CN113929729B

CN113929729B - Veratramine compound, preparation method and application thereof

Info

Publication number: CN113929729B
Application number: CN202010606520.2A
Authority: CN
Inventors: 张卫东; 孙青�; 李霞; 郭靖文; 陈昊旻; 张盼盼
Original assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd
Current assignee: China Pharmaceutical Industry Research Institute Co ltd; Shanghai Pharmaceutical Industry Research Institute Co ltd
Priority date: 2020-06-29
Filing date: 2020-06-29
Publication date: 2023-04-28
Anticipated expiration: 2040-06-29
Also published as: CN113929729A

Abstract

The invention discloses veratramine compounds, a preparation method and application thereof. The invention provides a veratramine compound which can be used forAs a series of novel AP-1 inhibitors and for preparing medicaments for corresponding diseases. Preliminary activity researches show that the compound provided by the invention has strong activity of inhibiting proliferation of tumor cells; has the potential of preparing novel antitumor drugs and has better market prospect.

Description

Veratramine compound, preparation method and application thereof

Technical Field

The invention relates to veratramine compounds, a preparation method and application thereof.

Background

Malignant tumors are diseases that severely threaten human health and are characterized by clonal expansion of abnormal cells, manifested by uncontrolled proliferation, unresponsiveness to normal homeostatic signals, invasion and metastasis to adjacent tissues. Metastasis of malignant tumor cells to vital organs is the biggest obstacle to successful treatment of tumors and is also the leading cause of death in tumor patients. At present, malignant tumors are mainly treated by methods such as surgery, chemotherapy, radiotherapy and the like. Despite significant advances in surgical techniques and chemotherapy, current medical approaches are still unable to cure metastatic cancers, and the molecular mechanisms of tumor metastasis must be fully recognized for the development of new therapies.

For example, triple negative breast cancer is a disease seriously threatening the health of women, the current treatment means mainly uses chemotherapy, the toxic and side effects are large, and patients are easy to generate drug resistance, so that the development of effective targeted therapies is urgently needed in clinic.

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 the expression of genes; AP-1 thus controls many cellular processes, including differentiation, proliferation and apoptosis. AP-1 upregulates transcription of genes containing TPA DNA response element (TRE; 5 '-TGAG/CTCA-3'). AP-1 heterodimers are formed by leucine zippers and bind genes through specific conserved sequences to initiate expression of the genes.

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, resulting in overexpression of transforming genes involved in growth and malignancy in various cells, and has become one of the important targets for tumor treatment and preventive intervention. It was 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, no antitumor drug targeting the transcription factor AP-1 or its specific DNA binding sequence has been successfully marketed.

Drug design aiming at a DNA short nucleotide sequence is the most effective and challenging design strategy, and development of an AP-1 inhibitor taking DNA as a target point can not only promote research of a new target point of cancer, but also further explore drug design taking the DNA short nucleotide sequence as the target point.

A series of in vitro experiments showed that Veratramine (Veratramine) acts on AP-1 downstream signaling, but does not interfere with EGF-induced cytoplasmic MAPK signaling cascades or other kinases associated with AP-1 activation, suggesting that gene regulation occurs on only a subset of genes controlled by AP-1. Animal experiments show that veratramine can inhibit the activation of an AP-1 reporter gene induced by ultraviolet rays in mice, and the veratramine can effectively prevent the occurrence of skin cancer induced by solar ultraviolet rays, so that the potential value of veratramine as an antitumor candidate drug is clarified.

Disclosure of Invention

The invention aims to overcome the defect of single AP-1 inhibition drugs in the prior art, and provides a veratramine compound, a preparation method and application thereof. The veratramine compound has stronger selective inhibition activity on an AP-1 pathway and stronger tumor cell inhibition activity; the biological activity test shows that the composition has stronger cell proliferation inhibition activity on triple negative breast cancer cells, and can be used for researching and developing triple negative breast cancer resistant medicaments.

The invention solves the technical problems through the following technical proposal.

The invention provides veratrame compounds shown in a formula I or pharmaceutically acceptable salts thereof:

wherein Y is ¹ Is that

(end a represents a connection with tertiary carbon)

R ¹ Is C ₁ -C ₄ Alkyl, C ₂ -C ₄ Alkenyl, benzyl or C ₁ -C ₄ alkyl-C (=o) -;

Y ² is that

(b-terminal represents the connection to the left carbon in formula I as shown above)

R ^a For HO-or C ₁ -C ₄ alkyl-C (=O) -O-, R ^b Is H; or, R ^a Is halogen, R ^b Is H or halogen;

R ^d is H or C ₁ -C ₄ alkyl-C (=o) -;

R ^c and R is ^e Independently HO-, C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )、N(R ^1b R ^1c ) -or benzyl-O-;

R ^1a 、R ^1b and R is ^1c Independently H or C ₁ -C ₄ An alkyl group;

or alternatively, the first and second heat exchangers may be,when Y is ¹ Is that

R ^c When HO-, R ¹ Is H;

is->

Representation->

Or a mixture thereof.

In certain preferred embodiments of the present invention, certain groups in the veratrame compounds of formula I are defined below (the groups not mentioned are as described in any of the embodiments herein),

when R is ¹ Is C ₁ -C ₄ Alkyl or C ₁ -C ₄ alkyl-C (=o) -said C ₁ -C ₄ Alkyl and C ₁ -C ₄ alkyl-C (=O) -C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl or ethyl, and also such as methyl.

when R is ¹ Is C ₂ -C ₄ In the case of alkenyl, said C ₂ -C ₄ Alkenyl groups being vinyl

1-propenyl group

2-propenyl->

Allyl->

1-butenyl->

2-butenyl->

2-methylallyl->

2-methylpropan-1-en-1-yl->

Or but-3-en-1-yl->

For example vinyl or allyl->

when R is ^a Is C ₁ -C ₄ alkyl-C (=o) -said C ₁ -C ₄ alkyl-C (=O) -C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl or ethyl, and also such as methyl.

when R is ^a And R is ^b When independently halogen, the halogen is independently fluorine, chlorine, bromine or iodine; such as fluorine.

when R is ^d Is C ₁ -C ₄ alkyl-C (=o) -said C ₁ -C ₄ alkyl-C (=O) -C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl or ethyl, and also such as methyl.

when R is ^c And R is ^e Independently C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) -when said C ₁ -C ₄ alkyl-O-and C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) C in ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; such as methyl, ethyl or t-butyl.

when R is ^1a 、R ^1b And R is ^1c Independently C ₁ -C ₄ In the case of alkyl, said C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

R ¹ is methyl, ethyl,

Benzyl or methyl-C (=o) -.

Y ¹ is that

R ^a For HO-or C ₁ -C ₄ alkyl-C (=O) -O-, R ^b Is H; for example->

(a-terminal represents a bond with tertiary carbon)/(A-terminal represents a bond with tertiary carbon)>

Y ¹ is that

R ^a Is halogen, R ^b Is H or halogen; for example->

(end a represents a connection with tertiary carbon)

Y ¹ is that

R ^1a H.

R ^1b and R is ^1c Independently H.

R ^e independently HO-or C ₁ -C ₄ alkyl-O-.

Y ¹ is that

For example

Y ² is that

For example->

Y ² is that

Y ² Is that

R ^e Independently HO-or C ₁ -C ₄ alkyl-O-; for example->

is that

is that

/>

R ¹ is C ₁ -C ₄ An alkyl group;

Y ¹ is that

R ^a Is HO-, R ^b Is H; or, R ^a Is halogen, R ^b Is H or halogen;

Y ² is that

Is->

And when Y ¹ Is that

R ^a Is HO-, R ^b Is H, Y ² Is->

When R is ^d Is C ₁ -C ₄ alkyl-C (=o) -.

R ¹ is C ₁ -C ₄ An alkyl group;

Y ¹ is that

R ^a Is halogen, R ^b Is H or halogen;

Y ² is that

Is->

Preferably, when R ^a Is halogen, R ^b When H is H, Y ² Is that

R ^d Is H;

alternatively, when R ^a Is halogen, R ^b When halogen is, Y ² Is that

R ^e Is HO-;

more preferably, R ^a Is halogen, R ^b Is halogen; y is Y ² Is that

/>

R ¹ is C ₁ -C ₄ An alkyl group;

Y ¹ is that

R ^a Is HO-, R ^b Is H;

Y ² is that

For example->

Also for example->

Is->

Preferably, R ^c Is HO-, C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )、N(R ^1e R ^1f ) -or benzyl-O-;

R ^d is H or C ₁ -C ₄ alkyl-C (=o) -;

and when R is ^c When HO-, R ^d Is H;

more preferably, R ^c Is C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) Or benzyl-O-;

R ^d h.

R ¹ is C ₂ -C ₄ Alkenyl groups;

Y ¹ is that

R ^c Is C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )；

Y ² Is that

Is->

R ¹ is C ₂ -C ₄ Alkenyl groups;

Y ¹ is that

R ^c Is C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )；/>

Y ² Is that

Is->

Preferably, when Y ¹ Is that

When R is ^a Is HO-; r is R ^b Is H; r is R ^d Is H;

more preferably, R ^d Is H; y is Y ¹ Is that

R ^c Is C ₁ -C ₂ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )。

R ¹ is C ₂ -C ₄ Alkenyl groups;

Y ¹ is that

R ^c Is C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )；

Y ² Is that

Is->

Preferably Y ² Is that

Y ¹ Is->

More preferably, R ^e Is C ₁ -C ₄ alkyl-O-; r is R ^a Is HO-; r is R ^b H.

R ¹ is benzyl; y is Y ¹ Is that

Y ² Is->

Is->

Preferably, R ^a Is HO-, R ^b Is H;

and/or R ^d H.

R ¹ is C ₁ -C ₄ alkyl-C (=o) -; y is Y ¹ Is that

Y ² Is->

Is->

Wherein R is ^a Is C ₁ -C ₄ alkyl-C (=O) -O-, R ^b Is H;

and/or R ^d Is C ₁ -C ₄ alkyl-C (=o) -.

In certain preferred embodiments of the present invention, the veratrame compound of formula I is selected from the group consisting of,

/>

In the present invention, the veratrame compounds of formula I or pharmaceutically acceptable salts thereof may be synthesized by methods including methods similar to those known in the chemical arts, and the procedures and conditions may be referred to in the art for similar reactions, particularly in accordance with the description herein. The starting materials are typically from commercial sources, such as Aldrich or can be readily prepared using methods well known to those skilled in the art (available via SciFinder, reaxys on-line databases).

In the invention, the veratramine compound shown in the formula I or the pharmaceutically acceptable salt thereof can also be prepared by adopting a conventional method in the field to obtain other veratramine compounds shown in the formula I or the pharmaceutically acceptable salt thereof through peripheral modification.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise indicated.

