CN112898224B

CN112898224B - Allyl alcohol-supported macrolide compound and application thereof

Info

Publication number: CN112898224B
Application number: CN201911227638.8A
Authority: CN
Inventors: 杨伟波; 楼丽广; 许忠良; 全海天; 陈露
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2019-12-04
Filing date: 2019-12-04
Publication date: 2023-02-17
Anticipated expiration: 2039-12-04
Also published as: CN112898224A

Abstract

The invention relates to an allyl alcohol-supported macrolide compound and application thereof. In particular, the present invention provides a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof. The compound of the formula I, or the isomer thereof, or the pharmaceutically acceptable salt thereof can enhance the antitumor activity of antitumor drugs.

Description

Allyl alcohol-supported macrolide compound and application thereof

Technical Field

The invention relates to the field of medicines, and particularly relates to an allyl alcohol supported macrolide compound and application thereof.

Background

Cancer is a serious disease that seriously harms human health, and is also one of the leading causes of death worldwide. In the prior art, a plurality of anti-tumor drugs are developed, however, in the process of anti-tumor therapy, multi-drug Resistance (MDR) of tumors is always a traditional Chinese medicine factor influencing the therapeutic effect of the anti-tumor drugs, so that the tumor cells generate Resistance to the anti-tumor drugs, the therapeutic effect of the anti-tumor drugs is reduced, and due to the multi-drug Resistance of tumors, the administration dosage of the anti-tumor drugs is always required to be increased continuously in the clinical therapy process of the tumors, the toxicity of the anti-tumor drugs to normal tissues is greatly increased, and pain is caused to patients. However, in the prior art, few drugs capable of inhibiting the multidrug resistance of tumors exist, and the inhibition activity is poor, so that the treatment effect of the antitumor drugs is greatly limited.

Therefore, there is an urgent need in the art to develop a drug that can effectively inhibit tumor-induced multidrug resistance, thereby enhancing the therapeutic effect of anti-tumor drugs.

Disclosure of Invention

An object of the present invention is to provide a novel compound of formula I having excellent antitumor activity of antitumor drug

The invention also aims to provide a compound shown in the formula II and a preparation method thereof, and the preparation method of the compound shown in the formula II has the advantages of mild conditions and simplicity and convenience in operation, and can successfully synthesize a novel allyl alcohol skeleton in one step for the first time.

In a first aspect of the invention, there is provided a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

r1, R2, R5 and R6 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester;

r3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, said substitution being such that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g. -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl-C1-C4 alkoxy-, 5-12 membered heteroaryl, C2-C4 ester;

the A ring is a substituted or unsubstituted C6-C20 aromatic ring, or a substituted or unsubstituted 5-20 membered heteroaromatic ring, a substituted or unsubstituted 3-12 membered heterocycloalkyl ring, a substituted or unsubstituted C3-C12 cycloalkane ring, a 3-8 membered heterocycloalkyl ring and a C6-C12 aromatic ring, and the substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-to 12-membered heteroaryl, C2-C4 ester group,

(C6-C20 aryl) (C1-C4 hydroxyalkyl) C = C (H) C1-C4 alkyl-, (C6-C20 aryl)The group) (C1-C4 hydroxyalkyl) C = C (C1-C4 alkyl) C1-C4 alkyl-, (5-12 membered heteroaryl) (C1-C4 hydroxyalkyl) C = C (H) C1-C4 alkyl-, (5-12 membered heteroaryl) (C1-C4 hydroxyalkyl) C = C (C1-C4 alkyl) C1-C4 alkyl-;

x is amino acid residue and polypeptide residue, wherein the polypeptide residue contains m amino acid residues, and m is a positive integer of 2-10;

is a double or single bond;

r7, R8, R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl; by substituted is meant that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl;

and the B ring is a substituted or unsubstituted C6-C20 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C3-C16 naphthenic ring and a substituted or unsubstituted 3-10 membered heterocycloalkyl ring, and the substitution refers to that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are independently substituted by a substituent selected from the following group: halogen, -CN, hydrogen, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl, carbonyl (C = O);

r11 is hydrogen, halogen, -CN, hydroxyl, nitro, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted haloC 1-C4 alkyl (e.g., -CF 3), substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted haloC 1-C6 alkoxy, substituted or unsubstituted haloC 1-C6 alkylthio, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted 5-12 membered heteroaryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted C2-C4 ester-, substituted or unsubstituted 3-12 membered heterocycloalkyl, said substitution referring to one or more (preferably 1,2,3 or 4) hydrogen atoms on the group, each independently selected from the group of substitution by: cyano, halogen, -CN, hydrogen, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl;

w is a substituted or unsubstituted 3-12 membered heterocycloalkyl, said substitution being such that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, -CN, hydrogen, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl;

a is 1,2,3, 4 or 5;

b is 0, 1,2 or 3;

the heterocyclic alkyl, heteroaryl, heterocycloalkyl ring and heteroaryl ring independently have 1-3 (preferably 1,2 or 3) heteroatoms selected from N, O and S.

In another preferred embodiment, R1, R2, R5 and R6 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, said substitution meaning that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

In another preferred embodiment, R1, R2, R5 and R6 are each independently hydrogen.

In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, said substitution being that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted phenyl, said substitution means that one hydrogen atom on the group is substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted phenyl, said substitution meaning that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with halogen.

In another preferred embodiment, the halogen is F, cl, br, I.

In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted phenyl, said substitution being that one hydrogen atom of the group is replaced by a halogen, preferably a fluorine atom.

In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted phenyl, said substitution being such that one hydrogen atom of the group is substituted with a halogen (e.g., fluorine atom) and the halogen substitution is para-substitution on the phenyl.

In another preferred embodiment, R3 is a substituted or unsubstituted C6-C12 aryl, or a substituted or unsubstituted 5-10 membered heteroaryl, said substitution referring to the replacement of one or more (preferably 1,2,3 or 4) hydrogen atoms on the group by substituents independently selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C4 alkyl (e.g., -CF 3).

In another preferred embodiment, R4 is hydrogen, substituted or unsubstituted C1-C4 alkyl, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C4 alkyl (e.g., -CF 3).

In another preferred embodiment, the A ring is a substituted or unsubstituted C6-C12 aromatic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted 3-10 membered heterocycloalkyl ring, a substituted or unsubstituted C3-C10 cycloalkane ring.

In another preferred embodiment, the A ring is a substituted or unsubstituted C6-C12 aromatic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted 5-8 membered heterocycloalkyl ring, a substituted or unsubstituted C5-C10 cycloalkane ring.

In another preferred embodiment, the A ring is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted 5-8 membered heterocycloalkyl ring, or a substituted or unsubstituted C5-C8 cycloalkane ring.

In another preferred embodiment, ring A is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted saturated 5-8 membered heterocycloalkyl ring, a substituted or unsubstituted unsaturated 5-8 membered heterocycloalkyl ring, a substituted or unsubstituted saturated C5-C8 cycloalkane ring, or a substituted or unsubstituted unsaturated C5-C8 cycloalkane ring.

In another preferred embodiment, ring A is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted saturated 5-8 membered heteroaromatic ring, a substituted or unsubstituted unsaturated 5-8 membered heteroaromatic ring, a substituted or unsubstituted saturated C5-C8 naphthenic ring, or a substituted or unsubstituted unsaturated C5-C8 naphthenic ring, wherein said substituted or unsubstituted unsaturated 5-8 membered heteroaromatic ring and said substituted or unsubstituted unsaturated C5-C8 naphthenic ring have 1 or 2 carbon-carbon double bonds in the ring.

In another preferred embodiment, ring A is

Wherein the content of the first and second substances,

each a double or single bond.

In another preferred embodiment, ring A is

Wherein, the first and the second end of the pipe are connected with each other,

is a double bond or a single bond.

In another preferred embodiment, the a ring is a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted isoindole ring, or a substituted or unsubstituted unsaturated cyclohexane ring having 1 or 2 carbon-carbon double bonds in the carbon ring.

In another preferred embodiment, in said substituted or unsubstituted indole ring and said substituted or unsubstituted isoindole ring, said substitution means that the hydrogen on the N atom of the indole ring and the isoindole ring is substituted.

In another preferred embodiment, ring A is substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Wherein Z is C, O, S or N atom, and N is 0, 1,2,3, 4 or 5.

In another preferred embodiment, said substituted or unsubstituted

The substitution means that hydrogen on the N atom of the indole ring and the isoindole ring is substituted.

In another preferred embodiment, ring A is substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Substituted or unsubstituted

Wherein Z is C, O, S or N atom, and N is 0, 1,2,3, 4 or 5.

In another preferred embodiment, Z is a C atom.

In another preferred embodiment, substituted or unsubstituted

Is substituted or unsubstituted

Wherein the 1-position, the 2-position and/or the 3-position are substituent positions.

In another preferred embodiment, substituted or unsubstituted

Is substituted or unsubstituted

Wherein position 1,2 and/or 3 is a substituent substitution position, and L1 is a site to which a carbonyl group (C = O) is attached.

In another preferred embodiment, substituted or unsubstituted

Is composed of

R12 and R13 are each independently hydrogen, halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, or a pharmaceutically acceptable salt thereof C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-to 12-membered heteroaryl, C2-C4 ester group,

In another preferred embodiment, substituted or unsubstituted

Is composed of

L1 is the site of attachment to the carbonyl group (C = O), R12 and 13 are each independently hydrogen, halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-to 12-membered heteroaryl, C2-C4 ester group,

In another preferred embodiment, R12 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio.

In another preferred embodiment, R13 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl,

In a further preferred embodiment of the present invention,

is composed of

In another preferred embodiment, ring A is substituted or unsubstituted

In another preferred embodiment, ring A is substituted or unsubstituted

In another preferred embodiment, ring A is substituted or unsubstituted

In another preferred embodiment, ring A is

L1 is the site of attachment to a carbonyl group (C = O), R12 and 13 are each independently hydrogen, halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloSubstituted C1-C6 alkylthio, C6-C12 aryl, 5-to 12-membered heteroaryl, C2-C4 ester group,

In another preferred embodiment, in the a ring, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-to 12-membered heteroaryl, C2-C4 ester group,

(C6-C20 aryl) (C1-C4 hydroxyalkyl) C = C (H) C1-C4 alkyl-, (C6-C20 aryl) (C1-C4 hydroxyalkyl) C = C (C1-C4 alkyl) C1-C4 alkyl-, (5-12 membered heteroaryl) (C1-C4 hydroxyalkyl) C = C (H) C1-C4 alkyl-, (5-12 membered heteroaryl) (C1-C4 hydroxyalkyl) C = C (C1-C4 alkyl) C1-C4 alkyl-.

In another preferred embodiment, R7, R8, R9 and R10 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl.

In another preferred embodiment, R7 and R8 are hydrogen.

In another preferred embodiment, R9 and R10 are each independently substituted or unsubstituted C1-C6 alkyl.

In another preferred embodiment, R9 and R10 are each independently isopropyl.

In another preferred embodiment, b is 1.

In another preferred embodiment, in R7, R8, R9 and R10, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl.

In another preferred embodiment, the B ring is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C3-C16 cycloalkane ring, or a substituted or unsubstituted 3-10 membered heterocycloalkyl ring.

In another preferred embodiment, ring B is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C3-C12 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocycloalkyl ring.

In another preferred embodiment, the B ring is a substituted or unsubstituted C6-C12 aromatic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C3-C8 cycloalkane ring, or a substituted or unsubstituted 3-10 membered heterocycloalkyl ring.

In another preferred embodiment, ring B is a substituted or unsubstituted C6-C12 aromatic ring, or a substituted or unsubstituted 5-12 membered heteroaromatic ring.

In another preferred embodiment, the B ring is a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted C5-C12 cycloalkane ring, a substituted or unsubstituted pyrazolone ring, or a substituted or unsubstituted uracil ring.

In another preferred embodiment, the B ring is a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring.

In another preferred embodiment, in the B ring, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydrogen, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g. -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl, carbonyl (C = O).

In another preferred embodiment, R11 is hydrogen, halogen, -CN, hydroxy, nitro, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted haloC 1-C4 alkyl (e.g., -CF 3), substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted haloC 1-C6 alkoxy, substituted or unsubstituted haloC 1-C6 alkylthio, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted 5-12 membered heteroaryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted C2-C4 ester, substituted or unsubstituted 3-10 membered heterocycloalkyl.

In another preferred embodiment, R11 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 3-10 membered heterocycloalkyl.

In another preferred embodiment, R11 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted 5-8 membered heterocycloalkyl.

In another preferred embodiment, R11 is a substituted or unsubstituted 5-8 membered heterocycloalkyl.

In another preferred embodiment, R11 is substituted or unsubstituted piperidinyl.

In another preferred embodiment, R11 is a substituted or unsubstituted piperidinyl group, and the N atom of said piperidinyl group is attached to the B ring.

In a further preferred embodiment of the method,

is composed of

In a further preferred embodiment of the method,

is composed of

In another preferred embodiment, a is 1.

In the present invention, it is understood that when a is greater than 1, each R11 is the same or different.

In the present invention, it is understood that when b is greater than 1, each of R9 and R10 is the same or different.

In another preferred embodiment, in R11, said substitution means that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: cyano, halogen, -CN, hydrogen, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester, 3-12 membered heterocycloalkyl, C3-C12 cycloalkyl.

