WO2018050110A1

WO2018050110A1 - Novel capsid protein assembly inhibitor

Info

Publication number: WO2018050110A1
Application number: PCT/CN2017/102054
Authority: WO
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: 正大天晴药业集团股份有限公司
Priority date: 2016-09-18
Filing date: 2017-09-18
Publication date: 2018-03-22
Also published as: CN109790123A; CN109790123B; CN113429341A

Abstract

The present invention relates to the field of pharmaceutical chemistry, and relates to a novel capsid protein assembly inhibitor, in particular, to a compound represented by formula I, a stereoisomer or pharmaceutically acceptable salt, preparation method, pharmaceutical composition and medical use thereof, including a use thereof in treating diseases benefiting from a capsid protein assembly inhibitor, in particular, diseases caused by hepatitis B virus infection, wherein the definitions of A, M, L and D of formula I are the same as those in the description.

Description

Novel capsid protein assembly inhibitor

Cross-reference to related applications

The present application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the disclosure.

Technical field

The present application relates to the field of medicinal chemistry, and in particular to a compound represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and to a process for the preparation thereof, a pharmaceutical composition and a pharmaceutical use, in particular as a treatment and prevention Application of drugs for hepatitis B virus infection.

Background technique

Chronic hepatitis B is widely distributed worldwide. About 360 million people worldwide continue to be infected with hepatitis B virus (HBV). China is the country with the largest number of HBV infections worldwide. At present, drugs for treating hepatitis B are difficult to completely eliminate viral infections, and there is still no effective cure in clinical practice. The incurable hepatitis B can only be controlled by treatment, and the therapeutic drugs are limited to interferon and nucleoside analogues/viruses. Two classes of inhibitors of polymerase. Clinical studies have shown that less than 50% of patients are sensitive to interferon therapy, while existing nucleoside analog drugs induce mutase-producing drug-resistant mutations, which are not effective against drug-resistant strains. These drugs are often difficult to completely eliminate HBV. Infection, even if you take it for a long time, you can't cure it.

Although prophylactic HBV vaccines can be used, the burden of chronic HBV infection remains a significant unmet medical problem worldwide due to the ratio of suboptimal treatment options to the persistence of new infections in most parts of the developing world. Current treatment regimens are incurable and can only be controlled and are limited to only two classes of agents (interferons and inhibitors of nucleoside analogs/viral polymerases). The low cure rate of 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 plan can not remove the cccDNA in the repository, and now has a deeper understanding of the life cycle of HBV (Thomas F Baumert, et al. Current Opinion in Virology 2015, 14:41–46). It is generally believed that some HBV New targets, core inhibitors (such as viral capsid protein formation or assembly inhibitors and cccDNA inhibitors and interferon-stimulated gene activators, etc.) are expected to bring hope to hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).

The HBV capsid is assembled from core proteins. The three core protein dimers aggregate into nuclei, which bind to other dimers by hydrophobic interaction, and finally obtain an icosahedral capsid protein composed of 120 dimers. Before reverse transcription, HBV reverse transcriptase, pgRNA needs to be properly encapsulated by the capsid protein. Therefore, blocking capsid protein assembly, or accelerating capsid protein degradation, blocks the assembly process of the capsid protein, thereby affecting viral replication. In addition, the N-terminal 149 amino acid residues (Cp149) constituting the core protein dimerization motif and the assembly domain have no human protein homologous sequences. In recent years, researchers have begun to develop non-nucleoside analogues to treat hepatitis B, instead of targeting reverse transcriptase, but instead choose to inhibit its life cycle. Its step, in which inhibitors targeting capsid protein assembly has potential, is a new target for anti-hepatitis B drug development.

Currently, compounds targeting the capsid protein assembly are NVR3-778, Bay41-4109, GLS4, AT-61, AT-130, and the like. Most capsid protein assembly inhibitors have been in the early stages of clinical research or have been discontinued, and there is a need in the art for more alternative effective capsid protein assembly inhibitors to treat, ameliorate or prevent HBV infection. The present invention synthesizes a series of novel derivatives and studies the HBV protein assembly activity.

Summary of invention

In one aspect, the invention provides a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

A-M-L-D

I

among them,

Part A is selected from

R ^{a is} selected from the group consisting of halogen, nitroso, nitro, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, hydroxy, C _1-6 alkyl-oxy, C _3-6 cycloalkyl -oxy, fluorenyl, C _1-6 alkyl-thio, C _3-6 cycloalkyl-thio, amino, C _1-3 alkyl-amino, (C _1-3 alkyl) ₂ -amino or C _1-3 alkyl-sulfonyl group, said C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkyl-oxy group, C _3-6 cycloalkyl-oxy group, C _{1 -6} alkyl - thio, C _3-6 cycloalkyl - group, C _1-3 alkyl - amino, (C _1-3 alkyl) ₂ - C _1-3 alkyl or amino _- - sulfonyl Optionally substituted by 1 to 3 R ^b , R ^{b is} selected from halogen, nitroso, nitro, cyano, hydroxy, decyl, amino, methoxy, cyclopropyl or methanesulfonyl;

Part M is selected from

Z is selected from C or Si, n is selected from 0 or 1, and R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, C _1-3 alkyl , hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxygen a substituent of thio, thio, amino, cyano, carboxy or halo, or optionally two of R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b or R ⁵ Forming a 3- to 8-membered saturated ring, and the ring atom of the 3- to 8-membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si or B, and the 3 to 8 membered saturated ring Substituted by m R ⁶ , the m is selected from 0 to 3, and the R ^{6 is} selected from C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 An alkyl group, 1 to 3 halogen-substituted C _1-3 alkyl groups, a C _1-4 alkoxy group, a hydroxyl group, an oxo group, a thio group, an amino group, a cyano group, a carboxyl group, a halogen, a C _1-6 alkoxy group, Phenyl or benzyl, provided that R ¹ and R ^{5 are} not joined to form a 3 to 8 membered saturated ring;

Part L is selected from

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

Part D is selected from a 5- to 10-membered aryl group or a 5- to 10-membered heteroaryl group having 1 to 3 atoms selected from N, O, S, Si or B atoms, and the 5 to 10 membered aryl group or 5 to 10 members heteroaryl optionally substituted with 1 to 3 R ^d, R ^d is selected from the halo, nitroso, nitro, cyano, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, Hydroxy-C _1-6 alkyl, 1 to 3 halogen-substituted C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, decyl, C _1-6 alkylthio, amino C _1-3 alkyl-amino, (C _1-3 alkyl) ₂ -amino or C _1-3 alkyl-sulfonyl.

Another aspect of the present application provides a compound of 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, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of Formula I for use in the treatment of a disease that would benefit from inhibition of capsid protein assembly.

Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable Carrier or excipient.

Another aspect of the present application provides a compound of 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 which is beneficial for inhibition of capsid protein assembly use.

In one aspect, the invention provides a method for treating a disease that is beneficial for inhibition of capsid protein assembly, comprising administering to a patient a therapeutically effective amount of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of Formula I, or Pharmaceutical composition.

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

Detailed description of the invention

A-M-L-D

I

among them,

Part A is selected from

Part M is selected from

Part L is selected from

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

In some embodiments of the present application, the R ^a is selected from F, Cl, Br, nitroso, nitro, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, hydroxyl, C _{1 -4} alkyl-oxy, C _3-6 cycloalkyl-oxy, decyl, C _1-4 alkyl-thio, C _3-6 cycloalkyl-thio, amino, C _1-3 alkyl -amino, (C _1-3 alkyl) ₂ -amino or C _1-3 alkyl-sulfonyl, said C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkyl-oxy , C _3-6 cycloalkyl-oxy, C _1-4 alkyl-thio, C _3-6 cycloalkyl-thio, C _1-3 alkyl-amino, (C _1-3 alkyl ) ₂ - C _1-3 alkyl or amino - substituted sulfonyl group optionally substituted with 1 to 3 R ^b, R ^b is selected from a F, Cl, Br, nitroso, nitro, cyano, hydroxy, Mercapto, amino, methoxy, cyclopropyl or methanesulfonyl.

In some embodiments of the present application, the R ^a is preferably selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, Ethoxy, cyclopropyloxy, decyl, methylthio, cyclopropylthio, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, monofluoromethyl, difluoromethyl , trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl or cyclopropylmethyl.

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

The R ^a as defined above.

The R ^a as defined above.

In some embodiments of the present application, the A portion is more preferably self

In some embodiments of the present application, the R ^{6 is} selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, Fluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl, Br, methoxyformyl, phenyl or benzene methyl.

In some embodiments of the present application, the R ⁶ is preferably selected from the group consisting of methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.

In some embodiments of the present application, the R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from the group consisting of H, methyl, ethyl, propyl, Hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, Oxo, amino, cyano, carboxyl, F, Cl or Br, or, optionally, two substituent phases of R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b or R ⁵ Connecting to form a 3- to 8-membered saturated ring, the ring atom of the 3- to 8-membered saturated ring optionally including 1 to 3 hetero atoms selected from O, N, S, Si or B, said 3 to 8 m is a saturated ring of R ^6, said R ⁶ and m are as previously defined, with the proviso that R ¹ and R ⁵ are not connected to form a 3- to 8-membered saturated ring.

In some embodiments of the present application, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, and R ^2a , R ^2b , R ^3a , R ^3b , R ^4a and R ^4b are each independently Selected from H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2 , 2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R Two substituents of ^4a , R ^4b or R ⁵ are bonded to form a 3 to 8 membered saturated ring, and the ring atom of the 3 to 8 membered saturated ring optionally includes 1 to 3 selected from O, N, and S. a hetero atom of Si or B, said 3 to 8 membered saturated ring being substituted by m R ⁶ , said m and R ^{6 being} as defined above, provided that R ¹ and R ^{5 are} not joined to form a 3 to 8 member Saturated ring.

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

In some embodiments of the present application, when two substituents of R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b or R ⁵ are optionally joined to form a 3 to 8 member saturation When ringing, the number of rings is one.

In some embodiments of the present application, when two substituents of R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b or R ⁵ are optionally joined to form a 3 to 8 member saturation Ring, selected from R ^2a and R ^2b , R ^3a and R ^3b , R ^4a and R ^4b , R ^2a and R ^3a , R ^3a and R ^4a , R ^2a and R ^4a , R ¹ and R ^2a , R ¹ and R ^3a , R ¹ and R ^4a , R ^2a and R ⁵ , R ^3a and R ⁵ or R ^4a and R ⁵ are bonded.

In some embodiments of the present application, when two substituents of R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b or R ⁵ are optionally joined to form a 3 to 8 member saturation In the ring, it is preferably a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring formed by the association of R ^2a and R ^2b , and 3, 4, and 5 elements formed by the connection of R ^3a and R ^3b . a 3- or 4-membered saturated monocyclic ring, a 4, 4, 5 or 6-membered saturated monocyclic ring formed by the association of R ^4a and R ^4b , and a 3 or 4 element formed by the association of R ^2a and R ^3a a 5-, 4- or 6-membered saturated monocyclic ring, a 3, 4, 5 or 6-membered saturated monocyclic ring formed by the association of R ^3a and R ^4a , and a combination of R ^2a and R ^4a membered, 4-membered, 5-membered, 6-membered or 7-membered saturated monocyclic ring, R ¹ and R ^2a is connected to three yuan formation 4, 5-, 6- or 7-membered saturated monocyclic ring, R ¹ and R ^3a phase a 3-, 4-, 5-, or 7-membered saturated monocyclic ring formed by ligation, a 3-, 4-, 5-, 6-, or 7-membered saturated monocyclic ring formed by the association of R ¹ and R ^4a , R ^2a and R ⁵ are connected to form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated monocyclic ring, R ^3a and R ⁵ are connected to form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated Cycloalkyl or R ^4a and R ⁵ are connected to form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated monocyclic ring.

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

The R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ⁵ , Z, R ⁶ and m are as defined above.

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

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

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

In some embodiments of the present application, the ^{Rd is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, C _1-4 alkyl, hydroxy, C _1-4 alkoxy, hydroxy- C _1-4 alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy-C _1-4 alkyl, decyl, C _1-4 alkyl Thio group, amino group, C _1-3 alkyl-amino group, dimethylamino group, diethylamino group, dipropylamino group, methyl (ethyl)amino group or C _1-3 alkyl-sulfonyl group.

In some embodiments of the present application, the R ^d is preferably from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, Hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, methoxyethyl, decyl, methylthio, amino, methylamino Ethylamino, dimethylamino or methylsulfonyl.

In some embodiments of the present application, the D moiety is selected from the group consisting of 5-, 6-, 7-, 8-, 9-, 10-membered aryl or 1 to 3 atoms selected from N, O, S or B atoms. Yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan heteroaryl, the 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan aryl or 5 yuan, 6 yuan, 7 yuan 8, 9- and 10-membered heteroaryl group is optionally substituted with 1 to 3 R ^d, R ^d a as previously defined.

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

Said R ^{d is} as defined above.

In some embodiments of the present application, the D portion is more preferably self

Said R ^{d is} as defined above.

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

A preferred embodiment of the compound of formula I provides a compound of formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

A ² -M ² -L ² -D ²

II,

among them,

Part A ² is selected from

R ^{a is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, fluorenyl , methylthio, cyclopropylthio, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-di Fluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl or cyclopropylmethyl;

M ^{2 is} selected from

n is selected from 0 or 1, Z is selected from C or Si, and R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, C _1-3 alkyl , hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxygen Substituted, thio, amino, cyano, carboxyl or halogen;

L ^{2 is} selected from

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

D ^{2 is} selected from

R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoro Base, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, methoxyethyl, decyl, methylthio, amino, methylamino, ethylamino, dimethylamino or a Sulfonyl.

In some embodiments of the present application, in the compound of Formula II, said R ^{a is} selected 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, methoxy Ethyl or cyclopropylmethyl.

In some embodiments of the present application, in the compound of Formula II, the A ² moiety is selected from

Said R ^{a is} as defined above.

In some embodiments of the present application, in the compound of Formula II, the A ² moiety is preferably selected from

The R ^a as defined above.

In some embodiments of the present application, in the compound of Formula II, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, A. Base, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoro Base, hydroxyl, methoxy, oxo, amino, cyano, carboxyl, F, Cl or Br.

In some embodiments of the present application, in the compound of Formula II, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, said R ^2a , R ^2b , R ^3a , R ^3b , R ^4a and R ^4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl Base, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br.

In some embodiments of the present application, in the compound of Formula II, the M ² moiety is selected from

The R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ^{5 are} as defined above.

In some embodiments of the present application, in the compound of Formula II, the M ² moiety is preferably selected from

In some embodiments of the present application, in the compound of Formula II, the R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy. Ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methanesulfonyl.

In some embodiments of the present application, in the compound of Formula II, D ^{2 is} selected from

Said R ^{d is} as defined above.