In the invention, the preparation method of veratrame compounds shown in the formula I comprises the following scheme I, scheme II, scheme III, scheme IV, scheme V, scheme VI, scheme seven, scheme eight, scheme nine, scheme ten or scheme eleven:

Scheme one, it includes the following steps: the compound shown as the formula IIa and R-containing ¹ The coupling reagent of the fragment is subjected to C-N coupling reaction as shown below to obtain the veratramine compound as shown in the formula I; wherein Y is ¹ 、R ¹ 、Y ² And

is as defined above; />

Scheme II, when the veratrame compound shown in the formula I is Y ² Is that

R ^d Is C ₁ -C ₄ alkyl-C (=o) -times; which comprises the following stepsThe steps are as follows: the compound shown in the formula IIb is mixed with a compound containing +.>

The acylating reagent of the fragment is subjected to the acylation reaction shown below to obtain the veratramine compound shown in the formula I; wherein Y is ¹ 、R ¹ And->

Is as defined above;

scheme III, in the veratrame compound shown in the formula I, Y ¹ Is that

When in use; the method comprises the following steps: carrying out the oxidation reaction of the compound shown in the formula IIc to obtain the veratramine compound shown in the formula I; wherein Y is ² Is->

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ¹ And->

Is as defined above;

scheme IV, in the veratrame compound shown in the formula I, Y ¹ Is that

When in use; the method comprises the following steps: combining a compound of formula IId with a compound of formula R ^c -NH ₂ The compounds shown in the formula I undergo imidization reaction as shown in the following to obtain veratramine compounds shown in the formula I; wherein Y is ² Is->

R ^c 、R ^d 、R ^e 、R ¹ And

is as defined above;

scheme five, when in the veratrame compound shown in the formula I, Y ² Is that

R ^d When H is the same as H; the method comprises the following steps: carrying out hydrolysis reaction on the compound shown in the formula IIe to obtain the veratramine compound shown in the formula I; wherein Y is ¹ Is->

R ^a Is HO-, R ^b Is H; or, R ^a Is halogen, R ^b Is H or halogen; r is R ^c 、R ¹ And->

Is as defined above;

scheme six, in the veratrame compound shown in the formula I, Y ¹ Is that

R ^a Is halogen, R ^b When H or halogen; the method comprises the following steps: carrying out halogenation (e.g. fluorine) reaction on a compound shown in a formula IIf and a compound shown in a halogenation (e.g. fluorine) reagent to obtain the veratramine compound shown in a formula I; wherein Y is ² Is that

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ^e 、R ¹ And->

Is as defined above; />

Scheme seven, when the veratramine compound shown in the formula I,

is->

Y ² Is->

When in use; the method comprises the following steps: carrying out the oxidation reaction of the compound shown in the formula IIg to obtain the veratramine compound shown in the formula I; wherein Y is ¹ And R is ¹ Is as defined above;

In the eighth scheme, when the veratram compound shown in the formula I,

is->

Y ² Is->

When in use; the method comprises the following steps: in the presence of aluminum isopropoxide and cyclohexanone, carrying out double bond migration-oxidation reaction on a compound shown in a formula IIg to obtain the veratramine compound shown in a formula I; wherein Y is ¹ And R is ¹ Is as defined above;

scheme nine, when the veratrame compound shown in the formula I is Y ² Is that

When in use; the method comprises the following steps: combining a compound of formula IIh with a compound of formula R ^e -NH ₂ The compounds shown in the formula I undergo imidization reaction as shown in the following to obtain veratramine compounds shown in the formula I; wherein Y is ¹ Is->

R ^a 、R ^b 、R ^c 、R ¹ 、R ^e And->

Is as defined above;

scheme ten, in the veratrame compound shown in the formula I, Y ¹ Is that

R ^a Is C ₁ -C ₄ alkyl-C (=o) -O-,

R ^b when H is the same as H; the method comprises the following steps: the compound shown as the formula IIi and the composition

The acylating reagent of the fragment is subjected to the acylation reaction shown below to obtain the veratramine compound shown in the formula I; wherein Y is ² Is->

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ^e 、R ¹ And->

Is as defined above;

in the eleventh scheme, when the veratram compound shown in the formula I,

Is->

When in use; the method comprises the following steps: the compound shown in the formula IIj is subjected to the following epoxidation reaction to obtain the veratramine compound shown in the formula I; wherein Y is ¹ 、R ¹ And Y ² Is as defined above; />

In the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh schemes, the conditions and operations of the reaction may be those conventional in the art.

The necessary starting materials or reagents for preparing veratrame compounds of formula I or pharmaceutically acceptable salts thereof are commercially available or may be prepared by synthetic methods known in the art. The compounds of the invention may be prepared as free bases or as salts thereof with acids, as 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. Pharmaceutically acceptable salts can be prepared by adding the corresponding acid to a suitable organic solvent for the organic base, and processing according to conventional methods.

Examples of salification include: for base addition salts, it is possible to prepare salts of alkali metals (such as sodium, potassium or lithium) or alkaline earth metals (such as aluminum, magnesium, calcium, zinc or bismuth) by treating a compound of the invention having a suitably acidic proton with an alkali metal or alkaline earth metal hydroxide or alkoxide (such as ethoxide or methoxide) or a suitably basic organic amine (such as diethanolamine, choline or meglumine) in an aqueous medium.

Alternatively, for acid addition salts, salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, platinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.

The invention provides a pharmaceutical composition, which comprises veratramine compounds shown in the formula I or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers. In the pharmaceutical composition, the veratramine compound shown in the formula I or the pharmaceutically acceptable salt thereof can be used in an effective amount for treatment.

The pharmaceutically acceptable carriers (pharmaceutical excipients) can be those excipients widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.

The invention also provides application of the veratramine compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of the AP-1 inhibitor.

In such applications, the AP-1 inhibitor may be used in mammalian organisms; it is also useful in vitro, mainly as an experimental use, for example: the kit can be used as a standard sample or a control sample for comparison or prepared according to a conventional method in the field to provide rapid detection for the inhibition effect of the AP-1.

The invention also provides application of the veratramine compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of medicines. The medicament can be used for preventing and/or treating cell proliferative diseases; alternatively, the agent may be an agent for the prophylaxis and/or treatment of a disease or condition associated with AP-1.

The invention also provides application of the veratrame compound shown in the formula I or pharmaceutically acceptable salt thereof or the pharmaceutical composition shown in the formula I in preparation of medicines for preventing and/or treating diseases or symptoms related to AP-1; the disease or condition associated with AP-1 may be a cell proliferative disease. The medicament can prevent and/or treat cell proliferation diseases by regulating the expression and/or activity of AP-1.

The present invention also provides a method for preventing and/or treating a cell proliferative disorder (e.g., AP-1-related) comprising administering to a subject, such as a human, in need thereof a therapeutically effective amount of the veratrame compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

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

Cell proliferative disorders as described above, including cancer; the cancer may 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 trophoblastoma, glioblastoma, myeloma, neuroblastoma, monocytic leukemia, B-cell leukemia, T-cell leukemia, B-cell lymphoma, T-cell lymphoma, and mast cell tumor, and combinations thereof.

When used as a medicament, the veratrame compound shown in the formula I or the pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition. These compositions may be prepared according to methods well known in the pharmaceutical arts and may be administered by various routes, depending upon the local or systemic treatment and the area to be treated. Administration may be in the form of topical (including epidermal 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 administration. Oral administration may 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 may be in the form of a single bolus dose or may be by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners and the like may be necessary or desirable.

As used herein, the term "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to: all or part of a symptom associated with a disease or disorder or condition, reducing the extent of a disease, stabilizing (i.e., not worsening) the disease state, delaying or slowing the progression of a disease, alleviating or alleviating the disease state (e.g., one or more symptoms of a disease), and detectable or undetectable alleviation (whether partial or complete). "treatment" may also refer to an extended survival period compared to the expected survival without treatment.

In certain embodiments, the veratrame compounds as shown in formula I, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, are useful for preventing diseases and disorders (e.g., cancer) as defined herein. The term "preventing" as used herein means preventing the onset, recurrence or spread of a disease or disorder or symptoms thereof described herein, in whole or in part.

The term "pharmaceutical excipients" or "excipients" refers to pharmaceutically acceptable chemicals, such as agents known to those of ordinary skill in the pharmaceutical arts for aiding in the administration of a pharmaceutical. It is a compound that can be used to prepare pharmaceutical compositions, is generally safe, non-toxic, and biologically or otherwise undesirable, and includes excipients that are acceptable for veterinary and human use. Typical excipients include binders, surfactants, diluents, disintegrants and lubricants.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato: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.

In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.

Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C ₁ -C ₆ Alkyl 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 reduced notation does not include carbon that may be present in a substituent of the group.

In this context, a numerical range as defined in substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.

The term "one(s)" or "one(s) or two or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

The term "comprising" is an open-ended expression, i.e. including what is indicated by the invention, but not excluding other aspects.

The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position.

In various parts of this specification, the invention discloses the extraction of compoundsSubstituents are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. The term "C _x -C _y Alkyl "refers to a straight or branched chain saturated hydrocarbon containing from x to y carbon atoms. For example, the term "C ₁ ～C ₆ Alkyl "or" C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group; "C _1-4 Alkyl "refers specifically to independently disclosed methyl, ethyl, C ₃ Alkyl (i.e. propyl, including n-propyl and isopropyl), C ₄ Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

The term "halogen" is selected from F, cl, br or I, especially F or Cl.

In the present application, as part of a group or other group (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" 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 saturated hydrocarbon chains containing 1 to 6 carbon atoms; for example, C ₁ -C ₆ Is a hydrocarbon group. As in "C ₁ ～C ₆ Alkyl "is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain structure. Wherein propyl is C ₃ Alkyl (including isomers such as n-propyl or isopropyl); butyl is C ₄ Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C ₅ Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, t-pentyl or neopentyl); hexyl is C ₆ Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl). In one embodiment, the term "alkyl" refers to C ₁ -C ₄ An alkyl group.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.

When none of the listed substituents indicates through which atom it is attached to a compound included in the chemical structural formula but not specifically mentioned, such substituents may be bonded through any of their atoms. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Where no substituent is explicitly indicated in a recited group, such a group is merely unsubstituted. For example when "C ₁ ～C ₄ Alkyl "not previously" substituted or unsubstituted "refers only to" C ₁ ～C ₄ Alkyl "as such or" unsubstituted C ₁ ～C ₄ An alkyl group.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" group, it will be understood that the "alkyl" represents a linked alkylene group.

In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C ₁ ～C ₆ C in alkyl' ₁ -C ₆ Alkyl is understood to mean C ₁ ～C ₆ An alkylene group.

The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Examples of alkylene groups include methylene (-CH) ₂ (-), ethylene { including-CH ₂ CH ₂ -or-CH (CH) ₃ ) - } isopropylidene { including-CH (CH) ₃ )CH ₂ Or-C(CH ₃ ) ₂ - }, and the like.

Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.

As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is an open-ended limitation and does not exclude other aspects, i.e. it includes the content indicated by the invention.

Unless otherwise indicated, the present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions are referred to in the art by conventional procedures and conditions.

The present invention employs, unless otherwise indicated, standard nomenclature for analytical chemistry, organic synthetic chemistry and optics, and standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and light emitting device performance detection.

In addition, unless explicitly indicated otherwise, the description of the invention as "…" independently is to be understood broadly as meaning that each individual described may be independent of the other, and may be the same or different. In more detail, the description "… is independently" may mean that specific options expressed between the same symbols in different groups do not affect each other; it may also be expressed that specific options expressed between the same symbols in the same group do not affect each other.

Those skilled in the art will appreciate that, in accordance with convention used in the art, the present application describes the structural formula of a group as used in

Meaning that the corresponding group is linked to other fragments, groups in the compound through this site.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the compound provided by the invention can be used as a series of novel AP-1 inhibitors and can be used for preparing medicaments for corresponding diseases. Preliminary activity researches show that the compound provided by the invention has strong activity of inhibiting proliferation of tumor cells; has the potential of preparing novel antitumor drugs and has better market prospect.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1

Weighed veratramine (3 g,7.33 mmol) was dissolved in 50ml of water, HCHO (893. Mu.l, 8.80 mmol) and HCOOH (1372. Mu.l, 36.67 mmol) were added, the reaction was refluxed for 12h at 100℃under argon protection, after TLC monitoring the reaction was completed, quenched with saturated NaOH solution, extracted with DCM (20 ml. Times.3), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=3:1-1:1) to give VT-1 as a white solid (2.3 g, 74%).

¹ H NMR(500MHz,CDCl3)δ7.25(d,J＝6.3Hz,1H),7.02(d,J＝7.7Hz,1H),5.48(brd,J＝5.1Hz,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＝15.0,7.5Hz,2H),2.66–2.53(m,2H),2.47(s,3H),2.41(dd,J＝12.9,4.3Hz,1H),2.33(s,3H),2.29–2.24(m,1H),2.16(d,J＝7.0Hz,1H),2.04–1.97(m,1H),1.91–1.70(m,8H),1.65–1.58(m,1H),1.42(d,J＝7.2Hz,3H),1.34–1.22(m,2H),1.13(s,3H),0.85(d,J＝6.5Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ145.12,144.30,142.59,140.96,132.70,123.75,122.03,120.84,71.91,70.78,67.50,64.84,57.09,42.82,41.99,41.89,41.30,38.13,37.02,34.34,31.41,30.49,30.45,28.65,19.34,19.27,16.15,12.86.HRMS(ESI):m/z calcd for C ₂₈ H ₄₂ NO ₂ ⁺ [M+H] ⁺ :424.3210,found 424.3214.

