Compounds as inhibitors of glutamine cyclase and uses thereof

Abstract

The application provides a kind of compound as glutamine cyclase inhibitor and its use, belong to the field of medicinal chemistry.The structure of the compound of the application is as shown in formula I.Such compounds have good inhibitory activity on sQC and gQC enzyme and its mutants, and the half inhibitory concentration of most compounds reaches sodium molar level, so it can be used to prepare glutamine cyclase inhibitor.In addition, such compounds can also be used to prepare drugs for preventing and treating diseases related to glutamine cyclase.The application lays a material foundation for the drug research and development of glutamine cyclase inhibitor, and has good application prospect.Formula I.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a class of compounds that are inhibitors of glutamine cyclase and their uses. Background Technology

[0002] Post-translational modifications are crucial mechanisms for regulating protein function, widely present in nature, enabling protein functional diversification and thus regulating complex biological processes. Pyroglutamate modification is a common type of post-translational modification found in nature, typically occurring at the N-terminus of proteins and peptide hormones. It protects proteins from hydrolysis by aminopeptidases, improves protein stability, maintains their biologically active conformation, and promotes protein-protein interactions. Pyroglutamate modification is primarily catalyzed by a zinc-dependent glutamine cyclase. Currently, secretory glutamine cyclase (sQC) and Golgi glutamine cyclase (gQC) have been identified in humans. Both sQC and gQC possess highly conserved active sites, including key zinc ions and coordinating amino acids, and triplet sequences (sQC: Glu201-Asp305-Asp248; gQC: Glu225-Asp326-Asp269).

[0003] sQC and gQC can catalyze intramolecular cyclization of glutamine or glutamate at the N-terminus of various proteins to form pyroglutamate, such as β-amyloid (Aβ), chemokine family members CCL2 / CCL7 / CX3CL1, and immunoglobulin superfamily member CD47. Abnormal N-terminal pyroglutamate modification of these proteins is closely related to Alzheimer's disease, Parkinson's disease, inflammation, tumors, colitis, and nephropathy. Studies have shown that targeting sQC and gQC to reduce N-terminal pyroglutamate modification of multiple pathologically related substrate proteins may exhibit synergistic therapeutic effects on complex diseases such as Alzheimer's disease, inflammation, and tumors; therefore, sQC / gQC is considered a highly promising drug target. Currently, several small molecule inhibitors targeting different backbones of sQC and gQC have been reported, the vast majority of which are substrate-competitive inhibitors. However, to date, only one sQC / gQC inhibitor (PQ912) has entered clinical trials as an anti-Alzheimer's disease candidate. Therefore, there is still a need to develop more novel sQC / gQC inhibitors to provide more lead or candidate drugs for innovative drug research on sQC / gQC-related diseases. Summary of the Invention

[0004] The purpose of this invention is to provide a class of compounds as inhibitors of glutamine cyclase and their uses.

[0005] This invention provides compounds of Formula I, their salts, their stereoisomers, or their prodrugs:

[0006]

[0007] Formula I

[0008] in,

[0009] It can be a single bond or a double bond; when When it is a single bond, X is selected from NR6, R6 is selected from hydrogen, C1~C6 alkyl, R4 and R5 form =Z, and Z is selected from O and S; when When it is a double bond, X is selected from N, R5 is absent, and R4 is selected from hydrogen, C1~C6 alkyl, and -OR7;

[0010] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl groups;

[0011] R1 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted 3~6 membered cycloalkyl, and -(CH2). n R8;

[0012] n is selected from 1, 2, 3, 4, or 5;

[0013] R8 is selected from -OC(O)R9, substituted or unsubstituted 3- to 6-membered cycloalkyl groups;

[0014] R9 is selected from hydrogen and C1-C6 alkyl groups;

[0015] R2 is located at any position on the ring and is selected from hydrogen, halogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted 6~10 aryl, substituted or unsubstituted 5~10 heteroaryl.

[0016] R3 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl.

[0017] The substituents of the alkyl, alkenyl, alkynyl, and alkoxy groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 3- to 6-membered cycloalkyl.

[0018] The substituents of the cycloalkyl, aryl, and heteroaryl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or, two substituents on the same carbon atom can form =Y;

[0019] Y is selected from O and S;

[0020] R 10 Selected from hydrogen and C1~C6 alkyl groups.

[0021] Furthermore, the compound is as shown in formula II-A or formula II-B:

[0022]

[0023] Formula II-A Formula II-B

[0024] In formulas II-A and II-B,

[0025] R1 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted 3~6 membered cycloalkyl, and -(CH2). n R8;

[0026] n is selected from 1, 2, 3, 4, or 5;

[0027] R8 is selected from -OC(O)R9, substituted or unsubstituted 3- to 6-membered cycloalkyl groups;

[0028] R9 is selected from hydrogen and C1-C6 alkyl groups;

[0029] R2 is located at any position on the ring and is selected from hydrogen, halogen, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl, substituted or unsubstituted 6~10 aryl, substituted or unsubstituted 5~10 heteroaryl.

[0030] R3 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C2~C6 alkenyl, substituted or unsubstituted C2~C6 alkynyl.

[0031] The substituents of the alkyl, alkenyl, alkynyl, and alkoxy groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 3- to 6-membered cycloalkyl.

[0032] The substituents of the cycloalkyl, aryl, and heteroaryl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or, two substituents on the same carbon atom can form =Y;

[0033] Y is selected from O and S;

[0034] R 10 Selected from hydrogen and C1-C6 alkyl groups;

[0035] In formula II-B,

[0036] R4 is selected from hydrogen, C1~C6 alkyl, and -OR7;

[0037] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl groups;

[0038] The substituents of the alkyl group are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, 3- to 6-membered cycloalkyl.

[0039] Furthermore,

[0040] R1 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C4 alkyl, substituted or unsubstituted C2~C4 alkenyl, substituted or unsubstituted C2~C4 alkynyl, 3~4 membered cycloalkyl, -(CH2). n R8; The substituents of the alkyl, alkenyl, and alkynyl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, and nitro.

[0041] n is selected from 1, 2, or 3;

[0042] R8 is selected from -OC(O)R9, 3-6 membered cycloalkyl groups;

[0043] R9 is selected from hydrogen and C1-C4 alkyl groups;

[0044] R2 is located at any position on the ring and is selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted... Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl, alkenyl, and alkynyl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, and nitro; the phenyl, pyridyl, naphthyl, and... , , , , , , , , The substituents are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or two substituents on the same carbon atom form =Y; the substituents of the alkoxy group are selected from one or more of the following groups: 3-6 membered cycloalkyl;

[0045] Y is selected from O and S;

[0046] R 10 Selected from hydrogen and C1-C4 alkyl groups;

[0047] R3 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl; the substituent of the alkyl, alkenyl, or alkynyl group is selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro.

[0048] Furthermore, the compound is as shown in formula III-A, formula III-B, or formula III-C:

[0049]

[0050] Formula III-A, Formula III-B, Formula III-C

[0051] In formulas III-A, III-B, and III-C,

[0052] R1 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1~C4 alkyl, substituted or unsubstituted C2~C4 alkenyl, substituted or unsubstituted C2~C4 alkynyl, 3~4 membered cycloalkyl, -(CH2). n R8; The substituents of the alkyl, alkenyl, and alkynyl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, and nitro.

[0053] n is selected from 1, 2, or 3;

[0054] R8 is selected from -OC(O)R9, 3-6 membered cycloalkyl groups;

[0055] R9 is selected from hydrogen and C1-C4 alkyl groups;

[0056] R2 is selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substituents of the alkyl, alkenyl, and alkynyl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, and nitro; the phenyl, pyridyl, naphthyl, and... , , , , , , , , The substituents are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or two substituents on the same carbon atom form =Y; the substituents of the alkoxy group are selected from one or more of the following groups: 3-6 membered cycloalkyl;

[0057] Y is selected from O and S;

[0058] R 10 Selected from hydrogen and C1-C4 alkyl groups;

[0059] R3 is selected from hydrogen, halogen, cyano, amino, hydroxyl, carboxyl, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl; the substituent of the alkyl, alkenyl, or alkynyl group is selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro.

[0060] In formula III-C,

[0061] R7 is selected from hydrogen, substituted or unsubstituted C1~C6 alkyl groups.

[0062] Furthermore,

[0063] R1 is selected from hydrogen, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, 3~4 membered cycloalkyl, , ;

[0064] R2 is selected from hydrogen, halogen, , , , , , , Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 ynyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted Replaced or not replaced ;

[0065] The substituents of the alkyl, alkenyl, and alkynyl groups are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro; the phenyl, pyridyl, naphthyl, ... , The substituents are selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 The substituent of the alkoxy group is selected from one or more of the following groups: 3-6 membered cycloalkyl;

[0066] R 10 Selected from hydrogen and C1-C4 alkyl groups;

[0067] R3 is selected from hydrogen, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, halogen, cyano, amino, and amino-substituted C1~C4 alkyl.

[0068] Furthermore, the compound is shown in Formula IV:

[0069]

[0070] Formula IV

[0071] in,

[0072] R1 and R2 are as described above.

[0073] Furthermore, the compound is as shown in Formula V:

[0074]

[0075] Formula V

[0076] in,

[0077] R1 and R2 are as described above.

[0078] Furthermore, the compound is as shown in formula VI-A or formula VI-B:

[0079]

[0080] Formula VI-A Formula VI-B

[0081] in,

[0082] R 12 Let m be a substituent at any position on the benzene ring, and let R be a substituent. 12 The number of;

[0083] m is selected from 0, 1, 2, 3, 4 or 5;

[0084] The R 12 Selected from the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 The substituent of the alkoxy group is selected from one or more of the following groups: 3-6 membered cycloalkyl; the substituent of the alkyl group is selected from one or more of the following groups: halogen, hydroxyl, carboxyl, amino, cyano, nitro.

[0085] R 10 Selected from hydrogen and C1~C4 alkyl groups.

[0086] Furthermore, the compound is as shown in Formula VII:

[0087]

[0088] Equation VII

[0089] in,

[0090] R1 is selected from C1~C4 alkyl groups;

[0091] R2 is as described above.

[0092] Furthermore, the compound is selected from one of the following compounds:

[0093] .

[0094] The present invention also provides the use of the aforementioned compounds, their salts, their stereoisomers or their prodrugs in the preparation of glutamine cyclase inhibitors or in the preparation of medicaments for the prevention and / or treatment of diseases related to glutamine cyclase;

[0095] The diseases associated with glutamine cyclase include Alzheimer's disease, Parkinson's disease, inflammatory bowel disease, tumors, and kidney disease.

[0096] Preferably,

[0097] The glutamine cyclase inhibitor is an inhibitor that inhibits glutamine cyclase and / or glutamine cyclase mutants;

[0098] More preferably,

[0099] The glutamine cyclase inhibitor is an inhibitor that inhibits secretory glutamine cyclase alone, an inhibitor that inhibits Golgi glutamine cyclase alone, or an inhibitor that inhibits both secretory glutamine cyclase and Golgi glutamine cyclase simultaneously.

[0100] And / or, the inflammatory bowel disease is colitis.

[0101] The present invention also provides a drug that is prepared by using the aforementioned compound, its salt, its stereoisomer or its prodrug as the active ingredient, plus pharmaceutically acceptable excipients.

[0102] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0103] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0104] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0105] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a ~C bAlkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1~C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkyl; "C1~C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms, specifically C1, C2, C3, C4, C5, and C6 alkoxy.

[0106] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of carbon atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 carbon atoms, that is, alkyl groups with 1, 2, 3, 4, 5, or 6 carbon atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0107] "Alkenyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups can be straight-chain or branched.

[0108] "Alynyl group" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. Alynyl groups can be straight-chain or branched.

[0109] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0110] "Cycloalkyl" refers to saturated or unsaturated all-carbon monocyclic or polycyclic (including fused, spiro, or bridged rings) that do not have a conjugated π-electron system, such as including but not limited to: , , , , , , , , , , , wait.

[0111] "Heterocyclic alkyl" refers to a cycloalkyl group in which at least one carbon atom of the ring is replaced by a heteroatom, which is O, N, or S, and is a saturated or unsaturated monocyclic or polycyclic (including fused rings, spirocyclic or bridged rings) that does not have a conjugated π-electron system, such as including but not limited to: , , , , , , , , , , , , , , , , wait.

[0112] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spirocyclic or bridged rings) with a conjugated π-electron system, such as, but not limited to, phenyl, naphthyl, phenanthryl, anthraceneyl, fluorenyl, and indene. The aromatic ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N, or S. Furthermore, the point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system, such as, but not limited to, [other types of rings]. , , , wait.

[0113] "Heteroaryl" refers to an aryl group in which at least one carbon atom on the ring of a conjugated π-electron system is replaced by a heteroatom, which is O, N, or S, such as including but not limited to thienyl, furanyl, isothiazolyl, etc.

[0114] The pharmaceutically acceptable salts described in this invention include acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides, hydrobromide, hydroiodates, hydroxyethyl sulfonates, lactates, malates, maleic acid esters, malonates, methyl sulfates, naphthates, theosulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxyacetate, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannins, tartrates, toluenesulfonates, trifluoroacetates, sine sulfonates, methanesulfonates, p-toluenesulfonates, quaternary ammonium salts, or succinates, etc.

[0115] The present invention has achieved the following beneficial effects:

[0116] This invention provides a class of compounds that act as inhibitors of glutamine cyclase. These compounds exhibit good inhibitory activity against sQC and gQC enzymes and their mutants, with most compounds reaching the sodium molar level of half-maximal inhibitory concentration (IC50). Therefore, they can be used to prepare glutamine cyclase inhibitors. Furthermore, these compounds can also be used to prepare drugs for the prevention and treatment of diseases related to glutamine cyclase (such as ulcerative colitis). This invention lays the material foundation for the drug development of glutamine cyclase inhibitors and has promising application prospects.

[0117] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0118] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0119] Figure 1 The figure shows the effects of compounds 33 and 73 on mouse body weight.

[0120] Figure 2 The figure shows the effects of compounds 33 and 73 on mouse DAI.