In some embodiments of the present application, in the compound of Formula II, D ² is preferably selected from

A preferred embodiment of the compound of formula I provides a compound of formula III, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

A ³ -M ³ -L ³ -D ³

III,

among them,

Part A ³ is selected from

M ^{3 is} selected from

n is selected from 0 or 1, Z is selected from C or Si, and R ¹ , R ^3a , R ^3b and R ⁵ are each independently selected from H, C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _{1 -3} alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxo, thio, amino, cyano, carboxy or Halogen, R ^2a and R ^4a are bonded to form a 3- to 8-membered saturated ring, and the ring atom of the 3- to 8-membered saturated ring optionally includes 1 to 3 impurities selected from O, N, S, Si, and B. The atom, the 3-8-membered saturated ring is substituted by m R ⁶ , the m is selected from 0 to 3, and the R ^{6 is} selected from C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _{1 -3} alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, C _1-4 alkoxy acyl, hydroxy, oxo, thio, amino, cyano, carboxy, Halogen, C _1-6 alkoxy, phenyl or benzyl;

L ^{3 is} selected from

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

D ^{3 is} selected from R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoro Base, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, methoxyethyl, decyl, methylthio, amino, methylamino, ethylamino, dimethylamino or a Sulfonyl.

In some embodiments of the present application, in the compound of Formula III, said R ^{a is} selected 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, methoxy Ethyl or cyclopropylmethyl.

In some embodiments of the present application, in the compound of Formula III, the A ³ moiety is selected from

Said R ^{a is} as defined above.

In some embodiments of the present application, in the compound of Formula III, the A ³ moiety is preferably selected from

The R ^a as defined above.

In some embodiments of the present application, in the compound of Formula III, the R ^{6 is} selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyB. , monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxyl, F, Cl, Br, methoxy Carbamoyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of Formula III, R ⁶ is preferably selected 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, R ¹ , R ^3a , R ^3b and R ⁵ are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, Hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino , cyano, carboxyl, F, Cl or Br, R ^2a and R ^4a are joined to form a 5 or 6 membered saturated monocyclic ring, the 5 or 6 membered saturated monocyclic ring atom optionally comprising 1 to 3 selected since hetero atoms O, N, S, Si or B, a 5- or 6-membered saturated monocyclic ring of R ⁶ is m, said m and R ⁶ are as previously defined.

In some embodiments of the present application, in the compound of Formula III, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, and R ^3a and R ^3b are each independently selected from H. , methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-di Fluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, R ^2a and R ^4a are joined to form a 5 or 6 membered saturated monocyclic ring, said 5 or 6 membered saturated The monocyclic ring atom optionally includes from 1 to 3 heteroatoms selected from O, N, S, Si or B, said 5 or 6 membered saturated monocyclic ring being substituted by m R ⁶ , said m and R ⁶ As previously defined.

In some embodiments of the present application, in the compound of Formula III, the M ³ moiety is selected from

The R ¹ , R ^3a , R ^3b , R ⁵ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula III, the M ³ moiety is preferably selected from

In some embodiments of the present application, in the compound of Formula III, the R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy. Ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methanesulfonyl.

In some embodiments of the present application, in the compound of Formula III, D ^{3 is} selected from

Said R ^{d is} as defined above.

In some embodiments of the present application, in the compound of Formula III, D ³ is preferably selected from

A preferred embodiment of the compound of formula I provides a compound of formula IV, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

A ⁴ -M ⁴ -L ⁴ -D ⁴

IV,

among them,

Part A ⁴ is selected from

M ^{4 is} selected from

n is selected from 0 or 1, Z is selected from C or Si, and R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, C _1-3 alkyl , hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxygen Substituents, thio, amino, cyano, carboxy or halogen, or substituents selected from the group consisting of R ^2a and R ^2b , R ^3a and R ^3b or R ^4a and R ^4b are bonded to each other to form 3 to 8 members. a saturated ring, the ring atom of the 3-8-membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3-8-membered saturated ring is m R ⁶ Substituting, m is selected from 0 to 3, and R ^{6 is} selected from C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1~ 3 halogen-substituted C _1-3 alkyl, C _1-4 alkoxy acyl, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C _1-6 alkoxy, phenyl or phenyl base;

L ^{4 is} selected from

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

D ^{4 is} selected from

In some embodiments of the present application, in the compound of Formula IV, said R ^{a is} selected 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, methoxy Ethyl or cyclopropylmethyl.

In some embodiments of the present application, in the compound of Formula IV, the A ⁴ moiety is selected from

Said R ^{a is} as defined above.

In some embodiments of the present application, in the compound of Formula IV, the A ⁴ moiety is preferably selected from

The R ^a as defined above.

In some embodiments of the present application, in the compound of Formula IV, the R ^{6 is} selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyB. , monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxyl, F, Cl, Br, methoxy Carbamoyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of Formula IV, R ⁶ is preferably selected 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, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, A. Base, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoro a group, a hydroxyl group, a methoxy group, an oxo group, an amino group, a cyano group, a carboxyl group, a F, a Cl or a Br, or a group selected from the group consisting of R ^2a and R ^2b , R ^3a and R ^3b or R ^4a and R ^4b The substituents are linked to each other to form a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring, optionally including a ring atom of a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring. 1 to 3 hetero atoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring being substituted by m R ⁶ , the m and R ⁶ as defined before.

In some embodiments of the present application, in the compound of Formula IV, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, R ^2a , R ^2b , R ^3a , R ^3b , R ^4a and R ^4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, Trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or selected from R ^2a and R ^2b , R ^3a and R ^3b Or the substituents in one of R ^4a and R ^4b are linked to each other to form a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring, said 3-, 4-, 5-, 6- or The 7-membered saturated monocyclic ring atom optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3, 4, 5, 6 or 7-membered saturated monocyclic ring. Substituted by m R ⁶ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula IV, the M ⁴ moiety is selected from

The R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ⁵ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula IV, the M ⁴ moiety is preferably selected from

In some embodiments of the present application, in the compound of Formula IV, the R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy. Ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methanesulfonyl.

In some embodiments of the present application, in the compound of Formula IV, D ^{4 is} selected from

Said R ^{d is} as defined above.

In some embodiments of the present application, in the compound of Formula IV, D ⁴ is preferably selected from

A preferred embodiment of the compound of formula I provides a compound of formula V, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

A ⁵ -M ⁵ -L ⁵ -D ⁵

V,

among them,

Part A ⁵ is selected from

M ^{5 is} selected from

n is selected from 0 or 1, Z is selected from C or Si, and R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, C _1-3 alkyl , hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxygen a substituent, a thio group, an amino group, a cyano group, a carboxyl group or a halogen, or a substituent selected from the group consisting of R ¹ and R ^2a , R ¹ and R ^3a or R ¹ and R ^4a are bonded to each other to form 3 to 8 a ring-saturated ring, the ring atom of the 3-8-membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3-8-membered saturated ring is m R ^{6 is} substituted, wherein m is selected from 0 to 3, and R ^{6 is} selected from C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 ~3 halogen-substituted C _1-3 alkyl, C _1-4 alkoxy acyl, hydroxy, oxo, thio, amino, cyano, carboxyl, halogen, C _1-6 alkoxy, phenyl or benzene methyl;

L ^{5 is} selected from

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

D ^{5 is} selected from

In some embodiments of the present application, the compounds of formula V, said R ^a is selected from F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, cyclopropyl, hydroxy , methoxy, ethoxy, cyclopropyloxy, amino, methylamino, ethylamino, dimethylamino, methylsulfonyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methoxy Ethyl or cyclopropylmethyl.

In some embodiments of the present application, in the compound of Formula V, the A ⁵ moiety is selected from

Said R ^{a is} as defined above.

In some embodiments of the present application, in the compound of Formula V, the A ⁵ moiety is preferably selected from

The R ^a as defined above.

In some embodiments of the present application, in the compound of Formula V, R ^{6 is} selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyB. , monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxyl, F, Cl, Br, methoxy Carbamoyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of Formula V, the R ⁶ is preferably selected 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 ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, A. Base, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoro a group, a hydroxyl group, a methoxy group, an oxo group, an amino group, a cyano group, a carboxyl group, a F, a Cl or a Br, or a group selected from the group consisting of R ¹ and R ^2a , R ¹ and R ^3a or R ¹ and R ^4a The substituents are linked to each other to form a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring, optionally including a ring atom of a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring. 1 to 3 hetero atoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring being substituted by m R ⁶ , the m and R ⁶ as defined before.

In some embodiments of the present application, in the compound of Formula V, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, R ^2a , R ^2b , R ^3a , R ^3b , R ^4a and R ^4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, Trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or selected from R ¹ and R ^2a , R ¹ and R ^3a Or the substituents in one of R ¹ and R ^4a are bonded to each other to form a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring, said 3-, 4-, 5-, 6- or The 7-membered saturated monocyclic ring atom optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3, 4, 5, 6 or 7-membered saturated monocyclic ring. Substituted by m R ⁶ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula V, the M ⁵ moiety is selected from

The R ^4a , R ^4b , R ⁵ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula V, the M ⁵ moiety is preferably selected from

In some embodiments of the present application, in the compound of Formula V, said ^{Rd is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy. Ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methanesulfonyl.

In some embodiments of the present application, in the compound of Formula V, D ^{5 is} selected from

Said R ^{d is} as defined above.

In some embodiments of the present application, in the compound of Formula V, D ⁵ is preferably selected from

A preferred embodiment of the compound of formula I provides a compound of formula VI, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

A ⁶ -M ⁶ -L ⁶ -D ⁶

VI,

among them,

Part A ⁶ is selected from

M ^{6 is} selected from

n is selected from 0 or 1, Z is selected from C or Si, and R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b and R ⁵ are each independently selected from H, C _1-3 alkyl , hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 to 3 halogen-substituted C _1-3 alkyl, hydroxy, C _1-3 alkoxy, oxygen a substituent, a thio group, an amino group, a cyano group, a carboxyl group or a halogen, or a substituent selected from the group consisting of R ⁵ and R ^2a , R ⁵ and R ^3a or R ⁵ and R ^4a are bonded to each other to form 3 to 8 a ring-saturated ring, the ring atom of the 3-8-membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3-8-membered saturated ring is m R ^{6 is} substituted, wherein m is selected from 0 to 3, and R ^{6 is} selected from C _1-3 alkyl, hydroxy-C _1-3 alkyl, C _1-3 alkoxy-C _1-3 alkyl, 1 ~3 halogen-substituted C _1-3 alkyl, C _1-4 alkoxy, hydroxy, oxo, thio, amino, cyano, carboxy, halogen, C _1-6 alkoxy, phenyl or benzene methyl;

L ^{6 is} selected from

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

D ^{6 is} selected from

In some embodiments of the present application, in the compound of Formula VI, said R ^{a is} selected 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, methoxy Ethyl or cyclopropylmethyl.

In some embodiments of the present application, in the compound of Formula VI, the A ⁶ moiety is selected from

Said R ^{a is} as defined above.

In some embodiments of the present application, in the compound of Formula VI, the A ⁶ moiety is preferably selected from

The R ^a as defined above.

In some embodiments of the present application, in the compound of Formula VI, R ^{6 is} selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyB. , monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxyl, F, Cl, Br, methoxy Carbamoyl, phenyl or benzyl.

In some embodiments of the present application, in the compound of Formula VI, R ⁶ is preferably selected 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, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^{4b ,} and R ⁵ are each independently selected from H, A. Base, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoro a group, a hydroxyl group, a methoxy group, an oxo group, an amino group, a cyano group, a carboxyl group, F, Cl or Br, or a group selected from the group consisting of R ⁵ and R ^2a , R ⁵ and R ^3a or R ⁵ and R ^4a The substituents are linked to each other to form a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring, optionally including a ring atom of a 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring. 1 to 3 hetero atoms selected from O, N, S, Si, B, the 3-, 4-, 5-, 6- or 7-membered saturated monocyclic ring being substituted by m R ⁶ , the m and R ⁶ as defined before.

In some embodiments of the present application, in the compound of Formula VI, preferably, R ¹ and R ⁵ are each independently selected from H or methyl, R ^2a , R ^2b , R ^3a , R ^3b , R ^4a and R ^4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, Trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or selected from R ⁵ and R ^2a , R ⁵ and R ^3a Or the substituents in one of R ⁵ and R ^4a are linked to each other to form a 3-, 4-, 5-, 6-, or 7-membered saturated monocyclic ring, said 3-, 4-, 5-, 6- or The 7-membered saturated monocyclic ring atom optionally includes 1 to 3 hetero atoms selected from O, N, S, Si, B, and the 3, 4, 5, 6 or 7-membered saturated monocyclic ring. Substituted by m R ⁶ , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula VI, the M ⁶ moiety is selected from

The R ¹ , R ^2a , R ^2b , m and R ^{6 are} as defined above.

In some embodiments of the present application, in the compound of Formula VI, the M ⁶ moiety is preferably selected from

In some embodiments of the present application, in the compound of Formula VI, the R ^{d is} selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, hydroxy, methoxy. Ethoxy, hydroxyethyl, trifluoromethyl, methoxyethyl or methanesulfonyl.

In some embodiments of the present application, in the compound of Formula VI, D ^{6 is} selected from

Said R ^{d is} as defined above.

In some embodiments of the present application, in the compound of Formula VI, D ⁶ is preferably selected from

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

In some embodiments of the present application, the disease that benefits 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 that benefits from inhibition of capsid protein assembly refers to a liver disease caused by hepatitis B virus (HBV) infection.

In some embodiments of the present application, the treatment, which benefits from inhibition of capsid protein assembly, refers to controlling, reducing or eliminating HBV to prevent, alleviate or cure liver disease in an infected patient.

Definition and description

The following terms and phrases used herein have the following meanings unless otherwise indicated. A particular term or phrase should not be considered as undefined or unclear without a particular definition, and should be understood in the ordinary meaning of the art. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

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

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, the description including the occurrence or non-occurrence of the event or circumstance. For example, an ethyl group "optionally" substituted with halo, refers to an ethyl group may be unsubstituted (CH ₂ CH _3), monosubstituted (e.g., CH _₂ CH ₂ F), polysubstituted (e.g. CHFCH ₂ F, CH ₂ CHF ₂ or the like) or completely substituted (CF ₂ CF ₃ ); 5 to 10 membered aryl or 5 to 10 membered heteroaryl optionally substituted by 1 to 3 R ^d , meaning 5 to 10 membered aryl Or a 5- to 10-membered heteroaryl group may be unsubstituted or substituted with 1 to 3 R ^d groups. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.

References throughout the specification to "an embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" or "in a part of an embodiment of the application" means At least one embodiment includes specific reference elements, structures, or characteristics associated with the embodiments. Thus, appearances of the phrases "in an embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" or "in" "In the embodiments," it is not necessary to refer to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

The word "comprise" and its English variants such as "comprises" and "comprising" should be interpreted as open-ended throughout the specification and the claims that follow. Inclusive meaning, including but not limited to.

It will be understood that the singular articles "a", "the", "the", "the" Regulations. Thus, for example, a reaction including a "catalyst" includes a catalyst, or two or more catalysts. It is also to be understood that the term "or" is generally used in its meaning including "and/or" unless it is specifically defined otherwise.

As used herein, C _{m to n} or C _mn means that m to n carbon atoms are present in the moiety. For example, "C _1-6 alkyl" means that the alkyl group has from 1 to 6 carbon atoms.

