 25 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 100:1~2:1, v / v) to obtain Compound 10 (110 mg).

[0075] [ka]

[0076] Example 11: Synthesis of Compound 11 [ka] Compound 1a (200 mg, 1 mmol, Bide Pharmatech), Compound 11a (283.6 mg, 1.5 mmol), and trifluoroacetic acid (138.2 mg, 1.2 mmol, Energy Chemical) were added to a sealed tube, followed by the addition of isopropanol (6 mL) as the solvent. The atmosphere was changed to Ar, and the reaction was carried out at 90°C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with DCM (20 mL x 4), the combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. Purification by column chromatography (DCM / MeOH = 100:1~10:1, v / v) yielded product 11 (37 mg).

[0077] [ka]

[0078] Example 12: Synthesis of Compound 12 [ka] Compound 1a (200 mg, 1 mmol, Bide Pharmatech), Compound 12a (336 mg, 1.5 mmol, Energy Chemical), and p-toluenesulfonic acid (174 mg, 1 mmol) were added to a sealed tube, followed by the addition of isopropanol (6 mL) as the solvent. The atmosphere was changed to Ar, and the reaction was carried out at 90°C for 12 hours. After the reaction was complete, the reaction mixture was quenched with water, extracted with EA (20 mL x 4), the combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product; the product was purified by column chromatography (DCM / MeOH = 100:1~10:1, v / v) to obtain product 12 (100 mg).

[0079] [ka]

[0080] Example 13: Synthesis of Compound 13 [ka] The preparation method for compound 13b was as follows: Under ice bath cooling, NaH (1.26 g, 31.5 mmol) was gradually added to a solution of compound 13a (2.0 g, 10.5 mmol, Bide Pharmatech) in DMF (20 mL) in a 75 mL sealed tube. After stirring for 10 minutes, t-BuOK (1.3 g, 11.6 mmol) and CF2Br2 (8.8 g, 42.0 mmol, Energy Chemical) were gradually added to the mixture. The tube was quickly sealed and heated to 70°C and allowed to react overnight. After the reaction was complete, the reaction solution was quenched with water, extracted with EA (20 mL x 4), the combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE=100%) to obtain compound 13b (1.8 g) as a colorless oil.

[0081] The preparation method for compound 13c was as follows: Under N2 conditions, compound 13b (4.0 g, 11.4 mmol) was dissolved in anhydrous DCM (60 mL), cooled to -78°C, and then AgBF4 (4.9 g, 25.2 mmol, Energy Chemical) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. NaHCO3 solution was added to the mixture until the pH exceeded 8. The mixture was extracted with DCM (30 mL x 4), the combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 13c (2.2 g) as brown oil. The preparation method for compound 13d was as follows: Compound 13c (210 mg, 0.72 mmol), benzophenone imine (156 mg, 0.86 mmol, Bide Pharmatech), Pd2(dba)3 (16 mg), BINAP (11 mg), potassium tert-butoxide (112 mg, 1.0 mmol), and 5 mL of anhydrous dioxane were sequentially added to a 25 mL sealed tube. The mixture was heated to 90°C and reacted for 4 hours. After the reaction was complete, the mixture was quenched with water, extracted with EA (20 mL x 4), the combined organic phase was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EA = 100:1 to 30:1, v / v) to obtain compound 13d (200 mg).

[0082] The preparation method for compound 13e was as follows: Compound 13d (200 mg, 0.51 mmol) was dissolved in 5 mL of methanol, and 1 N HCl (2 mL) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated to obtain compound 13e (79 mg).

[0083] Synthesis of compound 13: Compound 13e (270 mg, 1.52 mmol, 1.0 eq), isopropanol (10 mL), compound 1a (357 mg, 1.8 mmol, 1.5 eq, Bide Pharmatech), and CF3COOH (107 mg, 1.44 mmol, 1.2 eq) were added sequentially to a 75 mL sealed tube. The tube was sealed and heated to 100 °C for 48 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate / water. The combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EA = 100:1 to 97:3, v / v) to obtain compound 13 (200 mg).

[0084] [ka]

[0085] Example 14: Synthesis of Compound 14 [ka] The preparation method for compound 14b was as follows: Compound 14a (350 mg, 1.72 mmol, Bide Pharmatech), dissolved in methanol, was added to a one-necked flask, followed by 10% palladium-carbon (50 mg). The mixture was hydrogenated and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered by suction to remove the palladium-carbon, and the filtrate was concentrated to obtain compound 14b (250 mg).

[0086] Synthesis of compound 14: Compound 1a (200 mg, 1 mmol, Bide Pharmatech), compound 14b (210 mg, 1.2 mmol), Pd(OAc)2 (22.7 mg, 0.1 mmol), xanthophos (175.3 mg, 0.3 mmol), and Cs2CO3 (658 mg, 2 mmol) were added to a sealed tube. Then, tert-butanol (10 mL) was added as the solvent, the mixture was replaced with Ar, and the reaction was carried out at 90°C for 5 hours. After the reaction was complete, the reaction solution was quenched with water and extracted with EA (20 mL x 4). The combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. Compound 14 (80 mg) was obtained by purification by column chromatography (PE / EA = 100:1~3:1, v / v).

[0087] [ka]

[0088] Example 15: Synthesis of Compound 15 [ka] The preparation method for compound 15b was as follows: Compound 15a (350 mg, 1.57 mmol, Bide Pharmatech) dissolved in methanol was added to a one-necked flask, followed by 10% palladium-carbon (50 mg). The mixture was hydrogenated and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered by suction to remove the palladium-carbon, and the filtrate was concentrated to obtain compound 14b (220 mg).

[0089] Synthesis of Compound 15: Compound 1a (200 mg, 1 mmol, Bide Pharmatech), Compound 15b (195 mg, 1.2 mmol), Pd2(dba)3 (92.5 mg, 0.1 mmol), BINAP (188.6 mg, 0.3 mmol), and Cs2CO3 (658 mg, 2 mmol) were added to a sealed tube. Next, tert-butanol (10 mL) was added as the solvent, the mixture was replaced with Ar, and the reaction was carried out at 90°C for 4 hours. After the reaction was complete, water was added to the reaction solution, and the system was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain Compound 15 (120 mg).

[0090] [ka]

[0091] Example 16: Synthesis of Compound 16 [ka] Compound 16a (200 mg, 1.36 mmol, Bide Pharmatech), Compound 1a (140 mg, 0.71 mmol, Bide Pharmatech), and TFA (122 mg, 1.07 mmol) were added to a sealed tube. The mixture was dissolved in 5 mL of isopropanol, the system was heated, and the reaction was carried out overnight at 100°C. After the reaction was complete, 10 mL of water was added, and the pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~6:1, v / v) to obtain Compound 16 (50 mg).

[0092] [ka]

[0093] Example 17: Synthesis of Compound 17 [ka] Compound 17a (200 mg, 1.5 mmol, Bide Pharmatech), compound 1a (149 mg, 0.75 mmol, Bide Pharmatech), and TFA (134 mg, 1.18 mmol) were added to a sealed tube. The mixture was dissolved in 5 mL of isopropanol, the system was heated, and the reaction was carried out overnight at 100°C. After the reaction was complete, 10 mL of water was added, and the pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~6:1, v / v) to obtain compound 17 (200 mg).

[0094] [ka]

[0095] Example 18: Synthesis of Compound 18 [ka] Compound 18a (200 mg, 1.5 mmol, Bide Pharmatech), isopropanol (10 mL), and compound 1a (446 mg, 2.25 mmol, Bide Pharmatech) were added sequentially to a 75 mL sealed tube, followed by the addition of CF3COOH (134 mg, 1.8 mmol). The mixture was heated at 100 °C for 48 hours. After the reaction was complete, 30 mL of water was added to obtain a solid precipitate. The solid was filtered by suction to obtain compound 18 (100 mg).

[0096] [ka]

[0097] Example 19: Synthesis of Compound 19 [ka] Compound 1a (416 mg, 1.4 mmol), isopropanol (10 mL), and compound 19a (200 mg, 2.1 mmol, Energy Chemical) were added sequentially to a 75 mL sealed tube, followed by the addition of CF3COOH (125 mg, 1.68 mmol). The mixture was heated at 100 °C for 48 hours. After the reaction was complete, water (30 mL) was added to obtain a solid precipitate. The solid was filtered by suction to obtain compound 19 (200 mg).