[0121] Figure 3 The figure shows the effects of compounds 33 and 73 on colon length in mice.

[0122] Figure 4 The figure shows the effects of compounds 33 and 73 on the spleen index in mice. Detailed Implementation

[0123] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0124] The following are the preparation methods for intermediate compounds:

[0125] 1. Synthesis of intermediate compound A: 1-triphenylmethyl-4-vinylimidazole (A)

[0126]

[0127] Compound A-1 (4.36 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), and tributylvinyltin (6.3 g, 20 mmol), tris(dibenzylacetone)dipalladium (457.5 mg, 0.5 mmol), and triphenylphosphine (262.3 mg, 1 mmol) were added. The mixture was reacted at 90 °C for 15 h under an argon atmosphere. After the reaction was completed by TLC, it was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography was used to give intermediate A (1.5 g, 46%). ESI-MS: [M+H] + 337.16.

[0128] 2. Synthesis of intermediate compound AB: 1-Triphenylmethyl-4-ethylimidazole (AB)

[0129]

[0130] Compound A (1.01 g, 3 mmol) was dissolved in 9 mL of methanol, and 100 mg of palladium on carbon was added. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was complete as monitored by TLC, the solution was filtered through diatomaceous earth, and the solvent was evaporated to give intermediate AB (325 mg, 32%). ESI-MS: [M+H] + : 339.18.

[0131] 3. Intermediate compound AC: 1-Triphenylmethyl-4-ethynylimidazole

[0132]

[0133] Step 1: Synthesis of 1-triphenylmethyl-4-(trimethylsilyl)ethynyl (A-2)

[0134] Compound A-1 (4.36 g, 10 mmol) was dissolved in dry tetrahydrofuran (30 mL), and trimethylsilylacetylene (6.3 g, 20 mmol), tetra(triphenylphosphine)palladium (1.16 g, 1 mmol), cuprous iodide (190 mg, 1 mmol), and triethylamine (3.0 g, 30 mmol) were added. The mixture was reacted at 70 °C for 8 h under an argon atmosphere. After the reaction was complete as monitored by TLC, it was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography was used to give intermediate A-2 (1.25 g, 30%). ESI-MS: [M+H] + :407.19.

[0135] Step 2: Synthesis of 1-triphenylmethyl-4-ethynylimidazole (AC)

[0136] Intermediate A-2 (1.25 g, 3.01 mmol) was dissolved in 10 mL of a mixture of methanol and tetrahydrofuran (1:1 v / v), and anhydrous potassium carbonate (1.24 g, 9 mmol) was added. The reaction was carried out at room temperature until the starting material disappeared as monitored by TLC. After filtration to remove the solvent, column chromatography was performed to obtain intermediate AC (400 mg, 40%). ESI-MS: [M+H] + : 335.16.

[0137] 4. Synthesis of intermediate compound AD: 1-Triphenylmethyl-4-(prop-1-ynyl)imidazolium (AD)

[0138]

[0139] Compound AC (230 mg, 0.7 mmol) was dissolved in dry tetrahydrofuran (3 mL). Under an argon atmosphere, n-butyllithium (1.6 M, n-hexane) (1 mL, 1.6 mmol) was slowly added dropwise at -40 °C. The reaction was maintained at this temperature for 30 min, then the temperature was raised to -20 °C and TMEDA (162 mg, 1.4 mmol) was added dropwise. The reaction was maintained at the above temperature for another 30 min, then CH3I (397 mg, 2.8 mmol) was added. The reaction was then raised to room temperature and continued. After the reaction was monitored by TLC until complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate and water, and the organic layers were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and excess solvent was evaporated. Column chromatography yielded intermediate AD (190 mg, 79%). ESI-MS: [M+H] + : 349.16.

[0140] 5. Intermediate compound AE: 1-Triphenylmethyl-4-isopropylimidazolium

[0141]

[0142] Step 1: Synthesis of 1-triphenylmethyl-4-(prop-1-en-2-yl)imidazolium (A-3)

[0143] Compound A-1 (4.36 g, 10 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), and pinacol isopropenylborate (2.52 g, 15 mmol), bis(triphenylphosphine)palladium chloride (702 mg, 1 mmol), and sodium carbonate (10.6 g, 100 mmol) were added. The mixture was reacted at 90 °C for 15 h under an argon atmosphere. After the reaction was complete as monitored by TLC, it was cooled to room temperature, extracted with ethyl acetate and water, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography was used to give intermediate A-3 (1.4 g, 41%). ESI-MS: [M+H] + 351.18.

[0144] Step 2: Synthesis of 1-triphenylmethyl-4-isopropylimidazolium (AE)

[0145] Compound A-3 (1.4 g, 4 mmol) was dissolved in 12 mL of methanol, and 140 mg of palladium on carbon was added. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was complete as monitored by TLC, the solution was filtered through diatomaceous earth, and the solvent was evaporated to give intermediate AE (422 mg, 30%). ESI-MS: [M+H] + : 353.19.

[0146] 6. Intermediate compound AF: 1-Triphenylmethyl-4-cyclopropylimidazolium

[0147]

[0148] Compound A-4 (1 g, 9.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of triphenylchloromethane (2.85 g, 10.2 mmol) and triethylamine (1.8 g, 18.6 mmol). The mixture was stirred at room temperature, and the reaction was monitored by TLC until complete. The mixture was then filtered, and the solid was washed to give intermediate AF (2.3 g, 6.5 mmol). ESI-MS: [M+H] + 351.18.

[0149] 7. Synthesis of intermediate compound AG: 1-Triphenylmethyl-4-methylimidazole (AG)

[0150]

[0151] Using compound A-5 (820 mg, 10 mmol) as a starting material, intermediate AG (2.7 g, 8.5 mmol) was obtained by a similar synthetic method to that used for intermediate AF. ESI-MS: [M+H] + 325.16.

[0152] 8. Intermediate compound AH: Acetic acid-[1-(triphenylmethyl)imidazol-4-yl]methyl ester

[0153]

[0154] Step 1: Synthesis of [1-(triphenylmethyl)imidazol-4-yl]methanol (A-7)

[0155] Using compound A-6 (981 mg, 10 mmol) as a starting material, intermediate A-7 (2.38 g, 7 mmol) was obtained by following a similar synthetic method to that used for intermediate AF. ESI-MS: [M+H] + 341.16

[0156] Step 2: Synthesis of Acetic Acid-[1-(triphenylmethyl)imidazol-4-yl]methyl ester (AH)

[0157] Compound A-7 (680 mg, 2 mmol) was dissolved in 6 mL of pyridine, and 613 mg of acetic anhydride was added. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. After the reaction was complete as monitored by TLC, the solvent was evaporated, and the mixture was washed several times to obtain intermediate AH (422 mg, 30%). ESI-MS: [M+H] + 383.17.

[0158] 9. Intermediate compound AI: 4-(cyclopropylmethyl)-1-(triphenylmethyl)imidazolium

[0159]

[0160] Step 1: Synthesis of cyclopropyl[1-(triphenylmethyl)imidazol-4-yl]methanol (A-9)

[0161] Compound A-8 (3.38 g, 10 mmol) was dissolved in dry THF (10 mL). After argon protection and pre-cooling at 0 °C for 10 min, cyclopropylmagnesium bromide (24.0 mL, 12.0 mmol) was slowly added, and the mixture was reacted at room temperature for 3 h. After TLC detection of complete reaction, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with EA (50 mL × 3), washed with saturated brine (50 mL × 2), and the organic phase was collected. After concentration under reduced pressure to remove solvent, column chromatography (DCM:MeOH = 150:1 → 100:1) was performed to give intermediate A-9 (2.66 g, 70% yield, white solid). ESI-MS: [M+H] + : 381.19.

[0162] Step 2: Synthesis of 5-cyclopropyl-3H-imidazole (A-10)

[0163] Compound A-9 (2.66 g, 7 mmol) was dissolved in a mixed solvent of 1,2-dichloroethane (10 mL): trifluoroacetic acid (6 mL) in a volume ratio of 5:3. Triethylsilane (6.51 g, 56 mmol) was added, and the mixture was moved to 70 °C and reacted overnight. After the reaction was confirmed to be complete by TLC, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with EA (100 mL × 3) and water (50 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, and the organic phase was collected. After removing the solvent by vacuum concentration, the mixture was subjected to column chromatography (DCM:MeOH = 150:1 → 80:1) to give intermediate A-10 (513 mg, yield 60%, white solid).

[0164] Step 3: Synthesis of 4-(cyclopropylmethyl)-1-(triphenylmethyl)imidazolium (AI)

[0165] Using compound A-10 (488.7 g, 4 mmol) as a starting material, intermediate AI (1.27 g, 87%) was obtained by following a similar synthetic method to intermediate AF. ESI-MS: [M+H] + 365.19.

[0166] 10. Synthesis of intermediate compound AJ: 4-[(1E)-prop-1-enyl]-1-(triphenylmethyl)imidazolium (AJ)

[0167]

[0168] Compound AD (488 mg, 1.4 mmol) was dissolved in 10 mL of ultra-dry tetrahydrofuran. Anhydrous aluminum chloride (40 mg, 0.3 mmol) and lithium aluminum hydride (160 mg, 4.2 mmol) were slowly added, and the mixture was reacted at 70 °C for 5 hours. After TLC detection of complete reaction, the mixture was cooled to room temperature, and the reaction was quenched by slow addition of water. Anhydrous sodium sulfate was added for drying, and the mixture was filtered. The filtrate was collected, concentrated under reduced pressure to remove the solvent, and then subjected to column chromatography (PE:EA = 30:1 → 5:1) to give intermediate AJ (270 mg, 55% yield, white solid). ESI-MS: [M+H] + 351.18.

[0169] 11. Intermediate compound AK: 4-propyl-1-(triphenylmethyl)imidazolium

[0170]

[0171] The route for synthesizing AK from compound A-8 is similar to that for A-8 to AI, ultimately yielding 1.45 g of AK. ESI-MS: [M+H] + : 353.20.

[0172] 12. Synthesis of intermediate compound AL: 4-(2-methylprop-1-enyl)-1-(triphenylmethyl)imidazolium (AL)

[0173]

[0174] Using compound A-1 (4.36 g, 10 mmol) as a starting material, intermediate AL (2.62 g, 72%) was obtained by a similar synthetic method to that used for intermediate A-3. ESI-MS: [M+H] + 365.20.

[0175] 13. Synthesis of intermediate compound AM: 4-(2-methylpropyl)-1-(triphenylmethyl)imidazole (AM)

[0176]

[0177] Using compound AL (1.82 g, 5 mmol) as a starting material, intermediate AM (1.14 g, 62%) was obtained by a similar synthetic method to that used for intermediate AE. ESI-MS: [M+H] + 367.21.

[0178] 14. Intermediate compound AN: 4-Cyclobutyl-1-(triphenylmethyl)imidazolium

[0179]

[0180] Step 1: Synthesis of 5-cyclobutyl-3H-imidazolium (A-14)

[0181] Compound A-13 (1.0 g, 5.6 mmol) was dissolved in 10 mL of ethylene glycol. Formamidin acetate (2.9 g, 28.0 mmol) was added, and the mixture was moved to 135 °C and reacted overnight. After the reaction was completed, the mixture was cooled to room temperature, and water and ethanol were added. The mixture was stirred at room temperature for 18 hours. The organic layer was separated, dried over anhydrous sodium sulfate, and the organic phase was collected. The solvent was removed by concentration under reduced pressure to obtain A-14, which could be directly used for the next reaction without purification.

[0182] Step 2: Synthesis of 4-cyclobutyl-1-(triphenylmethyl)imidazolium (AN)

[0183] Using compound A-14 as a starting material, intermediate AN (1.83 g, 90%) was obtained by following a similar synthetic method to that used for intermediate AF.

[0184] 15. Intermediate compound AO: 4-(prop-2-enyl)-1-(triphenylmethyl)imidazolium

[0185]

[0186] The route for synthesizing AO from compound A-8 is similar to the method for synthesizing AI from A-8, ultimately yielding 1.45 g of AO.

[0187] 16. Intermediate compound AP: 4-(prop-2-ynyl)-1-(triphenylmethyl)imidazolium

[0188]

[0189] The route from compound A-8 to AP was similar to that from A-8 to AI, ultimately yielding 1.44 g of AP.

[0190] 17. Synthesis of intermediate compound AQ: 2-methyl-3-(triphenylmethyl)imidazole (AQ)

[0191]

[0192] Using compound A-19 (821 mg, 10 mmol) as a starting material, intermediate AQ (2.7 g, 8.5 mmol) was obtained by following a similar synthetic method to intermediate AF.

[0193] 18. Synthesis of intermediate compound AR: 2,4-dimethyl-1-(triphenylmethyl)imidazole (AR)

[0194]

[0195] Using compound A-20 (961 mg, 10 mmol) as a starting material, intermediate AR (2.87 g, 8.5 mmol) was obtained by following a similar synthetic method to intermediate AF.

[0196] 19. Synthesis of intermediate compound AS: 2-(bromomethyl)-6-methoxypyridine (AS)

[0197]

[0198] Compound A-21 (246.3 mg, 2 mmol) was dissolved in 10 mL of carbon tetrachloride solution, and AIBN (32.8 mg, 0.2 mmol) and NBS (711.92 mg, 4 mmol) were added sequentially. The mixture was reacted at 80 °C for 6 h, and the compound AS (299 mg, 74%) was obtained by column chromatography.

[0199] 20. Intermediate compound AT: 6-(bromomethyl)-2-oxoylide-3-phenylpyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0200]

[0201] Step 1: Synthesis of 3-bromo-6-methyl-1,2-dihydropyridin-2-one (A-22)

[0202] Compound A-21 (2.02 g, 10 mmol) was dissolved in 5 mL of concentrated hydrochloric acid and reacted at 100 °C for 2 h. After the reaction was completed by TLC, sodium hydroxide aqueous solution was added to adjust the pH to neutral, and the solvent was evaporated. After washing several times, intermediate A-22 (1.7 g, 90%) was obtained.

