Substituted n-(4-trifluoromethyl)-2-cyanocrotonamide compound, preparation method therefor, and pharmaceutical composition and use thereof

Abstract

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Description

Substituted N-(4-trifluoromethyl)-2-cyanocrotonamide compound, preparation method, pharmaceutical combination and use thereof Technical Field

[0001] The present invention relates to an N-(4-trifluoromethyl)-2-cyanocrotonamide compound, a preparation method, a pharmaceutical composition and use thereof. Background Art

[0002] Dihydroorotate dehydrogenase (DHODH) is located on the outer surface of the inner mitochondrial membrane. It is a key enzyme in pyrimidine synthesis in nucleic acid catalysis and a related enzyme in the electron transport chain. It is related to mitochondrial energy metabolism, cell proliferation, apoptosis, cell membrane potential, and the production of ROS reactive oxygen species. It mediates the occurrence of diseases such as cancer, autoimmune diseases, bacterial or viral infections, and parasites.

[0003] The isoxazole compound leflunomide is the first FDA-approved DHODH inhibitor. By blocking pyrimidine synthesis in immune cells, it inhibits the proliferation of activated immune cells and the secretion of cytokines. It is used to treat autoimmune diseases such as rheumatoid arthritis, lupus nephritis, and psoriatic arthritis. Leflunomide rapidly hydrolyzes upon entry into the body and is rapidly converted to its active metabolite, teriflunomide, which is stable in the matrix. However, with concurrent medication or in certain disease states, the enzymatic conversion of leflunomide in vivo may be impaired, affecting drug efficacy. When teriflunomide is administered directly, plasma drug concentrations are independent of enzymatic conversion, ensuring drug release and enhanced bioavailability while reducing exposure to minor metabolites. Therefore, teriflunomide's mechanism of action is to inhibit T cell proliferation, DNA and RNA synthesis in vitro, and cell surface and nuclear antigens directly involved in T cell activation and proliferation, thereby exerting anti-proliferative and anti-inflammatory effects and promoting immunomodulation.

[0004] Leflunomide and teriflunomide both demonstrate significant efficacy, good safety, and good tolerability in the treatment of a variety of diseases, including multiple sclerosis, rheumatoid arthritis, lupus nephritis, and acute leukemia. However, drug metabolism remains a critical issue for both. Leflunomide has a half-life of approximately 15 days, while its active metabolite, teriflunomide, enters the enterohepatic circulation in significant quantities and has a longer half-life, typically 1 to 4 weeks, remaining detectable in serum for up to 2 years after discontinuation. Therefore, even with discontinuation of the drug, serious adverse reactions (such as hepatotoxicity, hematotoxicity, or allergic reactions) may occur. If teriflunomide requires rapid clearance from the body for planned or unplanned pregnancy, the occurrence of the aforementioned side effects, or any other reason, a washout process must be followed.

[0005] In addition, teriflunomide cannot be metabolized by cytochrome P450 or flavin-containing monoamine oxidase, is an inhibitor of CYP2C8 enzyme, a weak inducer of CYP1A2, and can inhibit the activity of organic anion transporter 3 (OAT3) and organic anion transporting polypeptides B1 and B3 (OATP1B1 / 1B3), which may affect the in vivo exposure of multiple drugs.

[0006] Therefore, the development needs of this type of new inhibitors are to improve the inhibition of lymphocytes, reduce the level of inflammatory factors in the body, increase efficacy, reduce toxic side effects, improve the absorption, distribution, metabolism and excretion of drugs in the body, bring new treatment options to patients, and solve unmet clinical needs. Summary of the Invention

[0007] The present invention provides an N-(4-trifluoromethyl)-2-cyanocrotonamide compound, such as a compound represented by the following formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotopically labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof. The compound has significantly improved pharmaceutical activity and can effectively treat and / or prevent inflammation, pain, multiple sclerosis, neuromyelitis optica, autoimmune diseases, or cancer. Also provided are preparation methods, pharmaceutical compositions, and uses comprising the compound.

[0008] A compound represented by formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof,

[0009] in:

[0010] R1 is selected from: -H, alkyl, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 ;

[0011] R2 is selected from: -H, alkyl, aryl, cycloalkyl, -alkylene-aryl, -alkylene-C(=O)OH, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1, optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 、-alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ;

[0012] Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form an optionally substituted aliphatic heterocyclic group;

[0013] or R1 and R2 together with the nitrogen atom to which they are attached are

[0014] X is selected from -H, or X and R1 together form a cyclic amide structure;

[0015] R2' is selected from: -H, alkyl, aryl, cycloalkyl, -alkylene-aryl, -alkylene-C(=O)OH, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 、-alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ;

[0016] Optionally, R2' is -H;

[0017] Q is selected from O or -O-cycloalkyl;

[0018] Optionally, Q is O;

[0019] Each R3 is independently selected from: -H, alkyl or -alkylene-OC(=O)-OR 4-2 ;

[0020] R3 is selected from: -H, alkyl;

[0021] Optionally, R3 is: methyl;

[0022] A is selected from: -C(=O)-, alkylene;

[0023] R 4-1 Selected from: alkyl, hydroxy, amino, carboxyl, halogen, nitro, cyano; preferably R 4-1 is an alkyl group;

[0024] R 4-2 Selected from: -OH, aryl, alkyl, alkoxy, -alkenyl-carboxyl, -alkenyl-alkoxyacyl, -alkylene-R 4-9 ;

[0025] R 4-3 、R 4-4 are the same or different, each independently selected from: H, alkyl;

[0026] Or, R 4-3 and R 4-4 are bonded to each other and to the nitrogen atom to which they are bonded to form an optionally substituted aliphatic heterocyclic group;

[0027] R 4-5 Selected from: H, alkyl, -alkylene-aryl;

[0028] Linker is an optional group, which, when present, is selected from: alkylene, -B-alkylene-, -B-alkylene-arylene-, -B-arylene-alkylene-;

[0029] Each B is independently selected from -O-, -S-, and -NH-;

[0030] R 4-6 for

[0031] Each R' is independently selected from: -H, alkyl, -alkylene-aryl, hydroxy-substituted alkyl;

[0032] Each R 4-7 and R 4-8 are the same or different, each independently selected from: H, alkyl, -alkylene, -aryl;

[0033] R 4-9 Selected from: Aryl, -C(=O)O-alkyl;

[0034] The "optionally substituted monosaccharide group" refers to one or more hydrogen atoms on the monosaccharide group that are unsubstituted or substituted by a substituent selected from: -C(=O)OR 4-10 ;

[0035] The monosaccharide groups in the optional monosaccharide groups are selected from the following monosaccharide groups, wherein the monosaccharide 1-position substitution is α substitution or β substitution or both:

[0036] The monosaccharide 2-position is substituted with α configuration or β configuration or both:

[0037] R 4-10 Selected from: H, alkyl;

[0038] R 4-11 Selected from: alkyl, aryl;

[0039] "Optionally substituted aliphatic heterocyclic group" means that one or more hydrogen atoms on the aliphatic heterocyclic group are unsubstituted or substituted with a substituent, and the substituents in the "optionally substituted aliphatic heterocyclic group" are each independently selected from the group consisting of hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkylthio, alkanoyl, and hydroxy-substituted aryl;

[0040] The "hydroxy-substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms are not substituted or are substituted by a hydroxy group.

[0041] Another embodiment of the present invention, in formula (I):

[0042] R1 and R2 are the same or different and are independently selected from: -H, alkyl, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 ;

[0043] Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form an optionally substituted aliphatic heterocyclic group;

[0044] or R1 and R2 together with the nitrogen atom to which they are attached are

[0045] X is selected from -H, or X and R1 together form a cyclic amide structure

[0046] R3 is selected from: -H, alkyl;

[0047] A is selected from: -C(=O)-, alkylene;

[0048] R 4-1Selected from: alkyl, hydroxy, amino, carboxyl, halogen, nitro, cyano; preferably R 4-1 is an alkyl group;

[0049] R 4-2 Selected from: -OH, aryl, alkyl, alkoxy, -alkenyl-carboxyl, -alkenyl-alkoxyacyl, -alkylene-R 4-9 ;

[0050] R 4-3 、R 4-4 are the same or different, each independently selected from: H, alkyl;

[0051] Or, R 4-3 and R 4-4 are bonded to each other and to the nitrogen atom to which they are bonded to form an optionally substituted aliphatic heterocyclic group;

[0052] R 4-5 Selected from: H, alkyl, aryl;

[0053] Linker is an optional group, which, when present, is selected from: alkylene, -B-alkylene-, -B-alkylene-arylene-, -B-arylene-alkylene-;

[0054] Each B is independently selected from: -O-, -S-, -NH-;

[0055] R 4-6 for

[0056] Each R' is independently selected from: -H, alkyl, -alkylene-aryl, hydroxy-substituted alkyl;

[0057] R 4-7 and R 4-8 are the same or different, each independently selected from: H, alkyl, -alkylene, -aryl;

[0058] R 4-9 Selected from: Aryl, -C(=O)O-alkyl;

[0059] The "optionally substituted monosaccharide group" refers to one or more hydrogen atoms on the monosaccharide group that are unsubstituted or substituted by a substituent selected from: -C(=O)OR 4-10 ;

[0060] The monosaccharide groups in the optional monosaccharide groups are selected from the following monosaccharide groups, wherein the monosaccharide 1-position substitution is α substitution or β substitution or both:

[0061] The monosaccharide 2-position is substituted with α configuration or β configuration or both:

[0062] R 4-10 Selected from: H, alkyl;

[0063] The substituents in the "optionally substituted aliphatic heterocyclic group" are each independently selected from the group consisting of: hydroxy, amino, carboxyl, halogen, nitro, cyano, alkyl, alkylthio, alkanoyl, and hydroxy-substituted aryl;

[0064] The "hydroxy-substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms are not substituted or are substituted by a hydroxy group.

[0065] In one embodiment of the present invention,

[0066] Optionally, the halogen is selected from: F, Cl, Br, I; Optionally, the alkyl portion of the "alkyl", "alkanoyl", "hydroxy-substituted alkyl", "alkoxy", "-C(=O)O-alkyl", and "alkoxyacyl" is independently C 1-20 Straight or branched chain alkyl, optionally C 1-17 Straight or branched chain alkyl, optionally C 1-13 Straight or branched chain alkyl, optionally C 1-10 Straight or branched chain alkyl, optionally C 1-7 Straight or branched chain alkyl, optionally C 1-5 Straight-chain or branched alkyl, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or heptadecyl; optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl;

[0067] Optionally, the alkyl moieties in the "-alkylene-C(=O)O-alkyl" are each independently C 1-20 Straight or branched chain alkyl, optionally C 1-17 Straight or branched chain alkyl, optionally C 1-13 Straight or branched chain alkyl, optionally C 1-10 Straight or branched chain alkyl, optionally C 1-7 Straight or branched chain alkyl, optionally C 1-5Straight-chain or branched alkyl, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or heptadecyl; optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl;

[0068] Alternatively, "-alkylene-", "-alkylene-aryl", "-B-alkylene-", "-B-alkylene-arylene-", "-B-arylene-alkylene-", "-O-alkylene-R 4-5 ”, “-alkylene-R 4-9 The "alkylene" mentioned in the above is C 1-20 Straight or branched alkylene, optionally C 1-17 Straight or branched alkylene, optionally C 1-10 Straight or branched alkylene, optionally C 1-8 Straight or branched alkylene, optionally C 1-5 Straight or branched alkylene, optionally C 1-3 Straight-chain or branched alkylene, optionally, is methylene, ethylene, isoethylidene, n-propylene, isopropylene, n-butylidene, isobutylidene, tert-butylidene, sec-butylidene, n-pentylidene, isopentylidene, neopentylidene, tert-pentylidene, n-hexylidene, isohexylidene, heptylidene, n-octylidene, n-nonylidene, or n-decylidene;

[0069] Alternatively, the "-alkylene-C(=O)O-alkyl", "-alkylene-OC(=O)R 4-11 ”, “-alkylene-OP(=O)(OR 4-7 )OR 4-8 ”, “-alkylene-OC(=O)-OR 4-10 ”, “-alkylene-OC(=O)-OR 4-2 "-alkylene-C(=O)OH" means C 1-20 Straight or branched alkylene, optionally C 1-17 Straight or branched alkylene, optionally C 1-10 Straight or branched alkylene, optionally C 1-8 Straight or branched alkylene, optionally C 1-5 Straight or branched alkylene, optionally C 1-3Straight-chain or branched alkylene, optionally, is methylene, ethylene, isoethylidene, n-propylene, isopropylene, n-butylidene, isobutylidene, tert-butylidene, sec-butylidene, n-pentylidene, isopentylidene, neopentylidene, tert-pentylidene, n-hexylidene, isohexylidene, heptylidene, n-octylidene, n-nonylidene, or n-decylidene;

[0070] Optionally, the aliphatic heterocyclic group is a C-containing heteroatom selected from O, N, S. 3-8 (Preferably C 4-6 ) aliphatic heterocycle, optionally, dioxolane, aziridine, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, or piperazinyl;

[0071] Optionally, the aryl group in the "aryl group", "hydroxy-substituted aryl group" and "-alkylene-aryl group" is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, phenyl or naphthyl;

[0072] Optionally, the arylene group in the "-B-alkylene-arylene-", "-B-arylene-alkylene-", and "-alkylene-arylene-" is a 6-10 membered monocyclic or bicyclic condensed aromatic ring group; optionally, a phenylene group or a naphthylene group;

[0073] Alternatively, the alkenyl moieties in the "alkenyl-carboxyl" and "alkenyl-alkoxyacyl" are each independently a C2-C8 straight chain or branched alkenyl containing one or more double bonds, optionally a C2-C6 straight chain or branched alkenyl, optionally a C2-C4 straight chain or branched alkenyl; optionally, ethylene, propylene, butene, pentene, acetylene and hexylene;

[0074] Optionally, the cycloalkyl group in the "cycloalkyl group" and "-O-cycloalkyl group" is a 3-7 membered monocyclic cycloalkyl group, optionally selected from: cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl;

[0075] Alternatively, the present invention relates to the aforementioned compound and any attendant definitions, wherein the N-(4-trifluoromethyl)-2-cyanocrotonamide moiety is in the Z configuration or the E configuration.