Example 2

Veratramine (1 g,2.44 mmol) was dissolved in acetone and K was added ₂ CO ₃ (3.4 g,24.45 mmol) and diethyl sulfate (1.9 g,12.2 mmol) were reacted at 56℃under reflux for 12h. After TLC monitoring the reaction was completed, aqueous ammonia was added and stirred for 1h to quench, concentrated under reduced pressure to remove most of the solvent, washed with water and extracted with DCM (5 ml. Times.3), the organic phases combined, anhydrous Na ₂ SO ₄ After drying, concentration was performed under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/ea=3:1-1:1) to give VT-2 (836 mg, 78%) as a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.25(d,J＝8.6Hz,1H),7.02(d,J＝7.7Hz,1H),5.48(brd,J＝5.2Hz,1H),3.83(s,1H),3.69–3.62(m,1H),3.61–3.53(m,1H),2.98–2.88(m,2H),2.84(d,J＝10.9Hz,1H),2.77(dd,J＝15.0,7.4Hz,1H),2.65–2.52(m,3H),2.49–2.44(m,1H),2.41(ddd,J＝13.0,4.7,1.9Hz,1H),2.33(s,3H),2.31–2.23(m,1H),2.04–1.96(m,1H),1.92–1.76(m,5H),1.73–1.55(m,5H),1.38(d,J＝7.1Hz,3H),1.25–1.23(m,1H),1.13(s,3H),1.10(t,J＝7.1Hz,3H),0.88(d,J＝6.7Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ144.99,144.07,142.57,141.23,132.63,124.09,122.05,120.82,71.93,67.43,67.03,58.69,57.08,46.59,41.99,41.30,41.17,38.13,37.01,34.11,31.41,30.51,30.45,28.31,19.70,19.34,16.10,14.10,11.03.HRMS(ESI):m/z calcd for C ₂₉ H ₄₄ NO ₂ ⁺ [M+H] ⁺ :438.3367,found 438.3366.

Example 3

Veratramine is used as raw material, allyl reagent is 3-bromopropene, and the synthesis method is the same as VT-2

White solid, yield about 89%. ¹ H NMR(500MHz,CDCl ₃ )δ7.25(d,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),5.96(m,1H),5.48(brd,J＝5.2Hz,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＝14.4,7.7Hz,1H),2.95(td,J＝11.6,5.3Hz,1H),2.86(d,J＝10.9Hz,1H),2.76(dd,J＝14.9,7.4Hz,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＝7.1Hz,3H),1.30–1.25(m,1H),1.13(s,3H),0.87(d,J＝6.7Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ145.01,144.07,142.61,140.98,135.74,132.68,124.04,121.96,120.77,117.41,71.84,67.50,67.42,59.75,57.09,56.23,41.96,41.30,41.27,38.12,36.99,34.21,31.37,30.47,30.43,28.24,19.52,19.32,16.17,13.91.HRMS(ESI):m/z calcd for C ₃₀ H ₄₄ NO ₂ ⁺ [M+H] ⁺ :450.3367,found(450.3369)。

Example 4

Veratramine is used as raw material, benzyl reagent is benzyl bromide, and the synthesis method is the same as VT-2

White solid, yield about 90%. ¹ H NMR(500MHz,CDCl ₃ )δ7.37–7.30(m,5H),7.29–7.24(m,1H),7.07(d,J＝7.6Hz,1H),5.52(s,1H),4.35(d,J＝13.5Hz,1H),3.99(s,1H),3.83(s,1H),3.61–3.53(m,1H),3.22(d,J＝13.3Hz,1H),3.05–2.96(m,1H),2.86–2.76(m,2H),2.70–2.61(m,3H),2.43(dd,J＝12.8,4.0Hz,1H),2.39(s,3H),2.32–2.27(t,J＝12.1Hz,1H),2.10–2.01(m,1H),1.98(d,J＝11.7Hz,1H),1.93–1.81(m,3H),1.76–1.59(m,3H),1.54(d,J＝6.0Hz,3H),1.30(t,J＝12.4Hz,1H),1.19(s,3H),1.06–0.97(m,1H),0.82(d,J＝5.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ144.77,143.91,142.60,141.17,140.25,132.38,128.31,128.31,128.31,128.31,126.73,124.14,121.83,120.61,71.63,69.02,67.71,59.18,57.15,57.05,41.86,41.33,41.22,38.08,36.92,34.65,31.25,30.39,30.39,27.76,19.50,19.28,16.02,14.40.HRMS(ESI):m/z calcd for C ₃₄ H ₄₆ NO ₂ ⁺ [M+H] ⁺ :500.3523,found 500.3520.

Example 5

Veratramine (120 mg,0.27 mmol) was dissolved in THF, pyridine (214. Mu.l, 2.66 mmol) was added, acetyl chloride (188. Mu.l, 2.66 mmol) was added dropwise under ice bath conditions, the reaction was continued for 30 minutes, and after completion of the TLC plate monitoring, saturated NaHCO was added ₃ Quenching the solution, and the organic phase with anhydrous Na ₂ SO ₄ Dried, concentrated under reduced pressure and purified by silica gel column chromatography (PE/ea=5:1-1:1) to give VT-5 (58 mg, 44%) as a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.22(d,J＝7.8Hz,1H),6.97(d,J＝7.7Hz,1H),5.52(brd,J＝5.2Hz,1H),4.70–4.62(m,1H),3.54–3.46(m,1H),3.29(s,1H),2.96–2.30(m,2H),2.79(dd,J＝14.8,7.3Hz,1H),2.65–2.54(m,2H),2.53–2.42(m,2H),2.39–2.34(m,1H),2.32(s,3H),2.17–2.08(m,1H),2.05(s,3H),2.04–1.97(m,2H),1.94–1.80(m,4H),1.72–1.69(m,2H),1.40(d,J＝7.2Hz,3H),1.37–1.29(m,2H),1.25(s,2H),1.16(s,3H),1.00(dd,J＝23.1,12.0Hz,1H),0.83(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.63,144.01,143.11,141.47,140.34,132.82,125.39,123.14,120.04,74.04,70.82,67.12,56.98,54.04,44.10,41.30,37.90,37.11,36.23,32.05,30.61,30.49,29.82,27.61,21.55,19.50,19.29,18.92,15.96.HRMS(ESI):m/z calcd for C ₂₉ H ₄₂ NO ₃ ⁺ [M+H] ⁺ :452.3159,found 452.3155.

Example 6

Dissolving weighed veratramine (410 mg,1.0 mmol) in 5ml anhydrous EtOH, adding anhydrous K ₂ CO ₃ (1385 mg,10.0 mmol) and CH ₃ I (620. Mu.l, 10.0 mmol), stirring at room temperature for 5h, monitoring by TLC plate, after complete consumption of starting material, quenching with 2ml ammonia, extraction with DCM (5 ml. Times.3), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give crude product, which is chromatographed on silica gel (DCM/CH ₃ Oh=20:1-5:1) to give VT-6 as a white solid (350 mg, 83%).

¹ H NMR(500MHz,MeOD)δ7.57(d,J＝7.9Hz,1H),6.99(d,J＝7.9Hz,1H),5.50(brd,J＝5.2Hz,1H),4.25(td,J＝10.7,4.6Hz,1H),3.65–3.58(m,1H),3.54(dd,J＝10.5,1.5Hz,1H),3.45(ddd,J＝15.7,11.2,4.3Hz,2H),3.22(s,3H),3.12(t,J＝12.5Hz,1H),3.03(s,3H),2.91(td,J＝11.6,5.3Hz,1H),2.84(dd,J＝14.8,7.3Hz,1H),2.64–2.55(m,2H),2.39(s,3H),2.38–2.21(m,4H),1.97(dd,J＝15.5,12.6Hz,1H),1.88(ddd,J＝20.7,12.1,7.9Hz,2H),1.79(td,J＝12.0,7.3Hz,1H),1.66–1.55(m,1H),1.46(d,J＝7.1Hz,3H),1.44–1.35(m,1H),1.34–1.25(m,1H),1.15(s,3H),1.04(d,J＝6.4Hz,3H)； ¹³ C NMR(125MHz,MeOD)δ145.58,144.10,143.97,143.94,131.02,128.44,122.77,121.73,80.21,72.57,72.55,64.80,58.91,55.11,45.00,43.18,42.64,42.51,39.25,38.05,35.32,32.01,31.48,31.36,25.66,19.63,18.90,18.15,15.58.HRMS(ESI):m/z calcd for C ₂₉ H ₄₅ NO ₂ ⁺ [M] ⁺ :438.3367,found.(438.3368)。

Example 7

Weighed veratramine (200 mg,0.49 mmol) was dissolved in DCM and NaHCO was added ₃ (62 mg,0.74 mmol) and mCPBA (85 mg,0.49 mmol), stirred at room temperature for 2h, quenched by water after TLC monitoring the reaction, extracted with DCM (5 ml. Times.3), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give crude product, which is chromatographed on silica gel (DCM/CH ₃ Oh=20:1-5:1) to give a white solid, VT-7(55％)。

¹ H NMR(500MHz,MeOD)δ7.39(d,J＝7.7Hz,1H),6.97(d,J＝7.8Hz,1H),5.49(brd,J＝5.1Hz,1H),4.29–4.24(m,1H),3.99–3.97(m,1H),3.49–3.41(m,1H),3.39(dd,J＝9.9,3.0Hz,1H),3.21–3.11(m,2H),2.97–2.89(m,2H),2.82(dd,J＝14.8,7.3Hz,1H),2.63–2.55(m,2H),2.47–2.37(m,2H),2.36(s,3H),2.29–2.17(m,2H),2.01–1.73(m,5H),1.64–1.59(m,1H),1.40(d,J＝7.2Hz,3H),1.33–1.24(m,2H),1.16(s,3H),1.00(d,J＝6.8Hz,3H),0.89(t,J＝7.3Hz,3H)； ¹³ C NMR(125MHz,MeOD)δ145.64,145.05,144.12,143.97,131.06,127.79,122.79,121.63,78.77,72.56,70.55,66.52,65.14,59.02,43.32,42.65,42.46,39.25,38.06,34.76,32.02,31.54,31.28,24.87,20.46,19.66,18.25,15.37,9.26.HRMS(ESI):m/z calcd for C ₂₉ H ₄₄ NO ₃ ⁺ [M+H] ⁺ :454.3316,found(454.3310)。

Example 8

VT-1 (210 mg,0.50 mmol) was dissolved in anhydrous DCM, py (400 μl,4.96 mmol) was added and CH was added dropwise under ice-bath conditions ₃ COCl (351. Mu.l, 4.96 mmol), after the completion of the dropwise addition, at 0deg.C for 20min, after TLC monitoring the reaction, saturated NaHCO was added ₃ The solution was quenched, extracted with DCM (5 ml. Times.3), anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=3:1) to give VT-8 as a white solid (142 mg, 61%).

¹ H NMR(500MHz,CDCl ₃ )δ7.26(d,J＝7.5Hz,1H),7.01(d,J＝7.7Hz,1H),5.51(brd,J＝5.0Hz,1H),4.69–4.61(m,1H),3.85–3.81(m,1H),3.73–3.66(m,1H),2.94(td,J＝11.6,5.3Hz,1H),2.80–2.73(m,2H),2.65–2.53(m,2H),2.46(s,3H),2.43(dd,J＝4.9,1.7Hz,1H),2.39–2.34(m,1H),2.33(s,3H),2.15(dd,J＝8.5,3.6Hz,1H),2.05(s,3H),1.94–1.78(m,6H),1.74–1.64(m,2H),1.41(d,J＝7.2Hz,3H),1.37–1.26(m,2H),1.14(s,3H),0.85(d,J＝6.5Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.65,144.97,144.18,141.44,141.00,132.69,123.75,122.99,120.81,73.98,70.74,67.48,64.84,56.97,42.81,41.90,41.20,37.85,37.84,37.08,34.32,30.43,30.41,28.67,27.56,21.54,19.27,19.22,16.13,12.80.HRMS(ESI):m/z calcd for C ₃₀ H ₄₄ NO ₃ ⁺ [M+H] ⁺ :466.3316,found(466.3315)。

Example 9

Under the protection of argon, cooling an anhydrous DCM solution of oxalyl chloride (184 μl,2.15 mmol) to-78deg.C, adding an anhydrous DCM solution of DMSO (229 μl,3.23 mmol), reacting for 1h, adding an anhydrous DCM solution of VT-8 (500 mg,1.08 mmol), reacting for 1.5h, adding triethylamine (894 μl,6.45 mmol), protecting at-65deg.C for 1h, removing the low temperature, slowly rising to room temperature under stirring, then quenching with water, and adding saturated NH ₄ Washing with Cl and saturated NaCl solution for several times, anhydrous Na ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=19:1) to give VT-9 as a white solid (283 mg, 68%).