[0203] Step 2: Synthesis of 3-bromo-6-methyl-2-oxylidene-1-carboxylic acid-2-methylpropyl-2-yl ester (A-23)

[0204] Compound A-22 (1.7 g, 9 mmol) was dissolved in tetrahydrofuran (27 mL), and DMAP (549.8 mmg, 4.5 mmol) and di-tert-butyl dicarbonate (2.95 g, 13.5 mmol) were added sequentially. After reacting at room temperature for 1 h, column purification was performed to obtain intermediate A-23 (2.46 g, 95%).

[0205] Step 3: Synthesis of 6-methyl-2-oxoylide-3-phenylpyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (A-24)

[0206] Compound A-23 (576 mg, 2 mmol), phenylboronic acid (487.72 mg, 4 mmol), and anhydrous potassium carbonate (828.6 mg, 6 mmol) were weighed sequentially into a double-necked reaction flask. 12 mL of 1,4-dioxane:water (volume ratio 5:1) was added, and the mixture was purged. Tetra(triphenylphosphine)palladium (115.6 mg, 0.1 mmol) was added under an argon atmosphere, and the reaction was carried out at 100 °C for 6 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the solvent was evaporated, and column chromatography was used to obtain intermediate A-24 (410.9 mg, 72%).

[0207] Step 4: Synthesis of 6-(bromomethyl)-2-oxoylide-3-phenylpyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (AT)

[0208] Using compound A-24 (410.9 mg, 1.44 mmol) as a starting material, intermediate AT (351.2 mg, 67%) was obtained by following a similar synthetic method to intermediate AS.

[0209] 21. Intermediate compound AU: 6-(bromomethyl)-3-(2-ethoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0210]

[0211] The experimental method for synthesizing AU from A-23 was the same as that for synthesizing AT from A-23, with yields of A-25 (388.7 mg, 59%) and AU (303.52 mg, 63%), respectively.

[0212] 22. Intermediate compound AV: 6-(bromomethyl)-3-(2-methoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0213]

[0214] The experimental method for synthesizing AV from A-23 is the same as that for synthesizing AT from A-23, with yields of A-26 (378 mg, 60%) and AV (293 mg, 62%), respectively.

[0215] 23. Intermediate compound AW: 6-(bromomethyl)-3-(3-methoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0216]

[0217] The experimental method for synthesizing AW from A-23 is the same as that for synthesizing AT from A-23, with yields of A-27 (378 mg, 60%) and AW (293 mg, 62%), respectively.

[0218] 24. Intermediate compound AX: 6-(bromomethyl)-3-(4-methoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0219]

[0220] The experimental method for synthesizing AX from A-23 is the same as that for synthesizing AT from A-23, with yields of A-28 (378 mg, 60%) and AX (293 mg, 62%), respectively.

[0221] 25. Intermediate compound AY: 6-(bromomethyl)-3-(2,4-dimethoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0222]

[0223] The experimental method for synthesizing AY from A-23 was the same as that for synthesizing AT from A-23, with yields of A-29 (414.5 mg, 60%) and AY (315.5 mg, 62%), respectively.

[0224] 26. Intermediate compound AZ: 6-(bromomethyl)-3-(3,4-dimethoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0225]

[0226] The experimental method for synthesizing AZ from A-23 was the same as that for synthesizing AT from A-23, with yields of A-30 (414.5 mg, 60%) and AZ (315.5 mg, 62%), respectively.

[0227] 27. Intermediate compound BA: 6-(bromomethyl)-3-(2,3-dimethoxyphenyl)-2-oxoylidene-1-carboxylic acid-2-methylpropyl-2-yl ester

[0228]

[0229] The experimental method for synthesizing BA from A-23 was the same as that for synthesizing AT from A-23, with yields of A-31 (414.5 mg, 60%) and BA (315.5 mg, 62%), respectively.

[0230] 28. Intermediate compound BB: 6-(bromomethyl)-4-(4-methoxyphenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0231]

[0232] The experimental method for synthesizing BB from A-32 was the same as that for synthesizing AT from A-22, with yields of: A-33 (1.45 g, 95%), A-34 (378.4 mg, 60%), and BB (293 mg, 62%).

[0233] 29. Intermediate compound BC: 6-(bromomethyl)-3-(4-fluoro-3-methoxyphenyl)-2-oxoylidene-1-carboxylic acid-2-methylpropyl-2-yl ester

[0234]

[0235] The experimental method for synthesizing BC from A-23 was the same as that for synthesizing AT from A-23, with yields of A-35 (399.9 mg, 60%) and BC (306.7 mg, 62%), respectively.

[0236] 30. Intermediate compound BD:

[0237]

[0238] The experimental method for synthesizing BD from A-23 was the same as that for synthesizing AT from A-23, with yields of A-36 (379.6 mg, 60%) and BD (294.1 mg, 62%), respectively.

[0239] 31. Intermediate compound BE: 6-(bromomethyl)-3-(3,4-difluorophenyl)-2-oxoylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0240]

[0241] The experimental method for synthesizing BE from A-23 was the same as that for synthesizing AT from A-23, with yields of A-37 (385.6 mg, 60%) and BE (297.7 mg, 62%), respectively.

[0242] 32. Intermediate compound BF: 6-(bromomethyl)-3-(3-chloro-4-fluorophenyl)-2-oxoylidene-1-carboxylic acid-2-methylpropyl-2-yl ester

[0243]

[0244] The experimental method for synthesizing BF from A-23 was the same as that for synthesizing AT from A-23, with yields of A-38 (405.3 mg, 60%) and BF (310 mg, 62%), respectively.

[0245] 33. Synthesis of intermediate compound BG: 3-bromo-6-(bromomethyl)-2-methoxypyridine (BG)

[0246]

[0247] Using compound A-40 (2.91 g, 8.1 mmol) as a starting material, intermediate BG (1.79 g, 79%) was obtained by following a similar synthetic method to intermediate AS.

[0248] 34. Intermediate compound BH: methyl 3-[6-(bromomethyl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}-2-oxoylidenepyridin-3-yl]benzoate

[0249]

[0250] The experimental method for synthesizing BH from A-23 was the same as that for synthesizing AT from A-23, with yields of A-41 (412 mg, 60%) and BH (319.2 mg, 63%), respectively.

[0251] 35. Intermediate compound BI: 6-(bromomethyl)-3-(7-methoxynaphth-1-yl)-2-oxomylidene-1-carboxylic acid-2-methylpropyl-2-yl ester

[0252]

[0253] The experimental method for synthesizing BI from A-23 was the same as that for synthesizing AT from A-23, with yields of A-42 (438 mg, 60%) and BI (303.9 mg, 57%), respectively.

[0254] 36. Intermediate compound BJ: 6-(bromomethyl)-2-oxoylide-3-(2,4,5-trimethoxyphenyl)pyridine-1-carboxylic acid-2-methylpropyl-2-yl ester

[0255]

[0256] The experimental method for synthesizing BJ from A-23 is the same as that for synthesizing AT from A-23, with yields of A-43 (450 mg, 60%) and BJ (272 mg, 50%), respectively.

[0257] 37. Intermediate compound BK: 6-(bromomethyl)-2-methoxy-3-phenylpyridine

[0258]

[0259] The experimental method for synthesizing BK from A-39 was the same as that for synthesizing AT from A-23, with yields of A-44 (239 mg, 60%) and BK (167 mg, 50%), respectively.

[0260] The following are examples of the preparation of the compounds of the present invention.

[0261] Example 1: 3-Phenyl-6-[(4-vinylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0262]

[0263] Step 1: Synthesis of 3-[(1-{[(2-methylprop-2-yl)oxy]carbonyl}-6-oxoylide-5-phenylpyridin-2-yl)methyl]-1-(triphenylmethyl)-4-vinylimidazol-3-cation (1a)

[0264] Intermediate A (168 mg, 0.5 mmol) and AT (182 mg, 0.5 mmol) were dissolved in dry acetonitrile (5 ml) and reacted at 90 °C for 6 h. After the reaction was completed by TLC monitoring, the solvent was evaporated to obtain the crude product of compound 1a.

[0265] Step 2: Synthesis of 2-oxoylide-3-phenyl-6-[(4-vinylimidazol-3-yl)methyl]pyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (1b)

[0266] The crude product of compound 1a was dissolved in methanol (3 ml) and reacted overnight at 70 °C. After the reaction was completed by TLC monitoring, the solvent was evaporated after cooling to room temperature, and compound 1b (28.3 mg, 15%) was obtained by column chromatography.

[0267] Step 3: Synthesis of 3-phenyl-6-[(4-vinylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one (1)

[0268] Compound 1b was dissolved in 2 mL of 1,4-dioxane hydrochloric acid solution and reacted at room temperature for 1 h. After the reaction was complete, the solvent was evaporated by TLC and compound 1 (18.7 mg, 90%) was obtained by column chromatography. 1H NMR (400 MHz, MeOD) δ 9.07 (s,1H), 7.88 (s, 1H), 7.65 (m, 3H), 7.37 (m, 4H), 6.70 (m, 1H), 6.32 (m, 1H),5.98 (m, 1H), 5.64 (m, 1H), 5.49 (m, 2H).

[0269] Example 2: 6-[(4-ethylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0270]

[0271] The experimental method for synthesizing compound 2 (37.7 mg) using AB and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 7.68 (d, J = 7.0Hz, 1H), 7.66 – 7.61 (m, 2H), 7.44 (s, 1H), 7.40 (t, J = 7.2 Hz, 2H), 7.37 –7.31 (m, 1H), 6.33 (d, J = 7.1 Hz, 1H), 5.41 (s, 2H), 2.70 (q, J = 7.4 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H).

[0272] Example 3: 6-[(4-ethynylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0273]

[0274] The experimental method for synthesizing compound 3 (37.2 mg) using AC and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1Hz, 1H), 7.33 (s, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (dd, J= 8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 2H), 5.97 (d, J = 7.1 Hz, 2H), 5.26 (s, 2H), 4.13 (s,1H).

[0275] Example 4: 3-Phenyl-6-{[4-(prop-1-ynyl)imidazol-3-yl]methyl}-1,2-dihydropyridin-2-one

[0276]

[0277] The experimental method for synthesizing compound 4 (39 mg) using AD and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.82 (s, 1H), 7.69 – 7.57 (m,3H), 7.41 – 7.36 (m, 2H), 7.34 – 7.30 (m, 1H), 7.15 (s, 1H), 5.99 (d, J = 7.3Hz, 1H), 5.20 (s, 2H), 2.06 (s, 3H).

[0278] Example 5: 3-Phenyl-6-{[4-(prop-2-yl)imidazol-3-yl]methyl}-1,2-dihydropyridin-2-one

[0279]

[0280] The experimental method for synthesizing compound 5 (39.6 mg) using AE and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.88 (s, 1H), 7.63 – 7.50 (m, 3H), 7.39 (s, 1H), 7.27 (m, 3H), 6.25 (d, J = 6.9 Hz, 1H), 5.34 (s, 2H), 2.99 (m, J = 6.8 Hz, 1H), 1.21 (d, J = 6.7 Hz, 6H).

[0281] Example 6: 6-[(4-cyclopropylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0282]

[0283] The experimental method for synthesizing compound 6 (39.3 mg) using AF and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.89 (d, J = 1.5 Hz, 1H), 7.68– 7.44 (m, 3H), 7.33 – 7.15 (m, 4H), 6.28 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H), 1.70 (m, 1H), 1.03 – 0.85 (m, 2H), 0.66 (m, 2H).

[0284] Example 7: Acetic acid-{3-[(6-oxoylidene-5-phenyl-1H-pyridin-2-yl)methyl]imidazol-4-yl}methyl ester

[0285]

[0286] The experimental method for synthesizing compound 7 (43 mg) using AH and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.15 (s, 1H), 7.77 (s, 1H), 7.71 – 7.58 (m, 3H), 7.50 – 7.27 (m, 4H), 6.42 (d, J = 7.0 Hz, 1H), 5.51 (s,2H), 5.24 (s, 2H), 1.95 (s, 3H).

[0287] Example 8: 6-{[4-(cyclopropylmethyl)imidazol-3-yl]methyl}-3-phenyl-1,2-dihydropyridin-2-one

[0288]

[0289] The experimental method for synthesizing compound 8 (41 mg) using AI and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 7.71 – 7.59 (m,3H), 7.58 – 7.53 (m, 1H), 7.45 – 7.28 (m, 3H), 6.32 (d, J = 7.2 Hz, 1H), 5.38(s, 2H), 2.60 (d, J = 7.0 Hz, 2H), 1.07 (m, 1H), 0.71 – 0.60 (m, 2H), 0.31 –0.22 (m, 2H).

[0290] Example 9: 6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-3-phenyl-1,2-dihydropyridin-2-one

[0291]

[0292] The experimental method for synthesizing compound 9 (39 mg) using AJ and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.73 (s, 1H), 7.65 – 7.56 (m,3H), 7.41 – 7.34 (m, 3H), 7.34 – 7.30 (m, 1H), 7.11 (s, 1H), 6.20 (d, J = 5.5Hz, 1H), 5.82 (d, J = 7.2 Hz, 1H), 5.19 (s, 2H), 1.84 (d, J = 5.3 Hz, 3H).

[0293] Example 10: 3-Phenyl-6-[(4-propylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0294]

[0295] The experimental method for synthesizing compound 10 (39 mg) using AK and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.70 – 7.60 (m,3H), 7.45 – 7.32 (m, 4H), 6.39 – 6.27 (m, 1H), 5.38 (s, 2H), 2.70 – 2.62 (m,2H), 1.71 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H).

[0296] Example 11: 6-{[4-(2-methylprop-1-enyl)imidazol-3-yl]methyl}-3-phenyl-1,2-dihydropyridin-2-one

[0297]

[0298] The experimental method for synthesizing compound 11 (14 mg) using AL and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.60 – 7.49 (m,3H), 7.45 (s, 1H), 7.27 (m, 4H), 6.19 (d, J = 6.9 Hz, 1H), 5.92 (s, 1H), 5.29 (s, 2H), 1.86 (s, 3H), 1.76 (s, 3H).

