Chalcone derivative having benzopyran structure, preparation method therefor and use thereof

Abstract

The present invention provides a chalcone derivative having a benzopyran structure. The compound has anti-inflammatory and anti-tumor activity, and can inhibit tumor cell proliferation, promote tumor cell apoptosis, inhibit tumor cell colony formation, and inhibit tumor cell migration.

Description

A chalcone derivative with a benzopyran structure and its preparation method and application

[0001] This application claims priority to a prior application, patent application number 202311595446.9, filed with the State Intellectual Property Office of China on November 27, 2023, entitled “A chalcone derivative with a benzopyran structure, its preparation method, and application.” 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 with a benzopyran structure, 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, its enantiomer, pharmaceutically acceptable salt or solvate,

[0007] Where R1 is C 1-20 Alkyl, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, 5-10 membered heteroaryl, C1-20 Alkyloxy, C 6-10 Aromatic ring group oxygen, C 3-10 Cycloalkyloxy, 5-10 membered heterocyclyloxy or 5-10 membered heteroaryloxy, wherein the alkyl, aromatic ring group, cycloalkyl, heterocyclyl, heteroaryl, alkyloxy, aromatic ring group oxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy are optionally substituted by one or more selected from halogen, C 1-10 Alkyloxy, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, 5-10 membered heteroaryl, C 6- 10 Aromatic ring group oxygen, C 3-10 substituted with a cycloalkyloxy, 5-10 membered heterocyclyloxy or 5-10 membered heteroaryloxy group;

[0008] R2 is hydrogen, C 1-20 Alkyl, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl;

[0009] R3 is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 alkyloxy;

[0010] Each R4 is the same or different and is independently selected from hydrogen or C 1-12 alkyl.

[0011] In some embodiments of the present invention, C 6-10 The aromatic ring group is preferably a phenyl group.

[0012] 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.

[0013] In some embodiments of the present invention, the 5-10 membered heterocyclic group is preferably a 5-7 membered heterocyclic group, such as 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.

[0014] 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.

[0015] In some embodiments of the present invention, the halogen is preferably F, Cl or Br.

[0016] In some embodiments of the present invention, in Formula I, R1 is C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, C 1-12 Alkyloxy, phenyloxy, C 3-7 Cycloalkyloxy, 5-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein the alkyl, phenyl, cycloalkyl, heterocyclyl, heteroaryl, alkyloxy, phenyloxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy are optionally substituted by one or more groups selected from F, Cl, Br, or the alkyloxy is optionally substituted by one or more groups selected from C 1-6 Alkyloxy, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 Preferably, R1 is C 1-8 Alkyl, phenyl, cyclohexyl, cyclopentyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, tetrahydropyranyl, thiolanyl, piperidinyl, C 1-8 alkyloxy, phenyloxy, cyclohexyloxy, cyclopentyloxy, tetrahydrofuranyloxy, thiolanyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, thiolanyloxy, piperidinyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1-6 More preferably, R1 is C 1-8 Alkyl, phenyl, cyclohexyl, tetrahydrofuranyl, C 1-8 Alkyloxy, phenyloxy, cyclohexyloxy, tetrahydrofuranyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1- 6. Alkyloxy, phenyl, tetrahydrofuryl, cyclohexyl, phenyloxy, tetrahydrofuryloxy, cyclohexyloxy.

[0017] In some embodiments of the present invention, in Formula I, R2 is hydrogen or C 1-12 Alkyl; preferably R2 is hydrogen or C 1-4 More preferably, R2 is methyl.

[0018] In some embodiments of the present invention, in Formula I, R3 is hydrogen or C 1-4 Alkyl; preferably R3 is hydrogen.

[0019] In some embodiments of the present invention, in Formula I, R4 is hydrogen or C 1-4 More preferably, R4 is methyl.

[0020] In some embodiments of the present invention, in Formula I, R1 is C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, C 1-12 Alkyloxy, phenyloxy, C 3-7 Cycloalkyloxy, 5-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein the alkyl, phenyl, cycloalkyl, heterocyclyl, heteroaryl, alkyloxy, phenyloxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy are optionally substituted by one or more groups selected from F, Cl, Br, or the alkyloxy is optionally substituted by one or more groups selected from C 1-6 Alkyloxy, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 cycloalkyloxy, 5-7 membered heterocyclyloxy or 5-6 membered heteroaryloxy; R2 is hydrogen or C 1-12 Alkyl; R3 is hydrogen or C 1-4 Alkyl; R4 is hydrogen or C 1-4 Alkyl; preferably, R2 is hydrogen or C 1-4 Alkyl; more preferably, R2 is methyl, R3 is hydrogen, and R4 is methyl.

[0021] In some embodiments of the present invention, in Formula I, R1 is C 1-8 Alkyl, phenyl, cyclohexyl, cyclopentyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, tetrahydropyranyl, thiolanyl, piperidinyl, C 1-8 alkyloxy, phenyloxy, cyclohexyloxy, cyclopentyloxy, tetrahydrofuranyloxy, thiolanyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, thiolanyloxy, piperidinyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1-6 alkyloxy, phenyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl, thiolanyl, pyrrolidinyl, tetrahydropyranyl, thiolanyl, piperidinyl, phenyloxy, tetrahydrofuranyloxy, cyclohexyloxy, cyclopentyloxy, thiolanyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, thiolanyloxy, piperidinyloxy; R2 is hydrogen or C 1-12 Alkyl; R3 is hydrogen or C 1-4 Alkyl; R4 is hydrogen or C1-4 Alkyl; preferably, R2 is hydrogen or C 1-4 Alkyl; more preferably, R2 is methyl, R3 is hydrogen, and R4 is methyl.

[0022] In some embodiments of the present invention, in Formula I, R1 is C 1-8 Alkyl, phenyl, cyclohexyl, tetrahydrofuranyl, C 1-8 Alkyloxy, phenyloxy, cyclohexyloxy, tetrahydrofuranyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1-6 The group is substituted with an alkyloxy group, a phenyl group, a tetrahydrofuryl group, a cyclohexyl group, a phenyloxy group, a tetrahydrofuryloxy group, or a cyclohexyloxy group; R2 is a methyl group; R3 is a hydrogen group; and R4 is a methyl group.

