A veratrine compound, a preparation method thereof and application thereof

Abstract

The application discloses a veratramine compound, a preparation method and application thereof. The application provides a veratramine compound as shown in formula I, which can be used as a series of novel AP-1 inhibitors and used for preparing drugs for corresponding diseases. In preliminary activity research, the compound provided by the application has very strong inhibiting tumor cell proliferation activity, has the potential to be prepared into a novel antitumor drug, and has a good market prospect.

Description

[0001] The patent application is a divisional application of the patent application with application number 202010606717.6, the filing date of which is June 29, 2020, and the title of which is “Astragaline amine compound, preparation method thereof and application thereof”. TECHNICAL FIELD

[0002] The present application relates to a kind of astragaline amine compound, its preparation method and application. BACKGROUND

[0003] Malignant tumor is a serious threat to human health disease, its characteristics are abnormal cell clonal expansion, show uncontrolled proliferation, no response to normal homeostatic signal, invasion and metastasis to adjacent tissues. Metastasis of malignant tumor cells to important organs is the biggest obstacle to successful treatment of tumor, and is the main cause of death of tumor patients. At present, the treatment of malignant tumor is mainly through operation, chemotherapy and radiotherapy and other methods. Although there has been significant progress in surgical techniques and chemotherapy, but the current medical treatment still cannot cure metastatic cancer, and the development of new treatment methods must fully understand the molecular mechanism of tumor metastasis.

[0004] For example, triple-negative breast cancer is a serious threat to women's health disease, and the current treatment is mainly chemotherapy, which has great side effects and patients are prone to drug resistance, and there is an urgent need to develop effective targeted therapy in clinic.

[0005] AP-1 (activator protein-1, activator protein 1) is a transcriptional activator in cells. It responds to a variety of stimuli, including cytokines, growth factors, stress, bacterial and viral infections, by regulating gene expression; therefore, AP-1 controls many cellular processes, including differentiation, proliferation and apoptosis. AP-1 up-regulates the transcription of genes containing TPA DNA response elements (TRE; 5'-TGAG / CTCA-3'). AP-1 heterodimers are formed by leucine zippers and bind to genes through specific conserved sequences to initiate gene expression.

[0006] AP-1 plays an important role in the formation and development of tumors, and it transduces growth signals to the nucleus through signal transduction pathways, leading to overexpression of various genes involved in growth and malignant transformation in cells, and has become one of the important targets for tumor treatment and prevention intervention. Studies have found that AP-1 is highly expressed in various malignant tumors such as breast cancer, hepatocellular carcinoma, skin cancer and colorectal cancer. Although AP-1 is highly expressed in the occurrence and development of various cancers, there is no anti-tumor drug targeting transcription factor AP-1 or its specific DNA binding sequence successfully marketed.

[0007] The drug design for DNA short nucleotide sequence is the most effective and challenging design strategy, and the development of AP-1 inhibitor targeting DNA can promote the research of new cancer targets and further explore the drug design targeting DNA short nucleotide sequence.

[0008] A series of in vitro experiments show that veratramine acts on the downstream signal transduction of AP-1, but does not interfere with the cytoplasmic MAPK signal transduction cascade induced by EGF or other kinases related to AP-1 activation, indicating that gene regulation only occurs on a subset of genes controlled by AP-1. Animal experiments show that veratramine can inhibit the activation of AP-1 reporter gene induced by ultraviolet light in mice, indicating that veratramine can effectively prevent the occurrence of solar ultraviolet-induced skin cancer, thereby confirming the potential value of veratramine as an anti-tumor candidate drug SUMMARY

[0009] The problem to be solved by the present application is that the existing veratramine compounds have relatively single structure, therefore, the present application provides a veratramine compound, a preparation method and application thereof. The veratramine compound of the present application has an inhibitory effect on AP-1 signal pathway.

[0010] The present application provides a veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof:

[0011]

[0012] wherein,

[0013] is represents or a mixture thereof;

[0014] X is -CO-, (b represents the left side carbon connected to formula I as shown above)

[0015] R 1 is hydrogen, C1-C6 alkyl or -CO-R 3 ;

[0016] R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2;

[0017] R 4 is hydrogen or C1-C6 alkyl;

[0018] R 5 is amine or -O-R 7 ;

[0019] Y is -CO-, (a indicates attachment to a tertiary carbon)

[0020] R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is hydrogen or halogen;

[0021] R 11 is hydroxyl, amino or OR 14 ;

[0022] R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or -CO-R 13 ;

[0023] R 14 is hydrogen or C1-C6 alkyl;

[0024] R 3 , R 7 , R 12 and R 13 are independently C1-C6 alkyl;

[0025] The compound does not include veratramine.

[0026] In one aspect, certain groups in the veratramine compound of Formula I or a pharmaceutically acceptable salt thereof are defined as follows, and the undefined groups are as described in any of the preceding aspects (hereinafter "in one aspect"):

[0027] In one aspect, R 1 is -CO-R 3 .

[0028] In one aspect, R 1 is C1-C4 alkyl or -CO-R 3 .

[0029] In one aspect, R 2 is -O-R 4 .

[0030] In one aspect, R 2 is -O-R 4 or -NH-COR 5 .

[0031] In one aspect, R 2 is hydroxyl, -O-R 4 or -NH-COR 5 .

[0032] In one embodiment, R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or -CO-R 13 .

[0033] In one embodiment, R is hydrogen, C1-C4 alkyl, or C 2- C4 alkenyl.

[0034] In one embodiment, R 9 is hydroxyl, R 10 is hydrogen; or R 9 is halogen, R 10 is halogen.

[0035] In one embodiment, wherein,

[0036] is represents or mixtures thereof;

[0037] X is -CO-, (b end represents attachment to left side carbon in Formula I as shown above)

[0038] R 1 is hydrogen or -CO-R 3 ;

[0039] R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2;

[0040] R 4 is hydrogen or C1-C6 alkyl;

[0041] R 5 is amine or -O-R 7 ;

[0042] Y is -CO-, (a end represents attachment to tertiary carbon)

[0043] R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is halogen;

[0044] R 11 is hydroxyl or -O-R 14 ;

[0045] R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or -CO-R 13 ;

[0046] R 14 is hydrogen or C1-C6 alkyl

[0047] R 3 , R 7 , R 12 and R 13 are independently C1-C6 alkyl;

[0048] The compounds do not include veratramine.

[0049] In one aspect, wherein,

[0050] is represents or mixtures thereof;

[0051] X is (b end represents attachment to left side carbon in Formula I as shown above)

[0052] R 1 is -CO-R 3 ;

[0053] R 2 is -O-R 4 ;

[0054] Y is (a end represents attachment to tertiary carbon)

[0055] R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen;

[0056] R 11 is -O-R 14 ;

[0057] R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, or -CO-R 13 ;

[0058] R 14 is hydrogen or C1-C4 alkyl

[0059] R 3 , R 4 , R 12 and R 13 are independently C1-C4 alkyl;

[0060] The compounds do not include veratramine.

[0061] In one aspect, wherein,

[0062] is X is -CO-, (b end indicates attachment to left side carbon in Formula I as shown above) R 1 -CO-R 3 ;

[0063] R 2 -O-R 4 or -NH-COR 5 ;

[0064] R 5 -O-R 7 ;

[0065] Y is (a end indicates attachment to tertiary carbon)

[0066] R 9 hydroxyl or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is hydrogen or halogen;

[0067] R is hydrogen or C2-C4alkenyl;

[0068] R 3 , R 4 , R 12 and R 13 are independently C1-C4alkyl;

[0069] The compound does not include veratramine.

[0070] In one aspect, wherein,

[0071] is X is -CO-, (b end indicates attachment to left side carbon in Formula I as shown above) R 1 C1-C4alkyl or -CO-R 3 ;

[0072] R 2 hydroxyl, -O-R 4 or -NH-COR 5 ;

[0073] R 4 is hydrogen or C1-C4alkyl;

[0074] R 5 -O-R 7 ;

[0075] Y is (a end indicates attachment to tertiary carbon)

[0076] R 9 is hydroxyl, R 10 is hydrogen; or R 9 is halogen, R 10 is halogen;

[0077] R is hydrogen, C1-C4 alkyl or C 2- C4 alkenyl;

[0078] R 3 and R 7 are independently C1-C4 alkyl;

[0079] The compound does not include veratramine.

[0080] In one aspect, wherein

[0081] is X is -CO- or R 2 is hydroxyl or -O-R 4 ;

[0082] R 4 is hydrogen or C1-C4 alkyl;

[0083] Y is (a end indicates attachment to tertiary carbon)

[0084] R 9 is hydroxyl, R 10 is hydrogen; or R 9 is halogen, R 10 is halogen;

[0085] R is hydrogen or C1-C4 alkyl.

[0086] In one aspect, wherein

[0087] X is (b end indicates attachment to left carbon in Formula I as shown above)

[0088] R 1 is hydrogen or -CO-R 3 ;

[0089] Y is -CO-, (a end indicates attachment to tertiary carbon)

[0090] R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen; or the R 9 is halogen (e.g., fluorine, chlorine, bromine or iodine), R 10 is halogen (e.g., fluorine, chlorine, bromine or iodine);

[0091] R 11 is hydroxyl or -O-R 14 ;

[0092] R is hydrogen, C 1- C4alkyl, C 2- C4alkenyl or -CO-R 13 ;

[0093] R 3 , R 12 , R 13 and R 14 are independently C1-C4alkyl;

[0094] The compound does not include veratramine.

[0095] In one aspect, wherein

[0096] X is

[0097] R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2;

[0098] R 4 is hydrogen or C1-C4alkyl;

[0099] R 5 is amine or -O-R 7 ;

[0100] Y is -CO-, (a end indicates attachment to tertiary carbon)

[0101] R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen; or said R 9 is halogen (e.g., fluorine, chlorine, bromine or iodine), R 10 is hydrogen or halogen (e.g., fluorine, chlorine, bromine or iodine);

[0102] R 11 is hydroxyl or OR 14 ;

[0103] R is hydrogen, C1-C4alkyl, C 2- C4alkenyl or -CO-R 13 ;

[0104] R 14 is hydrogen or C1-C4alkyl;

[0105] R 13 , R12 and R 7 independently is C1-C4alkyl.

[0106] In one aspect, wherein,

[0107] X is -CO-;

[0108] Y is (a end indicates attachment to tertiary carbon)

[0109] R 9 is hydroxyl, R 10 is hydrogen; or R 9 is fluoro, R 10 is fluoro;

[0110] R is C 2- C4alkenyl or -CO-R 13 ;

[0111] R 13 is C1-C4alkyl.

[0112] In one aspect, when X is , said X is any of the following structures: (b end indicates attachment to left side carbon in Formula I as shown above)

[0113] In one aspect, when X is , said X is any of the following structures:

[0114] In one aspect, when Y is R 9 is halogen, R 10 is hydrogen or halogen, said is (a end indicates attachment to tertiary carbon)

[0115] In one aspect, when Y is R 9 is hydroxyl or -O-CO-R 12 , R 10 is hydrogen, said is any of the following structures: (a end indicates attachment to tertiary carbon)

[0116] In one aspect, when R 9 or R 10 is halogen, said halogen is fluoro, chloro, bromo or iodo, for example fluoro.

[0117] In one aspect, when R is -CO-R 13 , said -CO-R13 for

[0118] In a certain scheme, when R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 12 R 13 R 14 Or when R is a C1 to C6 alkyl group; the C1 to C6 alkyl group is a C1 to C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl).

[0119] In one embodiment, when R is a C2-C6 alkenyl group, the C2-C6 alkenyl group is a C2-C4 alkenyl group (e.g., )

[0120] In one embodiment, certain groups in the veratridine compounds represented by Formula I are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0121] for

[0122] In one embodiment, certain groups in the veratridine compounds represented by Formula I are defined as follows (groups not mentioned are as described in any embodiment of this application).

[0123] for

[0124] In this invention, the veratridine compound represented by general formula I includes any of the following compounds:

[0125]

[0126]

[0127] Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are defined as shown in Formula I.

[0128] In the present application, the veratramine compound as shown in formula I or its pharmaceutically acceptable salt can be synthesized by methods similar to those known in the art, and the steps and conditions can refer to the steps and conditions of similar reactions in the art, and are synthesized according to the description herein. The starting materials are usually obtained from commercial sources, such as Aldrich, or can be easily prepared by methods known to those skilled in the art (obtained by SciFinder, Reaxys online database).