[0299] Example 12: 6-{[4-(2-methylpropyl)imidazol-3-yl]methyl}-3-phenyl-1,2-dihydropyridin-2-one

[0300]

[0301] The experimental method for synthesizing compound 12 (46 mg) using AM and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 7.72 – 7.60 (m,3H), 7.48 (s, 1H), 7.43 – 7.33 (m, 3H), 6.35 (d, J = 7.1 Hz, 1H), 5.39 (s, 2H), 2.59 (d, J = 7.2 Hz, 2H), 1.91 (m, 1H), 0.99 (d, J= 6.6 Hz, 6H).

[0302] Example 13: 6-[(4-cyclobutylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0303]

[0304] The experimental method for synthesizing compound 13 (41.2 mg) using AN and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.67 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.54 (s, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.33 (t, J= 7.2 Hz, 1H), 6.29 (s, 1H), 5.32 (s, 2H), 3.62 – 3.56 (m, 1H), 2.35 (d, J =7.6 Hz, 2H), 2.16 (dd, J = 18.1, 8.9 Hz, 2H), 2.12 – 2.04 (m, 1H), 1.93 (d, J= 8.4 Hz, 1H).

[0305] Example 14: 3-Phenyl-6-{[4-(prop-2-enyl)imidazol-3-yl]methyl}-1,2-dihydropyridin-2-one

[0306]

[0307] The experimental method for synthesizing compound 14 (39 mg) using AO and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 7.66 (m, 4H),7.41 (m, 2H), 7.36 – 7.30 (m, 1H), 6.48 (m, 1H), 6.32 (m, 2H), 5.43 (s, 2H), 3.63 (m, 1H), 1.92 (d, J = 6.2 Hz, 2H).

[0308] Example 15: 3-Phenyl-6-{[4-(prop-2-ynyl)imidazol-3-yl]methyl}-1,2-dihydropyridin-2-one

[0309]

[0310] The experimental method for synthesizing compound 15 (39 mg) using AP and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.99 (s, 1H), 7.58 (d, J =6.9 Hz, 1H), 7.54 (d, J = 7.4 Hz, 2H), 7.42 (s, 1H), 7.30 (t, J = 7.3 Hz,2H), 7.27 – 7.21 (m, 1H), 6.28 (d, J = 6.6 Hz, 1H), 5.37 (s, 2H), 3.80 (s,2H), 3.59 – 3.46 (m, 1H)

[0311] Example 16: 3-Phenyl-6-{[4-(prop-1-en-2-yl)imidazol-3-yl]methyl}-1,2-dihydropyridin-2-one

[0312]

[0313] The experimental method for synthesizing compound 16 (13 mg) using A-3 and AT as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.06 (s, 1H), 7.71 – 7.59 (m,5H), 7.42 – 7.33 (m, 4H), 6.30 (d, J = 6.9 Hz, 1H), 5.56 (d, J = 1.7 Hz, 1H), 5.47 (s, 2H), 5.35 (s, 1H), 2.10 (s, 3H).

[0314] Example 17: Methyl 3-{2-oxoylide-6-[(4-propylimidazol-3-yl)methyl]-1H-pyridin-3-yl}benzoate

[0315]

[0316] The experimental method for synthesizing compound 17 (47 mg) using AK and BH as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.33 (d, J= 1.8Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.46 (s, 1H), 6.36 (d, J = 7.2 Hz, 1H), 5.42 (s,2H), 3.92 (s, 3H), 2.67 (t, J = 7.1 Hz, 2H), 1.71 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H).

[0317] Example 18: Methyl 3-[6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-2-oxonyl-1H-pyridin-3-yl]benzoate

[0318]

[0319] The experimental method for synthesizing compound 18 (15.7 mg) using AJ and BH as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 7.97 (d, J = 7.8Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.51 (t, J = 7.8 Hz,1H), 6.97 (s, 1H), 6.24 – 6.18 (m, 3H), 5.95 (d, J = 7.3 Hz, 1H), 5.07 (s, 2H), 3.91 (s, 3H), 2.35 (s, 3H).

[0320] Example 19: 3-(2-ethoxyphenyl)-6-[(4-propylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0321]

[0322] The experimental method for synthesizing compound 19 (45.5 mg) using AK and AU as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.45 (d, J =7.1 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.26 – 7.20 (m, 1H), 6.99 (d, J = 8.3 Hz,1H), 6.94 (t, J = 7.4 Hz, 1H), 6.83 (s, 1H), 5.81 (d, J = 7.1 Hz, 1H), 5.14(s, 2H), 4.00 (t, J = 7.0 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 1.67 – 1.58 (m,2H), 1.26 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H).

[0323] Example 20: 6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-3-(2-ethoxyphenyl)-1,2-dihydropyridin-2-one

[0324]

[0325] The experimental method for synthesizing compound 20 (15 mg) using AJ and AU as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.74 (s, 1H), 7.44 (d, J =7.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.12 (s,1H), 6.99 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.27 – 6.13 (m, 2H), 5.79 (d, J = 7.1 Hz, 1H), 5.18 (s, 2H), 4.01 (q, J = 6.9 Hz, 2H), 1.84 (d, J= 5.5 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H).

[0326] Example 21: 6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-3-(2-methoxyphenyl)-1,2-dihydropyridine-2-one

[0327]

[0328] The experimental method for synthesizing compound 21 (14.5 mg) using AJ and AV as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.73 (s, 1H), 7.41 (d, J =7.1 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.21 (dd, J = 7.5, 1.6 Hz, 1H), 7.11 (s,1H), 7.01 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.27 – 6.14 (m, 2H), 5.78 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 3.75 (s, 3H), 1.85 (d, J = 5.4 Hz,3H).

[0329] Example 22: 6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-3-(2-hydroxyphenyl)-1,2-dihydropyridin-2-one

[0330]

[0331] Compound 21 (32.1 mg, 0.1 mmol) was dissolved in dichloromethane (1 mL), and about 500 μL BBr3 was added dropwise to the above system. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the mixture was quenched with methanol and evaporated to dryness. After washing with diethyl ether several times, compound 22 (21.5 mg, 70%) was obtained. 1H NMR (400 MHz, CD3OD) δ 7.73 (s, 1H), 7.41 (d, J = 7.1 Hz,1H), 7.35 – 7.29 (m, 1H), 7.21 (dd, J = 7.5, 1.6 Hz, 1H), 7.11 (s, 1H), 7.01(d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.27 – 6.14 (m, 2H), 5.78 (d,J = 7.1 Hz, 1H), 5.17 (s, 2H), 1.85 (d, J = 5.4 Hz, 3H).

[0332] Example 23: 3-(2-methoxyphenyl)-6-[(4-propylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0333]

[0334] The experimental method for synthesizing compound 23 (43.6 mg) using AK and AV as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.79 (s, 1H), 7.44 (t, J =5.9 Hz, 1H), 7.31 (dd, J = 11.3, 4.4 Hz, 1H), 7.22 (dd, J = 7.4, 1.2 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.85 (s, 1H), 5.81 (d, J= 7.1 Hz, 1H), 5.15 (s, 2H), 3.75 (s, 3H), 2.52 (t, J = 7.6 Hz, 2H), 1.70 –1.57 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H).

[0335] Example 24: 3-(2-hydroxyphenyl)-6-[(4-propylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0336]

[0337] Using compound 23 (32.3 mg, 0.1 mmol) as a starting material, compound 24 (21.6 mg, 90%) was obtained by a similar synthetic method to that used for compound 22.1 H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.61 (d, J = 7.4Hz, 1H), 7.20 – 7.11 (m, 2H), 6.94 (s, 1H), 6.84 – 6.77 (m, 2H), 5.96 (d, J =7.3 Hz, 1H), 5.20 (s, 2H), 2.44 (t, J = 7.7 Hz, 2H), 1.53 (m, 2H), 0.88 (t, J= 7.3 Hz, 3H).

[0338] Example 25: 6-({4-[(1E)-prop-1-enyl]imidazol-3-yl}methyl)-3-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one

[0339]

[0340] The experimental method for synthesizing compound 25 (13.8 mg) using AJ and AW as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 7.73 (s, 1H), 7.41 (d, J =7.1 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.21 (dd, J = 7.5, 1.6 Hz, 1H), 7.11 (s,1H), 7.01 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.27 – 6.14 (m, 2H), 5.78 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 1.85 (d, J = 5.4 Hz, 3H).

[0341] Example 26: 3-(3-hydroxyphenyl)-6-[(4-propylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0342]

[0343] The experimental method for synthesizing compound 26 (32.4 mg) using AK and AW as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.61 (d, J= 7.4Hz, 1H), 7.20 – 7.11 (m, 2H), 6.94 (s, 1H), 6.84 – 6.77 (m, 2H), 5.96 (d, J =7.3 Hz, 1H), 5.20 (s, 2H), 2.44 (t, J = 7.7 Hz, 2H), 1.53 (m, 2H), 0.88 (t, J =7.3 Hz, 3H).

[0344] Example 27: 6-[(4-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0345]

[0346] The experimental method for synthesizing compound 27 (35.8 mg) using AG and AT as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.69 (d, J =7.0 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.45 – 7.37 (m, 3H), 7.34 (t, J = 7.3 Hz,1H), 6.33 (d, J = 6.8 Hz, 1H), 5.39 (s, 2H), 2.36 (s, 3H).

[0347] Example 28: 3-(2-methoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0348]

[0349] The experimental method for synthesizing compound 28 (39.8 mg) using AG and AV as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 7.52 (d, J =7.1 Hz, 1H), 7.42 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 9.3 Hz, 1H), 7.05 (d, J= 8.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.31 (d, J = 7.1 Hz, 1H), 5.39 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H).

[0350] Example 29: 3-(3-methoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0351]

[0352] The experimental method for synthesizing compound 29 (39.8 mg) using AG and AW as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.69 (d, J = 7.1Hz, 1H), 7.42 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H), 3.82 (s, 3H), 2.36 (s, 3H).

[0353] Example 30: 3-(4-methoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0354]

[0355] The experimental method for synthesizing compound 30 (39.8 mg) using AG and AX as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.68 – 7.57 (m, 3H), 7.41 (t, J = 1.4 Hz, 1H), 6.98 – 6.91 (m, 2H), 6.31 (d, J= 7.2 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H), 2.35 (s, 3H).

[0356] Example 31: 3-(2,4-dimethoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0357]

[0358] The experimental method for synthesizing compound 31 (43.9 mg) using AG and AY as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.56 (d, J = 7.1Hz, 1H), 7.42 (s, 2H), 6.74 (s, 1H), 6.32 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 2.36 (s, 3H).

[0359] Example 32: 3-(3,4-dimethoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0360]

[0361] The experimental method for synthesizing compound 32 (43.9 mg) using AG and AZ as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.97 (s, 1H), 7.68 (d, J = 7.2Hz, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 7.22 (d, J = 10.4 Hz, 1H), 7.00 (d, J = 8.4Hz, 1H), 6.31 (d, J = 7.2 Hz, 1H), 5.38 (s, 2H), 3.86 (s, 6H), 2.36 (s, 3H).

[0362] Example 33: 3-(2,3-dimethoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0363]

[0364] Step 1: Synthesis of 3-{[5-(2,3-dimethoxyphenyl)-1-{[(2-methylprop-2-yl)oxy]carbonyl}-6-oxoylidenepyridin-2-yl]methyl}-4-methyl-1-(triphenylmethyl)imidazolium-3-cation (33a)

[0365] Using compounds AG (162 mg, 0.5 mmol) and BA (212 mg, 0.5 mmol) as raw materials, crude intermediate 33a was obtained by following a similar synthetic method to that used for compound 1a.

[0366] Step 2: Synthesis of 3-(2,3-dimethoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-2-oxylidenepyridine-1-carboxylic acid-2-methylpropyl-2-yl ester (33b)

[0367] Using compound 33a as a starting material, compound 33b (63.8 mg, 30%) was obtained by a synthetic method similar to that used for compound 1b.

[0368] Step 3: Synthesis of 3-(2,3-dimethoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one (33)

[0369] Using intermediate 33b as a starting material, compound 33 (43.9 mg, 90%) was obtained by a synthetic method similar to that used for compound 1. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.41 (s,1H), 7.12 – 7.02 (m, 2H), 6.85 (d, J = 7.4 Hz, 1H), 6.32 (d, J = 7.1 Hz, 1H), 5.40 (s, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 2.37 (s, 3H).

[0370] Example 34: 3-(2-hydroxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0371]

[0372] Using compound 28b (39.5 mg, 0.1 mmol) as a starting material, compound 34 (19.7 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.80 (d, J = 7.4Hz, 1H), 7.44 (m, 1H), 7.33 – 7.22 (m, 2H), 6.97 – 6.87 (m, 2H), 6.45 (d, J =7.3 Hz, 1H), 5.49 (s, 2H), 2.37 (s, 3H).

[0373] Example 35: 3-(3-hydroxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0374]

[0375] Using compound 29b (39.5 mg, 0.1 mmol) as a starting material, compound 35 (19.7 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.42 (s, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.79 (m,1H), 6.38 (d, J = 7.2 Hz, 1H), 5.43 (s, 2H), 2.36 (s, 3H).

[0376] Example 36: 3-(4-hydroxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0377]

[0378] Using compound 30b (39.5 mg, 0.1 mmol) as a starting material, compound 36 (19.7 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.64 (d,J = 7.2Hz, 1H), 7.54 – 7.47 (m, 2H), 7.42 (s, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6.35 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H), 2.36 (s, 3H).

[0379] Example 37: 4-(4-methoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0380]

[0381] The experimental method for synthesizing compound 37 (39.8 mg) using AG and BB as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.03 (s, 1H), 7.72 (d, J = 8.9Hz, 2H), 7.43 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.05 – 7.00 (m, 2H), 5.55 (s, 2H), 3.87 (s, 3H), 2.37 (s, 3H).

[0382] Example 38: 6-Methoxy-2-[(5-methylimidazol-1-yl)methyl]pyridine

[0383]

[0384] The experimental method for synthesizing compound 38 (30.4 mg) using AG and AS as raw materials is consistent with the method for synthesizing 1b using A and AT as raw materials. 1 H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.52 – 7.45 (m, 1H), 6.83 (s, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 5.04(s, 2H), 3.88 (s, 3H), 2.16 (s, 3H).

