CN113429341A

CN113429341A - Novel capsid protein assembly inhibitors

Info

Publication number: CN113429341A
Application number: CN202110806054.7A
Authority: CN
Inventors: 张寅生; 敖汪伟; 李元; 沈杭州; 柳英帅; 李东旭; 刘保民; 王辉; 陆鹏
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2016-09-18
Filing date: 2017-09-18
Publication date: 2021-09-24
Also published as: CN109790123B; WO2018050110A1; CN109790123A

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a novel capsid protein assembly inhibitor, in particular to a compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method, a medicinal composition and a medicinal application thereof, wherein the compound comprises the application of treating diseases benefiting from capsid protein assembly inhibition, especially diseases caused by hepatitis B virus infection, and A, M, L, D in the general formula I is defined as the same as the specification. A-M-L-DI.

Description

Novel capsid protein assembly inhibitors

The present application is a divisional application of the following applications: application date 2017, 09 month 18; application No.: 201780055155.7, respectively; the invention name is as follows: "novel capsid protein assembly inhibitors".

Cross Reference to Related Applications

This application claims the benefit of the chinese patent application No. 201610829370.5 filed on 18/09/2016 with the national intellectual property office of the people's republic of china, the entire contents of which are hereby incorporated by reference in their entirety.

Technical Field

The application belongs to the field of pharmaceutical chemistry, and particularly relates to a compound shown in a formula I, a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method, a pharmaceutical composition and a medical application thereof, in particular to an application of the compound as a medicament for treating and preventing hepatitis B virus infection.

Background

Chronic viral hepatitis b is widely distributed worldwide, about 3.6 million people worldwide are persistently infected with Hepatitis B Virus (HBV), and china is the country infected with HBV the most worldwide. The existing medicines for treating the hepatitis B are difficult to completely eliminate virus infection, an effective cure means is still lacked clinically, the hepatitis B which cannot be cured can only be treated by control currently, and the treatment medicines are only limited to interferon and nucleoside analogue/viral polymerase inhibitors. Clinical studies show that only less than 50% of patients are sensitive to interferon treatment, while the existing nucleoside analogue drugs induce the generation of drug-resistant mutation by using transcriptase, have poor curative effect on drug-resistant strains, are generally difficult to completely eliminate HBV infection, and cannot be cured even if the drugs are taken for a long time.

Despite the availability of prophylactic HBV vaccines, the burden of chronic HBV infection remains a significant unmet medical problem worldwide due to suboptimal treatment options and the continuing new infected rates in most regions of developing countries. Current treatment regimens are incurable and can only be controlled and are limited to only two classes of agents (interferon and nucleoside analogs/inhibitors of viral polymerase). The low cure rate for HBV is due at least in part to the presence and persistence of covalently closed circular dna (cccdna) in the nucleus of infected hepatocytes. However, the current treatment scheme cannot eliminate cccDNA from the reservoir, so that the life cycle of HBV is deeply understood (Thomas F Baumet, et al. Current Opinion in Virology 2015,14: 41-46), and it is widely believed that Core inhibitors (Core inhibitors, such as inhibitors of capsid protein formation or assembly of virus and cccDNA inhibitors and interferon stimulated gene activators, etc.) as new targets of HBV are expected to bring hopes for curing hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).

The HBV capsid is assembled from the core protein. 3 core protein dimers are aggregated into a nucleus and combined with other dimers through hydrophobic acting force, and finally the icosahedral capsid protein consisting of 120 dimers is obtained. Before reverse transcription, HBV reverse transcriptase, pgRNA, needs to be correctly encapsulated by capsid proteins. Thus, blocking capsid protein assembly, or accelerating capsid protein degradation, blocks capsid protein assembly processes, thereby affecting viral replication. In addition, the 149N-terminal amino acid residues (Cp149) that make up the core dimerization motif and assembly domain are devoid of human protein homology sequences. In recent years, researchers have begun to develop non-nucleoside analogs for treating hepatitis B, instead of targeting reverse transcriptase, other steps in the viral life cycle are selected for inhibition, and inhibitors targeting capsid protein assembly have potential as new targets for anti-hepatitis B drug development.

Currently, compounds targeting capsid protein assembly are NVR3-778, Bay41-4109, GLS4, AT-61, AT-130, and the like. Existing capsid protein assembly inhibitors are mostly in the early clinical research stage or the research has been terminated, and there is a need in the art for more alternative effective capsid protein assembly inhibitors for the treatment, amelioration or prevention of HBV infection. The invention synthesizes a series of novel derivatives and researches the HBV protein assembly activity.

Summary of The Invention

In one aspect, the present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

a moiety selected from

R^aSelected from halogen, nitroso, nitro, cyano, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy, C_1-6Alkyl-oxy, C_3-6Cycloalkyl-oxy, mercapto, C_1-6Alkyl-thio radical, C_3-6Cycloalkyl-thio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl radical, said C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkyl-oxy, C_3-6Cycloalkyl-oxy, C_1-6Alkyl-thio radical, C_3-6Cycloalkyl-sulfurBase, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl optionally substituted with 1-3R^bSubstituted, R^bSelected from halogen, nitroso, nitro, cyano, hydroxy, mercapto, amino, methoxy, cyclopropyl or methanesulfonyl;

m is a moiety selected from

Z is selected from C or Si, n is selected from 0 or 1, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxy or halogen, or, optionally, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵Wherein two substituents of (a) are linked to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si or B, the 3-8 membered saturated ring is substituted with m R⁶Substituted, m is selected from 0 to 3, R⁶Is selected from C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl radical, C_1-4Alkoxyacyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C_1-6Alkoxy, phenyl or benzyl, with the proviso that R¹And R⁵Are not connected to form a 3-to 8-membered saturated ring;

l moiety is selected from

Or

X is selected from O or S, W is selected from single bond,

Or

D is a moiety selected from 5-to 10-membered aryl or 5-to 10-membered heteroaryl containing 1-3 atoms selected from N, O, S, Si or B, said 5-to 10-membered aryl or 5-to 10-membered heteroaryl optionally substituted with 1-3R^dSubstituted, said R^dSelected from halogen, nitroso, nitro, cyano, C_1-6Alkyl, hydroxy, C_1-6Alkoxy, hydroxy-C_1-6Alkyl, 1-3 halogen substituted C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl, mercapto, C_1-6Alkylthio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3An alkyl-sulfonyl group.

Another aspect of the present application provides a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as a capsid protein assembly inhibitor.

Another aspect of the present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating a disease benefiting from inhibition of capsid protein assembly.

Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

In another aspect, the present application provides the use of a compound represented by formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a disease benefiting from inhibition of capsid protein assembly.

One aspect of the present application provides a method for treating diseases benefiting from the inhibition of capsid protein assembly comprising administering to a patient a therapeutically effective amount of a compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above.

Another aspect of the present application provides the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, in the treatment of a disease benefiting from inhibition of capsid protein assembly.

Detailed Description

wherein the content of the first and second substances,

a moiety selected from

R^aSelected from halogen, nitroso, nitro, cyano, C_1-6Alkyl radical, C_3-6Cycloalkyl, hydroxy, C_1-6Alkyl-oxy, C_3-6Cycloalkyl-oxy, mercapto, C_1-6Alkyl-thio radical, C_3-6Cycloalkyl-thio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl radical, said C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkyl-oxy, C_3-6Cycloalkyl-oxy, C_1-6Alkyl-thio radical, C_3-6Cycloalkyl-thio radical, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl optionally substituted with 1-3R^bSubstituted, R^bSelected from halogen, nitroso, nitro, cyano, hydroxy, mercapto, amino, methoxy, cyclopropyl or methanesulfonyl;

m is a moiety selected from

l moiety is selected from

Or

X is selected from O or S, W is selected from single bond,

Or

D is a moiety selected from 5-to 10-membered aryl or 5-to 10-membered heteroaryl containing 1-3 atoms selected from N, O, S, Si or B, said 5-to 10-membered aryl or 5-to 10-membered heteroaryl optionally substituted with 1-3R^dSubstituted, said R^dSelected from halogen, nitroso, nitro, cyano, C_1-6Alkyl, hydroxy, C_1-6Alkoxy, hydroxy-C_1-6Alkyl, 1-3 halogen substituted C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl radicalMercapto group, C_1-6Alkylthio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3An alkyl-sulfonyl group.

In some embodiments of this application, R is^aSelected from F, Cl, Br, nitroso, nitro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, C_1-4Alkyl-oxy, C_3-6Cycloalkyl-oxy, mercapto, C_1-4Alkyl-thio radical, C_3-6Cycloalkyl-thio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl radical, said C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkyl-oxy, C_3-6Cycloalkyl-oxy, C_1-4Alkyl-thio radical, C_3-6Cycloalkyl-thio radical, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl optionally substituted with 1-3R^bSubstituted, said R^bSelected from F, Cl, Br, nitroso, nitro, cyano, hydroxyl, mercapto, amino, methoxy, cyclopropyl or methylsulfonyl.

In some embodiments of this application, R is^aPreferably selected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, mercapto, methylthio, cyclopropylthio, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl or cyclopropylmethyl.

In some embodiments of the present application, the moiety A is preferably selected from

The R is^aAs defined above.

The R is^aAs defined above.

In some embodiments of the present application, the moiety A is more preferably selected from

Or

In some embodiments of this application, R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxycarbonyl, phenyl or benzyl.

In some embodiments of this application, R is⁶Preferably from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of this application, R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵Wherein two substituents of (a) are linked to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si or B, the 3-8 membered saturated ring is substituted with m R⁶Substitution of said m and R⁶As previously defined, provided that R¹And R⁵Are not linked to form a 3-to 8-membered saturated ring.

In some embodiments of the present application, preferably, R is¹And R⁵Each independently selected from H or methyl, said R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵Wherein two substituents of (a) are linked to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si or B, the 3-8 membered saturated ring is substituted with m R⁶Substitution of said m and R⁶As previously defined, provided that R¹And R⁵Are not linked to form a 3-to 8-membered saturated ring.

In some embodiments of the present application, the 3-to 8-membered saturated ring is a monocyclic structure.

In some embodiments of this application, when R is optional¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵When two substituents in (1) are linked to form a 3-to 8-membered saturated ring, the number of rings is one.

In some embodiments of this application, when R is optional¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵When two substituents are linked to form a 3-to 8-membered saturated ring, R is selected from^2aAnd R^2b、R^3aAnd R^3b、R^4aAnd R^4b、R^2aAnd R^3a、R^3aAnd R^4a、R^2aAnd R^4a、R¹And R^2a、R¹And R^3a、R¹And R^4a、R^2aAnd R⁵、R^3aAnd R⁵Or R^4aAnd R⁵Are connected.

In some embodiments of this application, when R is optional¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵When two substituents in (1) are linked to form a 3-to 8-membered saturated ring, R is preferably selected from^2aAnd R^2bLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^3aAnd R^3bLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^4aAnd R^4bLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^2aAnd R^3aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^3aAnd R^4aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^2aAnd R^4aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R¹And R^2aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R¹And R^3aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R¹And R^4aLinked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^2aAnd R⁵Linked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, R^3aAnd R⁵Linked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring or R^4aAnd R⁵Linked to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring.

In some embodiments of the present application, the moiety M is selected from

Or

The R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4b、R⁵、Z、R⁶And m is as previously defined.

In some embodiments of the present application, the moiety M is preferably selected from

Or

In some embodiments of the present application, the moiety L is selected from

Or

X is selected from O or S, W is selected from a single bond or

In some embodiments of this application, R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, C_1-4Alkyl, hydroxy, C_1-4Alkoxy, hydroxy-C_1-4Alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxy-C_1-4Alkyl, mercapto, C_1-4Alkylthio, amino, C_1-3Alkyl radical-amino, dimethylamino, diethylamino, dipropylamino, methyl (ethyl) amino or C_1-3An alkyl-sulfonyl group.

In some embodiments of this application, R is^dPreferably selected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxyethyl, mercapto, methylthio, amino, methylamino, ethylamino, dimethylamino or methylsulfonyl.

In some embodiments of the present application, the D moiety is selected from a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered aryl or a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heteroaryl containing 1 to 3 atoms selected from N, O, S or B, said 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered aryl or 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heteroaryl optionally substituted with 1 to 3R^dSubstituted, said R^dAs previously defined.

In some embodiments of the present application, the moiety D is preferably selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, the moiety D is more preferably selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, the moiety D is further preferably selected from

Or

As a preferred mode of the compound represented by formula I, there is provided a compound represented by the following formula II:

wherein the content of the first and second substances,

A²part is selected from

R^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, mercapto, methylthio, cyclopropylthio, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl;

M²is selected from

n is 0 or 1, Z is C or Si, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxy or halogen;

L²is selected from

Or

X is selected from O or S, W is selected from a single bond or

D²Is selected from

Or

R^dSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxyethyl, mercapto, methylthio, amino, methylamino, ethylamino, dimethylamino, or methylsulfonyl.

In some embodiments of the present application, in the compound of formula II, the R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, N-methyl, N-ethyl, N-methyl, N-methyl, N-methyl, N-methyl, N-N, N-methyl, N-N,trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl.

In some embodiments of the present application, in the compounds of formula II, the A is²Part is selected from

The R is^aAs previously defined.

In some embodiments of the present application, in the compounds of formula II, the A is²Partially preferably from

The R is^aAs defined above.

Or

In some embodiments of the present application, in the compound of formula II, the R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br.

In some embodiments of the present application, in the compound of formula II, preferably, the R is¹And R⁵Each independently selected from H or methyl, said R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br.

In some embodiments of the present application, in the compound of formula II, M is²Part is selected from

Or

The R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵As previously defined.

In some embodiments of the present application, in the compound of formula II, M²Partially preferably from

Or

In some embodiments of the present application, in the compound of formula II, the R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methylsulfonyl.

In part of the present applicationIn an embodiment, in the compound of formula II, D²Is selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, in the compounds of formula II, D²Is preferably selected from

Or

As a preferred mode of the compound represented by formula I, there is provided a compound represented by the following formula III:

wherein the content of the first and second substances,

A³part is selected from

M³is selected from

n is 0 or 1, Z is C or Si, R¹、R^3a、R^3bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxyl or halogen, R^2aAnd R^4aLinked to form a 3-to 8-membered saturated ring, the ring atoms of said 3-to 8-membered saturated ring optionally including 1-3 heteroatoms selected from O, N, S, Si, B, said 3-to 8-membered saturated ring being interrupted by m R⁶Substituted, m is selected from 0 to 3, R⁶Is selected from C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl radical, C_1-4Alkoxyacyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C_1-6Alkoxy, phenyl or benzyl;

L³is selected from

X is selected from O or S, W is selected from a single bond or

D³Is selected from

Or

R^dSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxyethyl, mercapto, methylthio, amino, methylamino, ethylaminoDimethylamino or methylsulfonyl.

In some embodiments of the present application, in the compound of formula III, the R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl.

In some embodiments of the present application, in the compounds of formula III, the A is³Part is selected from

The R is^aAs previously defined.

In some embodiments of the present application, in the compounds of formula III, the A is³Partially preferably from

The R is^aAs defined above.

Or

In some embodiments of the present application, in the compound of formula III, the R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, ammoniaA cyano group, a carboxyl group, F, Cl, Br, a methoxyformyl group, a phenyl group or a benzyl group.

In some embodiments of the present application, in the compound of formula III, the R is⁶Preferably from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of the present application, in the compound of formula III, the R is¹、R^3a、R^3bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, R^2aAnd R^4aLinked to form a 5-or 6-membered saturated monocyclic ring, the ring atoms of said 5-or 6-membered saturated monocyclic ring optionally comprising 1-3 heteroatoms selected from O, N, S, Si or B, said 5-or 6-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula III, preferably, the R is¹And R⁵Each independently selected from H or methyl, said R^3aAnd R^3bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, R^2aAnd R^4aLinked to form a 5-or 6-membered saturated monocyclic ring, the ring atoms of said 5-or 6-membered saturated monocyclic ring optionally comprising 1-3 heteroatoms selected from O, N, S, Si or B, said 5-or 6-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula III, M is³Part is selected from

Or

The R is¹、R^3a、R^3b、R⁵M and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula III, M is³Partially preferably from

Or

In some embodiments of the present application, in the compound of formula III, the R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methylsulfonyl.

In some embodiments of the present application, in the compounds of formula III, D³Is selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, in the compounds of formula III, D³Is preferably selected from

Or

As a preferred mode of the compound represented by formula I, there is provided a compound represented by the following formula IV:

wherein the content of the first and second substances,

A⁴part is selected from

M⁴is selected from

n is 0 or 1, Z is C or Si, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxy or halogen, or is selected from R^2aAnd R^2b、R^3aAnd R^3bOr R^4aAnd R^4bThe substituents in one group of (A) are connected to each other to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si, B, the 3-8 membered saturated ring is substituted with m R⁶Substituted, m is selected from 0 to 3, R⁶Is selected from C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl radical, C_1-4Alkoxyacyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C_1-6Alkoxy, phenyl or benzyl;

L⁴is selected from

X is selected from O or S, W is selected from a single bond or

D⁴Is selected from

Or

In some embodiments of the present application, in the compound of formula IV, the R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl.

In some embodiments of the present application, in the compounds of formula IV, A is⁴Part is selected from

The R is^aAs previously defined.

In some embodiments of the present application, in the compounds of formula IV, A is⁴Partially preferably from

The R is^aAs defined above.

Or

In some embodiments of the present application, in the compound of formula IV, the R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxycarbonyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of formula IV, the R is⁶Preferably from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of the present application, in the compound of formula IV, the R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br,or is selected from R^2aAnd R^2b、R^3aAnd R^3bOr R^4aAnd R^4bThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula IV, preferably, the R is¹And R⁵Each independently selected from H or methyl, R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or R^2aAnd R^2b、R^3aAnd R^3bOr R^4aAnd R^4bThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula IV, M is⁴Part is selected from

Or

The R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4b、R⁵M and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula IV, M is⁴Partially preferably from

Or

In some embodiments of the present application, in the compound of formula IV, the R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methylsulfonyl.