[0023] In some embodiments of the present invention, the compound of formula I is selected from the following compounds:

[0024] The present invention also discloses a method for preparing a compound of formula I, comprising: subjecting a compound of formula A to an olefin metathesis reaction with a compound of formula B to obtain a compound of formula I, wherein R1, R2, R3, and R4 in formula A and formula B are defined as above, and Rx and Ry are independently selected from hydrogen, C 1-4 alkyl.

[0025] The compound of formula I of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate has anti-inflammatory and anti-tumor activities, and also has VEGF inhibitory activity.

[0026] The present invention also provides use of the compound of formula I, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of a drug for inhibiting inflammation.

[0027] The present invention also provides use of the compound of formula I, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of anti-tumor drugs.

[0028] The present invention also provides use of the compound of formula I, its enantiomer, pharmaceutically acceptable salt or solvate in the preparation of a VEGF inhibitor.

[0029] The present invention also provides a pharmaceutical composition comprising a compound of formula I, an enantiomer, 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 regulators, preservatives, lubricants, disintegrants, and the like.

[0030] The amount of the compound of formula I contained in the pharmaceutical composition (calculated as the compound of formula I) is 0.1-1000 mg, preferably 1-500 mg, more preferably 5-100 mg.

[0031] The mass percentage of the compound of formula I (calculated as the compound of formula I) in the pharmaceutical composition is 0.01%-95%, and can be, for example, 0.1%-10%, 0.3-5%, or 10%-90% depending on the dosage form.

[0032] 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.

[0033] 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.

[0034] The dosage of the compound of formula I (calculated as the compound of formula I) 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 can be administered in divided doses twice, three times or four times a day. The dosage of the compound of formula I (calculated as the compound of formula I) is 0.01-100 mg / kg / day, for example, 0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 5 mg / kg / day, etc.

[0035] The present invention also provides a method for inhibiting inflammation, which comprises administering to a patient in need thereof a compound of formula I of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition containing the compound of formula I of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate.

[0036] 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).

[0037] The present invention also provides a method for treating tumors, which comprises administering to a patient in need thereof the compound of formula I of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate, or a pharmaceutical composition containing the compound of formula I of the present invention, its enantiomer, pharmaceutically acceptable salt or solvate.

[0038] 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.

[0039] 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).

[0040] "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.

[0041] Alkyl: A linear or branched saturated aliphatic group. In the present invention, an alkyl group having 1 to 20 carbon atoms, preferably 1 to 12 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.

[0042] Alkyloxy: -O-alkyl, wherein alkyl is as defined above.

[0043] 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.

[0044] Cycloalkyloxy: -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0045] 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, 5- to 10-membered, more preferably 5- 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.

[0046] Heterocyclyloxy: -O-heterocyclyl, wherein heterocyclyl is as defined above.

[0047] 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.

[0048] Arylcyclyloxy: -O-arylcyclyl, wherein the arylcyclyl group is as defined above.

[0049] 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).

[0050] Heteroaryloxy: -O-heteroaryl, wherein heteroaryl is as defined above.

[0051] 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

[0052] Figure 1 is a statistical graph showing the detection of IL-6 content in the culture medium of RAW264.7 cells after treatment with compounds WR031-WR046 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.

[0053] Figure 2 is a statistical graph showing the detection of TNF-α content in the culture medium of RAW264.7 cells after treatment with compounds WR031-WR046 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.

[0054] Figure 3 IC50 (48h) of compound WR034 against four TNBCs, the data are plotted as a percentage relative to the DMSO control group

[0055] Figure 4 Effects of compounds WR034 and 5-Fu on apoptosis levels in Cal51 and MDA-MB-231 cells

[0056] Figure 5 Representative images and quantitative data analysis of colony formation by compound WR034 in Cal51 and MDA-MB-231 cells

[0057] Figure 6 Effects of compounds WR034 and 5-Fu on the migration levels of BT549 and MDA-MB-231 cells

[0058] Figure 7 Detection results of the inhibition of VEGF-induced HUVEC cell proliferation by compounds WR033, WR034 and WR045 at gradient concentrations (2 μM, 4 μM, 6 μM, 8 μM and 10 μM)

[0059] Figure 8 Detection results of the inhibition of HUVEC cell proliferation without VEGF induction by compounds WR033, WR034 and WR045 at gradient concentrations (2 μM, 4 μM, 6 μM, 8 μM and 10 μM)

[0060] Figure 9 Effects of compounds WR033, WR034, and WR045 on VEGF-induced HUVEC cell migration

[0061] Figure 10 Experimental results of the effects of compounds WR033, WR034 and WR045 on angiogenesis of HUVEC cells in vitro

[0062] Figure 11 Experimental results of compounds WR034, WR037, and WR043 inhibiting the proliferation of colorectal cancer cells HCT116 and HCT8 DETAILED DESCRIPTION

[0063] 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.

[0064] 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.

[0065] 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.

[0066] Example 1 Synthesis of WR031 compound

[0067] Specific experimental steps:

[0068] Compound 1 (2 g, 13.144 mmol), potassium carbonate (3.63 g, 26.288 mmol), 3-chloro-3-methyl-1-butyne (2.29 g, 22.33 mmol), cuprous iodide (0.13 g, 0.66 mmol) and potassium iodide (3.27 g, 19.72 mmol) were placed in a 250 mL round-bottom flask in sequence and dissolved with anhydrous DMF. The reaction system was then placed at room temperature and stirred. The reaction was monitored by TLC. After completion of the reaction, 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, treated with anhydrous sodium sulfate as a desiccant, filtered, and concentrated. The crude product was purified by flash silica gel chromatography to obtain compound 2 (2.324 g, 81%) as a light yellow solid.

[0069] 1 H NMR(400MHz,Chloroform-d)δ12.60(s,1H),7.63(d,J=8.9Hz,1H),6.88(d,J=2 .5Hz,1H),6.66(dd,J=8.9,2.5Hz,1H),2.66(s,1H),2.56(s,3H),1.72(s,6H).

[0070] 13 C NMR (100MHz, Chloroform-d) δ202.81,164.36,162.63,131.82,114.50,111.05,106.48,84.71,75.10,72.36,29.54,26.30.

[0071] Compound 2 (500 mg, 2.28 mmol) was dissolved in diethylaniline (15 mL) and placed in a 50 mL round-bottom flask. The reaction system was heated to 250°C and monitored by TLC. After completion, 200 mL of ethyl acetate was added to the system. The reaction solution was washed and extracted with sodium bicarbonate solution (100 mL × 3) and 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 3 (473 mg, 95%) as a white solid.