[0385] Example 39: 3-(2,3-dihydroxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0386]

[0387] Using compound 33b (42.5 mg, 0.1 mmol) as a starting material, compound 39 (20.8 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 7.83 (d, J = 7.4Hz, 1H), 7.44 (s, 1H), 6.85 (m, 1H), 6.81 – 6.78 (m, 2H), 6.43 (d, J = 7.2 Hz,1H), 5.50 (s, 2H), 2.36 (s, 3H).

[0388] Example 40: 3-(4-fluoro-3-methoxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0389]

[0390] The experimental method for synthesizing compound 40 (42.2 mg) using AG and BC as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 7.70 (d, J = 7.2Hz, 1H), 7.49 – 7.40 (m, 2H), 7.21 – 7.07 (m, 2H), 6.32 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H), 3.90 (s, 3H), 2.36 (s, 3H).

[0391] Example 41: 3-(4-fluoro-3-hydroxyphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0392]

[0393] Using compound 40b (41.3 mg, 0.1 mmol) as a starting material, compound 41 (20.9 mg, 70%) was obtained by a similar synthetic method to that used for compound 22.1 H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.66 (d, J = 7.2Hz, 1H), 7.42 (t, J = 1.4 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.10 – 7.04 (m, 2H), 6.35 (d, J = 7.2 Hz, 1H), 5.42 (s, 2H), 2.36 (s, 3H).

[0394] Example 42: 3-(3,4-difluorophenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0395]

[0396] The experimental method for synthesizing compound 42 (40.6 mg) using AG and BE as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.02 (s, 1H), 7.78 – 7.63 (m, 2H), 7.51 – 7.39 (m, 2H), 7.35 – 7.24 (m, 1H), 6.35 (d, J = 7.2 Hz, 1H), 5.42 (s, 2H), 2.36 (s, 3H).

[0397] Example 43: 3-(4-chloro-3-fluorophenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0398]

[0399] The experimental method for synthesizing compound 43 (42.8 mg) using AG and BF as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 7.87 (d, J = 7.3Hz, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.62 (m, 1H), 7.43 (s, 1H), 7.28 (t, J = 8.9Hz, 1H), 6.35 (d,J = 7.3 Hz, 1H), 5.42 (s, 2H), 2.36 (s, 3H).

[0400] Example 44: 3-(2-methoxypyridin-4-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0401]

[0402] The experimental method for synthesizing compound 44 (26.6 mg) using AG and BD as raw materials is consistent with the method for synthesizing compound 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 9.08 (s, 1H), 8.32 (d, J = 6.5Hz, 1H), 8.24 (d, J = 7.5 Hz, 1H), 8.11 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.46(s, 1H), 6.38 (d, J = 5.6 Hz, 1H), 5.52 (s, 2H), 4.27 (s, 3H), 2.36 (s, 3H).

[0403] Example 45: 3-(2-hydroxypyridin-4-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0404]

[0405] Using compound 44b (39.6 mg, 0.1 mmol) as a starting material, compound 45 (19.7 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.68 (d, J = 7.4Hz, 1H), 7.40 (d, J = 7.0 Hz, 1H), 6.93 (s, 1H), 6.81 (d, J = 7.0 Hz, 1H), 6.78(s, 1H), 5.82 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H), 2.17 (s, 3H).

[0406] Example 46: 3-(7-methoxynaphth-1-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0407]

[0408] The experimental method for synthesizing compound 46 (46.6 mg) using AG and BI as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.78 (d, J = 9.1 Hz, 2H), 7.73(s, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.34 (d, J = 7.4 Hz, 2H), 7.13 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H), 5.89 (d, J = 7.1 Hz, 1H), 5.12 (s, 2H), 3.77 (s, 3H), 2.20 (s, 3H).

[0409] Example 47: 3-(7-hydroxynaphth-1-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0410]

[0411] Using compound 46b (44.5 mg, 0.1 mmol) as a starting material, compound 47 (23.2 mg, 70%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 7.74 (d, J = 4.8 Hz, 2H), 7.71(d, J = 4.4 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.29 – 7.23 (m, 2H), 7.04 (dd, J =8.8, 2.4 Hz, 1H), 6.91 (d, J = 2.6 Hz, 1H), 6.81 (s, 1H), 5.93 (d, J= 7.0 Hz,1H), 5.15 (s, 2H), 2.23 (s, 3H).

[0412] Example 48: 6-[(4-methylimidazol-3-yl)methyl]-3-(2,4,5-trimethoxyphenyl)-1,2-dihydropyridine-2-one

[0413]

[0414] The experimental method for synthesizing compound 48 (44.4 mg) using AG and BJ as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.48 (d, J = 7.1Hz, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 6.72 (s, 1H), 5.82 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H), 3.87 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 2.20 (s, 3H).

[0415] Example 49: 3-(2,3-dihydrobenzo[2,1-b][1,4]dioxane-6-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0416]

[0417] The experimental method for synthesizing compound 49b (141 mg) using AG and BG as raw materials is consistent with the method for synthesizing 1b using A and AT as raw materials.

[0418] Using intermediate 49b (141 mg, 0.5 mmol) as a starting material, compound 49c (67 mg, 40%) was obtained by following a similar synthetic method to that used for intermediate A-24.

[0419] 1 mL of a mixed solvent of hydrobromic acid and acetic acid (volume ratio 1:1) was added to intermediate 49c (67 mg, 0.2 mmol), and the mixture was reacted at 60 °C for 3 h. After the reaction was completed, sodium bicarbonate aqueous solution was added until no more bubbles were generated. The solution was then evaporated to dryness and column chromatography was used to obtain compound 49 (38.8 mg, 60%). 1 H NMR (400 MHz, MeOD) δ 8.97 (s, 1H),7.63 (d, J= 7.1 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.11 (dd, J =8.5, 2.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 7.3 Hz, 1H), 5.37 (s, 2H), 4.25 (s, 4H), 2.35 (s, 3H).

[0420] Example 50: 3-(8-hydroxynaphth-2-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0421]

[0422] Using intermediate 49b (141 mg, 0.5 mmol) as a starting material, compound 50a (71 mg, 40%) was obtained by a synthetic method similar to that used for intermediate A-24.

[0423] Using compound 50a (71 mg, 0.2 mmol) as a starting material, compound 50 (39.7 mg, 60%) was obtained by a synthetic method similar to that used for compound 22 in Example. 1 H NMR (400 MHz, MeOD) δ 9.00 (s, 1H), 8.50 (s, 1H),7.82 – 7.77 (m, 2H), 7.75 (dd, J = 8.6, 1.8 Hz, 1H), 7.42 (s, 1H), 7.31 (m,2H), 6.83 (dd, J = 7.2, 1.3 Hz, 1H), 6.38 (d, J = 7.2 Hz, 1H), 5.41 (s, 2H), 2.37 (s, 3H).

[0424] Example 51: 3-(benzo[d][1,3]dioxanepentan-5-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0425]

[0426] The experimental method for synthesizing compound 51 (37.1 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.56 (d, J = 7.3 Hz,1H), 7.19 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.91 – 6.76 (m, 2H), 5.95 (s, 2H), 5.82 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H), 2.18 (s, 3H).

[0427] Example 52: 3-(2,3-dihydro-1-benzofuran-5-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0428]

[0429] The experimental method for synthesizing compound 52 (24.5 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.56 – 7.50 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.83 (d, J = 7.2Hz, 1H), 5.11 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 3.21 (t, J = 8.7 Hz, 2H), 2.18 (s, 3H).

[0430] Example 53: 3-(2,3-dihydro-1-benzofuran-6-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0431]

[0432] The experimental method for synthesizing compound 53 (24.5 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.57 (d, J= 7.1 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.04 (s, 1H), 6.79 (s,1H), 5.82 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H), 4.54 (t, J = 8.6 Hz, 2H), 3.20 (t, J =8.6 Hz, 2H), 2.18 (s, 3H).

[0433] Example 54: 3-(3-aminophenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0434]

[0435] The experimental method for synthesizing compound 54 (22.4 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.72 (s, 1H), 7.56 (d, J = 7.1 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.80 (s,1H), 6.72 – 6.67 (m, 1H), 5.83 (d, J = 7.1 Hz, 1H), 5.14 (s, 2H), 2.19 (s, 3H).

[0436] Example 55: 3-(4-acetylphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0437]

[0438] The experimental method for synthesizing compound 55 (24.5 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 8.02 (d, J = 8.6 Hz, 2H), 7.81 (d, J=8.6 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 6.81 (s, 1H), 5.85 (d, J = 7.3 Hz, 1H), 5.16 (s, 2H), 2.62 (s, 3H), 2.19 (s, 3H).

[0439] Example 56: 3-(4-Butylphenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0440]

[0441] The experimental method for synthesizing compound 56 (25.6 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 6.79 (s, 1H), 5.84 (d, J =7.3 Hz, 1H), 5.12 (s, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.65 – 1.55(m, 2H), 1.36 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).

[0442] Example 57: 3-(2,4-difluorophenyl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0443]

[0444] The experimental method for synthesizing compound 57 (24.1 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 8.13 (s, 1H), 7.57 (d, J = 7.4 Hz,1H), 7.52 – 7.41 (m, 1H), 7.01 (d, J= 7.6 Hz, 3H), 5.99 (d, J = 7.1 Hz, 1H), 5.24 (s, 2H), 2.25 (s, 3H).

[0445] Example 58: 6-[(4-methylimidazol-3-yl)methyl]-3-(naphth-2-yl)-1,2-dihydropyridin-2-one

[0446]

[0447] The experimental method for synthesizing compound 58 (25.3 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.86 (t, J = 8.3 Hz,3H), 7.80 – 7.71 (m, 3H), 7.48 (dd, J = 6.3, 3.3 Hz, 2H), 6.81 (s, 1H), 5.89(d, J = 7.3 Hz, 1H), 5.16 (s, 2H), 2.21 (s, 3H).

[0448] Example 59: 7-{6-[(4-methylimidazol-3-yl)methyl]-2-oxoylide-1H-pyridin-3-yl}-2,3-dihydro-1H-indol-2-one

[0449]

[0450] The experimental method for synthesizing compound 59 (25.6 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 9.90 (s, 1H), 7.69 (s, 1H), 7.43 (d, J = 7.1 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.70 (s, 1H), 5.71 (d, J= 7.1 Hz, 1H), 5.02 (s, 2H), 3.49 (s, 2H), 2.14 (s, 3H).

[0451] Example 60: 4-{6-[(4-methylimidazol-3-yl)methyl]-2-oxoylide-1H-pyridin-3-yl}-2,3-dihydro-1H-benzo[d]imidazol-2-one

[0452]

[0453] The experimental method for synthesizing compound 60 (25.7 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.77 (s, 1H), 7.67 (d, J = 7.2 Hz,1H), 7.07 (m, 3H), 6.82 (s, 1H), 5.92 (d, J = 7.2 Hz, 1H), 5.20 (s, 2H), 2.23(s, 3H).

[0454] Example 61: 4-{6-[(4-methylimidazol-3-yl)methyl]-2-oxoylide-1H-pyridin-3-yl}-2,3-dihydro-1H-indol-2-one

[0455]

[0456] The experimental method for synthesizing compound 61 (25.6 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 10.41 (s, 1H), 7.88 (s, 1H), 7.52 (d, J = 7.1 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.8 Hz, 2H), 5.70 (s, 1H), 5.10 (s, 2H), 3.42 (s, 2H), 2.15(s, 3H).

[0457] Example 62: 6-[(4-methylimidazol-3-yl)methyl]-3-(1-methylindazole-7-yl)pyridine-2-phenol

[0458]

[0459] Using intermediate 49b (141 mg, 0.5 mmol) as a starting material, compound 62a (107 mg, 80%) was obtained by a synthesis method similar to that in Example 49.

[0460] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 62 (38.3 mg, 20%) was obtained by following a synthetic method similar to that of intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.77 – 7.68 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.81 (s, 1H), 5.88 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 4.07 (s, 3H), 2.21 (s, 3H).

[0461] Example 63: 6-{6-[(4-methylimidazol-3-yl)methyl]-2-oxoylide-1H-pyridin-3-yl}-2,3-dihydro-1H-isoindol-1-one

[0462]

[0463] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 63 (19.2 mg, 10%) was obtained by following a similar synthetic method to intermediate A-24 in the examples. 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.04 (s,1H), 7.89 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.56 (d, J =8.0 Hz, 1H), 6.70 (s, 1H), 5.68 (d, J = 7.3 Hz, 1H), 5.05 (s, 2H), 4.37 (s, 2H), 2.12 (s, 3H).

[0464] Example 64: 3-(benzo[d][1,3]dioxanepentan-4-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0465]

[0466] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 64 (37.1 mg, 20%) was obtained by following a similar synthetic method to intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.71 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 7.9 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 2.9 Hz, 2H), 5.94(s, 2H), 5.82 (d, J = 7.3 Hz, 1H), 5.14 (s, 2H), 2.19 (s, 3H).

[0467] Example 65: 6-[(4-methylimidazol-3-yl)methyl]-3-(1-methylindazole-4-yl)-1,2-dihydropyridin-2-one

[0468]

[0469] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 65 (38.3 mg, 20%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.77 – 7.68 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.81 (s, 1H), 5.88 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 4.07 (s, 3H), 2.21 (s, 3H).

[0470] Example 66: 6-[(4-methylimidazol-3-yl)methyl]-3-[4-(propyloxy)phenyl]-1,2-dihydropyridin-2-one

[0471]

[0472] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 66 (38.8 g, 20%) was obtained by following a similar synthetic method to intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.71 (s, 1H), 7.61 – 7.55 (m, 3H), 6.93 (d, J = 8.9 Hz, 2H), 6.80 (s, 1H), 5.83 (s, 1H), 5.12 (s, 2H), 3.95 (t, J = 6.5 Hz, 2H), 2.19 (s, 3H), 1.84 – 1.74 (m, 2H), 1.04 (t, J = 7.4 Hz, 3H).

