WO2018050110A1 - Nouvel inhibiteur d'assemblage de protéine capsidique - Google Patents

Nouvel inhibiteur d'assemblage de protéine capsidique Download PDF

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WO2018050110A1
WO2018050110A1 PCT/CN2017/102054 CN2017102054W WO2018050110A1 WO 2018050110 A1 WO2018050110 A1 WO 2018050110A1 CN 2017102054 W CN2017102054 W CN 2017102054W WO 2018050110 A1 WO2018050110 A1 WO 2018050110A1
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Prior art keywords
amino
alkyl
group
nmr
dmso
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PCT/CN2017/102054
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English (en)
Chinese (zh)
Inventor
张寅生
敖汪伟
李元
沈杭州
柳英帅
李东旭
刘保民
王辉
陆鹏
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正大天晴药业集团股份有限公司
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Priority to CN201780055155.7A priority Critical patent/CN109790123B/zh
Publication of WO2018050110A1 publication Critical patent/WO2018050110A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • cccDNA covalently closed circular DNA
  • 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.
  • HBV New targets such as viral capsid protein formation or assembly inhibitors and cccDNA inhibitors and interferon-stimulated gene activators, etc.
  • core inhibitors such as viral capsid protein formation or assembly inhibitors and cccDNA inhibitors and interferon-stimulated gene activators, etc.
  • 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.
  • 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.
  • the N-terminal 149 amino acid residues (Cp149) constituting the core protein dimerization motif and the assembly domain have no human protein homologous sequences.
  • capsid protein assembly inhibitors 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.
  • the invention provides a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • 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 - - sulfony
  • 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 member
  • 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.
  • compositions 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.
  • 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.
  • the invention provides a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • 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 - - sulfony
  • 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 member
  • 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 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 optional
  • 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.
  • the A portion is preferably selected from The R a as defined above.
  • the A portion is preferably selected from The R a as defined above.
  • the A portion is more preferably self
  • 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.
  • the R 6 is preferably selected from the group consisting of methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl.
  • 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
  • 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 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.
  • the 3- to 8-membered saturated ring is a single ring structure.
  • 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.
  • R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b or R 5 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 .
  • 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.
  • the M portion is preferably selected from
  • the L moiety is selected from X is selected from O or S, and W is selected from a single bond or
  • 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.
  • 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.
  • 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.
  • the D portion is preferably selected from Said R d is as defined above.
  • the D portion is more preferably self Said R d is as defined above.
  • 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:
  • 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
  • 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.
  • 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.
  • the A 2 moiety is selected from Said R a is as defined above.
  • the A 2 moiety is preferably selected from The R a as defined above.
  • the A 2 moiety is preferably selected from
  • 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.
  • 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.
  • 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.
  • the M 2 moiety is preferably selected from
  • 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.
  • D 2 is selected from Said R d is as defined above.
  • 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:
  • Part A 3 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 3 is selected from n is selected from 0 or 1
  • Z is selected from C or Si
  • 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.
  • 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.
  • the A 3 moiety is selected from Said R a is as defined above.
  • the A 3 moiety is preferably selected from The R a as defined above.
  • the A 3 moiety is preferably selected from
  • 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.
  • R 6 is preferably selected from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl. .
  • 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.
  • R 1 and R 5 are each independently selected from H or methyl
  • 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.
  • the M 3 moiety is selected from The R 1 , R 3a , R 3b , R 5 , m and R 6 are as defined above.
  • the M 3 moiety is preferably selected from
  • 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.
  • D 3 is selected from Said R d is as defined above.
  • 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:
  • Part A 4 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 4 is selected from n is selected from 0 or 1
  • Z is selected from C or Si
  • 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.
  • 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 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.
  • 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.
  • the A 4 moiety is selected from Said R a is as defined above.
  • the A 4 moiety is preferably selected from The R a as defined above.