¹ H NMR(500MHz,CDCl ₃ )δ7.08(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.52(brd,J＝5.3Hz,1H),4.70–4.61(m,1H),3.61(d,J＝9.9Hz,1H),3.41–3.35(m,1H),2.97(td,J＝11.7,5.3Hz,1H),2.89(dd,J＝13.4,2.9Hz,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＝6.7Hz,3H),0.96(d,J＝6.5Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ210.25,170.60,143.53,142.66,141.44,140.11,131.21,125.23,123.21,120.06,74.04,73.25,61.73,56.97,50.05,41.32,37.90,37.89,37.09,36.82,35.12,32.11,30.49,30.46,27.59,21.53,21.02,19.29,19.29,15.50.HRMS(ESI):m/z calcd for C ₃₀ H ₄₂ NO ₃ ⁺ [M+H] ⁺ :464.3159,found(464.3162)。

Example 10

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 reacted at room temperature for 4h. After TLC monitoring the reaction was completed, quenched with water and extracted with DCM. Anhydrous Na for organic phase ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=5:1-3:1) to give VT-10 as a white solid (294 mg, 74%).

¹ H NMR(500MHz,CDCl ₃ )δ7.08(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,1H),5.52(d,J＝5.2Hz,1H),4.71–4.62(m,1H),3.49–3.42(m,2H),2.97(td,J＝11.6,5.3Hz,1H),2.93–2.82(m,2H),2.79(dd,J＝14.7,7.3Hz,1H),2.66–2.52(m,2H),2.45(ddd,J＝12.9,4.8,1.6Hz,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＝6.6Hz,3H),0.97(d,J＝6.3Hz,3H),0.91–0.83(m,1H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.62,143.37,142.50,141.28,141.28,131.32,124.67,123.12,120.01,73.98,69.08,59.99,59.98,56.88,53.44,41.16,37.77,36.97,34.87,30.57,30.43,30.36,29.24,28.99,27.48,21.44,20.82,19.62,19.20,15.70.HRMS(ESI):m/z calcd for C ₃₀ H ₄₃ N ₂ O ₃ ⁺ [M+H] ⁺ :479.3268,found 479.3270.

Example 11

VT-10 (150 mg,0.34 mmol) was dissolved in CH ₃ To OH, naOH (27 mg,0.68 mmol) was added and the reaction was refluxed at 65℃for 2h. After TLC monitoring the reaction was completed, quenched with water and extracted with DCM. Anhydrous Na for organic phase ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and purifying with silica gel column chromatography (PE/EA=3:1-1:1) to obtain white solid, namely VT-11 (112 mg, 82%).

¹ H NMR(500MHz,CDCl ₃ )δ7.07(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.49(brd,J＝5.2Hz,1H),3.63–3.55(m,1H),3.44(d,J＝22.6Hz,2H),2.97(td,J＝11.6,5.3Hz,1H),2.86(d,J＝11.8Hz,2H),2.78(dd,J＝14.7,7.4Hz,1H),2.66–2.53(m,3H),2.45–2.39(m,1H),2.30(s,3H),2.29–2.28(m,3H),2.07–2.00(m,4H),1.90–1.79(m,3H),1.66–1.56(m,2H),1.32–1.23(m,2H),1.14(s,3H),1.10(d,J＝6.5Hz,3H),0.97(d,J＝6.4Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ158.00,143.55,142.55,142.71,142.55,131.44,124.75,122.30,120.07,72.01,69.17,60.28,57.11,42.03,41.39,40.65,38.18,37.05,34.83,31.45,30.75,30.63,30.50,29.25,21.01,19.72,19.44,15.84.HRMS(ESI):m/z calcd for C ₂₈ H ₄₁ N ₂ O ₂ ⁺ [M+H] ⁺ :437.3163,found(437.3160)。

Example 12

VT-9 is used as raw material, and the synthesis method is the same as that of VT-10

Intermediate data: ¹ H NMR(500MHz,CDCl ₃ )δ7.10(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.52(dd,J＝3.2,2.0Hz,1H),4.70–4.61(m,1H),3.90(s,3H),3.40(s,2H),2.97(td,J＝11.6,5.3Hz,1H),2.89–2.76(m,2H),2.73–2.53(m,3H),2.45(ddd,J＝12.9,4.9,1.7Hz,1H),2.39–2.32(m,1H),2.30(s,3H),2.27–2.18(m,2H),2.07(s,3H),2.05(s,3H),1.95–1.81(m,3H),1.70(ddd,J＝14.0,11.8,6.2Hz,2H),1.38–1.24(m,3H),1.15(s,3H),1.09(d,J＝6.2Hz,3H),0.94(d,J＝6.1Hz,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ170.64,156.87,143.34,142.52,141.42,141.42,131.55,124.80,123.27,119.98,74.08,69.25,61.56,59.97,57.02,41.66,41.29,37.92,37.11,35.31,31.08,30.57,30.51,29.82,29.14,27.62,21.56,20.93,19.80,19.33,15.93.

further, the synthesis method is the same as VT-11

White solid, yield about 65%. ¹ H NMR(500MHz,CDCl ₃ )δ7.10(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.49(brd,J＝5.3Hz,1H),3.90(s,3H),3.61–3.55(m,1H),3.40(s,2H),2.97(td,J＝11.6,5.3Hz,1H),2.86(d,J＝10.6Hz,1H),2.79(dd,J＝14.7,7.4Hz,1H),2.71–2.53(m,3H),2.42(ddd,J＝12.9,4.8,1.9Hz,1H),2.31(s,3H),2.29–2.20(m,2H),2.09–2.00(m,4H),1.91–1.79(m,3H),1.67–1.56(m,2H),1.31–1.24(m,2H),1.14(s,3H),1.09(d,J＝6.2Hz,3H),0.95(d,J＝6.0Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ156.99,143.44,142.61,142.56,141.72,131.55,124.78,122.28,119.98,71.95,69.27,61.56,59.93,57.11,42.04,41.70,41.37,38.18,37.04,35.33,31.46,31.03,30.63,30.51,29.12,20.91,19.81,19.42,15.93.HRMS(ESI):m/z calcd for C ₂₉ H ₄₃ N ₂ O ₂ ⁺ [M+H] ⁺ :451.3319,found(451.3314)。

Example 13

VT-9 is used as raw material, and the synthesis method is the same as VT-10

White solid, yield about 85%. ¹ H NMR(500MHz,CDCl ₃ )δ7.10(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.52(brd,J＝5.2Hz,1H),4.71–4.62(m,1H),4.18–4.12(m,2H),3.41(s,2H),2.97(td,J＝11.6,5.3Hz,1H),2.86(d,J＝11.6Hz,1H),2.79(dd,J＝14.7,7.3Hz,1H),2.73(dd,J＝13.9,3.6Hz,1H),2.65–2.53(m,2H),2.48–2.42(m,1H),2.36(dd,J＝19.5,8.0Hz,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＝7.0Hz,4H),1.15(s,3H),1.09(d,J＝6.2Hz,3H),0.95(d,J＝6.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.64,143.28,143.25,142.48,141.86,141.41,131.51,124.79,123.28,119.98,74.07,69.30,69.01,60.10,56.99,41.29,41.26,37.91,37.10,35.28,31.29,30.56,30.50,29.18,27.62,21.56,20.99,19.82,19.33,15.91,15.02,14.78.HRMS(ESI):m/z calcd for C ₃₂ H ₄₇ N ₂ O ₃ ⁺ [M+H] ⁺ :507.3581,found(507.3580)。

Example 14

VT-13 is used as raw material, and the synthesis method is the same as VT-11

White solid, yield about 60%. ¹ H NMR(500MHz,CDCl ₃ )δ7.10(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.49(brd,J＝5.2Hz,1H),4.19–4.11(m,2H),3.62–3.54(m,1H),3.41(s,2H),2.97(td,J＝11.6,5.3Hz,1H),2.86(d,J＝11.5Hz,1H),2.78(dd,J＝14.7,7.4Hz,1H),2.72(d,J＝10.6Hz,1H),2.66–2.53(m,2H),2.41(ddd,J＝12.9,4.7,1.8Hz,1H),2.30(s,3H),2.29–2.22(m,2H),2.09–1.99(m,5H),1.92–1.79(m,4H),1.72–1.56(m,3H),1.28(t,J＝7.0Hz,5H),1.14(s,4H),1.11–1.07(m,3H),1.05(d,J＝6.8Hz,1H),0.95(d,J＝6.1Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ156.60,143.38,142.56,142.56,141.77,131.52,124.77,122.25,119.97,71.91,69.33,69.00,60.06,57.10,42.02,41.54,41.35,38.17,37.02,35.28,31.43,31.25,30.61,30.49,29.14,20.96,19.81,19.41,15.90,15.00.HRMS(ESI):m/z calcd for C ₃₀ H ₄₅ N ₂ O ₂ ⁺ [M+H] ⁺ :465.3476,found 465.3471.

Example 15

The intermediate is obtained by taking VT-9 as a raw material and adopting a synthesis method similar to VT-10

Further, the synthesis method is the same as VT-11

White solid, yield about 55%. ¹ H NMR(500MHz,CDCl ₃ )δ7.11(d,J＝7.8Hz,1H),6.98(d,J＝7.7Hz,1H),5.49(d,J＝5.3Hz,1H),3.58(tt,J＝11.2,4.5Hz,1H),3.47(s,2H),3.01–2.89(m,2H),2.87–2.76(m,2H),2.65–2.53(m,2H),2.42(ddd,J＝12.9,4.8,1.9Hz,1H),2.30(s,3H),2.20–1.99(m,5H),1.92–1.80(m,4H),1.61(ddd,J＝26.8,13.7,3.9Hz,2H),1.32(s,9H),1.31–1.24(m,2H),1.14(s,3H),1.11(d,J＝6.1Hz,3H),0.91(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ154.18,143.19,142.56,142.53,141.97,131.28,124.94,122.37,120.00,77.48,72.02,69.13,61.23,57.08,42.07,41.41,39.10,38.21,37.06,34.42,32.15,31.50,30.63,30.52,29.20,27.85,27.85,27.85,21.43,19.67,19.44,15.66.HRMS(ESI):m/z calcd for C ₃₂ H ₄₉ N ₂ O ₂ ⁺ [M+H] ⁺ :493.3789,found(493.3794).

Example 16

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Further, the synthesis method is the same as VT-11

White solid, yield about 59%. ¹ H NMR(500MHz,CDCl ₃ )δ7.41–7.26(m,5H),7.08(d,J＝7.7Hz,1H),6.97(d,J＝7.7Hz,1H),5.49(brd,J＝3.7Hz,1H),5.17(s,2H),3.63–3.54(m,1H),3.42(s,2H),2.97(td,J＝11.6,5.2Hz,1H),2.89–2.75(m,3H),2.67–2.53(m,2H),2.46–2.38(m,1H),2.30(s,4H),2.16(s,2H),2.02(s,3H),1.93–1.79(m,3H),1.71–1.56(m,2H),1.28(dd,J＝13.3,9.5Hz,2H),1.14(s,3H),1.04(d,J＝3.3Hz,3H),0.94(d,J＝4.1Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ157.51,143.36,142.56,142.56,141.73,138.64,131.45,128.38,128.38,128.15,128.15,127.69,124.76,122.29,119.98,75.60,71.95,69.19,60.14,57.09,42.04,41.37,41.03,38.18,37.03,34.96,31.64,31.45,30.62,30.50,29.34,20.99,19.79,19.42,15.86.HRMS(ESI):m/z calcd for C ₃₅ H ₄₇ N ₂ O ₂ ⁺ [M+H] ⁺ :527.3632,found(527.3636).

Example 17

Further, the synthesis method is the same as VT-11

White solid, yield about 45%. ¹ H NMR(500MHz,CDCl ₃ )δ8.21(s,1H),7.06(d,J＝7.8Hz,1H),6.97(d,J＝7.7Hz,1H),5.48(brd,J＝5.2Hz,1H),3.62–3.53(m,1H),3.46–3.37(m,2H),2.96(td,J＝11.6,5.3Hz,1H),2.86(d,J＝8.4Hz,1H),2.78(dd,J＝14.7,7.3Hz,1H),2.66–2.52(m,3H),2.42(ddd,J＝12.9,4.6,1.7Hz,1H),2.29(s,3H),2.28–2.24(m,2H),2.08(s,3H),2.06–1.99(m,2H),1.93–1.78(m,5H),1.66–1.56(m,1H),1.32–1.23(m,3H),1.14(s,3H),1.09(d,J＝6.2Hz,3H),0.96(d,J＝6.0Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ158.19,150.66,143.61,142.70,142.60,141.25,131.40,125.04,122.19,119.95,71.92,71.06,60.27,57.15,42.02,41.37,38.18,37.03,35.72,32.88,31.44,30.61,30.50,29.82,29.38,20.40,19.74,19.42,15.85.HRMS(ESI):m/z calcd for C ₂₉ H ₄₃ N ₄ O ₂ ⁺ [M+H] ⁺ :479.3381,found(479.3381).