[0072] 1H NMR (400MHz, Chloroform-d) δ12.97 (s, 1H), 7.50 (d, J = 8.8Hz, 1H), 6.70 (dd, J = 10.1, 0. 8Hz, 1H), 6.32 (dd, J=8.8, 0.8Hz, 1H), 5.57 (d, J=10.1Hz, 1H), 2.53 (s, 3H), 1.44 (s, 6H).

[0073] 13 C NMR (100MHz, Chloroform-d) δ202.77,159.62,131.66,128.22,115.79,113.85,109.22,108.31,77.72,28.31,26.18.

[0074] Under argon, compound 3 (0.88 g, 4.03 mmol) and sodium hydride (0.55 g, 22.91 mmol) were dissolved in anhydrous DMF and placed in a 50 mL round-bottom flask with stirring. Allyl bromide (1.19 ml, 10.31 mmol) was added under ice-cooling and stirred for 30 minutes. The reaction system was then 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 5 (784 mg, 88%) as a white solid.

[0075] 1 H NMR (400MHz, Chloroform-d) δ7.53–7.41(m,1H),6.52(ddd,J=13.2,9.7,3.0Hz,2H),5.98(dddd,J=15.9,10.8,5.4,2.8Hz,1H),5.72–5.50(m, 1H),5.35(ddd,J=17.1,3.0,1.5Hz,1H),5.20(ddd,J=10.5,3.0,1.5Hz,1H),4.29(dq,J=4.4,1.5Hz,2H),2.67–2.31(m,3H),1.59–0.87(m,6H).

[0076] 13C NMR(100MHz,Chloroform-d)δ198.32,157.86,155.24,132.98,131.03,130.56,125.59,118.12,116.75,115.08,112.75,76.87,76.61,30.35,28.00.

[0077] Compound 5 (0.88 g, 3.11 mmol) and Eu(fod)3 (0.16 mg, 0.16 mmol) were dissolved in chloroform and placed in a 50 mL round-bottom flask under reflux at 60°C. 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 6 (0.695 g, 78%) as a white solid.

[0078] 1 H NMR(400MHz,Chloroform-d)δ12.87(d,J=3.2Hz,1H),7.33(d,J=3.1Hz,1H),6.71(d,J=9.6Hz,1H),5.94(ddd,J=16.9,6.9 ,3.6Hz,1H),5.58(d,J=9.7Hz,1H),5.27–4.82(m,2H),3.27(d,J=6.3Hz,2H),2.54(d,J=3.2Hz,3H),1.44(d,J=3.0Hz,6H).

[0079] 13 C NMR(100MHz,Chloroform-d)δ202.76,158.34,157.55,136.67,131.25,127.99,119.13,116.09,115.67,113.37,108.99,77.67,33.46,28.31,26.22.

[0080] Compound 6 (0.6 g, 2.09 mmol) was dissolved in anhydrous N,N-dimethylformamide and placed in a 50 mL round-bottom flask with stirring. Iodomethane (0.26 mL, 4.19 mmol) and sodium hydride (0.25 g, 10.41 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 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 7 (559 mg, 89%) as a white solid.

[0081] Compound 7 (330 mg, 1.21 mmol) and benzaldehyde (535.8 mg, 5.049 mmol) were dissolved in anhydrous ethanol and placed in a 50 mL round-bottom flask with stirring. 4 M sodium hydroxide solution (0.841 mL, 3.367 mmol) was slowly added dropwise under an ice bath. After stirring for 30 minutes, the reaction system was placed at 50°C to continue the reaction. The reaction was 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 x 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 8 (698 mg, 86%) as a light yellow solid.

[0082] 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=15.8Hz,1H),7.67–7.50(m,3H),7.46–7.36(m,4H),6.65(d,J=10.0Hz,1H), 6.03–5.87(m,1H),5.70(d,J=10.0Hz,1H),5.15–4.92(m,2H),3.74(s,3H),3.33(dd,J=6.6,1.6Hz,2H),1.46(s,6H).

[0083] 13 C NMR(100MHz,Chloroform-d)δ190.89,155.18,155.03,142.91,136.36,135.29,131.50,130.42,130.18 ,128.91,128.43,126.33,124.96,124.12,116.77,115.82,114.49,77.26,76.89,63.53,33.67,28.14.

[0084] Intermediate 8 (50 mg, 0.138 mmol) was dissolved in anhydrous dichloromethane and placed in a 50 mL round-bottom flask with stirring. 2-phenoxyethyl acrylate (27 μL, 0.278 mmol) and Grubbs' second-generation catalyst (23 mg, 0.027 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 WR031 (40.81 mg, 71%) as a white solid.

[0085] 1 H NMR (400MHz, CDCl3) δ7.79–7.46(m,4H),7.43–7.34(m,4H),7.30–7.00(m,3H),6.90(dd,J=23.6,7.8Hz,3H),6.61(d,J=10.0Hz,1H),5.81( dt,J=15.5,1.6Hz,1H),5.66(d,J=10.0Hz,1H),4.44(t,J=4.8Hz,2H),4.15(t,J=4.8Hz,2H),3.71(s,3H),3.55–3.31(m,2H),1.40(s,6H).

[0086] 13 C NMR (100MHz, CDCl3) δ262.40,190.65,166.47,158.51,155.48,155.24,147.60,143.15,135.21,131.94,130.57,130.26,129.5 2,128.93,128.47,126.14,125.24,121.56,121.14,116.59,114.74,114.63,94.32,77.25,65.90,63.57,62.68,32.36,28.17.

[0087] Example 2 Preparation of other compounds

[0088] Using a method similar to Example 1, the following compound was prepared:

[0089] 1H NMR(400MHz,CDCl3)δ7.74(dd,J=15.5,2.9Hz,1H),7.66–7.53(m,3H),7.40(dt,J=8.4,2.8Hz,4H),7.05(dtd,J=16.2,6.8,3.0Hz,1H),6.65(dd,J=10.0,2.9Hz,1H),5.79(dt,J=15.5,1.8Hz,1H),5.70(dd,J=10.0,3.0Hz,1H),4.78(s,1H),3.74(d,J=3.0Hz,3H),3.51–3.39(m,2H),1.95–1.63(m,3H),1.61–1.14(m,13H).