In another preferred embodiment, the heterocycloalkyl, heteroaryl, heterocycloalkyl ring, or heteroaryl ring independently has 1 to 3 (preferably 1,2, or 3) heteroatoms selected from N, O, and S.

In another preferred embodiment, R12 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio.

In another preferred embodiment, R13 is C1-C6 alkyl, C3-C8 cycloalkyl,

In another preferred embodiment, m is 2,3, 4,5, 6,7, 8, 9 or 10.

In another preferred embodiment, m is 2,3, 4, 5.

In another preferred embodiment, m is 2 to 6, preferably 2 to 4, more preferably 2 to 3.

In the present invention, it is understood that, when m is greater than 1, the respective amino acid residues are the same or different.

In another preferred embodiment, the amino acid residue is a natural amino acid residue.

In another preferred embodiment, the amino acid residue is an L-amino acid residue.

In another preferred embodiment, the amino acids are classified according to the chemical structure of the R group, and the amino acid residue is an aliphatic amino acid residue, an aromatic amino acid residue, or a heterocyclic amino acid residue.

In another preferred embodiment, the amino acid residues have the following structure:

wherein, the 4-position and the 5-position are connecting sites, and R is the R group of amino acid.

In another preferred embodiment, the 4-position is linked to the O atom and the 5-position is linked to the carbonyl group (C = O).

In another preferred embodiment, the aliphatic amino acid residue is glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, serine residue, threonine residue, cysteine residue, methionine residue, aspartic acid residue, glutamic acid residue, asparagine, glutamine, lysine residue, arginine residue.

In another preferred embodiment, the aromatic amino acid residue is a phenylalanine residue, a tyrosine residue, or a tryptophan residue.

In another preferred embodiment, the heterocyclic amino acid residue is histidine residue or proline residue.

In another preferred embodiment, the amino acid residue is glycine residue or valine residue.

In another preferred embodiment, the individual amino acids in the polypeptide residues are the same or different.

In another preferred embodiment, the amino acid residue is glycine residue, alanine residue, valine residue, leucine residue, isoleucine residue, serine residue, threonine residue, cysteine residue, methionine residue, aspartic acid residue, glutamic acid residue, asparagine residue, glutamine residue, lysine residue, arginine residue.

In another preferred embodiment, the polypeptide residue has the formula:

In the present invention, in the structures of amino acid residues and polypeptide residues, R is an R group of amino acids, and "R" and "R group" are used interchangeably.

In another preferred embodiment, the 4-position is attached to the O atom and the 5-position is attached to the carbonyl group (C = O).

In another preferred embodiment, the R groups of each amino acid residue are the same or different in the polypeptide residue.

In another preferred embodiment, the R group is hydrogen, isopropyl, benzyl

In another preferred embodiment, the R group is hydrogen, isopropyl, methyl, benzyl, isopropyl-methyl-, (methyl) (ethyl) CH-, isopropyl, 2-cyclopentylamino, 2-methylpropyl, 2-butyl, methylthioethyl.

In another preferred embodiment, R14 and R15 are each independently hydrogen, isopropyl, methyl, benzyl, isopropyl-methyl-, (methyl) (ethyl) CH-, isopropyl, 2-cyclopentylamino, 2-methylpropyl, 2-butyl, methylthioethyl.

In another preferred embodiment, the naphthenic ring is a saturated or unsaturated naphthenic ring.

In another preferred embodiment, the unsaturated cycloalkane ring has 1 or 2 carbon-carbon double bonds in the carbon ring.

In another preferred embodiment, the cycloalkyl is a saturated or unsaturated cycloalkyl.

In another preferred embodiment, the unsaturated cycloalkyl has 1 or 2 carbon-carbon double bonds in the carbocyclic ring.

In another preferred embodiment, the heterocycloalkyl ring is a saturated or unsaturated heterocycloalkyl ring.

In another preferred embodiment, the unsaturated heterocyclic ring has 1 or 2 carbon-carbon double bonds in the ring.

In another preferred embodiment, the heterocycloalkyl group is a saturated or unsaturated heterocycloalkyl group.

In another preferred embodiment, the unsaturated heterocycloalkyl group has 1 or 2 carbon-carbon double bonds in the ring.

In another preferred embodiment, the compound of formula I is a compound of formula Ia:

wherein R1, R2, R3, R4, R5, R6, ring a and X are as defined above;

at g and k

Each independently is a double or single bond.

In another preferred embodiment, the compound of formula I is a compound of formula Ib:

wherein c is 1 or m;

r1, R2, R3, R4, R5, R6 and the A ring are as defined above, R is the R group of an L-amino acid.

It is to be understood in the context of the present invention that when c is greater than 1, the individual R groups are identical or different.

In another preferred embodiment, the compound of formula I is a compound of formula Ic:

wherein R1, R2, R3, R4, R5, R6 and A are as defined above, and R14 and R15 are each independently an R group of an L-amino acid.

In another preferred embodiment, R14 is isopropyl.

In another preferred embodiment, R15 is methyl.

In another preferred embodiment, the compound is selected from the group consisting of:

in a second aspect of the invention, there is provided a process for the preparation of a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, which process comprises:

(a) Reacting the compound of formula II with amino acid or polypeptide to produce the compound of formula I

R16 is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, said substitution being such that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl (such as-CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester group.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: (a) A compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises an anti-tumor drug.

In another preferred embodiment, the anti-tumor drug is a drug of a P-glycoprotein substrate.

In another preferred embodiment, the anti-tumor drug is a drug of a P-glycoprotein substrate which is resistant to multiple tumor cells.

In another preferred embodiment, the anti-tumor drug is selected from the group consisting of: vinorelbine, docetaxel, paclitaxel, gemcitabine, epirubicin, doxorubicin, colchicine, imatinib, topotecan, irinotecan, methotrexate, mitomycin C, mitoxantrone, actinomycin D, etoposide, teniposide, or combinations thereof.

In a fourth aspect of the invention, there is provided the use of a compound of formula I, as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect of the invention, for (I) the manufacture of a medicament for inhibiting or reversing the multidrug resistance of a tumor against an anticancer drug; (2) preparing a medicament for inhibiting the activity of P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.

In another preferred embodiment, the tumor is a P-glycoprotein high expression tumor.

In another preferred embodiment, the multidrug resistance is multidrug resistance caused by P-glycoprotein

In another preferred embodiment, the P-glycoprotein is tumor P-glycoprotein.

In another preferred embodiment, the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof.

In another preferred embodiment, the leukemia is chronic myelogenous leukemia.

In another preferred embodiment, the oral cancer is a human oral epidermoid carcinoma.

In another preferred embodiment, the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof; and/or

The anti-tumor drug is selected from the following groups: vinorelbine, docetaxel, paclitaxel, gemcitabine, epirubicin, doxorubicin, colchicine, imatinib, topotecan, irinotecan, methotrexate, mitomycin C, mitoxantrone, actinomycin D, etoposide, teniposide, or combinations thereof.

In a fifth aspect of the invention, there is provided a kit comprising:

(A) A first formulation comprising a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof;

(B) A second formulation comprising an anti-neoplastic agent; and

(D) Instructions for use.

In another preferred embodiment, the instructions specify that the first formulation and the second formulation are to be used in combination to enhance the anti-tumor activity of the anti-tumor agent.

In a sixth aspect of the invention, there is provided an active ingredient combination comprising the following components:

(1) A compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and

(2) An antitumor drug.

In a seventh aspect of the invention, there is provided the use of a kit according to the fifth aspect of the invention and/or an active ingredient combination according to the sixth aspect of the invention, in the preparation of a medicament for (i) inhibiting or reversing the multi-drug resistance of a tumour to an anti-cancer drug; (2) preparing a medicament for inhibiting P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.

In an eighth aspect of the invention, there is provided an in vitro non-therapeutic and non-diagnostic method for inhibiting tumor P-glycoprotein activity, said method comprising the steps of: contacting a compound of formula I according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, with a tumor cell in an in vitro culture system, thereby inhibiting tumor P-glycoprotein activity.

In a ninth aspect of the present invention, an in vitro non-therapeutic and non-diagnostic method for enhancing the anti-tumor activity of an anti-tumor drug, said method comprising the steps of: contacting a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention and an anti-tumor agent with tumor cells in an in vitro culture system, thereby enhancing the anti-tumor activity of the anti-tumor agent.

In a tenth aspect of the present invention, there is provided a method for preventing and/or treating tumors, said method comprising the steps of: administering to a subject suffering from a tumor a compound of formula I as described in the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and an antineoplastic agent, thereby preventing and/or treating the tumor.

In an eleventh aspect of the invention, there is provided a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

r1, R2, R3, R4, R5, R6 and the a ring are as described in the first aspect of the invention; or R1 and R3 are joined to form a 5-12 membered heteroaromatic ring and a C3-C10 cycloalkane ring;

is a double or single bond;

r16 is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C20 aryl, or substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, said substitution being such that one or more (preferably 1,2,3 or 4) hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, -CN, hydroxy, nitro, amino, C1-C6 alkyl, haloC 1-C4 alkyl (e.g., -CF 3), C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, haloC 1-C6 alkoxy, haloC 1-C6 alkylthio, C6-C12 aryl, 5-12 membered heteroaryl, C2-C4 ester;

in another preferred embodiment, R16 is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl.

In another preferred embodiment, R16 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl.

In another preferred embodiment, R16 is hydrogen or methyl.

In another preferred embodiment, the R1, R2, R3, R4, R5, R6 and A rings are as defined above; or R1 and R3 are joined to form a 5-8 membered heteroaromatic ring and a C5-C8 cycloalkane ring;

in another preferred embodiment, in said 5-12 membered heteroaromatic ring and C3-C10 cycloalkane ring, wherein cycloalkane ring is linked with

Are connected.

In another preferred embodiment, in said 5-8 membered heteroaromatic ring and C5-C8 cycloalkane ring, wherein cycloalkane ring is linked with

Are connected.

In another preferred embodiment, the compound of formula II is selected from the group consisting of:

in a twelfth aspect of the invention, there is provided a process for the preparation of a compound of formula II as described in the eleventh aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

when R16 is hydrogen, the method comprises the step (1)

(1) Under the action of a catalyst, a silver salt and a first alkali reagent, a compound of a formula C1 and a compound of a formula C2 are subjected to a carbon-hydrogen bond active reaction to generate a compound of a formula C3;

or when R16 is not hydrogen, said method comprises step (1) and step (2)

(2) Compounds of formula C3 and R ₁₆ -esterification of the halogen to form the compound of formula II.

In another preferred embodiment, in the step (1), the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer ([ Cp × RhCl) ₂ ] ₂ )。

In another preferred embodiment, in the step (1), the silver salt is silver hexafluoroantimonate (AgSbF) ₆ )。

In another preferred embodiment, in the step (1), the first alkali agent is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, or combinations thereof.

In another preferred example, in the step (1), the first alkali agent is potassium carbonate.

In another preferred embodiment, in the step (1), the reaction is carried out in the absence of a solvent and a first solvent.

In another preferred embodiment, the first solvent is selected from the group consisting of: toluene, chloroform, dichloromethane, 1, 2-dichloroethane, or combinations thereof.

In another preferred embodiment, in the step (1), the reaction temperature is 20-80 ℃, preferably 40-80 ℃, and more preferably 50-70 ℃.

In another preferred embodiment, in the step (1), the reaction time is 6 to 36 hours, preferably 8 to 24 hours, more preferably 10 to 16 hours, and most preferably 12 to 16 hours.

In another preferred embodiment, in the step (1), the molar ratio of the compound of formula C1 to the silver salt is 1:0.1-0.5.

In another preferred embodiment, in the step (1), the molar ratio of the silver salt to the first alkali agent is 1:0.5-10.

In another preferred embodiment, in the step (1), the molar ratio of the silver salt to the catalyst is 0.5 to 20, preferably 1 to 15, more preferably 1 to 10, more preferably 2 to 6:1.

in another preferred embodiment, in the step (1), the molar ratio of the catalyst to the first alkali agent is 1:2-40.

In another preferred embodiment, in the step (1), the molar ratio of the compound of formula C1 to the compound of formula C1 is 1:1-5, preferably 1:1-3, more preferably 1:1-2.

In another preferred embodiment, in the step (2), the esterification reaction is performed under a second alkaline reagent.

In another preferred embodiment, the second basic agent is selected from the group consisting of: sodium carbonate, potassium carbonate, cesium carbonate, triethanolamine (TEA), N-Diisopropylethylamine (DIEA), potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, or a combination thereof.

In another preferred example, in the step (2), the reaction temperature is room temperature.

In another preferred embodiment, in the step (2), the reaction time is 1-8h, preferably 2-5h.

In a thirteenth aspect of the invention, there is provided a compound of formula C3, or an isomer thereof, or a pharmaceutically acceptable salt thereof,

wherein R1, R2, R3, R4, R5, R6 and the A ring are as described in the first aspect of the invention; or R1 and R3 are joined to form a 5-12 membered heteroaromatic ring and a C3-C10 cycloalkane ring;

is a double bond or a single bond.

In a fourteenth aspect of the present invention, there is provided a process for the preparation of a compound of formula C3, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

In another preferred embodiment, in the step (1), the reaction temperature is 20 to 80 ℃, preferably 40 to 80 ℃, and more preferably 50 to 70 ℃.

In another preferred embodiment, in the step (1), the reaction time is 6-36h, preferably 8-24h, more preferably 10-16h, and most preferably 12-16h.