[0098] [ka]

[0099] Example 20: Synthesis of Compound 20 [ka] The preparation method for compound 20b was as follows: Compound 20a (350 mg, 1.83 mmol, Bide Pharmatech) dissolved in methanol was added to a one-necked flask, followed by 10% palladium-carbon (50 mg). The mixture was hydrogenated and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered by suction to remove the palladium-carbon, and the filtrate was concentrated to obtain compound 20b (230 mg).

[0100] Synthesis of compound 20: Compound 1a (200 mg, 1 mmol, Bide Pharmatech), compound 20a (162.6 mg, 1.2 mmol), Pd2(dba)3 (92.5 mg, 0.1 mmol), BINAP (188.6 mg, 0.3 mmol), and Cs2CO3 (658 mg, 2 mmol) were added to a sealed tube. Next, tert-butanol (10 mL) was added as the solvent, the mixture was substituted with Ar, and the reaction was carried out at 90°C for 4 hours. After the reaction was complete, the reaction solution was quenched with water and extracted with EA (20 mL x 4). The combined organic phases were separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 20 (100 mg).

[0101] [ka]

[0102] Example 21: Synthesis of Compound 21 [ka] The preparation method for compound 21b was as follows: Compound 21a (1 g, 1.0 eq, Bide Pharmatech), NCS (1.04 g, 1.2 eq, Bide Pharmatech), and 10 mL of chloroform were added to a single-necked flask. The mixture was heated and reacted at 90°C for 4 hours. After the reaction was complete, the reaction solution was distilled and evaporated to dryness under reduced pressure to obtain crude compound 21b (0.6 g).

[0103] Synthesis of compound 21: Compound 21b (300 mg, 1.0 eq), compound 21c (339 mg, 1.2 eq, Bide Pharmatech), Pd(OAc)2 (36 mg, 0.1 eq), cesium carbonate (1.04 g, 2.0 eq), and xanthophos (277 mg, 0.3 eq) were added to a sealed tube, followed by 5 mL of tert-butanol. The mixture was protected by argon displacement, heated, and reacted in an oil bath at 110°C for 10 hours. After the reaction was complete, twice the volume of methanol was added, and the reaction mixture was filtered by suction. The filtrate was washed with methanol. The filtrate was concentrated and purified by column chromatography (PE:EA = 100:1~6:1, v / v) to obtain compound 21 (30 mg).

[0104] [ka]

[0105] Example 22: Synthesis of Compound 22 [ka] The preparation method for compound 22b was as follows: In a sealed tube, compound 22a (2.75 g, 1.0 eq, Bide Pharmatech) and urea (10.62 g, 10.0 eq) were added, and the mixture was heated and stirred at 180°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and ice water was added while stirring. The mixture was filtered by suction, and the filter cake was washed with ice water. The solid was dissolved in a mixture of 200 mL of saturated sodium carbonate and 250 mL of water, and extracted with EA until no impurities remained in the aqueous phase. The pH was adjusted to 5-6 with concentrated HCl, stirred for 1 hour, and filtered by suction to obtain compound 22b (2.35 g).

[0106] The preparation method for compound 22c was as follows: Compound 22b (2.35 g, 1.0 eq), phosphorus oxychloride (3.99 g, 2.0 eq, Energy Chemical), and 20 mL of toluene were added to a single-necked flask, and the mixture was heated under reflux at 110°C for 6 hours. After the reaction was complete, the reaction solution was concentrated to dryness to obtain compound 22c (800 mg), which was used directly in the next step without purification.

[0107] Synthesis of compound 22: Compound 22c (800 mg, 1.0 eq), compound 21c (854 mg, 1.2 eq, Bide Pharmatech), and p-toluenesulfonic acid (830 mg, 1.0 eq) were added to a sealed tube and dissolved in 2-pentanol. The mixture was then heated and reacted at 105°C for 5 hours. After the reaction was complete, 2-pentanol was evaporated to dryness, water (30 mL) was added, and the mixture was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~5:1, v / v) to obtain 20 mg of compound 22.

[0108] [ka]

[0109] Example 23: Synthesis of Compound 23 [ka] The preparation method for compound 23b was as follows: Compound 23a (2 g, 1.0 eq, Bide Pharmatech), reduced iron powder (1.8 g, 3.0 eq), NH4Cl (1.8 g, 3.0 eq), and 40 mL of ethanol / water (3:1) were added to a one-necked flask, and the mixture was refluxed at 100°C overnight. After filtering to remove the iron powder, the ethanol was evaporated to dryness, and the mixture was extracted with water and EA. The organic phase was evaporated to dryness to obtain compound 23b (1.2 g).

[0110] The preparation method for compound 23c was as follows: Compound 23b (1.2 g, 1.0 eq) and urea (4.24 g, 10.0 eq, Bide Pharmatech) were added to a sealed tube, and the mixture was heated and stirred at 180°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and ice water was added while stirring. The mixture was filtered by suction, and the filtered cake was washed with ice water. The water in the filtered cake was evaporated to dryness to obtain compound 23c (1.2 g).

[0111] The preparation method for compound 23d was as follows: Compound 3 (1.1 g, 1.0 eq) and 10 mL of POCl3 were added to a one-necked flask, and the mixture was stirred under reflux at 110°C for 4 hours. After the reaction was complete, most of the POCl3 was removed by distillation under reduced pressure, and the remaining POCl3 was quenched with ice water. Solid impurities were removed by suction filtration, and the mixture was extracted with EA. The organic phase was evaporated to dryness to obtain compound 23d (400 mg).

[0112] Synthesis of compound 23: Compound 23d (400 mg, 1.0 eq), compound 21c (392 mg, 1.1 eq, Bide Pharmtech), and TsOH (415 mg, 1.2 eq) were added to a sealed tube. The mixture was dissolved in 2-pentanol and heated under reflux at 105°C for 4 hours. After the reaction was complete, 2-pentanol was removed by distillation under reduced pressure, water (30 mL) was added, and the mixture was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~4:1, v / v) to obtain compound 23 (55 mg).

[0113] [ka]

[0114] Example 24: Synthesis of Compound 24 [ka] The preparation method for compound 24b was as follows: Compound 5-chloro-2-fluorobenzaldehyde (24a, 3.02 g, 19.1 mmol, Bide Pharmatech) was dissolved in DMAC (10 mL), and four times the volume of guanidine carbonate (4 eq, Bide Pharmatech) was added. The mixture was reacted at 140°C for 3 hours. TLC monitoring showed no residual starting material, so heating was stopped, the mixture was cooled to room temperature, and then 100 mL of water was added. The mixture was cooled overnight at 0°C. The mixture was filtered by suction and dried in an oven to obtain the yellow solid compound 24b (2.2 g).

[0115] Synthesis of compound 24: In a round-bottom flask, 24b (180 mg, 1.0 mmol), dioxane (75 mL), 24c (240 mg, 1.0 mmol, Bide Pharmatech), Pd2(dba)3 (46 mg, 0.05 mmol), cesium carbonate (480 mg, 1.5 mmol), and xanthophos (29 mg, 0.05 mmol) were added sequentially. The mixture was then heated to 115°C under nitrogen protection and reacted for 6 hours. The reaction was stopped, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (3 × 20 mL) to combine the organic phases. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to silica gel column chromatography (PE / EA = 4:1 to 2:1, v / v) to obtain a yellow solid compound 24 (120 mg).

[0116] [ka]

[0117] Example 25: Synthesis of Compound 25 [ka] The preparation method for compound 25b was as follows: Compound 25a (3.0 g, 17.0 mmol, Bide Pharmatech) was dissolved in DMAC (10 mL), and four times the volume of guanidine carbonate (4 eq, Bide Pharmatech) was added. The mixture was reacted at 140°C for 3 hours. TLC monitoring showed no residual starting material, so heating was stopped, the mixture was cooled to room temperature, and then 100 mL of water was added. The mixture was cooled overnight at 0°C. The mixture was filtered by suction and oven-dried to obtain compound 25b (2.3 g) as a yellow solid. This was used directly in the next step without purification.

[0118] Synthesis of compound 25: In a round-bottom flask, 25b (198 mg, 1.0 mmol), dioxane (75 mL), 24c (240 mg, 1.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), cesium carbonate (480 mg, 1.5 mmol), and xanthophos (29 mg, 0.05 mmol) were added sequentially. The mixture was then heated to 115°C under nitrogen protection and reacted for 6 hours. The reaction was stopped, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (3 × 20 mL) to combine the organic phases. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to silica gel column chromatography (PE / EA = 4:1 to 2:1, v / v) to obtain a yellow solid compound 25 (110 mg).