Example 18

VT-9 (200 mg,0.43 mmol) and tert-butylcarbazole (571 mg,4.32 mmol) were dissolved in CH ₃ In OH, 3 drops of acetic acid solution are added dropwise for reflux reaction for 12h at 65 ℃, naOH (35 mg,0.86 mmol) is directly added without treatment for hydrolysis reaction after TLC monitoring reaction is finished, and after TLC monitoring reaction is finished, the solution is cooled to room temperature and quenched by water. Extracted with DCM, the organic phases combined and dried over anhydrous Na ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and purifying by silica gel column chromatography (PE/EA=3:1-1:1) to obtainThe white solid was VT-18 (185 mg, 80%).

¹ H NMR(500MHz,CDCl ₃ )δ7.16(d,J＝7.1Hz,1H),6.99(d,J＝7.4Hz,1H),5.48(d,J＝4.3Hz,1H),3.63–3.39(m,3H),2.96(td,J＝11.6,5.3Hz,2H),2.77(dd,J＝14.7,7.3Hz,1H),2.66–2.36(m,5H),2.29(s,6H),2.12–2.00(m,4H),1.89–1.78(m,5H),1.53(s,9H),1.29–1.24(m,2H),1.13(s,3H),1.11(d,J＝6.2Hz,3H),0.99(d,J＝6.2Hz,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ153.11,143.56,142.59,142.50,131.70,125.04,122.32,120.13,120.09,81.25,72.00,71.42,60.02,57.12,42.03,41.36,38.17,37.03,32.34,31.45,30.63,30.50,28.83,28.48,28.48,28.48,28.43,28.41,20.91,19.95,19.43,16.03.HRMS(ESI):m/z calcd for C ₃₃ H ₅₀ N ₃ O ₃ ⁺ [M+H] ⁺ :536.3847,found 536.3848.

Example 19

VT-18 (200 mg,0.37 mmol) was dissolved in anhydrous DCM, trifluoroacetic acid (832. Mu.l, 11.21 mmol) was added, stirred at room temperature for 30min, after LC-MS monitoring the reaction, saturated NaHCO was added ₃ The solution was quenched. Anhydrous Na for organic phase ₂ SO ₄ Drying, filtering, concentrating to obtain crude product, and using C ₁₈ Column chromatography (H) ₂ O/CH ₃ Cn=40% -60%) and freeze-drying to obtain white solid which is VT-19 (115 mg, 71%).

¹ H NMR(500MHz,CDCl ₃ )δ7.09(d,J＝7.8Hz,1H),6.97(d,J＝7.7Hz,1H),5.48(brd,J＝5.3Hz,1H),5.04(s,1H),3.62–3.46(m,2H),3.42–3.31(m,2H),2.97(td,J＝11.6,5.3Hz,1H),2.87–2.74(m,2H),2.67–2.38(m,4H),2.29(s,3H),2.28–2.16(m,3H),2.06(s,3H),2.02(dt,J＝14.3,3.0Hz,1H),1.92–1.78(m,4H),1.67–1.55(m,2H),1.26(ddd,J＝13.3,8.9,4.2Hz,1H),1.14(s,3H),1.06(d,J＝6.3Hz,3H),0.97(d,J＝6.2Hz,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ143.18,142.41,142.33,141.86,131.49,124.84,122.15,119.74,71.83,71.44,60.32,56.97,41.91,41.21,38.03,36.89,36.61,31.32,31.11,30.47,30.38,28.52,20.63,19.89,19.27,15.81.HRMS(ESI):m/z calcd for C ₂₈ H ₄₂ N ₃ O ⁺ [M+H] ⁺ :436.3322,found 436.3325.

Example 20

VT-9 (216 mg,0.47 mmol) was dissolved in anhydrous DCM (2.5 ml) under Ar protection, DAST (1.7 ml,14.00 mmol) was added dropwise under ice-bath, after half an hour of addition was completed, the ice-bath was removed, and the reaction was carried out at room temperature for 24h. After TLC monitoring that most of raw materials are reacted, slowly pouring the reaction solution into ice water for quenching, and after complete quenching, using anhydrous Na to make the organic phase ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=3:1) to give VT-20 as a white solid (115 mg, 51%).

¹ H NMR(500MHz,CDCl ₃ )δ7.12(d,J＝7.7Hz,1H),6.98(d,J＝7.8Hz,1H),5.52(brd,J＝5.2Hz,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＝6.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.65,143.48,142.72,141.63,141.42,130.62,125.57/123.54/121.54,125.07,123.27,119.94,74.06,66.97/66.80/66.63,63.02,57.05,43.42/43.23/43.04,41.31,38.31,37.93,37.91,37.13,33.67,30.52,30.49,27.62,25.13/25.07,21.58,19.92/19.88,19.33,18.36,15.55.HRMS(ESI):m/z calcd for C ₃₀ H ₄₂ F ₂ NO ₂ ⁺ [M+H] ⁺ :486.3178,found(486.3177).

Example 21

VT-20 is used as raw material, and the synthesis method is the same as VT-11

White solid, yield about 40%. ¹ H NMR(500MHz,CDCl ₃ )δ7.12(d,J＝7.7Hz,1H),6.99(d,J＝7.7Hz,1H),5.49(brd,J＝5.2Hz,1H),3.63–3.47(m,2H),2.98(td,J＝11.6,5.3Hz,2H),2.88(d,J＝9.5Hz,1H),2.78(dd,J＝14.7,7.4Hz,1H),2.66–2.53(m,2H),2.42(ddd,J＝12.9,4.7,1.7Hz,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＝27.2,13.8,4.0Hz,1H),1.50–1.39(m,1H),1.36(dd,J＝6.7,3.4Hz,3H),1.32–1.23(m,1H),1.14(s,3H),0.89(d,J＝6.0Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ143.72,142.90,142.54,141.36,130.59,126.15/123.33/120.82,125.01,122.26,120.07,71.96,67.09/66.89/66.75,62.96,57.14,43.25/43.07/42.87,42.02,41.37,38.48,38.17,37.04,33.69,31.44,30.58,30.47,25.05/24.99,20.00/19.96,19.42,18.31,15.56.HRMS(ESI):m/z calcd for C ₂₈ H ₄₀ F ₂ NO ⁺ [M+H] ⁺ :444.3072,found(444.3075).

Example 22

VT-21 is used as raw material, and the synthesis method is the same as VT-9

White solid, yield about 70%. ¹ H NMR(500MHz,CDCl ₃ )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,CDCl ₃ )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 ₂₈ H ₃₈ F ₂ NO ₊ [M+H] ⁺ :442.2916,found 442.2918.

Example 23

VT-22 is used as raw material, and the synthesis method is the same as VT-10

White solid, yield about 83%. ¹ H NMR(500MHz,CDCl ₃ )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),1.54–1.39(m,2H),1.35(dd,J＝6.9,3.2Hz,4H),1.26(s,1H),1.23(s,3H).HRMS(ESI):m/z calcd for C ₂₈ H ₃₉ F ₂ N ₂ O ⁺ [M+H] ⁺ :457.3025,found 457.3031.

Example 24

Under Ar protection, a solution of VT-8 (300 mg,0.65 mmol) in anhydrous DCM was placed at-78deg.C, DAST (2.4 ml,19.35 mmol) in anhydrous DCM was added, and after 30 min of reaction, the reaction solution was moved to room temperature for 12h. After TLC monitoring that most of raw materials are reacted, slowly pouring the reaction solution into ice water for quenching, and after complete quenching, using anhydrous Na to make the organic phase ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=2:1) to give white solid (185 mg, 61%). And then hydrolyzing according to a VT-11 method to obtain VT-24.

¹ H NMR(500MHz,CDCl ₃ )δ7.16(d,J＝7.1Hz,1H),6.98(d,J＝7.8Hz,1H),5.48(brd,J＝5.2Hz,1H),4.80(d,J＝47.9Hz,1H),3.67–3.53(m,2H),2.99(td,J＝11.5,5.2Hz,2H),2.78(dd,J＝14.8,7.4Hz,1H),2.67–2.56(m,3H),2.53(s,3H),2.42(ddd,J＝12.9,4.7,1.8Hz,1H),2.31(s,3H),2.29–2.24(m,1H),2.17(s,1H),2.06–1.95(m,3H),1.91–1.78(m,4H),1.66–1.56(m,1H),1.41(d,J＝6.7Hz,3H),1.31–1.23(m,2H),1.14(s,3H),0.93(d,J＝6.0Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ144.04,142.83,142.56,141.15,131.03,125.97,122.18,119.85,89.36/87.97,71.93,69.77/69.61,64.14,57.18,42.36,41.99,41.31,39.56/39.41,38.14,37.03,34.96,31.42,30.51,30.51,27.49,19.39,18.85,15.94,15.45.HRMS(ESI):m/z calcd for C ₂₈ H ₄₁ FNO ⁺ [M+H] ⁺ :426.3167,found 426.3169.

Example 25

Veratramine (500 mg,1.22 mmol) was dissolved in THF and Et was added ₃ N (1236 mg,12.22 mmol) was then added FmocCl (3161 mg,12.22 mmol) in THF, reacted at room temperature for 1h, quenched with water, the organic phase separated, concentrated and purified by silica gel column chromatography (PE/EA=5:1) to give a white intermediate. The next acetylation step is identical to VT-8. Then synthesizing the intermediate with VT-9

Synthesis of the same VT-10 method

The method for hydrolyzing acetyl is the same as VT-11.

Fmoc removal method: after completion of the reaction, which was monitored by tlc, by adding 5ml of water, three washes with water and extraction with DCM, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=3:1) to give VT-26 as a white solid in about 14% yield. ¹ H NMR(500MHz,CDCl ₃ )δ7.06(d,J＝7.8Hz,1H),7.01(d,J＝7.7Hz,1H),5.49(brd,J＝5.1Hz,1H),3.71–3.53(m,2H),3.36(d,J＝10.3Hz,1H),3.14–3.05(m,1H),2.97(td,J＝11.9,4.4Hz,2H),2.79(dd,J＝14.8,7.3Hz,1H),2.67–2.54(m,2H),2.41(dd,J＝12.8,4.6Hz,1H),2.38–2.34(m,1H),2.32(s,3H),2.31–2.24(m,1H),2.15–2.00(m,2H),1.96–1.80(m,5H),1.66–1.56(m,1H),1.31–1.25(m,1H),1.22(d,J＝6.7Hz,2H),1.14(s,3H),1.02(d,J＝7.0Hz,1H),0.96(d,J＝6.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ157.63,144.03,143.25,142.63,140.79,132.90,122.18,122.12,120.66,71.91,65.09,57.05,52.33,41.97,41.38,38.14,37.02,32.25,31.39,31.06,30.66,30.47,20.74,19.40,18.83,17.19,15.98.HRMS(ESI):m/z calcd for C ₂₇ H ₃₉ N ₂ O ₂ ⁺ [M+H] ⁺ :423.3006,found(423.3002)。

Example 26

VT-3 is used as raw material, and the synthesis method is the same as VT-8

White solid, yield about 55%. ¹ H NMR(500MHz,CDCl ₃ )δ7.25(d,J＝7.0Hz,1H),7.02(d,J＝7.7Hz,1H),6.01–5.92(m,1H),5.51(brd,J＝5.2Hz,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＝14.4,5.0Hz,1H),3.03(dd,J＝14.4,7.7Hz,1H),2.94(td,J＝11.6,5.2Hz,1H),2.86(d,J＝11.0Hz,1H),2.77(dd,J＝14.9,7.4Hz,1H),2.65–2.53(m,2H),2.49–2.42(m,2H),2.36(d,J＝11.4Hz,1H),2.31(s,3H),2.05(s,3H),2.01(dd,J＝9.6,7.1Hz,1H),1.95–1.78(m,5H),1.75–1.58(m,2H),1.40(d,J＝7.1Hz,3H),1.36–1.26(m,2H),1.15(s,3H),0.90(d,J＝12.1Hz,1H),0.87(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ170.48,144.78,143.87,141.33,140.91,135.66,132.59,123.92,122.87,120.66,117.27,73.84,67.35,67.26,59.66,56.85,56.11,41.21,41.08,37.73,37.73,36.95,34.07,30.32,30.29,28.17,27.44,21.42,19.42,19.10,16.06,13.73.HRMS(ESI):m/z calcd for C ₃₂ H ₄₆ NO ₃ ⁺ [M+H] ⁺ :492.3472,found 492.3474.