[0076] Alternatively, when R1 and R2 are connected to each other and the nitrogen atom to which they are connected, they form an optionally substituted aliphatic heterocyclic group, and the optionally substituted aliphatic heterocyclic group is selected from:

[0077] Optionally, R 4-1 C 1-5 Straight-chain or branched alkyl group;

[0078] Optionally, R 4-2 Selected from: -OH, phenyl, C 1-13Straight-chain or branched alkyl, C 1-5 Straight-chain or branched alkoxy, -C=C-COOH, -C=CC 1-5 Straight chain or branched alkoxy acyl, -C 1-5 Straight chain or branched alkylene-R 4-9 ;

[0079] Optionally, R 4-3 、R 4-4 The same or different, each independently selected from: H, alkyl, or R 4-3 and R 4-4 Together with the nitrogen atoms they are connected to form

[0080] Optionally, R 4-5 Selected from: H, C 1-5 Straight chain or branched alkyl, -C 1-5 straight-chain or branched alkylene-phenyl groups;

[0081] Alternatively, Linker is an optional group, which when present is selected from: C 1-5 Straight chain or branched alkylene, -BC 1-5 Straight chain or branched alkylene-, -BC 1-5 Straight chain or branched alkylene-phenylene-, -B-phenylene-C 1-5 Straight or branched alkylene-;

[0082] Optionally, R' is independently selected from: -H, C 1-5 Straight chain or branched alkyl, -C 1-5 Straight chain or branched alkylene-phenyl, hydroxy substituted C 1-5 Straight-chain or branched alkyl group;

[0083] Optionally, R 4-6 The amino acid portion is in D configuration or L configuration;

[0084] Optionally, R 4-7 and R 4-8 The same or different, each independently selected from: H, C 1-5 Straight chain or branched alkyl, -C 1-5 straight-chain or branched alkylene-phenyl groups;

[0085] Optionally, R 4-9 Selected from: phenyl;

[0086] Optionally, R 4-10 Selected from: H, C 1-5 Straight-chain or branched alkyl group;

[0087] Optionally, R3 is selected from: -H, C 1-5Straight-chain or branched alkyl group;

[0088] Optionally, A is selected from: -C(=O)-, C 1-5 straight-chain or branched-chain alkylene;

[0089] Optionally, R 4-11 Selected from: H, C 1-5 Straight-chain or branched alkyl, phenyl;

[0090] Alternatively, Q is O or -O-cyclopentyl;

[0091] Alternatively, the compound represented by formula (I), or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (optionally, the solvate is a hydrate), or its inclusion compound, or its racemate, or its cocrystal, or its isotope-labeled substance, or its nitrogen oxide, or its prodrug, or its active metabolite, wherein,

[0092] R1 and R2 are the same or different and are independently selected from: -H, C 1-5 Straight chain or branched alkyl, -C 1-5 Straight or branched alkylene -C(=O)OC 1-5 Straight or branched alkyl, -S(=O)2-C 1-5 Straight-chain or branched alkyl, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , the following monosaccharide groups, wherein the monosaccharide 1-position substitution is α-substitution or β-substitution:

[0093] in,

[0094] R 4-2 Selected from: -OH, phenyl, C 1-13 Straight-chain or branched alkyl, C 1-5 Straight-chain or branched alkoxy, -C=C-COOH, -C=CC 1-5 Straight chain or branched alkoxy acyl, -C 1-5 Straight chain or branched alkylene-R 4-9 ;

[0095] R 4-3 、R 4-4 The same or different, each independently selected from: H, C 1-5 Straight-chain or branched alkyl group;

[0096] Or, R4-3 and R 4-4 Together with the nitrogen atoms they are connected to form

[0097] R 4-5 Selected from: H, C 1-5 Straight chain or branched alkyl, -C 1-5 straight-chain or branched alkylene-phenyl groups;

[0098] Linker is an optional group, which is selected from: C 1-5 Straight chain or branched alkylene, -BC 1-5 Straight chain or branched alkylene-, -BC 1-5 Straight chain or branched alkylene-phenylene-, -B-phenylene-C 1-5 Straight or branched alkylene-;

[0099] A is selected from: -C(=O)-, C 1-5 straight-chain or branched-chain alkylene;

[0100] R3 is selected from: -H, C 1-5 Straight-chain or branched alkyl group;

[0101] R 4-7 and R 4-8 The same or different, each independently selected from: H, C 1-5 Straight chain or branched alkyl, -C 1-5 straight-chain or branched alkylene-phenyl groups;

[0102] R 4-9 Selected from: phenyl;

[0103] R 4-10 Selected from: H, C 1-5 Straight-chain or branched alkyl group;

[0104] Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form:

[0105] or R1 and R2 together with the nitrogen atom to which they are attached are

[0106] X is selected from -H

[0107] Each B is independently selected from -O-, -S-, and -NH-;

[0108] Or X and R1 together form a cyclic amide structure

[0109] R2' is selected from: -H, C1-5 Straight-chain or branched alkyl, phenyl, cyclopentyl, -C 1-5 Straight chain or branched alkylene-phenyl, -C 1-5 Straight or branched alkylene -C(=O)OH, -C 1-5 Straight or branched alkylene -C(=O)OC 1-5 Straight-chain or branched alkyl, -C(=O)-phenyl, -alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ; Optionally, R2' is: -H;

[0110] R 4-10 C 1-5 Straight-chain or branched alkyl group;

[0111] R 4-11 C 1-5 Straight-chain or branched alkyl, phenyl;

[0112] Q is O or -O-cyclopentyl; alternatively, Q is O;

[0113] R3 is selected from: C 1-5 Straight chain or branched alkyl, -C 1-5 Straight or branched alkylene-OC(=O)-OC 1-5 Straight-chain or branched-chain alkyl.

[0114] Optionally, the compound represented by formula (I) of the present invention, or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (optionally, the solvate is a hydrate), or its inclusion compound, or its racemate, or its cocrystal, or its isotope-labeled substance, or its nitrogen oxide, or its prodrug, or its active metabolite, is selected from the following compounds:

[0115] In another aspect, the present invention provides a method for preparing a compound of formula (I) or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled product thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof;

[0116] The method comprises the steps of: reacting compounds of formula (A) and formula (B) to obtain a compound of formula (I):

[0117] Step A:

[0118] In formula (A), X is as described in formula (I);

[0119] In formula (B), R1, R2 and R3 are as described in formula (I);

[0120] Alternatively, the compound of formula (I) is prepared by an addition elimination reaction of the compound of formula (A) and the compound of formula (B) in a suitable solvent (such as xylene or toluene) at a temperature of 50°C to 120°C.

[0121] Alternatively, formula (A) can be synthesized by method a, but is not limited to this method;

[0122] Method a:

[0123] Alternatively, the compounds of formula (C) and (D) are catalyzed by a condensation agent (such as EDCI, HATU, HBTU or PyBOP, etc.), in the presence or absence of a base (such as pyridine, TEA, DIPEA, DBU or DBN, etc.), in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 50°C to obtain the compound of formula (A).

[0124] Alternatively, formula (B) can be synthesized by method b, but is not limited to this method;

[0125] Method b:

[0126] Alternatively, the compound of formula (E) is subjected to an addition remethylation reaction in the presence of sodium methoxide and dimethyl sulfate in a solvent DMSO at -10°C to 30°C to obtain the compound of formula (B).

[0127] Alternatively, when R1 and R2 in formula (I) are the same or different and are independently H, alkyl, -alkylene-C(=O)O-alkyl, optionally substituted monosaccharide, or R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form an optionally substituted aliphatic heterocyclic group, formula (I) can be obtained by reacting compounds of formula (F) and formula (G) through step B:

[0128] Step B:

[0129] In formula (F), X and R3 are as described in formula (I), and W is dimethylamino, pyrrolyl, piperidinyl or morpholinyl; in formula (G), R1 and R2 are as described in formula (I).

[0130] Alternatively, compounds of formula (F) and formula (G) are catalyzed by a base (such as pyridine, TEA, DIPEA, DBU or DBN, etc.) in a suitable solvent (such as DMF, DMAC, DMSO, THF, DCM, DCE, MeOH, EtOH, Dioxane, etc.) at a temperature of 0°C to 100°C to obtain compounds of formula (I) by substitution reaction with or without deprotection.

[0131] Also included is when R1 and R2 in formula (I) are different, and R1 or R2 are each independently H, -S(=O)2R 4-1 、-C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , formula (I) can be obtained by reacting compounds of formula (H) and formula (J) through step C:

[0132] Step C:

[0133] In formula (H), X and R3 are as described in formula (I); in formula (J), M is halogen, hydroxyl, imidazolyl or p-nitrophenyloxy, Y is alkyl, carbonyl, alkylenecarbonyl, alkyleneoxycarbonyl, alkyleneoxyphosphoryl, sulfonyl or phosphoryl; or M and Y form an isocyanate; Z is optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkenyl, or optionally substituted alkylthio.

[0134] When M is halogen, p-nitrophenyloxy, imidazole or M and Y form an isocyanate, optionally, Formula (H) and Formula (J) are catalyzed by a base (such as pyridine, TEA, DIPEA, DBU, DBN or sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 30°C, through an acylation reaction, with or without deprotection, to obtain Formula (I).

[0135] When M is a hydroxyl group, optionally, Formula (H) and Formula (J) are catalyzed by a condensation agent (such as EDCI, HATU, HBTU or PyBOP, etc.), in the presence of a base (such as pyridine, TEA, DIPEA, DMAP, DBU, DBN or sodium hydride, etc.) and a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 50°C, and subjected to a condensation reaction with or without deprotection to obtain Formula (I).

[0136] Also included is when X and R1 in formula (I) together form a cyclic amide structure

[0137] R2' is as shown in formula (I), which can be obtained by cyclizing formula (H) itself and then reacting with a compound of formula (J) through step D:

[0138] Step D:

[0139] When R2' is H, Q is O, R3 is CH3; M is halogen (preferably iodide or bromide), Y is alkyl, carbonyl, alkylenecarbonyl, alkyleneoxycarbonyl, alkyleneoxyphosphoryl or phosphoryl; Z is optionally substituted alkyl, C3-C7 monocyclic cycloalkyl, optionally substituted alkyloxy, optionally substituted aryl, optionally substituted aryloxy.

[0140] Alternatively, formula (H) can be cyclized by reacting with carbonyldiimidazole or 4-nitrophenol chloromethyl ester or triphosgene under the catalysis of a base (such as potassium carbonate, cesium carbonate, pyridine, TEA, DIPEA, DBU, DBN, NaHCO3, sodium hydroxide, sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF, acetone or DMAC, etc.) at -10°C to 60°C, and then reacting with formula (J) under the catalysis of a base (such as potassium carbonate, cesium carbonate, pyridine, TEA, DIPEA, DBU, DBN or sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 80°C, with or without deprotection, to obtain formula (I).

[0141] The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, optionally, selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, formic acid, acetic acid, salicylic acid, citric acid, succinic acid, fumaric acid, maleic acid, benzoic acid, hydrobromic acid, hydroiodic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid.

[0142] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I) above or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion compound, or its racemate, or its cocrystal, or its isotope-labeled substance, or its nitrogen oxide, or its prodrug, or its active metabolite and pharmaceutically acceptable excipients.

[0143] Optionally, the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, solubilizers, cosolvents, antioxidants, anti-photolysis agents, pH regulators, emulsifiers, antibacterial preservatives, local analgesics, chelating agents, non-aqueous solvents, coating materials or other excipients.

[0144] Optionally, the pharmaceutically acceptable excipients, whose filler includes one or more combinations of lactose, mannitol, and calcium carbonate; the binder includes one or more combinations of sucrose, starch, povidone, and sodium carboxymethyl cellulose; the disintegrant includes one or more combinations of starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and effervescent disintegrants; the non-aqueous solvent includes one or more combinations of soybean oil, castor oil, and peanut oil; the solubilizer includes one or more combinations of Tween 80, Tween 60, and poloxamer 68; and the cosolvent includes one or more combinations of sodium benzoate, sodium salicylate, and sodium p-aminobenzoate.

[0145] Alternatively, the pharmaceutical composition may be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lotion), transdermally (e.g., electroporation of the skin, transdermal preparations such as creams, gels, lotions, and transdermal patches), or by inhalation (e.g., aerosols), and in the form of solid, liquid, or gaseous dosage forms, including tablets and suspensions. Administration may be performed in a single unit dose form, under continuous therapy, or as a random single dose therapy. The therapeutic composition may also be in the form of an oil emulsion or dispersion, combined with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.

[0146] Optionally, the pharmaceutical composition can be formulated as a solid oral preparation, a liquid oral preparation, an injection, or a transdermal preparation. Solid and liquid oral preparations include tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, syrups, and solutions. Injections include small injections, large infusions, and freeze-dried powder injections. Transdermal preparations include ointments, plasters, liniments, aerosols, traditional patches, adhesive dispersion patches, peripheral adhesive skeleton patches, reservoir patches, and cabu-shaped plasters.

[0147] In another aspect, the present invention provides a compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion compound, or its racemate, or its cocrystal, or its isotope-labeled substance, or its nitrogen oxide, or its prodrug, or its active metabolite, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and / or treating inflammation, pain, multiple sclerosis, neuromyelitis optica, autoimmune disease or cancer.

[0148] Optionally, the inflammation is selected from rheumatoid arthritis, dermatitis, etc.; optionally, the pain is selected from mild to moderate pain, etc.; the multiple sclerosis (MS) is selected from clinically isolated syndrome (CIS) MS, relapsing-remitting MS, primary progressive MS, secondary progressive MS, etc.; the neuromyelitis optica (NMO) is selected from monophasic NMO, relapsing NMO, progressive NMO, etc.; the autoimmune disease is selected from systemic lupus erythematosus, psoriasis, anti-transplant rejection, etc.; the cancer is selected from renal cancer, prostate cancer, and lung cancer. Optionally, the cancer cells include human renal cancer cell line 786-O, human prostate cancer cells LNCaP, PC3, DU145, human large cell lung cancer cell line H460, and human non-small cell lung cancer cell line A549.

[0149] As used herein, and unless otherwise indicated, the term "treating" refers to alleviating or reducing the severity of symptoms associated with the disease or condition being treated, e.g., inflammation, pain, multiple sclerosis, neuromyelitis optica, etc. The term "preventing" includes inhibiting the symptoms of a particular disease or condition, e.g., inflammation, pain, multiple sclerosis, neuromyelitis optica, autoimmune disease, etc.

[0150] The compounds of the present invention may exist in isotopically traced or enriched form, containing one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the atom found in the largest amount in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0151] As used herein, the term "optical isomer" refers to substances having identical molecular structures, similar physicochemical properties, but different optical rotations. This includes mixtures of optical isomers in any proportion. The compound of formula (I) may contain one or more asymmetric carbon atoms, and may exist as optically pure enantiomers, such as enantiomeric mixtures of racemates, optically pure diastereomers, diastereomeric mixtures, racemates of diastereomers, or mixtures of racemates of diastereomers. Optically active forms can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). The present invention includes all of these forms.

[0152] As used herein, the term "solvate" refers to a compound further bound by a chemical or non-chemical amount of a solvent through non-covalent intermolecular forces. For example, when the solvent is water, the solvate is a hydrate.

[0153] Abbreviations EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TEA: triethylamine DIPEA: N,N-diisopropylethylamine DBU: (1,8-diazabicyclo[5.4.0]undec-7-ene) DBN: 1,5-diazabicyclo[4.3.0]non-5-ene THF: Tetrahydrofuran TFA: Trifluoroacetic acid DCM: Dichloromethane DCE: Dichloroethane ACN: Acetonitrile DMF: N,N-dimethylformamide DMAC: N,N-dimethylacetamide DMSO: Dimethyl sulfoxide PyBOP: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate MTBE: tert-Butyl methyl ether DMAP: 4-Dimethylaminopyridine BRIEF DESCRIPTION OF THE DRAWINGS

[0154] FIG1 is a graph showing the neurological function scores of mice in Experimental Example 4;

[0155] FIG2 is a spinal cord section of a mouse in Experimental Example 4;

[0156] FIG3 is a graph showing the expression level of the inflammatory factor IL-17A in mice in Experimental Example 4;

[0157] FIG4 is a graph showing the expression level of the inflammatory factor IFN-γ in mice in Experimental Example 4;

[0158] FIG5 is a graph showing the survival rate of rat spleen lymphocytes in Experimental Example 6. DETAILED DESCRIPTION

[0159] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. If a term in this document has multiple definitions, this section will prevail unless otherwise stated.

[0160] The embodiments of the present invention are described in detail below, but the embodiments provided do not limit the present invention in any way.