[0119] [ka]

[0120] Example 26: Synthesis of Compound 26 [ka] Compound 22c (400 mg, 1.0 eq), compound 8a (418 mg, 1.2 eq, Bide Pharmatech), and TFA (179 mg, 1.2 eq) were added to a sealed tube. The mixture was dissolved in 5 mL of isopropanol, the system was heated, and stirred overnight at 100°C. After the reaction was complete, 10 mL of water was added, and the pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 26 (70 mg).

[0121] [ka]

[0122] Example 27: Synthesis of Compound 27 [ka] Compound 23d (200 mg, 1 mmol), compound 8a (191.4 mg, 1.1 mmol, Bide Pharmatech), and p-toluenesulfonic acid (207.6 mg, 1.2 mmol) were added to a sealed tube, followed by the addition of sec-amyl alcohol (6 mL) as the solvent. The atmosphere was changed to Ar, and the reaction was carried out at 90°C for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and then it was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 27 (30 mg).

[0123] [ka]

[0124] Example 28: Synthesis of Compound 28 [ka] Compound 22c (400 mg, 1.0 eq), compound 28a (384 mg, 1.2 eq, Bide Pharmatech), and p-toluenesulfonic acid (346 mg, 1.0 eq) were added to a sealed tube and dissolved in 2-pentanol. The mixture was then heated and stirred at 105°C for 10 hours. After the reaction was complete, 2-pentanol was evaporated to dryness, 10 mL of water was added, and the pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 28 (88 mg).

[0125] [ka]

[0126] Example 29: Synthesis of Compound 29 [ka] Compound 22c (500 mg, 1.0 eq), Compound 19a (94 mg, 0.25 eq, Energy Chemical), and p-toluenesulfonic acid (233 mg, 1.2 eq) were added to a sealed tube and dissolved in 2-pentanol. The mixture was then heated and stirred at 105°C for 10 hours. After the reaction was complete, 2-pentanol was evaporated to dryness, 10 mL of water was added, and the pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain Compound 29 (88 mg).

[0127] [ka]

[0128] Example 30: Synthesis of Compound 30 [ka] Compound 22c (500 mg, 1.0 eq), compound 18a (84 mg, 0.25 eq, Bide Pharmatech), and TFA (223 mg, 1.2 eq) were added to a sealed tube. The mixture was dissolved in 5 mL of isopropanol, the system was heated, and stirred overnight at 100°C. After the reaction was complete, the reaction mixture was concentrated and 10 mL of water was added. The pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 30 (65 mg).

[0129] [ka]

[0130] Example 31: Synthesis of Compound 31 [ka] Compound 22c (500 mg, 1.0 eq), compound 17a (84 mg, 0.25 eq, Bide Pharmatech), and TFA (223 mg, 1.2 eq) were added to a sealed tube. This mixture was dissolved in 3 mL of isopropanol, the system was heated, and the reaction was carried out overnight at 100°C. After the reaction was complete, the reaction solution was concentrated and 10 mL of water was added. The pH was adjusted to approximately 8 using an appropriate amount of K2CO3. The mixture was extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~10:1, v / v) to obtain compound 31 (100 mg).

[0131] [ka]

[0132] Example 32: Synthesis of Compound 32

Chemical Formula

[0133]

Chemical Formula

[0134] Example 33: Synthesis of Compound 33

Chemical Formula

[0135] Synthesis of compound 33: Compound 33b (200 mg, 1.0 eq), compound 24c (276 mg, 1.0 eq, Bide Pharmatech), Pd2(dba)3 (104 mg, 0.1 eq), tBuXphos (146 mg, 0.3 eq), and cesium carbonate (744 mg, 2.0 eq) were added to a sealed tube, followed by 5 mL of dioxane. The mixture was purged with argon for protection and heated to 90°C and reacted overnight. After the reaction was complete, 30 mL of water was added to the reaction solution and extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (PE / EA = 100:1~9:1, v / v). The concentrated solid was slurryed to obtain compound 33 (300 mg).

[0136] [ka]

[0137] Example 34: Synthesis of Compound 34 [ka] The preparation method for compound 34b was as follows: Compound 34a (5 g, 35.19 mmol, Bide Pharmatech) and guanidine carbonate (25.36 g, 140.75 mmol, Bide Pharmatech) were added to a sealed tube, followed by the addition of 30 mL of DMAC as a solvent. The reaction was carried out at 140°C for 6 hours. After the reaction was complete, the reaction solution was added dropwise to ice water and stirred to precipitate the solid. The resulting filtration cake was filtered by suction filtration and oven-dried to obtain crude compound 34b (3.1 g).

[0138] Synthesis of compound 34: Compound 34b (600 mg, 3.68 mmol), compound 24c (886 mg, 3.68 mmol, Bide Pharmatech), Pd2(dba)3 (168.4 mg, 0.184 mmol), xanthophos (212.8 mg, 0.368 mmol), and Cs2CO3 (1797 mg, 5.52 mmol) were added to a sealed tube. 1,4-dioxane (15 mL) was added as the solvent, and the atmosphere was replaced with Ar. The reaction was carried out at 100°C for 6 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. Compound 34 (100 mg) was obtained by purification using column chromatography (DCM / McOH = 100:1 to 10:1, v / v).

[0139] [ka]

[0140] Example 35: Synthesis of Compound 35 [ka] The preparation method for compound 35b was as follows: Compound 35a (1 g, 1.0 eq, Energy Chemical), guanidine carbonate (3.76 g, 4.0 eq, Bide Pharmatech), and 10 mL of DMAC were added to a sealed tube, the mixture was stirred, and the reaction was carried out at 140°C for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and stirred in an ice bath for 20 minutes. The mixture was filtered by suction and oven-dried to obtain 940 mg of compound 35b (940 mg).

[0141] Synthesis of compound 35: Into a sealed tube, compound 35b (940 mg, 1.0 eq), compound 24c (1.17 g, 1.1 eq, Bide Pharmatech), Pd₂(dba)₃ (404 mg, 0.1 eq), Xantphos (765 mg, 0.3 eq), and cesium carbonate (2.87 g, 2.0 eq) were added, followed by addition of 10 mL of dioxane. The mixture was purged with argon for protection, and reacted at 90°C overnight. After completion of the reaction, dioxane was evaporated to dryness. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (PE / EA=100:1~9:1, v / v), and the product was slurried to obtain compound 35 (200 mg).

[0142] [Chemical Formula]

[0143] Example 36: Synthesis of Compound 36 [Chemical Formula] The preparation method of the above compound 36b was as follows: Compound 36a (2 g, 13.41 mmol, Bide Pharmatech) and guanidine carbonate (9.67 g, 53.65 mmol, Bide Pharmatech) were added into a sealed tube, followed by addition of DMAC (20 mL) as a solvent, and the reaction was carried out at 140°C for 6 hours. After completion of the reaction, the reaction solution was added dropwise into ice water, stirred to precipitate a solid, the filter cake was collected by suction filtration, and dried in an oven to obtain crude compound 36b (1.7 g).

[0144] ESI-MS: m / z 171.2 [M+H] + .

[0145] Synthesis of Compound 36: Compound 36b (400 mg, 2.35 mmol), compound 24c (566 mg, 2.35 mmol, Bide Pharmatech), Pd2(dba)3 (108 mg, 0.12 mmol), xanthophos (136 mg, 0.24 mmol), and Cs2CO3 (1149 mg, 3.53 mmol) were added to a sealed tube. 1,4-dioxane (15 mL) was added as the solvent, and the atmosphere was replaced with Ar. The reaction was carried out at 100°C for 6 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 4). The combined organic extract was separated, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. Compound 36 (100 mg) was obtained by purification by column chromatography (PE / DCM = 100:1~2:1, v / v).