[0129] In the present application, the preparation method of the veratramine compound as shown in formula I comprises the following schemes one, scheme two, scheme three, scheme four, scheme five, scheme six, scheme seven, scheme eight and scheme nine:

[0130] Scheme one, when the veratramine compound as shown in formula I, X is R 1 is C1-C6 alkyl-C(=O)-, which comprises the following steps: reacting the compound as shown in formula I-a with an acylating agent to obtain the veratramine compound as shown in formula I; wherein, Y or R is as defined above;

[0131]

[0132] Scheme two, when the veratramine compound as shown in formula I, X is -CO-; which comprises the following steps: reacting the compound as shown in formula I-h with the oxidation reaction as shown below to obtain the veratramine compound as shown in formula I; wherein, is Y or R is as defined above;

[0133]

[0134] Scheme three, when the veratramine compound as shown in formula I, X is ; which comprises the following steps: reacting the compound as shown in formula I-b with the compound as shown in formula R 2 NH2 with the imination reaction as shown below to obtain the veratramine compound as shown in formula I; wherein, Y is R 2 , R 9 , R 10 , R 11 , Y or R is as defined above;

[0135]

[0136] Scheme four, when the veratramine compound as shown in formula I, for The process includes the following steps: subjecting the compound shown in Formula Ic to an epoxidation reaction as shown below to obtain the veratridine compound shown in Formula I; wherein, X is... (The b-end indicates a connection to the carbon on the left side of Formula I as shown above); Y is... (The a-end indicates connection to a tertiary carbon); R 1 R 9 Or R 10 The definitions are as described above;

[0137]

[0138] Option 5: When Y is -CO- in the veratridine compound shown in Formula I, it includes the following steps: reacting the compound shown in Formula Id with [a specific compound] to undergo the oxidation reaction shown below to obtain the veratridine compound shown in Formula I; wherein, for X is R, R 1 Or R 2 The definitions are as described above;

[0139]

[0140] Option 6: In the arsenic compounds shown in Formula I, Y is... The process includes the following steps: mixing a compound as shown in formula Ie with formula R. 11 The compound represented by -NH2 undergoes an imidization reaction as shown below to obtain the veratridine compound represented by Formula I; wherein, for X is -CO-, R 1 C1 to C6 alkyl-C(=O)-, R, R 11 Or R 2 The definitions are as described above;

[0141]

[0142] Option 7: In the veratridine compounds shown in Formula I, Y is... Time; (a-terminus indicates connection to tertiary carbon); R 9 For halogens, R 10 When the halogen is present, the process includes the following steps: reacting a compound of formula Ie with a compound of a halogenating agent (e.g., fluorination) as shown below to obtain the veratridine compound of formula I; wherein, for X is -CO-, R 1 is C1-C6alkyl-C(=O)-, R or R 2 are as defined above;

[0143]

[0144] Scheme VIII, when X is -CO- in the veratramine compound of formula I; comprising the following steps: subjecting a compound of formula I-f to a C-N coupling reaction with a coupling reagent containing the R fragment as shown below, to give the veratramine compound of formula I; wherein, Y or R are as defined above;

[0145]

[0146] Scheme IX, when X is -CO- in the veratramine compound of formula I; comprising the following steps: subjecting a compound of formula I-g to a migration-oxidation reaction in the presence of toluene, aluminum isopropoxide and cyclohexanone as shown below, to give the veratramine compound of formula I; wherein, is Y or R are as defined above;

[0147]

[0148] In the above-mentioned Scheme I, Scheme II, Scheme III, Scheme IV, Scheme V, Scheme VI, Scheme VII, Scheme VIII and Scheme IX, the reaction conditions and procedures can be conventional conditions and procedures for such reactions in the art.

[0149] In the present application, the veratramine compound of formula I or its pharmaceutically acceptable salt can also be prepared by peripherally modifying the prepared veratramine compound of formula I or its pharmaceutically acceptable salt using conventional methods in the art to obtain other veratramine compounds of formula I or its pharmaceutically acceptable salt.

[0150] The necessary raw materials or reagents for preparing the veratramine compound of formula I or its pharmaceutically acceptable salt can be commercially available or prepared by known synthetic methods in the art. The compounds of the present application can be prepared as free bases or their acid addition salts by the methods described in the experimental section below. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and has all the effects of the parent compound. The pharmaceutically acceptable salt can be prepared by adding the corresponding acid to the organic base in a suitable organic solvent according to conventional methods for treating pharmaceutically acceptable salts.

[0151] Examples of salt formation include, for base-addition salts, salts of alkali metals, such as sodium, potassium or lithium, or of alkaline earth metals, such as barium, calcium, magnesium or zinc, or of alkanol amines, such as ammonium, diethanolammonium, choline or meglumine, which are formed by treatment with inorganic acids, such as hydrochloric or hydrobromic acid, or with organic acids, such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, glycolic, hydroxynaphthalene carboxylic, 2-hydroxyethanesulfonic, lactic, maleic, malic, oxalic, pyruvic, malonic, mandelic, methanesulfonic, muconic, 2-naphthalenesulfonic, propionic, salicylic, xinafoic, tartaric, cinnamic, p-toluenesulfonic or trimethylacetic acid.

[0152] or, for acid-addition salts, salts of inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or of organic acids, such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, glycolic, hydroxynaphthalene carboxylic, 2-hydroxyethanesulfonic, lactic, maleic, malic, oxalic, pyruvic, malonic, mandelic, methanesulfonic, muconic, 2-naphthalenesulfonic, propionic, salicylic, xinafoic, tartaric, cinnamic, p-toluenesulfonic or trimethylacetic acid.

[0153] The present application provides a pharmaceutical composition comprising a veratramine compound of Formula I or a pharmaceutically acceptable salt thereof as described above, and one or more pharmaceutically acceptable carriers. In the pharmaceutical composition, the veratramine compound of Formula I or a pharmaceutically acceptable salt thereof can be present in a therapeutically effective amount.

[0154] The pharmaceutically acceptable carriers (pharmaceutical excipients) can be those widely used in the pharmaceutical production field. The excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for allowing the active ingredient to be dissolved at a desired rate after administration to a subject, or to facilitate effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavorings and sweeteners.

[0155] The pharmaceutical composition of the present application can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, dragee-making, encapsulating, entrapping or lyophilizing processes.

[0156] The pharmaceutical composition of the present application can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present application can also be a controlled or delayed release dosage form (e.g. liposome or microsphere). Examples of solid oral preparations include, but are not limited to, powder, capsule, caplet, soft capsule and tablet. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspension, emulsion, elixir and solution. Examples of topical preparations include, but are not limited to, emulsion, gel, ointment, cream, patch, paste, foam, lotion, drop or serum preparation. Examples of preparations for parenteral administration include, but are not limited to, injection solution, dry preparation which can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspension and injection emulsion. Examples of other suitable preparations of the pharmaceutical composition include, but are not limited to, eye drop and other ophthalmic preparations; aerosol: such as nasal spray or inhalant; liquid dosage form suitable for parenteral administration; suppository and lozenge.

[0157] The present application also provides a use of the veratramine compound of Formula I or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above in the preparation of an AP-1 inhibitor.

[0158] In the use, the AP-1 inhibitor can be used in vivo in a mammalian organism; it can also be used in vitro, mainly as a standard or control sample for comparison, or prepared into a kit according to the conventional method in the art, for rapid detection of the inhibitory effect of AP-1.

[0159] The present application also provides a use of the veratramine compound of Formula I or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above in the preparation of a medicament. The medicament can be for preventing and / or treating a cell proliferative disease; and / or, the medicament can be for preventing and / or treating a disease or disorder associated with AP-1.

[0160] The disease or disorder associated with AP-1 described above can be a cell proliferative disease. The medicament can prevent and / or treat the cell proliferative disease by modulating the expression and / or activity of AP-1.

[0161] The present application also provides a method for preventing and / or treating a cell proliferative disease (e.g. AP-1 associated) comprising administering to a subject in need thereof, such as a human, a therapeutically effective amount of the veratramine compound of Formula I or a pharmaceutically acceptable salt thereof as described above, or the pharmaceutical composition as described above.

[0162] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of the veracevine compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein or a pharmaceutical composition as described above.

[0163] A cell proliferative disease as described above, including cancer; the cancer can be skin cancer, ovarian cancer, colon cancer, breast cancer, liver cancer, pancreatic cancer, gall bladder cancer, gastrointestinal cancer, head and neck cancer, cervical cancer, prostate cancer, lung cancer, melanoma, germ cell tumor, gestational trophoblastic tumor, glioblastoma, myeloma, neuroblastoma-derived CNS tumor, monocyte leukemia, B-cell derived leukemia, T-cell derived leukemia, B-cell derived lymphoma, T-cell derived lymphoma, and mast cell derived tumor, and combinations thereof.

[0164] When used as a medicament, the veracevine compound of Formula I or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical art, and can be administered by a variety of routes, as necessary for local or systemic treatment and the area to be treated. Administration can be topical (including epicutaneous and transdermal, ocular, and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include dosage forms formulated for once-a-day or twice-a-day (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in single bolus doses, or can be by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, creams, lotions, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable.

[0165] The term "treatment" as used herein refers to therapeutic or prophylactic measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms associated with a disease or disorder or condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether or not detectable to the patient. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0166] In certain embodiments, the veraceamines of Formula I, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions described above, can be used for preventing diseases and disorders as defined herein (e.g., cancer). The term "preventing" as used herein means preventing, in whole or in part, the onset, recurrence, or spread of a disease or disorder described herein, or symptoms thereof.

[0167] The term "pharmaceutically acceptable excipient" or "excipient" refers to a chemically acceptable material, such as a pharmaceutically acceptable agent known to those of ordinary skill in the art of pharmacy to facilitate administration of a pharmaceutical agent. It is a compound that can be used in the preparation of a pharmaceutical composition, is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for use in humans and animals, e.g., in the formulation of pharmaceuticals. Common excipients include binders, surface active agents, diluents, disintegrants, and lubricants.

[0168] Unless otherwise indicated, the following definitions are to be applied to the terms used herein. For the purposes of the present application, chemical elements are identified by their atomic number as provided in the Periodic Table of the Elements, CAS version, and the Chemical and Physical Tables, 75th Edition, 1994. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0169] In this specification, groups of substituents can be selected by one of skill in the art to provide stable moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent is also meant to include the chemically equivalent substituent obtained by writing the formula from right to left.

[0170] In this specification, certain chemical groups are defined herein and are preceded by a shorthand notation to indicate the total number of carbon atoms in the group. For example, C1-C6alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5, or 6 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbon atoms that can be present in substituents of the group.

[0171] In this specification, numerical ranges are defined herein by their lower and upper values. The use of "to" in a range context means "from the lower value and inclusive of the upper value." For example, 1-6 means 1, 2, 3, 4, 5, or 6.

[0172] In addition to the foregoing, the following terms shall have the meanings indicated in this section, unless otherwise specifically indicated in the specification or claims.

[0173] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or more.

[0174] The term "comprising" is a open term, i.e. including the indicated features but not excluding others.

[0175] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, including deuterium and variants of hydrogen, as long as the valency of the designated atom is not exceeded and the resulting compound is stable.

[0176] In general, the term "substituted" means that one or more hydrogen atoms on the given structure are replaced with a particular substituent group. Further, when the group is substituted with more than one of the recited substituents, the substituents are independent of each other, i.e., the more than one substituents can be the same or different. Unless otherwise indicated, a substituent group can be substituted at any available substitutable position on the designated group. When more than one position on the given structure can be substituted with one or more substituents selected from a particular group, the substituents can be the same or different at each position.

[0177] Throughout various portions of the specification, the substituents of the compounds disclosed herein are disclosed according to group type or range. In particular, the present application includes each and every independent subcombination of the members of those groups and ranges. The term "C x -C y "Alkyl" means a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, the term "C1-C6alkyl" or "C1-C6alkyl" means an alkyl group containing from 1 to 6 carbon atoms. The term "C1-C6alkyl" or "C1-C6alkyl" means an alkyl group containing from 1 to 6 carbon atoms. 1-6 "Alkyl" specifically means methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl independently disclosed; "C 1-4 "Alkyl" specifically means methyl, ethyl, C3alkyl (i.e., propyl, including n-propyl and isopropyl), C4alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl).

[0178] The term "alkenyl" means a straight or branched chain unsaturated hydrocarbon having at least one site of unsaturation, i.e., a carbon-carbon sp 2A straight-chain or branched, monovalent hydrocarbon group of two to twelve carbon atoms having a double bond (e.g., C2-C6 alkenyl, and further, for example, C2-C4 alkenyl), and including groups having "cis" and "trans" orientation or "E" and "Z" orientation. Examples include, but are not limited to, vinyl, allyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0179] The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.