The numerical range in this document refers to each integer in a given range. For example, "C _{1 to 6} " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

In this paper, when one of the variables is selected from a single bond, it means that the two groups to which they are attached are directly connected, such as

When W is selected from a single bond, it means

The term "substituted" or "substituted" as used herein means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (ie, =0), it means that two hydrogen atoms are substituted and the oxo does not occur on the aryl group.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound herein, its definition in each case is independent. Thus, if a group is substituted by 0-3 R, the group may optionally be substituted at most by three R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When a bond of a substituent may be indefinitely attached to more than one atom on a ring, such a substituent may be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit

Indicates that 1, 2 or 3 R ^d can be substituted at any position on the phenyl ring, including

Another example

It is indicated that there is one R ^d substituent at the position determined on the benzene ring, and (R ^d ) ₀ indicates that no additional R ^d substituent is present at other positions.

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 M moiety is selected from structural units

At the left end, the N atom to which R ¹ is attached is connected to the A moiety; the right end thereof, that is, the N atom to which R ⁵ is attached, is connected to the L moiety. The respective preferred structures of the M portion are understood by the same definition.

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

When the defined n atom is selected from 0, it is represented as a single bond structure, for example

The respective preferred structures of the M portion are understood by the same definition.

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 structural units

At the left end, that is, C is connected to the M portion; at the right end, the W is connected to the D portion. The respective preferred structures of the L portion are understood by the same definition.

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

Wherein, when R ^2a and R ^4a are joined to form a 3 to 8 membered saturated ring, it is meant that R ^2a and R ^4a are bonded by a covalent bond, and a structural unit

Together form a 3 to 8 dollar saturated ring. This way of forming a ring is only allowed if it produces a stable compound.

The term "halogen" means fluoro, chloro, bromo or iodo.

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

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

The term "cyano" refers to a -CN group.

The term "oxo" refers to a =O group.

The term "thio" refers to a =S group.

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

The term "nitro" refers to a -NO ₂ group.

The term "carboxy" refers to a -COOH group.

The term "amino" means -NH ₂ group.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond. Non-limiting examples of the term include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, _{_{decyl, -CH (CH 3) 2,}} -CH (CH 3 (CH ₂ CH ₃ ), -CH(CH ₂ CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -C(CH ₂ CH ₃ ) ₃ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ CH (CH ₃ )(CH ₂ CH ₃ ) or the like. The term "C _1-6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The term "C _1-4 alkyl" refers to an alkyl group having from 1 to 4 carbon atoms. The term "C _1-3 alkyl" refers to an alkyl group having from 1 to 3 carbon atoms.

The terms "propane, butyl, pentane" and the like mean that the group of the number of carbon atoms and the group formed by the functional group include all of its isomeric forms, for example: 1) propyl includes CH ₃ CH ₂ CH ₂ -, (CH ₃ ₂ CH-; 2) Butyryl group includes CH ₃ CH ₂ CH ₂ CO-, (CH ₃ ) ₂ CHCO-.

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

The term "alkyl sulfonyl" refers to -SO ₂ - alkyl group.

The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group, for example " _C1-6 alkyl-oxy" includes methoxy, ethoxy, propoxy, butoxy , pentyloxy, hexyloxy.

The term "cycloalkoxy" or "cycloalkyloxy" refers to a -O-cycloalkyl group, for example "C _3-6 alkyl-oxy" includes cyclopropyloxy, cyclobutyloxy, Cyclopentyloxy, cyclohexyloxy.

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

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

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

The term "cycloalkyl" refers to a ring which is fully saturated and which may be in the form of a single ring, a fused ring or a spiro ring, all of which are carbon atoms. Unless otherwise indicated, the carbocyclic ring 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]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like. For example, C _3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and an atomic group containing these hetero atoms, including, 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 -C(=O)N(H)- optionally substituted , -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-; each of the above-mentioned "hetero" groups The number of "hetero" described on the group 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 from 5 to 14 carbon atoms, preferably from 5 to 10 carbon atoms, more preferably from 5 to 8 carbon atom. The aryl group may be unsubstituted or independently substituted by one or more substituents, and examples of the substituent include, but are not limited to, an alkyl group, an alkoxy group, an aryl group, an aralkyl group, an amino group, a halogen group, a hydroxyl group, a sulfo group. An acyl group, a sulfinyl group, a phosphoryl group and a heteroalicyclic group. The aryl group may be a monocyclic ring or a fused ring. When selected from a fused ring, at least one ring structure in the fused ring is a carbocyclic ring having a fully conjugated π-electron system, and other ring structures in the fused ring may be A fully conjugated π-electron system, either saturated or partially saturated, or containing or not containing heteroatoms. For example, non-limiting examples of structural groups "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. The heteroaryl group may be unsubstituted or independently substituted with one or more substituents, and examples of the substituent include, but are not limited to, an alkyl group, an alkoxy group, an aryl group, an aralkyl group, an amino group, a halogen group, a hydroxyl group, Sulfonyl, sulfinyl, phosphoryl and heteroalicyclic groups. The heteroaryl group may be a monocyclic or fused ring, and when selected from a fused ring, at least one ring structure in the fused ring is a hetero atom-containing ring having a fully conjugated π-electron system, in a fused ring Other ring structures may have a fully conjugated pi-electron system, either saturated or partially saturated, or contain or contain no heteroatoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, 1,2,4-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridyl Azinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.

The term "pharmaceutically acceptable" is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having a particular substituent found herein and a relatively non-toxic acid or base. When a compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. When the compound of the present application contains a relatively basic functional group, it can be dissolved in a pure solution or a suitable inert solution. The acid addition salt is obtained in a manner in which a sufficient amount of the acid is contacted with the neutral form of such a compound. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, as well as organic acid salts, salts of amino acids (such as 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 basic and acidic functional groups which can be converted to any base or acid addition salt.

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

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

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

including but not limited to

Or an enantiomerically or diastereomeric enriched mixture or racemic mixture.

In the present specification, "1SR, 2SR" means a mixture of two isomers of "1S, 2S" and "1R, 2R", and "1SR, 3RS" means two isomers of "1S, 3R" and "1R, 3S". Mixed, "1SR, 2RS" means a mixture of two isomers of "1S, 2R" and "1R, 2S", and "1RS, 3RS" means two isomers of "1R, 3R" and "1S, 3S" Mixing, that is, "SR, SR" generally refers to a mixture of two isomers of "SS" and "RR", and other meanings such as "SR, RS", "RS, RS" are similar.

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide purity. The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art. The diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

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 are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include recombination through some recombination of bonding electrons.

The compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, a compound can be labeled with a radioisotope such as hydrazine (3H), iodine-125 (125I) or C-14 (14C). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the invention.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.

The chemical reactions of the specific embodiments of the present application are accomplished in a suitable solvent which is suitable for the chemical changes of the present application and the reagents and materials required thereof. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes based on the prior embodiments.

An important consideration in any synthetic route planning in the art is the selection of a suitable protecting group for a reactive functional group, such as an amino group in the present application. For trained practitioners, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons) is the authority in this regard. All references cited in this application are hereby incorporated by reference in their entirety.

The reactions described herein can be monitored according to any suitable method known in the art. For example, it can be monitored by broad-spectrum methods such as nuclear magnetic resonance spectroscopy (eg 1H or 13C), infrared spectroscopy, spectrophotometry (eg UV-visible) or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The product formed.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. Additional information about the carrier, can refer to Remington:. The Science and Practice of Pharmacy, 21 st 27Ed, Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

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

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For an oral dosage form of the present application, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers 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 a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, most preferably a human.

The phrase "therapeutically effective amount" as used herein refers to an amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human causing a biological or medical response. Including one or more of the following: 1) preventing a disease, such as preventing a disease, disorder, or condition in an individual susceptible to a disease, disorder, or condition but having not experienced or developing a pathology or symptom of the disease; 2) inhibiting the disease, for example, is experiencing Inhibiting a disease, disorder, or condition (ie, preventing further progression of pathology and/or symptoms) in an individual who develops a pathology or symptom of a disease, disorder, or condition; 3) alleviating the disease: for example, while experiencing or developing a disease, disorder, or condition A disease, disorder, or condition (ie, reversing pathology and/or symptoms) is alleviated in an individual with a pathology or condition.

The therapeutic dose of a compound of the present application can depend, for example, on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present application in the pharmaceutical compositions may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration. For example, the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound. Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof. An effective dose can be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.

In some embodiments, the compounds of formula (I) of the present application can be prepared by those skilled in the art of organic synthesis by the following procedures and routes:

Route 1:

Route 2:

Wherein R ¹ , R ^2a , R ^2b , R ^3a , R ^3b , R ^4a , R ^4b , R ⁵ , R ^d , R ⁶ , m, n are as defined in the present application.

This application uses the following abbreviations:

Boc: tert-butoxycarbonyl

DCM: dichloromethane

DIPEA: N,N-diisopropylethylamine

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

EA: ethyl acetate

MeOH: methanol

PE: petroleum ether

HATU: 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate

HEPES: 4-hydroxyethylpiperazineethanesulfonic acid.

DNA deoxyribonucleic acid

HBV hepatitis B virus

mM millimolar

nM Namore

qPCR quantitative polymerase chain reaction

μM micromolar

Mg mg

Detailed ways

The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They are not to be considered as limiting the scope of the invention, but are merely illustrative and representative of the invention. Those skilled in the art will appreciate that there are other synthetic routes to form the compounds of the invention, and non-limiting examples are provided below.

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

The nuclear magnetic resonance chromatography (NMR) of the present invention is measured by BRUKER-300 and BRUKER-500 nuclear magnetic resonance spectrometer, and the chemical shift is tetramethylsilane (TMS=δ0.00) as an internal standard, and the format of the nuclear magnetic resonance data recording is: 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 is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.

Example 1 1-(3-Chloro-4-fluorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)urea

Reaction process:

Step A: To a 100 mL vial was added 3,4,5-trichloropyridine (736 mg), ethylenediamine (960 mg), and reacted at 70 ° C for 1 h. Was added dichloromethane (40 mL) After completion of the reaction, water (3 * 10mL) and washed three times, dried, and concentrated to give N ¹ - (3,5- dichloro-pyridin-4-yl) ethane-1,2-diamine (643 mg) crude was used directly in the next step.

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

Step B: To a 100 mL single-mouth bottle was added N ¹ -(3,5-dichloropyridin-4-yl)ethane-1,2-diamine (540 mg), dichloromethane (30 mL), and 3-chloro 4-fluorophenyl isocyanate (674 mg) was reacted at room temperature for 1 h. After the reaction is completed, the mixture is filtered, and the cake is washed with a small amount of dichloromethane, and dried to give 1-(3-chloro-4-fluorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)) Amino)ethyl)urea (900 mg, 90.9%).

^{1 H-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); ¹³ C-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: 377.0.

Example 2 1-(3-Chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)propyl)urea

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

^{1 H-NMR (500MHz, DMSO} -d6): δ8.15 (s, 2H), 3.70 (t, 2H), 2.61 (t, 2H), 1.60 (t, 2H); 13 C-NMR (125MHz, DMSO -d6): δ 148.37, 146.92, 117.28, 49.05, 43.65, 33.97. MS (ESI+, [M+H] ⁺ ).

Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino) was obtained by the procedure used in Step B. ) propyl) urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.86, 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: 39.

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

Step A: According to Example 1, (1SR, 2SR)-N ¹ -(3,5-dichloropyridine) was prepared by substituting (±) 1,2-trans cyclohexanediamine for ethylenediamine in step A. 4-yl)cyclohexane-1,2-diamine.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 148.40, 147.85, 118.63, 61.82, 55.87, 35.39, 33.60, 25.15, 24.98. HRMS (ESI+, [M+H] ⁺ ) m/z: 260.0756.

Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridine) was obtained by the method used in Step B. 4-yl)amino)cyclohexyl)urea.

^{1 H-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) ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.91, 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 4 3-(3-Chloro-4-fluorophenyl)-1-(2-((3,5-dichloropyridin-4-yl)(methyl)amino)ethyl)-1-methyl Urea

synthetic route:

Step A: To a 25 mL single-necked flask was added 3,4,5-trichloropyridine (3.65 g, 20 mmol) and N ¹ ,N ² -dimethylethane-1,2-diamine (4.41 g, 50 mmol) The mixture was heated to 70 ° C for 3 h. After cooling to room temperature, water (15 mL) and methylene chloride (20 mL) were added, and the mixture was evaporated, evaporated, evaporated, evaporated. The solvent was evaporated to give N ¹ -(3,5-dichloropyridin-4-yl)-N ¹ ,N ² -dimethylethane-1,2-diamine (2.0 g, 42.7%) as pale yellow Oily, used directly in the next step.

Step B: At 0 ° C, triphosgene (0.39 g, 1.32 mmol) was added to a solution of 3-chloro-4-fluoroaniline in dichloromethane (30 mL), and triethylamine (1.65 mL, 12 mmol) was slowly added dropwise. After completion, the mixture was stirred at 0 ° C for 1 h. Slowly dropwise addition of N ¹ -(3,5-dichloropyridin-4-yl)-N ¹ ,N ² -dimethylethane-1,2-diamine (0.93 g, 4 mmol) to the above mixture A solution of methyl chloride (10 mL) was stirred at room temperature overnight. After adding water (20 mL), the mixture was stirred and evaporated. EtOAcjjjjjjjjjjjjj 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 (0.70 g, 43.8%).

^{_{1 H 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 = 6.5 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 3.00 (s, 3H), 2.98 (s, 3H). ¹³ C NMR (CDCl _3, 125 MHz): 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 5 3-(3-Chloro-4-fluorophenyl)-1-(3-((3,5-dichloropyridin-4-yl)(methyl)amino)propyl)-1-methyl Urea

Step A: According to Example 4, in the step A, N ¹ ,N ³ -dimethylpropane-1,3-diamine was substituted for N ¹ ,N ² -dimethylethane-1,2-diamine, Preparation of N ¹ -(3,5-dichloropyridin-4-yl)-N ¹ ,N ³ -dimethylpropane-1,3-diamine as a pale yellow oil was used directly in the next step.

Step B: According to Example 4, 3-(3-chloro-4-fluorophenyl)-1-(3-((3,5-dichloropyridin-4-yl)) Methyl)amino)propyl)-1-methylurea.

^{_{1 H 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 = 6.7 Hz, 2H). ¹³ C NMR (CDCl _3, 125 MHz): 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 6 1-(2-((3,5-Dichloropyridin-4-yl)amino)ethyl)-3-(3,4-fluorophenyl)urea

Step A: To a 250 mL two-necked flask was added dichloromethane (100 mL), 3,4-difluoroaniline (440 mg), triphosgene (604 mg), and triethylamine (2.30 mL) was added dropwise in an ice bath. After 10 min, a solution of N ¹ -(3,5-dichloropyridin-4-yl)ethane-1,2-diamine (600 mg) in dichloromethane (20 mL) was evaporated. The reaction solution was concentrated to dryness and the obtained crude crystals was purified by column chromatography (PE: EA=7:1) to give 1-(2-(3,5-dichloropyridin-4-yl)amino)ethyl)-3-( 3,4-Difluorophenyl)urea (870 mg, 71.0%).

^{1 H-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 = 7.0 Hz, 1H), 6.38 (s, 1H), 6.19 (s, 1H), 3.72 (s, 2H), 3.40 (s, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 156.04, 148.42, 147.06, 117.72, 114.26, 107.71, 46.12. HRMS (ESI+, [M+H] ⁺ ) m/z: 361.0414.

