Chalcone derivative, preparation method therefor, and use thereof

Abstract

The present invention provides a Chalcone derivative. The compound has anti-inflammatory and anti-tumor activity.

Description

A chalcone derivative and its preparation method and application

[0001] This application claims priority to a prior application, patent application number 202311598560.7, filed with the State Intellectual Property Office of China on November 27, 2023, entitled “A chalcone derivative, its preparation method, and use.” The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical compounds, and in particular relates to a chalcone derivative, a preparation method thereof and pharmaceutical application thereof. Background Art

[0003] Chalcone is a simple chemical scaffold of many natural compounds, widely distributed in vegetables, fruits, tea and other plants. Chalcone compounds have a common chemical scaffold 1,3-diaryl-2-propen-1-one The therapeutic application of chalcones dates back thousands of years, through the use of plants and herbs to treat different medical conditions, such as cancer, inflammation, and diabetes. Several chalcone-based compounds have been approved for clinical use; for example, metochalcone was once marketed as a choleretic drug, while sofarone was previously used as an anti-ulcer and mucosal protective agent.

[0004] Chalcones exhibit a wide range of biological activities, likely due to their small structure and Michael acceptor characteristics, which make them tolerant to different biomolecules and allow them to bind readily or reactively to different biomolecules. The biological activities of chalcones include anticancer activity, cancer prevention effects, anti-inflammatory activity, antimicrobial activity, antituberculosis activity, antidiabetic activity, antioxidant activity, antibacterial activity, antiviral activity, antimalarial activity, and neuroprotective effects.

[0005] Due to their ease of synthesis, numerous chalcone derivatives have been prepared. These natural and synthetic compounds have demonstrated numerous interesting biological activities and possess clinical potential against various diseases. Numerous studies have demonstrated their potent and positive effects in reducing inflammation, modulating immune responses, and supporting and restoring normal cellular function. Summary of the Invention

[0006] The present invention provides a compound having a structure of Formula I or preferably Formula II, its enantiomer, pharmaceutically acceptable salt or solvate,

[0007] in,

[0008] In formula I, ring A is phenyl, naphthyl, phenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl;

[0009] In Formula I and Formula II:

[0010] n is 0, 1, 2, 3, 4 or 5;

[0011] Each R1 is the same or different and is independently selected from hydroxy, halogen, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl, C 2-8 Alkenyloxy, C 2-8 Alkynyl, C 2-8 Alkynyloxy, C(O)R7, C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryloxy, C 3-10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, 5-10 membered heteroaryloxy, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy are optionally substituted by one or more selected from hydroxy, halogen, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution;

[0012] R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl;

[0013] R4 is hydrogen, C 1-12 Alkyl, C(O)R 10 ;

[0014] R5 is hydrogen or C 1-12 alkyl;

[0015] R7 is selected from hydroxyl, C 1-12 Alkyl, C 1-12 Alkyloxy, NR8R9;

[0016] R8 and R9 are independently selected from hydrogen or C 1-12 alkyl;

[0017] R 10 Selected from hydroxyl, C 1-12 Alkyl, C 1-12 Alkyloxy.

[0018] In some embodiments of the present invention, C 6-10 Aryl is preferably phenyl.

[0019] In some embodiments of the present invention, C 3-10 The cycloalkyl group is preferably C 3-7 Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0020] In some embodiments of the present invention, the 3-10 membered heterocyclic group is preferably a 3-7 membered heterocyclic group, such as oxirane, thioethane, aziridine, oxetane, N heterocyclobutane, α-lactam ring, β-lactam ring, β-lactone, tetrahydrofuran, thiolane, pyrrolidine, dioxolane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, tetrahydropyran, piperidine, 1,4-dioxane, piperazine, azepane, oxirane, thipane, 1,4-oxazepane, 1,4-thiazepane.

[0021] In some embodiments of the present invention, the 5-10 membered heteroaryl group is preferably a 5-6 membered heteroaryl group, such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxadiazole, thiadiazole, pyridine, pyridone, pyrimidine, pyridazine, pyrazine, and triazine.

[0022] In some embodiments of the present invention, the halogen is preferably F, Cl or Br.

[0023] In some embodiments of the present invention, in Formula I or Formula II, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl, C 2-8 Alkenyloxy, C 2-8 Alkynyl, C 2-8 Alkynyloxy, C(O)R7, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 Cycloalkyloxy, 3-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, phenyl, phenyloxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy are optionally substituted by one or more selected from hydroxy, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy group substituted; R7 is selected from hydroxyl, C 1-8 Alkyl, C 1-8 Alkyloxy, NR8R9; R8 and R9 are independently selected from hydrogen or C 1-8Preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C(O)R7, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted by one or more selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy group substituted; R7 is selected from hydroxyl, C 1-4 Alkyl, C 1-4 More preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy, wherein alkyl, alkyloxy is optionally substituted by one or more groups selected from F, Cl, Br. More preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy.

[0024] In some embodiments of the present invention, in Formula I or Formula II, R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl; preferably, R2 and R3 are independently selected from hydrogen, C 1-12 More preferably, R2 and R3 are independently selected from C 1-4 More preferably, R2 and R3 are methyl.

[0025] In some embodiments of the present invention, in Formula I or Formula II, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-8 Alkyl, C 1-8 Alkyloxy; preferably, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-4 Alkyl, C 1-4 More preferably, R4 is hydrogen.

[0026] In some embodiments of the present invention, in Formula I or Formula II, R5 is hydrogen or C 1-8 Alkyl; preferably, R5 is C 1-4 More preferably, R5 is methyl.