[0180] In the present application, the term "alkyl" as a group or as part of another group (e.g., in groups such as halo-substituted alkyl and the like) is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms; such as straight or branched chain saturated hydrocarbon chains containing 1 to 6 carbon atoms; for example, C1-C6 alkyl. As defined in "C1-C6 alkyl" groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain structure are included. Thus, propyl is a C3 alkyl group (including isomers, e.g., n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, e.g., n-butyl, sec-butyl, isobutyl, or t-butyl); pentyl is a C5 alkyl group (including isomers, e.g., n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl, or neopentyl); and hexyl is a C6 alkyl group (including isomers, e.g., n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). In one embodiment, the "alkyl" group is a C1-C4 alkyl group.

[0181] The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally recognized chemical entities that are built into or appended to molecules.

[0182] When a recited substituent does not specify through which atom of the chemical structure formula it is attached to a compound included but not specifically named in the formula, the substituent can be bonded through any atom thereof. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0183] When a group is recited without explicit indication that it has substituents, such group means unsubstituted. For example, when "C1-C4alkyl" is recited without the qualifier "substituted or unsubstituted", it means "C1-C4alkyl" per se or "unsubstituted C1-C4alkyl".

[0184] In various portions of the application, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be understood to be a connecting group. For example, if the structure requires a connecting group and the Markush group definition recites "alkyl" for that variable, then it should be understood that "alkyl" represents a connected alkylene group.

[0185] In some specific structures, when an alkyl group is clearly indicated to be a connecting group, then the alkyl group represents a connected alkylene group. For example, the C1-C6alkyl in the group "halo-C1-C6alkyl" should be understood to be C1-C6alkylene.

[0186] The term "alkylene" denotes a saturated, divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated, straight- or branched-chain hydrocarbon. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and the like.

[0187] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In case there is a plurality of definitions for a term, those definitions are understood to be equivalent for the purposed of the present application.

[0188] It should be understood that the singular forms "a", "an", and "the" include plural referents unless otherwise specified. In addition, the term "comprising" is to be construed as open-ended, not meaning closing, i.e. including but not limited to the recited elements.

[0189] Unless otherwise indicated, the application employs conventional methods of mass spectroscopy, elemental analysis, and the like, following standard procedures of the art.

[0190] Unless otherwise indicated, the application employs standard nomenclature and standard laboratory procedures of analytical chemistry, organic synthesis chemistry and optics. In certain instances, standard techniques are used for chemical synthesis, chemical analysis, testing of luminescent device performance.

[0191] In addition, it should be noted that the description "… independently" used in the present application should be understood in a broad sense, unless otherwise explicitly indicated, which means that each individual described is independent of each other, and can be the same or different specific groups. More specifically, the description "… independently" can mean that the specific options expressed by the same symbols in different groups do not affect each other; or it can mean that the specific options expressed by the same symbols in the same group do not affect each other.

[0192] As understood by those skilled in the art, according to the convention used in the art, the means that the corresponding group is connected to other fragments, groups in the compound through the site.

[0193] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, to obtain each preferred example of the present application.

[0194] The reagents and raw materials used in the present application are commercially available.

[0195] The positive progress effect of the present application is that it can be used as a series of new AP-1 inhibitors and for the preparation of corresponding drugs for diseases. In preliminary activity studies, it is shown that the compounds provided by the present application have strong inhibitory activity on tumor cell proliferation; have the potential to be prepared into new anti-tumor drugs, and have good market prospects. DETAILED DESCRIPTION

[0196] The present application will be further described below by way of examples, but the present application is not limited in the scope of the examples described. The experimental methods in the following examples are not specified, which are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0197] Example 1

[0198]

[0199] A weighed amount of veratramine (3 g, 7.33 mmol) was dissolved in 50 ml of water, HCHO (893 μl, 8.80 mmol) and HCOOH (1372 μl, 36.67 mmol) were added, and the reaction was refluxed at 100°C under argon protection for 12 h. After the reaction was completed as monitored by TLC, saturated NaOH solution was added for quenching, extracted with DCM (20 ml x 3), dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 3:1-1:1) to obtain the intermediate

[0200] Intermediate 1H NMR (500 MHz, CDC13) δ 7.25 (d, J = 6.3 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.48 (br d, J = 5.1 Hz, 1H), 3.87 - 3.82 (m, 1H), 3.73 - 3.67 (m, 1H), 3.61 - 3.53 (m, 1H), 2.97 - 2.91 (m, 1H), 2.77 (dd, J = 15.0, 7.5 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.47 (s, 3H), 2.41 (dd, J = 12.9, 4.3 Hz, 1H), 2.33 (s, 3H), 2.29 - 2.24 (m, 1H), 2.16 (d, J = 7.0 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.91 - 1.70 (m, 8H), 1.65 - 1.58 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.34 - 1.22 (m, 2H), 1.13 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 145.12, 144.30, 142.59, 140.96, 132.70, 123.75, 122.03, 120.84, 71.91, 70.78, 67.50, 64.84, 57.09, 42.82, 41.99, 41.89, 41.30, 38.13, 37.02, 34.34, 31.41, 30.49, 30.45, 28.65, 19.34, 19.27, 16.15, 12.86. HRMS (ESI): m / z calcd for C 28 H 42 NO2 + [M+H] + : 424.3210, found 424.3214.

[0201] The above intermediate (210 mg, 0.50 mmol) was dissolved in anhydrous DCM, Py (400 μl, 4.96 mmol) was added, CH3COCI (351 μl, 4.96 mmol) was added dropwise under ice bath condition, after the addition was completed, 0 °C reaction for 20 min, TLC monitoring reaction was completed, saturated NaHC03solution was added to quench, extracted with DCM (5 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA = 3: 1) to give white solid, which was VT-8 (142 mg, 61%).

[0202] 1H NMR (500 MHz, CDC13) δ 7.26 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 5.51 (br d, J = 5.0 Hz, 1H), 4.69 - 4.61 (m, 1H), 3.85 - 3.81 (m, 1H), 3.73 - 3.66 (m, 1H), 2.94 (td, J = 11.6, 5.3 Hz, 1H), 2.80 - 2.73 (m, 2H), 2.65 - 2.53 (m, 2H), 2.46 (s, 3H), 2.43 (dd, J = 4.9, 1.7 Hz, 1H), 2.39 - 2.34 (m, 1H), 2.33 (s, 3H), 2.15 (dd, J = 8.5, 3.6 Hz, 1H), 2.05 (s, 3H), 1.94 - 1.78 (m, 6H), 1.74 - 1.64 (m, 2H), 1.41 (d, J = 7.2 Hz, 3H), 1.37 - 1.26 (m, 2H), 1.14 (s, 3H), 0.85 (d, J = 6.5 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 170.65, 144.97, 144.18, 141.44, 141.00, 132.69, 123.75, 122.99, 120.81, 73.98, 70.74, 67.48, 64.84, 56.97, 42.81, 41.90, 41.20, 37.85, 37.84, 37.08, 34.32, 30.43, 30.41, 28.67, 27.56, 21.54, 19.27, 19.22, 16.13, 12.80. HRMS (ESI): m / z calcd for C 30 H 44 NO3 + [M+H] + : 466.3316, found (466.3315).

[0203] Example 2

[0204]

[0205] A solution of oxalyl chloride (184 μΐ, 2.15 mmol) in anhydrous DCM was cooled to -78 °C under argon, a solution of DMSO (229 μΐ, 3.23 mmol) in anhydrous DCM was added, after 1 h, a solution of VT-8 (500 mg, 1.08 mmol) in anhydrous DCM was added, after 1.5 h, triethylamine (894 μΐ, 6.45 mmol) was added, the reaction was protected from -65 °C for 1 h, then the low temperature was removed, slowly warmed to room temperature, then quenched with water, washed with saturated NH4CI and saturated NaCI solution several times, dried over anhydrous Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA = 19: 1) to give VT-9 (283 mg, 68%) as a white solid.

[0206] 1 H NMR (500 MHz, CDC13) δ 7.08 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 5.52 (br d, J = 5.3 Hz, 1H), 4.70 - 4.61 (m, 1H), 3.61 (d, J = 9.9 Hz, 1H), 3.41 - 3.35 (m, 1H), 2.97 (td, J = 11.7, 5.3 Hz, 1H), 2.89 (dd, J = 13.4, 2.9 Hz, 1H), 2.82 - 2.70 (m, 2H), 2.63 - 2.53 (m, 3H), 2.52 - 2.42 (m, 2H), 2.38 - 2.32 (m, 1H), 2.28 (s, 3H), 2.20 - 2.13 (m, 1H), 2.05 (s, 6H), 1.94 - 1.83 (m, 3H), 1.74 - 1.64 (m, 1H), 1.39 - 1.24 (m, 2H), 1.15 (s, 3H), 1.09 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 210.25, 170.60, 143.53, 142.66, 141.44, 140.11, 131.21, 125.23, 123.21, 120.06, 74.04, 73.25, 61.73, 56.97, 50.05, 41.32, 37.90, 37.89, 37.09, 36.82, 35.12, 32.11, 30.49, 30.46, 27.59, 21.53, 21.02, 19.29, 19.29, 15.50. HRMS (ESI): m / z calcd for C 30 H 42 NO3 + [M+H] +:464.3159, found (464.3162).

[0207] Example 3

[0208]

[0209] VT-9 (387 mg, 0.84 mmol) was dissolved in anhydrous EtOH, hydroxylamine hydrochloride (581 mg, 8.4 mmol) and anhydrous sodium acetate (686 mg, 8.4 mmol) were added, and the reaction was carried out at room temperature for 4 h. After the reaction was completed as monitored by TLC, water was added to quench, and extraction was performed with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE / EA = 5:1-3:1) to give VT-10 (297 mg, 74%) as a white solid.

[0210] 1 H NMR (500 MHz, CDC13) δ 7.08 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.52 (d, J = 5.2 Hz, 1H), 4.71 - 4.62 (m, 1H), 3.49 - 3.42 (m, 2H), 2.97 (td, J = 11.6, 5.3 Hz, 1H), 2.93 - 2.82 (m, 2H), 2.79 (dd, J = 14.7, 7.3 Hz, 1H), 2.66 - 2.52 (m, 2H), 2.45 (ddd, J = 12.9, 4.8, 1.6 Hz, 1H), 2.40 - 2.32 (m, 2H), 2.30 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 1.96 - 1.79 (m, 3H), 1.76 - 1.63 (m, 1H), 1.39 - 1.25 (m, 3H), 1.16 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H), 0.91 - 0.83 (m, 1H); 13 C NMR (125 MHz, CDC13) δ 170.62, 143.37, 142.50, 141.28, 141.28, 131.32, 124.67, 123.12, 120.01, 73.98, 69.08, 59.99, 59.98, 56.88, 53.44, 41.16, 37.77, 36.97, 34.87, 30.57, 30.43, 30.36, 29.24, 28.99, 27.48, 21.44, 20.82, 19.62, 19.20, 15.70. HRMS (ESI): m / z calcd for C 30 H 43N2O3 + [M+H] + : 479.3268, found 479.3270.

[0211] Example 4

[0212]

[0213] VT-9 was used as starting material, synthesis method same as VT-10

[0214] White solid, yield about 85%. 1 H NMR (500 MHz, CDC13) δ 7.10 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 5.52 (br d, J = 5.2 Hz, 1H), 4.71 - 4.62 (m, 1H), 4.18 - 4.12 (m, 2H), 3.41 (s, 2H), 2.97 (td, J = 11.6, 5.3 Hz, 1H), 2.86 (d, J = 11.6 Hz, 1H), 2.79 (dd, J = 14.7, 7.3 Hz, 1H), 2.73 (dd, J = 13.9, 3.6 Hz, 1H), 2.65 - 2.53 (m, 2H), 2.48 - 2.42 (m, 1H), 2.36 (dd, J = 19.5, 8.0 Hz, 2H), 2.30 (s, 3H), 2.28 - 2.22 (m, 1H), 2.15 - 2.07 (m, 3H), 2.05 (s, 4H), 1.95 - 1.81 (m, 4H), 1.75 - 1.65 (m, 1H), 1.39 - 1.32 (m, 1H), 1.29 (t, J = 7.0 Hz, 4H), 1.15 (s, 3H), 1.09 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.2 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 170.64, 143.28, 143.25, 142.48, 141.86, 141.41, 131.51, 124.79, 123.28, 119.98, 74.07, 69.30, 69.01, 60.10, 56.99, 41.29, 41.26, 37.91, 37.10, 35.28, 31.29, 30.56, 30.50, 29.18, 27.62, 21.56, 20.99, 19.82, 19.33, 15.91, 15.02, 14.78. HRMS (ESI): m / z calcd for C 32 H 47 N2O3 + [M+H] +: 507.3581, found (507.3580).