Example 7 1-(3-Chlorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)urea

Step A: According to Example 6, substituting 3-chloroaniline for 3,4-difluoroaniline to prepare 1-(3-chlorophenyl)-3-(2-((3,5-dichloro)) Pyridin-4-yl)amino)ethyl)urea.

^{1 H-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 = 5.5 Hz, 1H), 6.19 (t, J = 6.0 Hz, 1H), 3.71-3.75 (m, 2H), 3.40 - 3.36 (m, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.98, 148.42, 142.39, 133.54, 121.22, 117.65, 116.63, 46.14. HRMS (ESI+, [M+H]+) m/z: 359.0239.

Example 8 1-(2-((3,5-Dichloropyridin-4-yl)amino)ethyl)-3-(3-fluorophenyl)urea

Step A: Preparation of 1-(2-((3,5-dichloropyridin-4-yl)amino)ethyl) by using 3-fluoroaniline in place of 3,4-difluoroaniline according to Example 6. )-3-(3-fluorophenyl)urea.

^{1 H-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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 163.82, 161.91, 156.11, 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 9 1-(2-((3,5-Dichloropyridin-4-yl)amino)ethyl)-3-(3,4,5-trifluorophenyl)urea

Step A: According to Example 6, substituting 3,4,5-trifluoroaniline for 3,4-difluoroaniline in step A to prepare 1-(2-((3,5-dichloropyridin-4-yl) Amino)ethyl)-3-(3,4,5-trifluorophenyl)urea.

^{1 H-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 = 6.0 Hz, 1H), 3.71-3.75 (m, 2H), 3.33 - 3.35 (m, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.79, 148.42, 147.02, 137.35, 134.77, 117.45, 102.28, 45.90. HRMS (ESI+, [M+H]+) m/z: 379.0324.

Example 10 1-(4-Chloro-3-fluorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)urea

Step A: According to Example 6, 3-(4-chloro-4-chlorophenyl)-3-(2-) was prepared by substituting 3-fluoro-4-chloroaniline for 3,4-difluoroaniline in Step A. ((3,5-Dichloropyridin-4-yl)amino)ethyl)urea.

^{1 H-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 = 6.0 Hz, 1H), 6.18 (t, J = 6.0 Hz, 1H), 3.71-3.75 (m, 2H), 3.35 (t, J = 6.0 Hz, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 158.54, 156.11, 148.41, 147.03, 141.68, 130.70, 117.44, 115.06, 110.99, 106.29, 46.03. HRMS (ESI+, [M+H]+) m/z: 377.0.

Example 11 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(3,4-difluorophenyl)urea

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

^{1 H-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 = 6.5 Hz, 2H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.82, 148.44, 144.81, 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.

Example 12 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(3-chlorophenyl)urea

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

^{1 H-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 = 6.5 Hz, 2H); ¹³ C-NMR (125 MHz, DMSO-d6) ): δ148.42, 144.82, 142.22, 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 13 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(3-fluorophenyl)urea

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

^{1 H-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 = 6.5 Hz, 2H) ¹³ C-NMR (125 MHz, DMSO-d6): δ 163.84, 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 14 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(4-chloro-3-fluorophenyl)urea

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

¹ H-NMR (500MHz, DMSO-d6): δ 8.84 (s, 1H), 8.17 (s, 2H), 7.62 (dd, J = 2.5, 10 Hz, 1H), 7.39 (t, J = 9 Hz, 1H) ), 7.09 (dd, J = 2, 7 Hz, 1H), 6.34 (t, J = 6 Hz, 1H), 6.25 (t, J = 7 Hz, 1H), 3.65 (q, J = 7 Hz, 2H), 3.15 ( q, J = 6.5 Hz, 2H), 1.70 (t, J = 7 Hz, 2H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.62, 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: 39.

Example 15 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(3,4,5-trifluorophenyl)urea

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

^{1 H-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); 13 C-NMR (125 MHz, DMSO-d6): δ 155.57, 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 16 1-((1SR,2SR)-2-((3,5-Dichloropyridin-4-yl)amino)cyclohexyl)-3-(3,4-fluorophenyl)urea

Step A: Preparation of 1-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl) according to Example 6. -3-(3,4-fluorophenyl)urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.89, 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] ⁺ ).

Example 17 1-((1SR,2SR)-2-((3,5-Dichloropyridin-4-yl)amino)cyclohexyl)-3-(3,4-fluorophenyl)urea

Step A: Preparation of 1-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)-3-(3-fluorophenyl)urea according to Example 6. .

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 170.78, 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] ⁺ ).

Example 18 1-(3-Chloro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

Step A: Preparation of 1-(3-chloro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl) according to Example 6. Urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.83, 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] ⁺ ).

Example 19 1-(4-Chloro-3-fluoro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

Step A: Preparation of 1-(4-chloro-3-fluoro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino) according to Example Cyclohexyl)urea.

^{1 H-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); ¹³ C-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]+).

Example 20 1-(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.

¹ H-NMR (500MHz, DMSO-d6): δ 8.74 (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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.65, 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] ⁺ ).

Example 21 1-(3-Chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)amino)propan-2-yl)urea

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

^{1 H-NMR (500MHz, DMSO} -d6): δ8.15 (s, 2H), 3.62 (m, 1H), 3.30 (m, 1H), 2.99 (m, 1H), 1.01 (d, 3H); 13 C-NMR (125 MHz, DMSO-d6): δ 148.30, 147.11, 146.84, 118.32, 117.41, 52.32, 47.01, 22.19. MS (ESI+, [M+H] ⁺ ).

Step B: According to the procedure of Example 1, 1-(3-chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)amino) ) prop-2-yl)urea.

^{1 H-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); ¹³ C-NMR ( 125 MHz, DMSO-d6): δ 155.51, 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] ⁺ ).

Example 22 3-(3-Chloro-4-fluorophenyl)-1-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)-1-methylurea

Step A: According to Example 1, N ¹ -(3,5-dichloropyridin-4-yl)-N ² -methylethane was prepared by substituting N-methylethylenediamine for ethylenediamine in Step A. -1,2-diamine.

MS (ESI+, [M+H] ⁺ ).

Step B: According to Example 1, 3-(3-chloro-4-fluorophenyl)-1-(2-((3,5-dichloropyridin-4-yl)amino). Ethyl)-1-methylurea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 156.13, 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] ⁺ ).

Example 23 1-(3-Chloro-4-fluorophenyl)-3-(2-((3,5-dichloropyridin-4-yl)amino)propyl)urea

Reaction process:

Step A: To a 250 mL three-necked flask was added 1,4-dioxane (100 mL), 1-methyl-1,2-ethanediamine (18.7 mg), and then di-tert-butyl dicarbonate (6.95 g) was added dropwise. The 1,4-dioxane solution was reacted overnight at room temperature. After completion of the reaction, water (80 mL) was added, and the mixture was evaporated with m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ One step reaction.

Step B: To a 100 mL single-mouth bottle was added tert-butyl (2-aminopropyl)carbamate (1.74 g), trichloropyridine (912 mg), and reacted at 70 ° C for 2 h. After completion of the reaction, dichloromethane (30 mL) was added, and water (3*8 mL) was washed, dried and concentrated to dryness (DCM: MeOH = 50:1) to give (2-((3,5) Pyridin-4-yl)amino)propyl)carbamic acid tert-butyl ester (200 mg).

Step C: To a 25 mL vial was added (2-((3,5-dichloropyridin-4-yl)amino)propyl)carbamic acid tert-butyl ester (600 mg), 10% EtOAc in MeOH (5 mL). The reaction was carried out at 50 ° C for 2 h. After the reaction was concentrated to dryness, aqueous sodium hydroxide solution to give free N ² - (3,5-dichloro-4-yl) propane-1,2-diamine (260mg).

Step D: To a 100 mL single-mouth bottle was added N ² -(3,5-dichloropyridin-4-yl)propane-1,2-diamine (260 mg), dichloromethane (3 mL), and 3-chloro- 4-fluorophenyl isocyanate (304 mg) was reacted at room temperature for 1 h. After completion of the reaction, it was concentrated to dryness and purified by column chromatography (PE: EA=4:1) to give 1-(3-chloro-4-fluorophenyl)-3-(2-((3,5-dichloropyridine-4) -yl)amino)propyl)urea (60 mg).

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 156.05, 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.

Example 24 1-(3-Chloro-4-fluorophenyl)-3-((1SR,3RS)-3-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

Step A: According to Example 1, substituting cis-1,3-cyclohexanediamine for ethylenediamine in step A to prepare 1-(3-chloro-4- Fluorophenyl)-3-((1SR,3RS)-3-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea.

^{1 H-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=7.5 Hz, 1H), 5.32 (d, J=9.5 Hz, 1H), 4.02 (s, 1H), 3.49 (s, 1H), 1.73-2.14 (m, 4H), 1.7-1.35 (m, 4H) ). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.69, 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 25 1-(3-Chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methylpropyl)urea

Step A: According to Example 1, 2-(3-chloro-4-fluorophenyl)-3-(3-) was prepared by substituting 2-methyl-1,3-propanediamine for ethylenediamine in Step A. ((3,5-Dichloropyridin-4-yl)amino)-2-methylpropyl)urea.

^{1 H-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 = 6.0 Hz, 2H), 3.48-3.49 (t, J = 6.5 Hz, 2H), 3.03-3.13 (m, 2H), 1.83-1.87 (m, 1H), 0.84 (d, J = 7.0) Hz, 3H).

¹³ C-NMR (125 MHz, DMSO-d6): δ 156.06, 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 26 1-(3,4-Difluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)2,2-dimethylpropyl)urea

Step A: According to Example 1, in the step A, 2,2-dimethyl-1,3-propanediamine was used instead of ethylenediamine to prepare N ¹ -(3,5-dichloropyridin-4-yl) -2,2-dimethylpropane-1,3-diamine.

HRMS (ESI+, [M+H] ⁺ ) m/z: 248.0716.

Step B: According to Example 1, 1-(3,4-difluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino) was obtained by the method used in Step B. 2,2-dimethylpropyl)urea.

^{1 H-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 = 6.5 Hz, 1H), 6.28 (t, J = 6.5 Hz, 1H), 3.50 (d, J = 7 Hz, 2H), 3.03 (d, J = 6.5 Hz, 2H), 0.81 (s, 6H); ¹³ C NMR (125 MHz, DMSO-d6): δ 156.48, 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: 42.

Example 27 1-(3-Chloro-4-fluorophenyl)-3-((1SR,2RS)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

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

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 148.37, 146.92, 117.28, 49.05, 43.65, 33.97.

Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-((1SR,2RS)-2-((3,5-dichloropyridine) was obtained by the method used in Step B. 4-yl)amino)cyclohexyl)urea.

^{1 H-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 = 9 Hz, 1H), 5.31 (d, J = 8.5 Hz, 1H), 4.36 (d, J = 3 Hz, 1H), 4.09 - 4.03 (m , 1H), 1.76 (d, 8.5 Hz, 1H), 1.65 (s, 3H), 1.50-1.38 (m, 4H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.42, 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 28 1-(3-Chloro-4-fluorophenyl)-3-((1R,2R)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

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

^{1 H-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 = 9 Hz, 1H), 5.89 (d, J = 8.5 Hz, 1H), 3.99 (d, J = 3 Hz, 1H), 3.71-3.65 (m) , 1H), 2.04 (d, 7.5 Hz, 1H), 1.88 (d, J = 7.5 Hz, 1H), 1.69 (q, J = 8 Hz, 2H), 1.39-1.24 (m, 4H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.90, 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 29 1-(3-Chloro-4-fluorophenyl)-3-((1S,2S)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

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

^{1 H-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 = 9 Hz, 1H), 5.90 (d, J = 8.5 Hz, 1H), 3.99 (d, J = 3 Hz, 1H), 3.71-3.67 (m , 1H), 2.03 (d, 7.5 Hz, 1H), 1.88 (d, J = 7.5 Hz, 1H), 1.68 (q, J = 8 Hz, 2H), 1.39-1.25 (m, 4H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.89, 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 30 3-(3-Chloro-4-fluorophenyl)-1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-1-methylurea

Step A: According to Example 1, N ¹ -(3,5-dichloropyridin-4-yl)-N ^{3 was} prepared by substituting N-methyl-1,3-propanediamine for ethylenediamine in step A. -methylpropane-1,3-diamine.

^{1 H-NMR (500MHz, DMSO} -d6): δ8.44 (s, 1H), 8.14 (s, 2H), 6.82 (s, 1H), 3.71 (q, J 1 = 6.0Hz, J 2 = 6.0Hz , 2H), 2.54 (q, J ₁ = 6.5 Hz, J ₂ = 6.0 Hz, 2H), 2.26 (s, 3H), 1.64-1.69 (m, 2H); ¹³ C-NMR (125 MHz, DMSO-d6) : δ 148.37, 146.98, 117.15, 49.80, 44.58, 36.57, 29.87. MS (ESI+, [M+H] ⁺ ).

Step B: According to Example 1, 3-(3-chloro-4-fluorophenyl)-1-(3-((3,5-dichloropyridin-4-yl)amino) was obtained by the procedure used in Step B. ) propyl)-1-methylurea.

^{1 H-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=9 Hz, 1H), 6.25-6.28 (t, J=6.5 Hz, 1H), 3.61 (q, J ₁ =7.0 Hz, J ₂ =6.5 Hz, 2H), 3.37 (t, 7.0 Hz, 2H), 2.95 (s, 3H), 1.74-1.80 (m, 2H); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.89, 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] ⁺ ).

Example 31 3-Chloro-N-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)-4-fluorobenzamide

Reaction process:

Step A: To a 100 mL single-mouth bottle was added DMF (8 mL), N ¹ -(3,5-dichloropyridin-4-yl)ethane-1,2-diamine (412 mg), 3-chloro-4-fluoro Benzoic acid (349 mg), DIPEA (516 mg), HATU (837 mg). After completion of the reaction, water (20 mL) was added dropwise, filtered and dried to give 3-chloro-N-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)-4-fluorobenzamide (480 mg, 66.2%).

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 165.03, 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] ⁺ ).

Example 32 3-Chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-4-fluorobenzamide

Step A: According to Example 31, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - 4-Chloro-ethane-1,2-diamine to prepare 3-chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-4-fluorobenzamide .

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 164.65, 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-, [MH] ^- ) m/z: 374.0.

Example 33 1-(3-Chloro-4-fluorophenyl)-3-(1-(thiazol-2-yl)piperidin-3-yl)urea

Reaction process:

Step A: To a 10 mL microwave tube was added 2-bromothiazole (378 mg), 3-aminopiperidine (576 mg), and subjected to microwave reaction at 90 ° C for 1 h. After the reaction, the crude product was purified byjjjjjjjjjjj

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 171.81, 139.85, 107.71, 57.54, 48.84, 47.59, 33.83, 23.53. MS (ESI+, [M+H] ⁺ ).

Step B: According to Example 1, substituting 1-(thiazol-2-yl)piperidin-3-amine for N ¹ -(3,5-dichloropyridin-4-yl)ethane-1 in step B, 2-Diamine to give 1-(3-chloro-4-fluorophenyl)-3-(1-(thiazol-2-yl)piperidin-3-yl)urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 171.96, 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-, [MH] ^- ) m/z:353.