[0027] In some embodiments of the present invention, in Formula I or Formula II, n is 0, 1, 2 or 3;

[0028] Each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy, C 2- 8-alkenyl, C 2-8 Alkenyloxy, C 2-8 Alkynyl, C 2-8 Alkynyloxy, C(O)R7, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 Cycloalkyloxy, 3-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, phenyl, phenyloxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy are optionally substituted by one or more selected from hydroxy, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution;

[0029] R7 is selected from hydroxyl, C 1-8 Alkyl, C 1-8 Alkyloxy, NR8R9;

[0030] R8 and R9 are independently selected from hydrogen or C 1-8 alkyl;

[0031] R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl;

[0032] R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-8 Alkyl, C 1-8 alkyloxy;

[0033] R5 is hydrogen or C 1-8 alkyl;

[0034] Preferably, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-4 Alkyl, C 1-4 Alkyloxy; R5 is C 1-4 Alkyl, and / or, R2 and R3 are independently selected from hydrogen, C 1-4 alkyl;

[0035] More preferably, R4 is hydrogen, R5 is methyl, and / or R2 and R3 are methyl.

[0036] In some embodiments of the present invention, in Formula I or Formula II, n is 0, 1, 2 or 3;

[0037] Each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy, C 2- 4-alkenyl, C 2-4 Alkenyloxy, C(O)R7, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted by one or more selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy group substitution;

[0038] R7 is selected from hydroxyl, C 1-4 Alkyl, C 1-4 alkyloxy;

[0039] R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl;

[0040] R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-8 Alkyl, C 1-8 alkyloxy;

[0041] R5 is hydrogen or C 1-8 alkyl;

[0042] Preferably, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-4 Alkyl, C 1-4 Alkyloxy; R5 is C 1-4 Alkyl, and / or, R2 and R3 are independently selected from hydrogen, C 1-4 alkyl;

[0043] More preferably, R4 is hydrogen, R5 is methyl, and / or R2 and R3 are methyl.

[0044] In some embodiments of the present invention, in Formula I or Formula II, n is 0, 1, 2 or 3;

[0045] Each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy, wherein the alkyl group and the alkyloxy group are optionally substituted with one or more groups selected from F, Cl, and Br;

[0046] R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl;

[0047] R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-8 Alkyl, C 1-8 alkyloxy;

[0048] R5 is hydrogen or C 1-8 alkyl;

[0049] Preferably, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-4 Alkyl, C 1-4 Alkyloxy; R5 is C 1-4 Alkyl, and / or, R2 and R3 are independently selected from hydrogen, C 1-4 alkyl;

[0050] More preferably, R4 is hydrogen, R5 is methyl, and / or R2 and R3 are methyl.

[0051] In some embodiments of the present invention, in Formula I or Formula II, n is 0, 1, 2 or 3;

[0052] Each R1 is the same or different and is independently selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 alkyloxy;

[0053] R2 and R3 are methyl groups;

[0054] R4 is hydrogen;

[0055] R5 is methyl.

[0056] In some embodiments of the present invention, the compound of formula I is selected from the following compounds:

[0057] The present invention also discloses a method for preparing a compound of formula I, comprising: reacting a compound of formula A with a compound of formula B through an aldol condensation reaction to obtain a compound of formula C; and then subjecting the compound of formula C to a photo-radical oxidation reaction (e.g., using a Rose Bengal reagent) to obtain a compound of formula I, wherein the substituents R1-R5 and ring A in formulas A, B, and C have the same definitions as above. Those skilled in the art will appreciate that this method is also applicable to the preparation of a compound of formula II.

[0058] The compounds of formula I or formula II of the present invention, their enantiomers, pharmaceutically acceptable salts or solvates have anti-inflammatory and anti-tumor activities.

[0059] The present invention also provides use of the compound of formula I or formula II, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of anti-inflammatory drugs.

[0060] The present invention also provides use of the compound of formula I or formula II, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of anti-tumor drugs.

[0061] The present invention also provides a pharmaceutical composition comprising a compound of Formula I or Formula II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt, or a solvate thereof, and optionally further comprising one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carriers are various excipients commonly used or known in the pharmaceutical field, including but not limited to diluents, binders, antioxidants, pH adjusters, preservatives, lubricants, disintegrants, and the like.

[0062] The amount of the compound of formula I or formula II contained in the pharmaceutical composition (calculated as the compound of formula I or formula II) is 0.1-1000 mg, preferably 1-500 mg, more preferably 5-100 mg.

[0063] The mass percentage of the compound of formula I or formula II (calculated as the compound of formula I or formula II) in the pharmaceutical composition is 0.01%-95% of the pharmaceutical composition. Depending on the dosage form, the content can be, for example, 0.1%-10%, 0.3-5%, or 10%-90%.

[0064] The pharmaceutical composition may be in the form of an oral dosage form, such as a tablet, capsule, pill, powder, granule, suspension, syrup, etc.; or in the form of an injectable dosage form, such as an injection solution, powder injection, etc., which is administered by intravenous, intraperitoneal, subcutaneous, or intramuscular injection. All dosage forms are well known to those skilled in the pharmaceutical field.

[0065] Routes of administration of the pharmaceutical composition include, but are not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous; by implanted reservoir or reservoir.

[0066] The dosage of the compound of formula I or II (calculated as the compound of formula I or II) will depend on the age, health and weight of the recipient, the type of the combined drug, the frequency of treatment, the route of administration, etc. The drug can be administered in a single daily dose, administered once a day, once every two days, once every three days, once every four days, or the total daily dose is administered in divided doses twice, three times or four times a day. The dosage of the compound of formula I or II (calculated as the compound of formula I or II) is 0.01-100 mg / kg / day, preferably 0.1-10 mg / kg / day, for example, 0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 5 mg / kg / day, etc.