In some embodiments of the present application, in the compounds of formula IV, D⁴Is selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, in the compounds of formula IV, D⁴Is preferably selected from

Or

As a preferred mode of the compound represented by formula I, there is provided a compound represented by the following formula V:

wherein the content of the first and second substances,

A⁵part is selected from

M⁵is selected from

n is 0 or 1, Z is C or Si, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxy or halogen, or, R is selected from¹And R^2a、R¹And R^3aOr R¹And R^4aThe substituents in one group of (A) are connected to each other to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si, B, the 3-8 membered saturated ring is substituted with m R⁶Substituted, m is selected from 0 to 3, R⁶Is selected from C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl radical, C_1-4Alkoxyacyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C_1-6Alkoxy, phenyl or benzyl;

L⁵is selected from

X is selected from O or S, W is selected from a single bond or

D⁵Is selected from

Or

In some embodiments of the present application, in the compound of formula V, R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl.

In the present applicationIn some embodiments, in the compound of formula V, A is⁵Part is selected from

The R is^aAs previously defined.

In some embodiments of the present application, in the compounds of formula V, A is⁵Partially preferably from

The R is^aAs defined above.

Or

In some embodiments of the present application, in the compound of formula V, R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxycarbonyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of formula V, R is⁶Preferably from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of the present application, in the compound of formula V, R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or R¹And R^2a、R¹And R^3aOr R¹And R^4aThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula V, preferably, the R is¹And R⁵Each independently selected from H or methyl, R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or R¹And R^2a、R¹And R^3aOr R¹And R^4aThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula V, M is⁵Part is selected from

Or

The R is^4a、R^4b、R⁵M and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula V, M is⁵Partially preferably from

Or

In some embodiments of the present application, in the compound of formula V, R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methylsulfonyl.

In some embodiments of the present application, in the compounds of formula V, D⁵Is selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, in the compounds of formula V, D⁵Is preferably selected from

Or

As a preferred mode of the compound represented by formula I, there is provided a compound represented by the following formula VI:

wherein the content of the first and second substances,

A⁶part is selected from

M⁶is selected from

n is 0 or 1, Z is C or Si, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl, hydroxy, C_1-3Alkoxy, oxo, thio, amino, cyano, carboxy or halogen, or, R is selected from⁵And R^2a、R⁵And R^3aOr R⁵And R^4aThe substituents in one group of (A) are connected to each other to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si, B, the 3-8 membered saturated ringRing is substituted by m R⁶Substituted, m is selected from 0 to 3, R⁶Is selected from C_1-3Alkyl, hydroxy-C_1-3Alkyl radical, C_1-3alkoxy-C_1-3Alkyl, 1-3 halogen substituted C_1-3Alkyl radical, C_1-4Alkoxyacyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C_1-6Alkoxy, phenyl or benzyl;

L⁶is selected from

X is selected from O or S, W is selected from a single bond or

D⁶Is selected from

Or

In some embodiments of the present application, in the compound of formula VI, the R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl.

In some embodiments of the present application, in the compounds of formula VI, the A is⁶Part is selected from

The R is^aAs previously defined.

In some embodiments of the present application, in the compounds of formula VI, the A is⁶Partially preferably from

The R is^aAs defined above.

Or

In some embodiments of the present application, in the compound of formula VI, the R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxycarbonyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of formula VI, the R is⁶Preferably from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of the present application, in the compound of formula VI, the R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethylHydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or selected from R⁵And R^2a、R⁵And R^3aOr R⁵And R^4aThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compound of formula VI, preferably, the R is¹And R⁵Each independently selected from H or methyl, R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or R⁵And R^2a、R⁵And R^3aOr R⁵And R^4aThe substituents in one group of (a) are linked to each other to form a 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring, the ring atoms of the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring optionally include 1 to 3 heteroatoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6-or 7-membered saturated monocyclic ring being substituted by m R⁶Substitution of said m and R⁶As previously defined.

In some embodiments of the present application, in the compounds of formula VI, M is⁶Part is selected from

Or

The R is¹、R^2a、R^2bM and R⁶As previously defined.

In some embodiments of the present application, in the compounds of formula VI, M is⁶Partially preferably from

Or

In some embodiments of the present application, in the compound of formula VI, the R is^dSelected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy, ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methylsulfonyl.

In some embodiments of the present application, in the compounds of formula VI, D⁶Is selected from

Or

The R is^dAs previously defined.

In some embodiments of the present application, in the compounds of formula VI, D⁶Is preferably selected from

Or

In some embodiments of the present application, there is provided the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

In some embodiments of the present application, the disease benefiting from inhibition of capsid protein assembly refers to a disease caused by Hepatitis B Virus (HBV) infection.

In some embodiments of the present application, the disease benefiting from inhibition of capsid protein assembly refers to liver disease caused by Hepatitis B Virus (HBV) infection.

In some embodiments of the present application, the treatment of a disease benefiting from inhibition of capsid protein assembly refers to the control, reduction or elimination of HBV to prevent, ameliorate or cure liver disease in an infected patient.

Definitions and explanations

The following terms and phrases used herein have the following meanings, unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be considered as indefinite or unclear but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The term "compound" as used herein includes all stereoisomeric, geometric isomeric, tautomeric and isotopic forms of the compound.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)₂CH₃) Monosubstituted (e.g. CH)₂CH₂F) Polysubstituted (e.g. CHFCH)₂F、CH₂CHF₂Etc.) or completely substituted (CF)₂CF₃) (ii) a 5-to 10-membered aryl or 5-to 10-membered heteroaryl optionally substituted with 1-3R^dSubstituted, meaning that the 5-to 10-membered aryl or 5-to 10-membered heteroaryl group may be unsubstitutedOr 1 to 3R^dAnd (3) substituted. It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.

Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" or "in portions of this application" means that a particular reference element, structure or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to be open-ended, inclusive meaning that "includes but is not limited to".

It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

C as used herein_m～nOr C_m-nMeaning that the moiety has m to n carbon atoms. For example, "C_1～6The alkyl group means that the alkyl group has 1 to 6 carbon atoms.

Numerical ranges herein refer to each integer in the given range. E.g. "C_1～6By "meansThe group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When one of the variables is selected from a single bond, it is meant herein that the two groups to which it is attached are directly connected, e.g.

Wherein when W is selected from a single bond, it represents

The term "substituted" or "substituted" herein means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound herein, its definition in each case is independent. Thus, if a group is substituted with 0-3R, the group may optionally be substituted with up to three R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When a substituent's bond can be variably attached to more than one atom on a ring, such substituent can be bonded to any atom on the ring. When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit

Represents 1,2 or 3R^dCan be in benzeneSubstitution at any position on the ring, including

Also for example

Indicates that there are 1R at the defined position on the phenyl ring^dSubstituent group (R)^d)₀Indicates that there is no additional R at other positions^dAnd (4) a substituent.

In the present application, the left end of the M portion is connected to the a portion, and the right end of the M portion is connected to the L portion. For example, the moiety M is selected from the structural elements

At its left end, R is connected¹The N atom of (A) is attached to the A moiety; at its right end, i.e. with R⁵Is attached to the L moiety. The various preferred structures of the M moiety are understood with the same definitions.

In the present application, the moiety M is selected from the structural elements

When the defined n atom is selected from 0, it represents a single bond structure, e.g.

. The various preferred structures of the M moiety are understood with the same definitions.

In the present application, the left end of the L portion is connected to the M portion, and the right end of the L portion is connected to the D portion. For example, the L moiety is selected from the structural elements

At the left end, i.e. the C and M partsSub-connecting; the right end of the connecting rod is connected with a part W and a part D. The respective preferred structures of the L moiety are to be understood with the same definitions.

In the present application, the phrase "two substituents are linked to form a 3-8 membered saturated ring" means that the two substituents are linked by a covalent bond to form a 3-8 membered saturated ring together with the atom or structural group to which the two substituents are linked. For example, a structural unit

In when R is^2aAnd R^4aWhen they are linked to form a 3-to 8-membered saturated ring, it means R^2aAnd R^4aLinked to the building block by covalent bonds

Together form a 3-8 membered saturated ring. This form of ring-forming linkage is permitted only if it results in a stable compound.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to an-OH group.

The term "mercapto" refers to the-SH group.

The term "cyano" refers to the group — CN.

The term "oxo" refers to an ═ O group.

The term "thio" refers to an ═ S group.

The term "nitroso" refers to the-NO group.

The term "nitro" means-NO₂A group.

The term "carboxyl" refers to the-COOH group.

The term "amino" refers to the group-NH₂A group.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the rest of the molecule by a single bond. Non-limiting examples of this term include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -CH (CH)₃)₂、-CH(CH₃)(CH₂CH₃)、-CH(CH₂CH₃)₂、-C(CH₃)₃、-C(CH₂CH₃)₃、-CH₂CH(CH₃)₂、-CH₂CH(CH₃)(CH₂CH₃) And the like. The term "C_1～6The alkyl group "means an alkyl group having 1 to 6 carbon atoms. The term "C_1～4The alkyl group "means an alkyl group having 1 to 4 carbon atoms. The term "C_1～3The alkyl group "means an alkyl group having 1 to 3 carbon atoms.

The terms "C, D, E" and the like indicate that the number of carbon atoms and the functional group forming the group includes all isomeric forms thereof, for example: 1) propyl includes CH₃CH₂CH₂-、(CH₃)₂CH-; 2) butyryl comprises CH₃CH₂CH₂CO-、(CH₃)₂CHCO-。

The term "alkanoyl" refers to a-CO-alkyl group.

The term "alkylsulfonyl" refers to-SO₂-an alkyl group.

The term "alkoxy" or "alkyloxy" refers to an-O-alkyl group, e.g., "C_1-6Alkyl-oxy "includes methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.

The term "cycloalkoxy" or "cycloalkyloxy" refers to an-O-cycloalkyl group, e.g. "C_3-6Alkyl-oxy "includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

The term "alkylthio" or "alkylthio" refers to the group-S-alkyl.

The term "cycloalkylthio" or "cycloalkylthio" refers to the group-S-cycloalkyl.

The term "saturated ring" refers to a cyclic structural unit that is fully saturated and may exist as a single ring, fused ring, or spiro ring, the ring atoms of which may optionally include C atoms or heteroatoms. For example, the structural unit "3-8 membered saturated ring" includes 3-8 membered saturated carbocyclic rings, and also includes 3-8 membered saturated heterocyclic rings containing the defined heteroatoms. The definition is only allowed if it results in a stable compound.

The term "cycloalkyl" refers to a ring which is fully saturated and whose ring atoms, which may exist as a single ring, fused ring or spiro ring, are all carbon atoms. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring, preferably a 3 to 8 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1 ] n]Heptyl), bicyclo [2.2.2]Octyl, adamantyl, and the like. E.g. C_3-6Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including atoms other than carbon (C) and hydrogen (H) and radicals containing these heteroatoms, and includes, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -O, - (S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, -S (═ O)₂-, and optionally substituted-C (═ O) n (h) -, -C (═ NH) -, -S (═ O)₂N (h) -or-S (═ O) n (h) -; the number of said "hetero" on each of the above "hetero" containing groups is optionally 1,2, 3,4 or 5.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 5 to 14 carbon atoms, preferably having 5 to 10 carbon atoms, more preferably having 5 to 8 carbon atoms. The aryl group may be unsubstituted or independently substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkoxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. The aryl group may be a monocyclic or fused ring, and when selected from fused rings, at least one ring structure in the fused ring is a carbocyclic ring having a completely conjugated pi-electron system, and the other ring structures in the fused ring may have a completely conjugated pi-electron system, or may be saturated, or partially saturated, or contain heteroatoms, or may not contain heteroatoms. For example, non-limiting examples of the structural group "10-membered aryl" include

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Heteroaryl groups may be unsubstituted or independently substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkoxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic. The heteroaryl group may be a monocyclic or fused ring, and when selected from fused rings, at least one ring structure of the fused rings is a heteroatom-containing ring having a fully conjugated pi-electron system, and the other ring structures of the fused rings may have a fully conjugated pi-electron system, or may be saturated, or partially saturated, or contain a heteroatom or may not contain a heteroatom. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, 1,2, 4-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared from the compounds found herein to have particular substituents with relatively nontoxic acids or bases. When compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. When compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition Salts include inorganic acid Salts, and organic acid Salts, and also include Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present application contain both basic and acidic functionalities and thus can be converted to any base or acid addition salt.

Certain compounds of the present application may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present application.

The illustrations of enantiomers, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J.chem.Ed.1985,62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present application.

The compounds of the present application may exist in specific geometric or stereoisomeric forms, the optical isomeric properties of which may be provided by asymmetric atoms such as asymmetric C atoms, Si atoms, N atoms, or double bonds. The present application contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present application. For example, a structural unit

Including but not limited to

Or enantiomerically or diastereomerically enriched or racemic mixtures.

As used herein, "1 SR,2 SR" refers to the mixture of "1S, 2S" and "1R, 2R" isomers, "1 SR,3 RS" refers to the mixture of "1S, 3R" and "1R, 3S" isomers, "1 SR,2 RS" refers to the mixture of "1S, 2R" and "1R, 2S" isomers, "1 RS,3 RS" refers to the mixture of "1R, 3R" and "1S, 3S" isomers, i.e., "SR, SR" refers generally to the mixture of "SS" and "RR" isomers, and others like "SR, RS", "RS, RS" and the like are as defined above.

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The intermediates and compounds of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.

The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound such as tritium (3H), iodine-125 (125I) or C-14(14C) may be labeled with a radioisotope. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.

The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

An important consideration in any synthetic route planning in the art is the selection of suitable protecting groups for reactive functional groups (e.g., amino groups in the present application). Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons) are the authorities In this regard for trained practitioners. All references cited herein are incorporated in their entirety.

The reactions described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by broad spectrum methods such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible light), or mass spectrometry, or by chromatography such as High Performance Liquid Chromatography (HPLC) or thin layer chromatography.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent herein, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on The vector, reference may be made to Remington, The Science and Practice of Pharmacy,21^st27Ed.,Lippincott,Williams&Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms herein, an "effective amount" of one active agent in a composition is the amount needed to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.

The phrase "therapeutically effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that a researcher, veterinarian, medical doctor or other clinician is seeking in a tissue, system, animal, individual, or human, which includes one or more of the following: 1) preventing a disease, e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or exhibited disease pathology or symptomatology; 2) inhibiting a disease, e.g., inhibiting a disease, disorder or condition (i.e., arresting the further development of pathology and/or condition) in an individual who is experiencing or presenting with pathology or symptomatology of the disease, disorder or condition; 3) and (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.

Therapeutic dosages of the compounds of the present application may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present application can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

In some embodiments, the compounds of formula (i) herein may be prepared by one skilled in the art of organic synthesis by the following steps and routes:

route one:

and a second route:

wherein R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4b、R⁵、R^d、R⁶M, n are as defined in the application.

The following abbreviations are used in this application:

boc: tert-butyloxycarbonyl radical

DCM: methylene dichloride

DIPEA: n, N-diisopropylethylamine

DMF: dimethyl formamide

DMSO, DMSO: dimethyl sulfoxide

EA: ethyl acetate

MeOH: methanol

PE: petroleum ether

HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HEPES (high efficiency particulate air): 4-hydroxyethyl piperazine ethanesulfonic acid.

DNA deoxyribonucleic acid

HBV hepatitis B virus

mM millimole

nM nanomolar

qPCR quantitative polymerase chain reaction

Micromolar at μ M

mg of

Detailed Description

The following specific examples are included to provide those skilled in the art with a clear understanding of the invention and are included to provide a further understanding of the invention. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. Those skilled in the art will understand that: there are other synthetic routes to the compounds of the present invention, and the following non-limiting examples are provided.

All starting materials were commercial starting materials unless otherwise indicated and were not further purified prior to use.

The nuclear magnetic resonance chromatogram (NMR) of the invention is measured by a BRUKER-300 nuclear magnetic resonance instrument and a BRUKER-500 nuclear magnetic resonance instrument, the chemical shift takes tetramethylsilane (TMS ═ delta 0.00) as an internal standard, and the format of the nuclear magnetic resonance hydrogen spectrum data record is as follows: proton number, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in hertz Hz). The instrument used for mass spectrometry was AB SCIEX Triple TOF4600 or AB SCIEX 3200 QTRAP.

Example 11- (3-chloro-4-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea

The reaction process comprises the following steps:

step A: 3,4, 5-trichloropyridine (736mg) and ethylenediamine (960mg) were added to a 100mL single-neck flask and reacted at 70 ℃ for 1 hour. After the reaction was complete dichloromethane (40mL) was added, washed three times with water (3 x 10mL), dried and concentrated to give N¹Crude- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine (643mg) was used directly in the next reaction.

¹H-NMR(500MHz,DMSO-d6)：δ8.16(s，2H),3.60(t，2H)，2.76(t，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.32,147.03,117.38,47.20,42.06。HRMS(ESI+,[M+H]⁺)m/z：206.0248。

And B: adding N into a 100mL single-mouth bottle¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine (540mg), methylene chloride (30mL), and 3-chloro-4-fluorobenzeneisocyanate (674mg) were added dropwise to the mixture, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the filter cake was filtered, washed with a small amount of dichloromethane, and dried to obtain 1- (3-chloro-4-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea (900mg, 90.9%).

¹H-NMR(500MHz,DMSO-d6)：δ8.77(s，1H),8.17(s，2H)，7.73(m，1H)，7.21-7.29(m，2H)，6.41(t，1H)，6.20(t，1H)，3.74(m，2H)，3.35(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.05，153.35，151.44，148.41，147.04，138.16，119.40，118.36，117.30，117.06，46.13，39.96。HRMS(ESI+,[M+H]⁺)m/z：377.0125。

Example 21- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea

Step A: preparation of N according to example 1, substituting 1, 3-propanediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine.