[0161] Example

[0162] General synthetic method 1:

[0163] Formula (F) (1 equivalent) and formula (G) (1 equivalent) are dispersed in ethanol, DIPEA (1 equivalent) is added or not, and the mixture is heated to reflux for reaction. After the reaction is completed, the mixture is cooled, the solid is precipitated, filtered, and then subjected to acid, base, or palladium carbon reduction deprotection or non-deprotection to obtain formula (I).

[0164] Example 1: Preparation of Compound 1

[0165] Prepared by general synthetic method 1, a white solid was obtained with a yield of 78.8%.

[0166] 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H),9.35(s,1H),8.71(s,1H),7.81(d,J=8.6Hz,2H),7.62(d,J=8.7Hz,2H),2.19(s,3H).

[0167] Example 2: Preparation of Compound 2

[0168] Synthesis method:

[0169] In a 25 mL reaction flask, compound TLFA-3 (25 mg, 0.08 mmol) and anhydrous potassium carbonate (5 mg, 0.04 mmol) were weighed and added to methanol (2 mL). The reaction was allowed to react at room temperature. After the reaction, the reaction solution was washed twice with ethyl acetate (50 mL) and saturated NaCl (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified with petroleum ether / ethyl acetate = 5 / 1 to obtain 10 mg of a light yellow solid with a yield of 45%.

[0170] 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),7.97(d,J=8.5Hz,2H),7.68(d,J=8.6Hz,2H),6.91(s,1H),3.68(s,3H),1.56(s,3H).

[0171] Example 3: Preparation of Compound 3

[0172] Synthesis method:

[0173] The compound p-trifluoromethylaniline (161 mg, 1 mmol), 4,4-bis(methylthio)-3-butene-2-one (162 mg, 1 mmol), and 1,4-dioxane (3 mL) were weighed, and the reaction mixture was slowly heated from room temperature to 150 degrees and stirred overnight. The reaction solution was extracted with ethyl acetate (100 mL) and saturated ammonium chloride (50 mL). The organic phase was washed once with water (50 mL) and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. It was then purified with petroleum ether / ethyl acetate = 10 / 1 to obtain a light yellow oily product, totaling 132 mg, with a yield of 48%.

[0174] The above product (60 mg, 0.2 mmol) and PhI(OAc)2 (105 mg, 0.3 mmol) were weighed and added to DCE (3 mL) in a 25 mL reaction flask. The reaction was allowed to react at room temperature. After the reaction, the reaction solution was washed twice with ethyl acetate (100 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The product was then purified with petroleum ether:ethyl acetate = 7:1 to obtain 25 mg of the product as a light yellow oil with a yield of 34%.

[0175] 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),7.85(d,J=8.5Hz,2H),7.72(d,J=8.7Hz,2H),2.35(s,3H),2.26(s,3H),2.08(s,3H).

[0176] Example 4: Preparation of Compound 4

[0177] Prepared by general synthetic method 1, a yellow solid was obtained with a yield of 56.3%.

[0178] 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),9.03(d,J=15.2Hz,1H),8.60(s,1H),7.84(d,J=8.5Hz,2H),7.65(dd,J=14.6,8.7Hz,3H).

[0179] Example 5: Preparation of Compound 5

[0180] Prepared by general synthetic method 1, a white solid was obtained with a yield of 66.6%.

[0181] 1H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 7.3Hz, 2H), 7.82 (d, J = 8.5Hz, 2H), 7.62 (d, J = 8.6Hz, 2H).

[0182] General synthetic method 2:

[0183] Formula (C) (1 equivalent) and formula (D) (1.1 equivalents) were dispersed in DMF, cooled to 0°C, and EDAC (1.2 equivalents) was slowly added. After the addition was complete, the temperature was raised to room temperature for reaction. After the reaction was complete, water was added, and the solid was precipitated and filtered to obtain formula (A) as a white solid.

[0184] Formula (E) (1 equivalent) and dimethyl sulfate (1 equivalent) were reacted at 90°C for 1 hour, cooled to -5°C, and a methanol solution of sodium methoxide (1.5 equivalents) was slowly added dropwise. The reaction was continued for 1 hour, MTBE was added, filtered, and the filtrate was concentrated to obtain formula (B) as a yellow oil.

[0185] Formula (A) (1 equivalent) and formula (B) (1.1 equivalents) are dispersed in xylene, heated to 100°C for reaction, and after the reaction is completed, cooled, petroleum ether is added, solids are precipitated, filtered, and dried to obtain formula (J) as a white or off-white solid.

[0186] Example 6: Preparation of Compound 6

[0187] Prepared by general synthetic method 2, a white solid was obtained with a yield of 84.1%.

[0188] 1 H NMR (400MHz, DMSO-d6) δ9.94(s,1H),7.78(d,J=8.5Hz,2H),7.63(d,J=8.5Hz,2H),3.04(s,6H),2.32(s,3H).

[0189] General synthetic method 3:

[0190] Formula (H) (1 equivalent) is dispersed in DMAC, cooled to 0°C, sodium hydride (1.5 equivalents) or DBU (1.5 equivalents) is added, stirred for half an hour, and a DMF solution of formula (J) (1.5 equivalents) is slowly added. The mixture is warmed to room temperature for reaction. After the reaction is completed, EA is added, the mixture is washed three times with saturated ammonium chloride and once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the product is purified by column chromatography, and then subjected to acid, base, or palladium carbon reduction deprotection or non-deprotection to obtain formula (I).

[0191] Alternatively, formula (H) (1 equivalent), formula (J) (2-3 equivalents) and HATU (2-3 equivalents) are dispersed in DMF, DBU (2-3 equivalents) is added, and the mixture is heated to 45°C for reaction. After the reaction is completed, EA is added, and the mixture is washed with saturated ammonium chloride three times and saturated sodium chloride once. The mixture is dried over anhydrous sodium sulfate, filtered, concentrated, and the product is purified by column chromatography, and then subjected to acid, base, or palladium-carbon reduction deprotection or non-deprotection to obtain the compound of formula (I).

[0192] Example 7: Preparation of Compound 7

[0193] Prepared by general synthetic method 3, a white solid was obtained with a yield of 70.0%.

[0194] 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),7.71(d,J=8.5Hz,2H),7.61(d,J=8.6Hz,2H),3.03(s,3H),2.44(s,3H).

[0195] Example 8: Preparation of Compound 8

[0196] Prepared by general synthetic method 3, a yellow solid was obtained with a yield of 48.1%.

[0197] 1 H NMR (400MHz, DMSO-d6) δ12.55(s,1H),10.01(s,1H),7.80(d,J=8.6Hz,2H),7.70(d,J=8.7Hz,2H),2.96(s,6H),2.66(s,3H).

[0198] Example 9: Preparation of Compound 9

[0199] Prepared by general synthetic method 3, a white solid was obtained with a yield of 56.3%.

[0200] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),10.06(s,1H),7.79(d,J=8.6Hz,2H),7.71(d,J=8.7Hz,2H),3.71-3.55(m,4H),3.47-3.38(m,4H),2.65(s,3H).

[0201] Example 10: Preparation of Compound 10

[0202] Prepared by general synthetic method 3, a white solid was obtained with a yield of 56.0%.

[0203] 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),10.31(s,1H),7.92(d,J=7.3Hz,2H),7.83( d,J=8.5Hz,2H),7.72(dd,J=13.8,8.0Hz,3H),7.62(t,J=7.6Hz,2H),2.83(s,3H).

[0204] Example 11: Preparation of Compound 11

[0205] Prepared by general synthetic method 3, a white solid was obtained with a yield of 55.0%.

[0206] 1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.21(s,1H),7.82(d,J=8.6Hz,2H),7 .72(d,J=8.7Hz,2H),2.66(s,3H),2.65-2.59(m,1H),1.12(d,J=6.9Hz,6H).

[0207] Example 12: Preparation of Compound 12

[0208] Prepared by general synthetic method 1, a white solid was obtained with a yield of 66.6%.

[0209] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.77(s,1H),7.83-7.71(m,4H),7.49-7.22(m,5H),5.00(d,J=10.1Hz,2H),1.95(s,3H).

[0210] Example 13: Preparation of Compound 13

[0211] Prepared by general synthetic method 1, a white solid was obtained with a yield of 46.0%.

[0212] 1 H NMR (400MHz, DMSO-d6) δ9.17 (s, 1H), 7.82 (d, J = 8.5Hz, 2H), 7.67 (d, J = 9.3Hz, 4H), 2.34 (s, 3H).

[0213] Example 14: Preparation of Compound 14

[0214] Prepared by general synthetic method 1, a white solid was obtained with a yield of 46.0%.

[0215] 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),7.80(d,J=8.8Hz,3H),7.74(d,J=8.7Hz,2H),4.16-4.07(m,2H),1.92(s,3H),1.22-1.19(m,3H).

[0216] Example 15: Preparation of Compound 15

[0217] Prepared by general synthetic method 3, a white solid was obtained with a yield of 20.0%.

[0218] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),10.22(s,1H),7.82(d,J=8.6Hz,2H),7.71(d,J=8.7Hz,2H),2.64(s,3H),2.17(s,3H).

[0219] Example 16: Preparation of Compound 16

[0220] The compound was prepared by general method synthesis method 3 to obtain a white solid with a yield of 49.3%.

[0221] 1 H NMR(400MHz,DMSO-d6)δ12.52(s,1H),10.02(s,1H),7.79(d,J=8.5Hz,2H),7 .71(d,J=8.8Hz,2H),3.47-3.39(m,4H),2.63(s,3H),1.54(d,J=22.8Hz,6H).

[0222] Example 17: Preparation of Compound 17

[0223] Prepared by general synthetic method 3, a white solid was obtained with a yield of 26.0%.

[0224] 1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.04(s,1H),7.75(dd,J=35.6,8.6Hz,4H ),3.83(s,2H),3.57-3.45(m,2H),2.64(d,J=16.9Hz,4H),1.10(d,J=6.2Hz,6H).

[0225] Example 18: Preparation of Compound 18

[0226] Prepared by general synthetic method 3, a white solid was obtained with a yield of 43.0%.

[0227] 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),10.20(s,1H),7.82(d,J=8.6Hz,2H),7.71(d,J=8.7Hz,2H),2.66(s,3H),2.46(s,2H),1.04(t,J=7.4Hz,3H).

[0228] Example 19: Preparation of Compound 19

[0229] Prepared by general synthetic method 3, a white solid was obtained with a yield of 33.0%.

[0230] 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),10.16(s,1H),7.81(d,J=8.5Hz,2H),7.70(d,J=8.7Hz,2H),3.73(s,3H),2.65(s,3H).

[0231] Example 20: Preparation of Compound 20

[0232] Prepared by general synthetic method 3, a white solid was obtained with a yield of 20.0%.

[0233] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.15(s,1H),7.82(d,J=8.5Hz,2H),7. 70(d,J=8.7Hz,2H),4.17(d,J=7.1Hz,2H),2.65(s,3H),1.24(t,J=7.1Hz,3H).

[0234] Example 21: Preparation of Compound 21

[0235] Prepared by general synthetic method 3, a white solid was obtained with a yield of 19.0%.

[0236] 1 H NMR (400MHz, DMSO-d6) δ12.63(s,1H),10.00(s,1H),7.82(d,J=8.6Hz,2H),7.72(t ,J=9.1Hz,2H),3.30-3.20(m,4H),2.66(s,3H),1.55(s,4H),0.87(t,J=6.8Hz,6H).

[0237] Example 22: Preparation of Compound 22

[0238] Prepared by general synthetic method 3, a light yellow solid was obtained with a yield of 36.0%.

[0239] 1 H NMR (400MHz, DMSO-d6) δ11.63(d,J=10.9Hz,1H),10.07(s,1H),7.82(d,J=8.5Hz,2H),7.70(d,J=8.7Hz,2H),3.79(s,3H),3.76(s,3H),2.45(s,3H).

[0240] Example 23: Preparation of Compound 23

[0241] Prepared by general synthetic method 3, a light yellow solid was obtained with a yield of 83.0%.

[0242] 1 H NMR (400MHz, DMSO-d6) δ11.63(d,J=11.3Hz,1H),10.01(s,1H),7.81(d,J=8.6Hz,2H) ,7.71(d,J=8.7Hz,2H),7.47-7.32(m,10H),5.15(dd,J=9.2,1.7Hz,4H),2.33(s,3H).

[0243] Example 24: Preparation of Compound 24

[0244] Prepared by general method synthesis method 3, a light yellow solid was obtained with a yield of 50.0%.

[0245] 1H NMR (400MHz, DMSO-d6) δ11.22(d,J=9.9Hz,1H),9.77(s,1H),7.81(d,J=8.6Hz,2H),7.67(d,J=8.7Hz,2H),2.47(s,3H).

[0246] Example 25: Preparation of Compound 25

[0247] The compound was prepared by general method synthesis method 1 to obtain a white solid with a yield of 25.0%.

[0248] 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.46(s,1H),7.81(d,J=8.6Hz,2H),7.64(d,J=8.7 Hz, 2H), 4.37 (d, J = 5.6Hz, 2H), 4.18 (d, J = 7.1Hz, 2H), 2.24 (s, 3H), 1.23 (t, J = 7.1Hz, 3H).

[0249] Example 26: Preparation of Compound 26

[0250] Synthesis method:

[0251] Formula (A) (1 equivalent) and p-methoxyacetophenone (1 equivalent) were dispersed in ethanol, and p-toluenesulfonic acid (1.0 equivalent) was added and heated under reflux for reaction. After the reaction was completed, an off-white solid product was obtained with a yield of 7.8%.

[0252] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),7.64(d,J=11.8Hz,4H),7.40(s,2H),6.94(s,2H),3.76(s,3H).

[0253] Example 27: Preparation of Compound 27

[0254] The synthesis method was the same as that in Example 26 to obtain an off-white solid with a yield of 5.9%.

[0255] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.03-7.54(m,4H),3.18(d,J=7.3Hz,6H),1.95(s,3H),1.47(s,3H).

[0256] Example 28: Preparation of Compound 28

[0257] Prepared by general synthetic method 1, a white solid was obtained with a yield of 26.9%.

[0258] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),7.78(s,2H),7.65(s,2H),3.66(s,4H),3.34(s,4H),2.34(s,3H).

[0259] Example 29: Preparation of Compound 29

[0260] Prepared by general synthetic method 1, a white solid was obtained with a yield of 60.9%.

[0261] 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 7.78 (d, J = 8.6Hz, 2H), 7.63 (d, J = 8.7Hz, 2H), 3.38 (s, 4H), 2.32 (s, 3H), 1.60 (s, 6H).

[0262] Example 30: Preparation of Compound 30

[0263] Prepared by general synthetic method 1, obtained as a yellow oil with a yield of 63.3%.

[0264] 1 H NMR (400MHz, DMSO-d6) δ9.88(d,J=120.9Hz,1H),7.79(d,J=8.5Hz,2H),7.62(d,J=8.6Hz,2H),3.64(s,4H),2.33(s,3H),1.87(s,4H).

[0265] Example 31: Preparation of Compound 31

[0266] Synthesis method:

[0267] Compound TLFA-3 (50 mg, 0.15 mmol) and m-chloroperbenzoic acid (27 mg, 0.16 mmol) were weighed, dichloromethane (3 mL) was added, and the mixture was reacted at room temperature in a 25 mL reaction flask. After the reaction, the reaction solution was washed twice with ethyl acetate (50 mL) and saturated brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. It was then purified with petroleum ether: ethyl acetate = 1:1 to obtain 6 mg of a light yellow solid with a yield of 11.5%.

[0268] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),7.79(d,J=8.5Hz,2H),7.62(d,J=8.6Hz,2H),3.64(s,3H),2.33(s,3H),1.87(s,3H).