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

Reaction process:

Step A: According to Example 1, in the step A, 4-aminopiperidine was used in place of ethylenediamine, and the crude product was subjected to column chromatography (DCM: MeOH = 10:1) to give two isomers which eluted first. Isomer b, followed by isomer a, namely 3,5-dichloro-N-(piperidin-4-yl)pyridin-4-amine.

^{1 H-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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 148.42, 146.56, 118.94, 52.82, 45.22, 34.86. HRMS (ESI+, [M+H] ⁺ ) m.

Step B: According to Example 1, substituting isomer a for N ¹ -(3,5-dichloropyridin-4-yl)ethane-1,2-diamine in step B to obtain N-(3- Chloro-4-fluorophenyl)-4-((3,5-dichloropyridin-4-yl)amino)piperidine-1-carboxamide.

^{1 H-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= 10.5 Hz, 2H), 1.54-1.62 (m, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.96, 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 35 1-(3-Chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)piperidin-4-yl)urea

Reaction process:

Step A: According to Example 34, the isomer b, i.e., 1-(3,5-dichloropyridin-4-yl)piperidin-4-amine, eluted first in column chromatography.

^{1 H-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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 151.79, 149.33, 127.94, 49.53, 48.27, 36.40. HRMS (ESI+, [M+H] ⁺ ) m/z: 246.0574.

Step B: According to Example 35, in the step B, the isomer b was replaced with the isomer b to obtain 1-(3-chloro-4-fluorophenyl)-3-(1-(3,5-dichloro). Pyridin-4-yl)piperidin-4-yl)urea.

^{1 H-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=7.5 Hz, 1H), 3.71 (t, J=4.0 Hz, 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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.79, 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 36 N-(3-Chloro-4-fluorophenyl)-3-((3,5-dichloropyridin-4-yl)amino)piperidine-1-carboxamide

Reaction process:

Step A: According to Example 1, in the step A, 3-aminopiperidine was used instead of ethylenediamine, and the crude product was subjected to column chromatography (PE: EA = 2:1) to obtain two isomers which were eluted. It is an isomer, i.e., N-(3-chloro-4-fluorophenyl)-3-((3,5-dichloropyridin-4-yl)amino)piperidine-1-carboxamide.

^{1 H-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=9.0 Hz, 1H), 5.46 (d, J=9.0 Hz, 1H), 4.17 (t, J=4.0 Hz, 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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.33, 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 37 1-(3-Chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)piperidin-3-yl)urea

Step A: According to Example 36, the isomer II was first eluted, ie 1-(3-chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridine-4- Basepiperidin-3-yl)urea.

^{1 H-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=7.5 Hz, 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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.83, 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 38 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclo)yl)methyl) Urea

Reaction route:

Step A: Dissolve malononitrile (4.95 g, 75 mmol) in N,N-dimethylformamide (50 mL) and slowly add 1,4-dibromobutane (17.8 g, 82.5 mmol) under ice bath. The reaction flask was transferred to an oil bath to heat the reaction, and the mixture was heated to 80 ° C to stir the reaction for 2 hours. The reaction mixture was poured into 200 mL of water, 200 mL of ethyl acetate, and the mixture was stirred, and then the mixture was separated, and the aqueous layer was added again to ethyl acetate (200 mL), and the organic layer was combined, and the organic layer was washed three times with 100 mL of water. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness to dry brown crystals.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.42 ( quint, J ₁ = 3.0 Hz, 7.5 Hz, 4H), 1.98 (quint, J ₁ = 4.0 Hz, 7.0 Hz, 4H). ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 116.62, 39.31, 33.68, 24.03. MS (ESI-, [MH] ^- ): m/z 119.0.

Step B: The cyclopentane-1,1-dicarbonitrile (1.8 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), the reaction flask was cooled to -15 ° C, and the borane tetrahydrofuran solution (60 mL, 60 mmol) was slowly added to the reaction. In a bottle, the reaction was stirred overnight at room temperature. The reaction solution was added with 6N hydrochloric acid to adjust the pH to about 4, and heated at 60 ° C for 3 hours. The reaction solution was added with sodium hydroxide in an ice bath to adjust the pH to about 9, and the mixture was allowed to stand for separation. The aqueous layer was extracted with 50 mL of ethyl acetate. The organic layer was combined, dried over anhydrous sodium sulfate and evaporated. Column chromatography purified 1.7 g of a colorless liquid.

MS (ESI+, [M+H] ⁺ ): m.

Step C: According to Example 1, N-((1-(aminomethyl)cyclopentyl)methyl)- was prepared by substituting cyclopentane-1,1-diylmethylamine for ethylenediamine in Step A. 3,5-Dichloropyridin-4-amine.

¹ H-NMR (500MHz, CDCl ₃ ): δ 8.12 (s, 2H), 3.73 (d, J = 5.0 Hz, 2H), 2.81 (s, 2H), 1.62 to 1.68 (m, 4H), 1.44~ 1.54 (m, 4H). ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 148.06, 147.70, 117.73, 54.15, 50.29, 47.41, 33.95, 24.94. MS (ESI, [M+H] ⁺ ): m.

Step D: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-((1-(((3,5-) Dichloropyridin-4-yl)amino)methyl)cyclopentyl)methyl)urea.

¹ H-NMR (500MHz, DMSO-d6): δ 8.73 (s, 1H), 8.19 (s, 2H), 7.75 (dd, J ₁ = 2.0 Hz, J ₂ = 6.5 Hz, 1H), 7.22 to 7.29 (m, 2H), 6.58 (t, J = 6.5 Hz, 1H), 6.29 (d, J = 6.5 Hz, 1H), 3.59 (d, J = 7.0 Hz, 2H), 3.15 (d, J = 6.5 Hz) , 2H), 1.58 (d, J = 2.0 Hz, 4H), 1.33 (d, J = 6.5 Hz, 4H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 156.59, 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 44.

Example 39 1-(3-Chloro-4-fluorophenyl)-3-((4-((3,5-dichloropyridin-4-yl)amino)methyl)tetrahydro-2H-pyran -4-yl)methyl)urea

Step A: According to Example 38, in the step A, 1-bromo-2-(2-bromoethoxy)ethane was used instead of 1,4-dibromobutane to prepare dihydro-2H-pyran-4. 4-(3H)-dicarbonitrile.

¹ H-NMR (500 MHz, DMSO-d6): δ 3.71 (t, J = 5.0 Hz, 4H), 2.30 (t, J = 5.0 Hz, 4H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 116.18, 63.10, 32.87, 30.70.

Step B: According to Example 38, (tetrahydro-2H-pyran-4,4-diyl)dimethylamine was prepared by the method of Step B.

¹ H-NMR (500MHz, CDCl ₃ ): δ 3.61 (t, J = 5.5 Hz, 4H), 2.67 (s, 4H), 1.74 (s, 4H), 1.40 (t, J = 5.5 Hz, 4H) . ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 63.54, 46.71, 35.54, 31.63.

Step C: Preparation of N-((4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methyl)-3,5-dichloropyridine by the method of Step C according to Example 38 4-amine.

^{1 H-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 = 5.5 Hz, 2H), 2.77 (s, 2H), 1.38 to 1.44 (m, 4H). ¹³ C-NMR (500 MHz, DMSO-d6): δ 148.39, 147.69, 117.33, 63.14, 61.22, 54.44, 48.80, 35.02, 31.91, 29.67. MS (ESI, [M+H] ⁺ ): m.

Step D: Preparation of 1-(3-chloro-4-fluorophenyl)-3-((4-((3,5-dichloropyridin-4-yl)). Amino)methyl)tetrahydro-2H-pyran-4-yl)methyl)urea.

^{1 H-NMR (500MHz, DMSO} -d6): δ8.75 (s, 1H), 8.20 (s, 2H), 7.74 (dd, J 1 = 2.0Hz, J 2 = 6.5Hz, 1H), 7.24 ~ 7.28 (m, 2H), 6.59 (t, J = 6.5 Hz, 1H), 6.30 (t, J = 6.5 Hz, 1H), 3.62 (d, J = 6.5 Hz, 2H), 3.55 (t, J = 4.5 Hz) , 4H), 3.31 (s, 2H), 1.29 to 1.32 (m, 4H). ¹³ C-NMR (DMSO, 500 MHz): δ 156.59, 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 46.

Example 40 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclohexyl)methyl)urea

Step A: According to Example 38, cyclohexane-1,1-dicarbonitrile was prepared by substituting 1,5-dibromopentane for 1,4-dibromobutane in step A.

¹ H-NMR (500 MHz, DMSO-d6): δ 2.14 (t,J=6 Hz, 4H), </ RTI></RTI></RTI><RTIgt; ¹³ C-NMR (125 MHz, DMSO-d6): δ 115.96, 34.70, 32.49, 23.96, 21.69.

Step B: According to Example 38, cyclohexane-1,1-diylmethylamine was prepared by the method of Step B.

Step C: N-((1-(Aminomethyl)cyclohexyl)methyl)-3,5-dichloropyridin-4-amine was prepared according to the procedure of Example 38 using the procedure of Step C.

Step D: 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl))amino) )methyl)cyclohexyl)methyl)urea.

^{1 H-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=6 Hz, 1H), 6.24 (t, J=6 Hz, 1H), 3.54 (d, J=6.5 Hz, 2H), 3.20 (d, J=6 Hz, 1H), 1.38 (t, 8 Hz, 4H) ), 1.22-1.18 (m, 6H); ¹³ C-NMR (125MHz, DMSO-d6): δ 156.67, 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 41 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl)amino)methyl)cycloheptyl)methyl) Urea

Step A: According to Example 38, 1-(3-chloro-4-fluorophenyl)-3-(() was prepared by substituting 1,6-dibromohexane for 1,4-dibromobutane in Step A. 1-(((3,5-Dichloropyridin-4-yl)amino)methyl)cyclobutyl)methyl)urea.

^{1 H-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 = 6.5 Hz, 1H), 6.33 (t, J = 6.5 Hz, 1H), 3.49 (d, J = 6.5 Hz, 2H), 3.10 (d, J = 6.5 Hz, 2H), 1.40-1.45 (m, 8H), 1.27-1.28 (m, 4H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 156.69, 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 42 1-(3-Chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclopentyl)urea

Reaction route:

Step A: Anhydrous tetrahydrofuran (150 mL) was added to a 500 mL round bottom flask, followed by benzylamine (10.7 g, 0.1 mol), cyclopentanone (8.4 g, 0.1 mol) and anhydrous sodium sulfate (71 g, 0.5 mol). ). The reaction solution was cooled in an ice bath, and then cyanotrimethylsilane (10.5 g, 0.105 mol) was slowly added, and stirred at room temperature overnight. The reaction mixture was successively added with 300 mL of water and 300 mL of ethyl acetate, and the mixture was thoroughly stirred and separated. The organic layer was washed successively with 200 mL of water, washed with saturated brine, dried over anhydrous sodium sulfate and then evaporated to dryness to yield 20.95 g of colorless liquid, column layer The precipitate was purified to obtain 8.10 g of a colorless oily liquid, i.e., 1-(benzylamino)cyclopentanenitrile.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.27 - 7.38 (m, 5H), 3.91 (s, 2H), 2.12 - 2.19 (m, 4H), 1.79 - 1.92 (m, 4H). ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 139.27, 128.53, 128.32, 127.38, 122.92, 60.38, 50.19, 39.01, 23.23. HRMS (ESI+, [M+H] ⁺ ): m/z 201.1388.

Step B: Lithium aluminum hydride (0.93 g, 25 mmol) was added to a nitrogen-protected dry round bottom flask, and anhydrous tetrahydrofuran (25 mL) was poured into a reaction flask and cooled in an ice bath. A solution of 1-(benzylamino)cyclopentanenitrile (4.0 g, 20 mmol) dissolved in tetrahydrofuran (15 mL) was slowly poured into a reaction flask, and the reaction was continued for 1 hour under ice bath. The reaction solution was slowly poured into 50 mL of ice water mixture, 100 mL of dichloromethane was added, and the mixture was separated. The aqueous layer was again added with 100 mL of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. Purification afforded 1.55 g of a colorless viscous liquid, l-(aminomethyl)-N-benzylcyclopentylamine.

¹ H-NMR (500MHz, CDCl ₃ ): δ 7.24 - 7.33 (m, 5H), 3.68 (s, 2H), 2.68 (s, 2H), 1.72 to 1.76 (m, 4H), 1.61 to 1.66 (m) , 4H). ¹³ C-NMR (125 MHz, CDCl ₃ ): δ 143.23, 141.32, 128.27, 127.07, 126.82, 66.29, 47.23, 35.71, 24.32. HRMS (ESI+, [M+H] ⁺ ): m/z 205.1693.

Step C: 1-(Aminomethyl)-N-benzylcyclopentylamine (1.70 g, 8.33 mmol) was dissolved in methanol (20 mL), then 50% aqueous 10% Pd/C (1.70 g) and concentrated Hydrochloric acid (0.15 mL). The gas in the reaction flask was replaced with hydrogen three times, and the reaction was stirred by heating in a hydrogen atmosphere, and the temperature of the reaction liquid was set to 60 °C. After 7 hours TLC showed the reaction was complete. The reaction flask was cooled to room temperature and filtered under reduced pressure. The filter cake was washed with 5 mL of methanol, and the filtrate was concentrated under reduced pressure to give a colorless viscous liquid, 1-(aminomethyl)cyclopentylamine (0.98 g).

¹ H-NMR (500 MHz, CDCl ₃ ): δ 2.63 (s, 2H), 1.74 - 1.79 (m, 2H), 1.42 - 1.63 (m, 6H). ¹³ C-NMR (500 MHz, CDCl ₃ ): δ 62.42, 52.19, 38.33, 24.19. MS (ESI+, [M+H] ⁺ ): m.

Step D: According to Example 1, N-((1-aminocyclopentyl)methyl)-3,5-dichloride was prepared by substituting 1-(aminomethyl)cyclopentylamine for ethylenediamine in step A. Pyridin-4-amine.

MS (ESI+, [M+H] ⁺ ): m/z 260.0.

Step E: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)) was obtained by the procedure used in Step B. Amino)methyl)cyclopentyl)urea.

^{1 H-NMR (500MHz, DMSO} -d6): δ8.47 (s, 1H), 8.16 (s, 2H), 7.66 (dd, J 1 = 2.5Hz, J 2 = 7.0Hz, 1H), 7.24 (t , J = 9.0 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 6.26 (s, 1H), 5.89 (t, J = 5.5 Hz, 1H), 3.91 (d, J = 5.0 Hz, 2H) ), 1.62 to 1.68 (m, 4H), 1.15 to 1.18 (m, 4H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 170.86, 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/z 430.9.

Example 43 1-(3-Chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)amino)methyl)cycloheptyl)urea

Step A: According to Example 42, substituting cycloheptanone for cyclopentanone in step A to obtain 1-(3-chloro-4-fluorophenyl)-3-(1-((3,5-di) Chloropyridin-4-yl)amino)methyl)cycloheptyl)urea.

^{1 H-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 = 5.5 Hz, 1H), 3.85 (d, J = 5.5 Hz, 2H), 1.23-1.61 (m, 12H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.01, 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 44 1-(3-Chloro-4-fluorophenyl)-3-(1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclohexyl)urea

Step A: According to Example 42, substituting cyclohexanone for cyclopentanone in step A to obtain 1-(3-chloro-4-fluorophenyl)-3-(1-((3,5-di) Chloropyridin-4-yl)amino)methyl)cyclohexyl)urea.