¹H-NMR(500MHz,DMSO-d6)：δ8.15(s，2H),3.70(t，2H)，2.61(t，2H)，1.60(t，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.37,146.92,117.28,49.05,43.65,33.97。MS(ESI+,[M+H]⁺)m/z：220.0。

And B: 1- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.70(s，1H),8.15(s，2H)，7.76(m，1H)，7.23-7.24(m，2H)，6.30(t，1H)，6.24(t，1H)，3.65(t，2H)，3.16(t，2H)，1.70(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.86，153.30，151.39，148.37，146.79，138.27，119.50，118.29，117.13，116.96，42.38，36.75,31.98。HRMS(ESI+,[M+H]⁺)m/z：391.0239。

Example 31- (3-chloro-4-fluorophenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A:preparation of (1SR,2SR) -N according to example 1, substituting in step A (. + -.) 1, 2-Trans-cyclohexanediamine for ethylenediamine¹- (3, 5-dichloropyridin-4-yl) cyclohexane-1, 2-diamine.

¹H-NMR(500MHz,DMSO-d6)：δ8.21(s，2H),5.37(d，1H)，3.65(m，1H)，2.62(m，1H)，1.94(m，1H)，1.84(m，1H)，1.63(m，2H)，1.08-1.28(m，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.40,147.85,118.63,61.82,55.87,35.39,33.60,25.15,24.98。HRMS(ESI+,[M+H]⁺)m/z：260.0756。

And B: 1- (3-chloro-4-fluorophenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to the procedure used in step B, according to example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.59(s，1H),8.15(s，2H)，7.70(m，1H)，7.19-7.25(m，2H)，6.34(t，1H)，5.90(t，1H)，4.01(t，1H)，3.70(t，1H)，2.02(m，1H)，1.88(m，1H)，1.68(m，2H)，1.29-1.39(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.91，153.38，151.47，148.32，146.72，138.03，119.50，118.35，117.41，116.98，59.71，53.38,34.10,32.69,25.06,24.33。HRMS(ESI+,[M+H]⁺)m/z：431.0562。

Example 43- (3-chloro-4-fluorophenyl) -1- (2- ((3, 5-dichloropyridin-4-yl) (methyl) amino) ethyl) -1-methylurea

The synthetic route is as follows:

step A to a 25mL single necked flask was added 3,4, 5-trichloropyridine (3.65g, 20mmol) and N¹,N²-dimethylethane-1, 2-diamine (4.41g, 50mmol) and the mixture was heated to 70 ℃ for 3 h. Cooled to room temperature, water (15mL) and dichloromethane (20mL) were added, the mixture was stirred, the mixture was separated, and the organic layer was washed with water (1)5mL), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent to give N¹- (3, 5-dichloropyridin-4-yl) -N¹,N²Dimethylethane-1, 2-diamine (2.0g, 42.7%) as a pale yellow oil was used directly in the next reaction.

And B: triphosgene (0.39g, 1.32mmol) was added to a solution of 3-chloro-4-fluoroaniline in dichloromethane (30mL) at 0 deg.C, triethylamine (1.65mL, 12mmol) was slowly added dropwise, and the mixture was stirred at 0 deg.C for 1 h. Slowly adding N dropwise into the mixture¹- (3, 5-dichloropyridin-4-yl) -N¹,N²A solution of dimethylethane-1, 2-diamine (0.93g, 4mmol) in dichloromethane (10mL) was stirred at room temperature overnight. Water (20mL) was added thereto, followed by stirring, liquid separation was performed, the organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered under suction, and the solvent was evaporated under reduced pressure to give 1.2g of an oil, which was subjected to silica gel column chromatography (200 to 300 mesh silica gel, DCM: MeOH ═ 20:1) to give 3- (3-chloro-4-fluorophenyl) -1- (2- ((3, 5-dichloropyridin-4-yl) (methyl) amino) ethyl) -1-methylurea (0.70g, 43.8%).

¹H NMR(CDCl_3,500MHz):δ8.39(s,2H),7.53(dd,J＝2.5,6.5Hz),7.18-7.15(m,1H),7.05(dd,J＝8.5,8.5,1H),6.53(s,1H),3.59(t,J＝6.5Hz,2H),3.45(t,J＝6.5Hz,2H),3.00(s,3H),2.98(s,3H)。¹³C NMR(CDCl_3,125MHz):δ(155.29,155.17),153.23,152.63,(135.69,135.66),130.12,122.35,120.93,120.78,(119.80,119.74),116.45,116.27,52.77,47.41,40.08,34.79。

Example 53- (3-chloro-4-fluorophenyl) -1- (3- ((3, 5-dichloropyridin-4-yl) (methyl) amino) propyl) -1-methylurea

Step A Using N in step A according to example 4¹,N³-dimethylpropane-1, 3-diamine instead of N¹,N²Preparation of N from-dimethylethane-1, 2-diamine¹- (3, 5-dichloropyridin-4-yl) -N¹,N³-dimethylpropane-1, 3-diamine as a pale yellow oil which is used directly in the next reaction。

Step B3- (3-chloro-4-fluorophenyl) -1- (3- ((3, 5-dichloropyridin-4-yl) (methyl) amino) propyl) -1-methylurea was prepared according to the procedure used in step B, according to example 4.

¹H NMR(CDCl_3,500MHz):δ8.38(s,2H),7.53(dd,J＝2.5,6.5Hz),7.18-7.16(m,1H),7.03(dd,J＝8.5,8.5,1H),6.62(s,1H),3.39-3.35(m,4H),2.97(s,3H),2.94(s,3H),1.78(quint,J＝6.7Hz,2H)。¹³C NMR(CDCl_3,125MHz):δ(155.19,155.09),153.15,151.89,149.29,(135.79,135.77),130.25,122.35,(120.85,120.71),(119.78,119.72),116.39,116.21,51.22,46.52,40.36,34.62,26.44。

Example 61- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3, 4-fluorophenyl) urea

Step A: dichloromethane (100mL), 3, 4-difluoroaniline (440mg) and triphosgene (604mg) were added to a 250mL two-necked flask, triethylamine (2.30mL) was added dropwise in an ice bath, the mixture was stirred for 10min, and N was added dropwise¹A solution of (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine (600mg) in methylene chloride (20mL) was reacted at room temperature for 1 hour. The reaction was concentrated to dryness, and the resulting crude product was isolated by column chromatography (PE: EA ═ 7:1) to give 1- (2- (3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3, 4-difluorophenyl) urea (870mg, 71.0%).

¹H-NMR(500MHz,DMSO-d6)：δ8.77(s,1H),8.17(s,2H),7.59(t,J＝12Hz,1H),7.24-7.30(m,1H),7.02(d,J＝7.0Hz,1H),6.38(s,1H),6.19(s,1H),3.72(s,2H),3.40(s,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ156.04,148.42,147.06,117.72,114.26,107.71,46.12。HRMS(ESI+,[M+H]⁺)m/z：361.0414。

Example 71- (3-chlorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea

Step A: 1- (3-chlorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea was prepared according to example 6, substituting 3, 4-difluoroaniline for 3, 4-difluoroaniline in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.76(s,1H),8.17(s,2H),7.64(t,J＝2.0Hz,1H),7.18-7.25(m,2H),6.92-6.94(m,1H),6.39(t,J＝5.5Hz,1H),6.19(t,J＝6.0Hz,1H),3.71-3.75(m,2H),3.40-3.36(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ155.98,148.42,142.39,133.54,121.22,117.65,116.63,46.14。HRMS(ESI+,[M+H]+)m/z：359.0239。

Example 81- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3-fluorophenyl) urea

Step A: 1- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3-fluorophenyl) urea was prepared according to example 6, substituting 3-fluoroaniline for 3, 4-difluoroaniline in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.79(s,1H),8.17(s,2H),7.41-7.45(m,1H),7.21-7.26(m,1H),7.02-7.04(m,1H),6.68-6.71(m,1H),6.37-6.40(m,1H),6.19-6.21(m,1H),3.71-3.75(m,2H),3.32-3.36(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ163.82,161.91,156.01,148.42,142.80,130.60,117.42,113.93,107.96,105.00,46.18。HRMS(ESI+,[M+H]+)m/z：343.0515。

Example 91- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3,4, 5-trifluorophenyl) urea

Step A: 1- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -3- (3,4, 5-trifluorophenyl) urea was prepared according to example 6, substituting 3,4, 5-trifluoroaniline for 3, 4-difluoroaniline in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.92(s,1H),8.17(s,2H),7.28-7.33(m,2H),6.50(t,J＝6.0Hz,1H),6.17(t,J＝6.0Hz,1H),3.71-3.75(m,2H),3.33-3.35(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ155.79,148.42,147.02,137.35,134.77,117.45,102.28,45.90。HRMS(ESI+,[M+H]+)m/z：379.0324。

Example 101- (4-chloro-3-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea

Step A: 1- (4-chloro-3-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) urea was prepared according to example 6, substituting 3, 4-difluoroaniline for 3, 4-difluoroaniline in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.91(s,1H),8.16(s,2H),7.59-7.62(m,1H),7.37-7.40(m,1H),7.08-7.10(m,1H),6.44(t,J＝6.0Hz,1H),6.18(t,J＝6.0Hz,1H),3.71-3.75(m,2H),3.35(t,J＝6.0Hz,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ158.54,156.61,148.41,147.03,141.68,130.70,117.44,115.06,110.99,106.29,46.03。HRMS(ESI+,[M+H]+)m/z：377.0120。

Example 111- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3, 4-difluorophenyl) urea

Step A: 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3, 4-difluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.70(s，1H),8.17(s，2H)，7.63-7.59(q，1H)，7.26(d，1H)，7.03(d，1H)，6.27(d，2H)，3.65(d，2H)，3.14(d，2H)，1.69(t，J＝6.5Hz，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.82，148.44，146.81，143.51，143.40，138.21，117.69，117.55，117.46，114.15，107.09，106.92，42.39，36.74，31.97。MS(ESI+,[M+H]⁺)m/z：374.9。

Example 121- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3-chlorophenyl) urea

Step A: 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3-chlorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.70(s，1H),8.16(d，2H)，7.65(d,1H)，7.24-7.18(m，2H)，6.92(d，1H)，6.30-6.24(m，2H)，3.67-3.63(q，2H)，3.17-3.13(q，2H)，1.69(t，J＝6.5Hz，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.42，146.82，142.52，133.55，130.65，121.08，117.58，117.48，116.56，42.40，36.74，31.98。HRMS(ESI+,[M+H]⁺)m/z：373.0389。

Example 131- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3-fluorophenyl) urea

Step A: 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3-fluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.70(s，1H)，8.17(s，2H)，7.45(d,1H)，7.45-7.21(m，1H)，7.04-7.02(q，1H)，6.71-6.67(td，1H)，6.29-6.25(q，2H)，3.67-3.63(q，2H)，3.17-3.13(q，2H)，1.70(t，J＝6.5Hz，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ163.84,161.93,155.78,148.45,146.82,142.94,142.85,130.59,130.51,117.47,113.86,107.81,107.65,104.92,104.71,42.40,36.70,32.00。HRMS(ESI+,[M+H]⁺)m/z：357.0661。

Example 141- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (4-chloro-3-fluorophenyl) urea

Step A: 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (4-chloro-3-fluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.84(s，1H)，8.17(s，2H)，7.62(dd,J＝2.5，10Hz，1H)，7.39(t，J＝9Hz，1H)，7.09(dd，J＝2,7Hz，1H)，6.34(t，J＝6Hz，1H)，6.25(t，J＝7Hz，1H)，3.65(q，J＝7Hz，2H)，3.15(q，J＝6.5Hz，2H)，1.70(t，J＝7Hz，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.62，148.45，146.81，130.69，117.47，115.01，106.22，106.01，42.40，36.77，31.92。HRMS(ESI+,[M+H]⁺)m/z：391.0293。

Example 151- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3,4, 5-trifluorophenyl) urea

Step A: 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3,4, 5-trifluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.84(s，1H)，8.17(s，2H)，7.30(dd,J＝6.5，11Hz，2H)，6.41(t，J＝6Hz，1H)，6.24(t，J＝6.5Hz，1H)，3.64(q，J＝6.5Hz，2H)，3.15(q，J＝6.5Hz，2H)，1.70(t，J＝7Hz，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.57,148.44,146.80,117.47,102.21,102.01,42.39,36.79,31.86。HRMS(ESI+,[M+H]⁺)m/z：393.0490。

Example 161- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) -3- (3, 4-fluorophenyl) urea

Step A: 1- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) -3- (3, 4-fluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.61(s，1H)，8.16(s，2H)，7.57(m，1H)，7.26(m，1H)，7.00(m，1H)，6.33(t，1H)，5.91(m，1H)，4.01(m，1H)，3.70(m，1H)，2.01(m，2H)，1.89(m，2H)，1.70(m，2H)，1.35(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.89，150.38，148.40，146.73，145.41，143.48，137.98，117.65，114.20，107.05，59.70，53.33，34.07，32.69，25.05，24.33。MS(ESI+,[M+H]⁺)m/z：415.3。

Example 171- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) -3- (3, 4-fluorophenyl) urea

Step A: 1- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) -3- (3-fluorophenyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.63(s，1H)，8.15(s，2H)，7.42(d，1H)，7.23(m，1H)，6.99(d，1H)，6.68(t，1H)，6.33(d，1H)，5.94(d，1H)，4.01(m，1H)，3.70(m，1H)，2.01(m，2H)，1.89(m，2H)，1.70(m，2H)，1.35(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ170.78，163.80，161.89，155.88，148.33，146.71，142.63，130.54，117.73，113.90，107.85，104.90，59.98，53.25，34.07，32.69，25.04，24.29。MS(ESI+,[M+H]⁺)m/z：397.0。

Example 181- (3-chloro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: 1- (3-chloro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.59(s，1H),8.16(s，2H)，7.61-7.62(m，1H)，7.21-7.24(m，1H)，7.14-7.16(m，1H)，6.91-6.93(m，1H)，6.33(d，1H)，5.91(d，1H)，3.98-4.02(m，1H)，3.68-3.72(m，1H)，2.01-2.02(m，1H)，1.88-1.91(m，1H)，1.68-1.72(m，2H)，1.28-1.34(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.83，148.37，146.73，142.29，133.52，130.66，121.22，117.75，117.69，116.64，59.71，53.33，34.09，32.70，25.05，24.33。MS(ESI+,[M+H]⁺)m/z：412.9。

Example 191- (4-chloro-3-fluoro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: 1- (4-chloro-3-fluoro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to example 6.

¹H-NMR(500MHz,DMSO-d6)：δ8.73(s，1H)，8.16(s，2H)，7.57-7.60(m，1H)，7.36-7.40(m，1H)，7.04-7.06(m，1H)，6.38(d，1H)，5.86(d，1H)，3.98-4.01(m，1H)，3.68-3.69(m，1H)，1.99-2.05(m，1H)，1.88-1.89(m，1H)，1.6-1.71(m，2H)，1.28-1.40(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ158.51，156.59，155.68，148.36，146.75，141.53，130.70，117.78，115.06，110.94，106.18，59.62，53.39，34.07，32.68，25.03，24.35。MS(ESI+,[M+H]+)m/z：430.9。

Example 201- (3,4, 5-trifluoro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: according to example 6, 1- (3,4, 5-trifluoro-phenyl) -3- ((1SR,2SR) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea.

¹H-NMR(500MHz,DMSO-d6)：δ8.74(s，1H),8.16(s，2H)，7.25-7.28(m，2H)，6.45(d，1H)，5.83(d，1H)，3.98-4.04(m，1H)，3.66-3.72(m，1H)，2.03-2.05(m，1H)，1.87-1.89(m，1H)，1.66-1.71(m，2H)，1.33-1.40(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.65，151.60，149.67，148.37，146.75，137.39，134.71，132.79，117.75，102.19，59.52，53.44，34.08，32.64，25.02，24.37。MS(ESI+,[M+H]⁺)m/z：432.9。

Example 211- (3-chloro-4-fluorophenyl) -3- (1- ((3, 5-dichloropyridin-4-yl) amino) propan-2-yl) urea

Step A: preparation of N according to example 1, substituting 1, 2-diaminopropane for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 2-diamine.

¹H-NMR(500MHz,DMSO-d6)：δ8.15(s，2H)，3.62(m，1H)，3.30(m，1H)，2.99(m，1H)，1.01(d，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.30，147.11，146.84，118.32，117.41，52.32，47.01，22.19。MS(ESI+,[M+H]⁺)m/z：220.0。

And B: 1- (3-chloro-4-fluorophenyl) -3- (1- ((3, 5-dichloropyridin-4-yl) amino) propan-2-yl) urea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.65(s，1H)，8.17(s，2H)，7.70(m，1H)，7.20-7.28(m，1H)，7.18-7.20(m，1H)，6.22(d，1H)，6.07(t，1H)，3.96(m，1H)，3.79(m，1H)，3.56(m，1H)，1.13(d，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.51，153.36，151.45，148.38，147.07，138.12，119.49，119.34，118.39，117.65，117.15，51.34，46.11，18.82。MS(ESI+,[M+H]⁺)m/z：390.9。

Example 223- (3-chloro-4-fluorophenyl) -1- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -1-methylurea

Step A: preparation of N according to example 1, substituting N-methylethylenediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) -N²-methyl ethane-1, 2-diamine.