In another preferred embodiment, in step (1), the molar ratio of the compound of formula C1 to the silver salt is 1:0.1-0.5.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows the inhibitory effect of different compounds in test example 1 in combination with vinorelbine and docetaxel on KB cells.

FIG. 2 is a graph showing the inhibitory effect of different compounds in test example 1 in combination with vinorelbine and docetaxel on KBV200 cells.

FIG. 3 is a graph showing the inhibitory effect of different compounds in test example 1 in combination with vinorelbine and docetaxel on K562/ADR cells.

FIG. 4 is a Westernblotting assay for P-gp expression in test example 2, where con is a blank control without any drug added; 4g is compound 4g; VPL is verapamil.

FIG. 5 shows the result of fluorescence microscopy in the drug accumulation experiment in test example 3, wherein control is a blank control without any drug added; 4g is compound 4g.

FIG. 6 shows the result of FACS detection by flow cytometry in the drug accumulation experiment in test example 3, wherein control is a blank without any drug; 4g is compound 4g.

FIG. 7 shows the result of fluorescence microscopy in the drug efflux assay in test example 3, where control is a blank control without any drug; 4g is compound 4g.

FIG. 8 shows the results of FACS detection by flow cytometry in the drug efflux assay of test example 3, wherein control is a blank without any drug; 4g is compound 4g.

Detailed Description

The invention provides a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, which can remarkably inhibit the multidrug resistance of tumor cells to antitumor drugs, thereby remarkably enhancing the treatment of the antitumor drugs to tumors. In addition, the application also provides a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof, a compound of formula C3, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a preparation method of the compound of formula C3, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the preparation method of the compound of formula C3, or an isomer thereof, or a pharmaceutically acceptable salt thereof has the advantages of mild conditions and simple and convenient operation, successfully synthesizes a novel allyl alcohol skeleton for the first time, the skeleton widely exists in natural products, and the skeleton cannot be simply, conveniently and quickly obtained by other methods before. On the basis of this, the inventors have completed the present invention.

Term(s)

As used herein, the terms "comprising," "including," "containing," and "containing" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of 8230; \8230; composition;" consisting essentially of 8230; \8230; composition 8230).

It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to produce chemically stable compounds that may be synthesized by techniques known in the art as well as the methods set forth below. If substituted with more than one substituent group, it is understood that the multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

As used herein, the term "substituted" or "substituted" is a radical in which a hydrogen atom on the radical is replaced with a non-hydrogen atom, but which needs to satisfy its valence requirements and which results from the substitution into a chemically stable compound, i.e., a compound which does not spontaneously undergo a transformation such as cyclization, elimination, etc.

As used herein,' A "

"denotes the attachment site of a group.

As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When an alkyl group is preceded by a carbon atom number limitation (e.g., C1-C10 alkyl) means that the alkyl group contains 1-10 carbon atoms, for example, C1-C4 alkyl means an alkyl group containing 1-4 carbon atoms, representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

In the present invention, the term "halogen" means F, cl, br or I.

In the present invention, the term "halo" means substituted by halogen.

As used herein, the term "haloalkyl" means an alkyl group wherein one or more (preferably 1,2,3 or 4) hydrogens are replaced with a halogen, said alkyl and halogen being as defined above, when the alkyl group previously has a carbon atom number limitation (e.g., haloC 1-C10 alkyl) meaning that said alkyl group contains 1-10 carbon atoms, for example, haloC 1-C4 alkyl means haloalkyl containing 1-4 carbon atoms, representative examples include, but are not limited to, -CF ₃ 、-CHF ₂ Monofluoroisopropyl, difluorobutyl, or the like.

As used herein, the term "hydroxyalkyl" means that one or more (preferably 1,2,3, or 4) hydrogens of an alkyl group, as defined above, are replaced with a hydroxyl group (-OH), and when an alkyl group previously has a carbon number limitation (e.g., haloc 1-C4 alkyl) means that the alkyl group contains 1 to 10 carbon atoms, for example, C1-C4 hydroxyalkyl means hydroxyalkyl containing 1 to 4 carbon atoms, representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl, cyanopropyl, or the like.

As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic (fused, bridged, or spiro) ring system radical having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g., C3-C8), it is intended that the cycloalkyl group has 3 to 8 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like. "spirocycloalkyl" refers to a bicyclic or polycyclic group having a single ring with a common carbon atom (called the spiro atom) between them, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused cyclic alkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly connected, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Representative examples of cycloalkyl groups include, but are not limited to:

as used herein, the term "cycloalkane ring" refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring having a saturated or partially saturated unit. When a certain cycloalkane ring is preceded by a carbon number limitation (e.g., C3-C8), it is meant that the cycloalkane ring has from 3 to 8 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkane ring" refers to a saturated or partially saturated monocyclic or bicyclic alkane ring having from 3 to 8 ring carbon atoms and includes cyclopropane, cyclobutane, cyclopentane, cycloheptane, or similar groups. "spirocycloalkane ring" refers to bicyclic or polycyclic rings which share a carbon atom (called a spiro atom) between single rings, and which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. "fused cycloalkane ring" refers to an all-carbon bi-or polycyclic ring in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. "bridged cycloalkane ring" refers to all-carbon polycyclic rings in which any two rings share two carbon atoms not directly attached, and these may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Representative examples of cycloalkyl groups include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cycloheptane, or the like.

The term "alkoxy" refers to the group R-O-, wherein R is alkyl, and alkyl is as defined herein, when alkoxy is previously defined by the number of carbon atoms, e.g., C ₁ -C ₆ Alkoxy means that the alkyl group in the alkoxy group has 1 to 6 carbon atoms. Representative examples of alkoxy groups include (but are not limited to): methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.

As used herein, the term "alkylthio" refers to the group R-O-wherein R is alkyl, and alkyl is as defined herein, whenAlkylthio radicals having a carbon number limitation in front thereof, e.g. C ₁ -C ₆ Alkylthio means an alkyl group in the alkoxy group having 1 to 6 carbon atoms. Representative examples of alkylthio groups include (but are not limited to): methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, or the like.

As used herein, the term "haloalkoxy" refers to haloalkyl-O-, said haloalkyls being as defined above, e.g., haloC 1-C4 alkoxy refers to haloalkoxy groups containing 1-4 carbon atoms, representative examples including, but not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or the like.

As used herein, the term "haloalkylthio" refers to haloalkyl-S-, said haloalkyls are as defined above, e.g., halo C1-C4 alkylthio refers to haloalkylthio having 1-4 carbon atoms, representative examples include, but are not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or the like.

The term "heterocycloalkyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring systems) in which at least one heteroatom is present in the ring having at least one carbon atom. Where the heterocycloalkyl group is preceded by a finite number of elements, this refers to the number of ring atoms in the heterocycloalkyl group, for example, 3-12 membered heterocycloalkyl refers to a heterocycloalkyl group having 3-12 ring atoms, each heteroatom-containing heterocycle may carry one or more (e.g., 1,2,3, or 4) heteroatoms selected from nitrogen atoms, oxygen atoms, or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may be quaternized. The heterocycloalkyl group may be attached to the residue of any heteroatom or carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidyl, tetrahydropyranyl, morphinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocycloalkyl includes spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.

The term "heterocycloalkyl ring" refers to a fully saturated or partially unsaturated ring (including but not limited to, for example, a 4-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring system) in which at least one heteroatom is present in the ring having at least one carbon atom. Where the heterocycloalkyl ring is preceded by a finite number of members, this is the number of ring atoms in the heterocycloalkyl ring, for example a 3-12 membered heterocycloalkyl ring is a heterocycloalkyl ring having 3-12 ring atoms, each heteroatom-containing heterocycle may carry one or more (e.g. 1,2,3 or 4) heteroatoms selected from nitrogen, oxygen or sulfur atoms, which may be oxidized or quaternized. The heterocycloalkyl ring may be attached to any heteroatom or residue of a carbon atom of the ring or ring system molecule. Typical monocyclic heterocycloalkyl rings include, but are not limited to, azetidine rings, pyrrolidine rings, oxetane rings, pyrazoline rings, imidazoline rings, imidazolidine rings, oxazolidine rings, isoxazolidine rings, thiazolidine rings, isothiazolidine rings, tetrahydrofuran rings, piperidine rings, piperazine rings, 2-oxopiperazine rings, 2-oxopiperidine rings, 2-oxopyrrolidine rings, hexahydroazepine rings, 4-piperidone rings, tetrahydropyran rings, morpholine rings, thiomorpholine sulfoxide rings, thiomorpholine sulfone rings, 1, 3-dioxane rings, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocycloalkyl rings include spiro, fused and bridged heterocyclic rings; wherein the heterocyclic rings of the spiro, fused and bridged rings are optionally linked to other groups by single bonds or further fused to other cycloalkane, heterocyclic, aromatic and heteroaromatic rings by any two or more atoms in the ring.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon group, when an aryl group has a carbon atom number limitation as in C6-C12, it means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with the conjugated pi-electron system. Representative examples of aryl groups include, but are not limited to:

the term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., rings which share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and is an aromatic cyclic hydrocarbon compound, when the aromatic ring has a carbon number limitation as defined above, e.g., C6-C20 aryl, and refers to said aromatic ring having 6-20 ring carbon atoms, such as a benzene ring and a naphthalene ring. The aromatic ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with the conjugated pi-electron system. Representative examples of aryl groups include, but are not limited to: benzene ring and naphthalene ring.

The term "heteroaryl" refers to an aromatic heterocyclic group having one to more (preferably 1,2,3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and each heteroatom-containing heterocycle may carry one more (e.g., 1,2,3, 4) heteroatoms each independently selected from the group consisting of: oxygen, sulfur and nitrogen. When a heteroaryl group is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl group, for example 5-12 membered heteroaryl refers to heteroaryl groups having 5-12 ring atoms, representative examples include, but are not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, and the like.

The term "heteroaromatic ring" refers to an aromatic heterocyclic ring having one to more (preferably 1,2,3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) fused together or covalently linked, and each heteroatom-containing heterocyclic ring may carry one or more (e.g., 1,2,3, 4) heteroatoms each independently selected from the group consisting of: oxygen, sulfur and nitrogen. When the heteroaryl ring is preceded by a number of members, this refers to the number of ring atoms of the heteroaryl ring, for example a 5-20 membered heteroaryl ring refers to a heteroaryl ring having 5-20 ring atoms, representative examples include, but are not limited to: pyrrole rings, pyrazole rings, imidazole rings, oxazole rings, isoxazole rings, thiazole rings, thiadiazole rings, isothiazole rings, furan rings, pyridine rings, pyrazine rings, pyrimidine rings, pyridazine rings, triazine rings, triazole rings, tetrazole rings, and the like.

<xnotran> , "" R-CO-O- -CO-O-R , R , , "C </xnotran> ₂ by-C4 ester group "is meant C ₁ -C ₃ Radicals of alkyl-CO-O-structure or-CO-O-C ₁ -C ₃ Representative examples of alkyl structures, ester groups include (but are not limited to): CH (CH) ₃ COO-、C ₂ H ₅ COO-、C ₃ H ₈ COO-、(CH ₃ ) ₂ CHCOO-、-COOCH ₃ 、-COOC ₂ H ₅ 、-COOC ₃ H ₈ Or the like.

As used herein, the term "amino", alone or as part of another substituent, denotes — NH2.

As used herein, the term "nitro", alone or as part of another substituent, denotes — NO2.

As used herein, the term "cyano", alone or as part of another substituent, denotes a-CN group

As used herein, the term "hydroxy", alone or as part of another substituent, denotes — OH.

As used herein, "R" refers to a group of atoms ₁ "," R1 "and" R ¹ "has the same meaning as" and can be substituted for "another, and other similar definitions have the same meaning.

As used herein, the term "amino acid residue" refers to an amino acid lacking a hydrogen on the amino group and a hydroxyl group on the carboxyl group, and the group formed by the amino group lacking a hydrogen and the carboxyl group lacking a hydroxyl group is capable of participating in the formation of a peptide bond, e.g., L-glycine residue-NH-CH 2-C (O) -.

In another preferred embodiment, in the amino acid residue, the carboxyl group loses one hydroxyl group to form C (O) to be connected with N atom.

As used herein, the term "amino acid residue" refers to an amino acid lacking a hydrogen atom from the amino group and lacking a hydroxyl group from the carboxyl group. In amino acid residues, groups formed after the amino group has lost one hydrogen and the carboxyl group has lost one hydroxyl group are able to participate in the formation of peptide bonds. Typically, an amino acid residue (e.g., an L-amino acid residue) has the formula (-NH-CH (R) -C (O) -):

wherein, the 4-position and the 5-position are connecting sites, and R is the R group of amino acid. In a preferred embodiment, in said compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, the carboxyl group of said amino acid residue is deprived of a hydroxyl group to form a C (O) linkage to an O atom, i.e. the amino acid residue is linked to an O atom at position 4 and to a carbonyl group (C = O) at position 5.

As used herein, the term "polypeptide residue" refers to a plurality of amino acid residues (e.g., m amino acid residues, m being a positive integer from 2 to 10) linked by peptide bonds (-NH-C (O) -), typically the polypeptide residue has the formula:

wherein, the 4-position and the 5-position are connecting sites, R is the R group of amino acid, and m is a positive integer of 2-10. In a preferred embodiment, in said compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, the polypeptide residue is attached at position 4 to the O atom and at position 5 to the carbonyl group (C = O). It will be appreciated that in the polypeptide residues described, the R groups of each amino acid residue may be the same or different. For example, the polypeptide residue is formed by m amino acid residues, m is a positive integer of 2 to 10, and the R groups of the respective amino acid residues may be the same or different.