Example 27

VT-27 is used as raw material, and the synthesis method is the same as VT-9

A white solid was used as a solid,the yield was about 75%. ¹ H NMR(500MHz,CDCl ₃ )δ7.07(d,J＝7.8Hz,1H),6.96(d,J＝7.8Hz,1H),5.52(brd,J＝5.2Hz,1H),5.35–5.24(m,1H),4.95–4.87(m,2H),4.70–4.61(m,1H),3.55(d,J＝9.6Hz,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＝6.7Hz,3H),0.97(d,J＝6.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ210.71,170.65,143.62,142.52,141.43,140.23,136.16,131.35,125.64,123.22,119.93,116.79,74.19,74.07,57.11,55.25,53.61,48.38,41.27,37.92,37.10,33.39,32.74,30.51,30.50,27.63,21.57,20.61,19.56,19.35,19.30,15.79.HRMS(ESI):m/z calcd for C ₃₂ H ₄₄ NO ₃ ⁺ [M+H] ⁺ :490.3316,found 490.3313.

Example 28

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VT-28 is taken as raw material, and the synthesis method is the same as VT-10, thus obtaining intermediate

Further synthesis method is similar to VT-11

White solid, yield about 68%. ¹ H NMR(500MHz,CDCl ₃ )δ7.08(d,J＝7.8Hz,1H),6.96(d,J＝7.7Hz,1H),5.49(brd,J＝5.1Hz,1H),5.31(dd,J＝16.8,9.3Hz,1H),4.89(d,J＝13.6Hz,2H),3.89(s,3H),3.62–3.55(m,1H),3.40–3.38(m,2H),3.01–2.83(m,3H),2.79(dd,J＝14.6,7.3Hz,2H),2.66–2.53(m,2H),2.45(ddd,J＝17.1,13.6,5.3Hz,3H),2.31(s,3H),2.19–1.99(m,3H),1.92–1.78(m,3H),1.73(s,1H),1.67–1.56(m,1H),1.32–1.23(m,2H),1.16(s,3H),1.07(d,J＝6.1Hz,3H),0.98(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ158.19,143.61,142.70,142.60,141.25,131.40,125.04,122.19,119.95,77.41,77.16,76.91,71.92,71.06,60.27,57.15,42.02,41.37,38.18,37.03,35.72,32.88,31.44,30.61,30.50,29.82,29.38,20.40,19.74,19.42,15.85.HRMS(ESI):m/z calcd for C ₃₁ H ₄₅ N ₂ O ₂ ⁺ [M+H] ⁺ :477.3476,found477.3478.

Example 29

Further synthesis method is similar to VT-11

White solid, yield about 64%. ¹ H NMR(500MHz,CDCl ₃ )δ7.09(d,J＝7.8Hz,1H),6.96(d,J＝7.8Hz,1H),5.49(brd,J＝5.1Hz,1H),5.31(dt,J＝15.7,6.4Hz,1H),4.89(d,J＝13.6Hz,2H),4.18–4.11(m,2H),3.62–3.55(m,1H),3.42–3.35(m,2H),3.01–2.84(m,3H),2.83–2.75(m,2H),2.66–2.39(m,5H),2.31(s,3H),2.29–2.25(m,1H),2.24–1.99(m,3H),1.92–1.78(m,3H),1.71(s,1H),1.66–1.57(m,1H),1.28(t,J＝7.0Hz,4H),1.16(s,3H),1.06(d,J＝6.0Hz,3H),0.98(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ157.85,143.46,142.53,142.34,141.97,136.80,132.07,125.11,122.27,119.89,116.41,71.96,68.96,68.57,59.51,57.18,55.11,42.05,41.31,38.18,37.01,31.46,30.61,30.54,30.17,29.10,27.04,20.18,20.14,19.43,16.25,15.00.HRMS(ESI):m/z calcd for C ₃₂ H ₄₇ N ₂ O ₂ ⁺ [M+H] ⁺ :491.3632,found 491.3638.

Example 30

Further synthesis method is similar to VT-11

White solid, yield about 66%. ¹ H NMR(500MHz,CDCl ₃ )δ7.09(d,J＝7.8Hz,1H),6.97(d,J＝7.7Hz,1H),5.50(brd,J＝5.2Hz,1H),5.35–5.27(m,1H),4.89(d,J＝13.1Hz,2H),3.63–3.55(m,1H),3.42(s,2H),3.01–2.76(m,5H),2.66–2.49(m,3H),2.42(ddd,J＝13.0,4.8,1.9Hz,1H),2.35(dd,J＝15.4,7.6Hz,1H),2.31(s,3H),2.20–2.11(m,2H),2.08–2.00(m,1H),1.93–1.79(m,3H),1.72–1.57(m,3H),1.31(s,9H),1.29–1.24(m,1H),1.16(s,3H),1.05(d,J＝6.2Hz,3H),0.96(d,J＝6.2Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ155.54,143.29,142.53,142.30,142.19,137.00,131.96,125.18,122.31,119.84,116.26,77.16,71.99,67.41,68.51,58.31,57.17,55.55,42.06,41.33,38.19,37.02,36.22,31.48,30.62,30.56,30.40,29.18,27.80,27.80,27.80,20.48,20.17,19.44,16.12.HRMS(ESI):m/z calcd for C ₃₄ H ₅₁ N ₂ O ₂ ⁺ [M+H] ⁺ :519.3945,found 519.3947.

Example 31

Further synthesis method is similar to VT-11

White solid, yield about 60%. ¹ H NMR(500MHz,CDCl ₃ )δ7.41–7.27(m,5H),7.05(d,J＝7.8Hz,1H),6.95(d,J＝7.8Hz,1H),5.49(d,J＝5.2Hz,1H),5.32–5.24(m,1H),5.15(s,2H),4.90–4.83(m,2H),3.63–3.55(m,1H),3.44–3.36(m,2H),3.01–2.89(m,2H),2.85–2.73(m,3H),2.65–2.39(m,5H),2.30(s,3H)，2.22–1.99(m 3H)，1.92–1.78(m 3H)，1.67–1.53(m 3H)，1.32–1.24(m 1H)，1.16(s，3H)，1.00(dJ＝6.2Hz,3H),0.96(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ158.77,143.47,142.52,142.35,141.89,138.64,136.79,132.00,128.38,128.38,128.11,128.11,127.69,125.09,122.30,119.89,116.45,75.51,71.99,68.29,59.18,57.18,55.00,42.06,41.32,38.18,37.02,36.32,31.48,30.62,30.55,30.35,29.32,20.18,20.18,19.44,16.21.HRMS(ESI):m/z calcd for C ₃₇ H ₄₉ N ₂ O ₂ ⁺ [M+H] ⁺ :553.3789,found 553.3792.

Example 32

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VT-28 is used as raw material, and the synthesis method is the same as VT-18

White solid, yield about 63%. ¹ H NMR(500MHz,CDCl ₃ )δ7.54(s,1H),7.13(d,J＝7.8Hz,1H),6.95(d,J＝7.7Hz,1H),5.47(brd,J＝5.1Hz,1H),5.36–5.22(m,1H),4.86(d,J＝12.2Hz,2H),3.63–3.51(m,2H),3.38–3.32(m,1H),3.01–2.69(m,5H),2.64–2.32(m,4H),2.29(s,3H),2.06–1.76(m,9H),1.66–1.56(m,1H),1.52(s,9H),1.31–1.21(m,1H),1.14(s,3H),1.06(d,J＝6.9Hz,3H),0.98(d,J＝6.6Hz,3H)； ¹³ C NMR(125MHz,CDCl ₃ )δ154.36,153.01,143.45,142.47,142.18,142.00,136.62,132.04,125.26,122.23,119.90,116.38,81.07,71.88,71.40,60.16,57.15,55.16,41.98,41.24,38.13,36.95,31.75,31.38,30.56,30.49,28.47,28.44,28.44,28.44,20.15,20.12,19.39,16.31.HRMS(ESI):m/z calcd for C ₃₅ H ₅₂ N ₃ O ₃ ⁺ [M+H] ⁺ :562.4003,found 562.4004.

Example 33

VT-1 (1.22 mmol) and aluminum isopropoxide (499 mg,2.44 mmol) were dissolved in toluene, cyclohexanone (1.3 ml,12.22 mmol) was added, the reaction was refluxed at 110℃for 6h, after completion of the reaction by TLC plate monitoring, the reaction solution was filtered, the filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE/EA=2:1-1:1), to give VT-35 (418 mg, 83%) as a white solid.

White solid, yield about 60%. ¹ H NMR(500MHz,CDCl ₃ )δ7.27(d,J＝7.9Hz,1H),7.02(d,J＝7.7Hz,1H),5.82(s,1H),3.87–3.83(m,1H),3.72–3.65(m,1H),3.03(td,J＝12.0,2.9Hz,1H),2.80(d,J＝10.8Hz,1H),2.73(dd,J＝14.7,7.0Hz,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＝5.4Hz,1H),2.02(ddd,J＝13.2,5.0,2.5Hz,1H),1.94–1.69(m,6H),1.50–1.44(m,1H),1.42(d,J＝7.2Hz,3H),1.28(s,3H),0.86(d,J＝6.6Hz,4H)； ¹³ C NMR(125MHz,CDCl ₃ )δ199.38,169.81,143.83,143.27,141.26,132.72,125.18,123.89,120.26,70.67,67.34,64.61,59.48,43.65,42.66,41.75,38.48,36.13,34.27,33.75,33.07,29.96,29.50,28.42,19.11,16.74,15.98,12.88.HRMS(ESI):m/z calcd for C ₂₈ H ₄₀ NO ₂ ⁺ [M+H] ⁺ :422.3054,found(422.3055).

Example 34

Method for synthesizing VT-36 by combining VT-3 with VT-35

White solid, yield about 58%. ¹ H NMR(500MHz,CDCl ₃ )δ7.26(d,J＝7.7Hz,1H),7.02(d,J＝7.7Hz,1H),5.98–5.90(m,1H),5.82(d,J＝1.1Hz,1H),5.25–5.15(m,2H),3.83(s,1H),3.72–3.65(m,1H),3.55(d,J＝11.1Hz,1H),3.04(td,J＝11.9,3.1Hz,2H),2.87(d,J＝10.1Hz,1H),2.73(dd,J＝14.7,7.0Hz,1H),2.64–2.37(m,7H),2.31(s,3H),2.03(ddd,J＝13.2,5.0,2.5Hz,1H),1.93–1.59(m,5H),1.50–1.43(m,1H),1.40(d,J＝7.0Hz,3H),1.29(s,3H),0.87(d,J＝6.6Hz,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ199.47,169.90,143.90,143.20,141.40,135.07,132.71,125.31,124.41,120.40,117.85,71.88,67.70,67.28,59.61,56.24,43.78,41.20,38.61,36.25,34.42,33.87,33.20,30.10,29.62,27.97,19.45,16.89,16.14,14.31.HRMS(ESI):m/z calcd for C ₃₀ H ₄₂ NO ₂ ⁺ [M+H] ⁺ :448.3210,found 448.3216.

Example 35

VT-36 (100 mg,0.22 mmol) was dissolved in anhydrous EtOH, hydroxylamine hydrochloride (155 mg,2.24 mmol) and anhydrous sodium acetate (184 mg,2.24 mmol) were added and reacted at room temperature for 4h. After TLC monitoring the reaction was completed, quenched with water and extracted with DCM. Anhydrous Na for organic phase ₂ SO ₄ Dried, filtered and concentrated to give crude product, which was purified by silica gel column chromatography (PE/ea=5:1) to give VT-45 (67 mg, 63%) as a white solid.

White solid, yield about 45%. ¹ H NMR(500MHz,CDCl ₃ )δ7.25(d,J＝7.9Hz,1H),7.01(d,J＝7.5Hz,1H),5.98–5.90(m,1H),5.87(d,J＝1.7Hz,1H),5.21(t,J＝13.7Hz,2H),3.87(s,3H),3.86(s,1H),3.72–3.65(m,1H),3.58(dd,J＝14.2,4.5Hz,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＝19.7,12.5,5.4Hz,3H),1.52(td,J＝13.9,5.0Hz,1H),1.40(d,J＝7.1Hz,3H),1.39–1.18(m,7H),1.15(s,3H),0.96–0.89(m,1H),0.87(d,J＝6.6Hz,4H).HRMS(ESI):m/z calcd for C ₃₁ H ₄₅ N ₂ O ₂ ⁺ [M+H] ⁺ :477.3476,found 477.3472.