[0473] Example 67: 3-(1-Cyclopropylindazole-4-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0474]

[0475] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 67 (41.4 mg, 20%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.89 (s, 1H), 7.73 (s,1H), 7.67 (dd, J = 7.8, 3.9 Hz, 2H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 7.0 Hz,1H), 6.80 (s, 1H), 5.87 (d, J = 7.3 Hz, 1H), 5.14 (s, 2H), 3.62 (m, 1H), 2.19 (s, 3H), 1.20 – 1.13 (m, 3H).

[0476] Example 68: 3-(1H-indazol-4-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0477]

[0478] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 68 (18.3 mg, 10%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.98 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.29 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 5.89 (d, J = 7.3 Hz, 1H), 5.16 (s, 2H), 2.22 (s, 3H).

[0479] Example 69: 6-[(4-methylimidazol-3-yl)methyl]-3-[1-(prop-2-yl)indazol-4-yl]-1,2-dihydropyridin-2-one

[0480]

[0481] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 69 (41.6 mg, 20%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.94 (s, 1H), 7.75 (s,1H), 7.70 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.5, 7.1 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 6.82 (s, 1H), 5.88 (d, J = 7.2 Hz, 1H), 5.16 (s,2H), 4.97 (m, 1H), 2.21 (s, 3H), 1.55 (d, J = 6.6 Hz, 6H).

[0482] Example 70: 6-[(4-methylimidazol-3-yl)methyl]-3-[2-(propyloxy)phenyl]-1,2-dihydropyridin-2-one

[0483]

[0484] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 70 (38.8 mg, 20%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.74 (s, 1H), 7.47 (dd, J =9.2, 7.1 Hz, 1H), 7.30 (m, 1H), 7.25 (dd, J = 7.5, 1.8 Hz, 1H), 7.00 (d, J = 8.3Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.81 (s, 1H), 5.84 (d, J = 7.1 Hz, 1H), 5.14(s, 2H), 3.92 (t, J = 6.3 Hz, 2H), 2.19 (s, 3H), 1.67 (m, 2H), 0.92 (t, J = 7.4Hz, 3H).

[0485] Example 71: 3-{2-[(cyclopropylmethyl)oxy]phenyl}-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0486]

[0487] Using compound 62a (161 mg, 0.6 mmol) as a starting material, compound 71 (40.2 mg, 20%) was obtained by following a synthetic method similar to that used for intermediate A-24 in the examples. 1 H NMR (400 MHz, MeOD) δ 7.77 – 7.71 (m, 1H), 7.48(d, J = 7.1 Hz, 1H), 7.31 – 7.23 (m, 2H), 6.99 (dd, J = 8.3, 1.1 Hz, 1H), 6.97 –6.93 (m, 1H), 6.81 (s, 1H), 5.85 (d, J = 7.1 Hz, 1H), 5.14 (s, 2H), 3.83 (d, J=6.5 Hz, 2H), 2.21 (s, 3H), 0.50 – 0.43 (m, 2H), 0.26 (m, 2H).

[0488] Example 72: 6-[(4-methylimidazol-3-yl)methyl]-3-[2-(prop-2-yl)indazol-4-yl]-1,2-dihydropyridin-2-one

[0489]

[0490] Using intermediate 62a (141 mg, 0.5 mmol) as a starting material, compound 72 (41.6 mg, 0%) was obtained by following a similar synthetic method to that used for intermediate A-24. 1 H NMR (400 MHz, MeOD) δ 8.17 (d, J = 0.9 Hz, 1H), 7.77– 7.67 (m, 2H), 7.60 (d, J = 8.6 Hz, 1H), 7.33 (dd, J = 8.7, 6.9 Hz, 1H), 7.22(d, J = 6.9 Hz, 1H), 6.81 (s, 1H), 5.89 (d, J = 7.2 Hz, 1H), 5.16 (s, 2H), 4.80(m, 1H), 2.21 (s, 3H), 1.61 (d, J = 6.7 Hz, 6H).

[0491] Example 73: 6-[(4-ethynylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0492]

[0493] Using compounds AC (167 mg, 0.5 mmol) and BA (212 mg, 0.5 mmol) as raw materials, crude intermediate 73a was obtained by following a similar synthetic method to that used for compound 1a.

[0494] Using compound 73a as a starting material, compound 73b (65.2 mg, 30%) was obtained by a synthetic method similar to that used for compound 1b.

[0495] Using intermediate 73b as a starting material, compound 73 (30.1 mg, 90%) was obtained by a synthetic method similar to that used for compound 1. 1H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.33(s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (dd,J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 4.13 (s, 1H), 3.86 (s, 3H), 3.67 (s, 3H).

[0496] Example 74: 3-(imidazo[1,2-a]pyridin-3-yl)-6-[(4-methylimidazo-3-yl)methyl]-1,2-dihydropyridin-2-one

[0497]

[0498] The experimental method for synthesizing compound 74 (24.4 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.50 (s, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J =8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 2.21 (s, 3H).

[0499] Example 75: 3-(1H-indazol-3-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0500]

[0501] The experimental method for synthesizing compound 75 (24.4 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 2.21(s, 3H).

[0502] Example 76: 6-[(4-methylimidazol-3-yl)methyl]-3-(1-methylindazole-3-yl)-1,2-dihydropyridin-2-one

[0503]

[0504] The experimental method for synthesizing compound 76 (25.5 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 3.95(s, 2H), 2.21 (s, 3H).

[0505] Example 77: 3-(1-Ethylindazole-3-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0506]

[0507] The experimental method for synthesizing compound 77 (26.6 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 3.95(q, J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0508] Example 78: 3-(1-Cyclopentylindazole-3-yl)-6-[(4-methylimidazol-3-yl)methyl]-1,2-dihydropyridin-2-one

[0509]

[0510] The experimental method for synthesizing compound 78 (29.8 mg) using 49b as a starting material is consistent with the method for synthesizing 49 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 6.85 (dd, J = 7.5, 1.7 Hz, 1H), 5.97 (d, J = 7.1 Hz, 1H), 5.26 (s, 2H), 3.76(m, 1H), 2.21 (s, 3H), 1.73 (m, 8H).

[0511] Example 79: 6-[(2,4-dimethylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0512]

[0513] The experimental method for synthesizing compound 79 (33.5 mg) using AR and BK as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.68 – 7.59 (m, 3H), 7.40(t, J= 7.3 Hz, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.31 (s, 1H), 6.12 (d, J = 7.1 Hz,1H), 5.34 (s, 2H), 2.68 (s, 3H), 2.31 (s, 3H).

[0514] Example 80: 6-[(2-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0515]

[0516] The experimental method for synthesizing compound 80 (31.8 mg) using AQ and BK as raw materials is consistent with the method for synthesizing 1 using A and AT as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.70 (d, J = 7.1 Hz, 1H), 7.66– 7.60 (m, 2H), 7.57 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.41 (t, J =7.2 Hz, 2H), 7.35 (dd, J = 8.4, 6.1 Hz, 1H), 6.40 (d, J = 7.1 Hz, 1H), 5.36 (s, 2H), 2.71 (s, 3H).

[0517] Example 81: 6-[(2-bromoimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0518]

[0519] Using compounds 81a (73 mg, 0.5 mmol) and BK (139 mg, 0.5 mmol) as starting materials, intermediate 81b (86.1 mg, 50%) was obtained by following a similar synthetic method to that used for compound 1a.

[0520] Using intermediate 81b (34 mg, 0.1 mmol) as a starting material, compound 81 (26.4 mg, 80%) was obtained by a synthetic method similar to that used for compound 49. 1H NMR (400 MHz, MeOD) δ 7.63 m, 3H), 7.43 – 7.34 (m,3H), 7.36 – 7.28 (m, 1H), 7.08 (d, J = 1.6 Hz, 1H), 5.93 (d, J = 7.2 Hz, 1H), 5.18 (s, 2H).

[0521] Example 82: 6-[(2-clomizol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0522]

[0523] The experimental method for synthesizing compound 82 (34.2 mg) using 82a and BK as raw materials is consistent with the method for synthesizing 81 using 81a and BK as raw materials. 1 H NMR (400 MHz, MeOD) δ 7.63 (d, J = 7.1 Hz, 3H), 7.39 (t, J = 7.4 Hz, 2H), 7.35 – 7.29 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.00 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H).

[0524] Example 83: 3-[(6-oxoylidene-5-phenyl-1H-pyridin-2-yl)methyl]imidazolium-2-carboxynitrile

[0525]

[0526] The experimental method for synthesizing compound 83 (37.2 mg) using 83a and BK as raw materials is consistent with the method for synthesizing 81 using 81a and BK as raw materials. 1 H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 7.72 (s,1H), 7.66 (dd, J = 16.4, 7.1 Hz, 3H), 7.38 (t, J = 7.3 Hz, 2H), 7.34 – 7.25 (m,2H), 6.01 (s, 1H), 5.31 (s, 2H).

[0527] Example 84: 6-[(2-ethynylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0528]

[0529] Compound 81 (500 mg, 1.5 mmol) was dissolved in 5 mL of DMF, and triethylamine (455.4, 4.5 mmol) and TIPSCl (578.4, 3 mmol) were added. The mixture was reacted overnight at room temperature, and post-treatment column chromatography was used to obtain 84a (146.1 mg, 20%).

[0530] Using compound 84a (146.1 mg, 0.3 mmol) as the starting material, trimethylsilylacetylene (98.22 mg, 1 mmol), cuprous iodide (9.5 mg, 0.05 mmol), triethylamine (151.8 mg, 1.5 mmol), and Pd(PPh)3 (57.8 mg, 0.05 mmol) were added sequentially. Under an argon atmosphere, 5 mL of ultradry DMF was added and the reaction was carried out overnight at 80 °C. Post-treatment column chromatography yielded 84b (75.6 mg, 50%).

[0531] Dissolve 84b (75.6 mg, 0.15 mmol) in a mixed solvent of 1 mL tetrahydrofuran and 1 mL methanol, add potassium carbonate (41.43 mg, 0.3 mmol), react at room temperature for 1 h, filter and evaporate the filtrate, and then column chromatography to obtain 84c (55 mg, 85%).

[0532] Using 84c (55 mg, 0.12 mmol) as the starting material, compound 84 (29.5 mg, 85%) was obtained by following a similar synthetic method to compound 1. 1 H NMR (400 MHz, MeOD) δ 7.63 (d, J = 7.1 Hz, 3H), 7.39 (t, J = 7.4Hz, 2H), 7.35 – 7.29 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.00 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H), 4.03 (s, 1H).

[0533] Example 85: 6-[(2-chloro-4-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0534]

[0535] Using compounds AG (162 mg, 0.5 mmol) and BK (139 mg, 0.5 mmol) as starting materials, intermediate 85a was obtained by a synthetic method similar to that used for compound 1a.

[0536] Using compound 85a as a starting material, compound 85b (41.9 mg, 30%) was obtained by a synthetic method similar to that used for compound 1b.

[0537] Compound 85b (41.9 mg, 0.15 mmol) was dissolved in 3 mL of ultra-dry tetrahydrofuran. TMPMgCl·LiCl (300 μL, 0.3 mmol, 1 mol / L) and hexachloroethane (71 mg, 0.3 mmol) were added under an argon atmosphere, and the mixture was reacted at room temperature for 3 h. Post-treatment column chromatography yielded compound 85c (28.2 mg, 60%).

[0538] Using 85c (31.3 mg, 0.1 mmol) as the starting material, compound 85 (26.9 mg, 90%) was obtained by a similar synthetic method to that used for compound 49. 1 H NMR (400 MHz, MeOD) δ 7.67 (d, J = 7.4 Hz, 1H), 7.62 (d, J =7.0 Hz, 2H), 7.47 (s, 1H), 7.40 (t, J = 7.4 Hz, 2H), 7.36 – 7.31 (m, 1H), 6.31(d, J = 7.3 Hz, 1H), 5.41 (s, 2H), 2.37 (s, 3H).

[0539] Example 86: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0540]

[0541] Compound 85b (279 mg, 1 mmol) was dissolved in 10 mL of ultradry tetrahydrofuran. The solution was placed at -78 °C, and n-butyllithium (1 mL, 1.6 mmol) was added dropwise under an argon atmosphere. The reaction was maintained for 30 min, followed by the addition of NBS (214 mg, 1.2 mmol) and the reaction was continued for another 30 min. Post-treatment column chromatography yielded intermediate 86a (100 mg, 27.9%).

[0542] Compound 86a (100 mg, 0.28 mmol) was dissolved in 2 mL of ammonia water, and copper powder (7 mg, 0.1 mmol) was added. The mixture was reacted at 80 °C overnight, and then column chromatography was performed to obtain compound 86b (40 mg, 48.5%). 1 H NMR (400 MHz, MeOD) δ 7.65(d, J = 7.4 Hz, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J =7.3 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.27 (s, 1H), 4.98 (s, 2H), 3.89 (s, 3H), 2.13 (s, 3H).

[0543] Using 86b (40 mg, 0.14 mmol) as a starting material, compound 86 (33.4 mg, 85%) was obtained by a similar synthetic method to that used for compound 49. 1 H NMR (400 MHz, MeOD) δ 7.65 (d, J = 7.4 Hz, 1H), 7.51 (d, J =6.9 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 7.4Hz, 1H), 6.27 (s, 1H), 4.98 (s, 2H), 2.13 (s, 3H).

[0544] Example 87: 6-[(2-bromo-4-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0545]

[0546] Using 86a (35.8 mg, 0.1 mmol) as the starting material, compound 87 (28.2 mg, 82%) was obtained by following a similar synthetic method to compound 49. 1 H NMR (400 MHz, MeOD) δ 7.66 – 7.57 (m, 3H), 7.38 (t, J = 7.3Hz, 2H), 7.32 (d,J = 7.3 Hz, 1H), 6.87 (s, 1H), 5.60 (d, J = 7.3 Hz, 1H), 5.15(s, 2H), 2.25 (s, 3H).