MS(ESI+,[M+H]⁺)m/z：220.1。

And B: 3- (3-chloro-4-fluorophenyl) -1- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -1-methylurea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.45(s，1H)，8.14(s，2H)，7.73(m，1H)，7.40(m，1H)，7.26(m，1H)，6.27(t，1H)，3.83(m，2H)，3.55(m，2H)，2.97(s，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.13，153.76，151.85，148.35，146.90，138.21，121.49，120.18，119.01，117.32，116.76，116.59，48.92，43.76，35.18。MS(ESI+,[M+H]⁺)m/z：391.9。

Example 231- (3-chloro-4-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea

The reaction process comprises the following steps:

step A: 1, 4-dioxane (100mL) and 1-methyl-1, 2-ethylenediamine (18.7mg) were added to a 250mL three-necked flask, and a solution of di-tert-butyl dicarbonate (6.95g) in 1, 4-dioxane was added dropwise thereto, followed by reaction at room temperature overnight. After the reaction was completed, water (80mL) was added, extracted with dichloromethane (3 x 70mL), dried, and concentrated to dryness to give tert-butyl (2-aminopropyl) carbamate (5.7g, 100%) which was used in the next reaction.

And B: to a 100mL single-necked flask were added tert-butyl (2-aminopropyl) carbamate (1.74g) and trichloropyridine (912mg), and the mixture was reacted at 70 ℃ for 2 hours. After the reaction was completed, dichloromethane (30mL) was added, washed with water (3 × 8mL), dried, and concentrated to dryness, and the resulting crude product was subjected to column chromatography (DCM: MeOH ═ 50:1) to give tert-butyl (2- ((3, 5-dichloropyridin-4-yl) amino) propyl) carbamate (200 mg).

And C: to a 25mL single-necked flask was added tert-butyl (2- ((3, 5-dichloropyridin-4-yl) amino) propyl) carbamate (600mg), 10% HCl/MeOH solution (5mL), and reacted at 50 ℃ for 2 h. After the reaction is finished, the reaction solution is concentrated and dried, and is dissociated by sodium hydroxide aqueous solution to obtain N²- (3, 5-dichloropyridin-4-yl) propane-1, 2-diamine (260 mg).

Step D: adding N into a 100mL single-mouth bottle²- (3, 5-dichloropyridin-4-yl) propane-1, 2-diamine (260mg) and methylene chloride (3mL) were added dropwise to 3-chloro-4-fluorobenzeneisocyanate (304mg) and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated to dryness and subjected to column chromatography (PE: EA ═ 4:1) to give 1- (3-chloro-4-fluorophenyl) -3- (2- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea (60 mg).

¹H-NMR(500MHz,DMSO-d6)：δ8.75(s，1H)，8.19(s，2H)，7.72(m，1H)，7.25(m，1H)，7.20(m，1H)，6.43(t，1H)，5.65(d，1H)，4.43(m，1H)，3.28(m，2H)，1.15(d，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.05，153.38，151.47，148.41，146.99，138.06，119.47，118.38，117.10，51.51，45.35，19.95。MS(ESI+,[M+H]⁺)m/z：391.0。

Example 241- (3-chloro-4-fluorophenyl) -3- ((1SR, 3RS) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1SR, 3RS) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to example 1, substituting cis-1, 3-cyclohexanediamine for ethylenediamine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.47(s,1H),8.24(s,2H),7.71-7.73(m,1H),7.17-7.27(m,2H),6.21(d,J＝7.5Hz,1H),5.32(d,J＝9.5Hz,1H),4.02(s,1H),3.49(s,1H),1.73-2.14(m,4H),1.17-1.35(m,4H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.69,153.28,148.48,146.76,138.22,119.51,117.23,53.22,47.85,41.19,33.45,23.00。HRMS(ESI+,[M+H]⁺)m/z：431.0595。

Example 251- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea was prepared according to example 1, substituting 2-methyl-1, 3-propanediamine for ethylenediamine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.67(s，1H)，8.17(s，2H)，7.74(d，J＝6.0Hz，1H)，7.20-7.28(m，2H)，6.35(d，J＝6.0Hz，2H)，3.48-3.49(t，J＝6.5Hz，2H)，3.03-3.13(m，2H)，1.83-1.87(m，1H)，0.84(d，J＝7.0Hz，3H)。

¹³C-NMR(125MHz,DMSO-d6)：δ156.06，153.29，148.47，138.25，119.51，118.31，117.24，47.97，42.38，35.63，15.50。HRMS(ESI+,[M+H]⁺)m/z：405.0766。

Example 261- (3, 4-difluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) 2, 2-dimethylpropyl) urea

Step A: preparation of N according to example 1, substituting 2, 2-dimethyl-1, 3-propanediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine.

HRMS(ESI+,[M+H]⁺)m/z：248.0716。

And B: 1- (3, 4-difluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) 2, 2-dimethylpropyl) urea was prepared according to the procedure used in step B, as in example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.72(s，1H),8.19(s，2H)，7.76(d，1H)，7.30-7.22(m，2H)，6.51(t，J＝6.5Hz,1H)，6.28(t，J＝6.5Hz,1H)，3.50(d，J＝7Hz，2H)，3.03(d，J＝6.5Hz，2H)，0.81(s，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.48，153.40，151.49，48.61，147.56，138.06，138.04，119.57，119.45，119.42，118.44，118.38，117.83，117.31，117.14，50.75，46.55，38.01，23.28。HRMS(ESI+,[M+H]⁺)m/z：420.0650。

Example 271- (3-chloro-4-fluorophenyl) -3- ((1SR,2RS) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: preparation of (1RS, 2SR) -N according to example 1, substituting cis-cyclohexanediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) cyclohexane-1, 2-diamine.

¹H-NMR(500MHz,DMSO-d6)：δ8.18(s，2H),6.40(d，J＝8.5Hz,,1H)，4.08-4.04(m，1H)，2.98(d，1H)，1.75(t，2H)，1.64(t，2H)，1.57(t，2H)，1.36(t，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.37,146.92,117.28,49.05,43.65,33.97。

And B: 1- (3-chloro-4-fluorophenyl) -3- ((1SR,2RS) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6):δ8.60(s，1H),8.22(s，2H),7.71(dd,J＝2.5,7Hz,1H),7.27(t，J＝9Hz,1H),7.18-7.15(m,1H),6.54(d,J＝9Hz,1H),5.31(d,J＝8.5Hz,1H),4.36(d,J＝3Hz,1H),4.09-4.03(m,1H),1.76(d,8.5Hz,1H),1.65(s,3H),1.50-1.38(m,4H)；¹³C-NMR(125MHz,DMSO-d6):δ155.42,153.41,151.50,148.37,146.25,137.94,137.92,119.61,119.46,119.32,118.88,118.27,118.22,117.33,117.16,54.61,48.64,29.70,29.02,23.13,20.89.HRMS(ESI+,[M+H]⁺)m/z:431.0595.

Example 281- (3-chloro-4-fluorophenyl) -3- ((1R,2R) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1R,2R) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to example 1, substituting (1R,2R) -cyclohexanediamine for ethylenediamine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.58(s，1H),8.16(s，2H)，7.69(dd，J＝2.5，7Hz，1H)，7.25(t，J＝9Hz，1H)，7.20-7.17(m，1H)，6.35(d，J＝9Hz,1H)，5.89(d，J＝8.5Hz，1H)，3.99(d，J＝3Hz，1H)，3.71-3.65(m，1H)，2.04(d，7.5Hz，1H)，1.88(d，J＝7.5Hz,1H)，1.69(q，J＝8Hz，2H)，1.39-1.24(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.90，148.38，146.74，119.50，117.73，59.68，53.39，34.09，32.69，25.05，24.34。HRMS(ESI+,[M+H]⁺)m/z：431.0586。

Example 291- (3-chloro-4-fluorophenyl) -3- ((1S,2S) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1S,2S) -2- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to example 1 substituting (1S,2S) -cyclohexanediamine for ethylenediamine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.58(s，1H),8.16(s，2H)，7.69(dd，J＝2.5，7Hz，1H)，7.25(t，J＝9Hz，1H)，7.20-7.17(m，1H)，6.35(d，J＝9Hz,1H)，5.90(d，J＝8.5Hz，1H)，3.99(d，J＝3Hz，1H)，3.71-3.67(m，1H)，2.03(d，7.5Hz，1H)，1.88(d，J＝7.5Hz,1H)，1.68(q，J＝8Hz，2H)，1.39-1.25(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.89,153.35,151.44,148.37,146.73,138.06,138.04,119.48,119.33,118.41,118.35,117.72,117.24,117.07,59.68,53.37,34.09,32.69,25.05,24.34。HRMS(ESI+,[M+H]⁺)m/z：431.0568。

Example 303- (3-chloro-4-fluorophenyl) -1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -1-methylurea

Step A: preparation of N according to example 1, substituting N-methyl-1, 3-propanediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) -N³-methylpropane-1, 3-diamine.

¹H-NMR(500MHz,DMSO-d6)：δ8.44(s，1H),8.14(s，2H),6.82(s，1H),3.71(q，J₁＝6.0Hz，J₂＝6.0Hz，2H),2.54(q，J₁＝6.5Hz，J₂＝6.0Hz，2H),2.26(s，3H),1.64-1.69(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.37,146.98,117.15,49.80,44.58,36.57,29.87。MS(ESI+,[M+H]⁺)m/z：234.0。

And B: 3- (3-chloro-4-fluorophenyl) -1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -1-methylurea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.43(s，1H),8.16(s，2H)，7.75-7.77(m，1H)，7.42-7.45(m，1H)，7.28(t，J＝9Hz，1H)，6.25-6.28(t，J＝6.5Hz，1H)，3.61(q，J₁＝7.0Hz，J₂＝6.5Hz，2H)，3.37(t，7.0Hz，2H)，2.95(s，3H)，1.74-1.80(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.89，153.71，151.80，148.43，146.82，138.37，121.42，120.22，119.02，117.46，116.74，45.63，42.32，34.82，29.39。MS(ESI+,[M+H]⁺)m/z：405.0。

Example 313-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -4-fluorobenzamide

The reaction process comprises the following steps:

step A: to a 100mL single neck flask was added DMF (8mL), N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine (412mg), 3-chloro-4-fluorobenzoic acid (349mg), DIPEA (516mg), HATU (837mg), and reacted at room temperature for 1 hour. After the reaction was completed, water (20mL) was added dropwise, followed by filtration and drying to give 3-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -4-fluorobenzamide (480mg, 66.2%).

¹H-NMR(500MHz,DMSO-d6)：δ8.67(s，1H)，8.17(s，2H)，8.02(m，1H)，7.85(m，1H)，7.53(m，1H)，6.23(t，1H)，3.83(m，1H)，3.48(m，1H)；¹³C-NMR(125MHz,DMSO-d6)：δ165.03，160.36，158.36，148.39，146.94，132.49，130.11，128.93，119.99，117.48，44.68，40.35。MS(ESI+,[M+H]⁺)m/z：361.9。

Example 323-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -4-fluorobenzamide

Step A: according to example 31, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, preparation of 3-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -4-fluorobenzamide.

¹H-NMR(500MHz,DMSO-d6)：δ8.64(s，1H)，8.16(s，2H)，8.04(m，1H)，7.88(m，1H)，7.53(m，1H)，6.28(t，1H)，3.68(m，2H)，3.31(m，2H)，1.78(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ164.65，160.32，158.33，148.44，146.69，132.56，130.06，128.85，120.06，117.42，42.34，36.97，31.24。MS(ESI-,[M-H]^-)m/z：374.0。

Example 331- (3-chloro-4-fluorophenyl) -3- (1- (thiazol-2-yl) piperidin-3-yl) urea

The reaction process comprises the following steps:

step A: 2-bromothiazole (378mg), 3-aminopiperidine (576mg) was added to a 10mL microwave tube, and the mixture was reacted at 90 ℃ for 1 hour with microwaves. After the reaction was complete, the crude product was purified by column chromatography (DCM: MeOH ═ 50:1) to give 1- (thiazol-2-yl) piperidin-3-amine (273mg, 65%).

¹H-NMR(500MHz,DMSO-d6)：δ7.11(t，1H)，6.75(t，1H)，3.79(d，1H)，3.72(d，1H)，2.92(m，2H)，2.72(m，2H)，1.84(d，1H)，1.73(d，1H)，1.53(dd，1H)，1.20(dd，1H)；¹³C-NMR(125MHz,DMSO-d6)：δ171.81，139.85，107.71，57.54，48.84，47.59，33.83，23.53。MS(ESI+,[M+H]⁺)m/z：184.1。

And B: according to example 1,1- (thiazol-2-yl) piperidin-3-amine is used in step B instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine to give 1- (3-chloro-4-fluorophenyl) -3- (1- (thiazol-2-yl) piperidin-3-yl) urea.

¹H-NMR(500MHz,DMSO-d6)：δ8.61(s，1H)，7.77(d，1H)，7.26(m，1H)，7.19(m，1H)，7.14(d，1H)，6.81(d，1H)，6.40(d，1H)，3.74(d，2H)，3.50(m，1H)，3.28(m，1H)，3.13(m，1H)，1.85(d，1H)，1.76(d，1H)，1.63(t，1H)，1.55(t，1H)；¹³C-NMR(125MHz,DMSO-d6)：δ171.96，154.84，153.34，151.43，139.86，138.09，119.43，118.21，117.20，108.21，53.97，48.88，45.35，29.86，22.52。MS(ESI-,[M-H]^-)m/z：353.2。

Example 34N- (3-chloro-4-fluorophenyl) -4- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide

The reaction process comprises the following steps:

step A: according to example 1, in step a 4-aminopiperidine was used instead of ethylenediamine and the crude product was subjected to column chromatography (DCM: MeOH ═ 10:1) to give two isomers, isomer b eluting first and isomer a, i.e. 3, 5-dichloro-N- (piperidin-4-yl) pyridin-4-amine, eluting second.

¹H-NMR(500MHz,DMSO-d6)：δ8.22(s,2H),5.22(d,J＝9.0Hz,1H),3.97-4.05(m,1H),2.92(d,J＝2.5Hz,4H),2.45-2.51(m,1H),1.79-1.82(m,2H),1.41-1.44(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ148.42,146.56,118.94,52.82,45.22,34.86。HRMS(ESI+,[M+H]⁺)m/z：246.0570。

And B: according to example 1, the N is replaced by the isomer a in step B¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine to give N- (3-chloro-4-fluorophenyl) -4- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide.

¹H-NMR(500MHz,DMSO-d6)：δ8.73(s,1H),8.26(s,2H),7.75-7.77(m,1H),7.40-7.43(m,1H),7.26-7.30(m,1H),5.45(d,J＝9.0Hz,1H),4.15-4.21(m,1H),4.03-4.09(m,2H),2.88-2.93(m,2H),1.89(d,J＝10.5Hz,2H),1.54-1.62(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.96,153.65,151.74,148.52,146.81,138.48,121.13,119.28,116.91,52.51,43.26,33.36。HRMS(ESI+,[M+H]⁺)m/z：417.0456。

Example 351- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-4-yl) urea

The reaction process comprises the following steps:

step A: the first isomer b, 1- (3, 5-dichloropyridin-4-yl) piperidin-4-amine, eluted in the column chromatography according to example 34.

¹H-NMR(500MHz,DMSO-d6)：δ8.34(s,2H),3.26(d,J＝12.5Hz,2H),3.14(t,J＝11.5Hz,2H),2.72-2.75(m,1H),1.75-1.77(m,4H),1.34-1.40(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ151.79,149.33,127.94,49.53,48.27,36.40。HRMS(ESI+,[M+H]⁺)m/z：246.0574。

And B: following example 35, substituting isomer B for isomer a in step B, 1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-4-yl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.52(s,1H),8.42(s,2H),7.75-7.77(m,1H),7.21-7.28(m,2H),6.38(d,J＝7.5Hz,1H),3.71(t,J＝4.0Hz,1H),3.31-3.36(m,2H),3.24-3.29(m,2H),1.91-1.94(m,2H),1.56-1.61(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.79,153.29,151.67,149.45,138.23,128.06,119.53,117.24,49.33,46.32,33.07。HRMS(ESI+,[M+H]⁺)m/z：417.0445。

Example 36N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide

The reaction process comprises the following steps:

step A: according to example 1, 3-aminopiperidine is used instead of ethylenediamine in step a, and the crude product is subjected to column chromatography (PE: EA ═ 2:1) to obtain two isomers, which are then eluted as isomer i, i.e. N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide.

¹H-NMR(500MHz,DMSO-d6)：δ8.74(s,1H),8.25(s,2H),7.71-7.72(m,1H),7.35-7.39(m,1H),7.27(t,J＝9.0Hz,1H),5.46(d,J＝9.0Hz,1H),4.17(t,J＝4.0Hz,1H),3.80-3.84(m,1H),3.60(s,1H),3.35-3.39(s,1H),3.26(s,1H),1.63-1.71(m,2H),1.18-1.23(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ155.33,153.71,151.80,148.49,146.41,138.31,121.13,119.96,116.91,50.79,49.23,44.67,30.95,23.01。HRMS(ESI+,[M+H]⁺)m/z：417.0423。

Example 371- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea

Step A: according to example 36, the isomer II, 1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea, elutes first.

¹H-NMR(500MHz,DMSO-d6)：δ8.63(s,1H),8.44(s,2H),7.72-7.74(m,1H),7.24-7.27(m,1H),7.17-7.20(m,1H),6.26(d,J＝7.5Hz,1H),3.75(s,1H),3.44-3.47(m,1H),3.12-3.24(m,2H),2.98-3.02(m,1H),1.73-1.79(m,2H),1.18-1.47(m,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.83,153.32,151.40,149.49,138.12,128.39,119.54,118.28,117.27,56.12,50.59,46.84,30.20,24.48。HRMS(ESI+,[M+H]⁺)m/z：417.0429。

Example 381- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclopentyl) methyl) urea

The reaction route is as follows:

step A: malononitrile (4.95g, 75mmol) is dissolved in N, N-dimethylformamide (50mL), 1, 4-dibromobutane (17.8g, 82.5mmol) is slowly added under ice bath conditions, the reaction flask is moved to an oil bath to heat the reaction, and the reaction is stirred for 2 hours when the temperature is raised to 80 ℃. 200mL of water and 200mL of ethyl acetate were added to the reaction mixture, followed by sufficient stirring and liquid separation, 200mL of ethyl acetate was added again to the aqueous layer, liquid separation was performed by extraction, the organic layers were combined, and 100mL of water was added to the organic layer and washed three times. After drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain a brown liquid, and purifying by column chromatography to obtain 5.9g of colorless viscous liquid.

