A chalcone derivative and its preparation method and application

Abstract

The invention provides a chalcone derivative, which has anti-inflammatory and anti-tumor activities.

Description

Technical Field

[0001] The 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

[0002] 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 can be traced back thousands of years, through the use of plants and herbs to treat different medical diseases, 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 drug.

[0003] Chalcones exhibit a wide range of biological activities, probably due to their small structure and Michael acceptor characteristics, which make them tolerant to different biomolecules and allow them to bind to different biomolecules easily or reactively. The biological activities of chalcones include anticancer activity, cancer prevention effect, anti-inflammatory activity, antimicrobial activity, antituberculosis activity, antidiabetic activity, antioxidant activity, antibacterial activity, antiviral activity, antimalarial activity, neuroprotective effect, etc.

[0004] Due to the ease of synthesis, many chalcone derivatives have also been prepared. These natural products and synthetic compounds have shown many interesting biological activities and have clinical potential against various diseases. Numerous studies have shown that they have strong positive effects in reducing inflammation, regulating immune responses, and supporting and restoring the normal function of cells. Summary of the invention

[0005] The present invention provides a compound having a structure of Formula I or preferably Formula II, an enantiomer, a pharmaceutically acceptable salt or a solvate thereof,

[0006]

[0007] in,

[0008] In formula I, ring A is phenyl, naphthyl, phenyl 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, C1-8 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;

[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 ethylene oxide, ethylene thiol, 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, thiolane, 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 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 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 2-4Alkenyloxy, 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 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 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.

[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 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 Alkyloxy; 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 Alkyl; 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, C1-8 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;

[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 with 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 alkyl and alkyloxy are optionally substituted by 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]

[0058]

[0059] 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-free radical oxidation reaction (for example, using a Rose Bengal reagent) to obtain a compound of formula I, wherein the definitions of substituents R1-R5 and ring A in formula A, formula B, and formula C are the same as those defined above. Those skilled in the art will appreciate that this method is also applicable to the preparation of a compound of formula II.

[0060]

[0061] The compounds of formula I or II of the present invention, their enantiomers, pharmaceutically acceptable salts or solvates have anti-inflammatory and anti-tumor activities.

[0062] 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.

[0063] The present invention also provides use of the compound of formula I or formula II of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of anti-tumor drugs.

[0064] The present invention also provides a pharmaceutical composition, which comprises the compound of formula I or formula II of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate, and optionally further comprises 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, adhesives, antioxidants, pH regulators, preservatives, lubricants, disintegrants, etc.

[0065] 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, and more preferably 5-100 mg.

[0066] 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%. Depending on the dosage form, the content range may be, for example, 0.1%-10%, 0.3-5%, or 10%-90%.

[0067] The pharmaceutical composition may be in the form of an oral dosage form, such as tablets, capsules, pills, powders, granules, suspensions, syrups, etc.; or in the form of an injectable dosage form, such as an injection, a powder injection, etc., which is administered by intravenous, intraperitoneal, subcutaneous or intramuscular injection. All dosage forms used are well known to those skilled in the art of pharmacy.

[0068] Routes of administration of the pharmaceutical composition include, but are not limited to: oral; buccal; sublingual; transdermal; pulmonary; rectal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous; by implanted reservoir or reservoir.

[0069] The dosage of the compound of formula I or II (in terms of 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, 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 (in terms of 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.

[0070] 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 II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the compound of formula I or II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof.

[0071] The 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, 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 (e.g., ... 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, leukocytodestructive vasculitis, Churg-Strauss syndrome, cryoglobulinemic vasculitis, and giant cell arteritis).

[0072] 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 II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition containing the compound of formula I or II of the present invention, an enantiomer thereof, a pharmaceutically acceptable salt or solvate thereof.

[0073] 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 myelo-monocytic leukemia, acute monocytic leukemia, acute leukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera), lymphomas (Hodgkin's disease, non-Hodgkin's disease), primary 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, colon cancer, pancreatic cancer, breast cancer (e.g., 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, colon 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.

[0074] 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. Therefore, 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 aspects: 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).