[0215] Example 5

[0216]

[0217] VT-9 (216 mg, 0.47 mmol) was dissolved in anhydrous DCM (2.5 ml) under Ar protection condition, DAST (1.7 ml, 14.00 mmol) was added dropwise under ice bath, and the addition was completed within half an hour. After that, the ice bath was removed, and the reaction was carried out at room temperature for 24 h. After most of the raw materials were reacted, the reaction solution was slowly poured into ice water to quench, and after complete quenching, the organic phase was dried with anhydrous Na2SO4, filtered and concentrated to obtain the crude product, which was purified by silica gel column chromatography (PE / EA = 3:1) to obtain white solid VT-20 (115 mg, 51%).

[0218] 1 H NMR (500 MHz, CDC13) δ 7.12 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.52 (br d, J = 5.2 Hz, 1H), 4.71 - 4.62 (m, 1H), 3.53 - 3.44 (m, 1H), 3.02 - 2.75 (m, 4H), 2.65 - 2.53 (m, 2H), 2.48 - 2.42 (m, 1H), 2.39 - 2.32 (m, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.22 - 2.12 (m, 3H), 2.05 (s, 3H), 1.95 - 1.81 (m, 3H), 1.75 - 1.65 (m, 1H), 1.48 - 1.31 (m, 5H), 1.15 (s, 3H), 0.87 (d, J = 6.2 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 170.65, 143.48, 142.72, 141.63, 141.42, 130.62, 125.57 / 123.54 / 121.54, 125.07, 123.27, 119.94, 74.06, 66.97 / 66.80 / 66.63, 63.02, 57.05, 43.42 / 43.23 / 43.04, 41.31, 38.31, 37.93, 37.91, 37.13, 33.67, 30.52, 30.49, 27.62, 25.13 / 25.07, 21.58, 19.92 / 19.88, 19.33, 18.36, 15.55. HRMS (ESI): m / z calcd for C 30 H 42 F2NO2+ [M+H] + :486.3178, found (486.3177).

[0219] Example 6

[0220]

[0221] VT-20 (165 mg, 0.34 mmol) was dissolved in CH3OH, NaOH (27 mg, 0.68 mmol) was added, and the reaction was refluxed at 65 °C for 2 h. After the reaction was completed by TLC monitoring, it was quenched with water and extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (PE / EA = 3:1-1:1) to give the white solid intermediate

[0222] Intermediate 1 H NMR (500 MHz, CDC13) δ 7.12 (d, J = 7.7 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 5.49 (br d, J = 5.2 Hz, 1H), 3.63 - 3.47 (m, 2H), 2.98 (td, J = 11.6, 5.3 Hz, 2H), 2.88 (d, J = 9.5 Hz, 1H), 2.78 (dd, J = 14.7, 7.4 Hz, 1H), 2.66 - 2.53 (m, 2H), 2.42 (ddd, J = 12.9, 4.7, 1.7 Hz, 1H), 2.29 (s, 3H), 2.27 (s, 3H), 2.23 - 2.13 (m, 2H), 2.09 - 1.99 (m, 1H), 1.92 - 1.79 (m, 4H), 1.61 (ddd, J = 27.2, 13.8, 4.0 Hz, 1H), 1.50 - 1.39 (m, 1H), 1.36 (dd, J = 6.7, 3.4 Hz, 3H), 1.32 - 1.23 (m, 1H), 1.14 (s, 3H), 0.89 (d, J = 6.0 Hz, 3H); 13C NMR (125MHz, CDCl3) δ143.72,142.90,142.54,141.36,130.59,126.15 / 123. 33 / 120.82,125.01,122.26,120.07,71.96,67.09 / 66.89 / 66.75,62.96,57.1 4,43.25 / 43.07 / 42.87,42.02,41.37,38.48,38.17,37.04,33.69,31.44,30 .58,30.47,25.05 / 24.99,20.00 / 19.96,19.42,18.31,15.56.HRMS(ESI):m / z calcd for C 28 H 40 F2NO + [M+H] + :444.3072,found(444.3075)

[0223] Using the aforementioned intermediate as a raw material, VT-22 was synthesized using the same method as VT-9.

[0224] White solid, yield approximately 70%. 1 H NMR (500MHz, CDCl3) δ7.13(d,J=7.4Hz,1H),6.99(d,J=7.4Hz,1H),5.82(brd,J=1 .1Hz,1H),3.51–3.45(m,1H),3.12–2.72(m,4H),2.64–2.37(m,7H),2.28(s,3H),2 .24(s,3H),2.21–2.00(m,4H),1.90(td,J=14.2,4.5Hz,1H),1.82–1.76(m,1H),1 .52–1.40(m,2H),1.34(dd,J=6.8,3.2Hz,3H),1.29(s,3H),0.88(d,J=6.3Hz,3H). 13 C NMR (125MHz, CDCl3) δ199.50,170.20,142.57,142.51,141.98,130.84,125.30,125.27,119.56,66.94 / 66.77 / 66.60,63.00,59.70 ,43.91,38.68,38.32,36.34,33.95,33.66,33.36,30.20,29.72,25.10 / 25.04,19.88 / 19.83,18.34,17.00,15.52.HRMS(ESI):m / z calcd for C 28H 38 F2NO + [M+H] + :442.2916,found 442.2918.

[0225] Example 7

[0226]

[0227] Using VT-22 as raw material, the synthesis method is the same as that of VT-10.

[0228] White solid, yield approximately 83%. 1 H NMR(500MHz, CDCl3)δ7.12(d,J=7.8Hz,1H),6.98(d,J=7.8Hz,1H),5.60–5.51( m,1H),3.51–3.44(m,1H),3.06–2.78(m,5H),2.66–2.56(m,2H),2.46–2.31(m, 2H),2.29(s,3H),2.24(s,3H),2.23–2.02(m,5H),1.98–1.85(m,2H),1.54–1.3 9(m,2H),1.35(dd,J=6.9,3.2Hz,4H),1.26(s,1H),1.23(s,3H).HRMS(ESI):m / z calcdfor C 28 H 39 F2N2O + [M+H] + :457.3025,found457.3031.

[0229] Example 8

[0230]

[0231] Veratridine (500 mg, 1.22 mmol) was dissolved in THF, and Et3N (1236 mg, 12.22 mmol) was added. Then, a THF solution of FmocCl (3161 mg, 12.22 mmol) was added. The reaction was carried out at room temperature for 1 h, quenched with water, and the organic phase was separated and concentrated. It was then purified by silica gel column chromatography (PE / EA = 5:1) to obtain a white intermediate. The subsequent acetylation steps were the same as for VT-8. The intermediate was then dissolved in DMF, and 2 ml of piperidine was added. The mixture was stirred at room temperature for 30 min. After the reaction was completed by TLC monitoring, 5 ml of water was added and the mixture was washed three times. The mixture was extracted with DCM, and the organic phase was dried over anhydrous Na2SO4. After filtration, the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 3:1) to obtain a white solid (45 mg, 35%).

[0232] 1 H NMR (500 MHz, CDC13) δ 7.22 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 5.52 (br d, J = 5.0 Hz, 1H), 4.69 - 4.62 (m, 1H), 3.53 - 3.46 (m, 1H), 3.31 - 3.26 (m, 1H), 3.00 - 2.89 (m, 2H), 2.79 (dd, J = 14.8, 7.4 Hz, 1H), 2.65 - 2.54 (m, 2H), 2.51 - 2.42 (m, 2H), 2.36 (dd, J = 8.5, 5.5 Hz, 1H), 2.32 (s, 3H), 2.11 (dd, J = 15.1, 8.0 Hz, 1H), 2.05 (s, 3H), 1.99 (dd, J = 7.8, 5.6 Hz, 1H), 1.94 - 1.82 (m, 3H), 1.74 - 1.64 (m, 2H), 1.57 - 1.46 (m, 2H), 1.39 (d, J = 7.2 Hz, 3H), 1.37 - 1.24 (m, 2H), 1.16 (s, 3H), 1.00 (dd, J = 23.0, 12.1 Hz, 1H), 0.82 (d, J = 6.6 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 170.65, 143.99, 143.10, 141.47, 140.40, 132.82, 125.39, 123.16, 120.02, 74.04, 70.89, 67.12, 56.98, 54.07, 44.14, 41.30, 37.90, 37.90, 37.11, 36.24, 32.15, 30.61, 30.49, 27.61, 21.57, 19.50, 19.30, 18.94, 15.97. HRMS (ESI): m / z calcd for C 29 H 42 NO3 + [M+H] + : 452.3159, found (452.3153).

[0233] Example 9

[0234]

[0235] Veratramine (1 g, 2.44 mmol) was dissolved in acetone, K2CO3(3.4 g, 24.45 mmol) and 3-bromopropene (1.5 g, 12.2 mmol) were added and the reaction was refluxed at 56 °C for 12 h. After the reaction was completed by TLC monitoring, ammonia water was added and stirred for 1 h to quench, most of the solvent was removed under reduced pressure, washed with water and extracted with DCM (5 ml x 3), the combined organic phase was dried over anhydrous Na2SO4and concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE / EA = 3:1-1:1) to give the intermediate

[0236] Intermediate 1 H NMR (500 MHz, CDC13) δ 7.25 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 5.96 (m, 1H), 5.48 (br d, J = 5.2 Hz, 1H), 5.26 - 5.16 (m, 2H), 3.81 - 3.86 (m, 1H), 3.74 - 3.65 (m, 1H), 3.61 - 3.51 (m, 2H), 3.04 (dd, J = 14.4, 7.7 Hz, 1H), 2.95 (td, J = 11.6, 5.3 Hz, 1H), 2.86 (d, J = 10.9 Hz, 1H), 2.76 (dd, J = 14.9, 7.4 Hz, 1H), 2.66 - 2.53 (m, 2H), 2.50 - 2.34 (m, 2H), 2.31 (s, 3H), 2.29 - 2.22 (m, 1H), 2.04 - 1.96 (m, 1H), 1.93 - 1.76 (m, 7H), 1.68 - 1.54 (m, 2H), 1.40 (d, J = 7.1 Hz, 3H), 1.30 - 1.25 (m, 1H), 1.13 (s, 3H), 0.87 (d, J = 6.7 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 145.01, 144.07, 142.61, 140.98, 135.74, 132.68, 124.04, 121.96, 120.77, 117.41, 71.84, 67.50, 67.42, 59.75, 57.09, 56.23, 41.96, 41.30, 41.27, 38.12, 36.99, 34.21, 31.37, 30.47, 30.43, 28.24, 19.52, 19.32, 16.17, 13.91. HRMS (ESI): m / z calcd for C 30 H 44 NO2 + [M+H] + : 450.3367, found 450.3369).

[0237] The above intermediate was used as the starting material, and the synthetic method was the same as VT-8.

[0238] White solid, yield about 55%. 1 H NMR (500 MHz, CDC13) δ 7.25 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.01 - 5.92 (m, 1H), 5.51 (br d, J = 5.2 Hz, 1H), 5.30 - 5.17 (m, 2H), 4.70 - 4.61 (m, 1H), 3.85 - 3.80 (m, 1H), 3.73 - 3.66 (m, 1H), 3.57 (dd, J = 14.4, 5.0 Hz, 1H), 3.03 (dd, J = 14.4, 7.7 Hz, 1H), 2.94 (td, J = 11.6, 5.2 Hz, 1H), 2.86 (d, J = 11.0 Hz, 1H), 2.77 (dd, J = 14.9, 7.4 Hz, 1H), 2.65 - 2.53 (m, 2H), 2.49 - 2.42 (m, 2H), 2.36 (d, J = 11.4 Hz, 1H), 2.31 (s, 3H), 2.05 (s, 3H), 2.01 (dd, J = 9.6, 7.1 Hz, 1H), 1.95 - 1.78 (m, 5H), 1.75 - 1.58 (m, 2H), 1.40 (d, J = 7.1 Hz, 3H), 1.36 - 1.26 (m, 2H), 1.15 (s, 3H), 0.90 (d, J = 12.1 Hz, 1H), 0.87 (d, J = 6.6 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 170.48, 144.78, 143.87, 141.33, 140.91, 135.66, 132.59, 123.92, 122.87, 120.66, 117.27, 73.84, 67.35, 67.26, 59.66, 56.85, 56.11, 41.21, 41.08, 37.73, 37.73, 36.95, 34.07, 30.32, 30.29, 28.17, 27.44, 21.42, 19.42, 19.10, 16.06, 13.73. HRMS (ESI): m / z calcd for C 32 H 46 NO3 + [M+H] + : 492.3472, found 492.3474.