^{1 H-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 = 5 Hz, 1H), 6.02 (s, 1H), 5.88 (t, J = 5 Hz, 1H), 3.87 (d, J = 5 Hz, 2H), 2.02 (d, 12.5 Hz, 2H) , 1.58-1.21 (m, 8H); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.00, 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: 44.

Example 45 1-(3-Chloro-4-fluorophenyl)-3-((1RS,3RS)-3-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

Step A: According to Example 1, substituting trans-1,3-cyclohexanediamine for ethylenediamine in step A, (1RS, 3RS)-N ¹ -(3,5-dichloropyridine-4- Base) cyclohexane-1,3-diamine.

Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-((1RS,3RS)-3-((3,5-dichloropyridine)- 4-yl)amino)cyclohexyl)urea.

^{1 H-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 = 4.5 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 5.25 (d, J = 9.0 Hz, 1H), 4.27 (t, J = 4.5 Hz, 1H), 3.92 (s, 1H), 1.47-1.90 (m, 8H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.80, 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 46 1-(3,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)propyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - 4-(3)5-dichlorophenylamine-3-(3- (3,5-Dichloropyridin-4-yl)amino)propyl)urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.47,148.41,146.81,143.52,134.41 , 120.49, 117.48, 116.21, 42.40, 36.83, 31.86. MS (ESI+, [M+H] ⁺ ).

Example 47 1-(3,4-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)propyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - Preparation of 1-(3,4-dichlorophenyl)-3-(3-(4-yl)ethane-1,2-diamine, 3,4-dichloroaniline in place of 3,4-difluoroaniline (3,5-Dichloropyridin-4-yl)amino)propyl)urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.62, 148.42, 144.81, 141.22, 131.34, 130.85, 122.68, 119.25, 118.26, 117.48, 42.40, 36.79 Œ 31.91. MS (ESI+, [M+H] ⁺ ).

Example 48 1-(3-((3,5-Dichloropyridin-4-yl)amino)propyl)-3-(3,4,5-trichlorophenyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - Preparation of 1-(3-((3,5-dichloropyridine-4-) 4-yl)ethane-1,2-diamine, 3,4,5-trichloroaniline instead of 3,4-difluoroaniline Amino)propyl)-3-(3,4,5-trichlorophenyl)urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.38, 148.43, 146.82, 141.27, 133.11, 121.19, 118.16, 117.48, 42.40, 36.88, 31.70. MS (ESI+, [M+H] ⁺ ).

Example 49 1-(3-Chloro-5-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)propyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - Preparation of 1-(3-chloro-5-fluorophenyl)-3-(3) 4-yl)ethane-1,2-diamine, 3-fluoro-5-chloroaniline instead of 3,4-difluoroaniline -((3,5-Dichloropyridin-4-yl)amino)propyl)urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 163.79, 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.

Example 50 1-(3-Chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea

Step A: According to Example 1, substituting 1,3-diamino-2-hydroxypropane for ethylenediamine in step A to prepare 1-amino-3-((3,5-dichloropyridin-4-yl) Amino) propan-2-ol.

^{1 H-NMR (500MHz, DMSO} -d6): δ8.18 (s, 2H), 6.06 (br, 1H), 3.74 (m, 1H), 3.56 (m, 1H), 2.60 (m, 2H); 13 C-NMR (125 MHz, DMSO-d6): δ 148.33, 147.22, 117.59, 71.31, 49.14, 45.96. MS (ESI+, [M+H]+).

Step B: According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino) was obtained by the procedure used in Step B. )-2-hydroxypropyl)urea.

^{1 H-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); ¹³ C-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]+).

Example 51 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclobutyl)methyl) Urea

Step A: According to Example 38, in the step A, 1,3-dibromopropane was substituted for 1,4-dibromobutane to prepare 1-(3- Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyridin-4-yl)amino)methyl)cyclobutyl)methyl)urea.

^{1 H-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 = 6.0 Hz, 1H), 6.14 (t, J = 6.5 Hz, 1H), 3.72 (d, J = 6.5 Hz, 2H), 3.29 (d, J = 6.0 Hz, 2H), 1.83 to 1.85 (m, 2H), 1.72 (t, J = 8.0 Hz, 4H). ¹³ C-NMR (DMSO-d6, 125 MHz): δ 156.49, 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.

Example 52 1-(3,4-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methylpropyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) -2-methyl-1,3-diamine for N ¹ - (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-methylpropyl)urea.

^{1 H-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); ¹³ C-NMR ( 125 MHz, DMSO-d6): δ 155.85, 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] ⁺ ).

Example 53 1-(3,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methylpropyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) -2-methyl-1,3-diamine for N ¹ - (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-methylpropyl)urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.69, 148.48, 144.83, 143.47, 134.43, 130.87, 120.54, 117.33, 116.22, 117.52, 48.06, 42.49, 35.57, 30.63, 15.52. MS (ESI+, [M+H] ⁺ ).

Example 54 1-(3-Chloro-5-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methylpropyl)urea

Step A: According to Example 6, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) -2-methyl-1,3-diamine for N ¹ - (3, Preparation of 1-(3-chloro-5-fluorophenyl) 5-(2-chloropyridin-4-yl)ethane-1,2-diamine, 3-chloro-5-fluoroaniline instead of 3,4-difluoroaniline --3-(3-((3,5-Dichloropyridin-4-yl)amino)-2-methylpropyl)urea.

^{1 H-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); ¹³ C-NMR ( 125 MHz, DMSO-d6): δ 163.80, 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] ⁺ ).

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

Step A: Preparation of (R)-1-(3-chloro-4-fluorophenyl)-3- by substituting (R)-3-aminopiperidine for 3-aminopiperidine according to Example 37 (1-(3,5-Dichloropyridin-4-yl)piperidin-3-yl)urea.

^{1 H-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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.83, 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: Preparation of (R)-N-(3-chloro-4-fluorophenyl)-3- by substituting (R)-3-aminopiperidine for 3-aminopiperidine according to Example 36 ((3,5-Dichloropyridin-4-yl)amino)piperidine-1-carboxamide.

^{1 H-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). ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.34, 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 57 1-(3-Chloro-4-fluorophenyl)-3-(4-((3,5-dichloropyridin-4-yl)amino)pentan-2-yl)urea

Reaction process:

Step A: 2,4-Pentanediol (3.20g), dichloromethane (60mL), triethylamine (10mL) was added to a 250mL single-mouth bottle, and methanesulfonyl chloride (5.90mL) was slowly added dropwise under ice bath. The mixed solution of dichloromethane (20 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 h. The reaction mixture was washed with water (50 mL), saturated aqueous sodium hydrogen carbonate (50 mL), The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated.

Step B: 2,4-pentyldimethyl sulfonate (2.45 g) and dimethyl sulfoxide (50 mL) were added to a 250 mL single-necked flask, sodium azide (1.84 g) was added, and the reaction was carried out in an oil bath at 60 ° C for 3 h. The mixture was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Dry over anhydrous sodium sulfate, suction-filter, and the filtrate was dried to give 2,4-pentanediazide (1.60 g) oil.

Step C: 2,4-pentanediazide (1.60g), anhydrous methanol (60mL) was added to a 500mL single-mouth bottle, 10% Pd/C (0.30g) was added, hydrogen was replaced, and reacted at room temperature for 90h, diatom The mixture was filtered with suction, dried and evaporated, and then evaporated,

Step D: 2,4-diaminopentane (1.17g), trichloropyridine (597mg), triethylamine (0.5mL) was added to a 25mL single-mouth bottle, and reacted in a 70°C oil bath for 3 hours under nitrogen atmosphere. (2 * 100mL) after completion of the reaction was extracted with dichloromethane, dried over anhydrous sodium sulfate, suction filtered, the crude product was purified by column chromatography (dichloromethane: methanol = 10: 1) to give N ² - (3,5- Dichloropyridin-4-yl)pentane-2,4-diamine (100 mg) oil was used directly in the next step.

MS (ESI+, [M+H] ⁺ ).

Step E: Add N ² -(3,5-dichloropyridin-4-yl)pentane-2,4-diamine (100 mg), dichloromethane (5 mL) to a 50 mL single-necked bottle, add 4- A mixed solution of fluoro-3-chlorophenylisocyanate (68 mg) and dichloromethane (1 mL) was stirred at room temperature for 1 h. After the completion of the reaction, the crude product was obtained by column chromatography (PE: EA=2:1) to give 1-(3-chloro-4-fluorophenyl)-3-(4-((3,5-dichloropyridine)-4- Amino)pentan-2-yl)urea (25 mg, yield 15%).

^{1 H-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 = 8.5 Hz, 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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.00, 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] ⁺ ).

Example 58 1-(3,4-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea

Step A: In accordance with Example 6, substituting N ¹ -(3,5-dichloropyridin-4-yl)-2,2-dimethylpropane-1,3-diamine for N ¹ -( Preparation of 1-(3,4-dichlorophenyl) by replacing 3,4-difluoroaniline with 3,5-dichloropyridin-4-yl)ethane-1,2-diamine and 3,4-dichloroaniline --3-(3-((3,5-Dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea.

^{1 H-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); ¹³ C-NMR (125 MHz, DMSO -d6): δ 155.28, 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] ⁺ ).

Example 59 1-(3,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea

Step A: In accordance with Example 6, substituting N ¹ -(3,5-dichloropyridin-4-yl)-2,2-dimethylpropane-1,3-diamine for N ¹ -( Preparation of 1-(3,5-dichlorophenyl) by 3,5-dichloropyridin-4-yl)ethane-1,2-diamine, 3,5-dichloroaniline instead of 3,4-difluoroaniline --3-(3-((3,5-Dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea.

^{1 H-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=6.0 Hz, 1H), 6.20 (t, J=7.0 Hz, 1H), 3.51 (d, 2H), 3.05 (d, 2H), 0.83 (s, 6H); ¹³ C-NMR (125 MHz, DMSO) -d6): δ 156.14, 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] ⁺ ).

Example 60 1-(3,4,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl) Urea

Step A: In accordance with Example 6, substituting N ¹ -(3,5-dichloropyridin-4-yl)-2,2-dimethylpropane-1,3-diamine for N ¹ -( Preparation of 1-(3,4,5- by 3,5-dichloropyridin-4-yl)ethane-1,2-diamine, 3,4,5-trichloroaniline instead of 3,4-difluoroaniline Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea.

^{1 H-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 = 6.5 Hz, 1H), 3.51 (d, 2H), 3.05 (d, 2H), 0.83 (s, 6H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 156.06, 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] ⁺ ).

Example 61 1-(3-Chloro-5-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea

Step A: In accordance with Example 6, substituting N ¹ -(3,5-dichloropyridin-4-yl)-2,2-dimethylpropane-1,3-diamine for N ¹ -( Preparation of 1-(3,4,5-di) by 3,5-dichloropyridin-4-yl)ethane-1,2-diamine, 3-chloro-5-fluoroaniline instead of 3,4-difluoroaniline Chlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)urea.

^{1 H-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 = 6.0 Hz, 1H), 6.21 (t, J = 6.0 Hz, 1H), 3.51 (d, 2H), 3.05 (d, 2H), 0.83 (s, 6H); ¹³ C-NMR (125 MHz) , 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] ⁺ ).

Example 62 1-(3-Chloro-4-fluorophenyl)-3-((1-((3,5-dichloropyrimidin-4-yl)amino)methyl)cyclopropyl)methyl) Urea

Step A: Preparation of 1-(3-chloro-4-fluorophenyl)-3-(1) by substituting 1,1-cyclopropane dimethanol for 2,4-pentanediol according to Example 57 -(((3,5-Dichloropyrimidin-4-yl)amino)methyl)cyclopropyl)methyl)urea.

^{1 H-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 = 5.5 Hz, 1H), 6.06 (t, J = 6.0 Hz, 1H), 3.61 (d, 2H), 3.11 (d, 2H), 0.44-0.46 (m, 4H); ¹³ C-NMR (125 MHz, DMSO- D6): δ 156.15, 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]+).

Example 63 1-(3-Chloro-4-fluorophenyl)-3-((2R,4R)-4-((3,5-dichloropyrimidin-4-yl)amino)pentan-2-yl Urea

Step A: Preparation of 1-(3-chloro-4-fluorophenyl)-3-(() in step A by substituting (2S,4S)-pentanediol for 2,4-pentanediol according to Example 57. 2R,4R)-4-((3,5-Dichloropyrimidin-4-yl)amino)pentan-2-yl)urea.

^{1 H-NMR (500MHz, DMSO} -d6): δ8.41 (s, 1H), 7.67 (q, J 1 = 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); ¹³ C-NMR (125MHz, DMSO-d6): δ 154.71, 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] ⁺ ).

Example 64 3-Chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)-2-methylpropyl)-4-fluorobenzenesulfonamide

Reaction process:

Step A: To a 100 mL single-mouth bottle, N ¹ -(3,5-dichloropyridin-4-yl)2-methylpropyl-1,3-diamine (200 mg) was added, and 20 ml of dichloromethane was added thereto to stir and dissolve. A solution of 4-chloro-3-fluorobenzenesulfonyl chloride in dichloromethane (194.8 mg/5 ml) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1.5 h, washed with 0.5N NaOH solution, and the organic layer was purified by silica gel to give 4-chloro -N-(3-((3,5-Dichloropyridin-4-yl)amino)2-methylpropyl)-3-fluorophenylsulfonamide (140 mg).

^{1 H-NMR (500MHz, DMSO} -d 6): 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); ¹³ C-NMR (125MHz, DMSO-d ₆ ): 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 65 3-Chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)-4-fluorophenylsulfonamide

Step A: According to Example 64, step A using N ¹ -3,5- dichloro-pyridin-4-yl) -2,2-dimethyl-1,3-diamine for N ¹ - (3 ,5-Dichloropyridin-4-yl)2-methylpropyl-1,3-diamine, 3-chloro-N-(3-((3,5-dichloropyridin-4-yl)amino) )-2,2-Dimethylpropyl)-4-fluorophenylsulfonamide.

^{1 H-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 = 6.5 Hz, 1H), 3.57 (d, 2H), 2.64 (d, 2H), 0.81 (s, 6H); ¹³ C-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 66 3-Chloro-N-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)-4-fluorophenylsulfonamide

Step A: According to Example 64, step A using N ^¹ - N ¹ (3,5- dichloro-pyridin-4-yl) ethane-1,2-diamine alternatively - (3,5-dichloropyridine -4-yl)2-methylpropyl-1,3-diamine, 3-chloro-N-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)-4 -Fluorophenylsulfonamide.

^{1 H-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 = 6.5 Hz, 1H), 3.65 (q, J ₁ = 6.5 Hz, 6.5 Hz, 2H), 3.05 (q, J ₁ = 6.0 Hz, 6.0 Hz, 2H); ¹³ C-NMR (125 MHz, DMSO) -d6): δ 160.79, 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 67 3,4-Chloro-N-(2-((3,5-dichloropyridin-4-yl)amino)ethyl)benzenesulfonamide

Step A: According to Example 64, step A using N ^¹ - N ¹ (3,5- dichloro-pyridin-4-yl) ethane-1,2-diamine alternatively - (3,5-dichloropyridine -4-yl)2-methylpropyl-1,3-diamine, 3,4-dichlorobenzenesulfonyl chloride in place of 4-chloro-3-fluorobenzenesulfonyl chloride to prepare 3,4-chloro-N-( 2-((3,5-Dichloropyridin-4-yl)amino)ethyl)benzenesulfonamide.