[0075] "Including" and "comprising" have the same meaning, are intended to be open ended and allow but not require the inclusion of additional elements or steps. When the terms "including" or "comprising" are used herein, the terms "consisting of" and / or "consisting essentially of" are also included and disclosed.

[0076] Alkyl: a straight 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, etc.

[0077] Alkyloxy: -O-alkyl, wherein alkyl is as defined above.

[0078] Cycloalkyl: saturated or partially unsaturated monocyclic or polycyclic cyclic alkyl. In the present invention, preferably 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms of cycloalkyl. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, etc.

[0079] Cycloalkyloxy: -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0080] Heterocyclic group: a stable 3 to 18-membered non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may include a spirocyclic, fused or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclic group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or completely saturated. In the present invention, a 3 to 10-membered, more preferably a 3 to 7-membered heterocyclic group is preferred. Examples of the heterocyclic group 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.

[0081] Heterocyclyloxy: -O-heterocyclyl, wherein heterocyclyl is as defined above.

[0082] Aromatic ring group: a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, which can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can 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, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrenes, pleiadene, pyrene and benzo[9,10]phenanthrene.

[0083] Aryloxy: -O-aryl, wherein the aryl is as defined above.

[0084] Heteroaryl: A 5- to 14-membered ring system radical containing hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, 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; and the nitrogen, carbon or sulfur atoms in the heteroaryl may be optionally oxidized; the nitrogen atom may be optionally quaternized. In the present invention, a 5- to 10-membered, more preferably a 5- to 6-membered heteroaryl is 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, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl (benzothienyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, 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-oxidopyridyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 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, quinazolinone, quinoxalinyl, quinoxalinone, quinolyl, isoquinolyl, tetrahydroquinolyl, thiazolyl, thiadiazolyl, thieno[3,2-d]pyrimidin-4-one, thieno[2,3-d]pyrimidin-4-one, triazolyl, tetrazolyl, triazinyl and thienyl (i.e., thienyl).

[0085] Heteroaryloxy: -O-heteroaryl, wherein heteroaryl is as defined above.

[0086] 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 to 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

[0087] Figure 1 After the RAW264.7 cells were treated with compound 15 and WR047-WR055, the RAW264.7 cells were then stimulated with LPS. The statistical graph of the IL-6 content in the culture fluid of the cells shows that ** represents P < 0.01 compared with the LPS treatment group, *** represents P < 0.001 compared with the LPS treatment group, and **** represents P < 0.0001 compared with the LPS treatment group.

[0088] Figure 2 After the RAW264.7 cells were treated with compound 15 and WR047-WR055, the RAW264.7 cells were then stimulated with LPS. The statistical graph of the detection of TNF-α content in the culture fluid of the cells, in the graph, ** represents, compared with the LPS treatment group, P < 0.01, *** represents, compared with the LPS treatment group, P < 0.001, **** represents, compared with the LPS treatment group, P < 0.0001

[0089] Figure 3 After treating DC2.4 cells with compound 15 and WR047-WR053, DC2.4 cells were then stimulated with LPS. The statistical graph of IL-6 content in the culture fluid of the cells shows that ** represents P < 0.01 compared with the LPS treatment group, *** represents P < 0.001 compared with the LPS treatment group, and **** represents P < 0.0001 compared with the LPS treatment group.

[0090] Figure 4 After treating DC2.4 cells with compound 15 and WR047-WR053, DC2.4 cells were then stimulated with LPS. The statistical graph of TNF-α content in the culture medium of the cells shows that ** represents P < 0.01 compared with the LPS treatment group, *** represents P < 0.001 compared with the LPS treatment group, and **** represents P < 0.0001 compared with the LPS treatment group.

[0091] Figure 5 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, compared with the blank control group, P < 0.05, ** represents, compared with the blank control group, P < 0.01, *** represents, compared with the blank control group, P < 0.001, **** represents, compared with the blank control group, P < 0.0001

[0092] Figure 6 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, compared with the blank control group, P < 0.05, ** represents, compared with the blank control group, P < 0.01, *** represents, compared with the blank control group, P < 0.001, **** represents, compared with the blank control group, P < 0.0001 DETAILED DESCRIPTION

[0093] The present invention is further described below in conjunction with the examples. It should be noted that the examples cannot be used as a limitation on the protection scope of the present invention, and those skilled in the art understand that any improvements and changes made on the basis of the present invention are within the protection scope of the present invention.

