CN117338788A

CN117338788A - Use of compounds in the treatment of fatty liver disease and related disorders

Info

Publication number: CN117338788A
Application number: CN202311301274.XA
Authority: CN
Inventors: 李红良; 张晓晶; 付家俊
Original assignee: Gannan Institute Of Innovation And Transformation Medicine
Current assignee: Gannan Institute Of Innovation And Transformation Medicine
Priority date: 2023-10-09
Filing date: 2023-10-09
Publication date: 2024-01-05

Abstract

The invention relates to the use of a compound in treating fatty liver disease and related diseases, in particular to the use of a compound shown in a formula O or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in preparing medicines for treating and/or preventing fatty liver disease and related diseases,

Description

Use of compounds in the treatment of fatty liver disease and related disorders

Technical Field

The invention relates to the field of medicines, in particular to application of a compound in treating fatty liver diseases and related diseases.

Background

Nonalcoholic fatty liver disease (Nonalcoholic fatty liver disease, NAFLD), a disease of excessive deposition of lipids in the liver of patients without history of alcohol abuse or other secondary causes of hepatic steatosis, is a major indication of liver transplantation in developed and developing countries, including: liver steatosis (NAFL, non-progressive stage of NAFLD), nonalcoholic steatohepatitis (NASH, progressive stage of NAFLD). NASH is a key element in exacerbation of NAFLD disease, 25% of patients with nasl may progress to NASH, with liver cell steatosis, balloon-like changes, inflammation and fibrosis, and 35% -50% of patients with NASH may progress to liver cancer. In addition, NAFLD is closely related to metabolic diseases such as insulin resistance, hypertension, dyslipidemia, obesity and the like, so that occurrence of the disease can also promote the gradual development of various metabolic syndromes such as diabetes and the like. It is estimated that the global prevalence of NAFLD is about 25%, and chinese NAFLD patients increase dramatically from 18% to nearly 30% within 10 years, with the expectation that chinese prevalence will exceed 3 billion by 2030.

The high incidence of NASH and related morbidity, it is currently believed that determining therapies capable of slowing, stopping or reversing the progression of NASH and NAFLD has not met medical needs. Although there are several drugs under treatment, none have been approved by the U.S. food and drug administration, and therefore, there is still a need to further discover safe and effective drugs to treat NAFLD.

Disclosure of Invention

The object of the present invention is to solve, at least to some extent, the above problems of the prior art.

The inventor of the application found that the compound of the invention can significantly inhibit lipid accumulation in liver cells without obvious toxic and side effects, and the compound of the invention can effectively relieve nonalcoholic fatty liver diseases after being orally taken.

For this reason, in a first aspect of the present invention, the present invention provides the use of a compound represented by formula O or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for the treatment and/or prophylaxis of fatty liver disease and related diseases,

or, there is provided a compound represented by formula O or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, which is useful for the treatment and/or prevention of fatty liver disease and related diseases,

Alternatively, there is provided a method for treating and/or preventing fatty liver disease and related diseases, which comprises administering to a subject in need thereof an effective amount of a compound represented by formula O or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

wherein:

a isAnd the 1 position is connected with carbonyl and the 2 position is connected with phenyl;

n is selected from 0, 1, 2;

R ^a 、R ^b each independently selected from H, C1-C6 alkyl;

R ^1a 、R ^1b each independently selected from H, aryl, alkyl, optionallySubstituted with a group selected from halogen, alkyl, haloalkyl, alkoxy, aryl; alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a heterocyclic group, which is optionally substituted with an alkyl group;

R ^2a 、R ^2b each independently selected from H, alkyl, cycloalkyl, aryl, benzyl, adamantyl, said alkyl, cycloalkyl, aryl, benzyl, adamantyl optionally substituted with halogen; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a heterocyclic group, which is optionally substituted with an alkyl group;

y is selected from

R ³ Selected from alkyl, cycloalkyl, aryl, benzyl, heteroaryl, optionally substituted with a group selected from halogen, alkyl;

Optionally, the medicament further comprises one or more pharmaceutically acceptable carriers or excipients.

In some embodiments, n is selected from 1, 2.

In some embodiments, R ^a 、R ^b Each independently selected from H, methyl.

In some embodiments, Y is selected from

In some embodiments, R ^1a 、R ^1b Each independently selected from H, C6-C10 aryl, C1-C6 alkyl, said C6-C10 aryl, C1-C6 alkyl optionally substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl; alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a 6-10 membered heterocyclic group, said 6-10 membered heterocyclic group being optionally substituted with a C1-C6 alkyl group.

In some embodiments, R ^1a 、R ^1b Each independently selected from:

1) H, C1C 6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

more preferably, R ^m 、R ⁿ Any one of the two is H, and the other is methyl;

R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ each independently selected from H, F, cl, br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;

preferably, R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Any one (e.g. R ⁴ 、R ⁵ Or R is ⁶ ) Selected from F, cl, br, I, C-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, the remaining four being H;

More preferably, R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Any one (e.g. R ⁴ 、R ⁵ Or R is ⁶ ) Selected from F, methyl, trifluoromethyl, methoxy, the remaining four are H;

3) Naphthyl optionally substituted with C1-C6 alkyl;

alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a 6-10 membered heterocyclic group, said 6-10 membered heterocyclic group being optionally substituted with a C1-C6 alkyl group.

In some embodiments, R ^1a 、R ^1b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached form a 9-10 membered heterocyclic group, preferably forming More preferably form->

1)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

2) A naphthyl group;

alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form Preferably form->

In some embodiments, R ^1a 、R ^1b Any one of them is H, and the other is selected from Alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form +.>

In some embodiments, R ^2a 、R ^2b Each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl, said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl optionally substituted with halogen; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclic group, said 5-10 membered heterocyclic group optionally being substituted with C1-C6 alkyl.

In some embodiments, R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ each independently selected from H, F, cl, br, I, C1-C6 alkyl;

preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one (e.g. R ¹¹ ) Selected from H, F, cl, br, I, C-C6 alkyl, the remaining four are H;

more preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one (e.g. R ¹¹ ) Selected from H, F, cl, br, I, the remaining four are all H;

most preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one (e.g. R ¹¹ ) Selected from H, F, the remaining four are all H;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclic group, said 5-10 membered heterocyclic group optionally being substituted with C1-C6 alkyl.

In some embodiments, R ^2a 、R ^2b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached form a 5-to 10-membered heterocyclic group, preferably formingMore preferably form->

1) Cycloheptyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form Preferably form->

In some embodiments, R ^2a 、R ^2b Any one of them is H, and the other is selected from Alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form

In some embodiments, R ³ Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl, said C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl optionally substituted with a group selected from halogen, C1-C6 alkyl.

In some embodiments, R ³ Selected from:

1)wherein L is ³ Selected from direct bond, methylene, ethylene, preferably selected from direct bond, methylene;

R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ each independently selected from H, F, cl, br, I, C1-C6 alkyl;

preferably, R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ Any one (e.g. R ¹⁶ ) Selected from H, F, cl, br, I, C-C6 alkyl, the remaining four are H;

more preferably, R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ Any one (e.g. R ¹⁶ ) Selected from H, F, cl and methyl, the remaining four are all H;

2) C3-C6 cycloalkyl, 9-10 membered heteroaryl, said C3-C6 cycloalkyl, 9-10 membered heteroaryl optionally substituted by C1-C6 alkyl.

In some embodiments, R ³ Selected from:

1)wherein L is ³ Selected from the group consisting of a direct bond,Methylene, ethylene, preferably selected from direct bonds, methylene;

2) C3-C6 cycloalkyl, indolyl (preferably))。

In some embodiments, R ³ Selected from the group consisting of

In a second aspect of the invention, the invention provides the use of a compound shown in formula I or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating and/or preventing fatty liver disease and related diseases,

Or, there is provided a compound represented by formula I or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, which is useful for the treatment and/or prevention of fatty liver disease and related diseases,

alternatively, there is provided a method for treating and/or preventing fatty liver disease and related diseases, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

wherein:

R ^1a 、R ^1b each independently selected from H, aryl, alkyl optionally substituted with a group selected from halogen, alkyl, haloalkyl, alkoxy, aryl; alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a heterocyclic group, which is optionally substituted with an alkyl group;

preferably, R ^1a 、R ^1b Each independently selected from H, C6-C10 aryl, C1-C6 alkyl, said C6-C10 aryl, C1-C6 alkyl optionally substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl; alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a 6-10 membered heterocyclyl, said 6-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

More preferably, R ^1a 、R ^1b Each independently selected from:

1) H, C1C 6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a 6-10 membered heterocyclyl, said 6-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

further preferably, R ^1a 、R ^1b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached form a 9-10 membered heterocyclic group, preferably formingMore preferably form->

Still more preferably, R ^1a 、R ^1b Any one of them is H, and the other is selected from:

1)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

more preferablyGround, R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Any one (e.g. R ⁴ 、R ⁵ Or R is ⁶ ) Selected from F, methyl, trifluoromethyl, methoxy, the remaining four are H;

2) A naphthyl group;

Most preferably, R ^1a 、R ^1b Any one of them is H, and the other is selected from Alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form +.>

preferably, R ^2a 、R ^2b Each independently selected from H, C C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl, said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl optionally taken by halogenSubstitution; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

more preferably, R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

further preferably, R ^2a 、R ^2b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached form a 5-to 10-membered heterocyclic group, preferably forming More preferably form->

Still more preferably, R ^2a 、R ^2b Any one of them is H, and the other is selected from:

1) Cycloheptyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

Most preferably, R ^2a 、R ^2b Any one of them is H, and the other is selected from Alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form +.>

Y is selected from

Preferably Y is selected from

preferably, R ³ Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl, said C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl optionally substituted with a group selected from halogen, C1-C6 alkyl;

More preferably, R ³ Selected from:

2) A C3-C6 cycloalkyl, 9-10 membered heteroaryl, said C3-C6 cycloalkyl, 9-10 membered heteroaryl optionally substituted with C1-C6 alkyl;

further preferably, R ³ Selected from:

2) C3-C6 cycloalkyl, indolyl (preferably))；

Most preferably, R ³ Selected from the group consisting of

In a third aspect of the invention, the invention provides the use of a compound shown in formula II or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for treating and/or preventing fatty liver disease and related diseases,