[0239] Example 10

[0240] Example 10

[0241] VT-27 is the starting material, synthesis method is the same as VT-9

[0242] White solid, yield about 75%. 1 H NMR (500 MHz, CDC13) δ 7.07 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.52 (br d, J = 5.2 Hz, 1H), 5.35 - 5.24 (m, 1H), 4.95 - 4.87 (m, 2H), 4.70 - 4.61 (m, 1H), 3.55 (d, J = 9.6 Hz, 1H), 3.52 - 3.44 (m, 1H), 3.06 - 2.92 (m, 2H), 2.83 - 2.74 (m, 3H), 2.63 - 2.54 (m, 3H), 2.47 - 2.41 (m, 2H), 2.39 - 2.32 (m, 1H), 2.28 (s, 3H), 2.17 - 2.11 (m, 1H), 2.05 (s, 3H), 1.95 - 1.79 (m, 4H), 1.74 - 1.67 (m, 1H), 1.38 - 1.27 (m, 2H), 1.16 (s, 3H), 1.09 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.2 Hz, 3H); 13 C NMR (125 MHz, CDC13) δ 210.71, 170.65, 143.62, 142.52, 141.43, 140.23, 136.16, 131.35, 125.64, 123.22, 119.93, 116.79, 74.19, 74.07, 57.11, 55.25, 53.61, 48.38, 41.27, 37.92, 37.10, 33.39, 32.74, 30.51, 30.50, 27.63, 21.57, 20.61, 19.56, 19.35, 19.30, 15.79. HRMS (ESI): m / z calcd for C 32 H 44 NO3 + [M+H] + : 490.3316, found 490.3313.

[0243] Example 11

[0244]

[0245] Veratrilamine (500 mg, 1.22 mmol) and aluminum isopropoxide (499 mg, 2.44 mmol) were dissolved in toluene, and cyclohexanone (1.3 ml, 12.22 mmol) was added. The reaction was refluxed at 110 °C for 6 h. After the reaction was completed by TLC, the reaction solution was filtered, the filtrate was concentrated under vacuum and purified by silica gel column chromatography (PE / EA = 2:1-1:1) to obtain a white solid, which was VT-34 (415 mg, 83%).

[0246] 1 H NMR (500MHz, CDCl3) δ7.24(d,J=7.8Hz,1H),6.97(d,J=7.7Hz,1H),5.82(s,1H),3.54–3.46(m,1H),3. 26(ddd,J=10.6,9.4,4.6Hz,1H),3.05(td,J=12.0,3.1Hz,1H),2.91(ddd,J=12.1,3.9,1.9Hz,1H),2.7 5(dd,J=14.6,6.9Hz,1H),2.64–2.36(m,7H),2.32(s,3H),2.14–1.97(m,3H),1.89(td,J=14.2,4.5Hz ,1H),1.82–1.63(m,4H),1.54–1.44(m,2H),1.38(d,J=7.2Hz,3H),1.29(s,3H),0.82(d,J=6.6Hz,3H); 13 C NMR (125MHz, CDCl3) δ199.56,170.15,142.95,142.29,140.72,133.02,125.58,125.25,119.55,70.88,67.10,59.57,54 .06,44.15,43.84,38.62,36.25,36.14,33.88,33.28,32.15,30.25,29.67,19.60,18.92,16.92,15.93.HRMS(ESI):m / z calcd for C 27 H 38 NO2 + [M+H] + :408.2897,found(408.2898).

[0247] Example 12

[0248]

[0249] by Using the same raw materials as VT-34, VT-35 was synthesized.

[0250] White solid, yield about 60%. 1 H NMR (500 MHz, CDC13) δ 7.27 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.82 (s, 1H), 3.87 - 3.83 (m, 1H), 3.72 - 3.65 (m, 1H), 3.03 (td, J = 12.0, 2.9 Hz, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.73 (dd, J = 14.7, 7.0 Hz, 1H), 2.64 - 2.50 (m, 3H), 2.47 (s, 3H), 2.46 - 2.37 (m, 3H), 2.33 (s, 3H), 2.18 (d, J = 5.4 Hz, 1H), 2.02 (ddd, J = 13.2, 5.0, 2.5 Hz, 1H), 1.94 - 1.69 (m, 6H), 1.50 - 1.44 (m, 1H), 1.42 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 0.86 (d, J = 6.6 Hz, 4H); 13 C NMR (125 MHz, CDC13) δ 199.38, 169.81, 143.83, 143.27, 141.26, 132.72, 125.18, 123.89, 120.26, 70.67, 67.34, 64.61, 59.48, 43.65, 42.66, 41.75, 38.48, 36.13, 34.27, 33.75, 33.07, 29.96, 29.50, 28.42, 19.11, 16.74, 15.98, 12.88. HRMS (ESI): m / z calcd for C 28 H 40 NO2 + [M+H] + : 422.3054, found (422.3055).

[0251] Example 13

[0252]

[0253] VT-25 was synthesized from VT-34 following the procedure described for VT-36

[0254] White solid, yield about 58%. 1H NMR (500 MHz, CDC13) δ 7.26 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 5.98 - 5.90 (m, 1H), 5.82 (d, J = 1.1 Hz, 1H), 5.25 - 5.15 (m, 2H), 3.83 (s, 1H), 3.72 - 3.65 (m, 1H), 3.55 (d, J = 11.1 Hz, 1H), 3.04 (td, J = 11.9, 3.1 Hz, 2H), 2.87 (d, J = 10.1 Hz, 1H), 2.73 (dd, J = 14.7, 7.0 Hz, 1H), 2.64 - 2.37 (m, 7H), 2.31 (s, 3H), 2.03 (ddd, J = 13.2, 5.0, 2.5 Hz, 1H), 1.93 - 1.59 (m, 5H), 1.50 - 1.43 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.29 (s, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDC13) δ 199.47, 169.90, 143.90, 143.20, 141.40, 135.07, 132.71, 125.31, 124.41, 120.40, 117.85, 71.88, 67.70, 67.28, 59.61, 56.24, 43.78, 41.20, 38.61, 36.25, 34.42, 33.87, 33.20, 30.10, 29.62, 27.97, 19.45, 16.89, 16.14, 14.31. HRMS (ESI): m / z calcd for C 30 H 42 NO2 + [M+H] + : 448.3210, found 448.3216.

[0255] Example 14

[0256]

[0257] VT-34 was synthesized using the same procedure as VT-10

[0258] White solid, yield about 51%. 1H NMR (500 MHz, MeOD) δ 7.11 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 5.85 (d, J = 1.6 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.44 - 3.37 (m, 1H), 3.11 - 2.90 (m, 4H), 2.76 (dt, J = 13.2, 6.6 Hz, 1H), 2.49 (qdd, J = 14.3, 10.9, 4.7 Hz, 5H), 2.34 (s, 3H), 2.24 - 2.06 (m, 2H), 1.95 - 1.73 (m, 3H), 1.69 - 1.47 (m, 2H), 1.43 (d, J = 7.3 Hz, 3H), 1.38 - 1.27 (m, 1H), 1.23 (t, J = 11.6 Hz, 2H), 1.18 (s, 2H), 0.94 (d, J = 6.6 Hz, 3H). HRMS (ESI): m / z calcd for C 27 H 39 N2O2 + [M+H] + : 423.3006, found 423.3001.

[0259] Example 15

[0260]

[0261] VT-34 was synthesized from the starting material VT-10

[0262] White solid, yield about 53%. 1 H NMR (500 MHz, MeOD) δ 7.10 (d, J = 7.8 Hz, 2H), 7.01 (dd, J = 7.7, 3.6 Hz, 2H), 5.83 (d, J = 1.7 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 1H), 3.70 - 3.63 (m, 2H), 3.33 (dd, J = 9.6, 3.6 Hz, 1H), 3.03 - 2.96 (m, 4H), 2.82 - 2.73 (m, 3H), 2.63 - 2.34 (m, 9H), 2.33 (s, 6H), 2.26 - 2.16 (m, 2H), 2.06 (d, J = 12.6 Hz, 2H), 1.73 - 1.47 (m, 5H), 1.40 (d, J = 7.2 Hz, 5H), 1.36 - 1.27 (m, 2H), 1.26 - 1.11 (m, 8H), 0.91 (d, J = 6.6 Hz, 5H). HRMS (ESI): m / z calcd for C 28 H 41 N2O2 + [M+H]+ :437.3163, found 437.3168.

[0263] Example 16

[0264]

[0265] VT-34 as starting material, synthesis as for VT-10

[0266] White solid, yield about 55%. 1 H NMR (500 MHz, MeOD) δ 7.10 (d, J = 7.8 Hz, 2H), 7.03 (dd, J = 7.7, 3.8 Hz, 2H), 5.84 (d, J = 1.7 Hz, 1H), 4.10 - 4.00 (m, 3H), 3.75 - 3.67 (m, 2H), 3.42 - 3.35 (m, 2H), 3.07 - 2.73 (m, 9H), 2.64 - 2.38 (m, 9H), 2.33 (s, 6H), 2.26 - 2.16 (m, 2H), 2.08 (d, J = 13.0 Hz, 2H), 1.81 - 1.47 (m, 6H), 1.41 (d, J = 7.3 Hz, 6H), 1.27 - 1.13 (m, 13H), 0.93 (d, J = 6.6 Hz, 6H). HRMS (ESI): m / z calcd for C 29 H 43 N2O2 + [M+H] + :451.3319, found (451.3315).

[0267] Example 17

[0268]

[0269] VT-34 as starting material, synthesis as for VT-10

[0270] White solid, yield about 47%. 1H NMR (500 MHz, MeOD) δ 7.13 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.81 - 3.74 (m, 1H), 3.52 - 3.42 (m, 1H), 3.16 - 2.96 (m, 3H), 2.83 - 2.40 (m, 7H), 2.35 (s, 3H), 2.12 (d, J = 12.8 Hz, 1H), 1.72 - 1.55 (m, 2H), 1.45 (d, J = 7.2 Hz, 3H), 1.40 - 1.22 (m, 5H), 1.20 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H). HRMS (ESI): m / z calcd for C 28 H 41 N4O2 + [M+H] + : 465.3224, found (465.4226).

[0271] Example 18

[0272]

[0273] VT-34 was used as starting material, synthesis method same as VT-10

[0274] Light yellow solid, yield about 35%. 1 H NMR (500 MHz, MeOD) δ 7.13 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.81 - 3.74 (m, 1H), 3.52 - 3.42 (m, 1H), 3.16 - 2.96 (m, 3H), 2.83 - 2.40 (m, 7H), 2.35 (s, 3H), 2.12 (d, J = 12.8 Hz, 1H), 1.72 - 1.55 (m, 2H), 1.45 (d, J = 7.2 Hz, 3H), 1.40 - 1.22 (m, 5H), 1.20 (s, 3H), 0.97 (d, J = 6.6 Hz, 3H). HRMS (ESI): m / z calcd for C 28 H 41 N4OS + [M+H] + : 481.2996, found (481.2993).

[0275] Example 19

[0276]

[0277] VT-34 was used as starting material, synthesis method same as VT-10

[0278] White solid, yield about 47%. 1 H NMR (500 MHz, MeOD) δ 7.12 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.00 (s, 1H), 3.75 - 3.69 (m, 1H), 3.44 - 3.38 (m, 1H), 3.08 - 3.92 (m, 3H), 2.79 - 2.66 (m, 2H), 2.59 - 2.39 (m, 5H), 2.34 (s, 3H), 2.31 - 2.20 (m, 1H), 2.10 (d, J = 12.8 Hz, 1H), 1.97 (d, J = 12.9 Hz, 1H), 1.79 (s, 1H), 1.69 - 1.56 (m, 2H), 1.52 (s, 9H), 1.42 (d, J = 7.2 Hz, 3H), 1.26 - 1.20 (m, 1H), 1.18 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H). HRMS (ESI): m / z calcd for C 32 H 48 N3O3 + [M+H] + : 522.3690, found 522.3693.

[0279] Example 20

[0280]

[0281] VT-34 was used as starting material, synthesis method same as VT-10

[0282] White solid, yield about 30%. 1 H NMR (500 MHz, MeOD) δ 7.12 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.00 (s, 1H), 3.75 - 3.69 (m, 1H), 3.44 - 3.38 (m, 1H), 3.08 - 3.92 (m, 3H), 2.79 - 2.66 (m, 2H), 2.59 - 2.39 (m, 5H), 2.34 (s, 3H), 2.31 - 2.20 (m, 1H), 2.10 (d, J = 12.8 Hz, 1H), 1.97 (d, J = 12.9 Hz, 1H), 1.79 (s, 1H), 1.69 - 1.56 (m, 2H), 1.52 (s, 9H), 1.42 (d, J = 7.2 Hz, 3H), 1.26 - 1.20 (m, 1H), 1.18 (s, 3H), 0.94 (d, J = 6.6 Hz, 3H). HRMS (ESI): m / z calcd for C27 H 40 N3O + [M+H] + :422.3166, found 422.3169.