^{1 H-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); 13 C-NMR (125MHz, DMSO-d6): δ 148.39, 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 68 3,4-Dichloro-N-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)benzenesulfonamide

Step A: According to Example 64, in the step A, N ¹ -(3,5-dichloropyridin-4-yl)-2,2-dimethylpropane-1,3-diamine was substituted for N ¹ -( 3,5-Dichloropyridin-4-yl)2-methylpropyl-1,3-diamine, 3,4-dichlorobenzenesulfonyl chloride in place of 4-chloro-3-fluorobenzenesulfonyl chloride, Preparation 3, 4-Dichloro-N-(3-((3,5-dichloropyridin-4-yl)amino)-2,2-dimethylpropyl)benzenesulfonamide.

^{1 H-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 = 6.5 Hz, 1H), 3.57 (d, J = 6.5 Hz, 2H), 2.64 (d, J = 6.5 Hz, 2H), 0.82 (s, 6H); ¹³ C-NMR (125 MHz , DMSO-d6): δ 148.57, 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 69 3,4-Dichloro-N-(3-((3,5-dichloropyridin-4-yl)amino)propyl)benzenesulfonamide

Step A: According to Example 64, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - 4-yl)2-methylpropyl-1,3-diamine, 3,4-dichlorobenzenesulfonyl chloride in place of 4-chloro-3-fluorobenzenesulfonyl chloride to prepare 3,4-dichloro-N-( 3-((3,5-Dichloropyridin-4-yl)amino)propyl)benzenesulfonamide.

^{1 H-NMR (500MHz, DMSO} -d 6): 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); ¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 148.40, 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 70 3-Chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-4-fluorobenzenesulfonamide

Step A: According to Example 64, step A using N ¹ - (3,5- dichloro-pyridin-4-yl) propane-1,3-diamine for N ¹ - (3,5- dichloropyridine - Preparation of 3-chloro-N-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-4- 4-yl) 2-methylpropyl-1,3-diamine Fluorobenzenesulfonamide.

^{1 H-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=12.0) Hz, 2H), 1.64 (quint, J = 7.0 Hz, 2H). ¹³ C-NMR (125 MHz, DMSO-d6): δ 160.81, 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 71 1-(3-Chlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea

Step A: Following the preparation of Example 6, substituting 1-amino-3-((3,5-dichloropyridin-4-yl)amino)propan-2-ol for N ¹ -(3,5-dichloro Preparation of 1-(3-chlorophenyl)-3-(3-((3,5-) by pyridin-4-yl)ethane-1,2-diamine, m-chloroaniline instead of 3,4-difluoroaniline Dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea.

^{1 H-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 = 7.5 Hz, 1H), 6.93 (d, J = 7 Hz, 1H), 6.32 (s, 1H), 5.98 (s, 1H), 5.27 (s, 1H), 3.72 to 3.67 (m, 2H), 3.55 ( t,1H), 3.22(t,1H), 3.15(t,1H); ¹³ C-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 72 1-(3,4-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea

Step A: Following the preparation of Example 6, substituting 1-amino-3-((3,5-dichloropyridin-4-yl)amino)propan-2-ol for N ¹ -(3,5-dichloro Preparation of 1-(3,4-dichlorophenyl)-3-(3) by using pyridin-4-yl)ethane-1,2-diamine, 3,4-dichloroaniline instead of 3,4-difluoroaniline -((3,5-Dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea.

^{1 H-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 = 2.5 Hz, 1H), 6.36 (t, J = 6 Hz, 1H), 5.97 (t, J = 6 Hz, 1H), 5.28 (d, J = 5 Hz, 1H), 3.75 to 3.66 (m) , 2H), 3.58 to 3.54 (m, 1H), 3.53 to 3.20 (m, 1H), 3.16 to 3.12 (m, 1H); ¹³ C-NMR (500 MHz, 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 73 1-(3-((3,5-Dichloropyridin-4-yl)amino)-2-hydroxypropyl)-3-(3,4,5-trichlorophenyl)urea

Step A: Following the preparation of Example 6, substituting 1-amino-3-((3,5-dichloropyridin-4-yl)amino)propan-2-ol for N ¹ -(3,5-dichloro Preparation of 1-(3-((3,5-dichloropyridine)-pyridin-4-yl)ethane-1,2-diamine, 3,4,5-trichloroaniline in place of 3,4-difluoroaniline 4-yl)amino)-2-hydroxypropyl)-3-(3,4,5-trichlorophenyl)urea.

^{1 H-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); 13 </ RTI>^<RTIgt; .

Example 74 1-(3,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea

Step A: Following the preparation of Example 6, substituting 1-amino-3-((3,5-dichloropyridin-4-yl)amino)propan-2-ol for N ¹ -(3,5-dichloro Pyridin-4-yl)ethane-1,2-diamine, 3,5-dichloroaniline was substituted for 3,4-difluoroaniline to prepare 1-(3,5-dichlorophenyl)-3-( 3-((3,5-Dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea.

^{1 H-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 to 3.68 (m, 2H), 3.55 (t, J = 7.5 Hz, 1H), 4.55 (t, 1H), 3.21 (t, 1H), 3.15 (t , 1H); ¹³ C-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 75 1-(3-Chloro-5-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea

Step A: Following the preparation of Example 6, substituting 1-amino-3-((3,5-dichloropyridin-4-yl)amino)propan-2-ol for N ¹ -(3,5-dichloro Pyridin-4-yl)ethane-1,2-diamine, 3-(3-chloro-5-chlorophenylamine) was substituted for 3,4-difluoroaniline to prepare 1-(3-chloro-5-fluorophenyl)-3 -(3-((3,5-Dichloropyridin-4-yl)amino)-2-hydroxypropyl)urea.

^{1 H-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 to 3.68 (m, 2H), 3.55 (t, 1H), 3.22 (t, 1H), 3.14 (t, 1H); ¹³ C-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 76 1-(3-Chloro-4-fluorophenyl)-3-((1R,3R)-3-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea

Referring to the preparation process of Example 1, 1-(3-) was prepared by using (1R,3R)-cyclohexanediamine, 3,4,5-trichloropyridine and 3-chloro-4-fluorophenyl isocyanate as starting materials. Chloro-4-fluorophenyl)-3-((1R,3R)-3-((3,5-dichloropyridin-4-yl)amino)cyclohexyl)urea.

^{1 H-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 = 4.5 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 5.25 (d, J = 9.0 Hz, 1H), 4.27 (t, J = 4.5 Hz, 1H), 3.92 (s, 1H), 1.47-1.90 (m, 8H). ¹³ C-NMR (125MHz, DMSO-d6): δ 154.80, 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 77 1-(3-Chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methoxypropyl)urea

Referring to the preparation procedure of Example 1, N ¹ -(3,5-dichloropyridin-4-yl)-2-methoxypropane-1,3-diamine (refer to Example 1, Step A, with 2- Substituting N ¹ -(3,5-dichloropyridin-4-yl)ethane-1,2-diamine by methoxypropane-1,3-diamine, 3,4,5-trichloropyridine Preparation of 1-(3-chloro-4-fluorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methoxypropyl)urea.

^{1 H-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 = 5.5 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 3.69 (t, J = 6.0 Hz, 2H), 3.41-3.45 (m, 1H), 3.23-30(m,5H); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.84, 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 78 1-(3,5-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methoxypropyl)urea

Referring to the preparation procedure of Example 6, N ¹ -(3,5-dichloropyridin-4-yl)-2-methoxypropane-1,3-diamine was substituted for N ¹ -(3,5-dichloro Pyridin-4-yl)ethane-1,2-diamine, 3,5-dichloroaniline was substituted for 3,4-difluoroaniline to prepare 1-(3,5-dichlorophenyl)-3-( 3-((3,5-Dichloropyridin-4-yl)amino)-2-methoxypropyl)urea.

^{1 H-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) ¹³ C-NMR (125 MHz, DMSO-d6): δ 155.50, 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 79 1-(3,4-Dichlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methoxypropyl)urea

Step A: Preparation of The procedure of Example 6 with reference to embodiments, with N ¹ - (3,5- dichloro-pyridin-4-yl) -2-methoxy-1,3-diamine for N ¹ - (3,5 -Dichloropyridin-4-yl)ethane-1,2-diamine, replacing 3,4-difluoroaniline with 3,4-dichloroaniline to prepare 1-(3,4-dichlorophenyl)- 3-(3-((3,5-Dichloropyridin-4-yl)amino)-2-methoxypropyl)urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.63, 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 80 1-(3-((3,5-Dichloropyridin-4-yl)amino)-2-methoxypropyl)-3-(3,4,5-trichlorophenyl)urea

Referring to the preparation procedure of Example 6, N ¹ -(3,5-dichloropyridin-4-yl)-2-methoxypropane-1,3-diamine was substituted for N ¹ -(3,5-dichloro Pyridin-4-yl)ethane-1,2-diamine, 3,4-difluoroaniline was replaced by 3,4-difluoroaniline to prepare 1-(3-((3,5-dichloropyridine) 4-yl)amino)-2-methoxypropyl)-3-(3,4,5-trichlorophenyl)urea.

¹ H-NMR (500 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.21. (s, 2H), 7.67 (s, 2H), 6.52 (s, 1H), 5.96 (s, 1H), 3.68 (t, J = 5.5 Hz, 2H), 3.44 (t, J = 5.0 Hz, 1H), 3.21-3.31 (m, 5H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 174.83, 148.43, 147.22, 133.17, 118.14, 79.48, 57.36, 45.82. HRMS (ESI+, [M+H] ⁺ ) m/z: 470.9782.

Example 81 1-(3-Chlorophenyl)-3-(3-((3,5-dichloropyridin-4-yl)amino)-2-methoxypropyl)urea

Referring to the preparation method of Example 6, N ¹ -(3,5-dichloropyridin-4-yl)-2-methoxypropane-1,3-diamine was used instead of N ¹ -(3,5-dichloro Pyridin-4-yl)ethane-1,2-diamine, replacing 3,4-difluoroaniline with m-chloroaniline to prepare 1-(3-chlorophenyl)-3-(3-((3,5) -Dichloropyridin-4-yl)amino)-2-methoxypropyl)urea.

^{1 H-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 = 8.0 Hz, 1H), 6.34 (s, 1H), 5.99 (s, 1H), 3.69 (t, J = 5.5 Hz, 2H), 3.43 (s, 1H), 3.22-3.31 (m, 5H); ¹³ C-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 82 1-(3-Chloro-4-fluorophenyl)-3-((3-(((3)5-dichloropyridin-4-yl)amino)methyl)methyloxy)propyl-3- Methyl)urea

Reaction process

Step A: Add tribromopentanol (8g), methanol (40ml), potassium hydroxide (1.38g) to a 250ml single-mouth bottle, heat to 70 ° C for 4h, and filter to dry 3,3-dibromomethyl Propylene oxide (4.48 g, 74.7%) was a colorless liquid.

Step B: Add 3,3-dibromomethyl propylene oxide (4g), DMSO (30ml), sodium azide (2.5g) to a 250ml single-mouth bottle, heat to 60 ° C, react for 3h, add water under ice bath The reaction was quenched with EtOAc (EtOAc)EtOAc.EtOAc.

Step C: To a 250 ml single-mouth bottle, 3,3-diazide methyl propylene oxide (2.5 g), methanol (30 ml), palladium carbon (200 mg), reacted at room temperature for 6 h, suction filtration, and the filtrate was dried to give 3 3-Diaminomethyl propylene oxide (1.5 g, 88.2%) was a colorless liquid.

Step D: Add 3,3-diaminomethyl propylene oxide (1.2g), 3,4,5-trichloropyridine (3g) to a 100ml single-mouth bottle, plus Heat to 70 ° C, reaction for 6 h, add dichloromethane, and purify by column chromatography to obtain N-((3-(aminomethyl) epoxide-3-yl)methyl)-3,5-dichloropyridine-4 -Amine (250 mg, 14.7%).

Step E: Add N-((3-(aminomethyl) propylene oxide-3-yl)methyl)-3,5-dichloropyridin-4-amine (220 mg) to a 100 mL vial, methylene chloride (20ml), 3-chloro-4-fluorophenylisocyanate (216mg), reacted for 6h, purified by column chromatography to give 1-(3-chloro-4-fluorophenyl)-3-((3-(((3) 5-Dichloropyridin-4-yl)amino)methyl)epoxypropyl-3-yl)methyl)urea (150 mg).

^{1 H-NMR (500MHz, DMSO} -d 6): 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); ¹³ C-NMR (125 MHz, DMSO-d ₆ ): 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

Reaction process:

Referring to the preparation method of Example 6, respectively, (R)-3,5-dichloro-N-(piperidin-3-yl)pyridin-4-amine and (R)-1-(3,5-dichloro Pyridin-4-yl)piperidin-3-amine (refer to Step A of Example 1, using (R)-3-aminopiperidine, 3,4,5-trichloroaniline), m-chloroaniline as a reaction material The crude product was subjected to column chromatography (PE: EA=2:1) to obtain two isomers, which eluted first as compound 83-II, (R)-1-(3-chlorophenyl)-3. -(1-(3,5-Dichloropyridin-4-yl)piperidin-3-yl)urea, followed by elution of compound 83-I, (R)-N-(3-chlorophenyl)- 3-((3,5-Dichloropyridin-4-yl)amino)piperidine-1-carboxamide.

^{83-I: 1 H-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 = 8.0 Hz, 1H), 5.49 (d, J = 9.0 Hz, 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). ¹³ C-NMR (125 MHz , DMSO-d6): δ 155.31, 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: 1 H-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=8.5 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.27 (d, J=7.5 Hz, 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). ¹³ C- NMR (125MHz, DMSO-d6): δ 154.75, 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, respectively, (R)-3,5-dichloro-N-(piperidin-3-yl)pyridin-4-amine and (R)-1-(3,5 -Dichloropyridin-4-yl)piperidin-3-amine, 3,4,5-trifluoroaniline as the starting material for the reaction, the crude product was subjected to column chromatography (PE: EA = 2:1) to obtain two isomers The compound 84-II is eluted first, ie (R)-1-(1-(3,5-dichloropyridin-4-yl)piperidin-3-yl)-3-(3,4,5 -Trifluorophenyl)urea, followed by elution of compound 84-oxime, ie (R)-3-((3,5-dichloropyridin-4-yl)amino)-N-(3,4,5- Trifluorophenyl) piperidine-1-carboxamide.

^{84-Ι: 1 H-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). ¹³ C-NMR (125MHz, DMSO-d6): δ 154.94, 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: 1 H-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). ¹³ C-NMR (125MHz, DMSO-d6): δ 154.63, 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: Prepared according to the preparation procedure of Example 1, using (R)-pyrrolidin-3-amine, 3,4,5-trichloropyridine, 3-chloro-4-fluorophenyl isocyanate as a starting material (R) )-1-(3-chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)pyrrole Alkyl-3-yl)urea.