[0269] Example 32: Preparation of Compound 32

[0270] Synthesis method:

[0271] Compound TLFA-3 (37 mg, 0.11 mmol) and potassium peroxymonosulfate (137 mg, 0.22 mmol) were weighed, acetone (0.6 mL) and water (0.2 mL) were added, and the mixture was reacted at room temperature in a 25 mL reaction flask. After the reaction, the reaction solution was washed twice with ethyl acetate (50 mL) and saturated brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. It was then purified with petroleum ether: ethyl acetate = 1:1 to obtain 5 mg of a light yellow solid with a yield of 12.5%.

[0272] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.79(d,J=8.6Hz,2H),7.66(d,J=8.7Hz,2H),5.76(s,1H),2.08(s,3H).

[0273] Example 33: Preparation of Compound 33

[0274] Prepared by general synthetic method 3, a white solid was obtained with a yield of 23.0%.

[0275] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),10.40(s,1H),7.82(d,J=8.5Hz,2H),7.72(d,J=8.9Hz,2H),7. 04(d,J=15.5Hz,1H),6.70(d,J=15.6Hz,1H),4.27-4.18(m,2H),2.65(s,3H),1.25(t,J=7.1Hz,3H).

[0276] Example 34: Preparation of Compound 34

[0277] Prepared by general synthetic method 3, a white solid was obtained with a yield of 23.0%.

[0278] 1H NMR (400MHz, DMSO-d6) δ8.52 (s, 1H), 8.01 (s, 1H), 6.95 (d, J = 10.3Hz, 1H), 6.51 (d, J=11.7Hz,1H),6.32(s,1H),6.20(s,1H),6.00(d,J=8.1Hz,3H),2.86-2.69(m,3H).

[0279] Example 35: Preparation of Compound 35

[0280] Prepared by general synthetic method 3, a white solid was obtained with a yield of 8.0%.

[0281] 1 H NMR(400MHz,DMSO-d6)δ12.14(s,1H),10.23(s,1H),7.79(s,2H),7.69(s,2H),7 .01(s,2H),3.67(t,J=6.9Hz,2H),2.71(t,J=6.9Hz,2H),2.59(d,J=12.1Hz,3H).

[0282] Example 36: Preparation of Compound 36

[0283] Prepared by general synthetic method 3, a white solid was obtained with a yield of 8.0%.

[0284] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.20(s,1H),7.82(d,J=8.6Hz,2H),7.71(d,J=8.7Hz,2H),7.00 (s,2H),2.65(d,J=6.5Hz,5H),2.43(d,J=7.4Hz,2H),1.59-1.44(m,4H),1.23(dd,J=15.2,8.7Hz,2H).

[0285] Example 37: Preparation of Compound 37

[0286] Prepared by general synthetic method 1, a yellow solid was obtained with a yield of 56.0%.

[0287] 1H NMR(400MHz,DMSO-d6)δ10.85(d,J=7.5Hz,1H),9.59(s,1H),7.95(s,1H),7.8 0(d,J=8.5Hz,2H),7.65(d,J=8.7Hz,2H),5.57(d,J=5.6Hz,1H),5.12(dd,J=3 1.2,5.3Hz,2H),4.65(dt,J=12.1,7.1Hz,2H),3.71-3.54(m,2H),3.50-3.41( m,1H),3.26(dd,J=14.1,5.7Hz,2H),3.11-3.05(m,1H),2.37(d,J=8.7Hz,3H).

[0288] Example 38: Preparation of Compound 38

[0289] Prepared by general synthetic method 3, a white solid was obtained with a yield of 8.0%.

[0290] 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),10.20(s,1H),7.81(d,J=8.6Hz,2H),7.73(d,J=8.7Hz,2H),2.70(s,3H),1.21(s,9H).

[0291] Example 39: Preparation of Compound 39

[0292] Prepared by general synthetic method 1, a light yellow solid was obtained with a yield of 62.0%.

[0293] 1 H NMR (400MHz, DMSO-d6) δ10.86(d,J=8.1Hz,1H),9.58(s,1H),7.81(d,J=8.4Hz,2H),7.64(d,J=8.6Hz,2H),5.38(d,J=5.3Hz,1H),4.91(d, J=5.6Hz,1H),4.71-4.60(m,2H),4.56(d,J=5.0Hz,1H),3.67(s,1H),3.54-3.47(m,3H),3.43(d,J=5.4Hz,1H),3.39(s,1H),2.37(s,3H).

[0294] Example 40: Preparation of Compound 40

[0295] Prepared by general synthetic method 1, a light yellow solid was obtained with a yield of 33.0%.

[0296] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),9.60(s,1H),7.79(d,J=8.5Hz,2H),7.63(d,J=8.4Hz,2H),4.72(s,1H),4.34(d,J=10.2Hz,1H),4. 16-4.08(m,2H),3.61-3.52(m,2H),3.26(d,J=8.8Hz,2H),3.10(dd,J=8.9,5.6Hz,2H),2.33(d,J=1.7Hz,3H),2.02(s,1H),1.76(s,3H).

[0297] Example 41: Preparation of Compound 41

[0298] Prepared by general synthetic method 1, a white solid was obtained with a yield of 47.0%.

[0299] 1 H NMR(400MHz,DMSO-d6)δ10.70(t,J=6.4Hz,1H),9.41(s,1H),8.08(s,2H),7 .81(d,J=8.5Hz,2H),7.63(d,J=8.6Hz,2H),3.83-3.60(m,3H),2.30(s,3H).

[0300] Example 42: Preparation of Compound 42

[0301] Prepared by general synthetic method 3, an off-white solid was obtained with a yield of 54.5%.

[0302] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),10.20(s,1H),7.82(d,J=8.5Hz,2H),7.71(d,J=8.5Hz ,2H),2.64(s,3H),2.42(t,J=7.3Hz,4H),1.88(s,6H),1.57-1.40(m,4H),1.30-1.19(m,2H).

[0303] Example 43: Preparation of Compound 43

[0304] Prepared by general synthetic method 3, a white solid was obtained with a yield of 20.0%.

[0305] 1H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.20(s,1H),7.81(d,J=8.6Hz,2H),7.71(d,J=8.7Hz,2 H),2.65(s,3H),2.42(t,J=7.4Hz,2H),1.60-1.47(m,2H),1.24(s,8H),0.84(t,J=6.9Hz,3H).

[0306] Example 44: Preparation of Compound 44

[0307] Prepared by general synthetic method 3, a white solid was obtained with a yield of 40.3%.

[0308] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),10.20(s,1H),7.82(d,J=8.6Hz,2H),7.70(d,J=8.7Hz,2H) ,2.65(s,3H),2.42(t,J=7.3Hz,2H),1.52(d,J=6.7Hz,2H),1.22(s,20H),0.84(t,J=6.8Hz,3H).

[0309] Example 45: Preparation of Compound 45

[0310] Prepared by general synthetic method 1, a yellow solid was obtained with a yield of 87.0%.

[0311] 1 H NMR (600MHz, DMSO-d6) δ10.87(s,1H),9.57(s,1H),7.80(d,J=8.5Hz,2H),7.63(d,J=8.4Hz,2H),4.67(s,1H),4.19(d,J=8.1Hz,1H),4.17-4 .03(m,3H),3.85(d,J=4.3Hz,1H),3.68(s,1H),3.43(m,J=10.9,9.5,5.5Hz,3H),3.27-3.24(m,1H),2.32(s,3H),1.22(q,J=7.1,6.5Hz,3H).

[0312] Example 46: Preparation of Compound 46

[0313] Prepared by general synthetic method 3, a white solid was obtained with a yield of 23.0%.

[0314] 1H NMR (400MHz, DMSO-d6) δ12.23(s,1H),10.20(s,1H),7.82(d,J=8.5Hz,2H),7.71(d,J=8.7Hz,2H),6.60(d,J=1.9Hz,1H),3.38(d,J=7 .0Hz,2H),2.66(d,J=11.0Hz,3H),2.42(t,J=7.4Hz,2H),1.97(d,J=1.8Hz,2H),1.50(m,J=19.5,15.0,7.5Hz,4H),1.28-1.21(m,2H).

[0315] Example 47: Preparation of Compound 47

[0316] Prepared by general synthetic method 1, a yellow solid was obtained with a yield of 23.0%.

[0317] 1 H NMR (400MHz, DMSO-d6) δ10.75(d,J=9.7Hz,1H),9.36(s,1H),7.79(d,J=8.6Hz,2H),7.62(d,J=8.7Hz,2H) ,7.02(s,1H),5.07(s,1H),3.68-3.43(m,6H),3.18(d,J=9.3Hz,2H),2.33(d,J=6.8Hz,3H),1.79(s,1H).

[0318] Example 48: Preparation of Compound 48

[0319] Prepared by general synthetic method 3, an off-white solid was obtained with a yield of 74.1%.

[0320] 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),10.44(s,1H),10.07(s,1H),8.52(s,3H),7.85(d,J=8.6Hz,2H),7.72(d,J=8. 6Hz,2H),7.51-7.44(m,2H),7.21-7.14(m,2H),4.27(t,J=6.6Hz,1H),3.69(s,3H),3.14-3.00(m,2H),2.72(s,3H).

[0321] Example 49: Preparation of Compound 49

[0322] Prepared by general synthetic method 3, a white solid was obtained with a yield of 77.6%.

[0323] 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),10.43(s,1H),10.07(s,1H),8.24(s,3H),7.85(d,J=8.5Hz,2H),7.72 (d,J=8.6Hz,2H),7.47(d,J=8.3Hz,2H),7.20(d,J=8.3Hz,2H),4.17(s,1H),3.11-2.98(m,2H),2.73(s,3H).

[0324] Example 50: Preparation of Compound 50

[0325] Prepared by general synthetic method 3, an off-white solid was obtained with a yield of 51.2%.

[0326] 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 8.54 (s, 3H), 7.83 (d, J = 8.6Hz, 2H), 7.72 (d, J=8.6Hz,2H),4.37(t,J=5.2Hz,1H),3.71(s,3H),3.20-3.07(m,2H),2.63(s,3H).

[0327] Example 51: Preparation of Compound 51

[0328] Prepared by general synthetic method 3, a white solid was obtained with a yield of 26.3%.

[0329] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),10.03-9.91(m,1H),8.34(s,1H),7.82(d,J=8.5Hz,2H),7.70(d,J=8.6Hz,2H),3.55-3.42(m,1H),3.36(s, 2H),3.06(dd,J=11.5,5.3Hz,2H),2.66(s,3H),1.81-1.70(m,1H),1.64 (td,J=14.1,12.8,5.9Hz,1H),1.51(m,J=12.1,6.6Hz,2H),1.11(s,1H).

[0330] Example 52: Preparation of Compound 52

[0331] Prepared by general synthetic method 3, a white solid was obtained with a yield of 26.5%.

[0332] 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),10.26(s,1H),8.55(s,3H),7.77(dd,J=40.6,8.4Hz,4H),4.08(s ,1H),3.76(d,J=13.2Hz,3H),2.66(s,3H),2.06(ddd,J=29.5,18.3,11.5Hz,2H),1.04(d,J=6.0Hz,1H).

[0333] Example 53: Preparation of Compound 53

[0334] Prepared by general synthetic method 3, a white solid was obtained with a yield of 82.2%.

[0335] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),9.95(s,1H),8.44-8.04(m,3H),7.82(d,J=8.4Hz,2H),7.70(d,J=8.4 Hz,2H),3.83(t,J=6.2Hz,1H),3.06(q,J=6.3Hz,2H),2.66(s,3H),1.76(m,J=7.2Hz,2H),1.52-1.20(m,5H).

[0336] Example 54: Preparation of Compound 54

[0337] Prepared by general synthetic method 3, a white solid was obtained with a yield of 71.8%.

[0338] 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),9.98(s,1H),8.63(s,3H),8.37(t,J=5.4Hz,1H),7.82(d,J=8.5Hz,2H),7.70(d ,J=8.7Hz,2H),4.13-4.04(m,1H),3.75(s,3H),3.23(m,J=26.8,6.8Hz,2H),2.67(s,3H),1.98(m,J=14.0,7.1Hz,2H).

[0339] Example 55: Preparation of Compound 55

[0340] Prepared by general synthetic method 3, a white solid was obtained with a yield of 22.3%.

[0341] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.65(s,1H),8.33(d,J=8.3Hz,1H),8.12(d,J=8 .5Hz,2H),8.08-7.98(m,7H),4.75(d,J=8.3Hz,1H),3.31(t,J=5.4Hz,2H),2.94(s,5H).

[0342] Example 56: Preparation of Compound 56

[0343] Prepared by general synthetic method 3, a white solid was obtained with a yield of 31.7%.

[0344] 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),10.24(s,1H),8.80(s,3H),7.81(d,J=8.6Hz, 2H),7.72(d,J=8.7Hz,2H),4.64-4.48(m,3H),3.86-3.68(m,3H),2.75-2.60(m,3H).

[0345] Example 57: Preparation of Compound 57

[0346] Prepared by general synthetic method 3, a white solid was obtained with a yield of 33.9%.

[0347] 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),10.36(s,1H),8.62(s,3H),7.77(dd,J=35.6, 8.5Hz,4H),4.40(s,1H),3.77(d,J=7.6Hz,3H),3.46(s,2H),2.65(d,J=16.7Hz,3H).

[0348] Example 58: Preparation of Compound 58

[0349] Prepared by general synthetic method 3, a white solid was obtained with a yield of 84.2%.

[0350] 1H NMR (400MHz, DMSO-d6) δ12.05(s,1H),10.25(s,1H),8.71(s,3H),7.81(d,J=8.6Hz,2H),7.73(d,J=8. 6Hz,2H),7.47-7.22(m,5H),5.35-5.21(m,2H),4.64(t,J=3.8Hz,1H),4.61-4.49(m,2H),2.62(s,3H).

[0351] Example 59: Preparation of Compound 59

[0352] Prepared by general synthetic method 3, a white solid was obtained with a yield of 56.7%.

[0353] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.31(s,1H),8.62(s,3H),7.96-7.60(m,4H),7.27(dd,J=36.5 ,8.6Hz,4H),4.32(t,J=6.3Hz,1H),3.70(d,J=8.0Hz,3H),3.15(qd,J=14.2,6.6Hz,2H),2.68(s,3H).

[0354] Example 60: Preparation of Compound 60

[0355] Prepared by general synthetic method 3, a white solid was obtained with a yield of 13.7%.

[0356] 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),10.23(s,1H),8.61(s,3H),7.77(dd,J=3 5.6,8.6Hz,4H),4.60(dd,J=12.0,2.5Hz,1H),4.56-4.35(m,2H),2.66(s,3H).

[0357] Example 61: Preparation of Compound 61

[0358] Prepared by general synthetic method 3, a white solid was obtained with a yield of 71.5%.

[0359] 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),10.24(s,1H),8.72(s,3H),7.81(d,J=8.5Hz,2H),7.73(d ,J=8.6Hz,2H),5.29-5.22(m,1H),4.44(s,1H),3.77(s,3H),2.65(s,3H),1.39(d,J=6.5Hz,3H).

[0360] Example 62: Preparation of Compound 62

[0361] Prepared by general synthetic method 3, a white solid was obtained with a yield of 73.8%.

[0362] 1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),10.23(s,1H),8.57(s,3H),7.77(dd,J=34. 3,8.7Hz,4H),5.36-5.19(m,1H),4.26(s,1H),2.66(s,4H),1.39(d,J=6.6Hz,3H).

[0363] Example 63: Preparation of Compound 63

[0364] Prepared by general synthetic method 3, a white solid was obtained with a yield of 43.9%.