  • the A 4 moiety is preferably selected from
  • 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.
  • R 6 is preferably selected from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl. .
  • 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
  • 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
  • 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.
  • the M 4 moiety is preferably selected from
  • 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.
  • D 4 is selected from Said R d is as defined above.
  • 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:
  • Part A 5 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 5 is selected from n is selected from 0 or 1
  • Z is selected from C or Si
  • 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,
  • 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 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.
  • 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.
  • the A 5 moiety is selected from Said R a is as defined above.
  • the A 5 moiety is preferably selected from The R a as defined above.
  • the A 5 moiety is preferably selected from
  • 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.
  • the R 6 is preferably selected from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl. .
  • 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-,
  • 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
  • the M 5 moiety is selected from The R 4a , R 4b , R 5 , m and R 6 are as defined above.
  • the M 5 moiety is preferably selected from
  • 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.
  • D 5 is selected from Said R d is as defined above.
  • 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:
  • Part A 6 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 6 is selected from n is selected from 0 or 1
  • Z is selected from C or Si
  • 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,
  • 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 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.
  • 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.
  • the A 6 moiety is selected from Said R a is as defined above.
  • the A 6 moiety is preferably selected from The R a as defined above.
  • the A 6 moiety is preferably selected from
  • 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.
  • R 6 is preferably selected from methyl, hydroxymethyl, hydroxy, methoxy, oxo, amino, F, Cl, Br or benzyl. .
  • 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-,
  • 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
  • the M 6 moiety is selected from The R 1 , R 2a , R 2b , m and R 6 are as defined above.
  • the M 6 moiety is preferably selected from
  • 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.
  • D 6 is selected from Said R d is as defined above.
  • D 6 is preferably selected from
  • 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.
  • compositions 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.
  • 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.
  • the disease that benefits from inhibition of capsid protein assembly refers to a disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the disease that benefits from inhibition of capsid protein assembly refers to a liver disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • 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.
  • compound as used herein includes all stereoisomeric forms, geometric isomer forms, tautomeric forms, and isotopic forms of the compounds.
  • 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.
  • 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.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • C m to n or C mn means that m to n carbon atoms are present in the moiety.
  • C 1-6 alkyl means that the alkyl group has from 1 to 6 carbon atoms.
  • 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.
  • 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.
  • any variable e.g., R
  • its definition in each case is independent.
  • the group may optionally be substituted at most by three R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • halogen means fluoro, chloro, bromo or iodo.
  • hydroxy refers to an -OH group.
  • mercapto refers to a -SH group.
  • cyano refers to a -CN group.
  • nitroso refers to a -NO group.
  • nitro refers to a -NO 2 group.
  • amino means -NH 2 group.
  • 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.
  • C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • 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-.
  • alkyl acyl refers to a -CO-alkyl group.
  • alkyl sulfonyl refers to -SO 2 - alkyl group.
  • alkoxy refers to an -O-alkyl group, for example " C1-6 alkyl-oxy” includes methoxy, ethoxy, propoxy, butoxy , pentyloxy, hexyloxy.
  • cycloalkoxy refers to a -O-cycloalkyl group, for example "C 3-6 alkyl-oxy” includes cyclopropyloxy, cyclobutyloxy, Cyclopentyloxy, cyclohexyloxy.
  • alkylthio or “alkylthio” refers to a -S-alkyl group.
  • cycloalkylthio or "cycloalkylthio” refers to a -S-cycloalkyl group.
  • 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.
  • 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.
  • 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.
  • C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • 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).
  • 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.
  • the aryl group may be a monocyclic ring or a fused ring.
  • at least one ring structure in the fused ring is a carbocyclic ring having a fully conjugated ⁇ -electron system
  • other ring structures in the fused ring may be A fully conjugated ⁇ -electron system, either saturated or partially saturated, or containing or not containing heteroatoms.
  • structural groups "10-membered aryl" include
  • 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 ⁇ -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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present 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.
  • 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.
  • a structural unit including but not limited to Or an enantiomerically or diastereomeric enriched mixture or racemic mixture.
  • “1SR, 2SR” means a mixture of two isomers of “1S, 2S” and “1R, 2R”