^{1 H-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=6.0 Hz, 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). ¹³ C-NMR (125MHz, DMSO-d6): δ 155.26, 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: According to the preparation process of Example 1, (S)-pyrrolidin-3-amine, 3,4,5-trichloropyridine, 3-chloro-4-fluorophenyl isocyanate was used as a starting material to prepare (S --1-(3-Chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)pyrrolidin-3-yl)urea.

^{1 H-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=5.5 Hz, 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). ¹³ C-NMR (125MHz, DMSO-d6): δ 155.26, 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: Prepared according to the preparation procedure of Example 1, using (R)-3-aminopiperidine, 3,4,5-trichloropyridine, 3-cyano-4-fluorophenyl isocyanate as a starting material (R) --1-(3-Cyano-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)piperidin-3-yl)urea.

^{1 H-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=8.0 Hz, 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). ¹³ C-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 88 1-(3-Chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)azetidin-3-yl)urea

Step A: Referring to the preparation process of Example 1, a 1-(1) was prepared using azetidin-3-amine, 3,4,5-trichloropyridine and 3-chloro-4-fluorophenyl isocyanate as starting materials. 3-Chloro-4-fluorophenyl)-3-(1-(3,5-dichloropyridin-4-yl)azetidin-3-yl)urea.

^{1 H-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); ¹³ C-NMR (125MHz, DMSO-d6): δ 155.02, 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

Reaction process:

Step A: Preparation of (S)-N-(3-chloro-4-fluorophenyl)-3- by substituting (S)-3-aminopiperidine for 3-aminopiperidine according to Example 36 ((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).

Compound 89-I: ¹ H-NMR (500MHz, DMSO-d6): δ 8.74 (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 = 9.0 Hz, 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 = 8.5 Hz, 1H), 1.63-1.67 (m, 2H), 1.48-1.49 (m, 1H); ¹³ C-NMR (125 MHz, DMSO-d6): δ 155. 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.

Compound ^{89-II: 1 H-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 = 8.0 Hz, 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) ¹³ C-NMR (125 MHz, DMSO-d6): δ 154.83, 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 HBV nucleocapsid protein assembly was evaluated by a capsid protein fluorescence quenching assay designed by the assembly domain consisting of the N-terminal 149 amino acids of the HBV core protein.

Materials and instruments

Compound: The compound of the example is a test sample, dissolved in 100% DMSO, and prepared into a 20 mM solution, and stored in a nitrogen cabinet. The compound of the following formula is a reference compound:

HBV core protein: HBV core protein C150 (aa1-150, C49A, C61A, C107A and 150C) was expressed and purified from E. coli by Shanghai WuXi PharmaTech Development Co., Ltd.

Reagents: fluorescent dye (BoDIPY-FL) (Invitrogen), dextran gel (source leaf organism).

Instruments: Molecule Device (Model SpectraMax M2); 5 ml Hitrap Desalting Column (GE Biosciences, 17-1408-1); Nanodrop (Thermo, Nanodrop 2000).

method

HBV core protein (C150) fluorescent label

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

To each tube of desalted C150 protein, 20 μL of 50 mM BoDIPY-FL fluorescent dye was added and mixed uniformly, and incubated overnight at 4 ° C in the dark.

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

Calculate C150 labeling efficiency: concentration of fluorescent label [BoDIPY-FL] = A50478,000M-1

Concentration of fluorescently labeled protein [C150Bo] = (A280-[BoDIPY-FL]x1300M-1) 60,900M-1

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

C150 protein assembly experiment:

Compound dilution: 3 μL of 20 mM compound mother liquor was added to 7 μL of DMSO, then 4 μL of this solution was taken to 36 μL of 50 mM HEPES, and then 8 concentrations were further serially diluted 3 times with 10% DMSO/50 mM HEPES.

The C150Bo was diluted to 2 μM with 50 m M HEPES.

37.5 μL of C150Bo and 2.5 μL of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes.

10 μL of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM. Control wells were assembled with 0% protein, 10 μL of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM; 100% protein was assembled into control wells, and 10 μL of 5 M NaCl/50 mM HEPES was added, and the final concentration of NaCl was 1 M. The final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 μM, and the final concentration of C150Bo was 1.5 μM.

Incubate for 1 hour at room temperature.

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

Data analysis: protein assembly % = [1 - (sample fluorescence value - 1 M NaCl fluorescence value) / (0 M NaCl fluorescence value - 1 M NaCl fluorescence value)] × 100.

The EC50 value is calculated by the prism software, and the equation is sigmoidal dose-response(variable slope)equation

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

X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape.

Experimental result

Table 2. Results of inhibitory activity of nucleocapsid protein assembly

化合物Compound	EC50EC50	化合物Compound	EC50EC50	化合物Compound	EC50EC50
实施例1Example 1	AA	实施例13Example 13	BB	实施例36Example 36	AA
实施例2Example 2	AA	实施例15Example 15	AA	实施例37Example 37	AA
实施例3Example 3	CC	实施例22Example 22	BB	实施例38Example 38	BB
实施例6Example 6	AA	实施例23Example 23	BB	实施例39Example 39	AA
实施例7Example 7	AA	实施例25Example 25	AA	实施例40Example 40	AA
实施例11Example 11	BB	实施例26Example 26	AA	实施例42Example 42	BB
实施例12Example 12	AA	实施例32Example 32	CC	对照品化合物Reference compound	CC

Note: 1 μM ≤ A ≤ 10 μM; 10 μM < B ≤ 20 μM; 20 μM < C ≤ 30 μM.

Experimental Example 2: HepG2.2.15 cytotoxic activity

Experimental Materials

cell

HepG2.2.15 cells were provided by WuXi PharmaTech.

Compound

Test compound: The compound of the present application was formulated into a 20 mM mother liquor temporary nitrogen cabinet using dimethyl sulfoxide (DMSO).

Control compound:

Primary reagent

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

experimental method

Compound dilution: The compounds used in the anti-HBV activity test and the cytotoxicity test were diluted 5 times in series, and 8 samples with different concentration values were used. The initial concentration of the cytotoxicity test and the control compound was 100 μM, the initial concentration of the anti-HBV activity test was 10 μM, and the final concentration of DMSO was 0.5%.

In vitro anti-HBV activity assay: HepG2.2.15 cells (4 x 10 ⁴ cells/well) were seeded into 96-well plates and incubated overnight at 37 ° C, 5% CO ₂ . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.

On the eighth day, the cell culture supernatant in the well plate was collected, the HBV DNA in the supernatant was extracted, and the HBV DNA content in the supernatant of HepG2.2.15 was detected by qPCR.

Cytotoxicity assay: HepG2.2.15 cells (4 x 10 ⁴ cells/well) were seeded into 96-well plates and incubated overnight at 37 ° C, 5% CO ₂ . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added. On the eighth day, Cell-titer Blue reagent was added to each well of the culture plate, and the fluorescence value of each well was measured by a microplate reader.

analyze data:

Calculate the percent inhibition using the following formula:

%Inh.=[(DMSO control PCR fluorescence value - sample PCR fluorescence value) / DMSO control PCR fluorescence value] * 100%

Calculate the percentage of cell activity using the following formula:

%Cell viability=[(sample fluorescence value - medium fluorescence value) / (DMSO fluorescence value - medium fluorescence value)] * 100%

The EC50 and CC50 values of the compounds were calculated using GraphPad Prism software, and the equation is the S-type quantity-effect (variable slope) equation:

Y = minimum suppression rate + (maximum inhibition rate - minimum inhibition rate) / (1 + 10 ^ ((LogIC50 - X) * slope))

X represents the concentration logarithm and Y represents the effector value.

Y starts from the bottom and is fitted to the top with an S shape.

The experimental results are shown in Table 3.

Table 3. HepG2.2.15 cytotoxicity (CC50), anti-HBV activity test (EC50) results

化合物编号Compound number	EC50EC50	CC50CC50	化合物编号Compound number	EC50EC50	CC50CC50
11	A++A++	++++++	55-R(37)55-R(37)	A++A++	++++
66	A++A++	++++++	56-R(36)56-R(36)	A+A+	++++++
77	A++A++	++++++	7070	AA	++++++
1111	AA	++++++	7171	A+A+	++++++
1313	AA	++++++	7272	AA	++++++
22twenty two	A+A+	++++++	7575	A+A+	++++
23twenty three	A+A+	++++++	7676	A+A+	++
2525	A++A++	++	8282	AA	++++++
3232	AA	++++++	83-II83-II	A+A+	++++
3636	A++A++	++	84-II84-II	A+A+	++++
3737	A++A++	++	8989	AA	++++++
5050	A+A+	++++++	对照品化合物Reference compound	A+A+	++++

Note: EC50: A++<0.4μM; 0.4μM≤A+<1μM; 1μM≤A≤10μM

CC50: + < 10 μM; 10 μM ≤ ++ < 30 μM; 30 μM ≤ +++.

Claims

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

among them,

Part A is selected from
R a is selected from the group consisting of halogen, nitroso, nitro, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, hydroxy, C 1-6 alkyl-oxy, C 3-6 cycloalkyl -oxy, fluorenyl, C 1-6 alkyl-thio, C 3-6 cycloalkyl-thio, amino, C 1-3 alkyl-amino, (C 1-3 alkyl) 2 -amino or C 1-3 alkyl-sulfonyl group, said C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 alkyl-oxy group, C 3-6 cycloalkyl-oxy group, C 1 -6- alkyl-thio, C 3-6 cycloalkyl-thio, C 1-3 alkyl-amino, (C 1-3 alkyl) 2 -amino or C 1-3 alkyl-sulfonyl Optionally, substituted with 1 to 3 R b , and R b is selected from halogen, nitroso, nitro, cyano, hydroxy, decyl, amino, methoxy, cyclopropyl or methylsulfonyl;

Part M is selected from
Z is selected from C or Si, n is selected from 0 or 1, and R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b and R 5 are each independently selected from H, C 1-3 alkyl , hydroxy-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, 1 to 3 halogen-substituted C 1-3 alkyl, hydroxy, C 1-3 alkoxy, oxygen a substituent of thio, thio, amino, cyano, carboxy or halo, or optionally two of R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b or R 5 Forming a 3- to 8-membered saturated ring, and the ring atom of the 3- to 8-membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si or B, and the 3 to 8 membered saturated ring Substituted by m R 6 , the m is selected from 0 to 3, and the R 6 is selected from C 1-3 alkyl, hydroxy-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 An alkyl group, 1 to 3 halogen-substituted C 1-3 alkyl groups, a C 1-4 alkoxy group, a hydroxyl group, an oxo group, a thio group, an amino group, a cyano group, a carboxyl group, a halogen, a C 1-6 alkoxy group, Phenyl or benzyl, provided that R 1 and R 5 are not joined to form a 3 to 8 membered saturated ring;

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

Part D is selected from a 5- to 10-membered aryl group or a 5- to 10-membered heteroaryl group having 1 to 3 atoms selected from N, O, S, Si or B atoms, and the 5 to 10 membered aryl group or 5 to 10 members heteroaryl optionally substituted with 1 to 3 R d, R d is selected from the halo, nitroso, nitro, cyano, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, Hydroxy-C 1-6 alkyl, 1 to 3 halogen-substituted C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, decyl, C 1-6 alkylthio, amino C 1-3 alkyl-amino, (C 1-3 alkyl) 2 -amino or C 1-3 alkyl-sulfonyl.
The compound according to claim 1, its pharmaceutically stereoisomer or a pharmaceutically acceptable salt thereof, wherein R a is selected from F, Cl, Br, nitroso, nitro, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, hydroxy, C 1-4 alkyl-oxy, C 3-6 cycloalkyl-oxy, decyl, C 1-4 alkyl-thio, C 3-6 cycloalkyl-thio, amino, C 1-3 alkyl-amino, (C 1-3 alkyl) 2 -amino or C 1-3 alkyl-sulfonyl, said C 1-4 alkane , C 3-6 cycloalkyl, C 1-4 alkyl-oxy, C 3-6 cycloalkyl-oxy, C 1-4 alkyl-thio, C 3-6 cycloalkyl-sulfur The group, C 1-3 alkyl-amino, (C 1-3 alkyl) 2 -amino or C 1-3 alkyl-sulfonyl is optionally substituted by 1 to 3 R b , and said R b is selected from F, Cl, Br, nitroso, nitro, cyano, hydroxy, decyl, amino, methoxy, cyclopropyl or methylsulfonyl; preferably, said R a is selected from the group consisting of F, Cl, Br, sub Nitro, nitro, cyano, methyl, ethyl, propyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropyloxy, decyl, methylthio, cyclopropylthio, Amino, methylamino, ethylamino, dimethylamino, A An acyl group, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, hydroxyethyl, methoxyethyl or cyclopropylmethyl.
The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2, wherein the A moiety is selected from the group consisting of
Preferably, the A moiety is selected from
More preferably, the A moiety is selected from
The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, Methoxymethyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, Carboxyl, F, Cl, Br, methoxycarbonyl, phenyl or benzyl; preferably, said R 6 is selected from the group consisting of methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.
The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 4, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b and R 5 are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, monofluoromethyl, Difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R 1 , R 2a And two substituents of R 2b , R 3a , R 3b , R 4a , R 4b or R 5 are bonded to form a 3-8 membered saturated ring, and the ring atom of the 3 to 8 membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si or B, said 3 to 8 membered saturated ring being substituted by m R 6 ; preferably, said R 1 and R 5 are each independently selected from H Or methyl, said R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxy. Methyl, methoxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, Hydroxy, methoxy, oxo, amino, cyano, carboxy, F, Cl or Br, or, optionally, R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b or R 5 The two substituents are joined to form a 3 to 8 membered saturated ring, and the ring atom of the 3 to 8 membered saturated ring optionally includes 1 to 3 hetero atoms selected from O, N, S, Si or B. The 3- to 8-membered saturated ring is substituted by m R 6 .
The compound according to any one of claims 1, 4 or 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 3- to 8-membered saturated ring is a monocyclic structure.
The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 4 to 6, wherein the M moiety is selected from the group consisting of

Preferably, the M moiety is selected from
The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the L moiety is selected from the group consisting of
X is selected from O or S, and W is selected from a single bond or
The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein said R d is selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, hydroxy-C 1-4 alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, A Oxy-C 1-4 alkyl, decyl, C 1-4 alkylthio, amino, C 1-3 alkyl-amino, dimethylamino, diethylamino, dipropylamino, methyl ( Ethyl)amino or C 1-3 alkyl-sulfonyl; preferably, said R d is selected from the group consisting of F, Cl, Br, nitroso, nitro, cyano, methyl, ethyl, propyl, hydroxy , methoxy, ethoxy, hydroxymethyl, hydroxyethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, methoxyethyl, decyl, A Alkylthio, amino, methylamino, ethylamino, dimethylamino or methylsulfonyl.
The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 9, wherein the D moiety is selected from the group consisting of

Preferably, the D portion is selected from

More preferably, the D portion is selected from
A compound according to any one of claims 1 to 10, which is a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts Accepted carrier or excipient.
A compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for use in the preparation of a composition for the treatment of capsid protein assembly inhibition Use in medicines for diseases.
The use according to claim 13, characterized in that the disease which benefits from inhibition of capsid protein assembly refers to a disease caused by hepatitis B virus infection.
The use according to claim 14, wherein the disease which benefits from inhibition of capsid protein assembly refers to a liver disease caused by hepatitis B virus infection.