[0365] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,1H),7.88-7.63(m,7H),4.53(d,J=8.2Hz,1H),4.18(t,J=5.6Hz,1H),2.71-2.59(m,3H),2.16(s,3H).

[0366] Example 64: Preparation of Compound 64

[0367] Prepared by general synthetic method 3, a white solid was obtained with a yield of 95.5%.

[0368] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.31(s,1H),8.39(s,3H),7.93-7. 67(m,4H),7.41-7.16(m,4H),4.20(s,1H),3.21-3.05(m,2H),2.68(s,3H).

[0369] Example 65: Preparation of Compound 65

[0370] Prepared by general synthetic method 3, a white solid was obtained with a yield of 84.1%.

[0371] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.31(s,1H),8.64(s,3H),7.93-7.65(m,4H),7.37(d,J=7.1Hz,3H),7.3 3-7.23(m,5H),7.18(d,J=8.5Hz,2H),5.16(q,J=12.3Hz,2H),3.18(ddd,J=26.4,15.2,8.9Hz,2H),2.68(s,3H).

[0372] Example 66: Preparation of Compound 66

[0373] Prepared by general synthetic method 3, a white solid was obtained with a yield of 55.6%.

[0374] 1 H NMR (400MHz, DMSO) δ12.46(s,1H),10.31(s,1H),8.64(s,3H),7.92-7.64(m,4H),7.27(dd,J=3 7.4,8.6Hz,4H),4.31(t,J=6.6Hz,1H),3.69(d,J=8.1Hz,3H),3.25-3.02(m,2H),2.68(s,3H).

[0375] Example 67: Preparation of Compound 67

[0376] Prepared by general synthetic method 3, a white solid was obtained with a yield of 95.8%.

[0377] 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.24(s,1H),8.81(s,3H),7.81(dt, J=35.3,8.6Hz,4H),4.70-4.41(m,3H),3.77(d,J=13.0Hz,3H),2.66(s,3H).

[0378] Example 68: Preparation of Compound 68

[0379] Prepared by general synthetic method 3, a white solid was obtained with a yield of 55.6%.

[0380] 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.25(s,1H),8.73(s,3H),7.91-7.67(m,4H) ,7.49-7.25(m,5H),5.28(dd,J=26.6,12.4Hz,2H),4.69-4.48(m,3H),2.62(s,3H).

[0381] Example 69: Preparation of Compound 69

[0382] Prepared by general synthetic method 3, obtained as a white oil with a yield of 44.7%.

[0383] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.31(s,1H),8.65(s,3H),8.06-7.60(m,4H),7.41-7.11(m,9 H), 5.16 (q, J = 12.3Hz, 2H), 4.38 (t, J = 6.5Hz, 1H), 3.16 (ddd, J = 21.6, 14.2, 6.7Hz, 2H), 2.68 (s, 3H).

[0384] Example 70: Preparation of Compound 70

[0385] Prepared by general synthetic method 3, a white solid was obtained with a yield of 80.6%.

[0386] 1 H NMR (400MHz, DMSO-d6) δ13.89(s,1H),12.46(s,1H),10.30(s,1H),8.44(s,3H),7.78(dd,J=46.6,8 .6Hz,4H),7.29(dd,J=50.4,8.6Hz,4H),4.19(s,1H),3.15(d,J=6.3Hz,2H),2.70(d,J=21.7Hz,3H).

[0387] Example 71: Preparation of Compound 71

[0388] Prepared by general synthetic method 3, a white solid was obtained with a yield of 48.9%.

[0389] 1H NMR (400MHz, DMSO-d6) δ12.14(s,1H),10.23(s,1H),8.58(s,3H),7.77(dd,J=35.3,8.7Hz,4H),4.70-4.32(m,3H),2.66(s,3H).

[0390] Example 72: Preparation of Compound 72

[0391] Prepared by general synthetic method 1, an off-white solid was obtained with a yield of 71.0%.

[0392] 1 H NMR(600MHz,DMSO-d6)δ10.85(d,J=7.5Hz,1H),9.58(s,1H),7.80(d,J=8.6Hz ,2H),7.64(d,J=8.7Hz,2H),5.62(d,J=5.6Hz,1H),5.35(d,J=5.5Hz,1H),5.23 (d,J=5.3Hz,1H),4.76(t,J=8.1Hz,1H),4.40-4.33(m,1H),4.13-4.07(m,1H) ,3.70(s,3H),3.59(s,1H),3.29-3.24(m,1H),3.17-3.09(m,2H),2.34(s,3H).

[0393] Example 73: Preparation of Compound 73

[0394] Prepared by general synthetic method 1, an off-white solid was obtained with a yield of 21.0%.

[0395] 1 H NMR (600MHz, DMSO-d6) δ10.87(d,J=7.7Hz,1H),9.57(s,1H),7.80(d,J=8.6Hz,2H),7.64(d,J=8.8Hz,2H),5.43(d,J=5.2Hz,1H),4.99(d,J=5.4Hz, 1H),4.85(d,J=5.2Hz,1H),4.69(d,J=7.7Hz,1H),4.22-4.16(m,2H),3.87 (d,J=4.6Hz,1H),3.69(d,J=13.8Hz,4H),3.46-3.41(m,2H),2.34(s,3H).

[0396] Example 74: Preparation of Compound 74

[0397] Prepared by general synthetic method 1, an off-white solid was obtained with a yield of 15.7%.

[0398] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.60(s,1H),7.80(d,J=8.7Hz,2H),7.64(d,J=8.9Hz,2H),5.28(s,1 H),5.18(s,2H),5.13-5.06(m,1H),4.96(s,2H),4.86(s,1H),4.55(s,2H),3.72(s,2H),2.43-2.35(m,3H).

[0399] Example 75: Preparation of Compound 75

[0400] Prepared by general synthetic method 3, a white solid was obtained with a yield of 37.7%.

[0401] 1 H NMR (600MHz, DMSO-d6) δ12.20(s,1H),10.17(s,1H),7.81(d,J=8.5Hz,2H),7.70(d,J=8.7Hz,2H),7.32-7.24 (m,2H),7.18(d,J=7.6Hz,3H),2.63(s,3H),2.61(d,J=7.5Hz,2H),2.44(t,J=7.3Hz,2H),1.89-1.82(m,2H).

[0402] Example 76: Preparation of Compound 76

[0403] Prepared by general synthetic method 3, a white solid was obtained with a yield of 59.1%.

[0404] 1 H NMR (600MHz, DMSO-d6) δ11.88(s,1H),9.96(s,1H),8.72(d,J=6.7Hz,1H),7.83(d,J=8.6Hz,2 H),7.70(d,J=8.7Hz,2H),4.29-4.16(m,1H),3.64(s,3H),2.64(s,3H),1.30(d,J=7.3Hz,3H).

[0405] Example 77: Preparation of Compound 78

[0406] Prepared by general synthetic method 3, a white solid was obtained with a yield of 56.5%.

[0407] 1 H NMR (600MHz, DMSO-d6) δ11.84(s,1H),9.95(s,1H),8.61(d,J=6.9Hz,1H),7.83(d,J=8.5Hz, 2H),7.70(d,J=8.6Hz,2H),4.11(p,J=7.2Hz,1H),2.63(d,J=21.5Hz,3H),1.41-1.15(m,3H).

[0408] Example 78: Preparation of Compound 79

[0409] Prepared by general synthetic method 3, a white solid was obtained with a yield of 57.4%.

[0410] 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),10.22(s,1H),8.38(s,3H),7.86-7.79(m,2H),7.71(d,J=8.7Hz,2H),3.94(s, 1H), 2.74(ddd,J=15.4,10.3,5.9Hz,1H),2.68-2.60(m,4H),2.15-2.08(m,1H),2.03(ddd,J=17.9,15.2,7.7Hz,1H).

[0411] Example 79: Preparation of Compound 80

[0412] Prepared by general synthetic method 3, a yellow solid was obtained with a yield of 71.3%.

[0413] 1 H NMR (600MHz, DMSO-d6) δ11.86(s,1H),9.92(s,1H),8.50(s,3H),8.22(s,1H),7.82(d,J=8.5Hz,2H),7.68(dd,J=15.0,8.7Hz, 2H),4.07-3.95(m,1H),3.75(d,J=5.7Hz,3H),3.05(d,J=5.5Hz,2H),2.71-2.61(m,3H),1.85-1.72(m,2H),1.48-1.36(m,4H).

[0414] Example 80: Preparation of Compound 81

[0415] Prepared by general synthetic method 3, a white solid was obtained with a yield of 83.5%.

[0416] 1 H NMR(600MHz,DMSO-d6)δ12.11(s,1H),10.20(s,1H),8.64(s,3H),7.81(d,J=8.6Hz,2H),7 .72(d,J=8.7Hz,2H),4.61-4.47(m,3H),3.80(s,3H),2.64(d,J=25.8Hz,3H),2.35(s,3H).

[0417] Example 81: Preparation of Compound 82

[0418] Prepared by general synthetic method 3, a white solid was obtained with a yield of 95.5%.

[0419] 1 H NMR(600MHz,DMSO-d6)δ12.12(s,1H),10.21(s,1H),8.61(s,3H),7.80(d,J=8 .6Hz,2H),7.72(d,J=8.7Hz,2H),4.63-4.47(m,3H),3.80(s,3H),2.66(s,3H).

[0420] Example 82: Preparation of Compound 83

[0421] Prepared by general synthetic method 3, a white solid was obtained with a yield of 70.1%.

[0422] 1 H NMR (600MHz, DMSO-d6) δ12.10(s,1H),10.20(s,1H),8.64(s,3H),7.85-7.76(m,2H),7.72(d,J=8.7Hz,2H),7.48(d,J=8.0Hz,2H),7.1 1(d,J=7.9Hz,2H),4.56(dd,J=9.0,3.5Hz,2H),4.50(dd,J=12.9,5.4Hz,1H),3.83-3.75(m,3H),2.63(d,J=24.1Hz,3H),2.29(s,3H).

[0423] Example 83: Preparation of Compound 84

[0424] Prepared by general synthetic method 3, a white solid was obtained with a yield of 86.2%.

[0425] 1H NMR (600MHz, DMSO-d6) δ12.11(s,1H),10.20(s,1H),8.61(s,3H),7.80(d,J=8.5Hz, 2H),7.72(d,J=8.6Hz,2H),4.61-4.42(m,3H),3.80(s,3H),2.64(d,J=27.0Hz,3H).

[0426] Example 84: Preparation of Compound 85

[0427] Prepared by general synthetic method 3, a white solid was obtained with a yield of 83.2%.

[0428] 1 H NMR(600MHz,DMSO-d6)δ12.11(s,1H),10.20(s,1H),8.66(s,3H),7.81(d,J=8.5Hz,2H),7 .72(d,J=8.5Hz,2H),4.58(d,J=3.9Hz,1H),4.57-4.48(m,2H),3.80(s,3H),2.66(s,3H).

[0429] Example 85: Preparation of Compound 86

[0430] Prepared by general synthetic method 3, a light yellow solid was obtained with a yield of 70.2%.

[0431] 1 H NMR(600MHz,DMSO-d6)δ12.11(s,1H),10.20(s,1H),8.63(s,3H),7.81(d,J=8.5Hz,2H),7 .73(d,J=8.6Hz,2H),4.59(d,J=5.3Hz,1H),4.58-4.48(m,2H),3.80(s,3H),2.66(s,3H).

[0432] Example 86: Preparation of Compound 87

[0433] Prepared by general synthetic method 3, a white solid was obtained with a yield of 42.5%.

[0434] 1H NMR (600MHz, DMSO-d6) δ12.12(d,J=16.9Hz,1H),10.20(s,1H),8.64(s,3H),7.81(d,J=8.4Hz,2H),7.72(d,J=8.5Hz,2H),4.60-4.53(m,2H),4.50(dd ,J=12.6,5.1Hz,1H),2.67(d,J=17.8Hz,5H),2.24(dt,J=18.0,3.8Hz,2H) ,1.94(t,J=4.6Hz,2H),1.89-1.83(m,2H),1.29-1.25(m,4H),0.75(s,6H).

[0435] Example 87: Preparation of Compound 88

[0436] Prepared by general synthetic method 3, a colorless oil was obtained with a yield of 56.9%.

[0437] 1 H NMR (600MHz, DMSO-d6) δ12.12(s,1H),10.20(s,1H),8.74(s,3H),7.81(d,J=8.5Hz,2H),7.72(d, J=8.5Hz,2H),4.61-4.50(m,3H),4.25(qt,J=7.8,4.1Hz,2H),2.66(s,3H),1.24(t,J=7.1Hz,3H).

[0438] Example 88: Preparation of Compound 89

[0439] Prepared by general synthetic method 3, a white solid was obtained with a yield of 64.5%.

[0440] 1 H NMR (600MHz, DMSO-d6) δ12.13(s,1H),10.20(s,1H),8.72(s,3H),7.80(d,J=8.5Hz,2H),7.71(d,J=8.6Hz,2H),4.61-4.51(m,3H),4.2 4(dt,J=10.9,6.5Hz,1H),4.17(dt,J=10.8,6.4Hz,1H),2.66(s,3H),1.65-1.57(m,2H),1.34(p,J=7.5Hz,2H),0.86(t,J=7.4Hz,3H).

[0441] Example 89: Preparation of Compound 90

[0442] Prepared by general synthetic method 3, a white solid was obtained with a yield of 56.6%.

[0443] 1 H NMR (600MHz, DMSO-d6) δ12.15(s,1H),10.21(s,1H),8.68(s,3H),7.80(d,J=8.5Hz,2H),7.71(d,J=8.6Hz,2H),4.54(d,J=3.4Hz,3H),4.25(dt,J =12.5,6.5Hz,1H),4.15(dt,J=11.0,6.6Hz,1H),2.66(s,3H),1.60(t,J= 8.3Hz,2H),1.30(t,J=7.4Hz,2H),1.25-1.20(m,4H),0.84-0.79(m,3H).

[0444] Example 90: Preparation of Compound 91

[0445] Prepared by general synthetic method 3, a white solid was obtained with a yield of 44.5%.

[0446] 1 H NMR (600MHz, DMSO-d6) δ12.14(s,1H),10.21(s,1H),8.80(s,3H),7.81(d,J=8.4Hz,2H),7.72(d ,J=8.5Hz,2H),5.07-4.99(m,1H),4.59-4.46(m,3H),2.66(s,3H),1.25(dd,J=10.4,6.1Hz,6H).

[0447] Example 91: Preparation of Compound 92

[0448] Prepared by general synthetic method 3, a white solid was obtained with a yield of 41.3%.

[0449] 1 H NMR (600MHz, DMSO-d6) δ12.11(s,1H),10.19(s,1H),8.74(s,3H),7.81(d,J=8.4Hz,2H),7.72(d,J=8.5Hz,2 H),4.89(s,1H),4.60-4.52(m,3H),4.22(q,J=4.3Hz,2H),3.61(t,J=4.9Hz,2H),2.66(s,3H),2.41(s,1H).

[0450] Example 92: Preparation of Compound 93

[0451] Prepared by general synthetic method 3, a white solid was obtained with a yield of 48.5%.

[0452] 1 H NMR (600MHz, DMSO-d6) δ12.11(s,1H),10.19(s,1H),8.78(s,3H),7.82(d,J=8.5Hz,2H),7.72(d,J=8.5Hz,2H),5.01(s,1H),4.70( s,1H),4.63-4.52(m,3H),4.27(dd,J=11.0,3.8Hz,1H),4.12-4.07(m,1H),3.70(t,J=5.2Hz,1H),3.45-3.34(m,2H),2.66(s,3H).