Alternatively, provided is a compound of formula II or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, which is useful for the treatment and/or prevention of fatty liver disease and related diseases,

alternatively, there is provided a method for treating and/or preventing fatty liver disease and related diseases, which comprises administering to a subject in need thereof an effective amount of a compound represented by formula II or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

wherein:

R ^a 、R ^b each independently selected from H, C1-C6 alkyl;

preferably, R ^a 、R ^b Each independently selected from H, methyl;

more preferably, R ^a 、R ^b Each independently selected from H, methyl, and R ^a 、R ^b Are not methyl at the same time;

R ^1a 、R ^1b each independently selected from:

1) H, C1C 6 alkyl;

2)wherein,

R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ any one (e.g. R ⁴ 、R ⁵ Or R is ⁶ ) Selected from F, cl, br, I, C-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, the remaining four being H;

preferably, R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Any one (e.g. R ⁴ 、R ⁵ Or R is ⁶ ) Selected from F, methyl, trifluoromethyl, methoxy, the remaining four are H;

3) Naphthyl optionally substituted with C1-C6 alkyl;

Preferably, R ^1a 、R ^1b Any one of them is H, the other is HAnd one is selected from:

1) C1-C6 alkyl;

2)wherein,

more preferably, R ^1a 、R ^1b Any one of them is H, and the other isWherein,

R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ any one (e.g. R ⁵ ) Selected from C1-C6 haloalkyl, the remaining four are H;

preferably, R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ Any one (e.g. R ⁵ ) Is trifluoromethyl, and the other four are H;

most preferably, R ^1a 、R ^1b Any one of them is H, and the other is

R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein the method comprises the steps of，L ² Selected from direct bond, methylene, preferably methylene;

R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ any one (e.g. R ¹¹ ) Selected from H, F, cl, br, I, C-C6 alkyl, the remaining four are H;

preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one (e.g. R ¹¹ ) Selected from F, cl, br, I, the remaining four are all H;

more preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one (e.g. R ¹¹ ) F, and the other four are H;

Preferably, R ^2a 、R ^2b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl;

2)wherein L is ² Selected from direct bond, methylene, preferably methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached,forming a 5-6 membered heterocyclic group;

more preferably, R ^2a 、R ^2b Any one of them is H, and the other isWherein L is ² Selected from direct bond, methylene, preferably methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, formPreferably->

Most preferably, R ^2a 、R ^2b Any one of them is H, and the other isAlternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form +.>

R ³ Selected from:

1)wherein L is ³ Selected from direct bond, methylene, ethylene, preferably selected from direct bond, methylene, more preferably direct bond;

R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ Any one (e.g. R ¹⁶ ) Selected from H, F, cl, br, I, C-C6 alkyl, the remaining four are H;

preferably, R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ Any one (e.g. R ¹⁶ ) Selected from H, F, cl and methyl, the remaining four are all H;

preferably, R ³ Is thatWherein L is ³ Selected from direct bond, methylene, ethylene, preferably selected from direct bond, methylene, more preferably direct bond;

R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ any one (e.g. R ¹⁶ ) Selected from H, C-C6 alkyl, the remaining four are H;

preferably, R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ All are H;

more preferably, R ³ Is that

In some embodiments, the compound is selected from the following:

/>

in some embodiments, the fatty liver disease is a non-alcoholic fatty liver disease.

In some embodiments, the fatty liver disease is simple steatosis.

In some embodiments, the fatty liver disease is non-alcoholic steatohepatitis.

In some embodiments, the fatty liver disease is liver fibrosis.

In some embodiments, the fatty liver disease is cirrhosis.

In some embodiments, the fatty liver disease is liver cancer.

In some embodiments, the fatty liver disease is a diet-induced non-alcoholic fatty liver disease.

In some embodiments, the fatty liver disease is a high-fat high-cholesterol diet-induced non-alcoholic fatty liver disease.

In some embodiments, the fatty liver-related disease is diabetes.

In some embodiments, the fatty liver-related disease is obesity.

In some embodiments, the fatty liver-related disease is hyperlipidemia.

In some embodiments, the fatty liver-related disease is insulin resistance.

In a fourth aspect of the invention, the invention provides a compound or stereoisomer thereof, prodrug thereof, pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate thereof,

/>

in a fifth aspect of the invention, the invention provides a pharmaceutical composition comprising a compound as hereinbefore described, or a stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, optionally together with one or more pharmaceutically acceptable carriers or excipients.

Definition of terms

The following terms and phrases as used herein are intended to have the following meanings unless otherwise indicated. In addition, unless specifically indicated, the groups and substituents of the present invention have the ordinary meaning in the field of organic chemistry.

Substituents of the compounds of the invention are disclosed in terms of the type or scope of the groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C1-C6 alkyl" particularly refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably "C1-C4 alkyl", more preferably "C1-C3 alkyl", and most preferably "C1-C2 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and the like. Examples of "C1-C3 alkyl" include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), and the like. Examples of "C1-C2 alkyl" include methyl, ethyl.

The term "C1-C6 haloalkyl" refers to a radical obtained by substituting one or more (e.g., 2, 3 or 4) hydrogen atoms in any of the above-mentioned C1-C6 alkyl groups with a halogen, preferably fluorine, examples including monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl and the like, preferably trifluoromethyl.

The term "C1-C6 alkoxy" refers to any of the above-mentioned C1-C6 alkyl groups attached to the remainder of the molecule through an oxygen atom (-O-) and examples include methoxy, ethoxy, isopropoxy, and the like.

The term "C3-C8 cycloalkyl" refers to a hydrocarbon having a 3-8 membered monocyclic ring system of saturated rings, such as cycloheptyl, preferably "C3-C6 cycloalkyl", which may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-membered (preferably 5-10-, 6-10-or 9-10-membered) saturated or unsaturated, mono-, bi-or polycyclic carbocyclic radicals in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur and in which, in the case of bi-or polycyclic, at least one of the rings in the bi-or polycyclic ring does not constitute an aromatic system and at least one of the carbon atoms in the ring not constituting an aromatic system is replaced by a heteroatom such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups are, for example, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, 1, 3-dioxolanyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, Etc., preferably->

The term "aryl" refers to all carbon atoms in each carbocyclic ring having a p-orbital forming a conjugate, preferably "C6-C10 aryl", such as phenyl or naphthyl.

The term "heteroaryl" refers to 5-, 6-, 7-, 8-, 9-or 10-membered (preferably 9-10 membered) aromatic monocyclic, bicyclic and tricyclic or more cyclic groups having at least one heteroatom (N, O or S) in at least one ring, the heteroatom-containing ring optionally also having 1, 2 or 3 heteroatoms selected from N, O or S. Heteroaryl groups that are bicyclic or tricyclic or more are required to have a fragrance system formed by each of the two or three or more rings. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaoxazolyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, and the like.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "heteroatom" refers to N, O or S.

The term "benzyl" refers to

The term "adamantyl" refers to

In the present invention, unless explicitly indicated otherwise, the description that "…" is each independently selected from "as used throughout this document may mean that the specific items expressed between the same or different symbols in different groups do not affect each other, or that the specific items expressed between the same or different symbols in the same groups do not affect each other.

In the present invention, "substituted" or "substituted with …" means that any hydrogen on a given atom or group is replaced by the choice of the given group, provided that the normal valence of the given atom is not exceeded.

In the present invention, "optionally" means either optional or not.

In the present invention, illustratively, "R ^1a 、R ^1b Each independently selected from H, C-C10 aryl, C1-C6 alkyl, said C6-C10 aryl, C1-C6 alkyl optionally substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl, "wherein" optionally "means that said C6-C10 aryl, C1-C6 alkyl may be unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl, and that the respective substituents may be the same or different when said C6-C10 aryl, C1-C6 alkyl is substituted with a substituent. The remaining similar definitions in the present invention are to be understood with reference to the foregoing.

In the present invention, for example, in the case of formula O, "R ^1a 、R ^1b And together with the N atom to which they are attached, formThe formula of formula O becomes +.>The remaining similar definitions in the present invention are to be understood with reference to the foregoing.

In the present invention, "direct bond" means that the groups on both sides thereof are directly connected, and, for example, if in formula O, R ^1a Is thatThen when L ¹ R is a direct bond ^1a Become->The structural formula of formula O becomes +.>The remaining similar definitions in the present invention are to be understood with reference to the foregoing.

The term "pharmaceutically acceptable salts" refers to salts of basic functional groups present in the compounds provided herein with suitable inorganic or organic anions (acids) and includes, but is not limited to, hydrohalic acid salts, such as hydrofluoric acid salts, hydrochloric acid salts, hydrobromide salts, hydroiodide salts, and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, etc.; lower alkane sulfonates such as methane sulfonate, trifluoro methane sulfonate, ethane sulfonate and the like; aryl sulfonates such as benzene sulfonate, p-benzene sulfonate, and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, and the like; amino acid salts such as glycinate, trimethylglycinate, arginate, ornithinate, glutamate, aspartate and the like; or the salt of an acidic functional group present in a compound provided herein with a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium, potassium, lithium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, and the like; inorganic basic salts such as ammonium salts; organic base salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt, and the like.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The term "solvate" refers to a compound of the invention that forms a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate.

The term "stereoisomers" refers to isomerism that occurs in a compound molecule of the same formula in which atoms or substituents are linked in the same order but in different spatial arrangements, and belongs to the category of organic chemistry.

The term "prodrug" refers to derivatives that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compounds of the invention. Prodrugs are only active compounds through this reaction under biological conditions, or they are inactive in their unreactive form. Prodrugs can generally be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178,949-982 (manufactured E.Wolff, 5 th edition).

The term "carrier" refers to a system that alters the manner and distribution of a drug into the body, controls the release rate of the drug, and delivers the drug to a targeted organ. The drug carrier release and targeting system can reduce drug degradation and loss, reduce side effects and improve bioavailability. For example, a polymer surfactant which can be used as a carrier can be self-assembled due to the unique amphiphilic structure of the polymer surfactant to form various forms of aggregates, and preferable examples are micelles, microemulsions, gels, liquid crystals, vesicles and the like. These aggregates have the ability to entrap drug molecules while having good permeability to membranes and can be used as good drug carriers.