[0094] 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 instructions in the corresponding experimental manual or kit instructions.

[0095] 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: europium tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate); Ac2O: acetic anhydride.

[0096] Example 1: Preparation Example of Compounds

[0097] 1. Preparation of intermediate compounds

[0098]

[0099] 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 in sequence, dissolved with anhydrous DMF, and the reaction system was placed at room temperature and continued to stir. The reaction was detected 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 a saturated sodium chloride solution (100 mL × 3). The organic phase was collected and treated with anhydrous sodium sulfate as a desiccant, filtered and concentrated, and the crude product was purified by flash silica gel chromatography to obtain a light yellow solid compound 10 (1.89 g, 93%).

[0100] Under argon, compound 10 (1.89 g, 11.50 mmol) and potassium carbonate (3.178 g, 23.00 mmol) were dissolved in anhydrous DMF, placed in a 50 mL round-bottom flask and stirred, 1-bromo-3-methyl-2-butene (1.99 ml, 17.25 mmol) was added under ice bath, stirred for 30 minutes, and the reaction system was placed at room temperature to continue the reaction. The reaction was detected 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 and treated with anhydrous sodium sulfate as a desiccant, filtered and concentrated. The crude product was purified by flash silica gel chromatography to obtain white solid compound 11 (1.78 g, 83%).

[0101]

[0102] Compound 11 (2 g, 8.54 mmol) was placed in a 250 mL round-bottom flask, dissolved with anhydrous N,N-diethylaniline, and the reaction system was placed at 230°C and continued to stir. The reaction was detected 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 1N hydrochloric acid solution (100 mL×3). The organic phase was collected and treated with anhydrous sodium sulfate as a desiccant, filtered and concentrated, and the crude product was purified by flash silica gel chromatography to obtain a light yellow solid compound 12 (1.89 g, 95%).

[0103] 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).

[0104] 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.

[0105]

[0106] After the intermediate 12 (350 mg, 1.495 mmol) was dissolved in anhydrous N,N-dimethylformamide, it was placed in a 50 mL round-bottom flask and stirred. Methyl iodide (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 placed at room temperature to continue the reaction. The reaction was detected 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 a saturated sodium chloride solution (100 mL × 3). The organic phase was collected and 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 a white solid compound 13 (332 mg, 95%).

[0107] Compound 13 (332 mg, 1.337 mmol) and benzaldehyde (278 mg, 2.579 mmol) were dissolved in anhydrous ethanol, placed in a 50 mL round-bottom flask and stirred, 4 M sodium hydroxide solution (0.96 mL, 3.876 mmol) was slowly added dropwise under an ice bath, stirred for 30 minutes, and the reaction system was placed at 50 ° C to continue the reaction. The reaction was detected 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 a saturated sodium chloride solution (100 mL × 3). The organic phase was collected and treated with anhydrous sodium sulfate as a desiccant, filtered and concentrated. The crude product was purified by flash silica gel chromatography to obtain a light yellow solid compound 14 (347 mg, 80%).

[0108] 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).

[0109] 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.

[0110]

[0111] Under ice bath, compound 14 (100 mg, 0.297 mmol) and Rose bengal (30.53 mg, 0.03 mmol) were dissolved in anhydrous dichloromethane, placed in a 50 mL round bottom flask and stirred, the system was placed under 500 W incandescent light, and the reaction was detected by TLC. After the reaction was complete, triphenylphosphine (116.98 mg, 0.446 mmol) was added to the system, and the reaction was continued to be detected 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), and the organic phase was collected and treated with anhydrous sodium sulfate as a desiccant, filtered and concentrated. The crude product was purified by flash silica gel chromatography to obtain white solid compound 15 (34 mg, 42%).

[0112] 2. Using the same method as above, the following compounds were prepared:

[0113]

[0114] 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).