[0067] The present invention also provides a method for inhibiting inflammation, which comprises administering to a patient in need thereof a compound of Formula I or Formula II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of Formula I or Formula II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof.

[0068] Such inflammation includes, but is not limited to, autoimmune diseases, disorders or conditions, inflammatory diseases, disorders or conditions; for example, idiopathic pulmonary fibrosis, inflammatory bowel disease (selected from Crohn's disease and ulcerative colitis), rheumatoid arthritis, osteoarthritis, Still's disease, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis, systemic sclerosis, acute respiratory distress syndrome, allergic rhinitis, asthma, inflammatory eye diseases (e.g., allergic conjunctivitis, dry eye and uveitis), atopic dermatitis, interstitial cystitis, chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), dermal contact hypersensitivity, eosinophilic gastrointestinal tract disorders, disorder), fibromyalgia, hepatic fibrosis, irritable bowel syndrome, ischemia-reperfusion disease, renal fibrosis, pancreatitis, postoperative inflammation, seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's syndrome), and vasculitis (e.g., Wegener's granulomatosis, polyarteritis nodosa, leukocytodestructive vasculitis, Churg-Strauss syndrome, cryoglobulinemic vasculitis, and giant cell arteritis).

[0069] The present invention also provides a method for treating tumors, which comprises administering to a patient in need thereof a compound of Formula I or Formula II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing a compound of Formula I or Formula II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof.

[0070] The tumors include, but are not limited to, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphomas (Hodgkin's disease, non-Hodgkin's disease), essential macroglobulinemia, heavy chain disease, solid tumors such as sarcomas and cancers (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, endotheliosarcoma, lymphangiosarcoma, angiosarcoma, lymphangioendotheliosarcoma, synovial vioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colorectal cancer, pancreatic cancer, breast cancer (e.g., triple-negative breast cancer), ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, skin cancer, The present invention relates to a tumor of the present invention comprising: a fat gland carcinoma, a papillary carcinoma, a papillary adenocarcinoma, a bronchogenic carcinoma, a medullary carcinoma, a renal cell carcinoma, a liver cancer, a Nile duct carcinoma, a choriocarcinoma, a seminoma, an embryonal carcinoma, a Wilms' tumor, a cervical cancer, a uterine cancer, a testicular cancer, a lung cancer, a small cell lung cancer, a bladder cancer, an epithelial cancer, a glioma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a neurilemmoma, a meningioma, a melanoma, a neuroblastoma, a retinoblastoma, an esophageal cancer, a gallbladder cancer, a kidney cancer, and a multiple myeloma); preferably, the tumor includes but is not limited to: pancreatic cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, colorectal cancer, breast cancer (such as triple-negative breast cancer), lymphoma, gallbladder cancer, kidney cancer, leukemia, multiple myeloma, ovarian cancer, cervical cancer and glioma, and any combination thereof.

[0071] In the present invention, "and / or" will be regarded as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" used in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0072] "Comprising" and "including" have the same meaning and are intended to be open ended and permit, but not require, the inclusion of additional elements or steps. When the terms "comprising" or "including" are used herein, the terms "consisting of" and / or "consisting essentially of" are also included and disclosed.

[0073] Alkyl: A linear or branched saturated aliphatic group. In the present invention, an alkyl group having 1 to 20 carbon atoms, preferably 1 to 13 carbon atoms, more preferably 1 to 8 carbon atoms, and most preferably 1 to 4 carbon atoms is preferred, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, 6-methylhept-2-yl, 5-ethyl-6-methylhept-2-yl, and the like.

[0074] Alkyloxy: -O-alkyl, wherein alkyl is as defined above.

[0075] Cycloalkyl: a saturated or partially unsaturated monocyclic or polycyclic cyclic alkyl group. In the present invention, a cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, is preferred. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, and the like.

[0076] Cycloalkyloxy: -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0077] Heterocyclyl: A stable 3- to 18-membered non-aromatic cyclic radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. It may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include spirocyclic, fused, or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl may be partially or fully saturated. In the present invention, 3- to 10-membered, more preferably 3- to 7-membered heterocyclyls are preferred. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, dioxenyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene, tetrahydrofuranyl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, and 1,6-dioxaspiro[4.5]decanyl.

[0078] Heterocyclyloxy: -O-heterocyclyl, wherein heterocyclyl is as defined above.

[0079] Aromatic ring group: a hydrocarbon ring radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system. In the present invention, aromatic ring groups with 6 to 10 carbon atoms are preferred. Aromatic ring groups include, but are not limited to, aromatic ring groups derived from aceanthrene, acenaphthene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and benzo[9,10]phenanthrene.

[0080] Arylcyclyloxy: -O-arylcyclyl, wherein the arylcyclyl group is as defined above.

[0081] Heteroaryl: A 5- to 14-membered ring radical comprising hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. The ring radical may be monocyclic, bicyclic, tricyclic, or tetracyclic, and may include fused or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. In the present invention, 5- to 10-membered, more preferably 5- to 6-membered heteroaryl groups are preferred. Examples of heteroaryl groups include, but are not limited to, aza-, acridinyl, benzimidazolyl, benzo[d]imidazolyl, benzimidazopyrimidinyl, benzo[4,5]imidazo[1,2-a]pyrimidinyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo[d]isoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, yl, benzodioxenyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzothienyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinone, benzimidazolylsulfinyl (benzimidazolthionyl), carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,5-a]pyrazinyl, imidazolyl, indolyl, indazolyl, isoindolyl, dihydroindolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 1,5-naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-pyridyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, 2,3-naphthyridinyl, pteridinyl , pteridinone, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridonyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridazinyl, pyrido[2,3-d]pyrimidonyl, pyrazolo[1,5-a]pyrimidinyl, quinazolinyl, quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thienyl).