[0090] 13 C NMR(100MHz,CDCl3)δ190.72,166.12,155.44,146.22,143.16,135.19,131.95,130.57,130.28,128.94,128.48,126.13,125.19,122.66,121.83,116.60,114.73,77.22,72.44,63.59,32.36,31.69,28.17,25.43,23.81。

[0091] 1 H NMR(400MHz,CDCl3)δ7.74(dd,J=15.9,2.5Hz,1H),7.67–7.51(m,3H),7.40(dt,J=5.3,2.6Hz,4H),7.17–6.97(m,1H),6.64(dd,J=10.2,2.5Hz,1H),5.90–5.65(m,2H),3.73(dd,J=12.3,2.5Hz,6H),3.46(d,J=6.6Hz,2H),1.45(d,J=2.5Hz,6H).

[0092] 13 C NMR(100MHz,CDCl3)δ190.70,167.09,155.46,155.25,146.96,143.18,135.19,131.90,130.58,130.29,128.94,128.49,126.11,125.21,121.70,116.60,114.74,77.24,63.60,51.50,32.29,28.19。

[0093] 1 H NMR(400MHz,CDCl3)δ7.79–7.51(m,4H),7.40(q,J=5.3,4.3Hz,4H),6.91(dd,J=15.9,6.5Hz,1H),6.63(dd,J=10.1,6.0Hz,1H),6.08(d,J=16.2Hz,1H),5.74–5.65(m,1H),3.73(d,J=5.9Hz,3H),3.46(t,J=6.1Hz,2H),2.55(q,J=7.1Hz,2H),1.44(d,J=5.9Hz,6H),1.06(q,J=7.0Hz,3H).

[0094] 13 C NMR(100MHz,CDCl3)δ201.23,190.68,155.49,155.27,144.39,143.20,135.16,131.88,130.80,130.55,130.31,128.95,128.48,126.07,125.22,121.75,116.60,114.74,77.24,63.60,33.14,32.61,28.22,8.12。

[0095] 1 H NMR(400MHz,CDCl3)δ7.81–7.49(m,4H),7.48–7.33(m,4H),7.05–6.88(m,1H),6.69–6.61(m,1H),5.79–5.66(m,2H),3.82–3.66(m,3H),3.48–3.37(m,2H),1.46(d,J=2.9Hz,15H).

[0096] 13 C NMR(100MHz,CDCl3)δ190.74,166.03,155.40,155.25,145.30,143.15,135.20,131.93,130.57,130.28,128.94,128.48,126.15,125.17,123.86,122.00,116.61,114.71,80.13,77.20,63.58,32.25,28.16.。

[0097] 1H NMR(400MHz,CDCl3)δ7.74(dd,J=15.9,1.5Hz,1H),7.66–7.61(m,2H),7.56(dd,J=15.8,1.6Hz,1H),7.45–7.28(m,9H),7.13(dtd,J=15.2,6.6,1.6Hz,1H),6.64(dd,J=10.0,1.6Hz,1H),5.85(dd,J=15.6,1.7Hz,1H),5.70(dd,J=10.0,1.6Hz,1H),5.16(d,J=1.6Hz,2H),3.74(d,J=1.6Hz,3H),3.47(dt,J=6.6,1.7Hz,2H),1.44(d,J=1.6Hz,6H).

[0098] 13 C NMR(100MHz,CDCl3)δ190.67,166.41,155.48,155.25,147.38,143.16,136.10,135.19,131.95,130.56,130.28,128.93,128.56,128.48,128.22,126.12,125.22,121.74,121.56,116.58,114.74,77.24,66.10,63.58,32.40,28.18.。

[0099] 1 H NMR(400MHz,CDCl3)δ7.73(d,J=15.8Hz,1H),7.67–7.51(m,3H),7.47–7.33(m,4H),7.11(d,J=15.6Hz,1H),6.64(d,J=10.1Hz,1H),5.83(dt,J=15.7,1.6Hz,1H),5.69(d,J=10.0Hz,1H),4.26(t,J=4.6Hz,2H),3.74(s,3H),3.59(t,J=4.7Hz,2H),3.51–3.41(m,2H),3.37(s,3H),1.44(s,6H).

[0100] 13C NMR(100MHz,CDCl3)δ190.66,166.57,155.46,155.23,147.35,143.14,135.20,131.96,130.56,130.26,128.92,128.47,126.14,125.22,121.66,121.57,116.59,114.73,77.23,70.54,63.56,63.32,59.02,32.27,28.18.。

[0101] 1 H NMR(400MHz,CDCl3)δ7.74(d,J=15.6Hz,1H),7.66–7.51(m,3H),7.40(dd,J=8.0,3.7Hz,4H),7.13–7.02(m,1H),6.64(d,J=10.0Hz,1H),5.80(d,J=15.6Hz,1H),5.70(d,J=10.0Hz,1H),4.16(q,J=7.1Hz,2H),3.74(s,3H),3.45(d,J=6.7Hz,2H),1.45(s,6H),1.26(t,J=7.1Hz,3H).

[0102] 13 C NMR(100MHz,CDCl3)δ190.69,166.64,155.45,155.24,146.61,143.16,135.19,131.91,130.57,130.27,128.93,128.47,126.13,125.20,122.12,121.72,116.60,114.73,77.22,63.57,60.22,32.28,28.17,14.28.。

[0103] 1H NMR(400MHz,CDCl3)δ7.74(dd,J=16.0,2.9Hz,1H),7.67–7.50(m,3H),7.48–7.32(m,4H),7.11(dddt,J=16.0,7.8,6.2,2.4Hz,1H),6.73–6.57(m,1H),5.89–5.78(m,1H),5.74–5.65(m,1H),4.20(dt,J=11.2,3.4Hz,1H),4.11(td,J=6.9,3.3Hz,1H),4.08–3.99(m,1H),3.87(ddd,J=7.1,4.4,2.6Hz,1H),3.82–3.70(m,4H),3.53–3.38(m,2H),2.08–1.79(m,3H),1.60(ddd,J=10.7,7.2,2.5Hz,1H),1.53–1.38(m,6H).