[0146] [ka]

[0147] Example 37: Synthesis of Compound 37 [ka] The preparation method for compound 37b was as follows: Compound 37a (3.0 g, 18.9 mmol, Bide Pharmatech) was dissolved in DMAC (10 mL), four times the volume of guanidine carbonate was added, and the mixture was reacted at 140°C for 3 hours. TLC monitoring showed no residual starting material, so heating was stopped, the mixture was cooled to room temperature, then 100 mL of water was added, and it was cooled overnight at 0°C. The mixture was filtered by suction and dried in an oven to obtain compound 37b (2.1 g), a yellow solid, which was used directly in the next step without purification. Synthesis of compound 37: In a round-bottom flask, 37b (179 mg, 1.0 mmol), dioxane (75 mL), 24c (240 mg, 1.0 mmol, Bide Pharmatech), Pd2(dba)3 (46 mg, 0.05 mmol), cesium carbonate (480 mg, 1.5 mmol), and xanthophos (29 mg, 0.05 mmol) were added sequentially. The mixture was then heated to 115°C under nitrogen protection and reacted for 6 hours. The reaction was stopped, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (3 × 20 mL) to combine the organic phases. The mixture was then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to silica gel column chromatography (PE / EA = 4:1 to 2:1, v / v) to obtain the yellow solid compound 37 (140 mg).

[0148] [ka]

[0149] Example 38: Synthesis of Compound 38 [ka] The preparation method for compound 38b was as follows: Compound 38a (2 g, 1.0 eq, Bide Pharmatech), ethyl acrylate (939 mg, 1.2 eq, Energy Chemical), palladium acetate (88 mg, 0.05 eq), tri(o-tolyl)phosphine (238 mg, 0.1 eq), and triethylamine (7.8 mL) were added to a sealed tube, and the mixture was heated to 125°C and reacted overnight. After the reaction was complete, 50 mL of water was added, and the mixture was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 100:1~10:1, v / v) to obtain compound 38b (1.8 g).

[0150] The preparation method for compound 38c was as follows: Compound 38b (1.8 g, 1.0 eq) was added to a sealed tube and dissolved in 10 mL of 1,4-dioxane. Then, 0.5 mL of concentrated hydrochloric acid was added dropwise, and the mixture was heated to 100°C and reacted overnight. After the reaction was complete, 30 mL of water was added, the pH was adjusted to above 7 with saturated NaHCO3 aqueous solution, and the mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was slurryed with hexane:ethyl acetate (10:1), and compound 38c (1.0 g) was obtained by suction filtration.

[0151] The preparation method for compound 38d was as follows: Compound 38c (1 g, 1.0 eq) was added to a 50 mL one-necked flask, followed by 10 mL of toluene, and then phosphorus oxychloride (1.34 g, 2.0 eq, Energy Chemical). The mixture was heated to 100°C and reacted overnight. After the reaction was complete, phosphorus oxychloride and toluene were removed as much as possible by distillation under reduced pressure, 50 mL of water was added, and the mixture was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain compound 38d (670 mg).

[0152] Synthesis of compound 38: Compound 38d (670 mg, 1.0 eq), compound 38e (414 mg, 1.2 eq, Energy Chemical), Pd(OAc)2 (61 mg, 0.1 eq), cesium carbonate (1.76 g, 2.0 eq), and xanthophos (470 mg, 0.3 eq) were added to a sealed tube, followed by 10 mL of tert-butanol. The mixture was thoroughly mixed, argon purging was performed for protection, and the sealed tube was closed. The system was heated and reacted in an oil bath at 110°C for 20 hours. After the reaction was complete, twice the amount of methanol was added, and the mixture was filtered by suction. The filtrate cake was washed with cold methanol. The filtrate was concentrated, and the residue was purified by column chromatography (PE:EA = 100:1 to 19:1, v / v), and then slurryed with petroleum ether to obtain compound 38 (82 mg).

[0153] [ka]

[0154] Example 39: Synthesis of Compound 39 [ka] Compound 38e (255 mg, Energy Chemical), DMSO (2 mL), and CDI (389 mg) were successively added to a 25 mL one-necked flask, and the mixture was stirred at room temperature. Compound 21c (354 mg, Bide Pharmatech) was dissolved in DMSO (2 mL) and added dropwise to the reaction mixture, followed by a reaction for 0.5 hours. After the reaction was complete, the mixture was stopped with 1 N HCl (16 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered by suction, and the filtrate was desolvated under vacuum to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 10 / 1, v / v) to obtain compound 39 (115 mg) as a white solid.

[0155] [ka]

[0156] Example 40: Synthesis of Compound 40 [ka] Compound 21a (1 g, 1.0 eq, Bide Pharmatech), Compound 21c (1.38 g, 1.2 eq, Bide Pharmatech), Pd(OAc)2 (73 mg, 0.05 eq), Cesium carbonate (4.24 g, 2.0 eq), and Xanthophos (1.38 g, 0.15 eq) were added to a 75 mL sealed tube, followed by the addition of tert-butanol (12 mL). The mixture was thoroughly mixed, argon purging was performed for protection, and the sealed tube was closed. The system was heated to 110 °C and reacted for 4 hours. After the reaction was complete, methanol (20 mL) was added, and the mixture was filtered by suction. The filtrate was washed with methanol. The filtrate was concentrated and purified by column chromatography (PE:EA = 100:1~2:1, v / v) to obtain Compound 40 (210 mg).

[0157] [ka]

[0158] Example 41: Synthesis of Compound 41 [ka] The preparation method for compound 41c was as follows: Compound 41a (1.00 g, Jiangsu Aikon) and compound 41b (8.64 g, Energy Chemical) were successively added to a 75 mL sealed tube. The mixture was heated to 150 °C and reacted for 2 hours, precipitating a large amount of off-white solid. The mixture was cooled to 0 °C, stirred for 15 minutes, and filtered by suction. The filtered cake was rinsed with petroleum ether (100 mL) and filtered to dryness by suction. The filtered cake was recovered and dried under an airflow at 50 °C for 1 hour to obtain 0.95 g of beige solid compound 41c (400 mg).

[0159] Synthesis of compound 41: Compound 41c (400 mg), DMAC (4 mL), Compound 21c (782 mg), Pd(OAc)2 (50 mg), xanthophos (383 mg), and DIPEA (885 mg) were successively added to a 15 mL sealed tube. The mixture was protected under argon and heated to 90°C for 15 hours. After the reaction was complete, the mixture was diluted with ethyl acetate (30 mL), followed by the addition of water (30 mL). The mixture was filtered by suction to remove the solid. The filtrate was separated, the organic phase was retained, and the aqueous phase was extracted with ethyl acetate (15 mL x 3). The organic phases were combined. The organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered by suction, the filtrate was desolvated under vacuum, and the residue was purified by column chromatography (eluent: EA / MeOH = 30:1, v / v) to obtain compound 41 as a beige solid (195 mg).

[0160] [ka]

[0161] Example 42: Synthesis of Compound 42 [ka] The preparation method for compound 42a was as follows: Compound 41 (110 mg) and POCl3 (2.6 g) were sequentially added to a 25 mL single-neck flask, heated to 90°C, and reacted for 6 hours to obtain a reddish-orange solution, at which point the reaction was stopped. The reaction solution was desolvated under vacuum to obtain a dark red liquid, to which ether (20 mL) was added to precipitate a dark red solid. The solid was filtered by suction to obtain a dark red solid compound 42a (100 mg).

[0162] Synthesis of compound 42: Compound 42a (100 mg), MeOH (1 mL), and MeONa (16 mg) were sequentially added to a 10 mL single-neck flask, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was desolvated under vacuum, and the residue was purified by column chromatography (eluate: PE / EA = 1:2, v / v) to obtain compound 42 as a yellow solid (65 mg).

[0163] [ka]

[0164] Example 43: Synthesis of Compound 43 [ka] The preparation method for compound 43b was as follows: Compound 43a (1.0 g, 4.28 mmol) was dissolved in acetonitrile (10 mL), and N,N,N'-trimethylethylenediamine (525 mg, 5.14 mmol) and DIPEA (1.66 g, 12.8 mmol) were added. The reaction was carried out at room temperature for 12 hours. TLC monitoring showed no residual starting material. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was slurryed with PE (3 mL) and isopropyl ether (5 mL), filtered by suction, and oven-dried to obtain compound 43b (890 mg) as a yellow solid.

[0165] Synthesis of compound 43: Compounds 43b (870 mg, 2.9 mmol) and 21c (620 mg, 3.5 mmol) were dissolved in isopropanol (10 mL), followed by the addition of trifluoroacetic acid (1.66 g, 14.6 mmol). The mixture was then heated to 90°C under nitrogen protection and reacted for 2 hours. The reaction was stopped, the mixture was cooled to room temperature, and allowed to stand overnight. The mixture was filtered by suction, and the filtered cake was washed with cold isopropanol. After drying, a yellow solid compound 43 (320 mg) was obtained.