[0082] Heteroaryloxy: -O-heteroaryl, wherein heteroaryl is as defined above.

[0083] The compounds of the present invention may contain asymmetric or chiral centers and therefore exist in different enantiomeric forms. All enantiomeric forms of these compounds and mixtures thereof (including racemic mixtures) are intended to form part of the present invention. Individual enantiomers of the compounds can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These resolution methods are exemplified by: (1) coupling the enantiomeric mixture with a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and freeing the optically pure product from the auxiliary; (2) forming salts using an optically active resolving agent; or (3) directly separating the mixture of optical enantiomers on a chiral chromatographic column. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Figure 1 is a statistical graph showing the detection of IL-6 content in the culture medium of RAW264.7 cells after treatment with compound 15 and WR047-WR055 and then stimulation with LPS. In the figure, ** represents P < 0.01 compared with the LPS-treated group, *** represents P < 0.001 compared with the LPS-treated group, and **** represents P < 0.0001 compared with the LPS-treated group.

[0085] Figure 2 is a statistical graph showing the detection of TNF-α content in the culture medium of RAW264.7 cells after treatment with compound 15 and WR047-WR055 and then stimulation with LPS. In the figure, ** represents P < 0.01 compared with the LPS-treated group, *** represents P < 0.001 compared with the LPS-treated group, and **** represents P < 0.0001 compared with the LPS-treated group.

[0086] Figure 3 is a statistical graph showing the detection of IL-6 content in the culture medium of DC2.4 cells after treatment with compound 15 and WR047-WR053 and then stimulation with LPS. In the figure, ** represents P < 0.01 compared with the LPS-treated group, *** represents P < 0.001 compared with the LPS-treated group, and **** represents P < 0.0001 compared with the LPS-treated group.

[0087] Figure 4 is a statistical graph showing the detection of TNF-α content in the culture medium of DC2.4 cells after treatment with compound 15 and WR047-WR053 and then stimulation with LPS. In the figure, ** represents P < 0.01 compared with the LPS-treated group, *** represents P < 0.001 compared with the LPS-treated group, and **** represents P < 0.0001 compared with the LPS-treated group.

[0088] FIG5 shows the experimental results of the inhibition of the proliferation of triple-negative breast cancer cells Cal51, MDA-MB-468 and BT549 by the compounds of the present invention. In the figure, * represents P < 0.05 compared with the blank control group, ** represents P < 0.01 compared with the blank control group, *** represents P < 0.001 compared with the blank control group, and **** represents P < 0.0001 compared with the blank control group.

[0089] FIG6 shows the experimental results of the inhibition of the proliferation of colorectal cancer cells HCT116 and HCT8 by the compounds of the present invention. In the figure, * represents P < 0.05 compared with the blank control group, ** represents P < 0.01 compared with the blank control group, *** represents P < 0.001 compared with the blank control group, and **** represents P < 0.0001 compared with the blank control group. DETAILED DESCRIPTION

[0090] The present invention is further described below with reference to the following examples. It should be noted that the examples are not intended to limit the scope of protection of the present invention, and those skilled in the art will understand that any improvements and variations based on the present invention are within the scope of protection of the present invention.

[0091] The conventional reagents used in the following examples are all commercially available. The biological experiments performed are conventional biological experiments in the art and can be performed according to the corresponding experimental manuals or kit instructions.

[0092] CH3I: iodomethane; K2CO3: potassium carbonate; THF: tetrahydrofuran; BBr3: boron tribromide; CuI: cuprous iodide; DMF: N,N-dimethylformamide; DEAD: diethyl azodicarboxylate; PPh3: triphenylphosphine; Eu(fod)3: tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium; Ac2O: acetic anhydride.

[0093] Example 1: Preparation Example of Compound

[0094] 1. Preparation of intermediate compounds

[0095] Compound 9 (2 g, 13.14 mmol), potassium carbonate (3.63 g, 26.28 mmol), and CH3I (1.54 mL, 26.28 mmol) were placed in a 250 mL round-bottom flask, dissolved in anhydrous DMF, and the reaction system was placed at room temperature and continued to stir. The reaction was monitored by TLC. After the reaction was complete, 200 mL of ethyl acetate was added to the system, and the reaction solution was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a desiccant, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to obtain compound 10 (1.89 g, 93%) as a light yellow solid.

[0096] Under argon, compound 10 (1.89 g, 11.50 mmol) and potassium carbonate (3.178 g, 23.00 mmol) were dissolved in anhydrous DMF and placed in a 50 mL round-bottom flask with stirring. 1-Bromo-3-methyl-2-butene (1.99 ml, 17.25 mmol) was added under ice-cooling. After stirring for 30 minutes, the reaction system was allowed to continue at room temperature. The reaction was monitored by TLC. Upon completion, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to yield compound 11 (1.78 g, 83%) as a white solid.

[0097] Compound 11 (2 g, 8.54 mmol) was placed in a 250 mL round-bottom flask and dissolved with anhydrous N,N-diethylaniline. The reaction system was then stirred at 230°C. The reaction was monitored by TLC. After completion, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with 1N hydrochloric acid solution (100 mL x 3). The organic phase was collected, treated with anhydrous sodium sulfate as a desiccant, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to obtain Compound 12 (1.89 g, 95%) as a pale yellow solid.