The term "excipient" refers to an adjunct to the drug formulation other than the primary drug, which may also be referred to as an adjuvant, including but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin, and the like.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Preventing diseases or symptoms which occur in patients who are susceptible to the diseases or symptoms but are not yet diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

The term "subject" includes human or non-human animals. Exemplary human subjects include humans (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). The term "non-human animals" in the present invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The term "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the dosages and for the periods of time necessary. The "therapeutically effective amount" of a compound of the invention can vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the compound to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the compound that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow, preferably stop to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow, preferably stop to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with cancer.

Advantageous effects

1. The compounds of the present invention, such as all specific compounds in series A, B, C, D, E, were able to significantly inhibit lipid accumulation in hepatocytes without significant toxic side effects.

2. Oral administration of a compound of the invention, such as all specific compounds in series A, B, C, D, E, is effective in alleviating fatty liver disease and related diseases (e.g., non-alcoholic fatty liver disease, such as, specifically, high-fat high-cholesterol diet-induced non-alcoholic fatty liver disease).

Drawings

Fig. 1 and 2 are diagrams of BODIPY staining imaging analysis of hepatocytes after treatment with different compounds, wherein: p < 0.05 for each treatment group compared to PO group; * ***: p < 0.0001 for each treatment group compared to PO group.

Fig. 3 shows liver weight and liver weight/body weight ratio results for different groups of mice.

FIG. 4 shows liver histopathological examination results of different groups of mice.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to the accompanying drawings and examples, but it will be understood by those skilled in the art that the following drawings and examples are only for illustrating the present invention and are not to be construed as limiting the scope of the present invention. Various objects and advantageous aspects of the present invention will become apparent to those skilled in the art from the following detailed description of the preferred embodiments and the accompanying drawings.

General synthetic scheme

The compounds of the present invention can be prepared in the following reaction schemes from commercially available starting materials, compounds known in the literature or readily prepared intermediates by using standard synthetic methods and procedures known to those skilled in the art. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvents, pressures, etc.) are given; other preparation conditions may also be used unless otherwise indicated. The reaction conditions may vary with the particular reactants or solvents used. Those skilled in the art will recognize that the nature and order of the synthetic steps provided may be varied for purposes of optimizing the formation of the compounds described herein.

The compounds prepared are identified according to any suitable method known in the art. For example, the light may be detected by nuclear magnetic resonance spectroscopy (e.g ¹ H or ¹³ C) Product formation is monitored by infrared spectroscopy, spectrophotometry, mass spectrometry, or by chromatography such as High Performance Liquid Chromatography (HPLC), gas Chromatography (GC), gel-permeation chromatography (GPC), or Thin Layer Chromatography (TLC).

The routes below, including those mentioned in the examples and preparations, illustrate the synthetic methods of the compounds of the present invention. It will be appreciated by those skilled in the art that the compounds of the present invention and intermediates thereof may be prepared by methods other than those specifically described herein. Thus, one skilled in the art can alter the methods described herein by synthetic methods known in the art.

When solvent ratios are given, the ratios are by volume.

It will be appreciated by those skilled in the art that the experimental conditions set forth in the schemes that follow illustrate suitable conditions for achieving the indicated transformations, and that it may be necessary or desirable to vary the precise conditions employed for preparing the compounds of the present invention.

Series A compound synthesis scheme

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Synthetic scheme for series B compounds

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Synthetic scheme for series C compounds

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Synthetic scheme for series D compounds

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Synthetic scheme for series E compounds

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The synthesis of the various compounds of the invention is illustrated below. The synthesis of these compounds is merely exemplary and is not intended to limit the scope of the invention. Additional compounds within the scope of the present invention may be prepared using the methods exemplified in these examples, alone or in combination with techniques generally known in the art.

Abbreviations (abbreviations)

In the examples and preparations set forth below and in the foregoing schemes, the following abbreviations or their english expressions may be mentioned, as well as other abbreviations common in the art. Standard IUPAC nomenclature is used.

AcOH, acetic acid;

boc is t-butoxycarbonyl;

the DEG C is the temperature;

CDCl ₃ : deuterated chloroform;

(COCl) ₂ : oxalyl chloride;

(COCl ₂ ) ₃ : triphosgene;

delta: chemical shift;

d: a double peak;

DCM: dichloromethane;

DMF: n, N-dimethylformamide;

DMSO: dimethyl sulfoxide;

DIPEA: n, N-diisopropylethylamine;

eq: equivalent weight;

EDCI:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;

EtOAc: ethyl acetate;

EtOH: ethanol;

g: g;

H ₂ o: water;

HCl: hydrochloric acid;

HPLC: high performance liquid chromatography;

¹ H-NMR: nuclear magnetic resonance hydrogen spectrum

HOBT: 1-hydroxybenzotriazole;

HATU:2- (7-azobenzotriazole) -N, N' -tetramethylurea hexafluorophosphate; KOH: potassium hydroxide;

K ₂ CO ₃ : potassium carbonate;

LC-MS: liquid chromatography mass spectrometry;

m: multiple peaks;

m: moles;

MeOH: methanol;

mg: milli-scale;

g: g;

MgSO ₄ : magnesium sulfate;

MHz: megahertz (megahertz);

min: minutes;

mL: milliliters;

mmol: millimoles;

mol: moles;

MS m/z: mass spectrum peaks;

Na ₂ CO ₃ : sodium carbonate;

NaOH: sodium hydroxide;

Na ₂ SO ₄ : sodium sulfate;

NMR is nuclear magnetic resonance;

pH: pH value;

ppm: parts per million;

prep-TLC, preparative thin layer chromatography;

py is pyridine;

q: a quartet;

rf: a displacement value;

RT: retention time;

s: single peak;

sat is saturated

THF: tetrahydrofuran;

TEA: triethylamine;

TFA: trifluoroacetic acid;

TLC: thin layer chromatography;

zn: zinc powder

Characteristic chemical shift (delta) is measured with a low magnetic field (for tetramethylsilane ¹ H-NMR), conventional abbreviations are used for the nomenclature of the main peaks: for example s, single peakThe method comprises the steps of carrying out a first treatment on the surface of the d, double peaks; t, triplet; q, quartet; m, multiple peaks; br, broad peak. The following abbreviations have been used for the usual solvents: CDCl ₃ Deuterated chloroform; DMSO-d ₆ Deuterated dimethyl sulfoxide; and MeOH-d ₄ Deuterated methanol. When appropriate, NMR data for the tautomer can be recorded; and some exchangeable protons may not be visible.

Mass spectra MS (m/z) were recorded using electrospray ionization (ESI) or Atmospheric Pressure Chemical Ionization (APCI).

In cases where preparative TLC or silica gel chromatography has been used, one skilled in the art can select any combination of solvents to purify the desired compound.

Typically, the reaction is followed by thin layer chromatography and/or liquid chromatography-mass spectrometry and, where appropriate, working up. Those skilled in the art will recognize that purification can vary from experiment to experiment; typically, the adsorbents, solvents, and solvent ratios used for the eluent/gradient are selected to provide the appropriate Rf or retention time. Those skilled in the art will also recognize that HPLC purification can be performed in a variety of ways, including the use of forward stationary phases, reverse stationary phases, chiral stationary phases, and supercritical eluents. One skilled in the art will recognize the appropriate choice of chromatographic and HPLC purification conditions.

Example 1 preparation of Compounds 1-2

Compound 1-1 (20 g,1 eq) was dissolved in THF (300 mL), EDCI (24.85 g,1.2 eq) and HOBT (17.52 g,1.2 eq) were added thereto, and stirred at 20℃for 0.5 h. Then compound 1a (9.2 g,1 eq) and DIPEA (57 ml,3 eq) were added. Stirring is carried out at 20℃for 12 hours. After completion of the LC-MS detection reaction, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL. Times.2), and the combined organic phases were washed with 1M hydrochloric acid (100 mL. Times.2) and saturated sodium bicarbonate solution (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 1-2: yellow oil (27.3 g, yield: 99%).

Example 2 preparation of Compounds 1-3

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Compound 1-2 (25.3 g,1 eq) was dissolved in DMF (300 mL), to which was added potassium carbonate (27.73 g,2 eq) and compound 1b (20 g,1 eq) and stirred at 70℃for 12 hours. After completion of the LC-MS detection reaction, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (200 ml×2), the combined organic phases were washed with water (100 ml×2), dried over anhydrous sodium sulfate and purified on a silica gel column (petroleum ether: ethyl acetate=10:1/60:40) to give compounds 1-3: yellow solid (34 g, yield: 79%, purity: 92%).

Example 3 preparation of Compounds 1-4

Compounds 1-3 (3 g,1 eq) were dissolved in DCM (40 mL) to which TFA (10 mL) was added and stirred at 20℃for 12 h. After the LC-MS detection reaction is completed, the reaction solution is decompressed and concentrated to obtain crude compounds 1-4: yellow oil (2.3 g, yield: 99%).

Example 4 preparation of Compounds 1-5

Compound 1c (1.12 g,1 eq) was dissolved in DCM (20 mL), cooled to 0deg.C, triphosgene (0.7 g,0.34 eq) was added thereto, and after stirring at 0deg.C for 10 min, TEA (1 mL,1 eq) was added thereto. Naturally heating to 20 ℃, and stirring for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was cooled to 0℃and Compound 1-4 (2.3 g,1 eq) and TEA (5 mL,5 eq) were added. Stirring is carried out at 20℃for 12 hours. After completion of LC-MS detection reaction, poured into water (20 mL), extracted with ethyl acetate (30 ml×2), and the combined organic phases were dried over anhydrous sodium sulfate and purified on a silica gel column (petroleum ether: ethyl acetate=10:1/18:82) to give compounds 1-5: yellow oil (3 g, yield: 83%, purity: 93%).