[0104] 13 C NMR(100MHz,CDCl3)δ190.66,166.57,155.46,155.25,147.34,143.14,135.19,131.98,130.57,130.27,128.93,128.48,126.11,125.20,121.66,121.56,116.59,114.73,77.23,76.57,68.47,66.34,63.59,32.27,28.19,28.01,25.67.。

[0105] 1 H NMR(400MHz,CDCl3)δ7.76(d,J=15.8Hz,1H),7.69–7.53(m,3H),7.48(s,1H),7.44–7.31(m,5H),7.30–7.18(m,2H),7.14–7.04(m,2H),6.67(d,J=9.9Hz,1H),6.01(dd,J=15.6,1.8Hz,1H),5.73(dd,J=10.0,1.8Hz,1H),3.76(d,J=1.8Hz,3H),3.62–3.49(m,2H),1.49(d,J=1.8Hz,6H).

[0106] 13C NMR(100MHz,CDCl3)δ190.68,164.97,155.57,155.28,150.75,149.02,143.25,135.19,131.99,130.61,130.31,129.41,128.95,128.49,126.13,125.72,125.32,121.66,121.36,116.61,114.82,77.34,63.60,32.56,28.23.。

[0107] 1 H NMR(400MHz,CDCl3)δ7.74(d,J=15.8Hz,1H),7.66–7.52(m,3H),7.40(dd,J=8.2,3.9Hz,4H),7.06(dt,J=15.3,6.7Hz,1H),6.64(d,J=10.0Hz,1H),5.80(d,J=15.6Hz,1H),5.70(d,J=10.0Hz,1H),4.11(t,J=6.6Hz,2H),3.74(s,3H),3.45(d,J=6.7Hz,2H),1.62(dq,J=14.1,6.5Hz,2H),1.45(s,6H),1.37(q,J=7.5Hz,2H),0.92(t,J=7.4Hz,3H).

[0108] 13 C NMR(100MHz,CDCl3)δ190.70,166.75,155.45,155.25,146.54,143.16,135.19,131.92,130.56,130.27,128.93,128.47,126.14,125.20,122.13,121.73,116.60,114.72,77.22,64.15,63.57,32.35,30.72,28.17,19.17,13.74.。

[0109] 1H NMR(400MHz,CDCl3)δ7.73(d,J=15.7Hz,1H),7.67–7.51(m,3H),7.48–7.31(m,4H),7.05(dt,J=15.8,6.6Hz,1H),6.75–6.57(m,1H),5.81(d,J=15.5Hz,1H),5.70(d,J=10.0Hz,1H),4.03(dd,J=5.9,3.5Hz,2H),3.74(d,J=2.1Hz,3H),3.45(d,J=6.7Hz,2H),1.58(dt,J=12.1,6.4Hz,1H),1.45(s,6H),1.36(qd,J=7.1,2.3Hz,2H),1.28(d,J=6.4Hz,6H),0.88(dt,J=8.0,4.2Hz,6H).

[0110] 13 C NMR(100MHz,CDCl3)δ190.69,166.84,155.47,155.26,146.39,143.15,135.22,131.92,130.52,130.25,128.92,128.46,126.17,125.21,122.21,121.74,116.61,114.71,77.21,66.68,63.54,38.81,32.44,30.43,28.94,28.16,23.79,22.97,14.05,11.00.。

[0111] 1 H NMR(400MHz,CDCl3)δ7.75(d,J=15.8Hz,1H),7.67–7.53(m,4H),7.46–7.37(m,4H),6.65(dd,J=10.2,2.2Hz,1H),5.91(dd,J=15.5,1.9Hz,1H),5.88–5.76(m,1H),5.71(dd,J=10.2,2.0Hz,1H),3.75(d,J=2.2Hz,3H),3.60–3.49(m,2H),1.44(d,J=2.2Hz,6H).

[0112] 13C NMR(100MHz,CDCl3)δ190.58,162.81,155.75,155.28,152.41,143.31,135.15,132.02,130.56,130.33,128.94,128.47,126.03,125.39,120.51,118.60,116.51,114.83,77.24,66.66,66.32,65.97,63.58,33.08,28.12.。

[0113] 1 H NMR(400MHz,CDCl3)δ7.73(d,J=15.8Hz,1H),7.67–7.50(m,3H),7.48–7.35(m,4H),7.06(dt,J=15.6,6.7Hz,1H),6.64(d,J=10.0Hz,1H),5.80(d,J=15.6Hz,1H),5.70(d,J=10.0Hz,1H),4.10(t,J=6.7Hz,2H),3.74(s,3H),3.53–3.36(m,2H),1.62(q,J=6.9Hz,2H),1.45(s,6H),1.37–1.20(m,18H),0.87(t,J=6.7Hz,3H).

[0114] 13 C NMR(100MHz,CDCl3)δ190.67,166.72,155.45,155.23,146.48,143.14,135.22,131.90,130.52,130.24,128.91,128.45,126.17,125.21,122.17,121.73,116.61,114.71,77.20,64.45,63.53,32.34,31.92,29.64,29.59,29.53,29.35,29.28,28.69,28.17,25.96,22.69,14.12.。

[0115] 1H NMR(400MHz,CDCl3)δ7.93–7.86(m,2H),7.74(d,J=15.8Hz,1H),7.65–7.49(m,4H),7.49–7.35(m,6H),7.14(dd,J=14.5,7.6Hz,1H),6.87(dt,J=15.3,1.6Hz,1H),6.66(d,J=10.0Hz,1H),5.71(d,J=10.0Hz,1H),3.75(s,3H),3.58(d,J=6.8Hz,2H),1.46(s,6H).

[0116] 13 C NMR(100MHz,CDCl3)δ191.06,190.67,155.51,155.27,147.16,143.19,137.94,135.20,132.62,131.93,130.55,130.26,128.92,128.56,128.53,128.45,126.17,125.25,121.80,116.63,114.78,77.26,63.55,33.06,28.21.。

[0117] 1 H NMR(400MHz,CDCl3)δ7.74(d,J=15.8Hz,1H),7.65–7.50(m,3H),7.47–7.33(m,4H),6.90(dd,J=14.6,7.9Hz,1H),6.65(d,J=10.0Hz,1H),6.13–6.01(m,1H),5.70(d,J=10.0Hz,1H),3.74(s,3H),3.52–3.41(m,2H),2.50(t,J=7.4Hz,2H),1.62(q,J=7.3Hz,2H),1.45(s,6H),0.91(t,J=7.4Hz,3H).