[0547] Example 88: 6-[(2-ethynyl-4-methylimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0548]

[0549] The experimental method for synthesizing compound 88 (11 mg) using 87 as a starting material is consistent with the method for synthesizing 84 using 81 as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.66 – 7.57 (m, 3H), 7.38 (t, J = 7.3 Hz, 2H), 7.32 (d, J = 7.3 Hz, 1H), 6.87 (s, 1H), 5.60 (d, J = 7.3 Hz, 1H), 5.15 (s, 2H), 4.03 (s, 1H) 2.25 (s, 3H).

[0550] Example 89: 6-[(2-aminoimidazol-3-yl)methyl]-3-phenyl-1,2-dihydropyridin-2-one

[0551]

[0552] Using compounds 89a (57 mg, 0.5 mmol) and BK (139 mg, 0.5 mmol) as starting materials, intermediate 89b (77.6 mg, 50%) was obtained by column chromatography following a similar synthetic method to that used for compound 1a.

[0553] Intermediate 89b (77.6 mg, 0.25 mmol) was dissolved in anhydrous ethanol. Zinc powder (65 mg, 1 mmol) and glacial acetic acid (1 mL) were added to the system. The mixture was reacted at 90 °C for 10 min and then filtered while hot. After the solvent was evaporated, the mixture was washed with dichloromethane and n-hexane to obtain compound 89c (49.1 mg, 70%).

[0554] Using intermediate 89c (49.1 mg, 0.2 mmol) as a starting material, compound 89 (42.6 mg, 80%) was obtained by a similar synthetic method to that used for compound 49. 1H NMR (400 MHz, MeOD) δ 7.72 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.0 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.38 – 7.31 (m, 1H), 6.98 –6.94 (m, 2H), 6.25 (d, J = 7.3 Hz, 1H), 5.12 (s, 2H).

[0555] Example 90: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(1-methylindazole-7-yl)-1,2-dihydropyridin-2-one

[0556]

[0557] Using intermediate 49b (282 mg, 1 mmol) as a starting material, compound 90a (100 mg, 30%) was obtained by a synthetic method similar to that used for intermediate A-24.

[0558] Using compound 90a (100 mg, 0.3 mmol) as a starting material, compound 90b (74.2 mg, 60%) was obtained by a similar synthetic method to 86a.

[0559] Using compound 90b (74.2 mg, 0.11 mmol) as a starting material, compound 90c (19.2 mg, 50%) was obtained by a similar synthetic method to 86b.

[0560] Using compound 90c (19.2 mg, 0.055 mmol) as a starting material, compound 90 (15.6 mg, 85%) was obtained by a similar synthetic method to that used for compound 49. 1 H NMR (400 MHz, MeOD) δ 7.77 – 7.68 (m, 2H), 7.54(d, J = 8.5 Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.27 (s, 1H), 5.88 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 4.07 (s, 3H), 2.21 (s, 3H).

[0561] Example 91: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(1-methylindazole-4-yl)-1,2-dihydropyridin-2-one

[0562]

[0563] The experimental method for synthesizing compound 91 (15.6 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.77 – 7.68 (m, 2H), 7.54 (d, J = 8.5Hz, 1H), 7.49 – 7.43 (m, 1H), 7.30 (d, J = 6.8 Hz, 1H), 6.27 (s, 1H), 5.88 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 4.07 (s, 3H), 2.21 (s, 3H).

[0564] Example 92: 6-{[2-(aminomethyl)imidazol-3-yl]methyl}-3-phenyl-1,2-dihydropyridin-2-one

[0565]

[0566] Compound 83 (41.4 mg, 0.15 mmol) was dissolved in 3 mL of ultra-dry tetrahydrofuran, and lithium aluminum hydride (11.4 mg, 0.3 mmol) was added at 0 °C. The reaction was carried out at room temperature, and the mixture was purified to obtain 92 (21 mg, 50%) after the reaction was completed. 1 H NMR (400 MHz, DMSO) δ 12.11 (s, 1H), 7.72 (s, 1H), 7.66 (dd, J = 16.4, 7.1 Hz, 3H), 7.38 (t, J = 7.3 Hz, 2H), 7.34 – 7.25 (m, 2H), 6.01 (s, 1H), 5.31 (s, 2H), 4.01 (s, 2H).

[0567] Example 93: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-fluorophenyl)-1,2-dihydropyridin-2-one

[0568]

[0569] The experimental method for synthesizing compound 93 (16 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.1 Hz, 1H), 7.43 (t, J =7.5 Hz, 1H), 7.39 – 7.33 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 8.8 Hz,1H), 6.43 (s, 1H), 5.82 (d, J = 7.3 Hz, 1H), 4.97 (s, 2H), 2.11 (s, 3H).

[0570] Example 94: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-chlorophenyl)-1,2-dihydropyridin-2-one

[0571]

[0572] The experimental method for synthesizing compound 94 (13 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.46 (d, J = 7.3 Hz, 2H), 7.33 (m, 3H), 6.45 (s, 1H), 5.84 (d, J = 7.1 Hz, 1H), 4.98 (s, 2H), 2.11 (s, 3H).

[0573] Example 95: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-[2-(trifluoromethyl)phenyl]-1,2-dihydropyridin-2-one

[0574]

[0575] The experimental method for synthesizing compound 95 (22 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.76 (d, J = 7.8 Hz, 1H), 7.64 (t, J =7.5 Hz, 1H), 7.55 (t,J = 7.7 Hz, 1H), 7.38 (d, J = 7.1 Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 6.48 (s, 1H), 5.86 (d, J = 7.1 Hz, 1H), 5.00 (s, 2H), 2.12 (s, 3H).

[0576] Example 96: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-methoxyphenyl)-1,2-dihydropyridine-2-one

[0577]

[0578] The experimental method for synthesizing compound 96 (13 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.43 (d, J = 7.1 Hz, 1H), 7.32 (t, J =7.9 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.96 (t, J = 7.4Hz, 1H), 6.43 (s, 1H), 5.78 (d, J = 7.3 Hz, 1H), 4.95 (s, 2H), 3.76 (s, 3H), 2.11 (s, 3H).

[0579] Example 97: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(3-methoxyphenyl)-1,2-dihydropyridin-2-one

[0580]

[0581] The experimental method for synthesizing compound 97 (17 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.61 (d, J = 7.3 Hz, 1H), 7.29 (t, J =7.9 Hz, 1H), 7.24 (s, 1H), 7.17 (d,J = 7.8 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.36 (s, 1H), 5.78 (d, J = 7.3 Hz, 1H), 4.93 (s, 2H), 3.81 (s, 3H), 2.08 (s, 3H).

[0582] Example 98: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(4-methoxyphenyl)-1,2-dihydropyridine-2-one

[0583]

[0584] The experimental method for synthesizing compound 98 (11 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.64 – 7.56 (m, 3H), 6.94 (d, J = 8.8Hz, 2H), 6.50 (s, 1H), 5.83 (d, J = 7.3 Hz, 1H), 4.97 (s, 2H), 3.81 (s, 3H), 2.11 (s, 3H).

[0585] Example 99: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-hydroxyphenyl)-1,2-dihydropyridin-2-one

[0586]

[0587] Using compound 96 (32 mg, 0.1 mmol) as a starting material, compound 99 (14 mg, 47%) was obtained by following a similar synthetic method to compound 22. 1 H NMR (400 MHz, MeOD) δ 7.85 (d, J = 7.5 Hz, 1H), 7.29 (d, J =7.6 Hz, 2H), 6.95 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 6.22 (d, J = 7.4 Hz, 1H), 5.22 (s, 2H), 2.17 (s, 3H).

[0588] Example 100: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one

[0589]

[0590] Using compound 97 (31 mg, 0.1 mmol) as a starting material, compound 100 (16 mg, 54%) was obtained by a similar synthetic method to that used for compound 22. 1 H NMR (400 MHz, MeOD) δ 7.65 (d, J = 7.3 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 6.73 (s, 1H), 5.98 (d, J = 7.3 Hz, 1H), 5.10 (s, 2H), 2.16 (s, 3H).

[0591] Example 101: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(4-hydroxyphenyl)-1,2-dihydropyridin-2-one

[0592]

[0593] Using compound 98 (31 mg, 0.1 mmol) as a starting material, compound 101 (12 mg, 41%) was obtained by following a similar synthetic method to compound 22. 1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 7.1 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 6.62 (s, 1H), 5.86 (d, J = 7.1 Hz, 1H), 5.01 (s, 2H), 2.13 (s, 3H).

[0594] Example 102: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-ethylphenyl)-1,2-dihydropyridin-2-one

[0595]

[0596] The experimental method for synthesizing compound 102 (18 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.38 (d, J = 7.1 Hz, 1H), 7.29 (d, J =3.9 Hz, 2H), 7.22 – 7.16 (m, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.53 (s, 1H), 5.88(d, J = 7.1 Hz, 1H), 5.00 (s, 2H), 2.53 (t, J = 7.6 Hz, 2H), 2.13 (s, 3H), 1.07(t, J = 7.6 Hz, 3H).

[0597] Example 103: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(4-ethylphenyl)-1,2-dihydropyridin-2-one

[0598]

[0599] The experimental method for synthesizing compound 103 (11 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.60 (d, J = 7.3 Hz, 1H), 7.55 (d, J =8.3 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 6.51 (s, 1H), 5.84 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.11 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H).

[0600] Example 104: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2-ethoxyphenyl)-1,2-dihydropyridine-2-one

[0601]

[0602] The experimental method for synthesizing compound 104 (17 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.46 (d, J = 7.0 Hz, 1H), 7.32 – 7.26(m, 1H), 7.22 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.5 Hz,1H), 6.52 (s, 1H), 5.83 (d, J = 7.0 Hz, 1H), 4.99 (s, 2H), 4.02 (q, J = 6.9 Hz,2H), 2.13 (s, 3H), 1.25 (d, J = 6.9 Hz, 3H).

[0603] Example 105: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(4-butylphenyl)-1,2-dihydropyridin-2-one

[0604]

[0605] The experimental method for synthesizing compound 105 (19 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.55 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 6.32 (s, 1H), 5.78 (d, J = 7.5 Hz, 1H), 4.91 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H),2.08 (s, 3H), 1.63 – 1.57 (m, 2H), 1.36 (q, J = 7.5 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H).

[0606] Example 106: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-[2-(propyloxy)phenyl]-1,2-dihydropyridin-2-one

[0607]

[0608] The experimental method for synthesizing compound 106 (16 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.45 (d, J = 7.1 Hz, 1H), 7.32 – 7.26(m, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.95 (t, J = 7.5 Hz,1H), 6.34 (s, 1H), 5.76 (d, J = 7.2 Hz, 1H), 4.92 (s, 2H), 3.91 (t, J = 6.4 Hz,2H), 2.08 (s, 3H), 1.67 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0609] Example 107: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2,3-dihydro-1-benzofuran-5-yl)-1,2-dihydropyridin-2-one

[0610]

[0611] The experimental method for synthesizing compound 107 (15 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 7.3 Hz, 1H), 7.52 (s, 1H), 7.36 (d, J = 6.3 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.54 (s, 1H), 5.83 (d, J = 7.3Hz, 1H), 4.98 (s, 2H), 4.55 (d, J= 8.8 Hz, 2H), 3.22 (t, J = 8.6 Hz, 2H), 2.12(s, 3H).

[0612] Example 108: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(2,3-dihydrobenzo[2,1-b][1,4]dioxane-6-yl)-1,2-dihydropyridin-2-one

[0613]

[0614] The experimental method for synthesizing compound 108 (15 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 7.2 Hz, 1H), 7.21 (d, J =2.1 Hz, 1H), 7.09 (dd, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.46 (s,1H), 5.79 (d, J = 7.3 Hz, 1H), 4.94 (s, 2H), 4.24 (s, 4H), 2.10 (s, 3H).

[0615] Example 109: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(1-ethylindazole-3-yl)-1,2-dihydropyridin-2-one

[0616]

[0617] The experimental method for synthesizing compound 109 (15 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.92 (t, J = 7.0 Hz, 2H), 7.57 (d, J =8.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.53 (s, 1H), 6.01 (d, J= 7.4 Hz, 1H), 5.04 (s, 2H), 4.50 (q, J = 7.2 Hz, 2H), 2.13 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H).

[0618] Example 110: 6-[(2-amino-4-methylimidazol-3-yl)methyl]-3-(1-cyclopentylindazole-3-yl)-1,2-dihydropyridin-2-one

[0619]

[0620] The experimental method for synthesizing compound 110 (14 mg) using 49b as a starting material is consistent with the method for synthesizing 90 using 49b as a starting material. 1 H NMR (400 MHz, MeOD) δ 7.99 (d, J = 7.4 Hz, 1H), 7.93 (d, J =8.3 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6Hz, 1H), 6.56 (s, 1H), 6.10 (d, J = 7.5 Hz, 1H), 5.16 (m, 1H), 5.05 (s, 2H), 2.21 (m, 2H), 2.14 (s, 3H), 2.01 – 1.92 (m, 2H), 1.79 (m, 2H), 1.33 – 1.27(m, 2H).

[0621] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0622] Experimental Example 1: Gene Mutation of sQC(Q16769) / gQC(Q9NXS2) Enzyme

[0623] 1. Experimental materials and equipment:

[0624] PCR tubes, cell culture dishes, PCR instrument, gel imaging system, constant temperature shaker, centrifuge, SDS-PAGE electrophoresis apparatus, constant temperature incubator.

[0625] 2. Experimental methods:

[0626] (1) The selected mutants were sQC-I321A, sQC-I321V, gQC-I342A, and gQC-I342V (i.e., isoleucine at position 321 of sQC enzyme or position 342 of gQC enzyme is mutated to alanine or valine). Specific point mutation forward and reverse primers were designed using CE design primer design software based on the sQC / gQC enzyme gene sequence and mutation site:

[0627] sQC-I321V forward primer: TGCATCTGgtgCCGAGTCCGTTTCCGGAA (SEQ ID NO.1); sQC-I321V reverse primer: ACTCGGcacCAGATGCAGAACCGGAACGC (SEQ ID NO.2); sQC-I321A forward primer: TGCATCTGgccCCGAGTCCGTTTCCGGAA (SEQ ID NO.3); sQC-I321A reverse primer: ACTCGGcggCAGATGCAGAACCGGAACGC (SEQ ID NO.4); gQC-I342V forward primer: TCTGCATCTGgtgAGCACCCCGTTCCCGGCAG (SEQ ID NO.5); gQC-I342V reverse primer: TGCTcacCAGATGCAGAACCGGAACACCGCGG (SEQ ID NO.5) NO.6); gQC-I342A forward primer: TCTGCATCTGgccAGCACCCCGTTCCCGGCAG (SEQ ID NO.7); gQC-I342A reverse primer: TGCTggcCAGATGCAGAACCGGAACACCGCGG (SEQ ID NO.8).