¹H-NMR(500MHz,CDCl₃):δ2.42(quint,J₁＝3.0Hz,7.5Hz,4H),1.98(quint,J₁＝4.0Hz,7.0Hz,4H)。¹³C-NMR(125MHz,CDCl₃):δ116.62,39.31,33.68,24.03。MS(ESI-,[M-H]^-):m/z 119.0。

And B: cyclopentane-1, 1-dinitrile (1.8g, 15mmol) was dissolved in anhydrous tetrahydrofuran (5mL), the flask was cooled to-15 deg.C, borane tetrahydrofuran solution (60mL,60mmol) was slowly added to the flask, and the reaction was stirred at room temperature overnight after the addition. Adding 6N hydrochloric acid into the reaction liquid to adjust the pH value to about 4, heating at 60 ℃ for 3 hours, adding sodium hydroxide into the reaction liquid under the ice bath condition to dissolve the reaction liquid to adjust the pH value to about 9, standing for liquid separation, adding 50mL of ethyl acetate into a water layer for extraction, combining organic layers, drying by anhydrous sodium sulfate, and concentrating under reduced pressure until the crude product is dried to obtain 5.75g of a colorless oily liquid crude product. Column chromatography purification yielded 1.7g of colorless liquid.

MS(ESI+,[M+H]⁺):m/z 129.1。

And C: n- ((1- (aminomethyl) cyclopentyl) methyl) -3, 5-dichloropyridin-4-amine was prepared according to example 1, substituting cyclopentane-1, 1-dimethylmethylamine for ethylenediamine in step A.

¹H-NMR(500MHz,CDCl₃):δ8.12(s,2H),3.73(d,J＝5.0Hz,2H),2.81(s,2H),1.62～1.68(m,4H),1.44～1.54(m,4H)。¹³C-NMR(125MHz,CDCl₃):δ148.06,147.70,117.73,54.15,50.29,47.41,33.95,24.94。MS(ESI,[M+H]⁺):m/z 274.0。

Step D: 1- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclopentyl) methyl) urea was prepared according to the procedure used in step B, according to example 1.

¹H-NMR(500MHz,DMSO-d6):δ8.73(s,1H),8.19(s,2H),7.75(dd,J₁＝2.0Hz,J₂＝6.5Hz,1H),7.22～7.29(m,2H),6.58(t,J＝6.5Hz,1H),6.29(d,J＝6.5Hz,1H),3.59(d,J＝7.0Hz,2H),3.15(d,J＝6.5Hz,2H),1.58(d,J＝2.0Hz,4H),1.33(d,J＝6.5Hz,4H)。¹³C-NMR(125MHz,DMSO-d6):δ156.59,153.40,151.49,148.59,147.51,138.06,119.49,118.47,118.03,117.29,49.96,49.21,44.50,33.37,24.94。MS(ESI,[M+H]⁺):m/z 445.0。

Example 391- (3-chloro-4-fluorophenyl) -3- ((4- (((3, 5-dichloropyridin-4-yl) amino) methyl) tetrahydro-2H-pyran-4-yl) methyl) urea

Step A: dihydro-2H-pyran-4, 4- (3H) -dinitrile is prepared according to example 38, substituting 1-bromo-2- (2-bromoethoxy) ethane for 1, 4-dibromobutane in step a.

¹H-NMR(500MHz,DMSO-d6):δ3.71(t,J＝5.0Hz,4H),2.30(t,J＝5.0Hz,4H)。¹³C-NMR(125MHz,DMSO-d6):δ116.18,63.10,32.87,30.70。

And B: (tetrahydro-2H-pyran-4, 4-diyl) dimethylamine was prepared according to example 38, using the procedure of step B.

¹H-NMR(500MHz,CDCl₃):δ3.61(t,J＝5.5Hz,4H),2.67(s,4H),1.74(s,4H),1.40(t,J＝5.5Hz,4H)。¹³C-NMR(125MHz,CDCl₃):δ63.54,46.71,35.54,31.63。

And C: n- ((4- (aminomethyl) tetrahydro-2H-pyran-4-yl) methyl) -3, 5-dichloropyridin-4-amine was prepared according to the procedure for example 38 using step C.

¹H-NMR(500MHz,DMSO-d6):δ8.13(s,2H),4.35(s,1H),3.75(s,2H),3.49～3.57(m,4H),3.91(t,J＝5.5Hz,2H),2.77(s,2H),1.38～1.44(m,4H)。¹³C-NMR(500MHz,DMSO-d6):δ148.39,147.69,117.33,63.14,61.22,54.44,48.80,35.02,31.91,29.67。MS(ESI,[M+H]⁺):m/z290.0。

Step D: utilizing the procedure of step D, 1- (3-chloro-4-fluorophenyl) -3- ((4- (((3, 5-dichloropyridin-4-yl) amino) methyl) tetrahydro-2H-pyran-4-yl) methyl) urea was prepared according to example 38.

¹H-NMR(500MHz,DMSO-d6):δ8.75(s,1H),8.20(s,2H),7.74(dd,J₁＝2.0Hz,J₂＝6.5Hz,1H),7.24～7.28(m,2H),6.59(t,J＝6.5Hz,1H),6.30(t,J＝6.5Hz,1H),3.62(d,J＝6.5Hz,2H),3.55(t,J＝4.5Hz,4H),3.31(s,2H),1.29～1.32(m,4H)。¹³C-NMR(DMSO,500MHz):δ156.59,153.40,151.49,148.59,147.51,138.06,119.49,118.47,118.03,117.29,49.96,49.21,44.50,33.37,24.94。MS(ESI,[M+H]⁺):m/z461.0。

Example 401- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclohexyl) methyl) urea

Step A: cyclohexane-1, 1-dinitrile is prepared according to example 38 by replacing 1, 4-dibromobutane with 1, 5-dibromopentane in step A.

¹H-NMR(500MHz,DMSO-d6)：δ2.14(t，J＝6Hz，4H)，1.80-1.75(m，4H),1.56(t，J＝5.5Hz,2H)。¹³C-NMR(125MHz,DMSO-d6)：δ115.96，34.70，32.49，23.96，21.69。

And B: cyclohexane-1, 1-dimethylmethylamine was prepared according to example 38, using the procedure of step B.

And C: utilizing the procedure of step C, N- ((1- (aminomethyl) cyclohexyl) methyl) -3, 5-dichloropyridin-4-amine was prepared according to example 38.

Step D: according to example 38, the procedure of step D was utilized, 1- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclohexyl) methyl) urea.

¹H-NMR(500MHz,DMSO-d6)：δ8.70(s，1H),8.20(s，2H)，7.74(d，J＝7Hz，1H)，7.30-7.22(m，2H)，6.50(d，J＝6Hz,1H)，6.24(t，J＝6Hz，1H)，3.54(d，J＝6.5Hz，2H)，3.20(d，J＝6Hz，1H)，1.38(t，8Hz，4H)，1.22-1.18(m，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.67，153.44，151.52，148.60，147.79，138.01，119.58，119.47，118.49，118.44，118.21，117.32，117.15，49.10，43.03，31.36，26.19，21.25。HRMS(ESI+,[M+H]+)m/z：459.0844。

Example 411- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cycloheptyl) methyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclobutyl) methyl) urea is prepared according to example 38, substituting 1, 6-dibromohexane for 1, 4-dibromobutane in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.71(s,1H),8.19(s,2H),7.54(t,J＝5.0Hz,1H),7.22-7.30(m,2H),6.54(t,J＝6.5Hz,1H),6.33(t,J＝6.5Hz,1H),3.49(d,J＝6.5Hz,2H),3.10(d,J＝6.5Hz,2H),1.40-1.45(m,8H),1.27-1.28(m,4H)。¹³C-NMR(125MHz,DMSO-d6)：δ156.69,153.44,151.53,148.62,137.98,119.58,117.98,49.43,44.69,43.29,33.78,31.05,22.60。HRMS(ESI+,[M+H]⁺)m/z：473.1075。

Example 421- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclopentyl) urea

The reaction route is as follows:

step A: anhydrous tetrahydrofuran (150mL) was added to a 500mL round bottom flask, followed by benzylamine (10.7g, 0.1mol), cyclopentanone (8.4g, 0.1mol), and anhydrous sodium sulfate (71g, 0.5 mol). The reaction solution was cooled in an ice bath, and cyanotrimethylsilane (10.5g, 0.105mol) was added slowly and stirred at room temperature overnight. And adding 300mL of water and 300mL of ethyl acetate into the reaction solution in sequence, fully stirring, separating liquid, adding 200mL of water into the organic layer in sequence, washing with saturated saline solution, drying with anhydrous sodium sulfate, performing rotary evaporation to dryness to obtain 20.95g of colorless liquid, and performing column chromatography purification to obtain 8.10g of colorless oily liquid, namely 1- (benzylamino) cyclopentanenitrile.

¹H-NMR(500MHz,CDCl₃):δ7.27～7.38(m,5H),3.91(s,2H),2.12～2.19(m,4H),1.79～1.92(m,4H)。¹³C-NMR(125MHz,CDCl₃):δ139.27,128.53,128.32,127.38,122.92,60.38,50.19,39.01,23.23。HRMS(ESI+,[M+H]⁺):m/z201.1388。

And B: lithium aluminum hydride (0.93g, 25mmol) was added to a dry round bottom flask under nitrogen blanket, and anhydrous tetrahydrofuran (25mL) was charged into the reaction flask and cooled in an ice bath. A solution of 1- (benzylamino) cyclopentanecarbonitrile (4.0g, 20mmol) in tetrahydrofuran (15mL) was slowly poured into the reaction flask and the reaction was continued for 1 hour under ice-bath conditions. Slowly pouring the reaction liquid into 50mL of ice-water mixture, adding 100mL of dichloromethane, separating, adding 100mL of dichloromethane into the water layer again, extracting, separating, combining organic layers, drying by anhydrous sodium sulfate, performing rotary evaporation to dryness, and purifying by column chromatography to obtain 1.55g of colorless viscous liquid, namely 1- (aminomethyl) -N-benzyl cyclopentyl amine.

¹H-NMR(500MHz,CDCl₃):δ7.24～7.33(m,5H),3.68(s,2H),2.68(s,2H),1.72～1.76(m,4H),1.61～1.66(m,4H)。¹³C-NMR(125MHz,CDCl₃):δ143.23,141.32,128.27,127.07,126.82,66.29,47.23,35.71,24.32。HRMS(ESI+,[M+H]⁺):m/z205.1693。

And C: 1- (aminomethyl) -N-benzylcyclopentylamine (1.70g, 8.33mmol) was dissolved in methanol (20mL), and aqueous 50% 10% Pd/C (1.70g) and concentrated hydrochloric acid (0.15mL) were added in that order. Replacing the gas in the reaction bottle with hydrogen for three times, heating and stirring the reaction solution in a hydrogen environment, and setting the temperature of the reaction solution to be 60 ℃. TLC after 7 hours showed the reaction was complete. The reaction flask is cooled to room temperature and then is filtered under reduced pressure, a filter cake is washed by 5mL of methanol, and the filtrate is concentrated under reduced pressure to obtain colorless viscous liquid, namely 1- (aminomethyl) cyclopentylamine (0.98 g).

¹H-NMR(500MHz,CDCl₃):δ2.63(s,2H),1.74～1.79(m,2H),1.42～1.63(m,6H)。¹³C-NMR(500MHz,CDCl₃):δ62.42,52.19,38.33,24.19。MS(ESI+,[M+H]⁺):m/z115.1。

Step D: n- ((1-Aminocyclopentyl) methyl) -3, 5-dichloropyridin-4-amine was prepared according to example 1, substituting 1- (aminomethyl) cyclopentylamine for ethylenediamine in step A.

MS(ESI+,[M+H]⁺):m/z260.0。

Step E: 1- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclopentyl) urea was prepared according to the procedure used in step B, according to example 1.

¹H-NMR(500MHz,DMSO-d6):δ8.47(s,1H),8.16(s,2H),7.66(dd,J₁＝2.5Hz,J₂＝7.0Hz,1H),7.24(t,J＝9.0Hz,1H),7.10(d,J＝4.0Hz,1H),6.26(s,1H),5.89(t,J＝5.5Hz,1H),3.91(d,J＝5.0Hz,2H),1.62～1.68(m,4H),1.15～1.18(m,4H)。¹³C-NMR(125MHz,DMSO-d6):δ170.86,155.23,153.35,151.44,148.27,137.83,119.40,118.58,118.27,117.25,64.62,60.24,36.47,23.60。MS(ESI+,[M+H]⁺):m/z430.9。

Example 431- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cycloheptyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cycloheptyl) urea was prepared according to example 42 by substituting cycloheptanone for cyclopentanone in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.61(s,1H),8.18(s,2H),7.66-7.68(m,1H),7.26(t,J＝9.0Hz,1H),7.09-7.12(m,1H),6.12(s,1H),5.78(t,J＝5.5Hz,1H),3.85(d,J＝5.5Hz,2H),1.23-1.61(m,12H)。¹³C-NMR(125MHz,DMSO-d6)：δ155.01,153.35,151.44,148.34,147.80,137.84,119.57,118.39,117.31,59.70,52.69,36.39,29.59,22.19。HRMS(ESI+,[M+H]⁺)m/z：459.0909。

Example 441- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclohexyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- (1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclohexyl) urea was prepared according to example 42 substituting cyclohexanone for cyclopentanone in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.64(s，1H),8.17(s，2H)，7.69(q，J＝2.5Hz，1H)，7.26(t，J＝9Hz，1H)，7.11(q，J＝5Hz,1H)，6.02(s，1H)，5.88(t，J＝5Hz，1H)，3.87(d，J＝5Hz，2H)，2.02(d，12.5Hz，2H)，1.58-1.21(m，8H)；¹³C-NMR(125MHz，DMSO-d6)：δ155.00，153.35,151.44,148.33,147.93,137.91,137.89,119.59,119.44,119.27，118.42,118.22,118.17,117.29,117.12,55.80,53.96,33.05,25.64,21.35。HRMS(ESI+,[M+H]⁺)m/z：445.0737。

Example 451- (3-chloro-4-fluorophenyl) -3- ((1RS, 3RS) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Step A: preparation of (1RS, 3RS) -N according to example 1, substituting trans-1, 3-cyclohexanediamine for ethylenediamine in step A¹- (3, 5-dichloropyridin-4-yl) cyclohexane-1, 3-diamine.

And B: 1- (3-chloro-4-fluorophenyl) -3- ((1RS, 3RS) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared according to the procedure used in step B, according to example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.51(s,1H),8.24(s,2H),7.75(t,J＝1.5Hz,1H),7.27(t,J＝9.0Hz,1H),7.17(t,J＝4.5Hz,1H),6.32(d,J＝7.5Hz,1H),5.25(d,J＝9.0Hz,1H),4.27(t,J＝4.5Hz,1H),3.92(s,1H),1.47-1.90(m,8H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.80,153.26,151.35,148.47,146.49,138.16,119.57,118.05,117.28,50.22,44.98,38.06,32.68,30.62,20.07。HRMS(ESI+,[M+H]⁺)m/z：431.0594。

Example 461- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹Preparation of 1- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea from (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine and 3, 5-dichloroaniline instead of 3, 4-difluoroaniline.

¹H-NMR(500MHz,DMSO-d6)：δ8.89(s，1H),8.16(s，2H)，7.47(s，2H)，7.05(d，1H)，6.43(t，1H)，6.24(t，1H)，3.65(q，2H)，3.15(q，2H)，1.70(t，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.47，148.41，146.81，143.52，134.41，120.49，117.48，116.21，42.40，36.83，31.86。MS(ESI+,[M+H]⁺)m/z：407.0。

Example 471- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹Preparation of 1- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea from (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine and 3, 4-dichloroaniline instead of 3, 4-difluoroaniline.

¹H-NMR(500MHz,DMSO-d6)：δ8.81(s，1H),8.17(s，2H)，7.83(d，1H)，7.44(d，1H)，7.26(dd，1H)，6.35(t，1H)，6.25(t，1H)，3.65(q，2H)，3.15(q，2H)，1.70(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.62，148.42，146.81，141.22，131.34，130.85，122.68，119.25，118.26，117.48，42.40，36.79，31.91。MS(ESI+,[M+H]⁺)m/z：407.0。

Example 481- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3,4, 5-trichlorophenyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3,4, 5-trichloroaniline instead of 3, 4-difluoroaniline, 1- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -3- (3,4, 5-trichlorophenyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.96(s，1H),8.17(s，2H)，7.69(s，2H)，6.49(t，1H)，6.23(t，1H)，3.65(q，2H)，3.15(q，2H)，1.70(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.38，148.43，146.82，141.27，133.11，121.19，118.16，117.48，42.40，36.88，31.70。MS(ESI+,[M+H]⁺)m/z：441.0。

Example 491- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3-fluoro-5-chloroaniline instead of 3, 4-difluoroaniline, 1- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.92(s，1H),8.16(s，2H)，7.32(s，1H)，7.27(d，1H)，6.87(d，1H)，6.41(t，1H)，6.26(t，1H)，3.65(q，2H)，3.15(q，2H)，1.70(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ163.79，161.85，155.50，148.31，146.86，143.72，134.25，117.45，113.68，108.40，103.50，42.39，36.79，31.86。MS(ESI+,[M+H]⁺)m/z：391.0。

Example 501- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea

Step A: 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was prepared according to example 1 substituting 1, 3-diamino-2-hydroxypropane for ethylenediamine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.18(s，2H),6.06(br，1H)，3.74(m，1H)，3.56(m，1H)，2.60(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.33，147.22，117.59，71.31，49.14，45.96。MS(ESI+,[M+H]+)m/z：236.1。

And B: 1- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea was prepared according to the procedure used in step B, example 1.