EXAMPLE 5 preparation of Compound 1

Compounds 1-5 (3 g,1 eq) were dissolved in MeOH (50 mL), cooled to 0deg.C, and zinc powder (1.89 g,5 eq) and acetic acid (1.65 mL,5 eq) were added thereto. Stirring is carried out at 70℃for 12 hours. After completion of the LC-MS detection reaction, ethyl acetate (30 mL) was added thereto, followed by filtration through celite, the filtrate was adjusted to ph=8 with 1M aqueous sodium hydroxide solution, filtered through celite, extracted with ethyl acetate (30 ml×2), dried and concentrated under reduced pressure to give compound 1: pale yellow solid (2.7 g, yield: 95%, MS M/z: M+H) ⁺ ＝490.1)。

EXAMPLE 6 preparation of Compounds A-1 to A-7

Taking the synthesis of the compound A-1 as an example: compound 1 (57.2 mg,1 eq) was dissolved in THF (3 mL), EDCI (94 mg,1.2 eq) and HOBT (66.24 mg,1.2 eq) were added thereto, and stirred at 20℃for 0.5 h. Compound 9 (200 mg,1 eq) and DIPEA (214 μl, 3 eq) were then added. Stirring is carried out at 20℃for 12 hours. After completion of the LC-MS detection reaction, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL. Times.2), the combined organic phases were washed with 1M aqueous hydrochloric acid (10 mL. Times.2) and saturated sodium bicarbonate solution (10 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product, which was prepared in reverse phase (20% -65% acetonitrile, 0.1% TFA) to give Compound A-1: white solid (120 mg, yield: 50%, purity: 96.13%, MS M/z: M+H) ⁺ ＝612.3)。

¹ H NMR(400MHz,DMSO)δ10.21(s,1H),8.67(s,1H),8.08-7.98(m,3H),7.81(d,J＝7.8Hz,1H),7.68(d,J＝8.4Hz,1H),7.55(s,1H),7.47(t,J＝7.9Hz,1H),7.37(t,J＝8.6Hz,2H),7.27(d,J＝7.3Hz,1H),7.11(d,J＝8.8Hz,1H),3.86(s,1H),3.60(d,J＝31.1Hz,4H),3.28(s,4H),3.10(d,J＝22.5Hz,3H),1.79(s,2H),1.54(s,2H),1.31(d,J＝32.7Hz,4H).

The synthesis of A-2 to A-7 refers to the synthesis of A-1.

Compound a-2: white solid (130 mg, yield 50%, purity 99.6%).

¹ H NMR(400MHz,DMSO)δ10.27(s,1H),8.67(s,1H),8.07-7.95(m,3H),7.81(d,J＝7.7Hz,1H),7.69(d,J＝8.0Hz,1H),7.64-7.53(m,3H),7.47(t,J＝7.8Hz,1H),7.27(d,J＝7.2Hz,1H),7.11(d,J＝8.7Hz,1H),3.86(s,1H),3.60(d,J＝31.3Hz,4H),3.28(s,4H),3.10(d,J＝29.3Hz,3H),1.80(s,2H),1.53(s,2H),1.34(s,4H).

Compound a-3: white solid (140 mg, yield 56%, purity 98.5%).

¹ H NMR(400MHz,DMSO)δ10.12(s,1H),8.67(s,1H),8.01(d,J＝9.7Hz,1H),7.87(d,J＝7.9Hz,2H),7.82(d,J＝8.1Hz,1H),7.71(dd,J＝8.7,1.9Hz,1H),7.57(d,J＝2.0Hz,1H),7.47(t,J＝7.9Hz,1H),7.33(d,J＝7.9Hz,2H),7.27(d,J＝7.6Hz,1H),7.10(d,J＝8.8Hz,1H),3.86(s,1H),3.60(d,J＝30.1Hz,4H),3.27(s,4H),3.09(d,J＝17.1Hz,3H),2.38(s,3H),1.80(s,2H),1.53(s,2H),1.34(s,4H).

Compound a-4: white solid (130 mg, 51% yield, 95.8% purity).

¹ H NMR(400MHz,DMSO)δ10.09(s,1H),8.65(s,1H),8.01(s,1H),7.80(d,J＝7.8Hz,1H),7.47(d,J＝6.7Hz,2H),7.40(s,1H),7.24(dd,J＝20.6,7.5Hz,3H),7.13(d,J＝7.4Hz,2H),7.06(d,J＝8.7Hz,1H),3.82(s,1H),3.58(d,J＝26.1Hz,6H),3.28-2.98(m,7H),2.27(s,3H),1.78(s,2H),1.54-1.20(m,6H).

Compound a-5: white solid (135 mg, yield 55%, purity 99.8%).

¹ H NMR(400MHz,DMSO)δ9.75(s,1H),8.65(s,1H),8.01(s,1H),7.80(d,J＝8.2Hz,1H),7.50-7.41(m,3H),7.26(d,J＝7.7Hz,1H),7.04(d,J＝8.8Hz,1H),3.82(s,1H),3.61(s,4H),3.19(d,J＝23.9Hz,4H),3.03(s,3H),2.27(dd,J＝15.6,7.3Hz,1H),1.75(t,J＝12.1Hz,6H),1.64(d,J＝10.3Hz,1H),1.55-1.16(m,11H).

Compound a-6: white solid (140 mg, yield 54%, purity 96.9%, MS M/z: m+h+= 633.3).

¹ H NMR(400MHz,DMSO)δ11.42(s,1H),10.09(s,1H),8.67(s,1H),8.27(s,1H),8.02(s,1H),7.82(d,J＝8.4Hz,1H),7.74(dd,J＝8.6,1.8Hz,2H),7.62(d,J＝2.5Hz,1H),7.51-7.45(m,3H),7.27(d,J＝7.6Hz,1H),7.11(d,J＝8.9Hz,1H),6.59(s,1H),3.87(s,1H),3.61(d,J＝26.2Hz,4H),3.27(s,4H),3.08(s,3H),1.80(s,2H),1.43(d,J＝73.9Hz,6H).

Compound a-7: white solid (0.458 g, yield 61%, purity 96.33%, MS M/z: M+H) ⁺ ＝594.1)。

¹ H NMR:(400MHz,DMSO)δ10.20(s,1H),8.66(s,1H),8.01(s,1H),7.98-7.92(m,2H),7.81(d,J＝8.4Hz,1H),7.70(dd,J＝8.9,2.5Hz,1H),7.62-7.50(m,4H),7.47(t,J＝8.0Hz,1H),7.27(d,J＝7.7Hz,1H),7.11(d,J＝8.9Hz,1H),3.87(d,J＝13.1Hz,1H),3.70-3.50(m,4H),3.32-3.20(m,4H),3.16-2.99(m,3H),1.89-1.72(m,2H),1.54(d,J＝7.3Hz,2H),1.36-1.33(m,4H).

EXAMPLE 7 preparation of Compound 2-1

To a solution of compounds 1 to 3 (10.0 g,1.0 eq) in MeOH (250 mL) at room temperature, zinc powder (6.25 g,4.0 eq) and acetic acid (5.85 g,4.0 eq) were added, the reaction mixture was warmed to 65℃and stirred at reflux overnight, the progress of the reaction was monitored by LC-MS, after completion of the reaction, the reaction mixture was suction filtered under reduced pressure, the cake was washed with MeOH (100 mL), the filtrates were combined and concentrated under reduced pressure, a saturated sodium bicarbonate solution (200 mL) was added after dilution with ethyl acetate (200 mL), the aqueous phase was extracted three times with ethyl acetate (100 mL), the organic phase was combined and dried over anhydrous sodium sulfate, and the crude compound 2-1 was obtained by suction filtration and concentration under reduced pressure: yellow oil (11.0 g, yield: 98%, MS M/z: M+H) ⁺ ＝403.26)。

Example 8 preparation of Compound 2-2

To a flask was successively added a7 (0.61 g,1.0 eq), EDCI (1.43 g,1.5 eq), HOBT (0.81 g,1.2 eq), DIPEA (1.9 g,3.0 eq) and THF (50 mL) at room temperature, after half an hour of stirring until the solution was clear, compound 2-1 (2.01 g,1.0 eq) was added, the reaction mixture was stirred overnight at room temperature, the progress of the reaction was monitored by LC-MS, after the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), saturated sodium bicarbonate solution (50 mL) was added, the aqueous phase was extracted 3 times with ethyl acetate (50 mL), the fractions were separated, the organic phases were combined and dried with anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to give the crude product, and compound 2-2 was purified by a silica gel column (petroleum ether: ethyl acetate=10:1/3:1) as a yellow solid (2.4 g, yield: 94.8%, purity: 95%, M/z: M+H) ⁺ ＝507.29)。

Example 9 preparation of Compound 2

Compound 2-2 (2.4 g,1.0 eq), DCM (30 mL) and TFA (10 mL) were added in sequence to a flask at room temperature, the reaction was stirred at room temperature for 4 hours, the progress of the reaction was monitored by LC-MS, after completion of the reaction, the reaction was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), saturated sodium bicarbonate solution was added to adjust pH to 8-9, the aqueous phase was extracted 3 times with ethyl acetate (50 mL), the liquid was separated, the organic phases were combined and dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to give crude compound 2: yellow solid (2.0 g, yield: 96.3%, MS M/z: M+H) ⁺ ＝407.24)。

EXAMPLE 10 preparation of Compounds B-1 to B-6

Taking the synthesis of the compound B-1 as an example: to the flask was added compound b1 (60 mg,1.0 eq) and DCM (5 mL) in order at room temperature, the solution was stirred, cooled to 0 ℃ and nitrogen protected. Triphosgene (50 mg,0.17 mmol, 0.33 eq) was dissolved in DCM (2 mL) and added dropwise to the reaction solution, after stirring for 20 min, TEA (50 mg) was added dropwise to the reaction solution, the reaction was monitored by TLC at a reaction temperature of 0 ℃, after the consumption of the starting material was completed and a new spot was formed, compound 2 (200 mg,0.497 mmol, 1.0 eq) was dissolved in DCM (2 mL) and added dropwise to the reaction solution, the reaction temperature was maintained at 0 ℃, the pH of the reaction solution was adjusted to 8 to 9 with TEA, and the reaction system was warmed to room temperature for 2 hours. LC-MS monitors the reaction progress, after the compound 2 is completely consumed, the reaction solution is decompressed and concentrated to obtain a crude product, and the crude product is purified by reverse preparation (20% -78% acetonitrile, 0.1% TFA) to obtain the compound B-1: pale yellow solid (50 mg, yield: 18.5%, purity: 95.9%, MS M/z: M+H) ⁺ ＝556.28)。

¹ H NMR(400MHz,DMSO)δ10.20(s,1H),8.16(s,1H),7.98-7.91(m,2H),7.69(dd,J＝8.8,2.6Hz,1H),7.62-7.50(m,4H),7.40-7.34(m,2H),7.10(d,J＝8.9Hz,1H),6.87-6.76(m,2H),3.70(s,3H),3.62-3.53(m,4H),3.28-3.03(m,8H),1.90-1.71(m,2H),1.64-1.54(m,2H),1.54-1.34(m,4H).