[0115] 13C NMR(100MHz,CDCl3)δ190.57,161.86,159.52,147.18,142.20,140.37,133.72,132.78,129.60,128.34,126.33,121.48,119.44,110.78,95.11,75.60,56.08,55.70,36.17,21.51,18.09.

[0116]

[0117] 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).

[0118] 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.

[0119]

[0120] 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).

[0121] 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.

[0122]

[0123] 1 H NMR(400MHz,CDCl3)δ7.58(dd,J=16.3,2.8Hz,2H),7.39(dd,J=15.7,2.6Hz,1H),6.82(d,J=2.7Hz,2H),6.49(d,J=2.4Hz,1H),4.94(s,1H),4.87–4.75(m,1H),4.29(dd,J=8.5,4.2Hz,1H),4.00–3.86(m,15H),2.92(dt,J=14.0,3.3Hz,1H),2.84–2.71(m,1H),1.81(s,3H).

[0124] 13 C NMR(100MHz,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.

[0125]

[0126] 1H NMR(400MHz,CDCl3)δ7.64(d,J=15.0Hz,2H),7.50(d,J=15.8Hz,1H),7.31(t,J=7.8Hz,1H),7.20(d,J=7.7Hz,1H),7.12(d,J=2.5Hz,1H),6.93(dd,J=8.1,2.7Hz,1H),6.48(s,1H),4.94(s,1H),4.83(s,1H),4.29(dd,J=8.5,4.2Hz,1H),3.93(d,J=5.3Hz,6H),3.84(s,4H),2.91(dd,J=13.9,4.2Hz,1H),2.77(dd,J=13.9,8.7Hz,1H),1.81(s,3H).

[0127] 13 C NMR(100MHz,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.

[0128]

[0129] 1 H NMR(400MHz,CDCl3)δ7.63(dd,J=18.1,3.3Hz,2H),7.46–7.35(m,2H),7.28(d,J=3.3Hz,2H),6.97(td,J=8.5,3.4Hz,1H),6.49(dd,J=6.8,3.3Hz,1H),4.97(s,1H),4.89–4.78(m,1H),4.31(dt,J=8.3,3.8Hz,1H),4.17(qd,J=7.0,3.1Hz,2H),3.97(dd,J=9.0,3.4Hz,6H),2.98–2.73(m,2H),1.84(d,J=3.3Hz,4H),1.50(td,J=7.0,3.4Hz,3H).

[0130] 13C NMR(100MHz,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.

[0131]

[0132] 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).

[0133] 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.

[0134]

[0135] 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).

[0136] 13C NMR (100MHz, CDCl3) δ190.60,161.72,160.67,159.42,147.18,142.21,133.69,130.04,128.02,1 24.92,121.61,119.34,114.79,110.80,95.09,75.65,63.62,56.10,55.71,36.19,18.12,14.79.

[0137]

[0138] 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).

[0139] 13 C NMR (100MHz, CDCl3) δ190.38,162.00,159.64,147.18,142.15,134.16,133.82,133.45,133.07,130.25,128.5 8,127.79,127.47,127.07,126.64,123.85,121.40,119.52,110.83,95.08,75.62,56.12,55.73,36.17,18.11.

[0140] Example 2 Anti-inflammatory activity

[0141] 1. Anti-inflammatory activity experimental methods

[0142] 1) Experimental Materials

[0143] Cells: dendritic cells (DC2.4), macrophages (RAW264.7)

[0144] Cytokine kits: IL-6 detection kit, TNF-α detection kit

[0145] Stimulant: Lipopolysaccharide (LPS)

[0146] Positive control: dexamethasone (Dex)

[0147] Solvent: dimethyl sulfoxide (DMSO)

[0148] Comparison compound: WR010

[0149] 2) Experimental procedures

[0150] Cell culture: DC2.4 cells and RAW264.7 cells were revived in T75 cell culture flasks and cultured in a constant temperature incubator at 37°C and 5% CO2. When the cell density in the cell culture flask reached more than 99%, the cells were subcultured for at least 2 times. Then, DC2.4 cells and RAW264.7 cells were plated in 24-well cell culture plates, with a cell concentration of 0.5×10 6 Overnight culture allowed cells to fully adhere to the wall.