[0283] Example 21

[0284]

[0285] VT-34 (120 mg, 0.29 mmol) was dissolved in CH3OH, CeCl3·7H2O (143 mg, 0.38 mmol) was added under ice bath, NaBH4(19 mg, 0.50 mmol) was added in three portions, the reaction was monitored by TLC spot plate after 30 min, quenched with water, extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to get the crude product, which was purified by silica gel column chromatography (PE / EA = 1:1-EA) to get white solid VT-44 (103 mg, 85%).

[0286] 1 H NMR (500 MHz, MeOD) δ 7.09 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 5.36 (s, 1H), 4.15 - 4.09 (m, 1H), 3.70 - 3.62 (m, 1H), 3.34 (dd, J = 9.9, 3.9 Hz, 1H), 3.03 - 2.88 (m, 2H), 2.82 - 2.67 (m, 2H), 2.52 - 2.34 (m, 4H), 2.33 (s, 3H), 2.24 - 2.15 (m, 1H), 2.07 (d, J = 12.6 Hz, 1H), 1.92 (d, J = 9.3 Hz, 1H), 1.78 - 1.44 (m, 5H), 1.41 (d, J = 7.2 Hz, 3H), 1.32 - 1.20 (m, 2H), 1.17 (s, 3H), 1.16 - 1.09 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H); 13 C NMR (125 MHz, MeOD) δ 146.79, 145.74, 144.28, 139.30, 133.94, 126.46, 126.31, 120.78, 69.96, 68.61, 67.61, 62.31, 53.32, 45.62, 43.82, 38.45, 36.74, 36.46, 33.62, 31.85, 31.15, 30.36, 29.38, 21.11, 18.80, 18.78, 16.05. HRMS (ESI): m / z calcd for C 27 H40 NO2 + [M+H] + : 410.3054, found 410.3055.

[0287] Example 22

[0288]

[0289] VT-36 as starting material, synthesis method same as VT-10 white solid, yield about 45%. 1 H NMR (500 MHz, CDC13) δ 7.25 (d, J = 7.9 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 5.98 - 5.90 (m, 1H), 5.87 (d, J = 1.7 Hz, 1H), 5.21 (t, J = 13.7 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 1H), 3.72 - 3.65 (m, 1H), 3.58 (dd, J = 14.2, 4.5 Hz, 1H), 3.11 - 2.86 (m, 5H), 2.73 - 2.67 (m, 1H), 2.58 - 2.34 (m, 8H), 2.30 (s, 4H), 2.24 - 2.17 (m, 1H), 1.95 - 1.83 (m, 4H), 1.67 (ddd, J = 19.7, 12.5, 5.4 Hz, 3H), 1.52 (td, J = 13.9, 5.0 Hz, 1H), 1.40 (d, J = 7.1 Hz, 3H), 1.39 - 1.18 (m, 7H), 1.15 (s, 3H), 0.96 - 0.89 (m, 1H), 0.87 (d, J = 6.6 Hz, 4H). HRMS (ESI): m / z calcd for C 31 H 45 N2O2 + [M+H] + : 477.3476, found 477.3472.

[0290] Example 23

[0291]

[0292] VT-36 as starting material, synthesis method same as VT-10

[0293] 1H NMR (500 MHz, CDC13) δ 7.25 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.99 - 5.91 (m, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.24 - 5.17 (m, 3H), 4.15 - 4.07 (m, 3H), 3.84 (s, 1H), 3.72 - 3.65 (m, 1H), 3.57 (d, J = 11.3 Hz, 1H), 3.07 - 2.93 (m, 4H), 2.87 (d, J = 10.6 Hz, 1H), 2.70 (dt, J = 12.3, 6.1 Hz, 1H), 2.58 - 2.34 (m, 8H), 2.31 (s, 4H), 2.22 (ddd, J = 17.4, 14.7, 5.1 Hz, 1H), 1.87 (dtd, J = 15.0, 12.7, 6.8 Hz, 4H), 1.72 - 1.59 (m, 3H), 1.53 (td, J = 13.8, 4.8 Hz, 1H), 1.40 (d, J = 7.1 Hz, 4H), 1.38 - 1.23 (m, 11H), 1.20 (s, 1H), 1.15 (s, 3H), 0.93 - 0.88 (m, 1H), 0.87 (d, J = 6.6 Hz, 4H). HRMS (ESI): m / z calcd for C 32 H 47 N2O2 + [M+H] + : 491.3632, found 491.3635.

[0294] Example 24

[0295]

[0296] V-47 (135 mg, 66%) was obtained as a white solid. HRMS (ESI): m / z calcd for C 33 H 46 NO6 + [M+H] + : 552.3320, found 552.3324.

[0297] 1 H NMR (500 MHz, CDC13) δ 7.01 (t, J = 8.3 Hz, 2H), 6.87 (ddd, J = 21.0, 16.6, 7.7 Hz, 2H), 5.26 (s, 1H), 5.19 (s, 1H), 5.10 (d, J = 10.5 Hz, 1H), 5.05 - 4.96 (m, 1H), 4.84 - 4.78 (m, 1H), 4.31 (t, J = 12.7 Hz, 1H), 4.03 (d, J = 9.8 Hz, 1H), 3.46 (s, 1H), 3.32 - 3.20 (m, 2H), 3.13 (dd, J = 13.9, 4.3 Hz, 1H), 3.07 - 3.04 (m, 1H), 2.99 - 2.83 (m, 4H), 2.73 - 2.54 (m, 3H), 2.52 - 2.35 (m, 3H), 2.23 (d, J = 8.2 Hz, 4H), 2.21 - 2.08 (m, 6H), 2.04 (dd, J = 14.8, 7.5 Hz, 15H), 1.99 - 1.88 (m, 5H), 1.87 (d, J = 3.8 Hz, 3H), 1.83 - 1.39 (m, 16H), 1.34 - 1.23 (m, 6H), 1.20 (d, J = 5.4 Hz, 3H), 1.12 (dd, J = 9.0, 2.9 Hz, 6H), 1.06 (d, J = 7.1 Hz, 2H). HRMS (ESI): m / z calcd for C 33 H46 NO6 + [M+H] + : 552.3320, found 552.3324).

[0298] Example 25

[0299]

[0300] Veratramine (120 mg, 0.27 mmol) was dissolved in THF, pyridine (214 μΐ, 2.66 mmol) was added, acetyl chloride (188 μΐ, 2.66 mmol) was added dropwise under ice bath condition, the reaction was monitored by TLC spot plate after 30 min, the reaction was complete, saturated NaHC03solution was added to quench, the organic phase was dried over anhydrous Na2S04, concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5: 1-1 : 1) to give intermediate White solid (58 mg, 44%).

[0301] 1 H NMR (500 MHz, CDC13) δ 7.22 (d, J = 7.8 Hz, 1 H), 6.97 (d, J = 7.7 Hz, 1 H), 5.52 (br d, J = 5.2 Hz, 1 H), 4.70 - 4.62 (m, 1 H), 3.54 - 3.46 (m, 1 H), 3.29 (s, 1 H), 2.96 - 2.30 (m, 2 H), 2.79 (dd, J = 14.8, 7.3 Hz, 1 H), 2.65 - 2.54 (m, 2 H), 2.53 - 2.42 (m, 2 H), 2.39 - 2.34 (m, 1 H), 2.32 (s, 3 H), 2.17 - 2.08 (m, 1 H), 2.05 (s, 3 H), 2.04 - 1.97 (m, 2 H), 1.94 - 1.80 (m, 4 H), 1.72 - 1.69 (m, 2 H), 1.40 (d, J = 7.2 Hz, 3 H), 1.37 - 1.29 (m, 2 H), 1.25 (s, 2 H), 1.16 (s, 3 H), 1.00 (dd, J = 23.1, 12.0 Hz, 1 H), 0.83 (d, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CDC13) δ 170.63, 144.01, 143.11, 141.47, 140.34, 132.82, 125.39, 123.14, 120.04, 74.04, 70.82, 67.12, 56.98, 54.04, 44.10, 41.30, 37.90, 37.11, 36.23, 32.05, 30.61, 30.49, 29.82, 27.61, 21.55, 19.50, 19.29, 18.92, 15.96. HRMS (ESI): m / z calcd for C 29 H 42 NO3 + [M+H] + : 452.3159, found 452.3155.

[0302] Synthetic procedure is same as VT-47 (The above intermediate was obtained by peroxidation reaction of mCPBA)

[0303] 1 H NMR (500 MHz, CDC13) δ 7.01 (t, J = 12.0 Hz, 1H), 6.85 (ddd, J = 24.1, 18.1, 7.7 Hz, 1H), 4.93 (d, J = 9.9 Hz, 1H), 4.18 (s, 1H), 3.93 (d, J = 5.2 Hz, 1H), 3.72 (s, 1H), 3.39 - 3.02 (m, 5H), 2.96 - 2.34 (m, 11H), 2.23 (d, J = 5.8 Hz, 4H), 2.14 (s, 6H), 2.12 - 1.89 (m, 6H), 1.87 (d, J = 4.0 Hz, 6H), 1.81 - 1.34 (m, 10H), 1.27 - 1.19 (m, 5H), 1.15 (d, J = 8.4 Hz, 6H), 1.08 (d, J = 7.0 Hz, 3H). HRMS (ESI): m / z calcd for C 29 H 42 NO4 + [M+H] + : 468.3108, found 468.3109. HRMS (ESI): m / z calcd for C 29 H 42 NO4 + [M+H] + : 468.3108, found 468.3109.

[0304] Example 26

[0305]

[0306] Veratramine (500 mg, 1.22 mmol) was dissolved in THF, Et3N (1236 mg, 12.22 mmol) was added, then FmocCl (3161 mg, 12.22 mmol) in THF was added, and the reaction was allowed to proceed at room temperature for 1 h. Water was added to quench the reaction, and the organic phase was separated and concentrated. The white intermediate was purified by silica gel column chromatography (PE / EA = 5:1). The intermediate (200 mg, 0.37 mmol) was dissolved in DCM, NaHCO3(63 mg, 0.75 mmol) was added, and mCPBA (97 mg, 0.56 mmol) was added under ice bath. After the ice bath was removed, the reaction was allowed to proceed at room temperature for 2 h. The white intermediate was purified by silica gel column chromatography (PE / EA = 4:1). Then the intermediate was dissolved in DMF, 2 ml of piperidine was added, and the reaction was allowed to proceed at room temperature for 30 min. After the reaction was completed as monitored by TLC, 5 ml of water was added in three portions, and the mixture was extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was prepared by silica gel preparative plate to give a white solid (62 mg, 32%).

[0307] 1 H NMR (500 MHz, CDCl3) δ 7.20-7.15 (m, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.99-3.91 (m, 1H), 3.51-3.42 (m, 1H), 3.24 (ddd, J = 12.7, 9.2, 3.1 Hz, 2H), 3.07 (d, J = 4.7 Hz, 1H), 3.01-2.86 (m, 3H), 2.73-2.59 (m, 2H), 2.53-2.38 (m, 4H), 2.28 (d, J = 7.0 Hz, 4H), 2.23-1.91 (m, 9H), 1.90-1.40 (m, 11H), 1.37 (dd, J = 7.2, 3.3 Hz, 5H), 1.25 (s, 1H), 1.18 (s, 3H), 1.11 (s, 1H), 1.02-0.94 (m, 1H), 0.81 (d, J = 6.6 Hz, 4H). HRMS (ESI): m / z calcd for C 27 H 40 NO3 + [M+H] + : 426.3003, found 426.3005.

[0308] Comparative Example 1

[0309]

[0310] VT-48 (100 mg, 0.21 mmol) was dissolved in a mixed solution of THF:H2O = 3:1, and F3CCOOH (48 mg, 0.42 mmol) was added dropwise. The mixture was stirred at room temperature for 6 h. After the reaction was completed by TLC, NaHCO3 solution was added to quench the reaction. The mixture was extracted with DCM (5 ml × 3), the organic phases were combined, concentrated and dried under reduced pressure, and purified by silica gel column chromatography (DCM / CH3OH = 10:1) to obtain a white solid VT-49.