In this specification, it is to be construed that all substituents are unsubstituted, unless explicitly described as "substituted" herein. The term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

A compound of formula I

As used herein, the terms "compound of formula I of the present invention", "compound of formula I", and the like are used interchangeably to refer to a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, with the understanding that the term also includes mixtures of the above components:

in particular, the compound of formula I is as described above in the first aspect of the invention.

In a preferred embodiment, the compound of formula I is selected from the group consisting of:

typically, the compound of formula I is selected from the group consisting of:

a compound of formula II

As used herein, the terms "compound of formula II of the present invention", "compound of formula II", and the like are used interchangeably to refer to a compound of formula II, or an isomer thereof, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components;

in particular, the compound of formula II is as described above in the eleventh aspect of the invention.

The present invention also provides a process for the preparation of a compound of formula II of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, said process comprising the steps of:

when R16 is hydrogen, the method comprises the step (1)

or when R16 is not hydrogen, said method comprises step (1) and step (2)

In another preferred example, in the step (1), the molar ratio of the silver salt to the catalyst is from 0.5 to 20, preferably from 1 to 15, more preferably from 1 to 10, more preferably from 2 to 6:1.

In another preferred example, in the step (2), the temperature of the reaction is room temperature.

In the preparation method of the compound shown in the formula II, the methodological conditions are mild, the operation is simple and convenient, a novel allyl alcohol skeleton is successfully synthesized for the first time in one step, and the skeleton is widely existed in natural products. Heretofore, such skeletons have not been readily and rapidly obtained by other methods.

Use of

The invention provides a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a use of the pharmaceutical composition of the invention, which is used for (I) preparing a medicament for inhibiting or reversing the multidrug resistance of tumors to anticancer drugs; (2) preparing a medicament for inhibiting the activity of P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.

In another preferred embodiment, the P-glycoprotein is tumor P-glycoprotein.

In another preferred embodiment, the leukemia is chronic myelogenous leukemia.

In another preferred embodiment, the oral cancer is human oral epidermoid carcinoma.

Compositions and methods of administration

The present invention provides a method for (i) inhibiting or reversing the multidrug resistance of tumors to anticancer drugs; (2) drugs that inhibit the activity of P-glycoprotein; and/or (3) preparing a medicament for enhancing the anti-tumor activity of the anti-tumor medicament.

Typically, the composition is a pharmaceutical composition comprising a compound of formula I as described herein, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In the compositions of the present invention, the amount of the compound of formula I is a therapeutically effective amount, wherein "therapeutically effective amount" refers to an amount that is functional or active and acceptable to humans and/or animals. It will be understood by those skilled in the art that the "therapeutically effective amount" may vary depending on the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs.

In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.

Representative include (but are not limited to): tablet, injection, infusion solution, paste, gel, solution, microsphere, and pellicle.

The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers which are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.

It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.

Typically, liquid dosage forms may contain, in addition to the active pharmaceutical ingredient, inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents and the like

The pharmaceutical preparation should be compatible with the mode of administration. The agents of the invention may also be used with (including before, during or after) other co-therapeutic agents. In using the pharmaceutical composition or formulation, a safe and effective amount of the drug, typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg body weight, preferably from about 10 micrograms/kg body weight to about 1 mg/kg body weight, is administered to a subject in need thereof (e.g., a human or non-human mammal). Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The present invention also provides a kit comprising:

(A) A first formulation comprising a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, as described herein;

(B) A second formulation comprising an anti-neoplastic agent; and

(D) Instructions for use.

The invention also provides an active ingredient combination, which comprises the following components:

(1) The compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and

(2) An antitumor drug.

In another preferred embodiment, at least one of the active ingredients in the active ingredient combination is independent.

In a preferred embodiment, the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof; and/or

The main advantages of the invention include:

(a) The invention provides a compound of formula I which has a novel structure and excellent antitumor activity of an antitumor drug.

(d) The compound of the formula I has good pharmacy.

(e) The invention also provides a compound of formula II and a preparation method thereof, and the preparation method of the compound of formula II has mild condition and simple operation, successfully synthesizes a novel allyl alcohol skeleton for the first time in one step, and the skeleton is widely existed in natural products. Heretofore, such skeletons have not been readily and quickly obtained by any of the other methods.

The preparation of the polysubstituted compound of the formula II is realized in one step for the first time, and the polysubstituted compound of the formula II has the characteristics of high atomic benefit, economic steps, easily available raw materials and the like.

Preparation examples:

the invention is further described below with reference to the preparation examples, without restricting the invention.

Process for preparing compounds ¹ H-NMR spectroscopic data measurements were determined using a Varian Mercury-300MHz or Varian Mercury-400MHz nuclear magnetic resonance, a Mass Spectrometry EI-MS using a Finnigan MAT 95 mass spectrometer, and an ESI-MS using a Finnigan LCQ Deca mass spectrometer. Flash column chromatography was performed on silica H (10-40. Mu.M). Reagent Purification reference to Purification of laboratory Chemicals; d.d.perrin; W.L.F.Armarego and D.R.Perrin Eds., pergamon Press: oxifond, 1980.

The reagents and methods employed in the present invention and the like are well known in the art unless otherwise specified.

Example 1 methyl (Z) -2- (4-hydroxy-3-phenyl-2-buten-1-yl) -6-methylbenzoate (3 aa)

To a 10mL stoppered tube was added o-methylbenzoic acid (13.6 mg, 0.1mmol), 4-phenyl-4-vinyl-1, 3-dioxolan-2-one (28.5mg, 0.15mmol), [ Cp. RhCl ₂ ] ₂ (3.1mg, 5 mol%), silver hexafluoroantimonate (6.8mg, 20mol%), potassium carbonate (6.9mg, 0.05mmol), and the reaction is carried out at 60 ℃ for 12 hours. Methyl iodide (42.6 mg,0.3 mmol), potassium carbonate (41.4 mg,0.3 mmol) and 1mL DMF were then added and reacted at room temperature for 3h. After the reaction was completed, a saturated NaCl solution was added, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and then the organic phase was concentrated and separated by silica gel column (petroleum ether: ethyl acetate = 3.

¹ H NMR(400MHz,CDCl ₃ ):δ7.52–7.48(m,2H),7.37–7.32(m,2H),7.30(d,J＝7.5Hz,1H),7.26(d,J＝7.0Hz,1H),7.14(dd,J＝9.5,7.5Hz,2H),5.94(t,J＝7.4Hz,1H),4.65(d,J＝4.7Hz,2H),3.86(s,3H),3.71(d,J＝7.3Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.87,140.70,139.46,137.70,135.59,133.39,129.87,129.49,128.54,128.45,127.27,127.16,126.32,59.56,52.25,33.11,19.86

HRMS(ESI)calcd.for C ₁₉ H ₂₀ NaO ₃ [M+Na ⁺ ]:319.1305,found:319.1312.

Example 2 (Z) -methyl 2- (4-hydroxy-3-phenyl-2-buten-1-yl) -5-methylbenzoate (3 ba)

The synthesis of compound 3ba was as described for compound 3aa except that 3-methylbenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one were used as starting materials to give a pale yellow oily liquid, 71%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.76(d,J＝1.8Hz,1H),7.56–7.46(m,2H),7.33(tt,J＝6.8,0.9Hz,3H),7.29–7.22(m,2H),5.90(t,J＝7.3Hz,1H),4.69(s,2H),4.00(d,J＝7.2Hz,2H),3.88(s,3H),2.39(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ168.26,141.18,139.26,138.96,136.17,133.29,131.37,131.13,130.42,129.10,128.36,127.05,126.28,59.86,52.20,33.41,20.85.

HRMS(ESI)calcd.for C ₁₉ H ₂₁ O ₃ [M+H ⁺ ]:297.1485,found:297.1481.

EXAMPLE 3 methyl (Z) -6- (4-hydroxy-3-phenyl-2-buten-1-yl) -2-methoxybenzoate (3 ca)

The synthesis method of the compound 3ca refers to the compound 3aa, and is different from the method in that 2-methoxybenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain a light yellow oily liquid, wherein the light yellow oily liquid is 64 percent.

¹ H NMR(400MHz,CDCl ₃ ):δ7.54–7.43(m,2H),7.37–7.30(m,3H),7.30–7.23(m,1H),6.92(d,J＝7.7Hz,1H),6.85(d,J＝8.3Hz,1H),5.94(t,J＝7.4Hz,1H),4.64(s,2H),3.86(s,3H),3.85(s,3H),3.67(d,J＝7.4Hz,2H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.31,156.83,140.67,139.63,139.14,130.91,129.07,128.43,127.28,126.34,123.26,121.84,109.40,59.50,55.99,52.56,32.71.

HRMS(ESI)calcd.for C ₁₉ H ₂₀ NaO ₄ [M+Na ⁺ ]:335.1254,found:335.1251.

Example 4 methyl (Z) -6- (4-hydroxy-3-phenyl-2-buten-1-yl) -2-phenylbenzoate (3 da)

Synthesis of Compound 3da see Compound 3aa, except starting with 2-phenylbenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one to give a pale yellow oily liquid, 49%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.52–7.48(m,2H),7.46(d,J＝7.7Hz,1H),7.44–7.39(m,2H),7.40–7.37(m,2H),7.37–7.29(m,5H),7.29–7.24(m,1H),5.95(t,J＝7.4Hz,1H),4.67(s,2H),3.82(d,J＝7.4Hz,2H),3.44(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.93,140.92,140.79,140.72,139.64,138.22,132.66,130.03,129.17,128.80,128.42,128.35,128.15,128.12,127.46,127.27,126.31,59.54,52.23,33.22.

HRMS(ESI)calcd.for C ₂₄ H ₂₂ NaO ₃ [M+Na ⁺ ]:381.1461,found:381.1465.

Example 5 (Z) -methyl 6- (4-hydroxy-3-phenyl-2-buten-1-yl) -2-bromobenzoate (3 ea)

The synthesis method of the compound 3ea refers to the compound 3aa, except that 2-bromobenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain pale yellow oily liquid, 62%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.52–7.46(m,3H),7.39–7.33(m,2H),7.31–7.27(m,2H),7.26(d,J＝7.5Hz,1H),5.91(t,J＝7.4Hz,1H),4.64(s,2H),3.90(s,3H),3.70(d,J＝7.5Hz,2H).

¹³ C NMR(101MHz,CDCl ₃ ):δ168.77,140.39,140.21,139.65,135.50,130.96,130.85,128.52,128.48,128.29,127.48,126.35,119.79,59.50,52.81,33.03.

HRMS(ESI)calcd.for C ₁₈ H ₁₇ NaO ₃ [M+Na ⁺ ]:383.0253,found:383.0264.

Example 6 methyl (Z) -2, 6-bis (4-hydroxy-3-phenyl-2-buten-1-yl) -4-methylbenzoate (3 fa)

The synthesis of compound 3fa was described in compound 3aa, except that 4-methylbenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one were used as starting materials to give a pale yellow oily liquid, 68%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.51–7.47(m,4H),7.39–7.32(m,4H),7.30–7.26(m,2H),7.02(s,2H),5.94(t,J＝7.3Hz,2H),4.65(s,4H),3.81(s,3H),3.69(d,J＝7.3Hz,4H),2.36(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ171.11,140.61,140.47,139.50,138.34,130.20,129.54,128.79,128.50,127.33,126.34,59.61,52.53,33.07,21.33.

HRMS(ESI)calcd.for C ₂₉ H ₃₀ NaO ₄ [M+Na ⁺ ]:465.2036,found:465.2030.

Example 7 methyl (Z) -2, 6-bis (4-hydroxy-3-phenyl-2-buten-1-yl) -3-methoxybenzoate (3 ga)

The synthesis of compound 3ga is described in compound 3aa, except that 3-methoxybenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as starting materials to give a pale yellow oily liquid, 44%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.51–7.44(m,4H),7.38–7.34(m,2H),7.34–7.30(m,2H),7.30–7.28(m,1H),7.27–7.24(m,1H),7.18(d,J＝8.4Hz,1H),6.93(d,J＝8.5Hz,1H),5.93(dt,J＝13.2,7.4Hz,2H),4.65(d,J＝7.9Hz,4H),3.87(d,J＝2.8Hz,6H),3.65(t,J＝6.9Hz,4H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.60,155.89,141.15,140.65,139.41,138.88,134.60,129.71,129.64,129.48,128.81,128.50,128.37,127.31,127.07,126.33,126.24,126.00,112.32,59.87,59.55,55.94,52.58,32.33,27.25.

HRMS(ESI)calcd.for C ₂₉ H ₃₀ NaO ₅ [M+Na ⁺ ]:481.1985,found:481.1977.

Example 8 methyl (Z) -2, 6-bis (4-hydroxy-3-phenyl-2-buten-1-yl) -3, 5-difluorobenzoate (3 ha)

The synthesis of compound 3ha is described in compound 3aa, except that 3, 5-difluorobenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as starting materials to give a pale yellow oily liquid, 71%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.49–7.43(m,4H),7.38–7.32(m,4H),7.30–7.27(m,2H),6.95(t,J＝9.5Hz,1H),5.82(t,J＝7.2Hz,2H),4.66(s,4H),3.88(s,3H),3.67(d,J＝7.3Hz,4H).