[0166] [ka]

[0167] Example 44: Synthesis of Compound 44 [ka] The preparation method for compound 44a was as follows: Compound 25a (1.45 g, 8.21 mmol, Bide Pharmatech) was dissolved in 1,4-dioxane (20 mL), followed by the addition of N,N,N'-trimethylethylenediamine (923 mg, 9.03 mmol, Energy Chemical) and DIPEA (2.12 g, 16.4 mmol, Sinopharm). The mixture was heated to 90°C and reacted for 3 hours. No residue of the starting materials was detected by TLC monitoring. Water (60 mL) was added, and the mixture was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by column chromatography (DCM / MeOH = 10:1, v / v) to obtain compound 44a (1.63 g).

[0168] Synthesis of compound 44b: Compound 44a (1.6 g, 5.36 mmol) and guanidine carbonate (3.86 g, 21.4 mmol, Bide Pharmatech) were added to a sealed tube, followed by the addition of 15 mL of DMAC as a solvent. The reaction was carried out at 140°C for 3 hours. After the reaction was complete, the reaction solution was added dropwise to ice water and stirred to precipitate the solid. The resulting cake was filtered by suction filtration and oven-dried to obtain crude compound 44b (0.98 g).

[0169] Synthesis of compound 44: Compound 44b (960 mg, 3.44 mmol), compound 24c (826 mg, 3.44 mmol), Pd2(dba)3 (157 mg, 0.17 mmol), xanthophos (98 mg, 0.17 mmol), and Cs2CO3 (1.6 g, 5.16 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (15 mL) as the solvent. The reaction was carried out at 115°C for 6 hours under argon protection. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and then concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (DCM / MeOH = 100:1~10:1, v / v) to obtain compound 44 (200 mg).

[0170] [ka]

[0171] Example 45: Synthesis of Compound 45 [ka] The preparation method for compound 45a was as follows: Compound 25a (2.0 g, 11.3 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of morpholine (1.09 g, 12.5 mmol) and DIPEA (2.93 g, 22.7 mmol). The mixture was heated to 100 °C and reacted for 4 hours. TLC monitoring confirmed that no starting materials remained. Water (60 mL) was added, and the mixture was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain a yellow oily compound 45a (1.52 g).

[0172] Synthesis of compound 45b: Compound 45a (1.5 g, 6.17 mmol) and guanidine carbonate (4.4 g, 24.4 mmol) were added to a sealed tube, followed by the addition of 20 mL of DMAC as a solvent. The reaction was carried out at 140°C for 6 hours. After the reaction was complete, 60 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and then concentrated. The residue was slurryed with PE (10 mL) and EA (1 mL), filtered by suction, and dried in an oven to obtain compound 45b (1.1 g) as a yellow solid.

[0173] Synthesis of compound 45: Compound 45b (1.05 g, 3.97 mmol), compound 24c (953 mg, 3.97 mmol), Pd2(dba)3 (185 mg, 0.20 mmol), xanthophos (117 mg, 0.20 mmol), and Cs2CO3 (1.94 g, 5.97 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (20 mL) as the solvent. The reaction was carried out at 115°C for 6 hours under argon protection. After the reaction was complete, water (60 mL) was added to the reaction mixture and extracted with EA (30 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was slurryed with PE (10 mL) and EA (2 mL), and the resulting solid was filtered by suction. The filtered cake was further purified by column chromatography (DCM / MeOH = 100:1 to 10:1, v / v) to obtain compound 45 (350 mg).

[0174] [ka]

[0175] Example 46: Synthesis of Compound 46 [ka] The preparation method for compound 46a was as follows: Compound 25a (2.0 g, 11.3 mmol) was dissolved in 1,4-dioxane (20 mL), and methylpiperazine (1.25 g, 12.5 mmol) and DIPEA (2.93 g, 22.7 mmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. TLC monitoring confirmed that no starting material remained. Water (60 mL) was added, and the mixture was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and then concentrated to obtain a yellow oily compound 46a (1.50 g).

[0176] Synthesis of compound 45b: Compound 46a (1.5 g, 6.17 mmol) and guanidine carbonate (4.5 g, 24.9 mmol) were added to a sealed tube, followed by the addition of 20 mL of DMAC as a solvent. The reaction was carried out at 140°C for 6 hours. After the reaction was complete, 60 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and then concentrated. The residue was slurryed with PE (10 mL), EA (1 mL), and i-PrOH (1 mL), filtered by suction, and dried in an oven to obtain compound 46b (1.0 g) as a yellow solid.

[0177] Synthesis of compound 46: Compound 46b (1.0 g, 3.61 mmol), compound 24c (960 mg, 3.99 mmol), Pd2(dba)3 (185 mg, 0.20 mmol), xanthophos (117 mg, 0.20 mmol), and Cs2CO3 (1.94 g, 5.97 mmol) were added to a sealed tube. 1,4-dioxane (20 mL) was added as the solvent, and the reaction was carried out at 115°C for 6 hours under argon protection. After the reaction was complete, water (60 mL) was added to the reaction mixture, followed by extraction with EA (30 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and then concentrated under vacuum to obtain the crude product. The crude product was slurryed with a mixed solvent of PE (10 mL), EA (2 mL), DCM (1 mL), and i-PrOH (1 mL), filtered by suction, and dried in an oven to obtain compound 46 (410 mg) as a yellow solid.

[0178] [ka]

[0179] Example 47: Synthesis of Compound 47 [ka] The preparation method for compound 47b was as follows: Compound 25a (1.46 g, 8.27 mmol) was dissolved in acetonitrile (20 mL), and then compound 47a (1.25 g, 8.67 mmol) and DIPEA (2.14 g, 16.6 mmol) were added. The mixture was heated to 50°C and reacted overnight. TLC monitoring showed no residual starting material. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 47b (1.90 g).

[0180] Synthesis of the above compound 47c: Compound 47b (1.9 g, 6.32 mmol) and guanidine carbonate (4.5 g, 24.9 mmol) were added to a sealed tube, followed by the addition of 20 mL of DMAC as a solvent. The reaction was carried out at 140°C for 6 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. By purification by column chromatography (PE / EA=3:1~EA / MeOH=20:1, v / v), compound 47c (1.7 g) was obtained as a yellow solid.

[0181] Synthesis of compound 47: Compound 47c (1.7g, 5.28 mmol), compound 24c (1.4g, 5.83 mmol), Pd2(dba)3 (242 mg, 0.26 mmol), xanthophos (458 mg, 0.79 mmol), and Cs2CO3 (3.4g, 10.5 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (20 mL) as the solvent. The mixture was substituted with Ar and reacted at 115°C for 3 hours. After the reaction was complete, water (60 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. Purification by column chromatography (PE / EA = 100:1 to 1:1, v / v) yielded 2.1 g of crude product, which was then slurryed in a mixed solvent of PE (10 mL), EA (10 mL), and MeOH (0.3 mL). The resulting solid was filtered by suction and dried in an oven to obtain compound 47 (1.4 g) as a yellow solid.

[0182] [ka]

[0183] Example 48: Synthesis of Compound 48 [ka] The preparation method for compound 48b was as follows: Compound 25a (4.7 g, 26.6 mmol) was dissolved in acetonitrile (30 mL), and compound 48a (3.3 g, 28.6 mmol) and DIPEA (6.9 g, 53.5 mmol) were added. The mixture was heated to 50°C and reacted overnight. No residue of the starting materials was detected by TLC monitoring. The solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography (DCM) to obtain compound 48b (5.8 g) as a yellow solid.

[0184] Synthesis of the above compound 48c: Compound 48b (5.8 g, 21.3 mmol) and guanidine carbonate (15.4 g, 85.5 mmol) were added to a sealed tube, followed by the addition of 70 mL of DMAC as a solvent. The reaction was carried out at 140°C for 2 hours. After the reaction was complete, 200 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The mixture was purified by column chromatography (PE / EA = 100:1 to 8:1, v / v) to obtain compound 48c (5 g) as a yellow solid.

[0185] Synthesis of compound 48: Compound 48c (1.3g, 4.44 mmol), compound 24c (1.2g, 5.0 mmol, Bide Pharmatech), Pd2(dba)3 (203mg, 0.22 mmol), xanthophos (381mg, 0.66 mmol), and Cs2CO3 (2.89g, 8.89 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (20 mL) as the solvent. The reaction was carried out at 115°C for 3 hours under argon protection. After the reaction was complete, water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (30 mL x 4). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1~3:1, v / v) to obtain compound 48 (1.0 g).