[0098] 1 H NMR(400MHz,Chloroform-d)δ12.64(s,1H),7.32(s,1H),6.31(s,1H),5.39–4.99( m,1H),3.78(s,3H),3.14(d,J=7.3Hz,2H),2.46(s,3H),1.68(s,3H),1.63(s,3H).

[0099] 13C NMR (100MHz, Chloroform-d) δ202.59,164.07,133.10,130.74,122.02,121.67,113.15,99.04,55.70,27.80,26.23,25.81,17.80.

[0100] Intermediate 12 (350 mg, 1.495 mmol) was dissolved in anhydrous N,N-dimethylformamide and placed in a 50 mL round-bottom flask with stirring. Iodomethane (0.11 mL, 1.794 mmol) and potassium carbonate (413.2 mg, 2.991 mmol) were slowly added dropwise under an ice bath. After stirring for 30 minutes, the reaction system was allowed to continue at room temperature. The reaction was monitored by TLC. Upon completion, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to yield compound 13 (332 mg, 95%) as a white solid.

[0101] Compound 13 (332 mg, 1.337 mmol) and benzaldehyde (278 mg, 2.579 mmol) were dissolved in anhydrous ethanol and placed in a 50 mL round-bottom flask with stirring. 4 M sodium hydroxide solution (0.96 mL, 3.876 mmol) was slowly added dropwise under an ice bath. After stirring for 30 minutes, the reaction system was placed at 50°C and continued to react. The reaction was monitored by TLC. Once the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to obtain compound 14 (347 mg, 80%) as a pale yellow solid.

[0102] 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=15.8Hz,1H),7.55–7.48(m,3H),7.46(d,J=15.8Hz,1H),7.35–7.23(m,3H ),6.37(s,1H),5.20(t,J=7.3Hz,1H),3.84(s,3H),3.82(s,3H),3.18(d,J=7.3Hz,2H),1.64(s,3H),1.62(s,3H).

[0103] 13C NMR(100MHz,Chloroform-d)δ190.61,161.75,159.16,141.65,135.65,132.64,131.97,129.8 6,128.83,128.28,127.45,122.84,122.24,121.13,94.95,56.11,55.60,27.72,25.83,17.79.

[0104] Compound 14 (100 mg, 0.297 mmol) and Rose bengal (30.53 mg, 0.03 mmol) were dissolved in anhydrous dichloromethane in an ice bath and stirred in a 50 mL round-bottom flask. The system was illuminated by 500 W incandescent light and the reaction was monitored by TLC. After the reaction was complete, triphenylphosphine (116.98 mg, 0.446 mmol) was added to the system and the reaction was further monitored by TLC. After the reaction was complete, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with saturated sodium chloride solution (100 mL × 3). The organic phase was collected, treated with anhydrous sodium sulfate as a desiccant, and then filtered and concentrated. The crude product was purified by flash silica gel chromatography to obtain Compound 15 (34 mg, 42%) as a white solid.

[0105] 2. Using the same method as above, the following compounds were prepared:

[0106] 1 H NMR (400MHz, CDCl3) δ7.73–7.58(m,2H),7.54–7.43(m,3H),7.20(d,J=7.8Hz,2H),6.48(s,1H),4.94(s,2H),4.29(dd,J=8. 6,4.2Hz,1H),3.93(d,J=5.0Hz,6H),2.91(dd,J=13.9,4.2Hz,1H),2.77(dd,J=13.8,8.7Hz,1H),2.38(s,3H),1.81(s,3H).

[0107] 13 C NMR (100MHz, CDCl3) δ190.57,161.86,159.52,147.18,142.20,140.37,133.72,132.78,129.6 0,128.34,126.33,121.48,119.44,110.78,95.11,75.60,56.08,55.70,36.17,21.51,18.09.

[0108] 1 H NMR(400MHz,CDCl3)δ7.67–7.56(m,2H),7.35(dd,J=15.7,10.5Hz,1H),7.26(s,1H),7.19(dd,J=8.3,2.0Hz,1H),7.12(d,J=2.0Hz,1H),6.88(d,J=8.3Hz,1H),6.49(d,J=5.9Hz,1H),4.94(s,1H),4.82(t,J=1.8Hz,1H),4.29(dd,J=8.5,4.2Hz,1H),3.92(t,J=2.6Hz,12H),2.99–2.67(m,2H),1.81(s,3H).

[0109] 13 C NMR(100MHz,CDCl3)δ190.61,161.72,159.36,150.98,149.16,147.19,142.42,133.63,131.41,128.50,125.39,122.60,121.58,119.43,111.14,110.77,110.31,95.18,56.10,56.00,55.92,55.70,36.17,18.09.

[0110] 1 H NMR(400MHz,CDCl3)δ7.70–7.29(m,8H),6.41(s,1H),δ4.87(s,1H),4.76(q,J=1.6Hz,1H),4.22(dd,J=8.8,4.2Hz,1H),3.87(dd,J=6.8,1.4Hz,6H),2.84(dd,J=13.9,4.2Hz,1H),2.70(dd,J=13.9,8.7Hz,1H),1.74(s,3H).

[0111] 13 C NMR(100MHz,CDCl3)δ189.97,162.19,159.72,147.17,140.41,134.52,133.85,132.08,129.68,127.82,124.07,121.08,119.61,110.83,94.97,75.57,56.08,55.73,36.12,18.10.