¹³ C NMR(101MHz,CDCl ₃ ):δ168.59,δ160.64(d,J＝12.7Hz),158.18(d,J＝12.9Hz),140.42,139.85,135.96(t,J＝5.2Hz),128.51,127.77,127.44,126.37,121.49(d,J＝7.7Hz),121.35(d,J＝7.8Hz),105.36(t,J＝26.7Hz),59.52,53.07,25.58.

HRMS(ESI)calcd.for C ₂₈ H ₂₇ F ₂ O ₄ [M+H ⁺ ]:465.1872,found:465.1872.

Example 9 (Z) -5- (4-hydroxy-3-phenyl-2-buten-1-yl) benzo [ d ] [1,3] dioxo-4-carboxylic acid methyl ester (3 ia)

The synthesis of compound 3ia was as described for compound 3aa, except that 1, 3-benzodioxole-4-carboxylic acid and 4-phenyl-4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 52%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.52–7.46(m,2H),7.38–7.30(m,2H),7.29–7.24(m,1H),6.88(d,J＝7.9Hz,1H),6.80(d,J＝8.0Hz,1H),6.06(s,2H),5.85(t,J＝7.2Hz,1H),4.65(d,J＝2.6Hz,2H),3.89(s,3H),3.85(d,J＝7.2Hz,2H).

¹³ C NMR(101MHz,CDCl ₃ ):δ166.31,148.11,146.85,140.97,139.25,134.13,130.24,128.41,127.16,126.31,123.32,113.41,110.97,101.78,59.70,52.41,33.06.

HRMS(ESI)calcd.for C ₁₉ H ₁₈ NaO ₅ [M+Na ⁺ ]:349.1046,found:349.1056.

Example 10 methyl (Z) -2- (4-hydroxy-3-phenyl-2-buten-1-yl) naphthoate (3 ja)

The synthesis of compound 3ja was as described for compound 3aa except that 1-naphthoic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one were used as starting materials to give a pale yellow oily liquid, 54%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.90(d,J＝8.5Hz,1H),7.89–7.80(m,2H),7.56(ddd,J＝8.4,6.8,1.6Hz,1H),7.54–7.48(m,3H),7.45(d,J＝8.5Hz,1H),7.37–7.31(m,2H),7.30–7.27(m,1H),6.03(t,J＝7.4Hz,1H),4.72(s,2H),4.03(s,3H),3.88(d,J＝7.5Hz,2H).

¹³ CNMR(101MHz,CDCl ₃ ):δ170.48,140.65,139.67,135.93,132.06,130.42,130.19,130.04,129.22,128.49,128.16,127.52,127.35,127.26,126.38,125.96,124.68,59.66,52.61,33.41.

HRMS(ESI)calcd.for C ₂₂ H ₂₀ NaO ₃ [M+Na ⁺ ]:355.1305,found:355.1312.

Example 12 (Z) -3- (4-hydroxy-3-phenyl-2-buten-1-yl) -N-methylindole-2-carboxylic acid methyl ester (3 la)

The synthesis of compound 3la is described in compound 3aa, except that 1-methylindole-2-carboxylic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain a pale yellow oily liquid, 62%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.78(dt,J＝8.1,1.0Hz,1H),7.49–7.44(m,2H),7.41(qd,J＝3.5,3.0,1.4Hz,2H),7.34–7.28(m,2H),7.26–7.22(m,1H),7.22–7.18(m,1H),6.00(t,J＝7.3Hz,1H),4.82(s,2H),4.15(d,J＝7.2Hz,2H),4.03(s,3H),3.99(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ163.08,141.05,138.86,138.23,130.36,128.95,128.38,127.04,126.28,125.66,124.79,123.47,120.62,120.21,110.37,59.89,51.78,32.41,24.87.

HRMS(ESI)calcd.for C ₂₁ H ₂₁ NNaO ₃ [M+Na ⁺ ]:358.1414,found:358.1405.

Example 13 methyl (Z) -2- (4-hydroxy-3-phenyl-2-buten-1-yl) -N-methylindole-3-carboxylate (3 ma)

See compound 3aa for the synthesis of compound 3ma, except that 1-methylindole-3-carboxylic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one were used as starting materials to give a pale yellow oily liquid, 37%.

¹ H NMR(400MHz,CDCl ₃ )δ8.15–8.07(m,1H),7.51–7.46(m,2H),7.39–7.35(m,1H),7.33(td,J＝5.5,4.9,2.2Hz,2H),7.31–7.28(m,2H),7.26(td,J＝5.3,4.9,2.4Hz,1H),5.78(t,J＝7.2Hz,1H),4.76(s,2H),4.32(d,J＝7.3Hz,2H),3.97(s,3H),3.85(s,3H).

¹³ C NMR(101MHz,CDCl ₃ )δ166.77,146.78,141.08,141.00,136.71,128.66,128.41,127.37,126.32,126.19,124.96,122.56,122.06,121.75,109.42,59.84,51.12,29.90,25.25.

HRMS(ESI)calcd.for C ₂₁ H ₂₁ NNaO ₃ [M+Na ⁺ ]:358.1414,found:358.142.

Example 14 methyl (Z) -2- (4-hydroxy-3-phenyl-2-buten-1-yl) cyclohexyl-1-en-1-carboxylate (3 na)

The synthesis method of the compound 3na refers to the compound 3aa, and is different from the method that the cyclohexene carboxylic acid and the 4-phenyl-4-vinyl-1, 3-dioxolane-2-ketone are used as raw materials to obtain light yellow oily liquid, wherein the light yellow oily liquid is 76%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.55–7.50(m,2H),7.37–7.31(m,2H),7.28–7.23(m,1H),5.84(t,J＝7.4Hz,1H),4.61(s,2H),3.73(s,3H),3.43(d,J＝7.4Hz,2H),2.35–2.25(m,4H),1.65(p,J＝3.3Hz,4H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.10,148.58,141.42,139.60,128.41,128.38,127.04,126.23,125.34,59.85,51.51,34.84,32.01,26.50,22.22,22.20.

HRMS(ESI)calcd.for C ₁₈ H ₂₂ NaO ₃ [M+Na ⁺ ]:309.1461,found:309.1461.

Example 15 (Z) -5- (4-hydroxy-3-phenyl-2-buten-1-yl) -3, 4-dihydro-2H-pyran-6-carboxylic acid methyl ester (3 oa)

The synthesis of compound 3oa is shown in compound 3aa, except that 5, 6-dihydro-4H-pyran-2-carboxylic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as starting materials to give a pale yellow oily liquid, 48%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.54–7.47(m,2H),7.38–7.32(m,2H),7.29–7.25(m,1H),5.84(t,J＝7.4Hz,1H),4.62(s,2H),4.12–4.00(m,2H),3.82(s,3H),3.47(d,J＝7.4Hz,2H),2.31(t,J＝6.5Hz,2H),1.97–1.89(m,2H).

¹³ C NMR(101MHz,CDCl ₃ ):δ163.78,141.24,139.90,139.64,128.42,128.31,127.13,126.25,124.79,65.99,59.81,52.14,32.06,27.11,22.13.

HRMS(ESI)calcd.for C ₁₇ H ₂₀ NaO ₄ [M+Na ⁺ ]:311.1254,found:311.1251.

Example 16 methyl (Z) -3- (4-hydroxy-3-phenyl-2-buten-1-yl) cyclopentyl-1-ene-1-carboxylate (3 pa)

The synthesis method of the compound 3pa refers to the compound 3aa, except that cyclopentenecarboxylic acid and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain a pale yellow oily liquid, 47%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.55–7.47(m,2H),7.39–7.32(m,2H),7.28(d,J＝4.3Hz,1H),5.86(t,J＝7.8Hz,1H),4.64(s,2H),3.76(s,3H),3.62(dt,J＝7.8,1.1Hz,2H),2.64(qd,J＝8.1,7.6,3.9Hz,4H),1.92–1.84(m,2H).

¹³ C NMR(101MHz,CDCl ₃ ):δ166.71,157.71,141.37,140.33,128.40,127.68,127.15,126.82,126.23,59.81,51.30,38.40,33.40,29.70,21.41.

HRMS(ESI)calcd.for C ₁₇ H ₂₁ O ₃ [M+H ⁺ ]:273.1483,found:273.1492.

Example 17 methyl (S, Z) -2-ethoxy-6- (4-hydroxy-3-phenyl-2-buten-1-yl) -4- (2- ((3-methyl-1-phenylbutyl) amino) -2-acetyl) benzoate (3 qa)

The synthesis method of the compound 3qa refers to the compound 3aa, and the difference is that repaglinide and 4-phenyl-4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain light yellow oily liquid, 38%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.53–7.43(m,2H),7.36–7.30(m,2H),7.29–7.23(m,2H),7.23–7.17(m,2H),7.10(dd,J＝7.5,1.5Hz,1H),7.05(ddd,J＝7.8,6.1,2.2Hz,1H),6.75(dd,J＝16.6,1.3Hz,3H),5.88(t,J＝7.4Hz,1H),5.40(td,J＝8.6,6.5Hz,1H),4.61(d,J＝3.0Hz,2H),4.06–3.90(m,2H),3.83(s,3H),3.63(d,J＝7.4Hz,2H),3.52(s,2H),2.96(d,J＝11.5Hz,2H),2.64(d,J＝10.1Hz,2H),2.32(s,1H),1.73(dd,J＝7.5,3.3Hz,3H),1.66–1.50(m,5H),1.43(dt,J＝13.3,6.6Hz,1H),1.35(t,J＝7.0Hz,3H),0.93(d,J＝6.5Hz,6H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.27,168.98,156.73,152.53,140.66,139.78,139.59,138.70,138.40,128.72,128.42,127.91,127.72,127.28,126.33,125.06,122.81,122.56,122.44,111.26,64.46,59.47,52.41,46.64,44.18,32.76,26.75,25.37,22.77,22.55,14.65.

HRMS(ESI)calcd.for C ₃₈ H ₄₉ N ₂ O ₅ [M+H ⁺ ]:613.3636,found:613.3621.

Example 18 methyl (Z) -4- (2- (((1r, 3R,5S, 7r) -3, 5-dimethyladamantan-1-yl) amino) -2-acetyl) -2-ethoxy-6- (4-hydroxy-3-phenyl-2-buten-1-yl) benzoate (3 ra)

See compound 3aa for the synthesis of compound 3ra, except that 4- (2- (((1r, 3r,5s, 7r) -3, 5-dimethyladamantan-1-yl) amino) -2-acetyl) -2-ethoxybenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 32%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.52–7.46(m,2H),7.33(t,J＝7.4Hz,2H),7.27(s,1H),6.76(d,J＝1.3Hz,1H),6.74(d,J＝1.3Hz,1H),5.91(t,J＝7.4Hz,1H),5.17(s,1H),4.63(s,2H),4.07(q,J＝7.0Hz,2H),3.84(s,3H),3.65(d,J＝7.4Hz,2H),3.44(s,2H),2.11(q,J＝3.2Hz,1H),1.79–1.75(m,2H),1.63–1.52(m,4H),1.39(t,J＝6.9Hz,3H),1.37–1.32(m,2H),1.28(q,J＝7.0Hz,4H),1.13(dt,J＝3.3,1.8Hz,2H),0.83(s,6H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.33,169.27,156.71,140.64,139.78,139.67,138.62,128.81,128.45,127.31,126.31,122.54,122.37,111.30,77.36,77.24,77.04,76.72,64.52,59.48,53.71,52.48,50.49,47.43,45.09,42.55,39.98,32.73,32.37,30.06,30.00,29.71,14.68.

HRMS(ESI)calcd.for C ₃₄ H ₄₄ NO ₅ [M+H ⁺ ]:546.3214,found:546.3206.

Example 19 methyl (Z) -4- (2- ((1- (3- (2-cyanobenzyl) -1-methyl-2, 6-dioxohexahydropyrimidin-4-yl) piperidin-4-yl) amino) -2-acetyl) -2-ethoxy-6- (4-hydroxy-3-phenyl-2-buten-1-yl) benzoate (3 sa)

The synthesis of compound 3sa was as described for compound 3aa, except that 4- (2- ((1- (3- (2-cyanobenzyl) -1-methyl-2, 6-dioxohexahydropyrimidin-4-yl) piperidin-4-yl) amino) -2-acetyl) -2-ethoxybenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 23%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.66(dd,J＝7.8,1.3Hz,1H),7.58(td,J＝7.7,1.4Hz,1H),7.51–7.42(m,2H),7.39(td,J＝7.6,1.1Hz,1H),7.31(dd,J＝8.3,6.5Hz,3H),7.27–7.22(m,1H),6.78(d,J＝1.2Hz,1H),6.73(s,1H),5.91(t,J＝7.4Hz,1H),5.33(s,1H),5.28(d,J＝15.6Hz,1H),5.17(d,J＝15.7Hz,1H),4.61(s,2H),4.04(q,J＝6.9Hz,3H),3.84(s,3H),3.61(d,J＝7.5Hz,2H),3.47(s,2H),3.30(s,3H),3.12(s,1H),2.79(s,1H),2.62(s,1H),2.04(s,3H),1.70(s,2H),1.60(s,1H),1.38(t,J＝6.9Hz,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.98,169.12,163.04,159.51,156.67,152.50,140.64,140.49,139.87,139.66,137.85,133.31,133.13,128.71,128.43,128.16,127.33,126.29,122.58,122.42,111.30,110.64,90.46,77.36,77.24,77.04,76.72,64.56,59.42,52.48,46.45,43.65,32.57,27.96,14.68.