  • “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”
  • “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.
  • 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.
  • 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.
  • 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).
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • 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.
  • 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 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.
  • broad-spectrum methods such as nuclear magnetic resonance spectroscopy (eg 1H or 13C), infrared spectroscopy, spectrophotometry (eg UV-visible) or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • 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.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "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.
  • 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.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • 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.
  • terapéuticaally effective amount 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.
  • a disease such as preventing a disease, disorder, or condition in an
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • DIPEA N,N-diisopropylethylamine
  • PE petroleum ether
  • HATU 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate
  • HEPES 4-hydroxyethylpiperazineethanesulfonic acid.
  • the instrument used for mass spectrometry is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.
  • 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.
  • 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%).
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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, evaporated.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step A According to Example 6, 1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-3-(3,4-difluorophenyl)urea was prepared.
  • Step A According to Example 6, 1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-3-(3-chlorophenyl)urea was prepared.
  • Step A According to Example 6, 1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-3-(3-fluorophenyl)urea was prepared.
  • Step A According to Example 6, 1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-3-(4-chloro-3-fluorophenyl)urea was prepared.
  • Step A According to Example 6, 1-(3-((3,5-dichloropyridin-4-yl)amino)propyl)-3-(3,4,5-trifluorophenyl)urea was prepared.
  • Step A Preparation of 1-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl) according to Example 6. -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. .
  • Step A Preparation of 1-(3-chloro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino)cyclohexyl) according to Example 6. 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.
  • Step A According to Example 6, 1-(3,4,5-trifluoro-phenyl)-3-((1SR,2SR)-2-((3,5-dichloropyridin-4-yl)amino Cyclohexyl)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 .
  • 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.
  • 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.
  • Step B According to Example 1, 3-(3-chloro-4-fluorophenyl)-1-(2-((3,5-dichloropyridin-4-yl)amino). Ethyl)-1-methylurea.
  • 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 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%).
  • 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 .
  • 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 byjjjjjjjj
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Step D According to Example 1, 1-(3-chloro-4-fluorophenyl)-3-((1-(((3,5-) Dichloropyridin-4-yl)amino)methyl)cyclopentyl)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.
  • Step B According to Example 38, (tetrahydro-2H-pyran-4,4-diyl)dimethylamine was prepared by the method of Step B.
  • 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.
  • 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.
  • Step A According to Example 38, cyclohexane-1,1-dicarbonitrile was prepared by substituting 1,5-dibromopentane for 1,4-dibromobutane in step A.
  • 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.
  • 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.
  • 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.
  • 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.
  • 1-(benzylamino)cyclopentanenitrile 4.0 g, 20 mmol
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-(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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • Example 6 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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 C150 (aa1-150, C49A, C61A, C107A and 150C) was expressed and purified from E. coli by Shanghai WuXi PharmaTech Development Co., Ltd.
  • fluorescent dye BoDIPY-FL (Invitrogen) (Invitrogen), dextran gel (source leaf organism).
  • Three tubes (3 mg/tube) of C150 protein were desalted using a 5 ml Hitrap desalting column.
  • the fluorescent dye not bound to C150 was removed by filtration with Sephadex G-25 gel.
  • the C150Bo was diluted to 2 ⁇ M with 50 m M HEPES.
  • the fluorescence signal (excitation light 485 nm emission light 535 nm) was measured.
  • 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
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape.
  • HepG2.2.15 cells were provided by WuXi PharmaTech.
  • Test compound The compound of the present application was formulated into a 20 mM mother liquor temporary nitrogen cabinet using dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • 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).
  • 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 ⁇ M
  • the initial concentration of the anti-HBV activity test was 10 ⁇ M
  • the final concentration of DMSO was 0.5%.
  • 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.
  • 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.
  • %Inh. [(DMSO control PCR fluorescence value - sample PCR fluorescence value) / DMSO control PCR fluorescence value] * 100%
  • %Cell viability [(sample fluorescence value - medium fluorescence value) / (DMSO fluorescence value - medium fluorescence value)] * 100%
  • 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.
  • CC50 + ⁇ 10 ⁇ M; 10 ⁇ M ⁇ ++ ⁇ 30 ⁇ M; 30 ⁇ M ⁇ +++.