The synthesis of B-2 to B-6 refers to the synthesis of B-1.

Compound B-2: white solid (32 mg, yield: 12.1%, purity: 95.8%, MS M/z: M+H) ⁺ ＝544.3)

¹ H NMR(400MHz,DMSO)δ10.21(s,1H),8.09(s,1H),8.00-7.90(m,2H),7.70(dd,J＝8.9,2.6Hz,1H),7.63-7.51(m,4H),7.50-7.42(m,1H),7.25-7.16(m,1H),7.16-7.06(m,3H),3.59-3.54(m,6H),3.30-3.24(m,2H),3.19(d,J＝8.5Hz,2H),3.14-3.08(m,2H),1.82(s,2H),1.53(s,4H),1.37(s,2H).

Compound B-3: pale yellow solid (35 mg, yield: 13.3%, purity: 96.4%, MS M/z: M+H) ⁺ ＝540.3)

¹ H NMR(400MHz,DMSO)δ10.20(s,1H),8.22(s,1H),8.01-7.85(m,2H),7.69(dd,J＝8.9,2.6Hz,1H),7.62-7.46(m,4H),7.34(s,1H),7.29(d,J＝8.0Hz,1H),7.17-7.03(m,2H),6.75(d,J＝7.5Hz,1H),4.09-4.00(m,2H),3.64-3.59(m,2H),3.59-3.50(m,2H),3.26(t,J＝4.9Hz,2H),3.17(d,J＝3.1Hz,2H),3.08(t,J＝4.8Hz,2H),2.25(s,3H),1.87-1.69(m,2H),1.50(s,4H),1.33(s,2H).

Compound B-4: white solid (49 mg, yield: 18.2%, purity: 97.2%, MS M/z: M+H) ⁺ ＝554.3)

¹ H NMR(400MHz,DMSO)δ10.20(s,1H),8.03-7.85(m,2H),7.69(dd,J＝8.9,2.6Hz,1H),7.62-7.50(m,4H),7.34-7.25(m,6H),7.22-7.15(m,1H),7.06(d,J＝8.9Hz,1H),6.59(d,J＝8.0Hz,1H),4.87(p,J＝7.1Hz,1H),3.47(dd,J＝14.4,8.4Hz,4H),3.19(s,2H),3.10(d,J＝5.0Hz,4H),1.76(s,2H),1.55(s,4H),1.37(d,J＝7.1Hz,5H),1.29(d,J＝7.0Hz,2H).

Compound B-5: white solid (50 mg, yield: 17.8%, purity: 98.9%, MS M/z: M+H) ⁺ ＝576.3)

¹ H NMR(400MHz,DMSO)δ10.20(s,1H),8.54(s,1H),8.07(d,J＝1.8Hz,1H),7.94(dd,J＝5.3,3.2Hz,2H),7.79(dd,J＝8.5,2.7Hz,2H),7.74(d,J＝8.0Hz,1H),7.69-7.66(m,2H),7.62-7.49(m,4H),7.46-7.39(m,1H),7.37-7.31(m,1H),7.12(d,J＝8.9Hz,1H),3.72-3.65(m,3H),3.65-3.59(m,2H),3.33-3.27(m,2H),3.26-3.14(m,2H),3.13-3.04(m,2H),1.84(s,2H),1.47(s,4H),1.35-1.23(m,3H).

Compound B-6: pale yellow solid (20 mg, yield: 7.2%, purity: 95.0%, MS M/z: M+H) ⁺ ＝566.3)

¹ H NMR(400MHz,DMSO)δ10.19(s,1H),7.97-7.90(m,2H),7.69(dd,J＝8.9,2.6Hz,1H),7.62-7.57(m,1H),7.54-7.51(m,3H),7.19-7.13(m,4H),7.09(d,J＝8.9Hz,1H),4.28(s,2H),4.05-4.01(m,2H),3.44(s,4H),3.40-3.33(m,2H),3.30-3.23(m,2H),3.16(t,J＝7.6Hz,2H),3.06(s,2H),2.86(t,J＝5.5Hz,2H),1.85-1.82(m,2H),1.50(s,2H),1.44-1.28(m,4H).

EXAMPLE 11 preparation of Compound 3-1

Compound 1c (5 g,1 eq) was dissolved in DCM (100 mL), cooled to 0 ℃, triphosgene (3.13 g,0.34 eq) was added thereto, and after stirring at 0 ℃ for 10 minutes, TEA (3 g,1 eq) was added thereto. Naturally heating to 20 ℃, and stirring for 2 hours. After completion of the LC-MS detection reaction, the reaction solution was cooled to 0℃and Compound 1b (6.21 g,1 eq) and TEA (15.6 g,5 eq) were added. Stirring at room temperature for 12 hours. After completion of LC-MS detection reaction, poured into water (200 mL), extracted with DCM (50 ml×2) and the combined organic phases were dried over anhydrous sodium sulfate and purified on a silica gel column (petroleum ether: ethyl acetate=10:1/1:1) to give compound 3-1: yellow oil (10 g, yield: 83.3%, purity: 90%).

EXAMPLE 12 preparation of Compound 3-2

Compound 3-1 (10 g,1 eq) was dissolved in DCM (70 mL), cooled to 0deg.C, and TFA (30 mL) was added thereto. Naturally heating to 20 ℃, and stirring for 2 hours. After the LC-MS detection reaction is completed, the reaction solution is decompressed and concentrated to obtain TFA salt of the compound 3-2: brown oil (10 g, purity: 90%).

EXAMPLE 13 preparation of Compound 3-3

Compounds 3-2 (10 g,1 eq) and 3a (5.2 g,1 eq) were dissolved in DMF (150 mL), cooled to 0deg.C, and potassium carbonate (28.8 g,8 eq) was added in portions. After stirring at 50℃for 4 hours. After the LC-MS detection reaction is completed, filtering, pouring the filtrate into water (200 mL), adjusting the pH to 7 by 6M hydrochloric acid, washing out solid, filtering, and drying a filter cake to obtain a compound 3-3: yellow solid (9 g, yield: 74%, purity: 92%).

EXAMPLE 14 preparation of Compounds 3-4

To a solution of compound 3-3 (9 g,1 eq) in MeOH (150 mL) under ice bath was added glacial acetic acid (5.8 g,5 eq) to which zinc powder (5.7 g,5 eq) was added in portions. Stirring for 4 hours at 70 ℃ under the protection of nitrogen. After the completion of the LC-MS detection reaction, the mixture was filtered, the filtrate was poured into water (200 mL), the pH was adjusted to 8 with 1M aqueous sodium hydroxide solution, extraction was performed three times with ethyl acetate (100 mL), and the organic phases were combined and concentrated to give the compound 3-4: yellow solid (7 g, yield: 83%, purity: 90%).

Example 15 preparation of Compounds 3-5

A solution of compound a7 (1.96 g,1 eq), HATU (7.94 g,1 eq), DIPEA (4.2 g,2 eq) in THF (100 mL) was stirred at room temperature for 10 minutes, and then compound 3-4 (7 g,1 eq) was added thereto. Stirring for 4 hours at room temperature under the protection of nitrogen. After completion of the LC-MS detection reaction, the mixture was poured into water (200 mL), the pH was adjusted to 6-7 with 1M diluted hydrochloric acid, extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (200 mL), concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=10:1/2:1) to give compound 3-5: yellow solid (5 g, yield: 57%, purity: 90%).

EXAMPLE 16 preparation of Compound 3

To a solution of compound 3-5 (5 g,1 eq) in THF (50 mL) was added a solution of lithium hydroxide monohydrate (3.1 g,8 eq) in water (25 mL), and the mixture was stirred at 50 ℃ for 4 hours under nitrogen. After the LC-MS detection reaction is completed, the pH is adjusted to 6-7 by using a 6M hydrochloric acid aqueous solution, the mixture is filtered, and a filter cake is concentrated and dried to obtain a compound 3: white solid (3 g, yield: 61.6%, purity: 92%, MS M/z: M+H) ⁺ ＝527.1)。

EXAMPLE 17 preparation of Compounds C-1 to C-7

Taking the synthesis of the compound C-1 as an example: to a solution of compound 3 (0.1 g,1 eq) in THF (2 mL) were added HATU (94 mg,1.3 eq) and DIPEA (49 mg,2 eq), and after stirring at room temperature under nitrogen for 10 minutes, compound c1 (16 mg,1.2 eq) was added thereto and stirred at room temperature for 4 hours. After completion of the LC-MS detection reaction, the mixture was poured into water (5 mL), the pH was adjusted to 6-7 with 1M aqueous hydrochloric acid, extraction was performed 3 times with ethyl acetate (10 mL), and the crude product was concentrated and purified by reverse phase column (50% -90% acetonitrile, 0.1% TFA) to give Compound C-1: yellow solid (70 mg, yield 42%, purity 99.2%, MS M/z: M+H) ⁺ ＝580.3)。

¹ H NMR(400MHz,DMSO)δ10.20(s,1H),8.67(s,1H),8.01(s,1H),7.94(d,J＝7.1Hz,2H),7.81(d,J＝8.2Hz,1H),7.68(dd,J＝8.8,2.5Hz,1H),7.61(d,J＝2.5Hz,1H),7.58(d,J＝7.2Hz,1H),7.53(t,J＝7.3Hz,2H),7.47(t,J＝8.0Hz,1H),7.27(d,J＝7.7Hz,1H),7.11(d,J＝8.9Hz,1H),3.67-3.54(m,4H),3.42(s,2H),3.25(d,J＝24.2Hz,5H),2.91(d,J＝10.1Hz,1H),1.73(d,J＝39.4Hz,6H).

The synthesis of C-2 to C-6 refers to the synthesis of C-1.

Compound C-2: yellow solid (80 mg, 44% yield, 99.4% purity).

¹ H NMR(400MHz,DMSO)δ10.23(d,J＝6.3Hz,1H),8.57(d,J＝13.5Hz,1H),7.97-7.89(m,3H),7.79-7.70(m,2H),7.64-7.61(m,1H),7.58(d,J＝7.2Hz,1H),7.53(t,J＝7.3Hz,2H),7.41(q,J＝7.8Hz,1H),7.26-7.21(m,1H),7.21-7.11(m,4H),7.02(dd,J＝52.5,8.0Hz,1H),5.00-4.58(m,1H),4.45-4.24(m,1H),4.02-3.72(m,1H),3.67-3.40(m,4H),3.36-3.13(m,4H),2.96(s,1H),2.88(t,J＝6.8Hz,1H),2.72(t,J＝5.6Hz,1H),1.79(d,J＝4.9Hz,1H),1.60(d,J＝64.3Hz,1H).