HRMS(ESI)calcd.for C ₄₀ H ₄₄ N ₅ O ₇ [M+H ⁺ ]:706.3235,found:706.3251.

Example 20 methyl (Z) -4- (2- ((4, 5-dimethyl-2-oxo-1-phenyl-2, 5-dihydro-1H-pyrazol-3-yl) amino) -2-acetyl) -2-ethoxy-6- (4-hydroxy-3-phenyl-2-buten-1-yl) benzoate (3 ta)

The synthesis of compound 3ta was described in compound 3aa, except that 4- (2- ((4, 5-dimethyl-2-oxo-1-phenyl-2, 5-dihydro-1H-pyrazol-3-yl) amino) -2-acetyl) -2-ethoxybenzoic acid and 4-phenyl-4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 31%.

¹ H NMR(400MHz,CDCl ₃ ):δ9.09(s,1H),7.51–7.47(m,2H),7.44(dd,J＝8.4,7.1Hz,2H),7.36–7.29(m,4H),7.27(d,J＝6.2Hz,1H),7.25–7.19(m,1H),6.92(d,J＝1.3Hz,1H),6.83(d,J＝1.3Hz,1H),5.92(t,J＝7.5Hz,1H),4.58(s,2H),4.03(q,J＝7.0Hz,2H),3.85(s,3H),3.62–3.54(m,4H),3.06(s,3H),2.11(s,3H),1.35(t,J＝7.0Hz,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.29,169.29,161.60,156.39,149.89,141.08,139.84,139.27,138.19,134.03,129.33,128.83,128.25,127.56,126.99,126.39,124.98,122.87,122.22,111.55,107.86,77.35,77.24,77.04,76.72,64.44,59.22,52.29,43.17,35.58,32.44,14.72,12.08.

HRMS(ESI)calcd.for C ₃₃ H ₃₆ N ₃ O ₆ [M+H ⁺ ]:570.2599,found:570.2607.

Example 21 methyl (Z) -2- (4-hydroxy-3- (4-methylphenyl) -2-buten-1-yl) -2-methylbenzoate (3 ab)

The synthesis of compound 3ab is described in compound 3aa, except that o-methylbenzoic acid and 4- (4-methylphenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to give a pale yellow oily liquid, 61%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.42–7.37(m,2H),7.29(t,J＝7.6Hz,1H),7.18–7.10(m,4H),5.91(t,J＝7.4Hz,1H),4.63(s,2H),3.86(s,3H),3.70(d,J＝7.4Hz,2H),2.35(s,6H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.87,139.32,137.81,137.72,137.01,135.54,133.41,129.84,129.16,128.56,128.49,127.15,126.19,59.52,52.24,33.06,21.07,19.84.

HRMS(ESI)calcd.for C ₂₀ H ₂₂ NaO ₃ [M+Na ⁺ ]:333.1461,found:333.1469.

Example 22 methyl (Z) -2- (4-hydroxy-3- (2-methoxyphenyl) -2-buten-1-yl) -2-methylbenzoate (3 ac)

The synthesis method of the compound 3ac refers to the compound 3aa, except that o-methylbenzoic acid and 4- (2-methoxyphenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain light yellow oily liquid, 46%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.30–7.24(m,2H),7.21–7.16(m,2H),7.11(d,J＝7.5Hz,1H),6.97–6.89(m,2H),5.75(t,J＝7.3Hz,1H),4.47(d,J＝5.1Hz,2H),3.92(s,3H),3.90(s,3H),3.69(d,J＝7.2Hz,2H),2.36(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.44,156.30,139.71,137.75,135.35,133.59,132.27,131.68,130.54,129.69,128.58,128.25,127.05,121.19,110.48,60.82,55.60,52.08,32.52,19.80.

HRMS(ESI)calcd.for C ₂₀ H ₂₂ NaO ₄ [M+Na ⁺ ]:349.141,found:309.349.1403.

Example 23 methyl (Z) -2- (4-hydroxy-3- (3-methoxyphenyl) -2-buten-1-yl) -2-methylbenzoate (3 ad)

The synthesis method of the compound 3ad refers to the compound 3aa, and is characterized in that o-methylbenzoic acid and 4- (3-methoxyphenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain light yellow oily liquid, wherein 69%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.31–7.23(m,2H),7.14(t,J＝7.7Hz,2H),7.11–7.06(m,1H),7.05(t,J＝2.1Hz,1H),6.83(dd,J＝8.2,2.5Hz,1H),5.94(t,J＝7.4Hz,1H),4.62(d,J＝4.0Hz,2H),3.87(s,3H),3.83(s,3H),3.70(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.83,159.72,142.32,139.43,137.64,135.58,133.40,129.86,129.65,129.40,128.53,127.14,118.84,112.67,112.19,59.61,55.24,52.23,33.05,19.85.

HRMS(ESI)calcd.for C ₂₀ H ₂₂ NaO ₄ [M+Na ⁺ ]:349.141,found:349.1409.

Example 24 methyl (Z) -2- (4-hydroxy-3- (4-phenoxyphenyl) -2-buten-1-yl) cyclohexyl-1-ene-1-carboxylate (3 ne)

The synthesis method of the compound 3ne refers to the compound 3aa, and the difference is that the cyclohexene carboxylic acid and the 4- (4-phenoxyphenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain light yellow oily liquid, 46%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.49–7.43(m,4H),7.43–7.38(m,2H),7.37–7.31(m,1H),7.07–6.92(m,2H),5.77(t,J＝7.4Hz,1H),5.09(s,2H),4.58(d,J＝4.8Hz,2H),3.73(s,3H),3.41(d,J＝7.4Hz,2H),2.36–2.23(m,4H),1.66(s,4H).

¹³ C NMR(101MHz,CDCl ₃ ):δ169.13,158.03,148.68,138.93,137.05,134.11,128.57,127.92,127.44,127.34,126.91,125.23,114.76,70.03,59.82,51.49,34.78,31.97,26.51,22.23,22.21.

HRMS(ESI)calcd.for C ₂₅ H ₂₉ O ₄ [M+H ⁺ ]:393.206,found:393.2056.

Example 25 methyl (Z) -2- (4-hydroxy-3- (4-fluorophenyl) -2-buten-1-yl) -2-methylbenzoate (3 af)

The synthesis of compound 3af was as described for compound 3aa except that o-methylbenzoic acid and 4- (4-fluorophenyl) -4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 76%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.50–7.42(m,2H),7.29(t,J＝7.7Hz,1H),7.14(dd,J＝7.6,4.8Hz,2H),7.05–6.97(m,2H),5.88(t,J＝7.4Hz,1H),4.60(s,2H),3.86(s,3H),3.69(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.91,162.19(d,J＝246.0Hz),138.44,137.60,136.84(d,J＝3.4Hz),135.66,133.33,129.92,129.40,128.61,127.93(d,J＝7.9Hz),127.18,115.20(d,J＝21.3Hz),59.53,52.25,33.14,19.86.

HRMS(ESI)calcd.for C ₁₉ H ₁₉ FNaO ₃ [M+Na ⁺ ]:337.121,found:337.1212.

Example 26 methyl (Z) -2- (4-hydroxy-3- (4-bromophenyl) -2-buten-1-yl) -2-methylbenzoate (3 ag)

The synthesis of compound 3ag was as described for compound 3aa, except that o-toluic acid and 4- (4-bromophenyl) -4-vinyl-1, 3-dioxolan-2-one were used as starting materials to give a pale yellow oily liquid, 72%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.49–7.42(m,2H),7.41–7.33(m,2H),7.29(t,J＝7.7Hz,1H),7.14(d,J＝7.8Hz,2H),5.93(t,J＝7.4Hz,1H),4.59(s,2H),3.85(s,3H),3.69(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.91,139.73,138.40,137.45,135.71,133.31,131.47,130.01,129.96,128.68,127.97,127.21,121.20,59.32,52.28,33.21,19.88.

HRMS(ESI)calcd.for C ₁₉ H ₁₉ BrNaO ₃ [M+Na ⁺ ]:397.041,found:397.041.

Example 27 methyl (Z) -2- (4-hydroxy-3- (4-trifluoromethylphenyl) -2-buten-1-yl) -2-methylbenzoate (3 ah)

The synthesis of compound 3ah is referred to as compound 3aa, except that o-methylbenzoic acid and 4- (4-trifluoromethylphenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain a pale yellow oily liquid, 65%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.66–7.54(m,4H),7.31(d,J＝7.6Hz,1H),7.15(dd,J＝7.7,2.7Hz,2H),6.01(t,J＝7.4Hz,1H),4.64(s,2H),3.86(s,3H),3.72(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.90,144.48,138.40,137.27,135.80,133.30,131.48,130.01,129.18(d,J＝32.2Hz),128.76,127.22,126.57,125.31(q,J＝3.8Hz),59.30,52.26,33.26,19.88.

HRMS(ESI)calcd.for C ₂₀ H ₁₈ F ₃ O ₃ [M-H ⁺ ]:363.1214,found:363.1205.

Example 28 methyl (Z) -2- (4-hydroxy-3- (3-fluorophenyl) -2-buten-1-yl) -2-methylbenzoate (3 ai)

The synthesis of compound 3ai is described in compound 3aa, except that o-methylbenzoic acid and 4- (3-fluorophenyl) -4-vinyl-1, 3-dioxolane-2-one are used as starting materials to give a pale yellow oily liquid, 70%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.33–7.26(m,3H),7.22(ddt,J＝10.6,2.2,1.1Hz,1H),7.16–7.11(m,2H),6.96(ddt,J＝8.4,7.1,2.6Hz,1H),5.96(t,J＝7.4Hz,1H),4.61(s,2H),3.86(s,3H),3.70(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.90,162.96(d,J＝245.1Hz),143.19(d,J＝7.6Hz),138.42(d,J＝1.8Hz),137.41,135.71,133.32,130.52,129.96,129.80(d,J＝8.4Hz),128.68,127.20,121.90,114.01(d,J＝21.2Hz),113.26(d,J＝22.0Hz),59.38,52.27,33.16,19.88.

HRMS(ESI)calcd.for C ₁₉ H ₁₉ FNaO ₃ [M+Na ⁺ ]:337.121,found:337.1205.

Example 29 methyl (Z) -2- (4-hydroxy-3- (3, 4-dichlorophenyl) -2-buten-1-yl) -2-methylbenzoate (3 aj)

The synthesis method of the compound 3aj refers to the compound 3aa, and the difference is that o-methylbenzoic acid and 4- (3, 4-dichlorophenyl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain light yellow oily liquid, and the content of the light yellow oily liquid is 68%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.60(d,J＝2.1Hz,1H),7.39(d,J＝8.4Hz,1H),7.36–7.31(m,1H),7.29(d,J＝7.7Hz,1H),7.14(d,J＝7.7Hz,2H),5.94(t,J＝7.4Hz,1H),4.62–4.53(m,2H),3.86(s,3H),3.69(d,J＝7.4Hz,2H),2.35(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.93,141.00,137.40,137.21,135.82,133.26,132.44,131.07,130.99,130.23,130.04,128.80,128.24,127.25,125.66,59.19,52.30,33.25,19.91.

HRMS(ESI)calcd.for C ₁₉ H ₁₇ Cl ₂ O ₃ [M+H ⁺ ]:363.056,found:363.0555.

Example 30 methyl (Z) -2- (4-hydroxy-3- (3-methoxyphenyl) -2-penten-1-yl) -2-methylbenzoate (3 ak)

The synthesis method of the compound 3ak is referred to as compound 3aa, except that o-methylbenzoic acid and 4- (3-methoxyphenyl) -4-vinyl-5-methyl-1, 3-dioxolane-2-one are used as raw materials to obtain a pale yellow oily liquid, 32%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.28(d,J＝7.7Hz,1H),7.22(t,J＝7.9Hz,1H),7.14(d,J＝7.7Hz,1H),7.11(d,J＝7.5Hz,1H),7.02(dt,J＝7.6,1.2Hz,1H),7.00(dd,J＝2.6,1.6Hz,1H),6.82(ddd,J＝8.3,2.6,1.0Hz,1H),5.63(dd,J＝8.7,6.0Hz,1H),5.11(q,J＝6.6,5.9Hz,1H),3.92(s,3H),3.89–3.84(m,1H),3.82(s,3H),3.54(dd,J＝15.8,6.0Hz,1H),2.34(s,3H),1.32(d,J＝6.6Hz,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.78,159.15,144.14,142.16,137.91,135.53,133.32,129.81,129.05,128.84,128.40,126.98,120.85,114.15,112.35,65.75,55.20,52.16,32.35,21.87,19.86.

HRMS(ESI)calcd.for C ₂₁ H ₂₄ NaO ₄ [M+Na ⁺ ]:363.1567,found:363.1564.

Example 31 methyl (Z) -2- (4-hydroxy-3- (thiophen-3-yl) -2-buten-1-yl) -2-methylbenzoate (3 al)

The synthesis method of the compound 3al is referred to as compound 3aa, except that o-methylbenzoic acid and 4- (thiophene-3-yl) -4-vinyl-1, 3-dioxolane-2-one are used as raw materials to obtain pale yellow oily liquid, 59%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.39(dd,J＝2.9,1.4Hz,1H),7.31–7.23(m,3H),7.13(t,J＝6.8Hz,2H),6.02(t,J＝7.5Hz,1H),4.58(s,2H),3.83(s,3H),3.69(d,J＝7.4Hz,2H),2.34(s,3H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.96,141.77,137.58,135.55,134.47,133.40,129.85,128.55,127.94,127.20,125.62,125.52,120.55,59.62,52.23,32.85,19.81.