[0151] Drug treatment: 20 μM of compound and Dex were added to the cells of the experimental group and the 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 the positive control group and incubated for 12 hours. The cell supernatant was collected for the detection experiment of cytokine TNF-α and IL-6 content.

[0152] Cytokine detection: ELISA kits for TNF-α and IL-6 were used to detect the cytokine levels in serum. 100 μL of TNF-α and IL-6 capture antibody solution was added to the 96-well plate and incubated overnight at 4°C. Wash 3 times with Wash Buffer, block with 200 μL / well of Assay Diluent A, incubate at 37°C for 1 hour, and wash 3 times. Add 100 μL / well of TNF-α and IL-6 standards and samples, incubate at 37°C for 2 hours, wash 3 times, add 100 μL of diluted TNF-α and IL-6 antibody solution, incubate at 37°C for 1 hour, wash 3 times, add 100 μL of Avidin-HRP solution, incubate at room temperature for 30 minutes, wash 3 times, add 100 μL of TMB, and incubate at room temperature in the dark for 30 minutes. Add 100 μL of stop solution to terminate the reaction. Read the absorbance at 450 nm with an enzyme reader within 15 minutes, and calculate the cytokine level according to the standard curve.

[0153] 2. Experimental results

[0154] The experimental results are as follows Figure 1-4 As shown, all the tested compounds can down-regulate the contents of IL-6 and TNF-α in RAW264.7 cells and DC2.4 cells after LPS stimulation, which are significantly different from those in the LPS group, and are better than the positive control dexamethasone, and are basically better than the comparison compound WR010.

[0155] 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 generated under LPS stimulation in a dose-effect relationship. The higher the concentration, the greater the inhibition intensity, and they were all better than the corresponding concentration of the positive control dexamethasone.

[0156] 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.

[0157] Example 3 Antitumor Activity

[0158] 1. Anti-triple negative breast cancer cell (TNBC) proliferation experiment - CCK-8 detection

[0159] 1) Experimental Materials

[0160] Cells: Human breast cancer cells MDA-MB-468, BT549, Cal51

[0161] Cell proliferation detection kit: Cell Counting Kit-8 (CCK8) kit (TargetMol)

[0162] Positive control drug: 5-fluorouracil (5-Fu, MCE)

[0163] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0164] 2) Experimental procedures

[0165] Cell culture: MDA-MB-468, BT549, and Cal51 cells were revived in T75 cell culture flasks and cultured in a constant temperature incubator at 37°C and 5% CO2. When the cell density in the cell culture flask reached more than 90%, the cells were subcultured for at least 2 times. The cells were then plated in 96-well cell culture plates at a cell concentration of 1×10 4 Overnight culture allowed cells to fully adhere to the wall.

[0166] Drug treatment: The test compound was added to the cells of the experimental group to make the final concentration of the compound 10 μM. The cells of the control group were only added with DMSO, the solvent for dissolving the compound, the positive control group was added with the same concentration of 5-Fu, and the blank group was only added with culture medium without cells, and incubated in a constant temperature incubator at 37°C and 5% CO2 for 48 hours.

[0167] Detection: After 48 hours, add 10 μL of CCK-8 solution to each well of the experimental group, control group, positive control group and blank group and incubate for 1-2 hours. Use an enzyme reader to measure the absorbance at 450 nm to calculate the cell survival rate.

[0168] Cell survival rate = [(As-Ab) / (Ac-Ab)] × 100%

[0169] As: experimental well; Ac: control well; Ab: blank well

[0170] Experimental Results

[0171] The experimental results are as follows Figure 5 As shown, the experiment showed that the test compound could significantly inhibit the proliferation of three TNBCs at the experimental concentration.

[0172] 2. Experiment on inhibiting the proliferation of colorectal cancer cells

[0173] Cells: Colorectal cancer cells HCT116 and HCT8. The experimental method is the same as point 1.

[0174] The experimental results are as follows Figure 6 As shown, all the tested compounds except WR050 had an inhibitory effect on the proliferation of HCT116 at the tested concentrations, and all the tested compounds except WR048, WR049 and WR050 had an inhibitory effect on the proliferation of HCT8 at the tested concentrations.