[0118] 13 C NMR(100MHz,CDCl3)δ200.72,190.66,155.48,155.24,144.45,143.18,135.20,131.85,131.11,130.50,130.26,128.92,128.45,126.14,125.24,121.73,116.61,114.72,77.22,63.53,41.93,32.59,28.20,17.67,13.82.。

[0119] Example 3 Anti-inflammatory activity

[0120] 1. Anti-inflammatory activity experimental methods

[0121] 1) Experimental Materials

[0122] Cells: Macrophages (RAW264.7)

[0123] Cytokine kits: IL-6 detection kit, TNF-α detection kit

[0124] Stimulant: Lipopolysaccharide (LPS)

[0125] Positive control: dexamethasone (Dex)

[0126] Solvent: dimethyl sulfoxide (DMSO)

[0127] Comparative compound: WR011 WR022

[0128] 2) Experimental steps

[0129] Cell culture: 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 above 99%, the cells were passaged for at least 2 times. The cells were then plated in 24-well cell culture plates at a cell density of 0.5×10 6 Overnight culture allowed cells to fully adhere to the wall.

[0130] 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 for the detection of cytokine TNF-α and IL-6 levels.

[0131] 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.

[0132] 2. Experimental results

[0133] The experimental results are shown in Figures 1 and 2. All the tested compounds can downregulate the levels of IL-6 and TNF-α in RAW264.7 cells after LPS stimulation, with significant differences compared with the LPS group, and are superior to the positive control dexamethasone and the comparison compounds WR011 and WR022.

[0134] 3. The inventors further conducted a concentration gradient experiment using WR034, WR037 and WR043 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 of cells, respectively, and the levels of cytokines TNF-α and IL-6 were detected. The results showed that WR034, WR037 and WR043 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 they were all better than the corresponding concentration of the positive control dexamethasone.

[0135] 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 in macrophages stimulated by LPS.

[0136] Example 4 Antitumor Activity

[0137] 1. Anti-Triple Negative Breast Cancer Cell (TNBC) Proliferation Experiment - CCK-8 Detection

[0138] 1) Experimental Materials

[0139] Cells: Human breast cancer cells MDA-MB-231, MDA-MB-468, BT549, Cal51

[0140] Cell proliferation detection kit: Cell Counting Kit-8 (CCK8) kit (TargetMol)

[0141] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0142] 2) Experimental steps

[0143] Cell culture: MDA-MB-231, 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 Overnight culture allowed cells to fully adhere to the wall.

[0144] Drug Treatment: Compound WR034 was added to the experimental group cells at a final concentration gradient of 1 μM, 5 μM, 10 μM, 15 μM, and 20 μM. Control group cells were treated with only DMSO, the solvent used to dissolve the compound. Blank group cells were treated with only cell-free culture medium. The cells were incubated at 37°C in a 5% CO2 incubator for 48 hours.

[0145] Detection: After 48 hours, 10 μL of CCK-8 solution was added to each well of the experimental group, 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.

[0146] Cell survival rate = [(As-Ab) / (Ac-Ab)] × 100%

[0147] As: experimental well; Ac: control well; Ab: blank well

[0148] 3) Experimental results

[0149] The experimental results are shown in Figure 3. The experiment showed that compound WR034 can significantly inhibit the proliferation of four TNBCs, with IC50 values ​​of: MDA-MB-468: 2.906 μM; MDA-MB-231: 7.388 μM; BT549: 7.771 μM; Cal51: 2.452 μM.

[0150] 2. Experiment on promoting apoptosis of triple-negative breast cancer cells

[0151] 1) Experimental Materials:

[0152] Cells: Human breast cancer cells Cal51, MDA-MB-231

[0153] Positive control drug: 5-fluorouracil (5-Fu, MCE)

[0154] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0155] Reagents: Annexin V-FITC / PI fluorescence double staining cell apoptosis detection kit (Procell)

[0156] 2) Experimental methods

[0157] Cells were seeded in 12-well plates, and MDA-MB-231 cells were seeded at 1.5×10 5 Cal51 is 2×10 5 Cells were cultured overnight to allow for full cell attachment. DMSO was added to the blank control group, and equal amounts of compound WR034 were added to the experimental group to achieve final concentrations of 5 μM and 10 μM. 5-Fu was added to the positive control group to achieve a final concentration of 10 μM. Culture was continued in an incubator for 48 hours.

[0158] After 48 hours, collect the cells from each well into a centrifuge tube, centrifuge at 300×g for 5 minutes, discard the supernatant, collect the cells, wash once with PBS, gently resuspend the cells and count them. 5 Resuspend the cells, centrifuge at 300×g for 5 minutes, and discard the supernatant. Wash the cells once with PBS, centrifuge and discard the supernatant, then add 100μL of diluted 1×Annexin V Binding Buffer to resuspend the cells. Add 2.5μL of Annexin V-FITC staining solution and 2.5μL of PI staining solution (50μg / mL) to the cell suspension. Gently vortex to mix, and incubate at room temperature in the dark for 15-20 minutes. Add 400μL of diluted 1×Annexin V Binding Buffer and mix the sample. Immediately detect on the flow cytometer. When detecting on the flow cytometer, select the FITC channel for Annexin V-FITC and the PerCP / Cy5.5 channel for PI.

[0159] 3) Experimental results

[0160] The experimental results are shown in Figure 4.

[0161] ① In Cal51 cells, compound WR034 promoted cell apoptosis, and the percentage of apoptosis increased with increasing drug concentration. At the same concentration, the percentage of apoptosis in the compound WR034 group was higher than that in the positive control drug 5-Fu group.

[0162] In MDA-MB-231 cells, compound WR034 can promote cell apoptosis, and as the dosage concentration increases, the percentage of apoptosis also increases. Moreover, the percentage of apoptosis in the low-concentration compound WR034 dosage group is higher than that in the positive control drug 5-Fu dosage group.

[0163] 3. Anti-triple negative breast cancer cell proliferation assay - colony formation assay

[0164] 1) Experimental Materials:

[0165] Cells: Human breast cancer cells Cal51, MDA-MB-231

[0166] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0167] Reagents: 4% paraformaldehyde, 0.1% crystal violet staining solution (Solarbio)

[0168] 2) Experimental methods

[0169] Cells were seeded in 12-well plates at 500 cells / well for MDA-MB-231 and 600 cells / well for Cal51. Cells were treated with various concentrations of compound WR034 (final concentrations of 1.25 μM and 2.5 μM) and DMSO (control group). The culture medium was changed every three days until visible colonies formed. Following the experiment, cells were fixed with 4% paraformaldehyde for 30 minutes and stained with 0.1% crystal violet for 30 minutes. Each well was photographed and colonies were counted.