LRMS(ESI)calcd.for C ₁₇ H ₁₈ NaO ₃ S[M+Na ⁺ ]:325.087,found:325.100.

Example 32 methyl (Z) -2- (2- (5-hydroxy-6, 7-dihydrobenzofuran-4 (5H) -ylidene) ethyl) -6-methylbenzoate (3 am)

The synthesis of compound 3am is referred to as compound 3aa, except that o-toluic acid and 8 b-vinyl-3a, 4,5, 8b-tetrahydro- [1,3] dioxolane [4,5-e ] benzofuran-2-one are used as starting materials to give a pale yellow oily liquid, 32%.

¹ H NMR(400MHz,CDCl ₃ ):δ7.36(d,J＝2.0Hz,1H),7.26(t,J＝7.6Hz,1H),7.11(dd,J＝7.7,4.3Hz,2H),6.64(d,J＝2.0Hz,1H),5.56(t,J＝7.1Hz,1H),4.40(dd,J＝5.8,2.4Hz,1H),3.79(s,3H),3.77–3.64(m,2H),2.96(ddd,J＝16.2,9.6,5.9Hz,1H),2.76(ddd,J＝17.0,6.3,3.8Hz,1H),2.34(s,3H),2.17(dtd,J＝13.3,5.7,3.8Hz,1H),1.97(dddd,J＝13.3,9.2,6.3,2.6Hz,1H).

¹³ C NMR(101MHz,CDCl ₃ ):δ170.44,153.02,141.46,137.69,135.32,133.70,133.15,129.64,128.26,126.64,123.15,114.91,109.33,71.96,52.03,32.70,29.83,19.65,19.55.

HRMS(ESI)calcd.for C ₁₉ H ₂₀ NaO ₄ [M+Na ⁺ ]:335.1254,found:335.1261.

Example 332- (4-hydroxy-3-phenyl-2-buten-1-yl) -6-methylbenzoic acid (3 a)

3aa (59mg, 0.2mmol) was dissolved in 3mL of methanol, 3mL of aqueous LiOH solution (31mg, 1.3mmol) was added, and after 1 hour of reaction at room temperature, the reaction mixture was concentrated. After dissolving with dichloromethane, pH =1 was adjusted with 1M hydrochloric acid solution, dichloromethane was extracted 3 times, dried over anhydrous sodium sulfate, concentrated and purified by column separation (petroleum ether: ethyl acetate = 1) to give a light-colored oil 3a, equivalent conversion.

¹ H NMR(400MHz,CDCl ₃ ):δ7.48–7.44(m,2H),7.35–7.29(m,2H),7.28–7.21(m,2H),7.15(dd,J＝7.7,4.1Hz,2H),5.89(t,J＝7.5Hz,1H),4.62(s,2H),3.71(d,J＝7.5Hz,2H),2.42(s,3H).

Example 342- (4-hydroxy-3-phenylbutyl) -6-methylbenzoic acid (3 h)

3aa (59mg, 0.2mmol) was dissolved in 3mL of methanol, pd/C (18.8mg, 0.02mmol) was added, and the mixture was stirred at room temperature under hydrogen at one atmosphere for 6h. The residue was then filtered and washed three times with dichloromethane, and the filtrate was concentrated to give the product as a pale yellow oily liquid (38mg, 65%). Then, the reaction mixture was dissolved in 2mL of methanol, 2mL of an aqueous solution of LiOH (31mg, 1.3 mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour, followed by concentrating the reaction mixture. After dissolving with dichloromethane, pH =1 was adjusted with 1M hydrochloric acid solution, dichloromethane was extracted 3 times, dried over anhydrous sodium sulfate and concentrated through a column for separation and purification (petroleum ether: ethyl acetate = 1) to give a light-colored oil for 3h, equivalent conversion. ¹ H NMR(400MHz，CDCl ₃ ):δ7.35(dd，J＝8.2，6.9Hz，2H)，7.30–7.20(m，4H)，7.08(d，J＝7.6Hz，1H)，6.99(d，J＝7.6Hz，1H)，5.50–5.34(m，1H)，3.84–3.68(m，2H)，2.86(dq，J＝8.8，6.3Hz，1H)，2.65(tt，J＝11.4，7.4Hz，2H)，2.42(s，3H)，2.13(ddt，J＝12.0，9.9，6.1Hz，1H)，2.02–1.88(m，1H).

EXAMPLE 35 preparation of Compound 4a

In a 25mL eggplant-shaped bottle, 3a (85mg, 0.3mmol), glycylglycine methyl ester (109mg, 0.6 mmol), EDCI (69mg, 0.36mmol), HOBt (61mg, 0.45mmol) and triethylamine (137mg, 1.35mmol) were dissolved in 3mL of DMF, reacted overnight at room temperature, and then water and ethyl acetate were added for extraction, and the mixture was washed with saturated salt water, dried over anhydrous sodium sulfate and then the solvent was spin-dried to obtain a crude product. After dissolving in 3mL of methanol, 3mL of an aqueous solution of LiOH (72mg, 3mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the solvent was dried, dissolved in dichloromethane, added with 1N hydrochloric acid solution to adjust pH =1, and the solvent was dried again, and the resulting crude product was dissolved in DMF/DCM (1. After the TLC detection reaction, the solvent was dried by spinning, and the mixture was directly separated and purified by silica gel column to obtain a white solid (27mg, 24%). ¹ H NMR(500MHz，DMSO-d ₆ ):δ8.80(t，J＝6.4Hz，1H)，8.71(t，J＝5.7Hz，1H)，7.35(d，J＝7.6Hz，2H)，7.32–7.18(m，5H)，7.11(d，J＝7.6Hz，1H)，5.92(t，J＝5.3Hz，1H)，4.83(s，2H)，3.84(s，2H)，2.22(s，3H).HRMS(EI)calcd.for C ₂₂ H ₂₂ N ₂ O ₄ [M] ⁺ :378.1571,found:378.1574.

EXAMPLE 36 preparation of Compound 4b

Synthesis of Compound 4b Compound 4a was synthesized as described for Compound 4a, except that 3a and L-valylglycine methyl ester were used as starting materials to give a white solid, 42%. ¹ H NMR(500MHz，DMSO-d ₆ ):δ8.91(t，J＝5.8Hz，1H)，8.56(d，J＝9.1Hz，1H)，7.34(d，J＝7.8Hz，2H)，7.32–7.20(m，4H)，7.16(d，J＝7.6Hz，1H)，7.11(d，J＝7.6Hz，1H)，5.91(dd，J＝6.6，4.0Hz，1H)，4.88(d，J＝11.9Hz，1H)，4.77(d，J＝11.9Hz，1H)，4.22(t，J＝9.5Hz，1H)，3.87–3.73(m，2H)，3.61(dd，J＝18.0，6.7Hz，1H)，3.50(dd，J＝18.0，4.0Hz，1H)，2.25(s，3H)，1.97–1.87(m，1H)，0.95(d，J＝6.5Hz，3H)，0.85(d，J＝6.6Hz，3H).HRMS(EI)calcd.for C ₂₅ H ₂₈ N ₂ O ₄ [M] ⁺ :420.2047,found:420.2044.

EXAMPLE 37 preparation of Compound 4c

Compound 4c was synthesized as described for compound 4a, except that 3a and glycylglycinyl-L-phenylalanine methyl ester were used as starting materials to give a white solid, 25%. ¹ H NMR(500MHz，DMSO-d ₆ )δ8.89(t，J＝6.1Hz，1H)，8.54–8.45(m，1H)，7.84(t，J＝5.1Hz，1H)，7.39–7.32(m，4H)，7.27(ddt，J＝12.9，7.4，1.5Hz，4H)，7.24–7.17(m，3H)，7.10(dd，J＝12.3，7.6Hz，2H)，6.21(t，J＝7.1Hz，1H)，4.96–4.87(m，2H)，4.31(dt，J＝8.9，6.4Hz，1H)，3.79(dd，J＝16.0，5.4Hz，1H)，3.62–3.50(m，3H)，3.04(dd，J＝13.8，5.9Hz，1H)，2.95(dd，J＝13.8，9.0Hz，1H)，2.24(s，3H).HRMS(EI)calcd.for C ₃₁ H ₃₁ N ₃ O ₅ [M] ⁺ :525.2254,found:525.2258.

EXAMPLE 38 preparation of Compound 4d

The synthesis of compound 4d was as described for compound 4a except that 3ma and L-valyl glycine methyl ester were used as starting materials and that 3ma was first hydrolyzed to formic acid and then the synthesis of 4a was followed to give a white solid, 28%. ¹ H NMR(600MHz，DMSO-d ₆ ):δ8.96(t，J＝5.6Hz，1H)，8.80(d，J＝9.7Hz，1H)，7.67(dt，J＝8.0，1.0Hz，1H)，7.50(dd，J＝8.4，1.0Hz，1H)，7.32–7.25(m，5H)，7.23–7.19(m，1H)，7.14(ddd，J＝7.9，7.0，1.0Hz，1H)，5.96(dd，J＝8.0，3.9Hz，1H)，5.06(d，J＝11.6Hz，1H)，4.81(d，J＝11.7Hz，1H)，4.34(t，J＝9.9Hz，1H)，3.94–3.86(m，2H)，3.82(dt，J＝17.3，5.4Hz，2H)，3.74(s，3H)，2.03–1.98(m，1H)，0.97(d，J＝6.7Hz，3H)，0.89(d，J＝6.7Hz，3H).HRMS(EI)calcd.for C ₂₇ H ₂₉ N ₃ O ₄ [M] ⁺ :459.2160,found:459.2153.

EXAMPLE 39 preparation of Compound 4e

The synthesis of compound 4e was performed as described for compound 4a, except that 3na and L-valylglycine methyl ester were used as starting materials, and the methyl ester was hydrolyzed from 3na to give formic acid, followed by reference to the synthesis of 4a, to give a white solid, 28%. ¹ H NMR(500MHz，DMSO-d ₆ ):δ8.70(t，J＝5.8Hz，1H)，7.98(d，J＝9.3Hz，1H)，7.39–7.29(m，4H)，7.27–7.22(m，1H)，5.98(t，J＝5.5Hz，1H)，4.82–4.74(m，2H)，4.00(t，J＝9.8Hz，1H)，3.88(dd，J＝16.4，5.5Hz，1H)，3.73(dd，J＝16.4，6.0Hz，1H)，3.17(dd，J＝17.4，6.1Hz，1H)，2.87(dd，J＝17.5，5.0Hz，1H)，2.19(dd，J＝17.1，6.0Hz，2H)，2.08(s，2H)，1.94–1.88(m，1H)，1.62(dd，J＝16.4，5.9Hz，4H)，0.85(d，J＝6.6Hz，3H)，0.81(d，J＝6.6Hz，3H).HRMS(EI)calcd.for C ₂₄ H ₃₀ N ₂ O ₄ [M] ⁺ :410.2200,found:410.2200.

EXAMPLE 40 preparation of Compound 4f

See compound 4a for compound 4f synthesis, except that 3af and L-alanyl-L-valine methyl ester are used as starting materials, 3af is first subjected to methyl ester hydrolysis to obtain formic acid, and then the synthesis is referred to 4a to obtain a white solid, 30%. <xnotran> 1H NMR (600MHz,DMSO-d 6): δ 8.69 (d, J =8.3Hz,1H), 8.41 (d, J =6.9Hz,1H), 7.35 (td, J =8.2,6.4Hz,1H), 7.27 (t, J =7.6Hz,1H), 7.21-7.16 (m, 3H), 7.13 (d, J =7.7Hz,1H), 7.07 (ddd, J =10.0,8.0,2.6Hz,1H), 6.01 (dd, J =6.4,4.4Hz,1H), 4.83 (s, 2H), 3.96 (t, J =7.0Hz,1H), 3.61 (dd, J =30.6,6.2Hz,1H), 3.57-3.47 (m, 2H), 2.24 (s, 3H), 2.04 (h, J =6.8Hz,1H), 1.21 (d, J =7.0Hz,3H), 0.96 (dd, J =10.8,6.8Hz,6H). HRMS (EI) calcd.for C26H29FN2O4[ M ] +:452.2113,found:452.2106. </xnotran>

EXAMPLE 41 preparation of 4g Compound

The synthesis of 4g was performed as described for compound 4a, except that 3an and L-alanyl-L-valine methyl ester were used as starting materials, and 3an was first hydrolyzed to obtain formic acid, followed by 4a synthesis to obtain a white solid, 21%. ¹ H NMR(600MHz，DMSO-d ₆ ):δ8.45(d，J＝8.6Hz，1H)，8.31(d，J＝7.5Hz，1H)，7.97(dd，J＝11.8，8.5Hz，1H)，7.44(dt，J＝8.1，1.4Hz，2H)，7.30(td，J＝7.8，2.2Hz，3H)，7.24–7.20(m，1H)，7.13(tt，J＝7.6，2.0Hz，1H)，7.07(dd，J＝8.0，1.4Hz，1H)，7.02–6.96(m，1H)，6.79(d，J＝7.1Hz，1H)，6.75(d，J＝1.5Hz，1H)，5.88(q，J＝7.7Hz，1H)，5.36(q，J＝9.2Hz，1H)，4.58–4.50(m，1H)，4.41(d，J＝6.2Hz，2H)，4.24(ddd，J＝26.6，8.5，6.2Hz，1H)，3.97(dt，J＝14.1，7.1Hz，2H)，3.64(s，2H)，3.56(td，J＝15.0，7.6Hz，1H)，3.49(dt，J＝15.2，7.2Hz，1H)，3.40(d，J＝3.1Hz，2H)，3.08(s，2H)，2.06–1.99(m，1H)，1.67(d，J＝9.8Hz，2H)，1.62–1.52(m，3H)，1.49(ddd，J＝14.3，9.9，4.8Hz，3H)，1.32–1.29(m，1H)，1.25(ddt，J＝19.8，7.1，3.9Hz，6H)，0.88(dt，J＝14.3，6.4Hz，12H).HRMS(ESI)calcd.for C ₄₅ H ₅₉ N ₄ O ₆ [M+H ⁺ ]:751.4429,found:751.4429.