[0453] Example 93: Preparation of Compound 94

[0454] Prepared by general synthetic method 3, a white solid was obtained with a yield of 95.0%.

[0455] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.21(s,1H),8.60(s,3H),7.80(d,J=8.6Hz,2H),7.72(d,J=8. 7Hz,2H),5.05(p,J=6.2Hz,1H),4.52(s,3H),2.66(s,3H),2.34(s,7H),1.26(dd,J=10.0,6.2Hz,6H).

[0456] Example 94: Preparation of Compound 95

[0457] Prepared by general synthetic method 3, a white solid was obtained with a yield of 85.6%.

[0458] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),10.21(s,1H),8.58(s,3H),7.80(d,J=8.6Hz,2H),7.72( d,J=8.7Hz,2H),5.06(h,J=6.2Hz,1H),4.52(s,3H),2.66(s,3H),1.26(dd,J=9.9,6.2Hz,6H).

[0459] Example 95: Preparation of Compound 96

[0460] Prepared by general synthetic method 3, a white solid was obtained with a yield of 58.0%.

[0461] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.21(s,1H),8.65-8.52(m,3H),7.80(d,J=8.6Hz,2H),7.72(d,J=8.6Hz,2H),7.50-7 .45(m,2H),7.11(d,J=7.9Hz,2H),5.05(p,J=6.2Hz,1H),4.52(s,3H),2.66(s,3H),2.29(s,3H),1.26(dd,J=9.7,6.2Hz,6H).

[0462] Example 96: Preparation of Compound 97

[0463] Prepared by general synthetic method 3, a white solid was obtained with a yield of 46.0%.

[0464] 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),10.21(s,1H),8.57(s,3H),7.80(d,J=8.6Hz,2H),7.72( d,J=8.6Hz,2H),5.05(p,J=6.2Hz,1H),4.52(s,3H),2.66(s,3H),1.26(dd,J=9.9,6.2Hz,6H).

[0465] Example 97: Preparation of Compound 98

[0466] Prepared by general synthetic method 3, a white solid was obtained with a yield of 50.4%.

[0467] 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.21(s,1H),8.61(s,3H),7.81(d,J=8.6Hz,2H),7.72( d,J=8.6Hz,2H),5.06(h,J=6.2Hz,1H),4.53(s,3H),2.66(s,3H),1.26(dd,J=10.1,6.3Hz,6H).

[0468] Example 98: Preparation of Compound 99

[0469] Prepared by general synthetic method 3, a white solid was obtained with a yield of 50.4%.

[0470] 1 H NMR (600MHz, DMSO-d6) δ12.12(d,J=16.9Hz,1H),10.20(s,1H),8.64(s,3H),7.81(d,J=8.4Hz,2H),7.72(d,J=8.5Hz,2H),4.60-4.53(m,2H),4. 50(dd,J=12.6,5.1Hz,1H),2.67(d,J=17.8Hz,5H),2.24(dt,J=18.0,3.8Hz,2H),1.29-1.25(m,4H),1.26(dd,J=10.1,6.3Hz,6H),0.75(s,6H).

[0471] Example 99: Preparation of Compound 100

[0472] Prepared by general synthetic method 3, a white solid was obtained with a yield of 47.5%.

[0473] 1 H NMR (600MHz, DMSO-d6) δ12.13(s,1H),10.20(s,1H),8.80(s,3H),7.81(d,J=8.4Hz,2H),7.72(d,J=8.5 Hz,2H),5.06-5.02(m,1H),4.59-4.52(m,2H),4.48(s,1H),2.66(s,3H),1.25(dd,J=15.5,6.2Hz,6H).

[0474] Example 100: Preparation of Compound 102

[0475] Prepared by general synthesis method 3 or general synthesis method 4, a yellow-white solid was obtained with a yield of 48.5%.

[0476] 1 H NMR (600MHz, DMSO-d6) δ12.48(s,1H),7.88-7.87(m,2H),7.57-7.55(m,2H),2.40(s,3H).

[0477] General synthetic method 4:

[0478] Formula (H) (1 equivalent) was dispersed in DMAC or DMF and stirred until dissolved. The mixture was cooled to -10°C, and then 60% NaH (1.5 equivalents) was added. The reaction mixture was stirred at -10°C for 30 minutes, and then chloromethyl p-nitrophenolate (1.3 equivalents) was slowly added. The reaction mixture was slowly warmed from -10°C to room temperature for reaction. After the reaction was completed, EA was added, and the mixture was washed three times with saturated ammonium chloride and once with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the self-cyclized product of formula (H).

[0479] The self-cyclized product of formula (H) (1 equivalent) is dispersed in ACN, cooled to 0°C, cesium carbonate (1.5 equivalents) or potassium carbonate (1.5-2 equivalents) is added, stirred for half an hour, and an ACN solution of formula (J) (1.5 equivalents) is slowly added. The reaction is slowly heated from 0°C to reflux. After the reaction is completed, EA is added, the mixture is washed three times with saturated ammonium chloride and once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography, and then subjected to acid, base, or palladium-carbon reduction deprotection or non-deprotection to obtain formula (I).

[0480] Alternatively, the compound of formula (K) (1 equivalent) is dispersed in DMAC or DMF, cooled to 0°C, NaH (1.5 to 2 equivalents) is added, stirred for half an hour, and a DMF solution of formula (J) (1.5 equivalents) is slowly added. The reaction liquid is slowly heated from 0°C to 60°C for reaction. After the reaction is completed, EA is added, the mixture is washed three times with saturated ammonium chloride and once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the product purified by column chromatography is then subjected to acid, base, or palladium-carbon reduction deprotection or non-deprotection to obtain the compound of formula (I).

[0481] Example 101: Preparation of Compound 104

[0482] Prepared by general synthetic method 4, a yellow solid was obtained with a yield of 32.0%.

[0483] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.3Hz,2H),7.54(d,J=8.2Hz,2H),3.44(s,3H),2.63(s,3H).

[0484] Example 102: Preparation of Compound 105

[0485] Prepared by general synthetic method 4, a white solid was obtained with a yield of 9.0%.

[0486] 1H NMR (600MHz, DMSO-d6) δ7.90(dd,J=7.6,1.3Hz,2H),7.64-7.59(m,2H),7.41-7.35(m,4H),7.32(ddt,J=8.4,5.8,2.0Hz,1H),5.25(s,2H),2.53(s,3H).

[0487] Example 103: Preparation of Compound 106

[0488] Prepared by general synthetic method 4, a yellow solid was obtained with a yield of 64.0%.

[0489] 1 H NMR (400MHz, CDCl3) δ7.77 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.3Hz, 2H), 4.06 (q, J = 7.1Hz, 2H), 2.70 (s, 3H), 1.38 (t, J = 7.1Hz, 3H).

[0490] Example 104: Preparation of Compound 107

[0491] Prepared by general synthetic method 4, a white solid was obtained with a yield of 37.0%.

[0492] 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 8.4Hz, 2H), 7.57 (d, J = 8.2Hz, 2H), 4.85 (s, 2H), 3.73 (s, 3H), 2.61 (s, 3H).

[0493] Example 105: Preparation of Compound 108

[0494] Prepared by general synthetic method 4, a pink solid was obtained with a yield of 46.0%.

[0495] 1 H NMR (400MHz, DMSO-d6) δ13.54(s,1H),7.90(d,J=8.3Hz,2H),7.57(d,J=8.2Hz,2H),4.76(s,2H),2.60(s,3H).

[0496] Example 106: Preparation of Compound 109

[0497] Prepared by general synthetic method 4, a white solid was obtained with a yield of 22.0%.

[0498] 1 H NMR (600MHz, DMSO-d6) δ7.89 (d, J = 8.4Hz, 2H), 7.58-7.41 (m, 2H), 3.46 (s, 3H), 2.92 (q, J = 7.6Hz, 2H), 1.30 (t, J = 7.6Hz, 3H).

[0499] Example 107: Preparation of Compound 110

[0500] Prepared by general synthetic method 4, a white solid was obtained with a yield of 47.0%.

[0501] 1 H NMR (400MHz, DMSO-d6) δ7.90(d,J=8.4Hz,2H),7.57(d,J=8.2Hz,2H),5.67(d,J=7.8Hz,2H),2.75(s,3H).

[0502] Example 108: Preparation of Compound 111

[0503] Prepared by general synthetic method 4, a white solid was obtained with a yield of 8.1%.

[0504] 1 H NMR(400MHz, DMSO-d6)δ7.88(d,J=8.4Hz,2H),7.55(s,2H),4.73(p,J=8.4Hz, 1H),2.70(s,3H),2.07-1.86(m,4H),1.78(s,2H),1.49(q,J=5.6,4.8Hz,2H).

[0505] Example 109: Preparation of Compound 112

[0506] Prepared by general synthetic method 4, a white solid was obtained with a yield of 29.2%.

[0507] 1 H NMR (400MHz, DMSO-d6) δ8.04-7.87(m,2H),7.73-7.52(m,2H),5.51(tt,J=5.2,2.3Hz,1H),2.48(s,3H),1.78(dtd, J=14.2,8.1,5.4Hz,2H),1.70-1.54(m,2H),1.47(qq,J=10.2,4.6,4.2Hz,2H),1.34(ddd,J=12.5,8.3,4.7Hz,2H).

[0508] Example 110: Preparation of Compound 113

[0509] The compound was prepared by general method synthesis method 4 to obtain a white solid with a yield of 74.0%.

[0510] 1 H NMR (400MHz, DMSO-d6) δ8.31-8.22(m,2H),7.88(dd,J=20.8,7.9Hz,3H),7.66(t,J=7.6Hz,4H),2.42(s,3H).

[0511] Example 111: Preparation of Compound 114

[0512] Prepared by general synthetic method 4, a white solid was obtained with a yield of 6.0%.

[0513] 1 H NMR (400MHz, DMSO-d6) δ7.91 (d, J = 8.4Hz, 2H), 7.66-7.51 (m, 2H), 5.93 (s, 2H), 2.70 (s, 3H), 1.17 (s, 9H).

[0514] Example 112: Preparation of Compound 115

[0515] Prepared by general synthetic method 4, a white solid was obtained with a yield of 32.0%.

[0516] 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 8.4Hz, 2H), 7.63-7.50 (m, 2H), 5.91 (s, 2H), 2.71 (s, 3H), 2.09 (s, 3H).

[0517] Example 113: Preparation of Compound 116

[0518] Prepared by general synthetic method 4, a yellow solid was obtained with a yield of 1.7%.

[0519] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.3Hz,2H),7.56(d,J=8.2Hz,2H),3.79(d,J=7.5Hz,2H),2.65(s,3H),2.22-1.99(m,1H),0.92(d,J=6.7Hz,6H).

[0520] Example 114: Preparation of Compound 117

[0521] Prepared by general synthetic method 4, a white solid was obtained with a yield of 56.0%.

[0522] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J = 8.3Hz, 2H), 7.38 (d, J = 8.2Hz, 2H), 2.71 (s, 3H), 2.56 (s, 3H).

[0523] Example 115: Preparation of Compound 118

[0524] Prepared by general synthetic method 4, a white solid was obtained with a yield of 8.6%.

[0525] 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.4Hz,2H),7.58(d,J=8.2Hz,2H),6.20(s,1H), 4.83-4.76(m,1H),4.42(t,J=6.0Hz,2H),3.01(t,J=6.0Hz,2H),1.29-1.14(m,6H).

[0526] Example 116: Preparation of Compound 119

[0527] Prepared by general synthetic method 4, a white solid was obtained with a yield of 55.0%.

[0528] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=7.8Hz,2H),7.90(d,J=8.3Hz,2H),7.71(t,J=7.4Hz,1H),7.62-7.50(m,4H),6.21(s,2H),2.81(s,3H).

[0529] Example 117: Preparation of Compound 120

[0530] Prepared by general synthetic method 4, a yellow liquid was obtained with a yield of 97.0%.

[0531] 1H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.3Hz,2H),7.58(d,J=8.2Hz,2H),5.96(s,2H),4.23-4.16(m,2H),2.71(s,3H),1.23(t,J=7.1Hz,3H).

[0532] Example 118: Preparation of Compound 121

[0533] The compound was prepared by general method synthesis method 4 to obtain a white solid with a yield of 47.4%.

[0534] 1 H NMR (400MHz, CD3OD) δ7.80 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.2Hz, 2H), 3.28 (s, 3H), 5.70 (d, J = 8.9Hz, 2H).

[0535] Example 119: Preparation of Compound 122

[0536] The compound was prepared by general method synthesis method 4 to obtain a white solid with a yield of 40.0%.

[0537] 1 H NMR (400MHz, DMSO-d6) δ7.91 (d, J = 8.4Hz, 2H), 7.58 (d, J = 8.3Hz, 2H), 5.93 (s, 2H), 2.70 (s, 3H), 2.66-2.57 (m, 1H), 1.11 (d, J = 7.0Hz, 6H).

[0538] Example 120: Preparation of Compound 123

[0539] The compound was prepared by general method synthesis method 4 to obtain a yellow solid with a yield of 64.0%.

[0540] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.4Hz,2H),7.58(d,J=8.2Hz,2H),5.96(s,2H),4.81(p,J=6.2Hz,1H),2.70(s,3H),1.24(d,J=6.2Hz,6H).

[0541] Test example

[0542] Experimental Example 1: Distribution of the test drug in the brain and spinal cord of mice

[0543] Methods: Adult male ICR mice aged 6-8 weeks, weighing 30 ± 20 g, were randomly divided into groups of 3. All mice were fasted for 12 hours before the experiment and had free access to water. All groups were administered 50 mg / kg of teriflunomide or the other examples by oral gavage. Eyeballs were removed and 0.5 mL of blood was collected in centrifuge tubes 0.5, 1, 2, and 4 hours after administration. Mice were sacrificed by cervical dislocation, and the heart, liver, spleen, lungs, kidneys, brain, stomach, small intestine, thymus, pancreas, and spinal cord were removed by dissection. Surface blood was washed with saline, the sample was blotted dry, and approximately 50 mg was weighed into a homogenization tube. 500 μL of saline was added. Homogenization parameters were set to 40 s x 3, with a 1-min interval, a speed of 6.00 m / s, and a temperature of 4°C. After vortexing, a certain volume was diluted 1-fold with methanol. This was then diluted 4-fold with a mixed extractant (acetonitrile:methanol = 7:3) containing 0.2% formic acid. After vortexing for 3 minutes, the sample was centrifuged at 13,000 rpm at 4°C for 10 minutes. 5 μL of the supernatant was sampled and analyzed. Pharmacokinetic parameters for each example were calculated using Winnonlin software. The results are shown in Table 1.

[0544] The results showed that the exposure of the active metabolites of the compound of the present invention in the brain and spinal cord of mice was significantly higher than that of teriflunomide in the brain and spinal cord. The mass spectrometry fragment structure of "other active metabolites" in Table 1 is compound 102:

[0545] Table 1. Distribution parameters of the tested drugs in the mouse brain and spinal cord

[0546] Test Example 2: Tolerance study of test drugs in mice

[0547] Methods: SPF male ICR mice, weighing 30 ± 2 g, were randomly divided into 6 groups, half male and half female. Teriflunomide, a control drug, and the compound of the present invention were intraperitoneally injected once daily for 4 consecutive days at a volume of 10 μL / g. Mice were observed for mortality within 4 hours after administration and observed for 7 days after discontinuation of administration. Body weight, motor coordination, urination and defecation, mental state, eyelid signs, respiration, and fur were observed and recorded over the 4-day period.