[0170] 3) Experimental results

[0171] The experimental results are shown in Figure 5. Compared with the control group, the number of colony formation in the treatment group decreased, and this effect was enhanced with increasing concentration. Therefore, compound WR034 inhibited the proliferation of Cal51 and MDA-MB-231 cells in a concentration-dependent manner.

[0172] 4. Inhibition of triple-negative breast cancer cell migration experiment

[0173] 1) Experimental Materials:

[0174] Cells: Human breast cancer cells BT549 and MDA-MB-231

[0175] Positive control drug: 5-fluorouracil (5-Fu, MCE)

[0176] Solvent: dimethyl sulfoxide (DMSO) (Solarbio)

[0177] 2) Experimental methods

[0178] Cells were seeded in 6-well plates, and MDA-MB-231 cells were seeded at 5.5×10 5 3.5×10 for BT549 5 Cells were cultured overnight to allow full attachment. Using a 200 μL pipette tip, scratch the well plate perpendicular to the back of the well, from one end to the other. Debris was removed by washing with PBS. DMSO was added to the blank control group, compound WR034 was added to the experimental group to a final concentration of 10 μM, and 5-Fu was added to the positive control group to a final concentration of 10 μM. The scratch width was observed under a microscope and photographed at 0 and 12 hours, then analyzed in ImageJ.

[0179] 3) Experimental results

[0180] The experimental results are shown in Figure 6. Compared to the control group, the migration rate of the WR034-treated group was reduced and was lower than that of the 5-Fu-treated group. Therefore, it can be seen that the WR034 compound can inhibit the migration of both BT549 and MDA-MB-231 cell lines, and this effect is superior to that of the positive control drug 5-Fu.

[0181] Anti-tumor angiogenesis activity of the compound of Example 5

[0182] 1. Compound concentration gradient test results

[0183] 1) Experimental Materials

[0184] Cells: Human umbilical vein endothelial cells (HUVEC)

[0185] Reagents: vascular endothelial growth factor (VEGF), cell viability detection kit (CCK-8)

[0186] Solvent: dimethyl sulfoxide (DMSO)

[0187] 2) Experimental steps

[0188] Cell Culture: HUVEC cells were revived and transferred to T75 culture flasks. Cultured in a cell culture incubator at 37°C, 5% CO2, and 90% humidity. Cells were passaged when the cell density reached 80% or higher. After the third passage, cells were plated in 96-well plates at 5,000 cells per well and cultured overnight to allow for full cell adhesion.

[0189] Drug Treatment: After cells were fully adhered, they were starved for 24 hours with 0.5% serum-containing cell culture medium. Cells were then treated with 50 ng / mL VEGF in 0.5% serum-containing cell culture medium and a gradient of compound concentrations (2 μM, 4 μM, 6 μM, 8 μM, and 10 μM) for 48 hours. The experimental group consisted of the compound dissolved in DMSO. Negative controls consisted of two groups: one containing 50 ng / mL VEGF and the other without VEGF.

[0190] CCK-8 assay: After 48 hours of drug treatment, 10 μL of CCK-8 was added to each well and incubated in a cell culture incubator for 2 hours. The absorbance at 450 nm was then read using a microplate reader, and the cell activity was calculated according to the formula.

[0191] 3) Experimental results

[0192] After VEGF induces HUVEC cells, it can effectively activate the VEGF-VEGFR2 signaling pathway of HUVEC cells, thereby promoting the proliferation of HUVEC cells and enhancing the ability of tumor angiogenesis. The results are shown in Figure 7. After VEGF induces HUVEC cells, the inhibitory effects of compounds WR033, WR034 and WR045 on their proliferation are detected at gradient concentrations (2μM, 4μM, 6μM, 8μM and 10μM). It is found that at each concentration, the compounds can have a certain inhibitory effect on the proliferation of HUVEC cells induced by VEGF, and the inhibitory effect is more obvious as the concentration increases. The IC of compound WR033 is 2μM, 4μM, 6μM, 8μM and 10μM. 50 The concentration of the compound was around 6 μM, so all subsequent experiments used 6 μM treatment. When testing the effects of the compounds on HUVEC cell proliferation without VEGF induction, the results are shown in Figure 8. It was found that the inhibitory effects of the compounds at different concentrations were not very obvious, indicating that the effects of the compounds on HUVEC cell proliferation are achieved by inhibiting the VEGF-VEGFR2 signaling pathway.

[0193] 2. Effect of compounds on VEGF-induced HUVEC cell migration

[0194] Experimental Materials

[0195] Cells: Human umbilical vein endothelial cells (HUVEC)

[0196] Reagent: Vascular endothelial growth factor (VEGF)

[0197] Positive control: Sorafenib, Sunitinib

[0198] Solvent: dimethyl sulfoxide (DMSO)

[0199] 1) Experimental steps

[0200] Cell culture: HUVEC cells were revived and placed in a T75 culture flask and cultured in a cell culture incubator at 37°C, 5% CO2 concentration, and 90% humidity. Cells were subcultured when the cell density reached over 80%. After the third passage, cells were plated in 6-well plates with 1×10 cells per well. 6 Culture overnight to allow cells to fully adhere to the wall.

[0201] Drug Treatment: After cells were fully adhered, they were starved for 24 hours with cell culture medium containing 0.5% serum. The cells were then scarified using a 200 μL yellow pipette tip. The cells were then treated with 6 μM compound in cell culture medium supplemented with 50 ng / mL VEGF and 0.5% serum for 12 hours. The experimental group received compound dissolved in DMSO. The positive control group received sorafenib and sunitinib dissolved in DMSO. The negative control group received cell culture medium supplemented with 50 ng / mL VEGF and DMSO for compound dissolution.

[0202] Finally, observe and take pictures under a microscope.

[0203] 2) Experimental results

[0204] The experimental results are shown in FIG9 . Compounds WR033, WR034, and WR045 all significantly inhibited VEGF-induced HUVEC cell migration. Compound WR034 had the best inhibitory effect, which was better than the positive control drugs Sorafenib and Sunitinib.

[0205] 3. Effect of Compounds on HUVEC Cell Angiogenesis in Vitro

[0206] Cell culture: HUVEC cells were revived and placed in a T75 culture flask and cultured in a cell culture incubator at 37°C, 5% CO2 concentration, and 90% humidity. Cells were subcultured when the cell density reached over 80%. After the third passage, cells were plated in a 12-well plate with 1×10 cells per well. 5 Culture overnight to allow cells to fully adhere to the wall.