Compound C-3: pale yellow solid (60 mg, yield 52.5%, purity 97.3%, MS M/z: M+H) ⁺ ＝602.3)。

¹ H NMR(400MHz,DMSO)δ11.60(s,1H),10.36(s,1H),8.64(s,1H),8.16(d,J＝2.6Hz,1H),8.05-7.90(m,4H),7.80(d,J＝8.3Hz,1H),7.74(d,J＝7.6Hz,2H),7.61(t,J＝7.3Hz,1H),7.55(t,J＝7.2Hz,2H),7.47(t,J＝7.9Hz,1H),7.36(d,J＝8.8Hz,1H),7.33-7.23(m,3H),7.05(t,J＝7.3Hz,1H),3.77-3.68(m,2H),3.63(t,J＝5.7Hz,2H),3.24-3.17(m,2H),1.97-1.87(m,2H),1.30-1.20(m,2H).

Compound C-4: yellow solid (52 mg, yield 41.5%, purity 97.2%, MS M/z: M+H) ⁺ ＝660.3。)

¹ H NMR(400MHz,DMSO)δ10.33(s,1H),9.48(s,1H),8.68(s,1H),8.11(d,J＝2.7Hz,1H),8.02(s,1H),8.00-7.96(m,2H),7.93(dd,J＝8.8,2.6Hz,1H),7.82(d,J＝8.0Hz,1H),7.63-7.58(m,1H),7.57-7.51(m,2H),7.47(t,J＝8.1Hz,1H),7.32(d,J＝8.8Hz,1H),7.28(d,J＝7.6Hz,1H),3.75-3.62(m,6H),3.36-3.27(m,2H),3.20-3.07(m,2H),2.04(s,6H),2.00(s,1H),1.95(s,4H),1.58(s,5H).

Compound C-5: pale yellow solid (46 mg, yield 38.9%, purity 95.1%, MS M/z: M+H) ⁺ ＝622.3。)

¹ H NMR(400MHz,DMSO)δ10.35(s,1H),9.73(d,J＝7.8Hz,1H),8.69(s,1H),8.12(d,J＝2.7Hz,1H),8.05(s,1H),8.02-7.90(m,3H),7.84(d,J＝8.7Hz,1H),7.63-7.57(m,1H),7.57-7.51(m,2H),7.48(t,J＝8.1Hz,1H),7.35(d,J＝8.8Hz,1H),7.28(d,J＝7.9Hz,1H),3.97-3.81(m,2H),3.73-3.68(m,4H),3.33(dd,J＝8.8,4.6Hz,2H),3.21-3.09(m,2H),1.99-1.80(m,4H),1.59-1.32(m,9H).

Compound C-6: white solid (49 mg, 40.7% yield, 98.3% purity, MS M/z: m+h+= 634.3.)

¹ H NMR(400MHz,DMSO)δ10.33(s,1H),10.05(t,J＝5.9Hz,1H),8.64(s,1H),8.12(d,J＝2.7Hz,1H),8.03-7.94(m,3H),7.91(dd,J＝8.8,2.7Hz,1H),7.81(d,J＝8.6Hz,1H),7.64-7.57(m,1H),7.57-7.51(m,2H),7.47(t,J＝8.0Hz,1H),7.37(dd,J＝8.7,5.6Hz,2H),7.32(d,J＝8.8Hz,1H),7.30-7.26(m,1H),7.17-7.11(m,2H),4.46(d,J＝5.8Hz,2H),3.63-3.56(m,4H),3.23-3.17(m,2H),3.15-3.08(m,2H),1.85-1.76(m,2H).

EXAMPLE 18 preparation of Compound 4-1

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Compound 1-1 (10 g,1 eq) was dissolved in THF (300 mL), EDCI (12.4 g,1.2 eq) and HOBT (8.86 g,1.2 eq) were added thereto, and stirred at 20℃for 0.5 h. Then compound c6 (6.76 g,1 eq) and DIPEA (28.5 ml,3 eq) were added. Stirring at room temperature for 12 hours. After completion of the LC-MS detection reaction, the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL. Times.2), and the combined organic phases were washed with 1M hydrochloric acid (100 mL. Times.2) and saturated sodium bicarbonate solution (100 mL. Times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 4-1: yellow oil (15 g, yield: 95%).

EXAMPLE 19 preparation of Compound 4-2

Compounds 4-1 (10 g,1 eq) and 1b (6.85 g,1 eq) were dissolved in DMF (150 mL), cooled to 0deg.C, and potassium carbonate (14.2 g,3 eq) was added thereto. After stirring at 50℃for 4 hours. After the LC-MS detection reaction is completed, filtering, pouring the filtrate into water (200 mL), adjusting the pH to 7 by 6M hydrochloric acid, washing out solid, filtering, and drying a filter cake to obtain a compound 4-2: yellow solid (14 g, yield: 86.5%, purity: 92%).

EXAMPLE 20 preparation of Compounds 4-3

To a one-necked flask at room temperature, compound 4-2 (14 g,1.0 eq), DCM (70 mL) and TFA (30 mL) were sequentially added, the reaction mixture was stirred at room temperature for 4 hours, the progress of the reaction was monitored by LC-MS, and after completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a TFA salt of crude compound 4-3: brown oil (1)3g，MS m/z：M+H ⁺ ＝373.1)。

Example 21 preparation of Compounds 4-4

With r=3-CH ₃ The following are examples: to a solution of m-methylaniline (0.5 g,1.0 eq) in DCM (10 mL) in ice bath was added triphosgene (0.46 g,0.33 eq), TEA (0.47 g,1 eq) was added dropwise to the reaction solution, the reaction was monitored by TLC at 0deg.C for 20 minutes, after the consumption of the starting material was completed, a solution of compound 4-3 (1.74 g,1.0 eq) in DCM (5 mL) was added dropwise to the reaction solution at 0deg.C, the pH of the reaction solution was adjusted to 8-9 by TEA addition, and the reaction system was warmed to room temperature for 2 hours. LC-MS monitors the reaction progress, after the compound 4-3 is completely consumed, the reaction solution is decompressed and concentrated to obtain a crude product, and the crude product is purified by reverse preparation (20% -78% acetonitrile, 0.1% TFA) to obtain the compound 4-4: pale yellow solid (1.2 g, yield: 50.8%, purity: 93%).

Other R substituents refer to meta-methylaniline.

Example 22 preparation of Compound 4

With r=3-CH ₃ The following are examples: to a solution of compound 4-4 (1.2 g,1.0 eq) in MeOH (20 mL), glacial acetic acid (0.57 g,4 eq) was added, zinc powder (0.62 g,4 eq) was added in portions to the reaction solution, stirred at 80 ℃ for 4 hours, the reaction was monitored by LC-MS, after complete consumption of the starting material, the product was formed, filtered, the filtrate was poured into water (100 mL), pH was adjusted to 8 by adding 1M aqueous sodium hydroxide solution, extracted three times with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated to give crude compound 4: yellow solid (0.8 g, yield: 70.8%, purity: 90%, MS M/z: M+H) ⁺ ＝476.1)。

Other R substituents refer to meta-methylaniline.

EXAMPLE 23 preparation of Compounds D-1 to D-4

Taking the synthesis of the compound D-1 as an example: to a solution of compound a3 (0.23 g,1.0 eq) in DMF (10 mL) was added HATU (1.09 g,1.3 eq) and DIPEA (0.57 g,2 eq), and after stirring at room temperature for 10 minutes, compound 4 (0.8 g,1 eq) was added and stirring at room temperature for 4 hours, the disappearance of starting material was detected by LC-MS, and the product was produced. The reaction solution was poured into water (50 mL), pH was adjusted to 7 by adding 1M aqueous hydrochloric acid, extracted three times with ethyl acetate (50 mL), concentrated, and purified (30% -90% acetonitrile, 0.1% trifluoroacetic acid) by reverse direction to give Compound D-1: yellow solid (0.65 g, yield: 65%, purity: 95%, MS M/z: M+H) ⁺ ＝594.3)。 ¹ H NMR(400MHz,DMSO)δ10.24(s,1H),10.10(t,J＝5.9Hz,1H),8.21(s,1H),8.12(d,J＝2.7Hz,1H),7.91(dd,J＝11.6,5.4Hz,3H),7.42-7.33(m,4H),7.29(dd,J＝10.5,7.3Hz,3H),7.18-7.08(m,3H),6.77(d,J＝7.5Hz,1H),4.46(d,J＝5.8Hz,2H),3.58-3.46(m,4H),3.10(dd,J＝19.3,14.6Hz,4H),2.39(s,3H),2.25(s,3H),1.78(s,2H).

The synthesis of D-2 to D-4 refers to the synthesis of D-1.

Compound D-2: white solid (70 mg, yield: 70%, purity: 96%, MS M/z: M+H) ⁺ ＝610.3.)

¹ H NMR(400MHz,DMSO)δ10.24(s,1H),10.12(t,J＝6.0Hz,1H),8.17-8.08(m,2H),7.94-7.87(m,3H),7.43-7.32(m,6H),7.29(d,J＝8.8Hz,1H),7.20-7.12(m,2H),6.85-6.80(m,2H),4.47(d,J＝5.9Hz,2H),3.71(s,3H),3.57-3.52(m,2H),3.51-3.46(m,2H),3.18-3.12(m,2H),3.11-3.06(m,2H),2.39(s,3H),1.79-1.76(m,2H).

Compound D-3: white solid (0.29 g, yield: 67%, purity: 97.1%, MS M/z: M+H) ⁺ ＝598.3)

¹ H NMR:(400MHz,DMSO)δ10.34(s,1H),10.09(t,J＝5.9Hz,1H),8.21(s,1H),8.07(m,J＝8.8,8.4,2.4Hz,3H),7.90(dd,J＝8.8,2.7Hz,1H),7.42-7.35(m,4H),7.34-7.27(m,3H),7.20-7.07(m,3H),6.77(d,J＝7.4Hz,1H),4.47(d,J＝5.8Hz,2H),3.55(d,J＝5.1Hz,2H),3.50(t,J＝6.0Hz,2H),3.17(d,J＝4.6Hz,2H),3.13-3.04(m,2H),2.25(s,3H),1.78(m,2H).