[0311] 1 H NMR (500MHz, MeOD) δ7.08(d,J=6.9Hz,1H),7.00(d,J=7.7Hz,1H),6.92(d,J=7.2Hz,1H),6.80(d,J=7.7Hz,1H ),4.24–3.94(m,6H),3.66(s,2H),3.22–3.12(m,3H),2.90(dd,J=33.7,12.3Hz,2H),2.65–2.55(m,2H),2.37( t,J=13.2Hz,2H),2.30–2.17(m,9H),2.16(s,6H),2.14–1.88(m,9H),1.84(d,J=7.3Hz,9H),1.71–1.47(m,6H ),1.29(t,J=4.4Hz,11H),1.22(d,J=6.5Hz,3H),1.16(d,J=7.1Hz,3H),1.08(d,J=7.1Hz,3H).HRMS(ESI):m / z calcd for C 29 H 44 NO5 + [M+H] + :486.3214,found 486.3220.

[0312] 2. Experimental Materials

[0313] (1) Cell line

[0314] HEK293 / AP-1-Luc cell line: constructed by Shanghai Taoshu Biotechnology Co., Ltd.

[0315] Using the AP-1 / DNA interaction site as the research object, the DNA binding site was selected as 5′-TGACTCA-3′, and a quadruple repeat sequence was constructed in the pGL4.32 vector. When the AP-1 pathway is activated, it will bind to the specific sequence and initiate reporter gene transcription.

[0316] (2) Plasmids

[0317] (3) Oligodeoxynucleotides

[0318] (4) Reagents

[0319]

[0320]

[0321] (5) Instruments and Consumables

[0322]

[0323] 3. Experimental Step (1) Cell Transfection

[0324] 1) Preparation of mother cells, select HEK293 cells with early cell passage number and good cell state.

[0325] 2) Cell plating before transfection, cells are plated in a six-well plate before transfection, and the cell confluence is preferably 60%-80% before transfection. Too full or too sparse are not suitable for transfection.

[0326] 3) Reagent preparation before transfection, lipofectamine 2000 is used as the transfection reagent. According to the ratio of 2 μg plasmid per well and 5 μl lipofectamine 2000, transfection is performed according to the transfection reagent instruction.

[0327] 4) After 24 hours of transfection, the cells are digested, and according to the previous observation, they are transferred to a 10 cm dish at a ratio of 1:10, 1:20, and 1:40. The specific ratio is determined according to the transfection efficiency.

[0328] 5) After 24 hours of cell transfer to a 10 cm dish, add antibiotics for antibiotic selection, and at the same time, do a non-transfected mother cell control. The hygromycin concentration is 100 μg / ml.

[0329] 6) Change the cell liquid every 3 days, and add new antibiotics. After about 10 days, the mother cells are all dead, and the cloned cells in the cell dish are grown to the naked eye, and then the cloned cells are selected into a 96-well plate.

[0330] 7) When the cells in the 96-well plate grow to 80%, they are subcultured into a 24-well plate. If the cells are too small in the early stage, they will not grow in the 24-well plate.

[0331] 8) According to the growth of the 24-well plate, select clones for detection.

[0332] (2) Clone Detection

[0333] 1) According to the growth of the 24-well plate, plate a 96-well plate for detection. If the confluence of the clone in the 24-well plate is greater than 50%, plate a 96-well plate according to the different densities based on the experience value. The 96-well plate needs to be coated with Matrigel before plating.

[0334] 2) Put the plate into 5% CO2 37°C incubator overnight.

[0335] 3) The next day, remove the medium and replace it with 80 μl DMEM medium containing 0.1% serum.

[0336] 4) Add PMA reagent to the final concentration of 10 nM to each well of 96-well plate. Incubate the compound with cells in 5% CO2 37°C incubator for 24 hours.

[0337] 5) After the incubation, add Bright Glo solution according to the product instruction of Bright Glo reagent, and immediately read the fluorescence value on the plate reader.

[0338] (3) Clone retest

[0339] 1) The clones with good signal window in the previous screening were transferred to 6-well plates. When the cell confluence reached 80%, prepare to plate 96-well plates for retest. The 96-well plates need to be coated with Matrigel before plating.

[0340] 2) Put the plate into 5% CO2 37°C incubator overnight.

[0341] 3) The next day, remove the medium and replace it with DMEM medium containing 0.1% serum.

[0342] 4) Prepare a compound solution of veratrine with a final concentration of 10 μM and add it to the cells.

[0343] 5) In the retest clones, add PMA reagent to the final concentration of 10 nM to each well of drug-treated wells and positive wells. Add medium containing DMSO solvent to negative control wells. Incubate the compound with cells in 5% CO2 37°C incubator for 24 hours.

[0344] 6) After the incubation, add Bright Glo solution according to the product instruction of Bright Glo reagent, and immediately read the fluorescence value on the plate reader.

[0345] (4) AP-1 reporter gene detection

[0346] 1) Count the trypsin-digested HEK293 / AP-1 cells, and plate 6x10 4 Cells were plated in 96-well white transparent bottom plates coated with matrigel in advance.

[0347] 2) Put the plate into 5% CO2 37°C incubator overnight.

[0348] 3) The next day, remove the culture medium, and replace it with DMEM medium containing 0.1% serum.

[0349] 4) On the day of the experiment, dissolve the compound in DMSO to a high concentration stock solution.

[0350] 5) Add 20 μl of 5X compound working solution to each well of the 96-well plate, which contains 5X PMA (50 nM). Incubate the compound with the cells in a 5% CO2 37°C incubator for 24 hours.

[0351] 6) After the incubation is completed, add the Bright Glo solution according to the Bright Glo reagent product instructions. Immediately read the fluorescence value on the readout.

[0352] 7) Inhibition calculation formula: Inhibition % = (1 - Reading test / Reading 0.5％ DMSO ) x 100.

[0353] Table 1 Proliferation inhibition activity of veratramine derivatives (30 μM) on HEK293 / AP-1 model cells

[0354]

[0355]

[0356] As can be seen from the above, at 30 μM, the compound of the present application has an inhibition activity equivalent to or better than that of Veratramine. At 30 μM, the compound of the present application has an inhibition activity better than that of Veratramine, and is significantly better than that of compound 49.

[0357] Table 2 Proliferation inhibition activity of veratramine derivatives (10 μM) on HEK293 / AP-1 model cells

[0358]

[0359] As can be seen from the above, at 10 μM, the compound of the present application has an inhibition activity equivalent to or better than that of Veratramine.

[0360] Effect Example 2

[0361] II. NF-κB luciferase reporter gene experiment

[0362] 1. Purpose of the experiment

[0363] To detect whether the compound specifically acts on the AP-1 signal pathway without affecting the NF-κB signal pathway.

[0364] 2. Experimental materials

[0365] (1) Cell strain

[0366] HEK293 / NF-κB cell strain: constructed by Shanghai Tao Shu Biological Technology Co., Ltd.

[0367] (2) Reagents

[0368]

[0369] (3) Instruments and consumables

[0370] 3. Experimental procedures

[0371]

[0372] (1) Cell recovery

[0373] The cells to be recovered were quickly taken out from the liquid nitrogen tank, melted in a 37°C water bath, and quickly added to preheated medium. After centrifugation at 1000 rpm for 5 min, the centrifuge tube was removed, the supernatant was discarded, and fresh preheated medium was added to the centrifuge tube. The cells were resuspended, and then the cell suspension was added to a culture dish and cultured at 37°C in a 5% CO2 incubator.

[0374] (2) Cell passage

[0375] Adherent cell passage: when the cells grow to 80-90% of the culture dish, the cells are digested with 0.25% trypsin, then resuspended with new medium, and the cells are passaged at an appropriate ratio, about 2-4 days per passage.

[0376] (3) Cell inoculation and drug treatment

[0377] 1) One day before detection, according to the growth rate of the cells, inoculate 40000 cells per well in a 96-well cell plate, inoculate 80μl of cell suspension per well, and incubate overnight in a 37°C, 5% CO2 incubator.

[0378] 2) According to the experimental requirements, add 10μl of compound working solution per well, incubate for 1 hour, then add 10μl of TNFα (200ng / ml), and incubate in a 5% CO2 37°C incubator for 24 hours in the dark.

[0379] 3) After the incubation is completed, add Bright glo 50μl / well, measure the chemiluminescence on NIVO, and calculate the inhibition rate.

[0380] 4) Inhibition % = ((RFU Cmpd - AVER(RFU Neg.Ctrl)) / ((AVER(RFU Day0) - AVER(RFU Neg.Ctrl)) x 100%. Wherein: RFU Cmpd: Luminescence value of sample well (test compound)

[0381] RFU Blank: Luminescence value of blank well (cells + medium + DMSO)

[0382] RFU Neg.Ctrl: Luminescence value of negative well (cells + medium + DMSO + TNFα)

[0383] Table 3 Inhibitory activity of veratrine amine derivatives on NF-κB signaling pathway

[0384]

[0385] As can be seen from the above, the IC 50 values of the inhibitory activity of the compounds of the present application on NF-κB signaling pathway are all greater than that of IMD-0354 which is a synthetic selective NF-kB inhibitor, also inhibits the entry of NF-kB subunit p65 into the nucleus, and are all greater than 30 μM; the inhibitory activity of the compounds of the present application on NF-κB signaling pathway is smaller or has no inhibitory activity relative to IMD-0354.

[0386] Effect Example 3

[0387] Three, triple negative breast cancer cell proliferation inhibition experiment

[0388] 1. Purpose of the experiment

[0389] The growth inhibition effect of the compound on MDA-MB-231 cells was detected by Cell Titer Glo (CTG) method.

[0390] 2. Experimental materials

[0391] (1) Cell strain

[0392] MDA-MB-231 cells: purchased from ATCC

[0393] (2) Reagent

[0394]

[0395] (3) Instruments and consumables

[0396]

[0397] Other conventional instruments: CO2 incubator, clean bench, centrifuge, Eppendorff pipette, etc.

[0398] 3. Experimental procedure

[0399] (1) Cell culture medium preparation

[0400] MDA-MB-231: DMEM + 10% FBS + 1% P / S

[0401] (2) Drug preparation

[0402] The compound was diluted with the cell culture medium to the concentration designed in the experiment.

[0403] (3) Cell proliferation experiment

[0404] 1) After counting, the cells were inoculated in a 384-well culture plate at the following density: 40 μl per well. Put into a 37℃, 5% CO2 incubator for overnight culture.

[0405] 2) MDA-MB-231 500 cells per well, add 10 μl of the compound to be tested to each well, so that the final concentration of the compound reaches the concentration in the Excel attachment data layout. After 72 h of continuous culture, add CTG 100 μl to each well.

[0406] 3) Stand at room temperature for 10 min, and measure the chemiluminescence value of each well on the enzyme marker.

[0407] Table 4 Proliferation inhibition activity of veratramine derivatives on triple-negative breast cancer cells

[0408]

[0409]

[0410] As can be seen from the above, the proliferation inhibition activity of the compound of the present application on triple-negative breast cancer cells is equivalent to or better than that of Veratramine.

Claims

1. A veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof, wherein, ， wherein, for , or ; denotes , or mixtures thereof; X is -CO-, or ; R 1 is hydrogen, C1-C6alkyl or -CO-R 3 ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C6alkyl; R 5 is an amine group or -O-R 7 ; Y is or ; R 9 is halogen, R 10 is hydrogen or halogen; R 11 is hydroxyl, amine or OR 14 ; R is hydrogen, C1-C6alkyl, C2-C6alkenyl, or -CO-R 13 ; R 14 is hydrogen or C1-C6alkyl; R 3 , R 7 , and R 13 are independently C1-C6alkyl.

2. The veratridine compound of formula I as described in claim 1, characterized in that, R 1 is C1-C4alkyl or -CO-R 3 ; and / or, R 2 is hydroxyl, -O-R 4 or -NH-COR 5 ; and / or R is hydrogen, C1-C4alkyl, C2-C4alkenyl or -CO-R 13 ; and / or, R 9 is halogen, R 10 is halogen.

3. The veratridine compound as shown in Formula I as described in claim 2, characterized in that, R 1 -CO-R 3 ; and / or, R 2 is -O-R 4 or -NH-COR 5 ; and / or R is hydrogen, C1-C4alkyl or C 2- C4alkenyl.

4. The veratridine compound of formula I as described in claim 3, characterized in that, R 2 is -O-R 4 .

5. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for , or ; denotes , or mixtures thereof; X is -CO-, or ; R 1 is hydrogen or -CO-R 3 ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C6alkyl; R 5 is an amine group or -O-R 7 ; Y is or ; R 9 is halogen, R 10 is halogen; R 11 is hydroxyl or -O-R 14 ; R is hydrogen, C1-C6alkyl, C2-C6alkenyl, or -CO-R 13 ; R 14 is hydrogen or C1-C6alkyl R 3 , R 7 , R 12 and R 13 are independently C1-C6alkyl.

6. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for or ; X is -CO-, or ; R 1 -CO-R 3 ; R 2 is -O-R 4 or -NH-COR 5 ; R 5 -O-R 7 ; Y is ; R 9 is halogen, R 10 is hydrogen or halogen; R is hydrogen or C2-C4 alkenyl; R 3 , R 4 , R 12 and R 13 are independently C1-C4alkyl.

7. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for or ; X is -CO-, or ; R 1 is C1-C4alkyl or -CO-R 3 ; R 2 is hydroxyl, -O-R 4 or -NH-COR 5 ; R 4 is hydrogen or C1-C4alkyl; R 5 -O-R 7 ; Y is ; R 9 is halogen, R 10 is halogen; R is hydrogen, C1-C4alkyl or C 2- C4alkenyl; R 3 and R 7 independently C1-C4alkyl.

8. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; For Or ; X is -CO- or ; R 2 is hydroxyl or -O-R 4 ; R 4 is hydrogen or C1-C4alkyl; Y is ; R 9 is halogen, R 10 is halogen; R is hydrogen or C1-C4 alkyl.

9. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; X is ; R 1 is hydrogen or -CO-R 3 ; Y is or ; R is halogen, R 9 is halogen, R 10 is halogen; R 11 is hydroxyl or -O-R 14 ; R is hydrogen, C 1- C4alkyl, C 2- C4alkenyl or -CO-R 13 ; R 3 , R 13 , and R 14 are independently C1-C4alkyl.

10. The veratridine compound of formula I as described in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; X is ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C4alkyl; R 5 is an amine group or -O-R 7 ; Y is or ; The R mentioned 9 For halogens, R 10 It is hydrogen or halogen; R 11 is hydroxyl or OR 14 ; R is hydrogen, C1-C4alkyl, C 2- C4alkenyl or -CO-R 13 ; R 14 is hydrogen or C1-C4alkyl; R 13 and R 7 independently C1-C4alkyl.

11. The veratridine compound of formula I as claimed in claim 1, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; X is -CO-; Y is ; R 9 is fluorine, R 10 is fluorine; R is C 2- C4alkenyl or -CO-R 13 ; R 13 R is CrC4alkyl.

12. The veratramine compound of Formula I or a pharmaceutically acceptable salt thereof according to any one of claims 5-11, wherein, wherein, When R 1 R 2 R 3 R 4 R 5 R 7 R 13 R 14 Or when R is a C1~C6 alkyl group; the C1~C6 alkyl group is a C1~C4 alkyl group; and / or, when R 9 or R 10 is halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or, when R is C2-C6 alkenyl, the C2-C6 alkenyl is C2-C4 alkenyl.

13. The veratridine compound of formula I as described in claim 12, characterized in that, wherein, When X is X is any of the following structures: or ; and / or, when X is then said X is any one of the following structures: , , , , , , or ; and / or, when Y is , R 9 is halogen, R 10 is hydrogen or halogen, said is ; and / or, when R is -CO-R 13 said -CO-R 13 is ; and / or, when R is C2-C4alkenyl, said C2-C4alkenyl is , , , or ; and / or, when R 9 or R 10 is halogen, said halogen is fluorine; and / or, when R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 13 , R 14 or R is C1-C4alkyl; said C1-C4alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

14. The veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof of claim 1, wherein, For Or ; and / or, To , , , , , , , , , , , or .

15. A veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof, wherein, ， wherein, for , or ; denotes , or mixtures thereof; X is -CO-, or ; R 1 is hydrogen, C1-C6alkyl or -CO-R 3 ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C6alkyl; R 5 is an amine group or -O-R 7 ; Y is -CO-, or ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is hydrogen or halogen; R 11 is hydroxyl, amine or OR 14 ; R is C2-C6 alkenyl; R 14 is hydrogen or C1-C6alkyl; R 3 , R 7 , and R 12 are independently C1-C6alkyl.

16. The veratridine compound of formula I as described in claim 15, characterized in that, R 1 is C1-C4alkyl or -CO-R 3 ; and / or, R 2 is hydroxyl, -O-R 4 or -NH-COR 5 ; and / or, R is C2-C4 alkenyl; and / or, R 9 is hydroxy, R 10 is hydrogen; or R 9 is halogen, R 10 is halogen.

17. The veratridine compound of formula I as described in claim 16, characterized in that, R 1 -CO-R 3 ; and / or, R 2 is -O-R 4 or -NH-COR 5 .

18. The veratridine compound of formula I as described in claim 17, characterized in that, R 2 is -O-R 4 .

19. The veratridine compound of formula I as described in claim 15, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for , or ; represents , or mixtures thereof; X is -CO-, or ; R 1 is hydrogen or -CO-R 3 ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C6alkyl; R 5 is an amine group or -O-R 7 ; Y is -CO-, or ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is halogen; R 11 is hydroxyl or -O-R 14 ; R is C2-C6 alkenyl; R 14 is hydrogen or C1-C6alkyl R 3 , R 7 , R 12 and R 13 are independently C1-C6alkyl.

20. The veratridine compound of formula I as described in claim 15, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for , or ; denotes , or mixtures thereof; X is or ; R 1 -CO-R 3 ; R 2 -O-R 4 ; Y is or ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; R 11 -O-R 14 ; R is C2-C4 alkenyl; R 14 is hydrogen or C1-C4alkyl R 3 , R 4 , R 12 and R 13 are independently C1-C4alkyl.

21. The veratridine compound of formula I as described in claim 15, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for or ; X is -CO-, or ; R 1 -CO-R 3 ; R 2 is -O-R 4 or -NH-COR 5 ; R 5 -O-R 7 ; Y is ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; or R 9 is halogen, R 10 is hydrogen or halogen; R is C2-C4 alkenyl; R 3 , R 4 , R 12 and R 13 are independently C1-C4alkyl.

22. The veratridine compound of formula I as described in claim 15, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; for or ; X is -CO-, or ; R 1 is C1-C4alkyl or -CO-R 3 ; R 2 is hydroxyl, -O-R 4 or -NH-COR 5 ; R 4 is hydrogen or C1-C4alkyl; R 5 -O-R 7 ; Y is ; R 9 is hydroxyl, R 10 is hydrogen; or R 9 is halogen, R 10 is halogen; R is C 2- C4 alkenyl; R 3 and R 7 are independently C1-C4alkyl.

23. The veratridine compound of formula I as described in claim 15, characterized in that, the veratramine compound as shown in formula I is as shown in the following scheme; X is ; R 1 is hydrogen or -CO-R 3 ; Y is -CO-, or ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; or said R 9 is halogen, R 10 is halogen; R 11 is hydroxyl or -O-R 14 ; R is C 2- C4 alkenyl; R 3 , R 12 , and R 14 are independently C1-C4alkyl.

24. The veratramine compound of claim 15, or a pharmaceutically acceptable salt thereof, having the formula: ###0002### I the veratramine compound as shown in formula I is as shown in the following scheme; X is ; R 2 is hydroxyl, amine, -O-R 4 , NH-COR 5 or -NH-CS-NH2; R 4 is hydrogen or C1-C4alkyl; R 5 is an amine group or -O-R 7 ; Y is -CO-, or ; R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen; or said R 9 is halogen, R 10 is hydrogen or halogen; R 11 is hydroxyl or OR 14 ; R is C 2- C4 alkenyl; R 14 is hydrogen or C1-C4alkyl; R 13 , R 12 , and R 7 are independently C1-C4alkyl.

25. The veratramine compound of claim 15, or a pharmaceutically acceptable salt thereof, having the formula: ###0002### I the veratramine compound as shown in formula I is as shown in the following scheme; X is -CO-; Y is ; R 9 is hydroxy, R 10 is hydrogen; or R 9 is fluoro, R 10 is fluoro; R is C 2- C4 alkenyl; R 13 is C1-C4alkyl.

26. The veratramine compound of any one of claims 19-25, or a pharmaceutically acceptable salt thereof, according to Formula I, wherein, When R 1 R 2 R 3 R 4 R 5 R 7 R 12 R 14 Or when R is a C1~C6 alkyl group; the C1~C6 alkyl group is a C1~C4 alkyl group; and / or, when R 9 or R 10 is halogen, said halogen is fluorine, chlorine, bromine or iodine; and / or, when R is C2-C6 alkenyl, the C2-C6 alkenyl is C2-C4 alkenyl.

27. The veratridine compound of formula I as described in claim 26, characterized in that, wherein, When X is X is any of the following structures: or ; and / or, when X is then said X is any one of the following structures: , , , , , , or ; and / or, when Y is , R 9 is halogen, R 10 is hydrogen or halogen, said is ; and / or, when Y is , R 9 is hydroxy or -O-CO-R 12 , R 10 is hydrogen, said is any one of the following structures: or ; and / or, when R is C2-C4alkenyl, said C2-C4alkenyl is , , , or ; and / or, when R 9 or R 10 is halogen, said halogen is fluorine; and / or, when R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 12 , R 14 or R is C1-C4alkyl; said C1-C4alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

28. The veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof of claim 15, wherein, For Or ; and / or, To , , , , , , , , , , , or .

29. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: when the veratramine compound of formula I, X is ; R 1 is C1-C6alkyl-C(=O)-, it comprises the following steps: reacting a compound of formula I-a with an acylating reagent to obtain the veratramine compound of formula I; wherein, , Y or R are each as defined in any one of claims 1-28. 。 30. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: When X is -CO- in the veratramine compound as shown in formula I, it includes the following steps: performing the oxidation reaction as shown below on the compound as shown in formula I-h to obtain the veratramine compound as shown in formula I; wherein, is Y or R is defined in any one of claims 1-28. 。 31. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: When X is in the veratramine compound as shown in formula I, the method comprises the following steps: carrying out imidization reaction between the compound as shown in formula I-b and the compound as shown in formula R 2 NH2to obtain the veratramine compound as shown in formula I; wherein Y is or ; , R 2 , R 9 , R 10 , R 11 , Y or R are as defined in any one of claims 1-28. 。 32. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: when the veratramine compound as shown in formula I is ; ; which comprises the following step: performing an epoxidation reaction on a compound as shown in formula I-c to obtain the veratramine compound as shown in formula I; wherein X is , Y is , and R 1 , R 9 or R 10 are as defined in any one of claims 1-28. 。 33. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: When Y is -CO- in the veratramine compound as shown in formula I, it includes the following steps: the compound as shown in formula I-d is subjected to oxidation reaction as shown below to obtain the veratramine compound as shown in formula I. is or ; X is or ; R, R 1 or R 2 are all as defined in any one of claims 1-28. 。 34. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: When Y is ; which comprises the following step: carrying out imidization reaction of the compound as shown in formula I-e with the compound as shown in formula R 11 -NH2, to obtain the veratramine compound as shown in formula I; wherein, ; X is -CO-, or ; R 1 is C1-C6 alkyl-C(=O)-, R, R 11 or R 2 are all as defined in any one of claims 1-28.​ 。 35. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: when Y is ; R 9 is halogen, R 10 is halogen; comprising the step of halogenating a compound as shown in formula I-e with a halogenating reagent as shown in formula I-f to obtain the veratramine compound as shown in formula I; wherein, ; X is -CO-, ; R ; or ; R 1 is C1-C6 alkyl-C(=O)-, R or R 2 are each as defined in any one of claims 1-28. 。 36. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: comprising the following steps: subjecting a compound as shown in Formula I-f to a C-N coupling reaction with a coupling reagent containing R fragment as shown below to obtain the said veratramine compound as shown in Formula I; subjecting a compound as shown in Formula I-f to a reaction as shown below to obtain the said veratramine compound as shown in Formula I; wherein, Y or R are as defined in any one of claims 1-28. 。 37. A method for preparing a veratrine-like compound as shown in Formula I according to any one of claims 1-28, characterized in that, which comprises the following scheme: When X is -CO- in the veratramine compound as shown in the formula I, it includes the following steps: the compound as shown in the formula I-g is subjected to the trans-oxidation reaction in the presence of toluene, aluminum isopropoxide and cyclohexanone to obtain the veratramine compound as shown in the formula I; wherein, is ; Y or R is defined as in any one of claims 1-28. 。 which comprises the following scheme:

38. A pharmaceutical composition comprising the veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof of any one of claims 1-28, and one or more pharmaceutically acceptable carriers.

39. Use of the veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof of any one of claims 1-28, or the pharmaceutical composition of claim 38, in the preparation of an AP-1 inhibitor.

40. Use of the veratramine compound as shown in formula I or a pharmaceutically acceptable salt thereof of any one of claims 1-28, or the pharmaceutical composition of claim 38, in the preparation of a medicament for preventing and / or treating a cell proliferative disorder.

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