[0207] Drug Treatment: After cells were fully adhered, they were starved for 24 hours using cell culture medium supplemented with 0.5% serum. Cells were then treated with cell culture medium supplemented with 0.5% serum and 6 μM of the compound for 30 minutes. The cells were then digested and used for further analysis. The experimental group received the compound dissolved in DMSO, the positive control group received sorafenib and sunitinib dissolved in DMSO, and the negative control group received the compound dissolved in DMSO. Because Matrigel naturally contains VEGF, it was not necessary to add it in this experiment.

[0208] In vitro angiogenesis: Matrigel and serum-free culture medium were mixed on ice, and 50 μL of diluted Matrigel was plated in each well of a 96-well plate. The plate was then placed in a cell culture incubator and incubated for 45-60 min to solidify. 30,000 cells were then taken from the previously digested cells, dispersed in 50 μL of culture medium, and plated on the solidified Matrigel. The plates were then placed in a cell culture incubator for incubation. After 4 h, the plates were observed under a microscope and photographed.

[0209] Experimental results:

[0210] As shown in Figure 10, compounds WR033, WR034, and WR045 all significantly inhibited HUVEC cell angiogenesis in vitro, with compound WR034 showing the best inhibitory effect, outperforming the positive control drugs Sorafenib and Sunitinib.

[0211] Example 6 Inhibition of colorectal cancer cell proliferation experiment

[0212] The same method as the CCK-8 detection experiment in point 1 of Example 4 was used to perform the experiment using colorectal cancer cell lines HCT116 and HCT8. The results are shown in FIG11 . WR034, WR037, and WR043 were all able to inhibit the proliferation of the colorectal cancer cells at the tested concentrations, and the effects of WR034 and WR037 were better than those of 5-FU.

[0213] 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, R1 is C 1-20 Alkyl, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, C 1-20 Alkyloxy, C 6-10 Aromatic ring group oxygen, C 3-10 Cycloalkyloxy, 5-10 membered heterocyclyloxy or 5-10 membered heteroaryloxy, wherein the alkyl, aromatic ring group, cycloalkyl, heterocyclyl, heteroaryl, alkyloxy, aromatic ring group oxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy are optionally substituted by one or more selected from halogen, C 1-10 Alkyloxy, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6- 10 Aromatic ring group oxygen, C 3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy or 5-10 membered heteroaryloxy; R2 is hydrogen, C 1-20 Alkyl, C 6-10 Aromatic ring group, C 3-10 Cycloalkyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl; R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkyloxy; Each R4 is the same or different and is independently selected from hydrogen or C 1-12 alkyl.

2. The compound of formula I according to claim 1, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: C 6-10 The aromatic ring group is phenyl, C 3-10 Cycloalkyl is C 3-7 Cycloalkyl, 5-10 membered heterocyclyl is 5-7 membered heterocyclyl, 5-10 membered heteroaryl is 5-6 membered heteroaryl, and halogen is F, Cl or Br.

3. The compound of formula I according to claim 1, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R1 is C 1-12 Alkyl, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, C 1-12 Alkyloxy, phenyloxy, C 3-7 Cycloalkyloxy, 5-7 membered heterocyclyloxy, 5-6 membered heteroaryloxy, wherein the alkyl, phenyl, cycloalkyl, heterocyclyl, heteroaryl, alkyloxy, phenyloxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy are optionally substituted by one or more groups selected from F, Cl, Br, or the alkyloxy is optionally substituted by one or more groups selected from C 1-6 Alkyloxy, phenyl, C 3-7 Cycloalkyl, 5-7 membered heterocyclic group, 5-6 membered heteroaryl, phenyloxy, C 3-7 cycloalkyloxy, 5-7 membered heterocyclyloxy or 5-6 membered heteroaryloxy; Preferably, R1 is C 1-8 alkyl, phenyl, cyclohexyl, cyclopentyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, tetrahydropyranyl, thiolanyl, piperidinyl, C 1-8 alkyloxy, phenyloxy, cyclohexyloxy, cyclopentyloxy, tetrahydrofuranyloxy, thiolanyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, thiohexyloxy, piperidinyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1-6 substituted with alkyloxy, phenyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl, thiolanyl, pyrrolidinyl, tetrahydropyranyl, thiolanyl, piperidinyl, phenyloxy, tetrahydrofuranyloxy, cyclohexyloxy, cyclopentyloxy, thiolanyloxy, pyrrolidinyloxy, tetrahydropyranyloxy, thiolanyloxy, piperidinyloxy; More preferably, R1 is C 1-8 Alkyl, phenyl, cyclohexyl, tetrahydrofuranyl, C 1-8 Alkyloxy, phenyloxy, cyclohexyloxy, tetrahydrofuranyloxy, wherein the alkyloxy is optionally substituted with one or more selected from F, Cl, Br, C 1-6 The alkyloxy group may be substituted with alkyloxy, phenyl, tetrahydrofuranyl, cyclohexyl, phenyloxy, tetrahydrofuranyloxy, or cyclohexyloxy.

4. A compound of formula I according to any one of claims 1 to 3, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R2 is hydrogen or C 1-12 alkyl; Preferably, R2 is hydrogen or C 1-4 alkyl; More preferably, R2 is methyl.

5. A compound of formula I according to any one of claims 1 to 4, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R3 is hydrogen or C 1-4 alkyl; Preferably R3 is hydrogen.

6. A compound of formula I according to any one of claims 1 to 5, its enantiomer, pharmaceutically acceptable salt or solvate, wherein: R4 is hydrogen or C 1-4 alkyl; Preferably, R4 is methyl.

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

8. A pharmaceutical composition, characterized in that The compound of formula I according to any one of claims 1 to 7, its enantiomer, pharmaceutically acceptable salt or solvate, preferably, further contains one or more pharmaceutically acceptable carriers.

9. Use of the compound of formula I according to any one of claims 1 to 7, its enantiomer, pharmaceutically acceptable salt or solvate, or the pharmaceutical composition according to claim 8 in the preparation of an anti-inflammatory drug or an anti-tumor drug or a VEGF inhibitor.

10. The use according to claim 9, characterized in that 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 disorders (eosiniphilic gastrointestinal tract disorders), inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., inflammatory bowel disease (e.g., 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, 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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