[0112] 1H NMR(400 MHz,CDCl3)δ7.58(dd,J=16.3,2.8 Hz,2H),7.39(dd,J=15.7,2.6 Hz,1H),6.82(d,J=2.7Hz,2H),6.49(d,J=2.4 Hz,1H),4.94(s,1H),4.87–4.75(m,1H),4.29(dd,J=8.5,4.2 Hz,1H),4.00–3.86(m,15H),2.92(dt,J=14.0,3.3 Hz,1H),2.84–2.71(m,1H),1.81(s,3H).

[0113] 13 C NMR(100 MHz,CDCl3)δ190.45,161.89,159.46,153.41,147.18,142.26,139.95,133.67,131.06,126.74,121.35,119.50,110.79,105.47,95.11,75.58,61.01,56.17,55.72,36.13,18.09.

[0114] 1 H NMR(400 MHz,CDCl3)δ7.64(d,J=15.0 Hz,2H),7.50(d,J=15.8 Hz,1H),7.31(t,J=7.8 Hz,1H),7.20(d,J=7.7 Hz,1H),7.12(d,J=2.5 Hz,1H),6.93(dd,J=8.1,2.7 Hz,1H),6.48(s,1H),4.94(s,1H),4.83(s,1H),4.29(dd,J=8.5,4.2 Hz,1H),3.93(d,J=5.3 Hz,6H),3.84(s,4H),2.91(dd,J=13.9,4.2 Hz,1H),2.77(dd,J=13.9,8.7 Hz,1H),1.81(s,3H).

[0115] 13 C NMR(100 MHz,CDCl3)δ190.38,162.01,159.87,159.63,147.18,141.87,136.97,133.78,129.82,127.60,121.29,120.95,119.50,115.58,113.48,110.81,95.04,75.59,56.07,55.71,55.32,36.14,18.09.

[0116] 1 H NMR(400 MHz,CDCl3)δ7.63(dd,J=18.1,3.3 Hz,2H),7.46–7.35(m,2H),7.28(d,J=3.3 Hz,2H),6.97(td,J=8.5,3.4 Hz,1H),6.49(dd,J=6.8,3.3 Hz,1H),4.97(s,1H),4.89–4.78(m,1H),4.31(dt,J=8.3,3.8 Hz,1H),4.17(qd,J=7.0,3.1 Hz,2H),3.97(dd,J=9.0,3.4 Hz,6H),2.98–2.73(m,2H),1.84(d,J=3.3Hz,4H),1.50(td,J=7.0,3.4 Hz,3H).

[0117] 13 C NMR(100 MHz,CDCl3)δ190.06,162.00,159.60,147.17,140.77,133.80,126.11,125.94,121.29,119.48,114.71,114.52,114.16,110.82,94.99,75.61,64.87,56.09,55.73,36.15,18.11,14.73.

[0118] 1 H NMR(400MHz,CDCl3)δ7.64(d,J=2.3Hz,2H),7.53–7.42(m,4H),6.48(d,J=2.2Hz,1H),4.94(s,1H),4.83(s,1H),4.29(dd,J=8.9,3.8Hz,1H),3.94(dd,J=7.0,2.3Hz,6H),2.90(s,1H),2.79(dd,J=8.6,2.3Hz,1H),1.81(d,J=2.1Hz,3H).

[0119] 13 C NMR(100MHz,CDCl3)δ189.97,162.19,159.72,147.17,140.40,134.52,133.85,132.08,129.69,127.81,124.06,121.06,119.61,110.83,94.96,75.57,56.07,55.74,36.12,18.10.

[0120] 1 H NMR(400MHz,CDCl3)δ7.69–7.50(m,4H),7.44–7.36(m,1H),6.94–6.86(m,2H),6.48(d,J=2.2Hz,1H),4.95(s,1H),4.83(d,J=2.6Hz,1H),4.29(dd,J=8.5,4.2Hz,1H),4.07(dd,J=7.0,2.2Hz,2H),3.93(dd,J=5.9,2.3Hz,6H),3.00–2.69(m,2H),1.81(s,3H),1.44(td,J=7.0,2.3Hz,3H).

[0121] 13 C NMR(100MHz,CDCl3)δ190.60,161.72,160.67,159.42,147.18,142.21,133.69,130.04,128.02,124.92,121.61,119.34,114.79,110.80,95.09,75.65,63.62,56.10,55.71,36.19,18.12,14.79.

[0122] 1 H NMR(400MHz,CDCl3)δ7.99(s,1H),7.86(dd,J=11.7,6.8Hz,4H),7.76(d,J=8.7Hz,1H),7.68–7.60(m,2H),7.51(dt,J=6.3,3.2Hz,2H),6.50(s,1H),5.01–4.78(m,2H),4.31(d,J=4.6Hz,1H),3.96(dd,J=12.7,2.9Hz,6H),3.00–2.68(m,2H),1.82(s,3H).

[0123] 13 C NMR(100MHz,CDCl3)δ190.38,162.00,159.64,147.18,142.15,134.16,133.82,133.45,133.07,130.25,128.58,127.79,127.47,127.07,126.64,123.85,121.40,119.52,110.83,95.08,75.62,56.12,55.73,36.17,18.11.

[0124] Example 2 Anti-inflammatory activity

[0125] 1. Anti-inflammatory activity experimental methods

[0126] 1) Experimental Materials

[0127] Cells: dendritic cells (DC2.4), macrophages (RAW264.7)

[0128] Cytokine kits: IL-6 detection kit, TNF-α detection kit

[0129] Stimulant: Lipopolysaccharide (LPS)

[0130] Positive control: dexamethasone (Dex)

[0131] Solvent: dimethyl sulfoxide (DMSO)

[0132] Comparative compound: WR010

[0133] 2) Experimental steps

[0134] Cell culture: DC2.4 cells and RAW264.7 cells were revived in T75 cell culture flasks and cultured in a 37°C 5% CO2 incubator. When the cell density in the cell culture flask reached above 99%, they were subcultured for at least 2 times. Then, DC2.4 cells and RAW264.7 cells were plated in 24-well cell culture plates at a cell density of 0.5×10 cells per well. 6 Culture overnight to allow cells to fully adhere to the wall.