Compound D-4: white solid (49 mg, yield: 58.2%, purity: 97.2%, MS M/z: M+H) ⁺ ＝619.3)

¹ H NMR(400MHz,DMSO)δ10.18(d,J＝9.5Hz,1H),9.57-9.54(m,1H),7.69-7.59(m,2H),7.53-7.44(m,1H),7.41-7.02(m,12H),4.40(dd,J＝23.4,5.9Hz,2H),3.66-3.55(m,2H),3.23(t,J＝5.7Hz,2H),3.16-3.05(m,2H),3.03-2.95(m,2H),2.34(d,J＝2.9Hz,3H),1.84-1.53(m,2H).

EXAMPLE 24 preparation of Compound 5-1

Compound 5a is exemplified by 4-t-butoxycarbonyl-2-methylpiperazine: triphosgene (0.6 g,0.33 eq) was added to a solution of compound 1c (1 g,1.0 eq) in DCM (10 mL) under ice bath, after stirring for 20 minutes, TEA (0.63 g,1 eq) was added dropwise to the reaction solution, the reaction was monitored by TLC at a reaction temperature of 0 ℃, after the consumption of the starting material was completed and a new spot was formed, a solution of compound 5a (1.24 g,1.0 eq) in DCM (5 mL) was added dropwise to the reaction solution, the reaction temperature was maintained at 0 ℃, the pH of the reaction solution was adjusted to 8 to 9 with TEA, and the reaction system was warmed to room temperature for 2 hours. After the TLC monitors the progress of the reaction, compound 1c is completely consumed, the reaction solution is concentrated under reduced pressure to obtain a crude product, and purified by a silica gel column (petroleum ether: ethyl acetate=10:1/2:1) to obtain compound 5-1: pale yellow solid (1.8 g, yield: 75%, purity: 90%).

EXAMPLE 25 preparation of Compound 5-2

By R ^a ＝CH ₃ ，R ^b =h is an example: compound 5-1 (1.8 g,1 eq) was dissolved in DCM (20 mL) to which it was addedTFA (10 mL) was added thereto, and the mixture was stirred at 20℃for 12 hours. After the LC-MS detection reaction is completed, the reaction liquid is decompressed and concentrated to obtain the trifluoroacetate salt of the crude compound 5-2: yellow brown oil (1.6 g, purity: 90%).

Other 5-1 substituents are synthesized with reference to the substituent.

EXAMPLE 26 preparation of Compounds 5-3

By R ^a ＝CH ₃ ，R ^b =h is an example: compounds 5-2 (1.6 g,1 eq) and 5b (1.1 g,1 eq) were dissolved in DMF (50 mL), cooled to 0deg.C, and potassium carbonate (6.15 g,8 eq) was added in portions. Stirred at 50℃for 4 hours. After the LC-MS detection reaction is complete, filtering, pouring the filtrate into water (100 mL), adjusting the pH to 7 with 6M hydrochloric acid, washing out solids, filtering, and drying the filter cake to obtain a compound 5-3: yellow solid (1.54 g, yield: 59%, purity: 92%).

Other 5-2 substituents are synthesized with reference to the substituent.

EXAMPLE 27 preparation of Compounds 5-4

By R ^a ＝CH ₃ ，R ^b =h is an example: to a solution of compound 5-3 (1.54 g,1 eq) in MeOH (30 mL) under ice bath was added glacial acetic acid (0.79 g,4 eq) followed by zinc powder (0.8 g,4 eq) in portions. Stirring for 4 hours at 70 ℃ under the protection of nitrogen. After completion of the LC-MS detection reaction, filtration, washing with ethyl acetate (100 mL), pouring the filtrate into water (200 mL), adjusting pH to 8 with 1M aqueous sodium hydroxide solution, separating the layers, extracting the aqueous layer with ethyl acetate (50 mL) three times, and concentrating the combined organic phases to obtain compound 5-4: yellow solid (1.2 g, yield: 84%, purity: 89%).

Other 5-3 substituents are synthesized with reference to the substituent.

Example 28 preparation of Compounds 5-5

By R ^a ＝CH ₃ ，R ^b =h is an example: a solution of compound a7 (0.34 g,1 eq), HATU (1.34 g,1.3 eq), DIPEA (0.77 g,2 eq) in THF (20 mL) was stirred at room temperature for 10 minutes, to which compound 5-4 (1.2 g,1 eq) was added. Stirring for 4 hours at room temperature under the protection of nitrogen. After completion of the LC-MS detection reaction, the mixture was poured into water (100 mL), the pH was adjusted to 6-7 with 1M diluted hydrochloric acid, extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine (100 mL), concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate=10:1/1:1) to give compound 5-5: yellow solid (1.3 g, yield: 89%, purity: 95%).

Other 5-4 substituents were synthesized with reference to this substituent.

Example 29 preparation of Compound 5

By R ^a ＝CH ₃ ，R ^b =h is an example: to a solution of compound 5-5 (1.3 g,1 eq) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (0.8 g,8 eq) in water (5 mL), and the mixture was stirred at 50℃for 4 hours under nitrogen. After the LC-MS detection reaction is completed, the pH is adjusted to 6-7 by using 6M hydrochloric acid aqueous solution, the mixture is filtered, and a filter cake is concentrated and dried to obtain a compound 5: white solid (1.26 g, yield: 98%, purity: 92%, MS M/z: M+H) ⁺ ＝527.1)。

Other 5-5 substituents are synthesized with reference to the substituent.

EXAMPLE 30 preparation of Compound E-1

Taking the synthesis of compound E-1 as an example: to a solution of compound 5 (0.1 g,1 eq) in THF (2 mL) were added HATU (94 mg,1.3 eq) and DIPEA (49 mg,2 eq), and after stirring at room temperature under nitrogen for 10 minutes, compound 1a (19 mg,1.2 eq) was added thereto and stirred at room temperature for 4 hours. After completion of the LC-MS detection reaction, the mixture was poured into water (5 mL), the pH was adjusted to 6-7 with 1M aqueous hydrochloric acid, extraction was performed 3 times with ethyl acetate (10 mL), and the crude product was concentrated and purified by reverse phase column (50% -90% acetonitrile, 0.1% TFA) to give Compound E-1: pale yellow solid (40 mg, yield: 35.5%, purity: 96%, MS M/z: M+H) ⁺ ＝594.1)。 ¹ H NMR(400MHz,CDCl ₃ )δ8.57(d,J＝71.2Hz,1H),7.90(dt,J＝4.9,3.2Hz,2H),7.87-7.69(m,3H),7.60-7.52(m,1H),7.48(dd,J＝11.4,4.4Hz,2H),7.40(t,J＝7.7Hz,1H),7.23(dd,J＝23.9,2.4Hz,1H),7.02(d,J＝8.8Hz,1H),4.40(dd,J＝124.4,9.3Hz,1H),4.20-4.07(m,2H),3.65-3.30(m,1H),3.28-3.15(m,3H),3.13-3.05(m,1H),3.02(dd,J＝14.1,6.9Hz,1H),2.95-2.82(m,1H),2.51(ddd,J＝20.5,11.8,6.0Hz,1H),1.73-1.66(m,1H),1.57(dd,J＝20.9,9.4Hz,3H),1.45-1.36(m,1H),1.31-1.22(m,4H).

The synthesis of E-2 to E-4 is referred to the synthesis of E-1.

Compound E-3: white solid (purity: 97%, MS M/z: M+H) ⁺ ＝580.2)

² H NMR:1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.90(d,J＝7.3Hz,2H),7.87-7.82(m,1H),7.72(s,1H),7.66(s,1H),7.57(s,1H),7.53(d,J＝7.8Hz,2H),7.44(s,1H),7.06(d,J＝12.9Hz,2H),3.75(d,J＝41.3Hz,4H),3.48(s,2H),3.22(s,4H),2.86(s,2H),1.69(s,4H),1.28(s,4H).

Activity test case

1. Experimental animals and raising

Experimental animals: male C57BL/6 mice with age of 8-10 weeks and weight of 22.0-26.0g are selected as experimental objects.

Feeding environment: SPF-grade laboratory animal center, SPF-grade mouse feed was purchased from Beijing Fukang Biotechnology Co.

Feeding conditions: the room temperature is between 22 and 24 ℃, the humidity is between 40 and 70 percent, the lighting time of light and dark alternation is 12 hours, and the food intake by free drinking water is realized.

2. Experimental cells and protocols

Experimental cells: human hepatocyte line L02 (human normal hepatocytes) was selected as the subject. Human hepatocyte line L02 was purchased from the national identification cell culture collection center.

Culture of human hepatocyte line L02: in DMEM high sugar medium (containing 10% fetal bovine serum+1% diabody, hereinafter simply referred to as medium), 37 ℃ and 5% CO ₂ Culturing in the environment.

The experimental steps are as follows:

(1) Plating cells: observing the cell state, selecting cells with better state activity, digesting and centrifuging to re-suspend the cells, diluting the cells according to 8000 cells/hole density after cell counting, and uniformly plating the cells in a high content cell imaging micro-pore plate.

(2) Pretreatment of medicines: after 12h of cell attachment growth, 20. Mu.M of the compound of the present invention was added to the medium (0.5% bovine serum albumin) and the cells were pretreated.

(3) Palmitic Acid (PA)/Oleic Acid (OA) induces lipid droplet accumulation: after pretreatment of the drug for 8 hours, palmitic acid and oleic acid were added to the medium, and the PA concentration in the medium was maintained at 0.2mM PA, OA concentration at 0.4mM OA, and the concentration of the compound of the present invention at 20. Mu.M, and the cells were treated to induce lipid droplets.

(4) Dyeing: after induction treatment for 18h, the cell waste liquid was discarded, PBS was washed twice, 4% paraformaldehyde was fixed at room temperature for 45min, the fixed liquid was discarded, PBS was washed twice, BODIPY was used for dyeing for 10min, the dyed liquid was discarded, and PBS was washed twice.

(5) And (5) performing on-machine detection by using a high content cell imaging system.

(6) The data were analyzed and plotted.

3. Pathology detection

The main operation procedure for preparing paraffin specimen sections is as follows: trimming liver, embedding frame treatment, running water flushing, dehydration, transparency, embedding, slicing, spreading, airing or baking for later use.