[0186] [ka]

[0187] Example 49: Synthesis of Compound 49 [ka] The preparation method for compound 49b described above was as follows: Compound 25a (1.58 g, 8.95 mmol) was dissolved in acetonitrile (30 mL), and compound 49a (1.0 g, 9.88 mmol) and DIPEA (2.3 g, 17.8 mmol) were added. The mixture was heated to 110°C and reacted for 2 hours. No residue of the starting materials was detected by TLC monitoring. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100:1 to 8:1, v / v) to obtain compound 49b (1.7 g) as a yellow solid.

[0188] Synthesis of the above compound 49c: Compound 49b (1.7 g, 6.59 mmol) and guanidine carbonate (4.7 g, 26.1 mmol) were added to a sealed tube, followed by the addition of 20 mL of DMAC as a solvent. The reaction was carried out at 140°C for 2 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 60 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain crude solid compound 49c (2.0 g).

[0189] Synthesis of compound 49: Compound 49c (2.0 g, 7.18 mmol), compound 24c (1.8 g, 7.50 mmol), Pd2(dba)3 (296 mg, 0.32 mmol), xanthophos (560 mg, 0.97 mmol), and Cs2CO3 (4.2 g, 12.9 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (40 mL) as the solvent. The mixture was substituted with Ar and reacted at 115°C for 4 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, and then extracted with EA (3 × 60 mL). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 49 (1.2 g).

[0190] [ka]

[0191] Example 50: Synthesis of Compound 50 [ka] The preparation method for compound 50b was as follows: Compound 25a (1.3 g, 7.36 mmol) was dissolved in acetonitrile (15 mL), and compound 50a (1.0 g, 8.26 mmol) and DIPEA (1.9 g, 14.7 mmol) were added. The mixture was heated to 50°C and reacted overnight. No residue of the starting materials was detected by TLC monitoring. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100:1 to 8:1, v / v) to obtain compound 50b (1.7 g) as a yellow solid.

[0192] Synthesis of the above compound 50c: Compound 50b (1.7 g, 6.12 mmol) and guanidine carbonate (4.4 g, 24.4 mmol) were added to a sealed tube, 15 mL of DMAC was added as the solvent, and the reaction was carried out at 140°C for 2 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain crude compound 50c (2.2 g).

[0193] Synthesis of compound 50: Compound 50c (2.0g, 6.69 mmol), compound 24c (1.8g, 7.50 mmol), Pd2(dba)3 (306mg, 0.33 mmol), xanthophos (581mg, 1.0 mmol), and Cs2CO3 (4.4g, 13.5 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (30 mL) as the solvent. The reaction was carried out at 115°C for 4 hours under argon protection. After the reaction was complete, water (60 mL) was added to the reaction mixture, and the mixture was extracted with EA (4 × 50 mL). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 50 (1.6 g).

[0194] [ka]

[0195] Example 51: Synthesis of Compound 51 [ka] The preparation method for compound 51b was as follows: Compound 25a (1.58 g, 8.95 mmol) was dissolved in acetonitrile (30 mL), and compound 49a (1.0 g, 9.88 mmol) and DIPEA (2.3 g, 17.8 mmol) were added. The mixture was heated to 110 °C and reacted for 2 hours. No residue of the starting materials was detected by TLC monitoring. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100:1 to 8:1, v / v) to obtain solid compound 51b (2.0 g).

[0196] Synthesis of the above compound 51c: Compound 51b (2.0 g, 7.76 mmol) and guanidine carbonate (5.6 g, 31.1 mmol) were added to a sealed tube, followed by the addition of 20 mL of DMAC as a solvent. The reaction was carried out at 140°C for 2 hours. After the reaction was complete, 100 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain crude compound 51c (2.2 g).

[0197] Synthesis of compound 51: Compound 51c (2.2g, 7.89 mmol), compound 24c (2.1g, 8.75 mmol), Pd2(dba)3 (361mg, 0.39 mmol), xanthophos (685mg, 1.18 mmol), and Cs2CO3 (5.1g, 15.6 mmol) were added to a sealed tube, followed by the addition of 1,4-dioxane (40 mL) as the solvent. The reaction was carried out at 115°C for 5 hours under argon protection. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with EA (3 × 80 mL). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the crude product. The product was purified by column chromatography (PE / EA = 100:1 to 10:1, v / v) to obtain compound 51 (1.3 g).

[0198] [ka]

[0199] Biological assays Test 1: Effect of the compound on the upward control of miR124 The effect of the test compound on miR124 expression levels was evaluated in human peripheral blood mononuclear cells (PBMCs). PBMC cells were thawed at 37°C, centrifuged at 400g for 10 minutes, resuspended in RPMI1640 complete medium (containing 10% FBS), and incubated at 37°C + 5% CO2 for 24 hours. Screening was performed using 6-well plates. Cells were placed in 2.0 × 10⁶ wells in the 6-well plates. 6 Cells were seeded at a density of 4 mL and activated for 48 hours in RPMI1640 complete medium containing PHA-L (5 ug / mL) and IL-2 (40 U / mL). The test compound (final concentration: 5 μM) was added for treatment at 37°C and 5% CO2 for 6 days, and the medium was changed on the 3rd day. The control group was treated with an equal volume of DMSO under the same conditions.

[0200] RNA extraction: On day 6, cells were collected in a 15 mL centrifuge tube, centrifuged at 400 g for 10 minutes, and the supernatant was removed. 500 μL of Trizol was added to the cell pellet, pipetted thoroughly, and then transferred to a 1 mL centrifuge tube (RNase-free) to dissolve at room temperature for 15 minutes. 100 μL of chloroform (Trizol:chloroform = 5:1, volume ratio) was added to each tube, mixed thoroughly, and left at room temperature for approximately 15 minutes. Centrifugation at 4°C and 12000 g for 15 minutes revealed distinctly different layers (from bottom to top: pink lower organic phase, white intermediate protein phase, and colorless upper aqueous phase). The upper RNA layer was aspirated into a clean 1.5 mL centrifuge tube (RNase-free), an equal volume of isopropanol was added, and the RNA was allowed to precipitate at room temperature for 10 minutes. Centrifugation at 4°C and 12000 g for 10 minutes yielded a small white pellet at the bottom of the tube. The precipitate was washed with 500 μL of 75% ethanol and allowed to stand at room temperature for 5 minutes. After centrifuging at 4°C and 7600 g for 5 minutes until the precipitate became clear, RNase-free H2O was added to dissolve the precipitate, and the RNA sample concentration was measured.

[0201] Reverse transcription: The reverse transcription system for the above RNA is configured as detailed in Table 1: [Table 1] cDNA reaction cycle conditions: 25°C, 5 minutes; 50°C, 15 minutes; 85°C, 5 minutes.

[0202] Fluorescence-based quantitative PCR reaction: miRNA quantification was performed using SYBR Green I intercalated fluorescence, with co-detection of housekeeping gene U6 transcript levels as an internal reference. The fluorescence-based quantitative PCR amplification reaction system was configured as detailed in Table 2.

[0203] [Table 2]

[0204] (1) Using the protocol described above, the mean fold change in miR-124 expression (compared to DMSO) was evaluated by relative quantification using PBMCs derived from different donors. The in vitro results are detailed in Table 3 below:

[0205] [Table 3-1] [Table 3-2]

[0206] Study 2: Prophylactic and therapeutic effects of the compound on ulcerative colitis (UC) in mice. The prophylactic and therapeutic effects of the positive drugs ABX464 and compound 23 of this disclosure against dextran sulfate sodium (DSS)-induced ulcerative colitis were evaluated using a DSS-induced ulcerative colitis (UC) model.

[0207] Female C57BL / 6 mice (20-22g) were randomly divided into seven groups according to their body weight after adaptive feeding, as shown in Table 4. On day 1, the mice were switched to a 3% DSS diet. Ten days after the DSS diet, until day 13, the mice were returned to normal drinking water. From day 1 to day 13, the mice were continuously administered the corresponding solvent and drug via enteral feeding. Body weight changes were recorded daily from day 1 to day 13. On day 13, after recording body weight, the mice were dissected and the length of the colon was measured. The prophylactic and therapeutic effects of the test drug on ulcerative colitis in mice were evaluated based on the relative body weight change rate and colon length.