¹H-NMR(500MHz,DMSO-d6)：δ8.80(s，1H),8.19(s，2H)，7.30(m，1H)，7.26(m，2H)，6.32(d，1H)，5.98(d，1H)，5.28(s，1H)，3.67-3.73(m，2H)，3.55(m，1H)，3.12-3.24(m，2H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.86，153.31，151.40，148.38，147.14，138.22，119.40，118.20，117.74，117.20，69.60，48.30，43.19。MS(ESI+,[M+H]+)m/z：407.0。

Example 511- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclobutyl) methyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyridin-4-yl) amino) methyl) cyclobutyl) methyl) urea is prepared according to example 38, substituting 1, 3-dibromopropane for 1, 4-dibromobutane in step A.

¹H-NMR(DMSO-d6,500MHz):δ8.73(s,1H),8.17(s,2H),7.75(dd,J＝2.5Hz,7.0Hz,1H),7.22～7.29(m,2H),6.54(t,J＝6.0Hz,1H),6.14(t,J＝6.5Hz,1H),3.72(d,J＝6.5Hz,2H),3.29(d,J＝6.0Hz,2H),1.83～1.85(m,2H),1.72(t,J＝8.0Hz,4H)。¹³C-NMR(DMSO-d6,125MHz):δ156.49,153.40,151.49,148.53,147.48,138.08,119.51,118.47,118.05,117.26,48.92,44.52,27.06,21.21。MS(ESI,[M+H]⁺):m/z 431.0。

Example 521- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2-methylpropyl-1, 3-diamine instead of N¹Preparation of 1- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea from (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine and 3, 4-dichloroaniline instead of 3, 4-difluoroaniline.

¹H-NMR(500MHz,DMSO-d6)：δ8.78(s，1H),8.17(s，2H)，7.83(m，1H)，7.23-7.26(m，1H)，7.43-7.46(m,1H)，6.41(t，1H)，6.20(t，1H)，3.51(m，2H)，3.12(m，2H)，1.86(m，1H)，0.85(s，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.85，148.46，146.83，141.17，131.36，130.87，122.72，119.24，118.26，117.52，48.03，42.44，35.60，15.51，14.32。MS(ESI+,[M+H]⁺)m/z：421.0。

Example 531- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2-methylSubstitution of propyl-1, 3-diamine for N¹Preparation of 1- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea from (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine and 3, 5-dichloroaniline instead of 3, 4-difluoroaniline.

¹H-NMR(500MHz,DMSO-d6)：δ8.86(s，1H),8.17(s，2H)，7.47(d，2H)，7.06(m，1H)，6.48(t，1H)，6.31(t，1H)，3.50(m，2H)，3.09(m，2H)，1.86(m，1H)，0.85(s，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.69，148.48，146.83，143.47，134.43，130.87，120.54，117.53，116.22，117.52，48.06，42.49，35.57，30.63，15.52。MS(ESI+,[M+H]⁺)m/z：421.0。

Example 541- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2-methylpropyl-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3-chloro-5-fluoroaniline instead of 3, 4-difluoroaniline, 1- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.87(s，1H),8.17(s，2H)，7.32(s，1H)，7.25-7.31(m,1H)，6.87-6.89(m，1H)，6.45(t，1H)，6.32(t，1H)，3.51(m，2H)，3.09(m，2H)，1.86(m，1H)，0.85(s，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ163.80，161.86，155.71，148.47，146.82，143.74，134.33，117.52，113.69，108.54,103.64，48.04，42.45，35.57，15.51。MS(ESI+,[M+H]⁺)m/z：405.0。

Example 55(R) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea

Step A: (R) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea was prepared according to example 37, substituting (R) -3-aminopiperidine for 3-aminopiperidine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.63(s，1H)，8.44(s，2H)，7.72-7.74(m，1H),7.24-7.25(m，1H)，7.18-7.20(m，1H)，6.26(d，J＝8.0Hz，1H)，3.73-3.74(s，1H)，3.44-3.47(m，1H)，3.12-3.24(m，2H)，2.98-3.02(m，1H)，1.73-1.79(m，2H)，1.24-1.47(m，2H)。¹³C-NMR(125MHz,DMSO-d6)：δ154.83，153.32，151.40，149.49，138.11，128.38，119.54，118.23，117.27，56.12，50.59，30.20，24.48。HRMS(ESI+,[M+H]⁺)m/z：417.0469。

Example 56(R) -N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide

Step A: (R) -N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide was prepared according to example 36 by substituting (R) -3-aminopiperidine for 3-aminopiperidine in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.74(s，1H)，8.24(s，2H))，7.70-7.72(m，1H)，7.35-7.38(m，1H)，7.27(t，J＝9.0Hz，1H)，5.47(d，J＝9.0Hz，1H)，4.17(t，J＝4.0Hz，1H)，3.80-3.84(m，1H)，3.60(s，1H)，3.35-3.39(s，1H)，3.26(s，1H)，1.66-1.71(m，2H)，1.23-1.39(m，2H)。¹³C-NMR(125MHz,DMSO-d6)：δ155.34，153.71，151.80，148.48，138.31，121.13，119.20，116.91，50.79，44.67，31.66，30.95，23.00。HRMS(ESI+,[M+H]⁺)m/z：417.0454。

Example 571- (3-chloro-4-fluorophenyl) -3- (4- ((3, 5-dichloropyridin-4-yl) amino) pent-2-yl) urea

The reaction process comprises the following steps:

step A: adding 2, 4-pentanediol (3.20g), dichloromethane (60mL) and triethylamine (10mL) into a 250mL single-neck bottle, slowly dropwise adding a mixed solution of methanesulfonyl chloride (5.90mL) and dichloromethane (20mL) in ice bath, after dropwise adding, turning to room temperature, stirring and reacting for 20h, washing reaction liquid with water (50mL), saturated sodium bicarbonate aqueous solution (50mL) and saturated sodium chloride aqueous solution (50mL), drying an organic layer with anhydrous sodium sulfate, performing suction filtration and spin drying to obtain 2, 4-pentamethylene dimethyl sulfonate (2.45g) oily matter, and directly using the oily matter in the next reaction.

And B: 2, 4-Pentyldimethyl sulphoxide (2.45g) and dimethyl sulphoxide (50mL) were added to a 250mL single-neck flask, sodium azide (1.84g) was added, an oil bath was carried out at 60 ℃ for 3h, the reaction was cooled to room temperature, quenched with 150mL of ice water, extracted with ethyl acetate (200mL), the organic layer was washed with water (150mL), saturated aqueous sodium bicarbonate (2X 150mL), saturated aqueous sodium chloride (150mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 2, 4-pentanediazide (1.60g) as an oil which was used directly in the next reaction.

And C: 2, 4-Pentadiazide (1.60g) and anhydrous methanol (60mL) were added to a 500mL one-necked flask, 10% Pd/C (0.30g) was added, hydrogen was replaced, the reaction was carried out at room temperature for 90 hours, and the mixture was suction-filtered through celite, and spin-dried to obtain 2, 4-diaminopentane (1.25g) as an oily substance, which was used in the next reaction.

Step D: adding 2, 4-diaminopentane (1.17g), trichloropyridine (597mg) and triethylamine (0.5mL) into a 25mL single-neck bottle, carrying out oil bath reaction at 70 ℃ for 3h under nitrogen atmosphere, extracting with dichloromethane (2X 100mL) after the reaction is finished, drying with anhydrous sodium sulfate, carrying out suction filtration, and carrying out column chromatography on a crude product (dichloromethane: methanol ═ 10:1) to obtain N²- (3, 5-dichloropyridin-4-yl) pentane-2, 4-diamine (100mg) as an oil was used directly in the next reaction.

MS(ESI+,[M+H]⁺)m/z：248.1。

Step E: will N²- (3, 5-dichloropyridin-4-yl) pentane-2, 4-diamine (100mg) and methylene chloride (5mL) were charged in a50 mL single-necked flask, and a mixed solution of 4-fluoro-3-chlorophenylisocyanate (68mg) and methylene chloride (1mL) was added dropwise thereto, followed by stirring at room temperature for 1 hour. After the reaction was completed, the crude product was subjected to column chromatography (PE: EA ═ 2:1) to give 1- (3-chloro-4-fluorophenyl) -3- (4- ((3, 5-dichloropyridin-4-yl) amino) pent-2-yl) urea (25mg, yield 15%).

¹H-NMR(500MHz,DMSO-d6)：δ8.40-8.52(m，1H)，8.21(s，1H)，8.15(s，1H)，7.66-7.75(m，1H)，7.18-7.27(m，2H)，6.07(d，J＝8.5Hz，1H)，5.33-5.36(m，1H)，4.31-4.50(m，1H)，3.72-3.85(m，1H),1.28-1.39(m，2H)，1.19-1.24(m，3H)，1.07-1.10(m，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.00，154.71，151.34，148.49，148.37，147.15，146.81，138.26，119.51，118.65，117.22，48.67，45.37，43.02，31.71，27.10，22.73。MS(ESI+,[M+H]⁺)m/z：419.1。

Example 581- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3, 4-dichloroaniline instead of 3, 4-difluoroaniline, 1- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.82(s，1H)，8.20(s，2H)，7.83-7.85(m，1H)，7.45-7.48(m，1H)，7.25-7.28(m，1H)，6.56(d，1H)，6.23(d，1H)，3.51(s，1H)，3.05(s，1H)，0.82-0.83(m，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.28，148.61，147.57，140.98，131.41，130.93，122.91，119.31，118.35，117.87，50.85，46.59，37.98，23.28。MS(ESI+,[M+H]⁺)m/z：435.0。

Example 591- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3, 5-dichloroaniline instead of 3, 4-difluoroaniline, 1- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.90(s，1H)，8.20(s，2H)，7.45(d，2H)，7.08(t，J＝2.0Hz，1H)，6.62(t，J＝6.0Hz，1H)，6.20(t，J＝7.0Hz，1H)，3.51(d，2H)，3.05(d，2H)，0.83(s，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.14，148.61，147.56，143.28，134.47，120.73，117.89，116.31，50.87，46.61，37.98，23.28，14.30。MS(ESI+,[M+H]⁺)m/z：435.0。

Example 601- (3,4, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3,4, 5-trichloroaniline instead of 3, 4-difluoroaniline, 1- (3,4, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.96(s，1H)，8.19(s，2H)，7.69(s，2H)，6.68(t，J＝6.5Hz，1H)，6.18(t，J＝6.5Hz，1H)，3.51(d，2H)，3.05(d，2H)，0.83(s，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.06，148.61，147.55，141.02，133.17，121.43，118.26，117.89，50.89，46.64，37.97，31.61，30.31，23.28。MS(ESI+,[M+H]⁺)m/z：468.9。

Example 611- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea

Step A: according to example 6, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3-chloro-5-fluoroaniline instead of 3, 4-difluoroaniline, 1- (3,4, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.92(s，1H)，8.19(s，2H)，7.34(s，1H)，7.27(d，1H)，6.90(d，1H)，6.61(t，J＝6.0Hz，1H)，6.21(t，J＝6.0Hz，1H)，3.51(d，2H)，3.05(d，2H)，0.83(s，6H)；¹³C-NMR(125MHz,DMSO-d6)：δ163.81，161.87，156.15，148.61，146.55，143.50，134.33，117.86，113.77，108.63，103.65，50.85，46.58，37.97，23.27。MS(ESI+，[M+H]⁺)m/z：418.8。

Example 621- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyrimidin-4-yl) amino) methyl) cyclopropyl) methyl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((1- (((3, 5-dichloropyrimidin-4-yl) amino) methyl) cyclopropyl) methyl) urea was prepared according to example 57 substituting 1, 1-cyclopropanedimethanol for 2, 4-pentanediol in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.72(s，1H)，8.20(s，2H)，7.73(d，1H)，7.21-7.29(m，2H)，6.46(t，J＝5.5Hz，1H)，6.06(t，J＝6.0Hz，1H)，3.61(d，2H)，3.11(d，2H)，0.44-0.46(m，4H)；¹³C-NMR(125MHz,DMSO-d6)：δ156.15，153.36，151.45，148.45，147.43，138.16，119.45，118.39，117.42，117.15，48.88，43.96，23.44，9.04。MS(ESI+,[M+H]+)m/z：417.0。

Example 631- (3-chloro-4-fluorophenyl) -3- ((2R,4R) -4- ((3, 5-dichloropyrimidin-4-yl) amino) pentan-2-yl) urea

Step A: 1- (3-chloro-4-fluorophenyl) -3- ((2R,4R) -4- ((3, 5-dichloropyrimidin-4-yl) amino) pentan-2-yl) urea was prepared according to example 57 by replacing 2, 4-pentanediol with (2S, 4S) -pentanediol in step A.

¹H-NMR(500MHz,DMSO-d6)：δ8.41(s，1H)，7.67(q，J₁＝2.5Hz，4.0Hz，1H)，7023(t，J＝9.0Hz，1H)，7.11-7.14(m，1H)，6.07(d，1H)，5.34(d，1H)，4.42-4.43(m，1H)，3.78-3.80(m，1H)，1.77-1.82(m，1H)，1.61-1.66(m，1H)，1.20(d，3H)，1.08(d，3H)；¹³C-NMR(125MHz,DMSO-d6)：δ154.71，153.19，151.28，147.14，138.30，119.37，118.58，118.14，117.02，48.34，44.70，42.77，22.73，22.26。MS(ESI+，[M+H]⁺)m/z：419.1。

Example 643-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methylpropyl) -4-fluorobenzenesulfonamide

The reaction process comprises the following steps:

step A: adding N into a 100mL single-mouth bottle¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine (200mg),adding 20ml of dichloromethane, stirring for dissolving, dropwise adding a dichloromethane solution (194.8mg/5ml) of 4-chloro-3-fluorobenzenesulfonyl chloride under ice bath, stirring for reacting for 1.5h at room temperature, washing with a 0.5N NaOH solution, and adding an organic layer into silica gel to pass through a column for purification to obtain 4-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) 2-methylpropyl) -3-fluorophenyl sulfonamide (140 mg).

¹H-NMR(500MHz,DMSO-d₆)：δ8.16(s，2H),7.92(m，1H)，7.75-7.80(m，2H),7.61-7.74(m，1H)，6.11(t,1H),3.50(m，1H),3.31(m，1H)，2.79(m,1H),2.62(m,1H)，1.86(m,1H)，0.84(s,3H)；¹³C-NMR(125MHz,DMSO-d₆)：δ160.78,158.77,148.43,146.49,138.45,128.34,121.10,118.45,117.60,47.91,46.09,34.74,15.39.MS(ESI+,[M+H]⁺)m/z：426.0.

Example 653-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) -4-fluorophenyl-sulphonamide

Step A: according to example 64, N is used in step A¹-3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, preparation of 3-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) -4-fluorophenylsulphonamide.

¹H-NMR(500MHz,DMSO-d6)：δ8.20(s,2H),7.98(d,J＝6.5Hz,1H),7.88(d,J＝5.5Hz,1H),7.81-7.82(m,1H),7.65-7.69(m,1H),5.60(t,J＝6.5Hz,1H),3.57(d,2H),2.64(d,2H),0.81(s,6H)；¹³C-NMR(125MHz,DMSO-d6)：δ160.84,158.82,148.56,147.33,138.48,132.34,129.54,128.40,121.17,118.51,51.55,50.59,37.34,23.06.MS(ESI+,[M+H]⁺)m/z：440.0.

Example 663-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -4-fluorophenylsulphonamide

Step A: according to example 64, N is used in step A¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, preparation of 3-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) -4-fluorophenylsulphonamide.

¹H-NMR(500MHz,DMSO-d6)：δ8.12(s,2H),7.92-7.97(m,2H),7.77-7.80(m,1H),7.57-7.60(m,1H),6.04(t,J＝6.5Hz,1H),3.65(q,J₁＝6.5Hz,6.5Hz,2H),3.05(q,J₁＝6.0Hz,6.0Hz,2H)；¹³C-NMR(125MHz,DMSO-d6)：δ160.79,158.78,148.38,146.25,138.38,132.24,129.43,128.31,124.26,121.14,118.41,117.21,43.85.MS(ESI+,[M+H]⁺)m/z：398.0.

Example 673, 4-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) benzenesulfonamide

Step A: according to example 64, N is used in step A¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, 3, 4-dichlorobenzenesulfonyl chloride instead of 4-chloro-3-fluorobenzenesulfonyl chloride, 3, 4-chloro-N- (2- ((3, 5-dichloropyridin-4-yl) amino) ethyl) benzenesulfonamide was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.13(s,2H),8.00-8.02(m,1H),7.93(d,J＝2.0Hz,1H),7.81(d,J＝8.5Hz,1H),7.71-7.73(m,1H),6.02(t,J＝6.5Hz,1H),3.65(q,J＝6.5Hz,2H),3.06(m,J＝6.0Hz,2H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.39,146.22,141.19,135.97,132.57,132.09,128.65,127.01,117.17,43.93,43.79.MS(ESI+,[M+H]⁺)m/z：413.8.

Example 683, 4-dichloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) benzenesulfonamide

Step A: according to example 64, N is used in step A¹- (3, 5-dichloropyridin-4-yl) -2, 2-dimethylpropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, 3, 4-dichlorobenzenesulfonyl chloride instead of 4-chloro-3-fluorobenzenesulfonyl chloride, 3, 4-dichloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) -2, 2-dimethylpropyl) benzenesulfonamide was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.20(s,2H),7.98(d,J＝2.0Hz,1H),7.89-7.94(m,2H),7.74-7.77(m,1H),5.59(t,J＝6.5Hz,1H),3.57(d,J＝6.5Hz,2H),2.64(d,J＝6.5Hz,2H),0.82(s,6H)；¹³C-NMR(125MHz,DMSO-d6)：δ148.57,147.33,141.25,135.99,132.61,132.20,128.78,127.13,118.10,51.56,50.59,37.35,23.05.MS(ESI+,[M+H]⁺)m/z：455.9.