Example 36

VT-36 is used as raw material, and the synthesis method is the same as VT-45

¹ H NMR(500MHz,CDCl ₃ )δ7.25(d,J＝7.8Hz,1H),7.02(d,J＝7.6Hz,1H),5.99–5.91(m,1H),5.89(d,J＝1.6Hz,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＝11.3Hz,1H),3.07–2.93(m,4H),2.87(d,J＝10.6Hz,1H),2.70(dt,J＝12.3,6.1Hz,1H),2.58–2.34(m,8H),2.31(s,4H),2.22(ddd,J＝17.4,14.7,5.1Hz,1H),1.87(dtd,J＝15.0,12.7,6.8Hz,4H),1.72–1.59(m,3H),1.53(td,J＝13.8,4.8Hz,1H),1.40(d,J＝7.1Hz,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＝6.6Hz,4H).HRMS(ESI):m/z calcd for C ₃₂ H ₄₇ N ₂ O ₂ ⁺ [M+H] ⁺ :491.3632,found 491.3635.

Example 37

Veratramine (500 mg,1.2 mmol) was dissolved in THF, py (967 mg,12.2 mmol) was added under ice-bath conditions, and then CH was slowly added dropwise ₃ COCl (480 mg,12.2 mmol), after the completion of the dropwise addition, the ice bath was removed, the reaction was carried out at room temperature for 1h, after the completion of the spot-on-plate monitoring, quenched by addition of sodium bicarbonate solution until no bubbles had been formed, extracted with DCM (10 ml×3), the organic phases were combined, the concentrated crude product was distilled under reduced pressure, and the intermediate was obtained as a white solid (4819 mg, 75%) by silica gel column chromatography. The intermediate (200 mg,0.37 mmol) was taken up in DCM and NaHCO was added ₃ (63 mg,0.75 mmol) was added to the ice bath, and after removal of the ice bath, reacted at room temperature for 2h, purified by silica gel column chromatography to give VT-47 (135 mg, 66%) as a white solid.

¹ H NMR(500MHz,CDCl ₃ )δ7.01(t,J＝8.3Hz,2H),6.87(ddd,J＝21.0,16.6,7.7Hz,2H),5.26(s,1H),5.19(s,1H),5.10(d,J＝10.5Hz,1H),5.05–4.96(m,1H),4.84–4.78(m,1H),4.31(t,J＝12.7Hz,1H),4.03(d,J＝9.8Hz,1H),3.46(s,1H),3.32–3.20(m,2H),3.13(dd,J＝13.9,4.3Hz,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＝8.2Hz,4H),2.21–2.08(m,6H),2.04(dd,J＝14.8,7.5Hz,15H),1.99–1.88(m,5H),1.87(d,J＝3.8Hz,3H),1.83–1.39(m,16H),1.34–1.23(m,6H),1.20(d,J＝5.4Hz,3H),1.12(dd,J＝9.0,2.9Hz,6H),1.06(d,J＝7.1Hz,2H).HRMS(ESI):m/z calcd for C ₃₃ H ₄₆ NO ₆ ⁺ [M+H] ⁺ :552.3320,found(552.3324).

Example 38

Synthesis method and VT-47 (VT-5 is obtained by peroxidation of mCPBA)

¹ H NMR(500MHz,CDCl ₃ )δ7.01(t,J＝12.0Hz,1H),6.85(ddd,J＝24.1,18.1,7.7Hz,1H),4.93(d,J＝9.9Hz,1H),4.18(s,1H),3.93(d,J＝5.2Hz,1H),3.72(s,1H),3.39–3.02(m,5H),2.96–2.34(m,11H),2.23(d,J＝5.8Hz,4H),2.14(s,6H),2.12–1.89(m,6H),1.87(d,J＝4.0Hz,6H),1.81–1.34(m,10H),1.27–1.19(m,5H),1.15(d,J＝8.4Hz,6H),1.08(d,J＝7.0Hz,3H).HRMS(ESI):m/z calcd for C ₂₉ H ₄₂ NO ₄ ⁺ [M+H] ⁺ :468.3108,found 468.3109.

Example 39

VT-48 (100 mg,0.21 mmol) was dissolved in (THF: H) ₂ O=3:1), F is added dropwise to the mixed solution ₃ CCOOH (48 mg,0.42 mmol), stirred at room temperature for 6h, after completion of the spot-on-plate monitoring reaction, naHCO was added ₃ The solution was quenched, extracted with DCM (5 ml. Times.3), the organic phases combined, concentrated to dryness under reduced pressure, and purified by column chromatography over silica gel (DCM/CH ₃ Oh=10:1) to afford VT-49 as a white solid.

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 NO ₅ ⁺ [M+H] ⁺ :486.3214,found 486.3220.

Effect example 1AP-1 luciferase reporter Gene experiment

1. Purpose of experiment

Verification of whether Compounds have an inhibitory Effect on the AP-1 Signal pathway

2. Experimental materials

(1) Cell strain

HEK293/AP-1-Luc cell line: construction of Shanghai Tao Shu Biotechnology Co., ltd

Taking the AP-1/DNA interaction site as a research object, selecting a DNA binding site of 5'-TGACTCA-3', setting 4 times of repeated sequences, and constructing on a pGL4.32 vector. When the AP-1 pathway is activated, it will bind to a specific sequence, initiating transcription of the reporter gene.

(2) Plasmid(s)

(3) Oligodeoxynucleotides

(4) Reagent(s)

Reagent name	Company (Corp)	Model number
			FBS	Biowest	S1820
DMEM medium	Wisent	319-005-CL
			0.25% pancreatin	Wisent	325-043-CL
DPBS	Gibco	14040117
			Lipofectamine2000	Lifetechnology	11668019
Hygromycin B	Yeasen	60225ES03
			Bright-Glo assay kit	Promega	E2620
PMA	Luo En	R038872-5mg

(5) Instrument and consumable

Instrument and model	Company (Corp)	Model number
			96-well cell culture plate	Corning	CLS3610
NIVO	Perkinelmer, USA

3. Experimental procedure

(1) Cell transfection

1) Preparation of blast cells HEK293 cells with early cell passage and good cell state were selected.

2) Plating before cell transfection, and plating the cells in six-hole plates, wherein the confluence of the cells is 60% -80% before transfection, and the cells are too full or too thin to be suitable for transfection.

3) Pre-transfection reagents were prepared using lipofectamine2000 as the transfection reagent. Transfection was performed at a rate of 2. Mu.g plasmid per well, 5. Mu.l lipofectamine2000, and was performed according to the transfection reagent instructions.

4) After 24 hours of transfection, the cells were digested according to the state observed earlier according to 1: 10. 1:20, 1:40 into 10cm dishes, the specific ratio was determined by transfection efficiency.

5) The cells were transferred to a 10cm dish and antibiotic screening was performed by adding antibiotics 24 hours later, while non-transfected parental control was performed with hygromycin at a concentration of 100 μg/ml.

6) Changing the liquid of the cells every 3 days, adding new antibiotics at the same time, and after about 10 days, all the mother cells die, continuing waiting until the cloned cells in the cell dish grow to be visible to the naked eye, and selecting the cloned cells into a 96-well plate.

7) When the cells grow to 80% on the 96-well plate, the cells are passaged into the 24-well plate, and too few early cells grow in the 24-well plate.

8) Clones were selected for detection according to 24 well plate growth.

(2) Clone detection

1) According to 24 well plates growing well plate 96 well plate detection, 24 well plate clone confluence degree is greater than 50%, according to experience value according to different density plate 96 well plate, 96 well plate needs to be coated with Matrigel before plate plating.

2) Placing the paved plate into 5% CO ₂ Culturing overnight in an incubator at 37 ℃.

3) The next day the medium was removed and replaced with 80. Mu.l of DMEM medium containing 0.1% serum.

4) PMA reagent was added to each well of a 96-well plate at a final concentration of 10nM, and the compound was incubated with the cells at 5% CO ₂ Incubate in incubator at 37℃for 24 hours.

5) After the incubation is completed, the fluorescent value is immediately read on the plate reader by adding the Bright Glo solution as indicated by the Bright Glo reagent product.

(3) Clone retesting

1) Clones with better signal window are screened in the early stage and transferred into a 6-well plate, after the cell confluency reaches 80%, 96-well plates are prepared for retesting, and the 96-well plates are coated with Matrigel before being plated.

3) The next day the medium was removed and replaced with DMEM medium containing 0.1% serum.

4) Veratramine was formulated as a compound solution with a final concentration of 10 μm and added to the cells.

5) In retested clones, drug wells and positive wells were added, each well with a final concentration of 10nM PMA reagent. Negative control wells were added with DMSO-containing medium. Compound and cell at 5% CO ₂ Incubate in incubator at 37℃for 24 hours.

6) After the incubation is completed, the fluorescent value is immediately read on the plate reader by adding the Bright Glo solution as indicated by the Bright Glo reagent product.

(4) AP-1 reporter gene detection

1) HEK293/AP-1 cells were counted after digestion with pancreatin at 6X10 per well ⁴ Cells were plated in 96 Kong Baibian clear plates previously coated with matrigel.

4) The day of the experiment compounds were dissolved in DMSO into high concentration stock solutions.

5) Mu.l of 5X compound working solution containing 5X PMA (50 nM) was added to each well of a 96-well plate, and the compound and cells were incubated in 5% CO ₂ 37℃Incubate in incubator for 24 hours.

6) After the incubation is completed, the Bright Glo solution is added as indicated by the Bright Glo reagent product. The fluorescence value is immediately read on the read trigger.

7) The inhibition rate calculation formula: inhibition% = (1-Reading) _test /Reading _0.5％DMSO )×100。

TABLE 1 proliferation inhibitory Activity of veratramine derivatives (30 μM) on HEK293/AP-1 model cells

TABLE 2 proliferation inhibitory Activity of veratramine derivatives (10. Mu.M) on HEK293/AP-1 model cells

Numbering of compounds	Inhibition ratio (%)	Numbering of compounds	Inhibition ratio (%)
				VT-14	40.41	VT-23	35.51
VT-15	38.63	VT-27	42.62
				VT-16	37.65	VT-29	53.52
VT-18	42.31	VT-30	61.58
				VT-19	45.98	VT-33	30.80
VT-22	54.715	Veratramine	31.05

From the above, it was found that the compounds of the present invention have inhibitory activity equivalent to or superior to Veratramine at 10. Mu.M. At 30. Mu.M, the compound of the invention has better inhibition activity than Veratramine and is obviously better than the compounds 6, 7, 17 and 49.

Effect example 2NF- κB luciferase reporter Gene experiments

1. Purpose of experiment

Whether the compound acts exclusively on the AP-1 signaling pathway is examined without affecting the NF- κB signaling pathway.

2. Experimental materials

(1) Cell strain

HEK293/NF- κB cell line: construction of Shanghai Tao Shu Biotechnology Co., ltd

(2) Reagent(s)

Reagent name	Company (Corp)	Model number
			DMEM medium	BI	06-1055-57-1ACS
FBS	Gibco in U.S	10099-141
			DMSO	Sigma in U.S	D8418
Penicillin&Streptomycin(P/S)	Procell	PB180120
			0.25% pancreatin-EDTA	Chinese source culture	S310KJ
Bright glo	Promega, USA	E2620
			TNFα	Peprotech in U.S	315-01A

(3) Instrument and consumable

3. Experimental procedure

(1) Cell resuscitation

And quickly taking out the cells to be recovered from the liquid nitrogen tank, melting the cells in a water bath at 37 ℃, and quickly adding the cells into the preheated culture medium. 1000 rpm, centrifuging for 5min, taking out the centrifuge tube, discarding supernatant, adding fresh preheated culture medium into the centrifuge tube, re-suspending cells, adding cell suspension into culture dish, and adding 5% CO ₂ Culturing at 37 ℃.

(2) Cell passage

Adherent cell passaging: when the cells grow up to 80-90% of the culture dish, the cells are digested with 0.25% pancreatin, then resuspended in fresh medium, and passaged at appropriate ratios for about 2-4 days for 1 passage.

(3) Cell seeding and drug treatment

1) 1 day before detection, cells were seeded at 40000 cells per well in 96-well cell plates, 80. Mu.l of cell suspension per well, 37℃and 5% CO, according to the cell growth rate ₂ Incubator, incubate overnight.