The following describes the main steps of hematoxylin-eosin (H & E) staining, CD11b staining, sirius red (PSR) staining used in the examples of the present invention:

the main steps of hematoxylin-eosin (H & E) staining are: paraffin specimen slices are taken for dewaxing until water, hematoxylin is used for dying cell nuclei, eosin is used for dying cytoplasm, dehydration sealing slice is carried out, microscopy is carried out, and image acquisition and analysis are carried out.

The main steps of CD11b staining are: paraffin sections were baked, dewaxed, hydrated, repaired, the liver sections of mice were first blocked with 10% goat serum, then incubated overnight with primary antibody (Boster, BM 3925) at 4 ℃, washed with PBS after incubation, incubated for 1H at 37 ℃ with secondary antibody (goat anti-rabit IgG (h+l) cross-adsorbed secondary antibody (sameifeishier technologies, a-11011, ma, usa)) after completion, and finally nucleated with 4', 6-diamidino-2-phenylindole (DAPI).

The steps of sirius red (PSR) staining are mainly as follows: dewaxing paraffin sample slice to water, red sirius staining liquid drop staining, slightly flushing with running water, removing surface staining liquid of slice, staining cell nucleus with Mayer' hematoxylin staining liquid, flushing with running water, and dewatering and sealing.

Test example 1 Effect of the inventive Compound treatment on fat accumulation in hepatocytes

Hepatocytes were divided into different compound-treated groups, control solution groups, BSA groups. After cells are attached for 12 hours, adding 20 mu M of different compounds into a culture medium, pretreating the compounds for 8 hours, adding 0.2mM PA and 0.4mM OA into the culture medium, and treating for 18 hours; a control solution group treated by pure PA/OA; the BSA group without PA/OA treatment; and (3) performing BODIPY staining after the treatment, and performing by using an operatta CLS high content analysis system.

Table 1 experiments to verify the effect of the treatment with the compounds of the invention on fat accumulation in hepatocytes

FIGS. 1 and 2 are diagrams of BODIPY staining imaging analysis of hepatocytes after treatment with different compounds. FIGS. 1 and 2 show that the relative fluorescence intensities of the A1, A2, A3, A4, A5, A6, A7, B3, B4, B5, B6, D1, D2, D3, C1, C2, C3, C4, C5, C6, E1, E3 fat droplets were significantly reduced and the cell numbers were substantially unchanged compared to the PA/OA group. The compound can obviously inhibit lipid accumulation in liver cells, and has no obvious toxic or side effect.

Test example 2 shadow of the Compound of the invention (e.g., A7) on high-fat high-cholesterol diet-induced nonalcoholic fatty liver disease Sound box

24C 57 wild type mice were divided into 4 groups of 6, and were fed with Normal diet (NC, composition: 19.2% protein, 67.3% carbohydrate, 4.3% fat, 20% protein, 70% carbohydrate, 10% fat, 3.85kcal/g total caloric mass) and high fat high cholesterol diet (high-fat/high-cholesterol diet; HFHC, composition: 18.3% protein, 20.8% carbohydrate, 60.9% fat, 5.2kcal/g total caloric mass), and were designated as NC group and HFHC group. After 8 weeks of feeding, NC-fed mice were given an oral gavage treatment of 60mg/kg A7 in one group and a solvent treatment in the other group. Likewise, HFHC fed mice were given 60mg/kg A7 oral gavage treatment in one group and solvent treatment in the other group. Dosing frequency was once daily for 8 weeks with continued NC or HFHC feeding.

Sampling after 16 weeks, measuring the weight and liver weight of the mice and calculating the liver weight/weight ratio; and performing pathological detection on liver tissues.

The results in figure 3 show that HFHC feeding induces non-alcoholic fatty liver disease, showing weight gain, increased liver weight to weight ratio, and reversed increases in body weight and liver weight ratio in mice orally administered with A7, compared to NC group; fig. 4 shows that HFHC-fed liver tissue exhibited steatosis and cavitation, increased inflammatory cell infiltration, and increased liver fibrosis compared to NC group, and that oral administration of A7 by NC group did not significantly alter, whereas under HFHC-fed conditions, steatosis, inflammatory cell infiltration, and fibrosis of the liver of mice administered with A7 were inhibited, indicating that oral administration of A7 was able to alleviate HFHC diet-induced non-alcoholic fatty liver disease.

It is to be understood that the invention described herein is not limited to particular methodologies, protocols, or reagents, as these may vary. The discussion and examples provided herein are presented for the purpose of describing particular embodiments only and are not intended to limit the scope of the present invention which is limited only by the claims.

Claims

1. The application of a compound shown in a formula O or a stereoisomer, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in preparing medicaments for treating and/or preventing fatty liver diseases and related diseases,

wherein:

n is selected from 0, 1, 2;

preferably, n is selected from 1, 2;

R ^a 、R ^b each independently selected from H, C1-C6 alkyl;

preferably, R ^a 、R ^b Each independently selected from H, methyl;

R ^2a 、R ^2b each independently ofAnd is selected from the group consisting of H, alkyl, cycloalkyl, aryl, benzyl, adamantyl, said alkyl, cycloalkyl, aryl, benzyl, adamantyl optionally substituted with halogen; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a heterocyclic group, which is optionally substituted with an alkyl group;

y is selected from

Preferably Y is selected from

2. Use according to claim 1, wherein R ^1a 、R ^1b Each independently selected from H, C6-C10 aryl, C1-C6 alkyl, said C6-C10 aryl, C1-C6 alkyl optionally substituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, phenyl; alternatively, R ^1a 、R ^1b And together with the N atom to which they are attached, form a 6-10 membered heterocyclyl, said 6-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

preferably, R ^1a 、R ^1b Each independently selected from:

1) H, C1C 6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

more preferably, R ^1a 、R ^1b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

1)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

2) A naphthyl group;

3. Use according to any one of claims 1-2, wherein R ^2a 、R ^2b Each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl, said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl optionally substituted with halogen; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

preferably, R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

more preferably, R ^2a 、R ^2b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

1) Cycloheptyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

4. Use according to any one of claims 1-3, wherein R ³ Selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl, said C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, benzyl, 5-to 10-membered heteroaryl optionally substituted with a group selected from halogen, C1-C6 alkyl;

Preferably, R ³ Selected from:

more preferably, R ³ Selected from:

1)wherein L is ³ Selected from the group consisting of a direct bond, methylene, ethylene,preferably selected from direct bond, methylene;

2) C3-C6 cycloalkyl, indolyl (preferably))；

Most preferably, R ³ Selected from the group consisting of

5. The use according to any one of claims 1 to 4, wherein the compound has the structure of formula I:

wherein:

more preferably, R ^1a 、R ^1b Each independently selected from:

1) H, C1C 6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

1) C1-C6 alkyl;

2)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

3) Naphthyl optionally substituted with C1-C6 alkyl;

1)wherein L is ¹ Selected from direct bond, -CR ^m R ⁿ -；

R ^m 、R ⁿ Each independently selected from H, C1-C4 alkyl;

preferably, R ^m 、R ⁿ Each independently selected from H, methyl;

2) A naphthyl group;

Preferably, R ^2a 、R ^2b Each independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl, said C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, benzyl, adamantyl optionally substituted with halogen; alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl optionally being substituted with C1-C6 alkyl;

more preferably, R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein the method comprises the steps of，L ² Selected from direct bond, methylene;

1) C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)Wherein L is ² Selected from direct bond, methylene;

more preferably, R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² 、R ¹³ Any one ofAnd (e.g. R ¹¹ ) Selected from H, F, cl, br, I, the remaining four are all H;

1) Cycloheptyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form Preferably form- >

Y is selected from

Preferably Y is selected from

more preferably, R ³ Selected from:

further preferably, R ³ Selected from:

2) C3-C6 cycloalkyl, indolyl (preferably))；

Most preferably, R ³ Selected from the group consisting of

6. The use according to any one of claims 1 to 4, wherein the compound has the structure shown in formula II:

wherein:

R ^a 、R ^b each independently selected from H, C1-C6 alkyl;

preferably, R ^a 、R ^b Each independently selected from H, methyl;

R ^1a 、R ^1b each independently selected from:

1) H, C1C 6 alkyl;

2)wherein the method comprises the steps of，

3) Naphthyl optionally substituted with C1-C6 alkyl;

preferably, R ^1a 、R ^1b Any one of them is H, and the other is selected from:

1) C1-C6 alkyl;

2)wherein (1)>

more preferably, R ^1a 、R ^1b Any one of them is H, and the other isWherein,

most preferably, R ^1a 、R ^1b Any one of them is H, and the other is

R ^2a 、R ^2b Each independently selected from:

1) H, C1C 1-C6 alkyl, C3-C8 cycloalkyl, adamantyl;

2)wherein L is ² Selected from direct bond, methylene, preferably methylene;

1) C1-C6 alkyl;

2)wherein L is ² Selected from direct bond, methylene, preferably methylene;

alternatively, R ^2a 、R ^2b And together with the N atom to which they are attached, form a 5-6 membered heterocyclyl;

Alternatively, R ^2a 、R ^2b And the N atom attached to themTogether, formPreferably->

R ³ Selected from:

preferably, R ³ Is thatWherein L is ³ Selected from direct bond, methylene, ethylene, preferably from direct bondMethylene, more preferably a direct bond;

preferably, R ¹⁴ 、R ¹⁵ 、R ¹⁶ 、R ¹⁷ 、R ¹⁸ All are H;

more preferably, R ³ Is that/>

7. Use according to any one of claims 1-6, wherein the compound is selected from the following:

/>

8. the use according to any one of claims 1-7, further having one or more technical features selected from the following (1) - (10):

(1) The fatty liver disease is non-alcoholic fatty liver disease;

(2) The fatty liver disease is simple steatosis;

(3) The fatty liver disease is non-alcoholic steatohepatitis;

(4) The fatty liver disease is liver fibrosis;

(5) The fatty liver disease is cirrhosis;

(6) The fatty liver disease is liver cancer;

(7) The fatty liver-related disease is diabetes;

(8) The fatty liver-related disease is obesity;

(9) The fatty liver-related disease is hyperlipidemia;

(10) The fatty liver-related disease is insulin resistance.

9. A compound or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof,

/>

10. a pharmaceutical composition comprising a compound of claim 9, or a stereoisomer, prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, optionally together with one or more pharmaceutically acceptable carriers or excipients.