[0208] [Table 4]

[0209] (1) Results of the weight experiment: Compared to the normal control group, the DSS model group began to show significant weight loss from day 8 (p<0.0001), and the degree of weight loss gradually increased, decreasing by 14% by day 10 (p<0.0001). Compared to the DSS model group, the 50 mg / kg study drug group 4 did not show sustained weight loss from day 8, and the 50 mg / kg study drug group showed a weight loss of 3.09% by day 9 (p=0.0004). Compared to the DSS model group, all treatment groups showed significant weight recovery by day 10. The ABX464-positive drug group experienced a weight loss of 6.02% (p=0.0001), while the study drug groups at doses of 6.25, 12.5, 25, and 50 mg / kg showed weight losses of 7.52% (p=0.0046), 8.99% (p=0.0498), 7.96% (p=0.0087), and 3.8% (p<0.0001), respectively. The degree of weight recovery at the experimental endpoint was as follows: the 50 mg / kg study drug group > 50 mg / kg ABX464, while the low-dose and medium-dose study drug groups showed comparable weight recovery effects to the positive drug ABX464 (details are shown in Table 5). These results indicate that compound 23 of this disclosure exhibits a favorable recovery effect on weight loss in DSS-induced ulcerative colitis mice.

[0210] (2) The colon length results showed that the DSS model group had a significant reduction in colon length (p<0.0001) compared to the normal control group, which was only 72.3% of the control group. Compared to the DSS model group, all treatment groups showed a significant increase in colon length. The positive drug groups and the study drug groups at different doses of 6.25, 12.5, 25, and 50 mg / kg showed colon lengths of 96.5% (p<0.0001), 89.79% (p=0.0002), 98.1% (p<0.0001), 90.9% (p<0.0001), and 103.3% (p<0.0001), respectively, compared to the control group (details are shown in Table 3). The above results indicate that compound 23 of this disclosure has a good therapeutic effect on colon shortening in DSS-induced ulcerative colitis mice.

[0211] [Table 5]

[0212] [Table 6]

[0213] Test 3: Pharmacokinetic study (1) SD male rats were used as test animals. Plasma drug concentrations were measured at various time points after enteral administration of ABX464 and compounds 23, 44, and 45, as well as after intravenous administration of test compounds 44 and 45, using liquid chromatography-tandem mass spectrometry (LC-MS / MS). The pharmacokinetic properties of compounds 23, 44, and 45 in rats were tested.

[0214] SD male rats (200-220g) were administered ABX464 and compound 23 at a dose of 20.0 mg / kg via enteral tube, and compounds 44 and 45 at doses of 25 mg / kg and 1 mg / kg via enteral tube and intravenous tube. Three animals were administered to each group. The administration solvent was physiological saline containing 10% DMSO + 10% polyoxyl castor oil (Cremophor EL). The rats were kept fasted for approximately 12 hours before administration, and free feeding was permitted for 4 hours after administration without restriction of water intake. 0.2 mL of blood was collected from the jugular vein before administration and at 5, 15, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration and placed in labeled EDTA-K2 anticoagulant tubes. The tubes were gently inverted to completely mix the anticoagulant EDTA-K2 with the blood, and then the tubes were immediately placed on moist ice. Immediately after blood collection, plasma was separated by centrifugation under the following conditions: 4°C, 3500 rpm, and 5 minutes. The upper plasma layer was transferred and stored at -80°C until sample analysis. Quantitative analysis of the plasma concentration of compound 23 was performed using LC-MS / MS. Pharmacokinetic parameters were calculated from the sample analysis results using WinNonlin software.

[0215] [Table 7]

[0216] The pharmacokinetic results were obtained after enteral administration of 20 mg / kg of the test compound and ABX464 to SD male rats, and then the C of compound 23 and ABX464. max The values ​​were 1853.3 ng / mL and 727.0 ng / mL, respectively, and AUC 0-t The values ​​were 5059.4 h*ng / mL and 2309.01 h*ng / mL, respectively, and the terminal elimination half-lives were 2.65 hours and 0.86 hours, respectively. SD rats were administered enterally with test compounds 44 and 45 at 25 mg / kg, respectively. The Cmax values ​​for compounds 44 and 45 were 389 ng / mL and 2547 ng / mL, respectively; the AUC0-t values ​​were 5573 h*ng / mL and 8400 h*ng / mL, respectively; the terminal elimination half-lives were 8.7 hours and 5.4 hours, respectively; and the absolute bioavailability values ​​were 34.3% and 27.6%, respectively. As shown in Table 7, at the same dose, compound 23 showed a longer elimination half-life and higher systemic exposure (C) compared to ABX464. max and AUC 0-t ), and also exhibited good pharmacokinetic properties. Compared to the positive compound ABX464, compound 45 showed a longer half-life and higher systemic exposure (Cmax and AUC0-t), while compound 44 showed a relatively long half-life. The test compounds exhibited good pharmacokinetic properties.

[0217] (2) Beagle dogs were used as test animals, and the drug concentrations in plasma at different time points after enteral and intravenous administration of test compound 45 were measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The pharmacokinetic properties of test compound 45 were investigated in beagle dogs.

[0218] Male Beagle dogs (9-12 kg), 3 dogs per group, were administered the test drug 45 at doses of 6 mg / kg (by tube feeding) and 1 mg / kg (intravenously), respectively. Vehicles were provided with a saline solution containing 10% DMSO + 10% polyoxycastor oil (Cremophor EL). The tube-feeding group was fasted for at least 12 hours prior to administration, and water was allowed unrestricted. Four hours after administration, the dogs fed evenly. 1 mL of blood was collected from the jugular vein before administration and at 5, 15, 30, 1, 2, 4, 8, 10, and 24 hours after administration and placed in labeled EDTA-2K anticoagulant tubes. The tubes were gently inverted to completely mix the EDTA-2K anticoagulant with the blood, and then the tubes were immediately placed on moist ice. Plasma was centrifuged one hour after blood collection under the following centrifugation conditions: 4°C, 6800g, and 6 minutes. The upper plasma layer was transferred and stored at -20°C until sample analysis. The concentration of the test compound in canine plasma was measured using LC-MS / MS. Pharmacokinetic parameters were fitted using WinNonlin software, and absolute bioavailability was calculated. The results are shown in Table 8.

[0219] [Table 8]

[0220] Pharmacokinetic results showed that after enteral administration of 6 mg / kg of test compound 45 to beagle dogs, the Cmax and AUC0-t of compound 45 were 204 ng / mL and 990 h* ng / mL, respectively, with a terminal elimination half-life of 7.18 hours and an absolute bioavailability of 10.7%.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 121】 In the formula, X and Y are selected independently from CH or N. A is selected from cyano, hydroxyl, carboxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, and optionally substituted aromatic ring, wherein the substituents of the optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and aromatic ring are hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr １ Selected independently from, HetAr １ This is an optionally substituted 4-10 membered heterocycle or 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S. R １ and R ２ The substituents are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, and optionally substituted C1-C6 alkylamino, and the substituents of the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and C1-C6 alkylamino are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino, Alternatively, R １ and R ２ These, together with the carbon atoms to which they are bonded, further form an optionally substituted saturated 5-6 membered heterocycle, the 5-6 membered heterocycle optionally containing heteroatoms selected from N and O, and the substituents of the optionally substituted saturated 5-6 membered heterocycle are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino. Alternatively, R １ and R ２ These, together with the carbon atoms to which they are bonded, further form optionally substituted 5-6 membered aromatic rings, and the substituents are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino. The following compounds a-x: 【Chemistry 122-1】 【Chemistry 122-2】 It is excluded, Preferably, in the compound of formula (I), X is CH, Y is N, A is a C2-C6 alkenyl, R1 and R2, together with the carbon atoms to which they are bonded, further form an optionally substituted 5-6 membered aromatic ring, bond to an adjacent benzene ring to form a fused ring, and the substituent is a halogen, more preferably, R1 and R2, together with the carbon atoms to which they are bonded, form a benzene ring, bond to an adjacent benzene ring to form a fused ring, and the substituent is a halogen, the compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I-1), or a pharmaceutically acceptable salt thereof, [Chemical 123] In the formula, X and Y are selected independently from CH or N. A is selected from cyano, hydroxyl, carboxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C6 cycloalkyl, and optionally substituted aromatic ring, and the substituents of said optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and aromatic ring are hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr １ are independently selected from HetAr １ is an optionally substituted 4-10 membered heterocycle or 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl. R ０ H or 【Chemistry 124】 And, R １ and R ２ These, together with the carbon atoms to which they are bonded, further form an optionally substituted 5-6 membered halogenated aromatic ring, the halogen in the halogenated aromatic ring is independently selected from F, Cl, and Br, and the substituents are hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, C1-C6 haloalkylamino, HetAr ４ , and 【Chemistry 125】 Selected independently from, HetAr ４ is an optionally substituted 4-10 membered heterocycle or 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S, wherein the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl. R ａ R is selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl. ｂ and R ｃ This is independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl. Alternatively, R ｂ and R ｃ These, together with the nitrogen atoms to which they are bonded, further form an optionally substituted saturated 5-6 membered heterocycle, the 5-6 membered heterocycle optionally containing heteroatoms selected from N and O, and the substituents of the optionally substituted saturated 5-6 membered heterocycle are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino. The following compounds a-x: 【Chemistry 126-1】 【Chemistry 126-2】 【Chemistry 126-3】 The compounds of formula (I-1) or their pharmaceutically acceptable salts are excluded.