[0135] Drug treatment: 20 μM of compound and Dex were added to the cells of the experimental group and positive control group, respectively. Only DMSO, the solvent for dissolving the compound, was added to the negative control. The cells were incubated in a constant temperature incubator at 37°C and 5% CO2 for 1 hour. Then, 5 μg / mL of LPS was added to each well of the experimental group and positive control group and incubated for 12 hours. The cell supernatant was collected and used for the detection of cytokine TNF-α and IL-6 levels.

[0136] Cytokine Assay: Serum cytokine levels were measured using TNF-α and IL-6 ELISA kits. Add 100 μL of TNF-α and IL-6 capture antibody solution to a 96-well plate and incubate overnight at 4°C. Wash three times with Wash Buffer, block with 200 μL / well of Assay Diluent A, incubate at 37°C for 1 hour, and wash three times. Add 100 μL / well of TNF-α and IL-6 standards and samples, incubate at 37°C for 2 hours, wash three times, add 100 μL of diluted TNF-α and IL-6 antibody solution, incubate at 37°C for 1 hour, wash three times, add 100 μL of Avidin-HRP solution, incubate at room temperature for 30 minutes, wash three times, add 100 μL of TMB, and incubate at room temperature in the dark for 30 minutes. Terminate the reaction by adding 100 μL of stop solution. Read the absorbance at 450 nm using a microplate reader within 15 minutes, and calculate cytokine levels based on the standard curve.

[0137] 2. Experimental results

[0138] The experimental results are shown in Figures 1-4. All the test compounds can downregulate the levels of IL-6 and TNF-α in RAW264.7 cells and DC2.4 cells after LPS stimulation. There are significant differences compared with the LPS group, and all are better than the positive control dexamethasone, and basically better than the reference compound WR010.

[0139] 3. The inventors further conducted a concentration gradient experiment using WR048-WR051 and compound 15 as examples: using the same experimental method as mentioned above, the experimental compounds and the positive control dexamethasone were treated with 20 μM, 10 μM, and 5 μM cells, respectively, and the levels of cytokines TNF-α and IL-6 were detected. The results showed that WR048-WR051 and compound 15 inhibited the levels of TNF-α and IL-6 produced under LPS stimulation in a dose-effect relationship. The higher the concentration, the greater the inhibitory intensity, and both were better than the corresponding concentration of the positive control dexamethasone.

[0140] The above experimental results show that the compound of the present invention has the effect of inhibiting the production of TNF-α and IL-6 by dendritic cells and macrophages under LPS stimulation.

[0141] Example 3 Antitumor Activity

[0142] 1. Anti-Triple Negative Breast Cancer Cell (TNBC) Proliferation Experiment - CCK-8 Detection

[0143] 1) Experimental Materials

[0144] Cells: Human breast cancer cells MDA-MB-468, BT549, Cal51

[0145] Cell proliferation detection kit: Cell Counting Kit-8 (CCK8) kit (TargetMol)

[0146] Positive control drug: 5-fluorouracil (5-Fu, MCE)

[0147] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0148] 2) Experimental steps

[0149] Cell culture: MDA-MB-468, BT549, and Cal51 cells were revived in T75 cell culture flasks and cultured in a 37°C 5% CO2 incubator. When the cell density in the cell culture flask reached above 90%, the cells were passaged for at least 2 times. The cells were then plated in 96-well cell culture plates at a cell density of 1×10 4 Culture overnight to allow cells to fully adhere to the wall.

[0150] Drug Treatment: Test compounds were added to cells in the experimental group to a final concentration of 10 μM. Control cells were treated with only DMSO, the solvent used to dissolve the compound. The positive control group was treated with the same concentration of 5-Fu. The blank control group was treated with only culture medium without cells. The cells were incubated at 37°C in a 5% CO2 incubator for 48 hours.

[0151] Detection: After 48 hours, 10 μL of CCK-8 solution was added to each well of the experimental group, control group, positive control group and blank group and incubated for 1-2 hours. The absorbance at 450 nm was measured using a microplate reader to calculate the cell survival rate.

[0152] Cell survival rate = [(As-Ab) / (Ac-Ab)] × 100%

[0153] As: experimental well; Ac: control well; Ab: blank well

[0154] Experimental results

[0155] The experimental results are shown in FIG5 , which show that the test compound can significantly inhibit the proliferation of the three TNBCs at the experimental concentrations.

[0156] 2. Inhibition of colorectal cancer cell proliferation experiment

[0157] Cells: Colorectal cancer cells HCT116 and HCT8. The experimental method is the same as point 1.

[0158] The experimental results are shown in FIG6 . All the test compounds except WR050 inhibited the proliferation of HCT116 at the tested concentrations, and all the test compounds except WR048, WR049 and WR050 inhibited the proliferation of HCT8 at the tested concentrations.