Example 693, 4-dichloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) benzenesulfonamide

Step A: according to example 64, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹Preparation of 3, 4-dichloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) benzenesulfonamide by substituting 4-chloro-3-fluorobenzenesulfonyl chloride with (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, 3, 4-dichlorobenzenesulfonyl chloride.

¹H-NMR(500MHz,DMSO-d₆)：δ8.15(s,2H),7.94(s,1H),7.85(t,2H),7.71(m,1H),6.04(t,1H),3.56-3.60(m,2H),2.82(m,2H),1.64(m,2H)；¹³C-NMR(125MHz,DMSO-d₆)：δ148.40,146.59,141.21,135.96,132.61,132.13,128.73,127.08,117.59,42.12,41.07,30.89.MS(ESI+,[M+H]⁺)m/z：429.8.

Example 703-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -4-fluorobenzenesulfonamide

Step A: according to example 64, N is used in step A¹- (3, 5-dichloropyridin-4-yl) propane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) 2-methylpropyl-1, 3-diamine, preparation of 3-chloro-N- (3- ((3, 5-dichloropyridin-4-yl) amino) propyl) -4-fluorobenzenesulfonamide.

¹H-NMR(500MHz,DMSO-d6):δ8.14(s,2H),7.93(dd,J1＝2.0Hz,J2＝7.0Hz,1H),7.76～7.80(m,2H),7.62(t,J＝9.0Hz,1H),6.03(t,J＝6.5Hz,1H),3.58(dd,J1＝7.0Hz,J2＝13.5Hz,2H),2.81(dd,J1＝6.5Hz,J2＝12.0Hz,2H),1.64(quint,J＝7.0Hz,2H)。¹³C-NMR(125MHz,DMSO-d6):δ160.81,158.80,148.38,146.59,138.41,132.28,129.49,128.38,121.23,118.52,117.58,42.21,30.87.MS(ESI)m/z 411.9[M+H]+。

Example 711- (3-chlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea

Step A: referring to the procedure for the preparation of example 6, 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was used instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, m-chloroaniline instead of 3, 4-difluoroaniline, 1- (3-chlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)δ:8.81(s,1H),8.19(s,2H),7.65(s,1H),7.24(t,J＝8Hz,1H),7.17(d,J＝7.5Hz,1H),6.93(d,J＝7Hz,1H),6.32(s,1H),5.98(s,1H),5.27(s,1H),3.72～3.67(m,2H),3.55(t,1H),3.22(t,1H),3.15(t,1H)；¹³C-NMR(500MHz,DMSO-d6)δ:155.78,148.36,147.15,142.44,133.59,130.72,121.14,117.74,117.47,116.47,69.61,48.31,43.16.MS(ESI,[M+H]⁺)m/z:389.0.

Example 721- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea

Step A: referring to the procedure for the preparation of example 6, 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was used instead of N¹Preparation of 1- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea from (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine and 3, 4-dichloroaniline instead of 3, 4-difluoroaniline.

¹H-NMR(500MHz,DMSO-d6)δ:8.91(s,1H),8.19(s,2H),7.82(d,J＝2.5Hz,1H),7.45(d,J＝9Hz,1H),7.22(q,J＝2.5Hz,1H),6.36(t,J＝6Hz,1H),5.97(t,J＝6Hz,1H),5.28(d,J＝5Hz,1H),3.75～3.66(m,2H),3.58～3.54(m,1H),3.53～3.20(m,1H),3.16～3.12(m,1H)；¹³C-NMR(500MHz,DMSO-d6)δ:155.91,148.34,147.15,141.38,131.31,130.87,122.44,118.87,117.97,117.72,69.62,48.29,43.15.MS(ESI,[M+H]⁺)m/z:422.9.

Example 731- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) -3- (3,4, 5-trichlorophenyl) urea

Step A: referring to the procedure for the preparation of example 6, 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was used instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, 3,4, 5-trichloroaniline instead of 3, 4-difluoroaniline, 1- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) -3- (3,4, 5-trichlorophenyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)δ:9.04(s,1H),8.20(s,2H),7.67(s,1H),6.48(t,J＝6Hz,1H),5.97(t,J＝6Hz,1H),5.29(br,1H),3.75～3.67(m,2H),3.58～3.53(m,1H),3.25～3.20(m,1H),3.16～3.11(m,1H)；¹³C-NMR(500MHz,DMSO-d6)δ:155.41,148.28,147.18,141.16,133.16,121.27,118.07,117.74,69.46,48.34,43.25.MS(ESI,[M+H]⁺)m/z:456.9.

Example 741- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea

Step A: referring to the procedure for the preparation of example 6, 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was used instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting 3, 5-dichloroaniline for 3, 4-difluoroaniline, 1- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.19(s,2H),7.45(s,1H),7.06(s,1H),6.42(s,1H),5.96(s,1H),5.29(s,1H),3.74～3.68(m,2H),3.55(t,J＝7.5Hz,1H),4.55(t,1H),3.21(t,1H),3.15(t,1H)；¹³C-NMR(500MHz,DMSO-d6)δ:155.49,148.36,147.14,143.41,134.46,120.58,117.75,116.12,69.50,48.33,43.22.MS(ESI,[M+H]⁺)m/z:422.9.

Example 751- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea

Step A: referring to the procedure for the preparation of example 6, 1-amino-3- ((3, 5-dichloropyridin-4-yl) amino) propan-2-ol was used instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting 3, 4-difluoroaniline with 3-fluoro-5-chloroaniline to prepare 1- (3-chloro-5-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-hydroxypropyl) urea.

¹H-NMR(500MHz,DMSO-d6)δ:9.06(s,1H),8.19(s,2H),7.30(s,1H),7.25(d,1H),6.88(d,J＝8Hz,1H),6.43(s,1H),5.97(s,1H),5.29(s,1H),3.73～3.68(m,2H),3.55(t,1H),3.22(t,1H),3.14(t,1H)；¹³C-NMR(500MHz,DMSO-d6)δ:155.49,148.36,147.14,143.41,134.46,120.58,117.75,116.12,69.50,48.33,43.22.MS(ESI,[M+H]⁺)m/z:406.9.

Example 761- (3-chloro-4-fluorophenyl) -3- ((1R, 3R) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea

Referring to the procedure of example 1,1- (3-chloro-4-fluorophenyl) -3- ((1R, 3R) -3- ((3, 5-dichloropyridin-4-yl) amino) cyclohexyl) urea was prepared starting from (1R,3R) -cyclohexanediamine, 3,4, 5-trichloropyridine, and 3-chloro-4-fluorophenylisocyanate.

¹H-NMR(500MHz,DMSO-d6)：δ8.51(s,1H),8.24(s,2H),7.75(t,J＝1.5Hz,1H),7.27(t,J＝9.0Hz,1H),7.17(t,J＝4.5Hz,1H),6.32(d,J＝7.5Hz,1H),5.25(d,J＝9.0Hz,1H),4.27(t,J＝4.5Hz,1H),3.92(s,1H),1.47-1.90(m,8H).¹³C-NMR(125MHz,DMSO-d6)：δ154.80,153.26,151.35,148.47,146.49,138.16,119.57,118.05,117.28,50.22,44.98,38.06,32.68,30.62,20.07.HRMS(ESI+,[M+H]⁺)m/z：431.0594.

Example 771- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea

Reference is made to the preparation of example 1, using N¹- (3, 5-dichloropyridin-4-yl) -2-methoxypropane-1, 3-diamine (prepared using 2-methoxypropane-1, 3-diamine and 3,4, 5-trichloropyridine, see example 1, step A) in place of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine, preparation of 1- (3-chloro-4-fluorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea.

¹H-NMR(500MHz,DMSO-d6)：δ8.78(s，1H)，8.21(s，2H)，7.74-7.75(m，1H)，7.25-7.28(m，1H)，7.19-7.21(m，1H)，6.33(t，J＝5.5Hz，1H)，5.99(t，J＝6.0Hz，1H)，3.69(t，J＝6.0Hz，2H)，3.41-3.45(m，1H)，3.23-30(m，5H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.84，153.35，151.44，148.42，147.28，138.15，119.56，118.29，117.28，79.60，57.32，45.63.HRMS(ESI+,[M+H]⁺)m/z：421.0432.

Example 781- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea

Reference is made to the preparation of example 6, using N¹- (3, 5-dichloropyridin-4-yl) -2-methoxypropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting 3, 5-dichloroaniline for 3, 4-difluoroaniline, 1- (3, 5-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.97(s，1H)，8.21(s，2H)，7.45(d，J＝2.0Hz，2H)，7.07(s，1H)，6.46(t，J＝6.0Hz，1H)，5.96(t，J＝6.5Hz，1H)，3.67-3.70(m，2H)，3.44(t，J＝5.5Hz，1H)，3.22-3.31(m，5H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.50，148.42，147.28，143.46，120.64，118.20，116.19，79.52，57.34，45.68.HRMS(ESI+,[M+H]⁺)m/z：437.0110.

Example 791- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea

Step A: reference is made to the preparation of example 6, using N¹- (3, 5-dichloropyridin-4-yl) -2-methoxypropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting 3, 4-dichloroaniline for 3, 4-difluoroaniline, 1- (3, 4-dichlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ8.88(s，1H)，8.21(s，2H)，7.83(s，1H)，7.45(d，J＝8.5Hz，1H)，7.23(d，J＝8.5Hz，1H)，6.38(s，1H)，5.98(s，1H)，3.68(d，J＝5.5Hz，2H)，3.42(d，J＝4.5Hz，1H)，3.23-3.31(m，5H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.63，148.43，147.27，141.06，131.40，122.81，119.20，118.23，79.55，57.33，45.66.HRMS(ESI+,[M+H]⁺)m/z：437.0106.

Example 801- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) -3- (3,4, 5-trichlorophenyl) urea

Reference is made to the preparation of example 6, using N¹- (3, 5-dichloropyridin-4-yl) -2-methoxypropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting 3,4, 5-trichloroaniline for 3, 4-difluoroaniline, 1- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) -3- (3,4, 5-trichlorophenyl) urea was prepared.

¹H-NMR(500MHz,DMSO-d6)：δ9.03(s，1H)，8.21(s，2H)，7.67(s，2H)，6.52(s，1H)，5.96(s，1H)，3.68(t，J＝5.5Hz，2H)，3.44(t，J＝5.0Hz，1H)，3.21-3.31(m，5H)；¹³C-NMR(125MHz,DMSO-d6)：δ174.83，148.43，147.22，133.17，118.14，79.48，57.36，45.82.HRMS(ESI+,[M+H]⁺)m/z：470.9782.

Example 811- (3-chlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea

Preparation method according to example 6, using N¹- (3, 5-dichloropyridin-4-yl) -2-methoxypropane-1, 3-diamine instead of N¹- (3, 5-dichloropyridin-4-yl) ethane-1, 2-diamine substituting m-chloroaniline for 3, 4-difluoroaniline prepared 1- (3-chlorophenyl) -3- (3- ((3, 5-dichloropyridin-4-yl) amino) -2-methoxypropyl) urea.

¹H-NMR(500MHz,DMSO-d6)：δ8.79(s，1H)，8.21(d，J＝2.0Hz，2H)，7.66(s，1H)，7.16-7.25(m，2H)，6.93(d，J＝8.0Hz，1H)，6.34(s，1H)，5.99(s，1H)，3.69(t，J＝5.5Hz，2H)，3.43(s，1H)，3.22-3.31(m，5H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.78，148.42，147.28，142.37，133.59，130.72，121.21，117.51，79.61，57.33，45.65.HRMS(ESI+,[M+H]⁺)m/z：403.0487.

Example 821- (3-chloro-4-fluorophenyl) -3- ((3- (((3, 5-dichloropyridin-4-yl) amino) methyl) epoxypropyl-3-yl) methyl) urea

Reaction scheme

Step A, tribromoneopentanol (8g), methanol (40ml) and potassium hydroxide (1.38g) are added into a 250ml single-neck bottle, heated to 70 ℃ for reaction for 4h, and filtered by suction and dried to obtain 3, 3-dibromomethyl propylene oxide (4.48g, 74.7%) as colorless liquid.

And step B, adding 3, 3-dibromomethyl propylene oxide (4g), DMSO (30ml) and sodium azide (2.5g) into a 250ml single-neck bottle, heating to 60 ℃, reacting for 3h, adding 100ml of water under ice bath to quench the reaction, extracting with ethyl acetate, drying with anhydrous sodium sulfate for 2h, filtering, and concentrating to obtain 3, 3-diazido methyl propylene oxide (2.5g, 89.2%) as colorless liquid.

And step C, adding 3, 3-diazido methyl propylene oxide (2.5g), methanol (30ml) and palladium carbon (200mg) into a 250ml single-mouth bottle, reacting at room temperature for 6 hours, performing suction filtration, and spin-drying filtrate to obtain 3, 3-diamino methyl propylene oxide (1.5g, 88.2%) as colorless liquid.

Step D, adding 3, 3-diaminomethyl propylene oxide (1.2g) and 3,4, 5-trichloropyridine (3g) into a 100ml single-neck bottle, heating to 70 ℃, reacting for 6h, adding dichloromethane, and purifying by column chromatography to obtain N- ((3- (aminomethyl) propylene oxide-3-yl) methyl) -3, 5-dichloropyridin-4-amine (250mg, 14.7%).

Step E, adding N- ((3- (aminomethyl) epoxypropan-3-yl) methyl) -3, 5-dichloropyridin-4-amine (220mg), dichloromethane (20ml) and 3-chloro-4-fluorobenzeneisocyanate (216mg) into a 100ml single-neck flask, reacting for 6h, and purifying by column chromatography to obtain 1- (3-chloro-4-fluorophenyl) -3- ((3- (((3, 5-dichloropyridin-4-yl) amino) methyl) epoxypropyl-3-yl) methyl) urea (150 mg).

¹H-NMR(500MHz,DMSO-d₆)：δ8.78(s，1H),8.21(s，2H)，7.74(m，1H)，7.22-7.29(m，2H)，6.63(t，1H)，6.29(t，1H),4.38(d，2H),4.31(d,2H),3.89(d,2H),3.48(d,2H)；¹³C-NMR(125MHz,DMSO-d₆)：δ156.32,153.44,151.53,148.66,147.19,138.04,119.54,118.53,118.01,117.21,117.10,75.74,47.01,45.54,42.86.MS(ESI+,[M+H]+)m/z：433.6.

Example 83(R) -N- (3-chlorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide and (R) -1- (3-chlorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea

The reaction process comprises the following steps:

referring to the preparation method of example 6, (R) -3, 5-dichloro-N- (piperidin-3-yl) pyridin-4-amine and (R) -1- (3, 5-dichloropyridin-4-yl) piperidin-3-amine (prepared using (R) -3-aminopiperidine, 3,4, 5-trichloroaniline and m-chloroaniline as reaction raw materials according to step a of example 1), and the crude product was subjected to column chromatography (PE: EA ═ 2:1) to obtain two isomers, and the compound 83-II, namely (R) -1- (3-chlorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea, was eluted first, the compound 83-I, i.e. (R) -N- (3-chlorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide, was eluted later.

83-I:¹H-NMR(500MHz,DMSO-d6)：δ8.75(s,1H),8.25(s,2H),7.62(s,1H),7.35-7.36(m,1H),7.22-7.26(m,1H),6.97(d,J＝8.0Hz,1H),5.49(d,J＝9.0Hz,1H),4.16-4.18(m,1H),3.81-3.84(m,1H),3.61-3.64(m,1H),3.35-3.38(m,1H),3.26-3.28(m,1H),1.92-1.99(m,2H),1.61-1.69(m,2H).¹³C-NMR(125MHz,DMSO-d6)：δ155.31,148.50,142.61,133.17,119.19,50.82,44.76,30.96,23.05.MS(ESI+,[M+H]⁺)m/z:399.2.

83-II：¹H-NMR(500MHz,DMSO-d6)：δ8.65(s,1H),8.45(s,2H),7.64(s,1H),7.21-7.24(m,1H),7.15(d,J＝8.5Hz,1H),6.93(d,J＝8.0Hz,1H),6.27(d,J＝7.5Hz,1H),3.73-3.74(m,1H),3.45-3.48(m,1H),3.22-3.25(m,1H),3.10-3.15(m,1H),2.98-3.02(m,1H),1.93-1.96(m,2H),1.71-1.81(m,2H).¹³C-NMR(125MHz,DMSO-d6)：δ154.75,151.40,142.34,133.58,130.72,121.18,117.46,56.13,50.59,46.80,30.19,24.47.MS(ESI+,[M+H]⁺)m/z:399.2.

Example 84(R) -3- ((3, 5-dichloropyridin-4-yl) amino) -N- (3,4, 5-trifluorophenyl) piperidine-1-carboxamide and (R) -1- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) -3- (3,4, 5-trifluorophenyl) urea

Step A: referring to the preparation method of example 6, (R) -3, 5-dichloro-N- (piperidin-3-yl) pyridin-4-amine, (R) -1- (3, 5-dichloropyridin-4-yl) piperidin-3-amine, and 3,4, 5-trifluoroaniline are used as reaction raw materials, the crude product is subjected to column chromatography (PE: EA ═ 2:1) to obtain two isomers, compound 84-ii, i.e., (R) -1- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) -3- (3,4, 5-trifluorophenyl) urea, is eluted first, compound 84-il, i.e., (R) -3- ((3, 5-dichloropyridin-4-yl) amino) -N- (3,4, 5-trifluorophenyl) piperidine-1-carboxamide.