3. A compound of formula (II) or a pharmaceutically acceptable salt thereof, 【Chemistry 127】 In the formula, R ３ These include hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr ２ Selected from, where R is a C1-C6 alkyl group, HetAr ２ It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, and forming a fused ring by bonding with an adjacent benzene ring, and the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl. R ４ R is selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, and R is C1-C6 alkyl. The following compounds A to U: 【Chemistry 128-1】 【Chemistry 128-2】 It is excluded, Preferably, in the compound of formula (II), R ３ is HetAr ２ Selected from, HetAr ２ is a substituted or unsubstituted 4-6 membered monocyclic aromatic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, and bonded to an adjacent benzene ring to form a fused ring, wherein the substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, and C1-C6 hydroxyalkyl, and further substituents are selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 haloalkylthio, and C1-C3 hydroxyalkyl, R ４ It is a halogen, More preferably, in the compound of formula (II), R ３ is HetAr ２ Selected from, HetAr ２ R is a substituted or unsubstituted 4- to 6-membered monocyclic saturated heterocycle containing one oxygen atom, which bonds with an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, cyano, hydroxyl, and carboxyl. ４ A compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein is a halogen.

4. A compound of formula (III) or a pharmaceutically acceptable salt thereof, 【Chemistry 129】 In the formula, R ６ These include hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr ３ Selected from, where R is a C1-C6 alkyl group, HetAr ３ It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, which bond to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, hydroxyl, and carboxyl. R ７ and R ８ A compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R is independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, and R is C1-C6 alkyl.

5. R ６ R is selected from C1-C6 haloalkoxy or C1-C6 haloalkylthio. ７ and R ８ is independently selected from hydrogen, halogen, C1-C6 haloalkyl, and C1-C6 alkoxy, preferably R ６ R is selected from C1-C3 haloalkoxy or C1-C3 haloalkylthio. ７ and R ８ is independently selected from hydrogen, halogen, C1-C3 haloalkyl, and C1-C3 alkoxy, and more preferably R ７ and R ８ Both are either hydrogen or preferably R ６ HetAr1 is selected from HetAr1, which is a substituted or unsubstituted 4-6 member monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, and is bonded to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen and halogens, R ７ and R ８ is independently selected from hydrogen and halogen, and more preferably R ７ and R ８ Both are not hydrogen, the compound according to claim 3 or a pharmaceutically acceptable salt thereof.

6. A compound of formula (III-1) or a pharmaceutically acceptable salt thereof, 【Chemistry 130】 In the formula, R ６ These include hydrogen, halogen, cyano, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylamino, C1-C6 haloalkylamino, and HetAr ３ Selected from, where R is a C1-C6 alkyl group, HetAr ３ It is a substituted or unsubstituted 4-6 membered monocyclic heterocycle having 1-3 heteroatoms independently selected from N, O, or S, which bond to an adjacent benzene ring to form a fused ring, and the substituents are selected from hydrogen, halogen, hydroxyl, and carboxyl. R ０ H or 【Chemistry 131】 And, R ７ and R ８ These are halogens, C1-C6 haloalkylaminos, and HetAr ４ , and 【Chemistry 132】 Selected independently from, HetAr ４ This is an optionally substituted 4-10 membered heterocycle or 5-10 membered aromatic ring having 1-3 heteroatoms independently selected from N, O, or S. R ａ R is selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl. ｂ and R ｃ is independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, and C1-C6 haloalkyl, or R ｂ and R ｃ The compounds of formula (III-1) or pharmaceutically acceptable salts thereof, wherein the atoms, together with the nitrogen atoms to which they are bonded, further form an optionally substituted saturated 5-6 membered heterocycle, the 5-6 membered heterocycle optionally containing heteroatoms selected from N and O, and the substituents of the optionally substituted saturated 5-6 membered heterocycle are independently selected from hydrogen, halogen, hydroxyl, carboxyl, COOR, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino.

7. R ６ is selected from C1-C6 haloalkoxy or C1-C6 haloalkylthio, preferably R ６ is selected from C1-C3 haloalkoxy or C1-C3 haloalkylthio, more preferably R ６ is trifluoromethyloxy, preferably R ７ is selected from F, Cl, or Br, preferably R ０ is H, preferably R ７ It is a halogen, R ８ HetAr ４ or 【Chemistry 133】 Selected from, preferably HetAr ４ This is an optionally substituted 4-10 membered heterocycle having 1-3 heteroatoms independently selected from N, O, or S, preferably HetAr ４ The substituents are selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, butyl, and C1-C3 haloalkyl, preferably R ａ R is selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, and butyl. ｂ and R ｃ is independently selected from hydrogen, halogen, hydroxyl, carboxyl, methyl, ethyl, propyl, and butyl, or R ｂ and R ｃ These, together with the nitrogen atoms to which they are bonded, further form an optionally substituted saturated 5-6 membered heterocycle containing N and O, wherein the substituents of the 5-6 membered heterocycle are independently selected from hydrogen, halogen, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 haloalkylamino, preferably R ｂ and R ｃ is independently selected from methyl, ethyl, propyl, and butyl, or R ｂ and R ｃ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the nitrogen atoms to which they are bonded further form a saturated 5-6 membered heterocycle containing N and O.

8. The compound or a pharmaceutically acceptable salt thereof, wherein the compound is as follows: 【Chemistry 134-1】 【Chemistry 134-2】 【Chemistry 134-3】 【Chemistry 134-4】 【Chemistry 134-5】 A compound selected from the above, or a pharmaceutically acceptable salt thereof.

9. A method for preparing a compound, wherein the method is as follows: (1) to (3): (1) A method for preparing the compound of formula (I), 【Chemistry 135】 The compound of formula (Ia) or a pharmaceutically acceptable salt thereof and the compound of formula (Ib) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (I) or a pharmaceutically acceptable salt thereof, where B is a halogen, preferably a chlorine atom, and X, Y, R １ and R ２ A method for preparing the compound of formula (I), as defined in claim 1. (2) A method for preparing the compound of formula (II), 【Transformation 136】 The compound of formula (IIa) or a pharmaceutically acceptable salt thereof and the compound of formula (IIb) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (II) or a pharmaceutically acceptable salt thereof, where B is a halogen, preferably a chlorine atom, and R ３ and R ４ A method for preparing the compound of formula (II), as defined in claim 2. (3) A method for preparing the compound of formula (III), 【Chemistry 137】 The compound of formula (IIIa) or a pharmaceutically acceptable salt thereof and the compound of formula (IIIb) or a pharmaceutically acceptable salt thereof undergo nucleophilic substitution to produce the compound of formula (III) or a pharmaceutically acceptable salt thereof, where B is a halogen, preferably a chlorine atom, and R ６ , R ７ , and R ８ A method for preparing the compound of formula (III), as defined in any one of claims 3 to 7. The method, which is one of the following.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

11. Use of the compound or a pharmaceutically acceptable salt thereof as a microRNA-124 regulator according to any one of claims 1 to 8.

12. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for the prevention or treatment of an inflammatory disease.

13. The use according to claim 12, wherein the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, osteoarthritis, atherosclerosis, ankylosing spondylitis, psoriasis, dermatitis, Sjögren's syndrome, bronchitis, asthma, and inflammation associated with colorectal cancer, and preferably the inflammatory disease is selected from inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, osteoarthritis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, bronchitis, and inflammation associated with colorectal cancer.

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