[0159] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound having a structure of formula I, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof, in, Ring A is phenyl, naphthyl, phenyl 3-10 Cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; n is 0, 1, 2, 3, 4 or 5; Each R1 is the same or different and is independently selected from hydroxy, halogen, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl, C 2-8 Alkenyloxy, C 2-8 Alkynyl, C 2-8 Alkynyloxy, C(O)R7, C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 Aryloxy, C 3-10 Cycloalkyloxy, 3-10 membered heterocyclyloxy, 5-10 membered heteroaryloxy, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy are optionally substituted by one or more selected from hydroxy, halogen, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution; R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; R4 is hydrogen, C 1-12 Alkyl, C(O)R 10 ; R5 is hydrogen or C 1-12 alkyl; R7 is selected from hydroxyl, C 1-12 Alkyl, C 1-12 Alkyloxy, NR8R9; R8 and R9 are independently selected from hydrogen or C 1-12 alkyl; R 10 Selected from hydroxyl, C 1-12 Alkyl, C 1-12 Alkyloxy; Preferably, the formula I is a structure of formula II:

2. The compound of formula I or II as claimed in claim 1, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl, C 2-8 Alkenyloxy, C 2-8 Alkynyl, C 2-8 Alkynyloxy, C(O)R7, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 Cycloalkyloxy, 3-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, phenyl, phenyloxy, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heteroaryl, heteroaryloxy are optionally substituted with one or more selected from hydroxy, F, Cl, Br, NH2, NO2, CN, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution; R7 is selected from hydroxyl, C 1-8 Alkyl, C 1-8 Alkyloxy, NR8R9; R8 and R9 are independently selected from hydrogen or C 1-8 alkyl; Preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C(O)R7, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl, wherein alkyl, alkyloxy, alkenyl, alkenyloxy, cycloalkyl, heterocyclyl, heteroaryl are optionally substituted with one or more selected from hydroxyl, F, Cl, Br, NH2, NO2, CN, C 1-4 Alkyl, C 1-4 Alkyloxy group substitution; R7 is selected from hydroxyl, C 1-4 Alkyl, C 1-4 Alkyloxy; Preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from hydroxyl, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy, wherein alkyl and alkyloxy are optionally substituted by one or more groups selected from F, Cl, and Br; More preferably, n is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy.

3. The compound of formula I or II as claimed in claim 1 or 2, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R2 and R3 are independently selected from hydrogen, C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 5-6 membered heteroaryl; Preferably, R2 and R3 are independently selected from hydrogen, C 1-12 alkyl; More preferably, R2 and R3 are independently selected from C 1-4 alkyl; More preferably, R2 and R3 are methyl.

4. A compound of formula I or II as claimed in any one of claims 1 to 3, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-8 Alkyl, C 1-8 Alkyloxy; Preferably, R4 is hydrogen, C(O)R 10 , R 10 Selected from hydroxyl, C 1-4 Alkyl, C 1-4 Alkyloxy; More preferably, R4 is hydrogen.

5. A compound of formula I or formula II, its enantiomer, pharmaceutically acceptable salt or solvate as claimed in any one of claims 1 to 4, wherein: R5 is hydrogen or C 1-8 alkyl; Preferably, R5 is C 1-4 alkyl; More preferably, R5 is methyl.

6. The compound of formula I structure as claimed in claim 1, its enantiomer, pharmaceutically acceptable salt or solvate, selected from the following compounds:

7. A pharmaceutical composition, characterized in that Containing the compound according to any one of claims 1 to 6, its enantiomer, pharmaceutically acceptable salt or solvate, preferably further containing one or more pharmaceutically acceptable carriers.

8. Use of the compound according to any one of claims 1 to 6, its enantiomer, pharmaceutically acceptable salt or solvate, or the pharmaceutical composition according to claim 7 in the preparation of anti-inflammatory or anti-tumor drugs.

9. The method of claim 8, wherein the inflammation is selected from the group consisting of autoimmune diseases, disorders or conditions, inflammatory diseases, disorders or conditions; preferably, idiopathic pulmonary fibrosis, inflammatory bowel disease (selected from Crohn's disease and ulcerative colitis), rheumatoid arthritis, osteoarthritis, Still's disease, Sjögren's syndrome, systemic lupus erythematosus, multiple sclerosis, psoriasis, systemic sclerosis, acute respiratory distress syndrome, allergic rhinitis, asthma, ocular inflammatory diseases (e.g., allergic conjunctivitis, dry eye and uveitis), atopic dermatitis, interstitial cystitis, chronic prostatitis / chronic pelvic pain syndrome (CP / CPPS), dermal contact hypersensitivity, eosinophilic gastrointestinal tract disorders (eosiniphilic gastrointestinal tract disorders), inflammatory bowel disease (such as inflammatory bowel disease ... disorder), fibromyalgia, liver fibrosis, irritable bowel syndrome, ischemia-reperfusion disease, renal fibrosis, pancreatitis, postoperative inflammation, seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's syndrome), and vasculitis (e.g., Wegener's granulomatosis, polyarteritis nodosa, leukocytic vasculitis, Churg-Strauss syndrome, cryoglobulinemic vasculitis, and giant cell arteritis); The tumor is selected from leukemia (such as acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute granulocytic leukemia, acute promyelocytic leukemia, acute myelo-monocytic leukemia, acute monocytic leukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphoma (Hodgkin's disease, non-Hodgkin's disease), primary macroglobulinemia, heavy chain disease, solid tumors such as sarcoma and cancer (such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, endotheliosarcoma, lymphangiosarcoma, angiosarcoma, lymphangioendotheliosarcoma, synovial vioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colorectal cancer, pancreatic cancer, breast cancer (such as triple negative breast cancer), ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland Preferably, the tumor includes but is not limited to pancreatic cancer, liver cancer, lung cancer, gastric cancer, esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, colorectal cancer, breast cancer (such as triple-negative breast cancer), lymphoma, gallbladder cancer, kidney cancer, leukemia, multiple myeloma, ovarian cancer, cervical cancer and glioma.

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