[0628] (2) PCR system: Using the pET-32a(+) recombinant plasmid containing the sQC / gQC enzyme gene as a template, a PCR kit was used to add template (final concentration 0.02 mg / L), forward and reverse primers (final concentration 0.5 μM / L), 1 μL of high-fidelity DNA polymerase, 1 μL of dNTPmix, 10 μL of 5XSF to a 50 μL reaction system, and the remainder was made up with ddH2O.

[0629] (3) Program settings: (95℃ 15 seconds, 60℃ 15 seconds, 72℃ 130 seconds) Repeat the part in parentheses 30 times, then 72℃ 480 seconds, save at 16℃.

[0630] (4) The PCR products were then digested with DpnI restriction endonuclease to remove the template plasmid. The digested PCR products were transformed into E. coli DH5α competent cells and cultured overnight at 37°C in solid medium. Single colonies were picked for sequencing verification. After successful sequencing verification, the sQC enzyme mutant proteins (sQC-I321A and sQC-I321V) and gQC enzyme mutant proteins (gQC-I342A and gQC-I342V) were expressed using the same protein expression and purification steps as in Experiment Example 2.

[0631] Experimental Example 2: In vitro inhibitory activity of the compounds of this invention against sQC / gQC enzymes and their mutants.

[0632] 1. Experimental materials and equipment:

[0633] Incubator, shaker, microplate reader, WHB 96-well flat-bottomed luminescent plate, WHB 96-well cell culture plate.

[0634] 2. Experimental methods:

[0635] 1.1 Protein expression and purification steps:

[0636] (1) The recombinant plasmids (the original plasmids of sQC and gQC and the mutant plasmid prepared in Experiment 1) were transformed into competent Escherichia coli cells and amplified at 37°C and 200 rpm. When the bacterial concentration reached OD 600 When the concentration was 0.5-0.6, 0.3 mM isopropyl-β-D-1-thiogalactopyranoside (IPTG) was added, and expression was induced at 16℃ and 150 rpm for 48 h.

[0637] (2) The bacterial culture was centrifuged at 25°C and 4000 rpm for 20 min, the precipitate was collected and resuspended in lysis buffer (50 mM Tris, 300 mM NaCl, pH 8.0). Then, 1 mM of the protease inhibitor phenylmethylsulfonyl fluoride (PMSF) was added to the bacterial culture. The bacteria were lysed using a high-pressure homogenizer at 4°C and 800 bar. Subsequently, the culture was centrifuged at 12000 rpm for 60 min in a low-temperature high-speed centrifuge and the supernatant was collected.

[0638] (3) The supernatant obtained by centrifugation was purified using a Ni-NTA column pre-equilibrated with QC Buffer A (sQC: 50 mM Tris-HCl, 150 mM NaCl, pH 8.0; gQC: 50 mM Tris-HCl, 150 mM NaCl, 5% glycerol, pH 7.5). Buffers containing 10 mM, 15 mM, and 20 mM imidazole were prepared by mixing Buffer A and Buffer B (with 500 mM imidazole added to the corresponding components of Buffer A) in different proportions. The Ni-NTA column was then eluted sequentially to remove non-specifically adsorbed proteins from the nickel column. Subsequently, the imidazole concentration was increased to prepare buffers containing 50 mM, 100 mM, and 250 mM imidazole for further elution. Due to the competitive effect of high-concentration imidazole, most of the target protein would elute, and the crudely purified protein could be collected.

[0639] (4) After identification by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the protein solution was replaced with imidazole-free Buffer A by centrifugation and concentrated, and stored at -80°C by liquid nitrogen for subsequent enzyme inhibition activity testing.

[0640] 1.2 Activity Test Experimental Procedure:

[0641] The test compound was dissolved in DMSO and prepared for use. It was then triple-diluted to 10 concentrations starting at 200 µM using test buffer (20 mM Tris, 150 mM NaCl, 10% glycerol, 1 Triton X-100, pH 8). The enzyme, substrate, and coenzyme PGP-1 required for the reaction were diluted to their respective concentrations using test buffer. Activity assays were performed in black 96-well plates with a total reaction volume of 70 μL. 10 μL of the compound, 30 μL of test buffer, and 10 μL of QC (final concentration 30 nM) were added sequentially, and the mixture was incubated at room temperature for 20 min. Then, 10 µL of PGP-1 (final concentration 0.1 µM) was added, followed by 10 µL of H-Gln-AMC (final concentration 3 µM) to initiate the reaction. Immediately afterward, fluorescence changes within 15 min (λex = 380 nm, λem = 460 nm) were detected using a microplate reader. In each experiment, a reaction well without the compound was set up as a positive control, and three sets of parallel experiments were performed for each compound.

[0642] Compound PQ912 (structure: () was used as a control compound.

[0643] 3. Experimental Results:

[0644] The inhibitory activities of the compounds of this invention and the control compounds against sQC, gQC enzymes and their mutants were tested using the above experimental methods. The half-maximal inhibitory concentrations (IC50) of the compounds of this invention and the control compounds against these enzymes were also determined. 50 (See Tables 1 and 2.) The results show that the compounds of this invention have good and broad-spectrum inhibitory activity against sQC, gQC enzymes and their mutants, and can be used to prepare inhibitors of sQC, gQC enzymes and their mutants.

[0645] Test results under the same conditions showed that the positive control compound PQ912 had an IC50 inhibitory activity against sQC and gQC enzymes. 50 Values ​​in the range of 10 nM to 1 µM; most compounds of this invention exhibit IC50 values ​​against sQC and gQC enzymes. 50 The values ​​were all less than 1 µM, and some compounds (including 34, 35, 50, 56, and 66) had IC50 values ​​of less than 1 µM. 50 The values ​​are even below 10 nM for sQC enzymes. Most of the compounds of this invention exhibit inhibitory activity against sQC and gQC enzymes comparable to or better than PQ912.

[0646] Table 1. Inhibitory activities of the compounds of the present invention against sQC and gQC enzymes (IC50, 100 mg / L) 50 )

[0647]

[0648]

[0649] In Table 1, +: IC 50 >100µM;++: IC 50 ≤100µM and IC 50 >10µM; +++: IC 50 ≤10µM and IC 50 >1µM; ++++: IC 50 ≤1µM and IC 50 >10nM; +++++: IC 50 ≤10nM.

[0650] Table 2. Inhibitory activity (IC50) of the compounds of the present invention against sQC / gQC enzyme mutants. 50 )

[0651]

[0652] In Table 2, +: IC 50 >100µM;++: IC 50 ≤100µM and IC 50 >10µM; +++: IC 50 ≤10µM and IC50 >1µM; ++++: IC 50 ≤1µM and IC 50 >10nM; +++++: IC 50 ≤10nM.

[0653] Experimental Example 3: Therapeutic effect of the compound of the present invention on a DSS-induced mouse colitis model

[0654] 1. Experimental materials and equipment:

[0655] C57BL / 6 mice (male, 6-8 weeks old), SPF-grade animal facility, electronic balance, gavage syringe, refrigerated centrifuge.

[0656] 2. Experimental methods:

[0657] Animal grouping: Mice were randomly divided into 5 groups (n=5): a control group, a DSS group, a low-dose compound 33 group (5 mg / kg), a high-dose compound 33 group (15 mg / kg), and a compound 73 group (15 mg / kg). Modeling procedure: From day 1 to day 5, all mice except the control group were given free access to 2.5% DSS in drinking water. From day 6 until the end of the experiment, all mice were given purified water. From day 1 until the end of the experiment, the three drug-treated groups were administered the drug via gavage once daily in the afternoon, with a dosage of approximately 100 μL. Disease Index (DAI) scores were calculated daily during the experiment. On day 9, the mice were sacrificed, and the colon, spleen, and other tissues were removed and analyzed.

[0658] 3. Experimental Results:

[0659] The above results indicate that ( Figures 1-4 Compound 33 of this invention has a certain therapeutic effect on a mouse DSS-induced ulcerative colitis model, and has good biosafety.

[0660] In summary, this invention provides a class of compounds that act as inhibitors of glutamine cyclase. These compounds exhibit good inhibitory activity against sQC and gQC enzymes and their mutants, with most compounds reaching the sodium molar level of half-maximal inhibitory concentration (IC50). Therefore, they can be used to prepare glutamine cyclase inhibitors. Furthermore, these compounds can also be used to prepare drugs for the prevention and treatment of diseases related to glutamine cyclase (such as ulcerative colitis). This invention lays the material foundation for the drug development of glutamine cyclase inhibitors and has promising application prospects.

Claims

1. A compound or a salt thereof, characterized in that: The compound is of formula II-A: Formula II-A In formula II-A, R1 is selected from hydrogen, C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, 3~6 membered cycloalkyl, and -(CH2). n R8; n is selected from 1; R8 is selected from -OC(O)R9, 3-6 membered cycloalkyl groups; R9 is selected from C1~C6 alkyl groups; R2 is located at any position on the ring and is selected from substituted or unsubstituted 6-10 aryl groups, substituted or unsubstituted pyridyl groups, and substituted or unsubstituted groups. Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substitution is selected from one or more of the following groups: halogen, hydroxyl, amino, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered cycloalkyl-substituted C1-C6 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or, two substituents on the same carbon atom form =Y; Y is selected from O; R 10 Selected from C1~C6 alkyl groups; R3 is selected from hydrogen, halogen, cyano, amino, C1~C6 alkyl, amino-substituted C1~C6 alkyl, and C2~C6 ynyl.

2. The compound or its salt according to claim 1, characterized in that: R1 is selected from hydrogen, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, 3~4 membered cycloalkyl, and -(CH2). n R8; n is selected from 1; R8 is selected from -OC(O)R9, 3-6 membered cycloalkyl groups; R9 is selected from C1~C4 alkyl groups; R2 is located at any position on the ring and is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted... Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substitution is selected from one or more of the following groups: halogen, hydroxyl, amino, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl-substituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Alternatively, two substituents on the same carbon atom can form =Y; Y is selected from O. R 10 Selected from C1~C4 alkyl groups; R3 is selected from hydrogen, halogen, cyano, amino, C1~C4 alkyl, amino-substituted C1~C4 alkyl, and C2~C4 alkynyl.

3. The compound or its salt according to claim 2, characterized in that: The compounds are shown as either Formula III-A or Formula III-B: III-A Formula III-B In Equations III-A and III-B, R1 is selected from hydrogen, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, 3~4 membered cycloalkyl, and -(CH2). n R8; n is selected from 1; R8 is selected from -OC(O)R9, 3-6 membered cycloalkyl groups; R9 is selected from C1~C4 alkyl groups; R2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted... Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced The substitution is selected from one or more of the following groups: halogen, hydroxyl, amino, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl-substituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 Or, two substituents on the same carbon atom can form =Y; Y is selected from O; R 10 Selected from C1~C4 alkyl groups; R3 is selected from hydrogen, halogen, cyano, amino, C1~C4 alkyl, amino-substituted C1~C4 alkyl, and C2~C4 alkynyl.

4. The compound or its salt according to claim 3, characterized in that: R1 is selected from hydrogen, C1~C4 alkyl, C2~C4 alkenyl, C2~C4 alkynyl, 3~4 membered cycloalkyl, , ; R2 is selected from , , , , , , substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted naphthyl, substituted or unsubstituted The substitution is selected from one or more of the following groups: halogen, hydroxyl, amino, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl-substituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 ; R 10 Selected from C1~C4 alkyl groups; R3 is selected from hydrogen, C1-C4 alkyl, C2-C4 alkynyl, halogen, cyano, amino, and amino-substituted C1-C4 alkyl.

5. The compound or its salt according to claim 3, characterized in that: The compound is shown in Formula IV: Formula IV in, R1 and R2 are as described in claim 3 or 4.

6. The compound or its salt according to claim 5, characterized in that: The compound is shown in formula V: Formula V in, R2 is as described in claim 3 or 4.

7. The compound or its salt according to claim 6, characterized in that: The compounds are shown as either formula VI-A or formula VI-B: Formula VI-A Formula VI-B in, R 12 Let m be a substituent at any position on the benzene ring, and let R be a substituent. 12 The number of; m is selected from 0, 1, 2, 3, 4 or 5; The R 12 Selected from the following groups: halogen, hydroxyl, amino, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl-substituted C1-C4 alkoxy, 3-6 membered cycloalkyl, -C(O)R 10 -C(O)OR 10 ;R 10 Selected from C1~C4 alkyl groups.

8. The compound or its salt according to claim 3, characterized in that: The compound is shown in Formula VII: Equation VII in, R1 is selected from C1~C4 alkyl groups; R2 is as described in claim 3 or 4.

9. A compound or a salt thereof, characterized in that: The compound is shown in Formula III-C: Formula III-C in, X is selected from N; R1 is selected from C1~C4 alkyl groups; R2 is selected from hydrogen; R3 is selected from hydrogen; R7 is selected from C1~C6 alkyl groups.

10. A compound or a salt thereof, characterized in that: The compound is selected from one of the following compounds: 。 11. Use of the compound or a salt thereof according to any one of claims 1 to 10 in the preparation of a glutamine cyclase inhibitor or in the preparation of a medicament for the prevention and / or treatment of diseases related to glutamine cyclase; The diseases associated with glutamine cyclase include Alzheimer's disease, Parkinson's disease, inflammatory bowel disease, tumors, and kidney disease.

12. A drug, characterized in that: It is prepared using the compound or its salt as the active ingredient as described in any one of claims 1 to 10, plus pharmaceutically acceptable excipients.

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