[0175] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope 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; n is 0, 1, 2, 3, 4 or 5; Each R1 is the same or different and is independently selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy, wherein alkyl, alkyloxy is optionally substituted by one or more selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution; R2 and R3 are independently selected from hydrogen, C 1-12 alkyl; R4 is hydrogen; R5 is C 1-12 alkyl; and the compound of formula I is not 2. The compound of formula I according to 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 F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy, wherein alkyl, alkyloxy is optionally substituted by one or more selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy groups are substituted.

3. The compound of formula I according to claim 2, 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 F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy, wherein the alkyl and alkyloxy groups are optionally substituted by one or more groups selected from F, Cl, and Br.

4. The compound of formula I structure as claimed in claim 3, 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 F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy.

5. A compound having the structure of formula I, its enantiomer, pharmaceutically acceptable salt or solvate, in, Ring A is phenyl; n is 1, 2, 3, 4 or 5; Each R1 is the same or different and is independently selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy, wherein alkyl, alkyloxy is optionally substituted by one or more selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution; R2 and R3 are independently selected from hydrogen, C 1-12 alkyl; R4 is hydrogen; R5 is C 1-12 alkyl.

6. The compound of formula I according to claim 5, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: n is 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, wherein alkyl, alkyloxy is optionally substituted by one or more selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy groups are substituted.

7. The compound of formula I according to claim 6, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: n is 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, wherein the alkyl and alkyloxy groups are optionally substituted by one or more groups selected from F, Cl, and Br.

8. The compound of formula I according to claim 7, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: n is 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.

9. A compound of formula I according to any one of claims 1 to 8, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R2 and R3 are independently selected from C 1-4 alkyl.

10. The compound of formula I according to claim 9, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R2 and R3 are methyl groups.

11. A compound of formula I according to any one of claims 1 to 8, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R5 is C 1-4 alkyl.

12. The compound of formula I, its enantiomer, pharmaceutically acceptable salt or solvate according to claim 11, wherein: R5 is methyl.

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

14. A pharmaceutical composition, characterized in that A compound comprising the compound according to any one of claims 1 to 13, its enantiomer, pharmaceutically acceptable salt or solvate.

15. The pharmaceutical composition according to claim 14, characterized in that It further contains one or more pharmaceutically acceptable carriers.

16. Use of a compound of formula I, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of an anti-inflammatory or anti-tumor drug, wherein the tumor is selected from colorectal cancer, breast cancer, in, Ring A is phenyl; n is 0, 1, 2, 3, 4 or 5; Each R1 is the same or different and is independently selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy, wherein alkyl, alkyloxy is optionally substituted by one or more selected from halogen, C 1-8 Alkyl, C 1-8 Alkyloxy group substitution; R2 and R3 are independently selected from hydrogen, C 1-12 alkyl; R4 is hydrogen; R5 is C 1-12 alkyl.

17. The use according to claim 16, wherein In Formula I, 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, wherein alkyl, alkyloxy is optionally substituted by one or more selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkyloxy groups are substituted.

18. The use according to claim 17, wherein In Formula I, 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, wherein the alkyl and alkyloxy groups are optionally substituted by one or more groups selected from F, Cl, and Br.

19. The use according to claim 18, wherein In Formula I, 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.

20. The use according to any one of claims 16 to 19, wherein In Formula I, R2 and R3 are independently selected from C 1-4 alkyl.

21. The use according to claim 20, wherein In formula I, R2 and R3 are methyl groups.

22. The use according to any one of claims 16 to 19, wherein In Formula I, R5 is C 1-4 alkyl.

23. The use according to claim 22, wherein In formula I, R5 is methyl.

24. The use according to claim 16, wherein The compound of formula I is selected from:

25. The use according to any one of claims 16-19 and 24, wherein the breast cancer is triple-negative breast cancer.

26. The use according to claim 20, wherein the breast cancer is triple-negative breast cancer.

27. The use according to claim 21, wherein the breast cancer is triple-negative breast cancer.

28. The use according to claim 22, wherein the breast cancer is triple-negative breast cancer.

29. The use according to claim 23, wherein the breast cancer is triple-negative breast cancer.

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