[0548] Table 2. Tolerance test of the tested drugs

[0549] Test Example 3: Effects on acetic acid-induced writhing reaction in mice

[0550] Methods: Kunming mice, 6-8 weeks old and weighing 20±2g, were divided into male and female groups, with eight mice per group. They were orally administered with normal saline (model group), the compound of the present invention, or the control drug, teriflunomide, at a dose of 40 mg / kg (10 μL / g). Thirty minutes after administration, each mouse was intraperitoneally injected with 0.2 mL of 0.6% acetic acid solution. The number of writhing responses (abdominal indentation accompanied by trunk twisting, hip elevation, and hind limb extension) within 20 minutes was observed and recorded, and the writhing inhibition rate was calculated.

[0551] Writhing inhibition rate (%) = (average number of writhing times in the control group - average number of writhing times in the drug-treated group) / average number of writhing times in the control group × 100%.

[0552] The results showed that the compounds of the present invention in Table 3 all had better analgesic effects than teriflunomide.

[0553] Table 3. Comparison of acetic acid-induced writhing reactions in mice of each group

[0554] Test Example 4: Effect on Experimental Autoimmune Encephalomyelitis (EAE) Mice

[0555] Methods: The MOG35-55 antigen was diluted to 2 mg / mL in phosphate buffered saline and emulsified with complete Freund's adjuvant (final H37Ra concentration: 5 mg / mL) at a 1:1 ratio. After emulsification, mice were anesthetized and immobilized. Female C57BL / 6 mice, aged 8-10 weeks and weighing 18-20 g, were injected subcutaneously at two points on either side of the spine. On the day of immunization and 48 hours later, 0.25 mL of PTX (250 ng / mouse) was injected intraperitoneally to establish an EAE model in mice.

[0556] After the mice became ill, they were divided into groups: a normal saline group, a compound of the present invention group (Compound 24, Compound 28, Compound 37, Compound 52, Compound 53, Compound 59, Compound 65, Compound 66, Compound 67, Compound 71, Compound 88, Compound 89, and Compound 91), and a control group (Teriflunomide). The dose of each group was 5 mg / kg, and the administration volume was 10 μL / g. The mice were administered for 14 consecutive days. The behavior of the mice (e.g., coat color, behavior, diet, etc.) was observed at the same time point every day. The mice were weighed and recorded every other day. Neurological function was scored according to the Kono 5-point scale (0 = no disease; 1 = tail weakness; 2 = mild hind limb weakness; 3 = severe hind limb paralysis; 4 = quadriplegia; 5 = near death or death). The neurological function scores of the mice are shown in Figure 1.

[0557] After 14 days of administration, serum, brain tissue, and spinal cord were collected for pathology and inflammatory factor testing of IL-17A and IFN-γ.

[0558] As shown in Figure 2, the LFB staining results show that the myelin sheath structure of the spinal cord tissue in the normal group is clear and intact, with no demyelination. In the spinal cord tissue of the model group, demyelination areas of varying sizes can be seen, appearing as blue low-stained areas or white destained areas, with varying degrees of loose myelin structure. Compared with the model group, the areas of blue low-stained areas or white destained areas in the spinal cord tissue of the test drug groups (compound 28, compound 65, and compound 66) were significantly reduced, and the demyelination areas of the compound 28, 37, 59, 65, 66, and 67 groups were significantly smaller than those of the marketed drug teriflunomide.

[0559] As shown in Figure 3, the detection results of the inflammatory factor IL-17A showed that the IL-17A inflammation level in the model group was significantly higher than that in the normal group, and teriflunomide was able to reduce the expression of IL-17A in mice. Compared with the model group, compounds 53, 65, 67, 88, 89, and 91 of the present invention significantly reduced the level of IL-17A in the spinal cord, and had obvious advantages over teriflunomide.

[0560] As shown in Figure 4, the detection results of the inflammatory factor IFN-γ showed that the inflammatory level of IFN-γ in the model group was significantly increased compared with the normal group, and teriflunomide was able to reduce the expression of IFN-γ in the spinal cord of mice. Compared with the model group, compounds 24, 28, 37, 53, 59, 65, 66, 67, 71, 88, 89, and 91 of the present invention significantly reduced the level of IFN-γ in the spinal cord, and had obvious advantages over teriflunomide.

[0561] The results showed that compared with teriflunomide, the compound of the present invention can significantly alleviate the clinical symptoms of mice with multiple sclerosis and neuromyelitis optica model EAE, reduce the levels of inflammatory factors IL-17A and IFN-γ, and reduce the area of ​​demyelination in the spinal cord. Therefore, the compound of the present invention has a more significant therapeutic effect on central nervous system diseases such as multiple sclerosis and neuromyelitis optica.

[0562] Test Example 5: Anticancer Activity

[0563] Method: Using Luminescent cell viability assay experiment. Collect logarithmic phase tumor cells, adjust the cell suspension concentration, and inoculate them into a black bottom 96-well plate (1200 786-O cells / well, 1500 A549 cells / well, 3000 A498, PC3 and DU145 cells / well, 1500 H460 cells / well, 3500 LNCaP cells / well). After culturing overnight, add the compound to the well and incubate in a 37°C incubator for 72 hours. Then, remove the culture medium, add the viability assay reagent, shake at 150 rpm / min to mix for 2 minutes, incubate at room temperature (25°C) for 10 minutes, and immediately detect the chemiluminescence intensity with an enzyme reader. The cell survival rate is calculated based on the chemiluminescence intensity value measured by the enzyme reader. The calculation formula is as follows: Cell survival rate (%) = (drug group - blank group) / (control group - blank group) × 100%

[0564] The results showed that the compounds of the present invention in Table 4 showed better anticancer efficacy than teriflunomide.

[0565] Table 4. Anticancer activity of the compounds of the present invention

[0566] Test Example 6: Inhibition of proliferation of rat splenocytes stimulated by lipopolysaccharide (LPS)

[0567] Methods: Splenocytes of 11-week-old female SD rats were collected and cultured at 2.5×10 6 The cells were inoculated at a density of 100 μg / mL in a 96-well plate and cultured overnight. DMSO, teriflunomide, and 50 μL of test drugs (Compound 6, Compound 20, Compound 24, Compound 52, Compound 53, Compound 56, Compound 59, Compound 66, Compound 67, Compound 88, Compound 91, Compound 113, Compound 114, Compound 115, Compound 118) (0.1, 1, 10, 100 μM) were added to the wells. The cells were incubated in a 37°C incubator for 2 hours, and then 10 μg / mL LPS was added for 24 hours. MTT assay was performed to calculate the cell survival rate. The cell survival rate was calculated based on the values ​​measured by the microplate reader. The calculation formula is as follows: Cell survival rate (%) = (OD 加药组 -OD 空白组 ) / (OD 对照组 -OD 空白组 )×100%

[0568] As shown in FIG5 , the results show that the compound of the present invention is a more effective drug for inhibiting lymphocyte proliferation than teriflunomide.

Claims

1. A compound represented by formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, in: R1 is selected from: -H, alkyl, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 ; R2 is selected from: -H, alkyl, aryl, cycloalkyl, -alkylene-aryl, -alkylene-C(=O)OH, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ; Alternatively, R1 and R2 are connected to each other and, together with the nitrogen atom to which they are connected, form an optionally substituted aliphatic heterocyclic group; or R1 and R2 together with the nitrogen atom to which they are attached are X is selected from -H, or X and R1 together form a cyclic amide structure R2' is selected from: -H, alkyl, aryl, cycloalkyl, -alkylene-aryl, -alkylene-C(=O)OH, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ; Q is selected from O, -O-cycloalkyl; R3 is independently selected from: -H, alkyl or -alkylene-OC(=O)-OR 4-2 ; A is selected from: -C(=O)-, alkylene; R 4-1 Selected from: alkyl, hydroxy, amino, carboxyl, halogen, nitro, cyano; preferably R 4-1 is an alkyl group; R 4-2 Selected from: -OH, aryl, alkyl, alkoxy, -alkenyl-carboxyl, -alkenyl-alkoxyacyl, -alkylene-R 4-9 ; R 4-3 , R 4-4 are the same or different, each independently selected from: H, alkyl; Or, R 4-3 and R 4-4 are bonded to each other and to the nitrogen atom to which they are bonded to form an optionally substituted aliphatic heterocyclic group; R 4-5 is selected from: H, alkyl, -alkylene-aryl; Linker is an optional group, which when present is selected from: alkylene, -B-alkylene-, -B-alkylene-arylene-, -B-arylene-alkylene-; Each B is independently selected from -O-, -S-, and -NH-; R 4-6 for Each R' is independently selected from: -H, alkyl, -alkylene-aryl, hydroxy-substituted alkyl; Each R 4-7 and R 4-8 are the same or different, and are independently selected from: H, alkyl, -alkylene-aryl; R 4-9 Selected from: Aryl, -C(=O)O-alkyl; The "optionally substituted monosaccharide group" refers to one or more hydrogen atoms on the monosaccharide group being unsubstituted or substituted by a substituent selected from: -C(=O)OR 4-10 ; The monosaccharide group in the optional monosaccharide group is selected from the following monosaccharide groups, and the monosaccharide 1-position substitution is α substitution or β substitution or both: The monosaccharide 2-position is substituted with α configuration or β configuration or both: Each R 4-10 Selected from: H, alkyl; R 4-11 Selected from: alkyl, aryl; "Optionally substituted alicyclic group" means that one or more hydrogen atoms on the alicyclic group are unsubstituted or substituted with a substituent, and the substituents in the "optionally substituted alicyclic group" are each independently selected from the group consisting of hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkylthio, alkanoyl, and hydroxy-substituted aryl; The "hydroxy-substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms are not substituted or are substituted by a hydroxy group.

2. The compound of formula (I) according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, in: R1 and R2 are the same or different and are independently selected from: -H, alkyl, -alkylene-C(=O)O-alkyl, -S(=O)2R 4-1 , optionally substituted monosaccharide, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 ; Alternatively, R1 and R2 are connected to each other and, together with the nitrogen atom to which they are connected, form an optionally substituted aliphatic heterocyclic group; or R1 and R2 together with the nitrogen atom to which they are attached are X is selected from -H, or X and R1 together form a cyclic amide structure R3 is selected from: -H, alkyl; A is selected from: -C(=O)-, alkylene; R 4-1 Selected from: alkyl, hydroxyl, amino, carboxyl, halogen, nitro, cyano; preferably R 4-1 is an alkyl group; R 4-2 Selected from: -OH, aryl, alkyl, alkoxy, -alkenyl-carboxyl, -alkenyl-alkoxyacyl, -alkylene-R 4-9 ; R 4-3 , R 4-4 are the same or different, each independently selected from: H, alkyl; Or, R 4-3 and R 4-4 are bonded to each other and to the nitrogen atom to which they are bonded to form an optionally substituted aliphatic heterocyclic group; R 4-5 Selected from: H, alkyl, aryl; Linker is an optional group, which when present is selected from: alkylene, -B-alkylene-, -B-alkylene-arylene-, -B-arylene-alkylene-; Each B is independently selected from: -O-, -S-, -NH-; R 4-6 for Each R' is independently selected from: -H, alkyl, -alkylene-aryl, hydroxy-substituted alkyl; R 4-7 and R 4-8 are the same or different, and are independently selected from: H, alkyl, -alkylene-aryl; R 4-9 Selected from: Aryl, -C(=O)O-alkyl; The "optionally substituted monosaccharide group" refers to one or more hydrogen atoms on the monosaccharide group being unsubstituted or substituted by a substituent selected from: -C(=O)OR 4-10 ; The monosaccharide group in the optional monosaccharide group is selected from the following monosaccharide groups, and the monosaccharide 1-position substitution is α substitution or β substitution or both: The monosaccharide 2-position is substituted with α configuration or β configuration or both: R 4-10 Selected from: H, alkyl; The substituents in the "optionally substituted aliphatic heterocyclic group" are each independently selected from: hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkylthio, alkanoyl, hydroxy-substituted aryl; The "hydroxy-substituted alkyl group" refers to an alkyl group in which one or more hydrogen atoms are not substituted or are substituted by a hydroxy group.

3. The compound of formula (I) according to claim 1 or 2, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: Optionally, the halogen is selected from: F, Cl, Br, I; Optionally, the alkyl moieties in the “alkyl”, “alkanoyl”, “hydroxy-substituted alkyl”, “alkoxy”, “-C(=O)O-alkyl” and “alkoxyacyl” are each independently C 1-20 A straight chain or branched chain alkyl group, optionally C 1-17 A straight chain or branched chain alkyl group, optionally C 1-13 A straight chain or branched chain alkyl group, optionally C 1-10 A straight chain or branched chain alkyl group, optionally C 1-7 A straight chain or branched chain alkyl group, optionally C 1-5 Straight chain or branched alkyl, optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or heptadecyl; optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl; Optionally, the alkyl moieties in the "-alkylene-C(=O)O-alkyl" are each independently C 1-20 A straight or branched chain alkyl group, optionally C 1-17 A straight or branched chain alkyl group, optionally C 1-13 A straight or branched chain alkyl group, optionally C 1-10 A straight or branched chain alkyl group, optionally C 1-7 A straight or branched chain alkyl group, optionally C 1-5 Straight chain or branched alkyl, optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, or heptadecyl; optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl; Alternatively, "-alkylene-", "-alkylene-aryl", "-B-alkylene-", "-B-alkylene-arylene-", "-B-arylene-alkylene-", "-O-alkylene-R 4-5 "、"-alkylene-R 4-9 The "alkylene" mentioned in the above is C 1-20 A straight or branched chain alkylene group, optionally C 1-17 A straight chain or branched alkylene group, optionally C 1-10 A straight or branched chain alkylene group, optionally C 1-8 A straight or branched chain alkylene group, optionally C 1-5 A straight or branched chain alkylene group, optionally C 1-3 Straight-chain or branched alkylene, optionally, is methylene, ethylene, isoethylidene, n-propylene, isopropylene, n-butylidene, isobutylidene, tert-butylidene, sec-butylidene, n-pentylidene, isopentylidene, neopentylidene, tert-pentylidene, n-hexylidene, isohexylidene, heptylidene, n-octylidene, n-nonylidene, n-decylidene; Optionally, the "-alkylene-C(=O)O-alkyl", "-alkylene-OC(=O)R 4-11 ", "-alkylene-OP(=O)(OR 4-7 )OR 4-8 ", "-alkylene-OC(=O)-OR 4-10 ", "-alkylene-OC(=O)-OR 4-2 ", "-alkylene-C(=O)OH" means C 1-20 A straight or branched chain alkylene group, optionally C 1-17 A straight or branched chain alkylene group, optionally C 1-10 A straight or branched chain alkylene group, optionally C 1-8 A straight or branched chain alkylene group, optionally C 1-5 A straight or branched chain alkylene group, optionally C 1-3 Straight-chain or branched alkylene, optionally, is methylene, ethylene, isoethylidene, n-propylene, isopropylene, n-butylidene, isobutylidene, tert-butylidene, sec-butylidene, n-pentylidene, isopentylidene, neopentylidene, tert-pentylidene, n-hexylidene, isohexylidene, heptylidene, n-octylidene, n-nonylidene, n-decylidene; Optionally, the alicyclic ring in the "alicyclic group" is a C ring containing 1-3 heteroatoms selected from O, N, S. 3-8 (Preferably C 4-6 ) alicyclic ring, optionally, dioxolane, aziridine, azetidinyl, tetrahydropyrrolyl, morpholinyl, piperidinyl, or piperazinyl; Optionally, the aryl in the "aryl", "hydroxy-substituted aryl" and "-alkylene-aryl" is a 6-10 membered monocyclic or bicyclic condensed aromatic ring group; optionally, phenyl or naphthyl; Optionally, the arylene group in the "-B-alkylene-arylene-", "-B-arylene-alkylene-", "-alkylene-arylene-" is a 6-10 membered monocyclic or bicyclic condensed aromatic ring group; optionally, a phenylene group or a naphthylene group; Optionally, the alkenyl moieties in the "alkenyl-carboxyl" and "alkenyl-alkoxyacyl" are each independently a C2-C8 straight chain or branched chain alkenyl containing one or more double bonds, optionally a C2-C6 straight chain or branched chain alkenyl, optionally a C2-C4 straight chain or branched chain alkenyl; optionally, ethylene, propylene, butene, pentene, acetylene and hexyne; Optionally, the cycloalkyl group in the "cycloalkyl group" and "-O-cycloalkyl group" is a 3-7 membered monocyclic cycloalkyl group, optionally selected from: cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl; Optionally, the N-(4-trifluoromethyl)-2-cyanocrotonamide moiety is in the Z configuration or the E configuration.