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Abstract

La présente invention concerne le domaine de la chimie pharmaceutique, et concerne un nouvel inhibiteur d'assemblage de protéine capsidique, en particulier, à un composé représenté par la formule I, un stéréoisomère ou un sel pharmaceutiquement acceptable, un procédé de préparation, une composition pharmaceutique et une utilisation médicale de celui-ci, y compris une utilisation de celui-ci dans le traitement de maladies bénéficiant d'un inhibiteur d'assemblage de protéine capsidique, en particulier, des maladies provoquées par une infection par le virus de l'hépatite B, les définitions de A, M, L et D de formule I étant les mêmes que celles de la description.
PCT/CN2017/102054 2016-09-18 2017-09-18 Nouvel inhibiteur d'assemblage de protéine capsidique WO2018050110A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020151252A1 (fr) * 2019-01-25 2020-07-30 正大天晴药业集团股份有限公司 Inhibiteur de l'ensemble de la capside contenant un anneau n-hétérocyclique à 5 éléments
WO2023001299A1 (fr) * 2021-07-23 2023-01-26 上海挚盟医药科技有限公司 Forme cristalline du composé représenté par la formule i, sa préparation et son application
US11597716B2 (en) 2018-03-30 2023-03-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof
EP4076648A4 (fr) * 2019-12-20 2024-01-10 Arbutus Biopharma Corporation Urées et amides bicycliques et tricycliques substitués, leurs analogues et procédés les utilisant

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2683817B1 (fr) * 1991-11-18 1994-02-25 Upsa Laboratoires Nouveaux derives d'alpha-amino n-pyridyl benzene propanamide, leurs procedes de preparation, compositions pharmaceutiques les contenant.
WO1994020468A1 (fr) * 1993-03-05 1994-09-15 Boehringer Mannheim Gmbh 4-aminopyridines, leur fabrication et leur utilisation comme agents antithrombotiques
WO2015073774A1 (fr) * 2013-11-14 2015-05-21 Novira Therapeutics, Inc. Dérivés d'azépane et procédés de traitement d'infections par le virus de l'hépatite b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2683817B1 (fr) * 1991-11-18 1994-02-25 Upsa Laboratoires Nouveaux derives d'alpha-amino n-pyridyl benzene propanamide, leurs procedes de preparation, compositions pharmaceutiques les contenant.
WO1994020468A1 (fr) * 1993-03-05 1994-09-15 Boehringer Mannheim Gmbh 4-aminopyridines, leur fabrication et leur utilisation comme agents antithrombotiques
WO2015073774A1 (fr) * 2013-11-14 2015-05-21 Novira Therapeutics, Inc. Dérivés d'azépane et procédés de traitement d'infections par le virus de l'hépatite b

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11597716B2 (en) 2018-03-30 2023-03-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof
WO2020151252A1 (fr) * 2019-01-25 2020-07-30 正大天晴药业集团股份有限公司 Inhibiteur de l'ensemble de la capside contenant un anneau n-hétérocyclique à 5 éléments
CN113365979A (zh) * 2019-01-25 2021-09-07 正大天晴药业集团股份有限公司 含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途
CN113365979B (zh) * 2019-01-25 2023-09-22 正大天晴药业集团股份有限公司 含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途
EP4076648A4 (fr) * 2019-12-20 2024-01-10 Arbutus Biopharma Corporation Urées et amides bicycliques et tricycliques substitués, leurs analogues et procédés les utilisant
WO2023001299A1 (fr) * 2021-07-23 2023-01-26 上海挚盟医药科技有限公司 Forme cristalline du composé représenté par la formule i, sa préparation et son application

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