EXAMPLE 42 preparation of Compound 4h

Synthesis of compound 4h see compound 4a, except starting with 3h and L-alanyl-L-valine methyl ester, a white solid was obtained, 11% (1.2. ¹ H NMR(500MHz，DMSO-d ₆ ):δ8.75–8.51(m，1H)，8.51–8.39(m，1H)，7.38–7.32(m，1H)，7.33–7.22(m，5H)，7.13(dt，J＝10.9，7.6Hz，1H)，7.04(t，J＝8.1Hz，1H)，6.88(d，J＝7.5Hz，1H)，5.01–4.78(m，1H)，4.34–3.94(m，3H)，2.96–2.67(m，2H)，2.42(td，J＝13.0，3.8Hz，1H)，2.24(d，J＝11.8Hz，3H)，2.21–2.15(m，1H)，2.07(dq，J＝50.9，6.7Hz，1H)，1.75–1.51(m，1H)，1.26(dd，J＝9.6，6.9Hz，3H)，0.99–0.89(m，6H).HRMS(EI)calcd.for C ₂₆ H ₃₂ N ₂ O ₄ [M] ⁺ :436.2361,found:436.2357.

Test example

In the following test examples, compounds 4a, 4b, 4c, 4d, 4e, 4f, 4g and 4h were prepared as in examples 35-42 above.

Test example 1

Compound reverses human oral epidermoid carcinoma KB cell, human oral epidermoid carcinoma drug-resistant cell strain KBV200 cell of high expression of P-gp and drug-resistant human chronic myeloid leukemia drug-resistant cell strain K562/ADR cell to vinorelbine and docetaxel

Cytotoxicity experiments were as follows: KB. KBV200 and K562/ADR cells were treated with 10% Fetal Bovine Serum (FBS) in RPMI-1640 medium at 5% CO ₂ The culture was carried out in a conventional incubator at 37 ℃. Cells were seeded in 96-well plates and cultured overnight, then Vinorelbine (VNR) or Docetaxel (DTX) at different concentrations, and 10 μ M of compound 4a, 4b, 4c, 4d, 4e, 4a, 4f, 4g or 4h were added and cultured for 72 hours, while Vinorelbine (VNR) or Docetaxel (DTX) alone was added as a control group. After the medicine effect is finished, for KB and KBV200 cells, trichloroacetic acid is used for fixing the cells, and then SRBDyeing the solution, finally adding a Tris solution to dissolve SRB, and measuring an OD value under the wavelength of 510nm of an enzyme-labeling instrument; for K562/ADR cells, MTT was added, 4 hours later the triple was added, overnight, and the OD was measured the next day with a microplate reader at 570 wavelengths. The inhibition was calculated from the OD and the IC was calculated using Graphpad Prism 5.0 software ₅₀ 。

After the combination of vinorelbine or docetaxel and different compounds, the inhibition effect of vinorelbine or docetaxel on cells is shown in table 1 and figures 1,2 and 3:

TABLE 1 reversal of drug resistance of KBV200 and K562/ADR to vinorelbine and docetaxel by different compounds

^a Remarking: "-" indicates no experiment was performed; a reversal factor is IC of vinorelbine or docetaxel drug alone ₅₀ IC divided by vinorelbine or docetaxel in combination with Compound 4a, 4b, 4c, 4d, 4e, 4f, 4g or 4h ₅₀ 。

It can be obtained from table 1 and fig. 2 and 3 that at 10 μ M, the compounds 4a, 4b, 4c, 4d, 4e, 4a, 4f, 4g and 4h all significantly reverse the drug resistance of KBV200 and K562/ADR with high expression of P-gp to vinorelbine and docetaxel, and the reversal multiple is between about 2 to 180, indicating that the compounds 4a, 4b, 4c, 4d, 4e, 4a, 4f, 4g and 4h can efficiently reverse the drug resistance of KBV200 and K562/ADR cells to vinorelbine and docetaxel, and significantly improve the inhibition effect of the KBV200 and K562/ADR cells to vinorelbine and docetaxel. However, as shown in figure 1, none of compounds 4a, 4b, 4c, 4d, 4e, 4a, 4f, 4g and 4h affected the cytotoxic effects of vinorelbine and docetaxel on KB cells, indicating that compounds 4a, 4b, 4c, 4d, 4e, 4a, 4f, 4g and 4h achieved reversal of multidrug resistance of tumor cells to vinorelbine and docetaxel through inhibition of P-gp.

Test example 2

Compound 4g did not affect P-gp expression

The expression of P-gp is detected by Western blotting, and the detection method specifically comprises the following steps: KB. KBV200 cells were first treated with 10. Mu.M compound 4g or the reported P-gp inhibitor Verapamil (VPL) for 24 hours, while KB, KBV200 cells without any drug served as a control, and then lysed with 1 XSDS gel loading buffer (50 mM Tris-HCl (pH 6.8), 100mM DTT,2% SDS,10% glycerol, 0.1% bromophenol blue). Heating and denaturing the cell lysate in a boiling water bath, performing SDS-PAGE electrophoresis, transferring proteins to a PVDF membrane by a wet transfer system after the electrophoresis is finished, sealing the PVDF membrane in a sealing solution (5% skimmed milk powder is diluted in TBS/T) for 1 hour at room temperature, and then performing anti-reaction on I and II; after washing, the film was developed with ECL reagent, tableted, and developed, and the result is shown in FIG. 4.

The P-gp inhibitor mainly exerts its effect by reducing the expression of P-gp or inhibiting its functional activity, and as can be seen from FIG. 4, the compounds 4g and verapamil do not reduce the expression of P-gp in KBV200 cells, indicating that the compounds 4g and verapamil inhibit the multi-drug resistance of tumor cells by inhibiting the activity of P-gp

Test example 3

Compound 4g inhibits the function of P-gp

FTU (fat-to-oil transfer) test is used for investigating the inhibition effect of 4g on inhibiting P-gp

Drug accumulation experiments were as follows: KB and KBV200 cells were incubated with 10. Mu.M of 4g or Verapamil (VPL) and 5. Mu.M of compound (MRho-123), respectively, for 1 hour and then examined by fluorescence microscopy and flow cytometry FACS, the results of fluorescence microscopy are shown in FIG. 5 and the results of flow cytometry FACS are shown in FIG. 6.

Drug efflux experiments were as follows: KB and KBV200 cells were incubated with 5. Mu.M Rho-123, respectively, for 1 hour, washed 3 times with the medium, replaced with medium without Rho-123, with or without 10. Mu.M compound 4g or verapamil, and incubated for 1 hour, followed by fluorescence microscopy (shown in FIG. 7) and flow cytometry (shown in FIG. 8).

As can be seen from FIGS. 5-8, compound 4g significantly promoted the accumulation of the P-pg substrate Rho-123 in KBV200 cells (FIGS. 5, 6) and significantly inhibited the efflux of Rho-123 (FIGS. 7, 8) with a significantly stronger effect than verapamil. They all had no effect on Rho-123 accumulation and efflux in KB cells. These results indicate that compound 4g exerts its activity by inhibiting the function of P-gp.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

r1, R2, R4, R5 and R6 are hydrogen;

r3 is a substituted or unsubstituted C6-C12 aryl, and the substitution means that one or more hydrogen atoms on the group are independently substituted by a substituent selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C4 alkyl;

ring a is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted unsaturated 5-8 membered heterocycloalkyl ring, or a substituted or unsubstituted unsaturated C5-C8 cycloalkane ring, wherein said substituted or unsubstituted unsaturated 5-8 membered heterocycloalkyl ring and said substituted or unsubstituted unsaturated C5-C8 cycloalkane ring have 1 or 2 carbon-carbon double bonds in the ring; the substituted refers to that one or more hydrogen atoms on the group are each independently substituted by a substituent selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenSubstituted C1-C6 alkoxy, halogenated C1-C6 alkylthio,

X is amino acid residue or polypeptide residue, the polypeptide residue contains m amino acid residues, and m is a positive integer of 2-4;

wherein the structure of the amino acid residues is as follows:

wherein, the 4-position and the 5-position are connecting sites, R is the R group of amino acid, the 4-position is connected with O atom, and the 5-position is connected with carbonyl;

the structural formula of the polypeptide residue is as follows:

the amino acid is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine and arginine;

in polypeptide residues, the R groups of each amino acid residue are the same or different;

is a double or single bond;

r7, R8, R9 are hydrogen, R10 is C1-C6 alkyl;

ring B is a C6-C12 aromatic ring;

r11 is 5-8 membered heterocycloalkyl;

a is 1;

b is 1;

the heterocyclic alkyl, the heterocyclic alkyl ring and the heterocyclic ring of the heteroaromatic ring respectively and independently have 1-3 heteroatoms selected from N, O and S.

2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted isoindole ring, or a substituted or unsubstituted unsaturated cyclohexane ring having 1 or 2 carbon-carbon double bonds in the carbocyclic ring.

3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R10 is isopropyl, ring B is a phenyl ring and R11 is piperidinyl.

4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is substituted or unsubstituted phenyl, said substitution being one of the hydrogen atoms in the group replaced by halogen.

5. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the amino acid residue is a glycine residue or a valine residue.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound having the structure of formula Ia:

wherein R1, R2, R3, R4, R5, R6, ring a and X are as defined in claim 1;

at g and k

Each independently a double or single bond.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is of formula Ib:

wherein c is 1 or m;

r1, R2, R3, R4, R5, R6, m and the ring A are as defined in claim 1, R is a group R of an L-amino acid, wherein when c is greater than 1, each group R is the same or different;

the L-amino acid is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, lysine and arginine.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is of formula Ic:

wherein R1, R2, R3, R4, R5, R6 and A are as defined in claim 1, R14 and R15 are each independently an R group of an L-amino acid;

9. The compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

10. the compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

11. a pharmaceutical composition, said composition comprising: (a) A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

12. Use of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for (1) the manufacture of a medicament for inhibiting or reversing the multidrug resistance of a tumor against an anticancer drug; (2) preparing a medicament for inhibiting the activity of P-glycoprotein; or (3) preparing the medicine for enhancing the anti-tumor activity of the anti-tumor medicine.

13. The use of claim 12, wherein the tumor is selected from the group consisting of: nasopharyngeal carcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, gallbladder cancer, bile duct cancer, lung cancer, liver cancer, kidney cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, endometrial cancer, lymphoma, leukemia, or a combination thereof; or

14. A process for preparing a compound of formula II, or a pharmaceutically acceptable salt thereof,

the method is characterized by comprising the following steps:

when R16 is hydrogen, the method comprises the step (1)

(1) Under the action of a catalyst, a silver salt and a first alkali reagent, a compound shown in a formula C1 and a compound shown in a formula C2 are subjected to a carbon-hydrogen bond activity reaction to generate a compound shown in a formula C3;

or when R16 is not hydrogen, said method comprises step (1) and step (2)

(2) Compounds of formula C3 and R ₁₆ -the halogen is esterified to produce a compound of formula II;

wherein, in the step (1), the catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer;

in the step (1), the silver salt is silver hexafluoroantimonate;

in the step (1), the first alkali reagent is potassium carbonate;

in the step (1), the reaction is carried out under the condition of no solvent;

wherein the content of the first and second substances,

r1, R2, R4, R5 and R6 are hydrogen;

ring a is a substituted or unsubstituted C6-C12 aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted unsaturated 5-8 membered heterocycloalkyl ring, or a substituted or unsubstituted unsaturated C5-C8 cycloalkane ring, said substitution being such that one or more hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio,

Wherein the unsaturated C5-C8 cycloalkane ring has 1 or 2 carbon-carbon double bonds in the carbocyclic ring, and the unsaturated 5-8 membered heterocycloalkyl ring has 1 or 2 carbon-carbon double bonds in the ring;

is a double or single bond;

r7, R8, R9 are hydrogen, R10 is C1-C6 alkyl;

ring B is a C6-C12 aromatic ring;

r11 is 5-8 membered heterocycloalkyl;

a is 1;

b is 1;

r16 is hydrogen, substituted or unsubstituted C1-C10 alkyl, said substitution being such that one or more hydrogen atoms on the group are each independently substituted with a substituent selected from the group consisting of: halogen, -CN, hydroxyl, nitro, amino, C1-C6 alkyl, halogenated C1-C4 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio;

the heterocyclic alkyl, the heterocyclic alkyl ring and the heterocyclic ring of the heteroaromatic ring respectively and independently have 1 to 3 heteroatoms selected from N, O and S.