4. The compound of formula (I) according to any one of claims 1 to 3, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: Alternatively, when R1 and R2 are connected to each other and the nitrogen atom to which they are connected, they form an optionally substituted alicyclic heterocyclic group, the optionally substituted alicyclic heterocyclic group is selected from: Optionally, R 4-1 C 1-5 Straight or branched chain alkyl; Optionally, R 4-2 Selected from: -OH, phenyl, C 1-13 Straight or branched alkyl, C 1-5 Straight or branched alkoxy, -C=C-COOH, -C=CC 1-5 Straight chain or branched chain alkoxy acyl, -C 1-5 Straight or branched alkylene-R 4-9 ; Optionally, R 4-3 , R 4-4 The same or different, each independently selected from: H, alkyl, or R 4-3 and R 4-4 Together with the nitrogen atoms they are connected to form Optionally, R 4-5 Selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; Optionally, Linker is an optional group, which when present is selected from: C 1-5 Straight or branched alkylene, -BC 1-5 Straight or branched alkylene-, -BC 1-5 Straight chain or branched alkylene-phenylene-, -B-phenylene-C 1-5 Straight or branched chain alkylene-; Optionally, R' is independently selected from: -H, C 1-5 Straight or branched alkyl, -C 1-5 Straight chain or branched alkylene-phenyl, hydroxy substituted C 1-5 Straight or branched chain alkyl; Optionally, R 4-6 The amino acid portion is in D configuration or L configuration; Optionally, R 4-7 and R 4-8 The same or different, each independently selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; Optionally, R 4-9 Selected from: Phenyl; Optionally, R 4-10 Selected from: H, C 1-5 Straight or branched chain alkyl; Optionally, R3 is selected from: -H, C 1-5 Straight or branched chain alkyl; Optionally, A is selected from: -C(=O)-, C 1-5 Straight or branched chain alkylene; Optionally, R 4-11 Selected from: H, C 1-5 Straight-chain or branched alkyl, phenyl; Alternatively, Q is O or -O-cyclopentyl.

5. The compound of formula (I) according to any one of claims 2 to 4, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: R1 and R2 are the same or different and are independently selected from: -H, C 1-5 Straight or branched alkyl, -C 1-5 Straight or branched alkylene -C(=O)OC 1-5 Straight or branched alkyl, -S(=O)2-C 1-5 Straight or branched alkyl, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , the following monosaccharide groups, wherein the monosaccharide 1-position substitution is α substitution or β substitution: in, R 4-2 Selected from: -OH, phenyl, C 1-13 Straight or branched alkyl, C 1-5 Straight or branched alkoxy, -C=C-COOH, -C=CC 1-5 Straight chain or branched chain alkoxy acyl, -C 1-5 Straight or branched alkylene-R 4-9 ; R 4-3 , R 4-4 The same or different, each independently selected from: H, C 1-5 Straight or branched chain alkyl; Or, R 4-3 and R 4-4 Together with the nitrogen atoms they are connected to form R 4-5 Selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; Linker is an optional group, which when present is selected from: 1-5 Straight or branched alkylene, -BC 1-5 Straight or branched alkylene-, -BC 1-5 Straight chain or branched alkylene-phenylene-, -B-phenylene-C 1-5 Straight or branched chain alkylene-; A is selected from: -C(=O)-, C 1-5 Straight or branched chain alkylene; R3 is selected from: -H, C 1-5 Straight or branched chain alkyl; R 4-7 and R 4-8 The same or different, each independently selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; R 4-9 Selected from: Phenyl; R 4-10 Selected from: H, C 1-5 Straight or branched chain alkyl; Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form: X is selected from -H; Each B is independently selected from -O-, -S-, and -NH-.

6. The compound of formula (I) according to claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: R1 and R2 are the same or different and are independently selected from: -H, C 1-5 Straight or branched alkyl, -C 1-5 Straight or branched alkylene -C(=O)OC 1-5 Straight or branched alkyl, -S(=O)2-C 1-5 Straight or branched alkyl, -C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-OR 4-5 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 , the following monosaccharide groups, wherein the monosaccharide 1-position substitution is α substitution or β substitution: in, R 4-2 Selected from: -OH, phenyl, C 1-13 Straight or branched alkyl, C 1-5 Straight or branched alkoxy, -C=C-COOH, -C=CC 1-5 Straight chain or branched chain alkoxy acyl, -C 1-5 Straight or branched alkylene-R 4-9 ; R 4-3 , R 4-4 The same or different, each independently selected from: H, C 1-5 Straight or branched chain alkyl; Or, R 4-3 and R 4-4 Together with the nitrogen atoms they are connected to form R 4-5 Selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; Linker is an optional group, which when present is selected from: 1-5 Straight or branched alkylene, -BC 1-5 Straight or branched alkylene-, -BC 1-5 Straight chain or branched alkylene-phenylene-, -B-phenylene-C 1-5 Straight or branched chain alkylene-; A is selected from: -C(=O)-, C 1-5 Straight or branched chain alkylene; R3 is selected from: -H, C 1-5 Straight or branched chain alkyl; R 4-7 and R 4-8 The same or different, each independently selected from: H, C 1-5 Straight or branched alkyl, -C 1-5 Straight-chain or branched alkylene-phenyl; R 4-9 Selected from: Phenyl; R 4-10 Selected from: H, C 1-5 Straight or branched chain alkyl; Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form: X is selected from -H or X and R1 together form a cyclic amide structure R2' is selected from: -H, C 1-5 Straight-chain or branched alkyl, phenyl, cyclopentyl, -C 1-5 Straight chain or branched alkylene-phenyl, -C 1-5 Straight or branched alkylene -C(=O)OH, -C 1-5 Straight or branched alkylene -C(=O)OC 1-5 Straight or branched alkyl, -C(=O)-phenyl, -alkylene-OC(=O)R 4-11 , -alkylene-OP(=O)(OR 4-7 )OR 4-8 , -alkylene-OC(=O)-OR 4-10 ; R 4-10 C 1-5 Straight or branched chain alkyl; R 4-11 C 1-5 Straight-chain or branched alkyl or phenyl; Each B is independently selected from -O-, -S-, and -NH-; Q is O or O-cycloalkyl; R3 is selected from: C 1-5 Straight or branched alkyl, -C 1-5 Straight or branched alkylene-OC(=O)-OC 1-5 Straight chain or branched chain alkyl.

7. A compound according to any one of claims 1 to 6, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: Selected from the following compounds:

8. A compound according to any one of claims 1 to 7, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (optionally, the solvate is a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, characterized in that: The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt. Optionally, it is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, formic acid, acetic acid, salicylic acid, citric acid, succinic acid, fumaric acid, maleic acid, benzoic acid, hydrobromic acid, hydroiodic acid, benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.

9. A method for preparing a compound of formula (I) according to any one of claims 1 to 7, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof; The method comprises the steps of obtaining a compound of formula (I) by reacting compounds of formula (A) and formula (B) through step A: Step A: In formula (A), X is as described in formula (I); In formula (B), R1, R2 and R3 are as described in formula (I); Alternatively, the compound of formula (I) is prepared by addition elimination reaction of the compound of formula (A) and the compound of formula (B) in a suitable solvent (such as xylene or toluene) at a temperature of 50° C. to 120° C.; Alternatively, formula (A) can be synthesized by method a, but is not limited to this method; Method a: Alternatively, the compounds of formula (C) and (D) are subjected to a condensation reaction under the catalysis of a condensing agent (such as EDCI, HATU, HBTU or PyBOP, etc.), in the presence or absence of a base (such as pyridine, TEA, DIPEA, DBU or DBN, etc.), in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC), at -10°C to 50°C to obtain the compound of formula (A); Alternatively, formula (B) can be synthesized by method b, but is not limited to this method; Method b: Alternatively, the compound of formula (E) is subjected to an addition remethylation reaction in the presence of sodium methoxide and dimethyl sulfate in a solvent DMSO at -10°C to 30°C to obtain the compound of formula (B). Optionally, when R1 and R2 in formula (I) are the same or different, and are independently H, alkyl, -alkylene-C(=O)O-alkyl, optionally substituted monosaccharide, or R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form an optionally substituted aliphatic heterocyclic group, formula (I) can be obtained by reacting compounds of formula (F) and formula (G) through step B: Step B: In formula (F), X and R3 are as described in formula (I), and W is dimethylamino, pyrrolyl, piperidinyl or morpholinyl; in formula (G), R1 and R2 are as described in formula (I); Alternatively, the compounds of formula (F) and (G) are catalyzed by a base (such as pyridine, TEA, DIPEA, DBU or DBN, etc.) in a suitable solvent (such as DMF, DMAC, DMSO, THF, DCM, DCE, etc.) at a temperature of 0° C. to 100° C., and are subjected to a substitution reaction with or without deprotection to obtain the compound of formula (I); It also includes when R1 and R2 in formula (I) are different, and R1 or R2 are each independently -S(=O)2R 4-1 、-C(=O)R 4-2 、-C(=O)N(R 4-3 )R 4-4 、-A-Linker-R 4-6 、-P(=O)(OR 4-7 )OR 4-8 When the formula (I) is used, the compound of formula (H) and formula (J) can be obtained by step C: Step C: In formula (H), X and R3 are as described in formula (I); in formula (J), M is halogen, hydroxyl, imidazolyl or p-nitrophenyloxy, Y is carbonyl, sulfonyl or phosphoryl; or M and Y form an isocyanate; Z is an optionally substituted alkyl, an optionally substituted alkyloxy, an optionally substituted aryl, an optionally substituted aryloxy, an optionally substituted amine, an optionally substituted alkenyl, or an optionally substituted alkylthio. When M is halogen, p-nitrophenyloxy, imidazole or M and Y form isocyanate, optionally, the compounds of formula (H) and (J) are catalyzed by a base (such as pyridine, TEA, DIPEA, DBU, DBN or sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 30°C, and subjected to acylation reaction with or without deprotection to obtain the compounds of formula (I). When M is a hydroxyl group, optionally, the compounds of formula (H) and (J) are catalyzed by a condensation agent (such as EDCI, HATU, HBTU or PyBOP, etc.), in the presence of a base (such as pyridine, TEA, DIPEA, DMAP, DBU, DBN or sodium hydride, etc.) and a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 50°C, and are subjected to a condensation reaction with or without deprotection to obtain the compound of formula (I); Optionally, it also includes when X and R1 in formula (I) together form a cyclic amide structure R2' is as described in formula (I); formula (I) can be obtained by cyclizing formula (H) itself and then reacting with a compound of formula (J) through step D: Step D: Alternatively, when R2' is H, Q is O, R3 is CH3; M is halogen (preferably iodide or bromide), Y is alkyl, carbonyl, alkylenecarbonyl, alkyleneoxycarbonyl, alkyleneoxyphosphoryl or phosphoryl; Z is optionally substituted alkyl, C3-C7 monocyclic cycloalkyl, optionally substituted alkyloxy, optionally substituted aryl, optionally substituted aryloxy; Optionally, formula (H) can be self-cyclized by reacting with carbonyldiimidazole or 4-nitrophenol chloromethyl ester or triphosgene under the catalysis of a base (such as potassium carbonate, cesium carbonate, pyridine, TEA, DIPEA, DBU, DBN, NaHCO3, sodium hydroxide, sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF, acetone or DMAC, etc.) at -10°C to 60°C, and then reacting with formula (J) under the catalysis of a base (such as potassium carbonate, cesium carbonate, pyridine, TEA, DIPEA, DBU, DBN or sodium hydride, etc.) in a suitable solvent (such as THF, DCM, DCE, ACN, DMF or DMAC, etc.) at -10°C to 80°C, by substitution reaction, deprotection or non-deprotection to obtain formula (I).

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a compound of formula (I) according to any one of claims 1 to 8 or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof, or a prodrug thereof, or an active metabolite thereof, and a pharmaceutically acceptable excipient; Optionally, the pharmaceutically acceptable excipient is selected from the group consisting of fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, solubilizers, cosolvents, antioxidants, anti-photolysis agents, pH regulators, emulsifiers, antibacterial preservatives, local analgesics, chelating agents, non-aqueous solvents, coating materials or other excipients; Optionally, the filler includes one or a combination of lactose, mannitol, and calcium carbonate; Optionally, the binder includes one or a combination of sucrose, starch, povidone, sodium carboxymethyl cellulose; Optionally, the disintegrant comprises one or a combination of starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and an effervescent disintegrant; Optionally, the non-aqueous solvent includes one or a combination of soybean oil, castor oil, and peanut oil; Optionally, the solubilizing agent comprises one or a combination of Tween 80, Tween 60, and Poloxamer 68; Optionally, the cosolvent includes one or a combination of sodium benzoate, sodium salicylate, sodium p-aminobenzoate; Optionally, the pharmaceutical composition can be prepared into a solid oral preparation, a liquid oral preparation, an injection or a transdermal preparation; Optionally, the solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, syrups and solutions; Optionally, the injection includes: small injection, large infusion, freeze-dried powder injection; Optionally, the transdermal preparation includes: ointments, plasters, liniments, aerosols, traditional patches, adhesive dispersion patches, peripheral adhesive skeleton patches, reservoir patches and papuam.

11. Use of a compound of formula (I) according to any one of claims 1 to 8 or its optical isomer, or a pharmaceutically acceptable salt, or a solvate (e.g., a hydrate), or an inclusion compound, or a racemate, or a cocrystal, or an isotope-labeled product, or a nitrogen oxide, or a prodrug, or an active metabolite, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for preventing and / or treating inflammation, pain, multiple sclerosis, neuromyelitis optica, autoimmune disease, or cancer; Optionally, the inflammation includes rheumatoid arthritis, dermatitis; Optionally, the multiple sclerosis (MS) includes: clinically isolated syndrome (CIS) MS, relapsing-remitting MS, primary progressive MS, secondary progressive MS; Optionally, the neuromyelitis optica (NMO) includes: monophasic NMO, relapsing NMO, and progressive NMO; Optionally, the autoimmune diseases include: systemic lupus erythematosus, psoriasis, and anti-transplant rejection; Optionally, the cancer is selected from renal cancer, prostate cancer, and lung cancer; Optionally, the cancer cells include: human renal cancer cell line 786-O, human prostate cancer cell line LNCaP, PC3, DU145, human large cell lung cancer cell line H460, and human non-small cell lung cancer cell line A549.