84-Ι：¹H-NMR(500MHz,DMSO-d6)：δ8.88(s,1H),8.24(s,2H),7.36-7.39(m,2H),5.46(d,J＝9.0Hz,1H),4.16-4.17(m,1H),3.81-3.85(m,1H),3.60-3.63(m,1H),3.23-3.37(m,2H),1.93-1.96(m,2H),1.65-1.72(m,2H).¹³C-NMR(125MHz,DMSO-d6)：δ154.94,148.50,146.38,119.22,103.53,50.77,49.17,44.59,30.92,22.98.MS(ESI+,[M+H]⁺)m/z:419.2.

84-Ⅱ：¹H-NMR(500MHz,DMSO-d6)：δ8.80(s,1H),8.45(s,2H),7.27-7.30(m,2H),6.39(d,J＝7.5Hz,1H),3.73-3.74(m,1H),3.43-3.46(m,1H),3.22-3.24(m,1H),2.98-3.14(m,2H),1.94-2.03(m,2H),1.79-1.80(m,2H).¹³C-NMR(125MHz,DMSO-d6)：δ154.63,151.39,149.51,102.13,55.99,50.57,46.85,30.12,24.46.MS(ESI+,[M+H]⁺)m/z:419.2.

Example 85(R) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) pyrrolidin-3-yl) urea

Step A: referring to the preparation process of example 1, (R) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) pyrrolidin-3-yl) urea was prepared using (R) -pyrrolidin-3-amine, 3,4, 5-trichloropyridine, and 3-chloro-4-fluorobenzeneisocyanate as starting materials.

¹H-NMR(500MHz,DMSO-d6)：δ8.64(s,1H),8.36(s,2H),7.75-7.76(m,1H),7.23-7.29(m,2H),6.54(d,J＝6.0Hz,1H),4.28-4.29(m,1H),3.84-3.87(m,1H),3.72-3.76(m,1H),3.37-3.40(m,1H),3.26-3.28(m,1H),2.20-2.24(m,1H),1.86-1.88(m,1H).¹³C-NMR(125MHz,DMSO-d6)：δ155.26,153.37,151.46,149.58,138.06,122.16,119.55,118.37,117.28,56.79,50.06,32.17.MS(ESI+,[M+H]⁺)m/z:403.2.

Example 86(S) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) pyrrolidin-3-yl) urea

Step A: referring to the procedure of example 1, (S) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) pyrrolidin-3-yl) urea was prepared using (S) -pyrrolidin-3-amine, 3,4, 5-trichloropyridine and 3-chloro-4-fluorobenzeneisocyanate as starting materials.

¹H-NMR(500MHz,DMSO-d6)：δ8.64(s,1H),8.36(s,2H),7.75-7.76(m,1H),7.22-7.29(m,2H),6.54(d,J＝5.5Hz,1H),4.28-4.29(m,1H),3.84-3.85(m,1H),3.73-3.75(m,1H),3.62-3.63(m,1H),3.38-3.39(m,1H),2.21-2.22(m,1H),1.86-1.87(m,1H).¹³C-NMR(125MHz,DMSO-d6)：δ155.26,153.43,151.46,148.61,138.06,122.16,119.38,117.28,56.79,50.06,32.17.MS(ESI+,[M+H]⁺)m/z:403.2.

Example 87(R) -1- (3-cyano-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea

Step A: referring to the procedure of example 1, (R) -1- (3-cyano-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea was prepared using (R) -3-aminopiperidine, 3,4, 5-trichloropyridine, 3-cyano-4-fluorobenzeneisocyanate as starting materials.

¹H-NMR(500MHz,DMSO-d6)：δ8.79(s,1H),8.45(s,2H),7.90-7.91(m,1H),7.61-7.63(m,1H),7.37-7.41(m,1H),6.37(d,J＝8.0Hz,1H),3.74-3.75(m,1H),3.45-3.47(m,1H),3.22-3.24(m,1H),2.99-3.15(m,2H),1.93-2.01(m,2H),1.71-1.81(m,2H).¹³C-NMR(125MHz,DMSO-d6)：δ158.46,156.48,151.39,138.03,128.40,125.40,117.24,100.21,56.06,50.58,46.88,30.17,24.49.MS(ESI+,[M+H]⁺)m/z:408.3.

Example 881- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) azetidin-3-yl) urea

Step A: referring to the procedure for preparation of example 1,1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) azetidin-3-yl) urea was prepared starting with azetidin-3-amine, 3,4, 5-trichloropyridine, 3-chloro-4-fluorobenzeneisocyanate.

¹H-NMR(500MHz,DMSO-d6)：δ8.82(s,1H),8.08(s,2H),7.74(s,1H),7.27(s,2H),6.93(s,1H),4.90(s,2H),4.46(s,2H),4.39(s,1H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.02,153.50,151.59,149.21,147.82,137.93,119.77,119.50,119.36,118.72,118.67,117.23,117.06,116.07,64.35,41.02.MS(ESI+,[M+H]⁺)m/z：389.2.

EXAMPLE 89(S) -N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide and (S) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea

The reaction process comprises the following steps:

step A: (S) -N- (3-chloro-4-fluorophenyl) -3- ((3, 5-dichloropyridin-4-yl) amino) piperidine-1-carboxamide (compound 89-I) and (S) -1- (3-chloro-4-fluorophenyl) -3- (1- (3, 5-dichloropyridin-4-yl) piperidin-3-yl) urea (compound 89-II) were prepared according to example 36 by substituting (S) -3-aminopiperidine for 3-aminopiperidine in step A.

Compound 89-I:¹H-NMR(500MHz,DMSO-d6)：δ8.74(s，1H),8.25(s，2H)，7.71-7.73(m，1H)，7.36-7.38(m，1H)，7.25-7.29(m，1H)，5.48(d，J＝9.0Hz，1H)，4.17-4.18(m，1H)，3.81-3.84(m，1H)，3.60(s，1H)，3.26-3.29(m，1H)，1.70(d，J＝8.5Hz，1H)，1.63-1.67(m，2H)，1.48-1.49(m，1H)；¹³C-NMR(125MHz,DMSO-d6)：δ155.33,153.71,151.80,148.49,146.41,138.31,121.13,119.96,116.91,50.79,49.23,44.67,30.95,23.01.MS(ESI+,[M+H]⁺)m/z：416.9。

compounds 89-II:¹H-NMR(500MHz,DMSO-d6)：δ8.62-8.63(m，1H),8.43-8.44(m，2H)，7.71-7.74(m，1H)，7.19-7.26(m，1H)，7.18-7.19(m，1H)，6.24-6.27(m，1H)，3.74(s，1H)，3.45(t，J＝6.0Hz，1H)，3.22(d，J＝8.0Hz，1H)，3.12(d，J＝8.0Hz，1H)，2.99-3.01(m，1H)，1.94-1.95(m，1H)，1.72-1.78(m，2H)，1.45-1.47(m，1H)；¹³C-NMR(125MHz,DMSO-d6)：δ154.83,153.32,151.40,149.49,138.12,128.39,119.54,118.28,117.27,56.12,50.59,46.84,30.20,24.48.MS(ESI+,[M+H]⁺)m/z：416.9。

experimental example 1 inhibitory Activity of nucleocapsid protein Assembly

The inhibitory activity of the example compounds on the assembly of HBV nucleocapsid protein was evaluated by capsid protein fluorescence quenching experiments designed from the 149 amino acids of the N-terminus of HBV core protein.

Materials and instruments

A compound: the compounds of the examples were test samples, dissolved in 100% DMSO, prepared at a concentration of 20mM, stored in a nitrogen cabinet, and the compounds of the formula:

HBV core protein: HBV core protein C150(aa1-150, C49A, C61A, C107A and 150C) was purified by expression from E.coli by Shanghai drug Mingkuda New drug development Co.

Reagent: fluorescent dye (BoDIPY-FL) (Invitrogen), sephadex (source leaf organism).

The instrument comprises the following steps: microplate reader (molecular Device, model SpectraMax M2); 5ml Hitrap desalting column (GE Biosciences, 17-1408-1); nanodrop (Thermo, Nanodrop 2000).

Method

HBV core protein (C150) fluorescent marker

3 tubes (3 mg/tube) of C150 protein were desalted using a 5ml Hitrap desalting column.

To each tube of desalted C150 protein was added 20. mu.L of 50mM BODIPY-FL fluorescent dye, mixed well, and incubated overnight at 4 ℃ in the dark.

The fluorescent dye not bound to C150 was removed by Sephadex G-25 gel filtration.

Calculating the C150 labeling efficiency: concentration of fluorescent label [ BoDIPY-FL ] ═ A504/78,000M-1

Concentration of fluorescent labeled protein [ C150Bo ] (A280- [ BODIPY-FL ] x 1300M-1)/60,900M-1

Fluorescent labeling efficiency (Number of dye per C150Bo) ═ BoDIPY-FL/[ C150Bo ].

C150 protein assembly experiment:

compound dilution: mu.L of 20mM compound stock was added to 7. mu.L DMSO, then 4. mu.L of this solution was taken to 36. mu.L 50mM HEPES, and then 8 concentrations were further serially diluted 3-fold with 10% DMSO/50mM HEPES.

C150Bo was diluted to 2 μ M with 50M HEPES.

37.5. mu. L C150Bo and 2.5. mu.L of compound were added to a 96-well plate and mixed well and incubated for 15 minutes at room temperature.

mu.L of 750mM NaCl/50mM HEPES was added to the reaction wells at a final concentration of 150mM NaCl. 0% protein assembly control wells, 10 μ L of 50mM HEPES, final concentration of NaCl 0 mM; control wells were assembled with 100% protein, and 10. mu.L of 5M NaCl/50mM HEPES, 1M NaCl final concentration, was added. The final DMSO concentration was 0.5%, the maximum final concentration of the compound was 30. mu.M, and the final concentration of C150Bo was 1.5. mu.M.

Incubate at room temperature for 1 hour.

The fluorescence signal was measured (excitation light 485nm emission 535 nm).

And (3) data analysis: and [% protein assembly ] - [1- (sample fluorescence value-1M NaCl fluorescence value)/(0M NaCl fluorescence value-1M NaCl fluorescence value) ] × 100.

EC50 value was calculated by prism software, equation sigmoidal dose-response (variable slope) equation

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。

X represents the log of the concentration, Y represents the effect value, and Y fits to the top in sigmoid form starting from the bottom.

Results of the experiment

TABLE 2 inhibitory Activity results for nucleocapsid protein Assembly

Compound (I)	EC50	Compound (I)	EC50	Compound (I)	EC50
						Example 1	A	Example 13	B	Example 36	A
Example 2	A	Example 15	A	Example 37	A
						Example 3	C	Example 22	B	Example 38	B
Example 6	A	Example 23	B	Example 39	A
						Example 7	A	Example 25	A	Example 40	A
Example 11	B	Example 26	A	Example 42	B
						Example 12	A	Example 32	C	Control Compounds	C

Note: a is more than or equal to 1 mu M and less than or equal to 10 mu M; b is more than 10 mu M and less than or equal to 20 mu M; c is more than 20 mu M and less than or equal to 30 mu M.

Experimental example 2: HepG2.2.15 cytotoxic Activity

Experimental Material

Cells

HepG2.2.15 cells are supplied by the drug Mingkude.

Compound (I)

Test compounds: compounds of the present application were formulated in a 20mM stock solution buffer nitrogen cabinet using dimethyl sulfoxide (DMSO).

Control compound:

primary reagent

The main reagents used in the experiment included QIAamp 96DNA Blood Kit (12) (Qiagen), FastStart Universal Probe Master (Roche), Cell-titer Blue detection reagent (Promega).

Experimental methods

Compound dilution: the compounds used in the in vitro anti-HBV activity experiment and the cytotoxicity experiment are serially diluted by 5 times to obtain 8 samples with different concentration values for later use. The initial concentration of the test and control compounds in the cytotoxicity test was 100. mu.M, the initial concentration in the anti-HBV activity test was 10. mu.M, and the final concentration of DMSO was 0.5%.

In vitro anti-HBV activity assay: HepG2.2.15 cell (4X 10)⁴Cells/well) to 96-well plates at 37 ℃, 5% CO₂The culture was carried out overnight. The following day, fresh medium containing different concentrations of the compounds was added to the culture wells. On the fifth day, old culture medium was aspirated from the culture wells, and fresh culture medium containing different concentrations of compounds was added.

And eighthly, collecting cell culture supernatant in the pore plate, extracting HBV DNA in the supernatant, and detecting the HBV DNA content in the HepG2.2.15 supernatant by qPCR.

Cytotoxicity experiments: HepG2.2.15 cell (4X 10)⁴Cells/well) to 96-well plates and incubated overnight at 37 ℃ with 5% CO 2. The following day, fresh medium containing different concentrations of the compounds was added to the culture wells. On the fifth day, old culture medium was aspirated from the culture wells, and fresh culture medium containing different concentrations of compounds was added. On the eighth day, Cell-titer Blue reagent was added to each well of the plate, and the fluorescence value of each well was measured with a microplate reader.

Analyzing data:

percent inhibition was calculated using the following formula:

% inh. ═ 100% of DMSO control PCR fluorescence value-sample PCR fluorescence value/DMSO control PCR fluorescence value%

The percentage of cell activity was calculated using the following formula:

% Cell viability ═ 100%

EC50 and CC50 values for compounds were calculated using GraphPad Prism software, and the equation is a sigmoidal quantity-effect (variable slope) equation:

y-min inhibition + (max-min)/(1 +10^ ((LogIC50-X) × slope))

X represents a concentration logarithm value, and Y represents an effect value.

Y starts from the bottom and fits to the top in sigmoid form.

The results of the experiment are shown in table 3.

TABLE 3 HepG2.2.15 cytotoxicity (CC50), anti-HBV Activity test (EC50) results

Compound numbering	EC50	CC50	Compound numbering	EC50	CC50
						1	A++	+++	55-R(37)	A++	++
6	A++	+++	56-R(36)	A+	+++
						7	A++	+++	70	A	+++
11	A	+++	71	A+	+++
						13	A	+++	72	A	+++
22	A+	+++	75	A+	++
						23	A+	+++	76	A+	+
25	A++	+	82	A	+++
						32	A	+++	83-II	A+	++
36	A++	+	84-II	A+	++
						37	A++	+	89	A	+++
50	A+	+++	Control Compounds	A+	++

Note: EC 50: a + + < 0.4. mu.M; a + is less than 1 mu M and is more than or equal to 0.4 mu M; a is more than or equal to 1 mu M and less than or equal to 10 mu M

CC50：+＜10μM；10μM≤++＜30μM；30μM≤+++。

Claims

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

A-M-L-D

I

wherein the content of the first and second substances,

a moiety selected from

m is a moiety selected from

l moiety is selected from

Or

X is selected from O or S, W is selected from single bond,

2. A compound, stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein R is^aSelected from F, ClBr, nitroso, nitro, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, C_1-4Alkyl-oxy, C_3-6Cycloalkyl-oxy, mercapto, C_1-4Alkyl-thio radical, C_3-6Cycloalkyl-thio, amino, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl radical, said C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_1-4Alkyl-oxy, C_3-6Cycloalkyl-oxy, C_1-4Alkyl-thio radical, C_3-6Cycloalkyl-thio radical, C_1-3Alkyl-amino, (C)_1-3Alkyl radical)₂-amino or C_1-3Alkyl-sulfonyl optionally substituted with 1-3R^bSubstituted, said R^bSelected from F, Cl, Br, nitroso, nitro, cyano, hydroxyl, mercapto, amino, methoxy, cyclopropyl or methylsulfonyl; preferably, said R is^aSelected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, mercapto, methylthio, cyclopropylthio, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl, or cyclopropylmethyl;

optionally, the A moiety is selected from

Preferably, the moiety A is selected from

More preferably, the moiety A is selected from

3. Root of herbaceous plantA compound, stereoisomer or pharmaceutically acceptable salt thereof, according to claim 1, wherein R is⁶Selected from methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxycarbonyl, phenyl or benzyl; preferably, said R is⁶Selected from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

4. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to any one of claims 1 or 3, wherein R is¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bAnd R⁵Each independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵Wherein two substituents of (a) are linked to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si or B, the 3-8 membered saturated ring is substituted with m R⁶Substitution; preferably, said R is¹And R⁵Each independently selected from H or methyl, said R^2a、R^2b、R^3a、R^3b、R^4aAnd R^4bEach independently selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R¹、R^2a、R^2b、R^3a、R^3b、R^4a、R^4bOr R⁵Wherein two substituents of (a) are linked to form a 3-8 membered saturated ring, the ring atoms of the 3-8 membered saturated ring optionally include 1-3 heteroatoms selected from O, N, S, Si or B, the 3-8 membered saturated ring is substituted with m R⁶Substitution;

optionally, the M moiety is selected from

Preferably, the moiety M is selected from

5. The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1,3, or 4, wherein the 3-to 8-membered saturated ring is a monocyclic structure.

6. The compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the L moiety is selected from

X is selected from O or S, W is selected from a single bond or

7. The compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the D moiety is selected from

Preferably, the moiety D is selected from

More preferably, the moiety D is selected from

Optionally, said R^dSelected from F, Cl, Br, nitroso, nitro, cyano, C_1-4Alkyl, hydroxy, C_1-4Alkoxy, hydroxy-C_1-4Alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxy-C_1-4Alkyl, mercapto, C_1-4Alkylthio, amino, C_1-3Alkyl-amino, dimethylamino, diethylamino, dipropylamino, methyl (ethyl) amino or C_1-3An alkyl-sulfonyl group; preferably, said R is^dSelected from F, Cl, Br, nitroso, nitroA group, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methoxyethyl, mercapto, methylthio, amino, methylamino, ethylamino, dimethylamino, or methylsulfonyl.

8. A compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from:

9. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of a compound of any one of claims 1-8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the manufacture of a medicament for the treatment of a disease benefiting from inhibition of capsid protein assembly;

optionally, the disease benefiting from inhibition of capsid protein assembly refers to a disease caused by hepatitis b virus infection;

optionally, the disease benefiting from inhibition of capsid protein assembly is liver disease caused by hepatitis b virus infection.