2) According to the experimental requirements, 10. Mu.l of working solution of the compound was added to each well and incubated for 1 hour, 10. Mu.l of TNFα (200 ng/ml), 5% CO were added ₂ Incubators at 37℃were incubated for 24 hours in the absence of light.

3) After the incubation was completed, 50. Mu.l/well of Bright glo was added, and chemiluminescence was measured on NIVO to calculate inhibition.

4) Inhibition% = ((RFUCmpd-AVER (rfuneg. Ctrl))/(AVER (RFUDay 0) -AVER (rfuneg. Ctrl)) ×100%), wherein RFUCmpd is the luminescence value of the sample well (test compound)

RFU Blank: blank well luminescence value (cell + Medium + DMSO)

Rfuneg.ctrl: negative well luminescence value (cell+Medium+DMSO+TNFα)

TABLE 3 inhibition activity of veratramine derivatives on NF- κB signaling pathway

Compounds of formula (I)	IC ₅₀ (μM)
		VT-14	21.62
VT-15	9.2
		VT-16	21.17
VT-18	>30
		VT-19	>30
VT-22	>30
		VT-23	>30
VT-27	>30
		VT-29	20.31
VT-30	16.59
		Veratramine	>30
IMD-0354	4.8

From the above, it is clear that the compounds of the present invention have an inhibitory activity on NF- κB signaling pathway ₅₀ Values are all greater than IMD-0354

(

It is a synthetic selective NF-kB inhibitor, and also inhibits the entry of NF-kB subunit p65 into the nucleus. ) And most of the compounds are greater than 20 μm; IC with partial compounds having inhibitory activity on NF- κB signaling pathway ₅₀ Values greater than 30 μm indicate that these derivatives have little inhibitory activity compared to IMD-0354.

It can be seen that the compounds of the present invention have selective inhibitory activity on the AP-1 signaling pathway.

Effect example 3 triple negative breast cancer cell proliferation inhibition experiment

1. Purpose of experiment

The growth inhibitory effect of the compounds on MDA-MB-231 cells was examined by the Cell Titer Glo (CTG) method.

2. Experimental materials

(1) Cell strain

MDA-MB-231 cells: purchased from ATCC

(2) Reagent(s)

Reagent name	Company (Corp)	Model number
			DMEM medium	BI	06-1055-57-1A
FBS	Biosera	FB-1058/500
			Penicillin&Streptomycin(P/S)	Wisent	450-201-EL
Cell Titer Glo reagent	Promega	G7572

(3) Instrument and consumable

Instrument and model	Company (Corp)	Model number
			96-well cell culture plate	Costar	3610
Cell culture dish	Nest
			Enzyme label instrument	PE	NIVO5

Other conventional instrumentation: CO ₂ Incubator, ultra clean bench, centrifuge, eppendorf pipettor, etc.

3. Experimental procedure

(1) Preparation of cell culture Medium

MDA-MB-231：DMEM+10％FBS+1％P/S

(2) Drug configuration

The compounds were diluted to experimental design concentrations with cell-corresponding culture broth.

(3) Cell proliferation assay

1) Cells were counted and plated in 384 well plates at the following densities, 40 μl per well. Placing at 37deg.C, 5% CO ₂ The incubator was cultured overnight.

2) MDA-MB-231 500 cells per well, 10. Mu.l of the test compound was added to each well to bring the final concentration of the compound to that of Excel-accessory data layout. After further culturing for 72 hours, 100. Mu.l of CTG was added to each well.

3) Standing at room temperature for 10min, and measuring chemiluminescence values of all the holes on an enzyme-labeled instrument.

Table 4 proliferation inhibitory Activity of veratramine derivatives against triple negative breast cancer cells

Numbering of compounds	IC ₅₀ (μM)
		VT-22	12.22
VT-23	10.89
		Veratramine	10.37

。

Claims

1. Veratrame compounds represented by formula I or pharmaceutically acceptable salts thereof;

wherein, the liquid crystal display device comprises a liquid crystal display device,

when R is ¹ Is C ₂ -C ₄ In the case of alkenyl groups, Y ¹ Is that

Y ² Is that

R ^a For HO-or C ₁ -C ₄ alkyl-C (=O) -O-, R ^b Is H; r is R ^d Is H or C ₁ -C ₄ alkyl-C (=o) -;

R ^c and R is ^e Independently HO-, C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) Or N (R) ^1b R ^1c )-；R ^1a 、R ^1b And R is ^1c Independently H or C ₁ -C ₄ An alkyl group;

is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When in use;

Y ² is that

R ^c Is HO-, C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )、N(R ^1b R ^1c ) -or benzyl-O-; r is R ^1a 、R ^1b And R is ^1c Independently H or C ₁ -C ₄ An alkyl group;

R ^d is H or C ₁ -C ₄ alkyl-C (=o) -;

is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When R is ^a Is halogen, R ^b Is H or halogen;

Y ² is that

R ^d Is H or C ₁ -C ₄ alkyl-C (=o) -;

R ^e is HO-, C ₁ -C ₄ alkyl-O-, C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )、N(R ^1b R ^1c ) -or benzyl-O-;

R ^1a 、R ^1b and R is ^1c Independently H or C ₁ -C ₄ An alkyl group;

is->

Or, the veratram compound shown in the formula I is selected from the following compounds:

2. the veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 1,

when R is ¹ Is C ₁ -C ₄ In the case of alkyl, said C ₁ -C ₄ Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ¹ Is C ₂ -C ₄ In the case of alkenyl, said C ₂ -C ₄ Alkenyl groups being

And/or when R ^a Is C ₁ -C ₄ alkyl-C (=O) -O-, said C ₁ -C ₄ C in alkyl-C (=O) -O-, C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

And/or when R ^a And R is ^b When independently halogen, the halogen is independently fluorine, chlorine, bromine or iodine;

and/or when R ^d Is C ₁ -C ₄ alkyl-C (=o) -said C ₁ -C ₄ alkyl-C (=O) -C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^c And R is ^e Independently C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) -when said C ₁ -C ₄ alkyl-O-and C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) C in ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R ^1a 、R ^1b And R is ^1c Independently C ₁ -C ₄ In the case of alkyl, said C ₁ -C ₄ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

3. The veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 2,

when R is ¹ Is C ₁ -C ₄ In the case of alkyl, said C ₁ -C ₄ Alkyl is methyl or ethyl;

And/or when R ^a Is C ₁ -C ₄ alkyl-C (=O) -O-, said C ₁ -C ₄ C in alkyl-C (=O) -O-, C ₁ -C ₄ Alkyl is independently methyl or ethyl;

And/or when R ^a And R is ^b When independently halogen, the halogen is independently fluorine;

and/or when R ^d Is C ₁ -C ₄ alkyl-C (=o) -said C ₁ -C ₄ alkyl-C (=O) -C ₁ -C ₄ Alkyl is independently methyl or ethyl;

and/or when R ^c And R is ^e Independently C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) -when said C ₁ -C ₄ alkyl-O-and C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a ) C in ₁ -C ₄ Alkyl is independently methyl, ethyl or tert-butyl.

4. The veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 1,

R ^1a is H;

and/or R ^1b And R is ^1c Independently H;

and/or R ^e For HO-or C ₁ -C ₄ alkyl-O-;

and/or when R ¹ Is C ₂ -C ₄ In the case of alkenyl groups, Y ¹ Is that

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When in use; y is Y ¹ Is->

And/or when R ¹ Is C ₂ -C ₄ In the case of alkenyl groups, Y ² Is that

/>

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When in use; y is Y ² Is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When in use; y is Y ² Is->

5. The veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 1,

when R is ¹ Is C ₂ -C ₄ Alkenyl groups;

is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When in use; />

Is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When (I)>

Is->

/>

And/or when R ¹ Is C ₂ -C ₄ In the case of an alkenyl group, the alkenyl group,

is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When (I)>

Is->

When R is ¹ Is C ₁ -C ₄ Alkyl, Y ¹ Is that

When (I)>

Is->

6. The veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 1,

R ¹ is C ₂ -C ₄ Alkenyl groups; y is Y ¹ Is that

R ^c Is C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )；

Y ² Is that

Is->

7. The veratrame compound represented by the formula I or a pharmaceutically acceptable salt thereof according to claim 1,

R ¹ is C ₂ -C ₄ Alkenyl groups; y is Y ¹ Is that

R ^c Is C ₁ -C ₄ alkyl-O-or C ₁ -C ₄ alkyl-O-C (=o) -N (R) ^1a )；

Y ² Is that

Is->

8. The veratramine compound shown in the formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the veratramine compound shown in the formula I is selected from the group consisting of,

/>

9. a method for preparing veratrame compounds of formula I according to any one of claims 1-8, comprising the following scheme one, scheme two, scheme three, scheme four, scheme five, scheme six, scheme seven, scheme eight, scheme nine, scheme ten or scheme eleven:

is as defined in any one of claims 1 to 8;

scheme II, when the veratrame compound shown in the formula I is Y ² Is that

R ^d Is C ₁ -C ₄ alkyl-C (=o) -times; the method comprises the following steps: the compound shown in the formula IIb is mixed with a compound containing +.>

Is as defined in any one of claims 1 to 8;

scheme III, in the veratrame compound shown in the formula I, Y ¹ Is that

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ¹ And->

Is as defined in any one of claims 1 to 8; />

Scheme IV, in the veratrame compound shown in the formula I, Y ¹ Is that

When in use; which comprises the following stepsThe steps are as follows: combining a compound of formula IId with a compound of formula R ^c -NH ₂ The compounds shown in the formula I undergo imidization reaction as shown in the following to obtain veratramine compounds shown in the formula I; wherein Y is ² Is->

R ^c 、R ^d 、R ^e 、R ¹ And->

Is as defined in any one of claims 1 to 8;

Is as defined in any one of claims 1 to 8;

/>

scheme six, when saidIn veratramine compounds shown in formula I, Y ¹ Is that

R ^a Is halogen, R ^b When H or halogen; the method comprises the following steps: carrying out halogenation reaction on a compound shown in a formula IIf and a compound shown in a halogenating reagent to obtain the veratramine compound shown in a formula I; wherein Y is ² Is->

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ^e 、R ¹ And->

Is as defined in any one of claims 1 to 8;

scheme seven, when the veratramine compound shown in the formula I,

is->

Y ² Is that

When in use; the method comprises the following steps: carrying out the oxidation reaction of the compound shown in the formula IIg to obtain the veratramine compound shown in the formula I; wherein Y is ¹ And R is ¹ Are all as defined in the right Any one of claims 1-8;

in the eighth scheme, when the veratram compound shown in the formula I,

is->

Y ² Is that

When in use; the method comprises the following steps: in the presence of aluminum isopropoxide and cyclohexanone, carrying out double bond migration-oxidation reaction on a compound shown in a formula IIg to obtain the veratramine compound shown in a formula I; wherein Y is ¹ And R is ¹ Is as defined in any one of claims 1 to 8; />

Scheme nine, when the veratrame compound shown in the formula I is Y ² Is that

R ^a 、R ^b 、R ^c 、R ¹ 、R ^e And->

Is as defined in any one of claims 1 to 8;

scheme ten, in the veratrame compound shown in the formula I, Y ¹ Is that

R ^a Is C ₁ -C ₄ alkyl-C (=O) -O-, R ^b When H is the same as H; the method comprises the following steps: the compound shown in the formula IIi is mixed with a compound containing +.>

R ^d Is C ₁ -C ₄ alkyl-C (=o) -; r is R ^e 、R ¹ And->

Is as defined in any one of claims 1 to 8;

in the eleventh scheme, the compound shown in the formula IIj is subjected to the following epoxidation reaction to obtain the veratramine compound shown in the formula I; wherein the compound shown in the formula I has the following structure

Y ¹ 、R ¹ And Y ² Is defined as +.>

Is described in (2);

10. a pharmaceutical composition comprising a veratrame compound of formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-8, and one or more pharmaceutically acceptable carriers.

11. Use of a veratrame compound of formula I according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 for the preparation of an AP-1 inhibitor.

12. Use of a veratrame compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prevention and/or treatment of a disease or disorder associated with AP-1.

13. The use of claim 12, wherein the disease or condition is 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 trophoblastoma, glioblastoma, myeloma, neuroblastoma-derived CNS tumor, monocytic 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.

14. Use of a veratrame compound according to any one of claims 1-8, as shown in formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prevention and/or treatment of: 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 trophoblastoma, glioblastoma, myeloma, neuroblastoma CNS tumor, monocytic leukemia, B cell leukemia, T cell leukemia, B cell lymphoma, T cell lymphoma, and mast cell tumor, and combinations thereof.