WO2020156494A1 - Pyrrolo-hétérocycle contenant un inhibiteur d'assemblage de protéines capsidiques - Google Patents

Pyrrolo-hétérocycle contenant un inhibiteur d'assemblage de protéines capsidiques Download PDF

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Publication number
WO2020156494A1
WO2020156494A1 PCT/CN2020/074071 CN2020074071W WO2020156494A1 WO 2020156494 A1 WO2020156494 A1 WO 2020156494A1 CN 2020074071 W CN2020074071 W CN 2020074071W WO 2020156494 A1 WO2020156494 A1 WO 2020156494A1
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alkyl
fluorine
optionally
chlorine
oxo
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PCT/CN2020/074071
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English (en)
Chinese (zh)
Inventor
张寅生
敖汪伟
王辉
李元
倪杰
张欢
吴杰
张立
曹凯
沈杭州
陆鹏
汪杰
赵天笑
田晓萌
卢丹丹
葛兴枫
陈硕
马雪琴
施伟
王晓金
徐宏江
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正大天晴药业集团股份有限公司
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Priority to CN202080011284.8A priority Critical patent/CN113365999B/zh
Publication of WO2020156494A1 publication Critical patent/WO2020156494A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This application relates to the compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition containing the compound, and its use as a medicine for treating and preventing hepatitis B virus infection application.
  • chronic viral hepatitis B is incurable and can only be controlled. At present, it is mainly limited to two types of agents (interferon and nucleoside analog/viral polymerase inhibitors).
  • the low cure rate of HBV is partly due to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected liver cells.
  • the current treatment plan cannot eliminate the cccDNA in the reservoir, and some new HBV targets such as core inhibitors, such as viral capsid protein formation or assembly inhibitors, cccDNA inhibitors and interferon-stimulated gene activators It is expected to bring hope to curing hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).
  • HBV capsid is assembled from core protein. Before reverse transcription, HBV reverse transcriptase and pgRNA need to be correctly encapsulated by the capsid protein. Therefore, blocking the assembly of the capsid protein or accelerating the degradation of the capsid protein will block the process of capsid protein assembly, thereby affecting virus replication.
  • capsid protein assembly inhibitors for the treatment, improvement or prevention of HBV infection.
  • a series of novel derivatives have been synthesized and their HBV protein assembly activity has been studied.
  • the application provides a compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof,
  • Ring A is selected from 5-10 membered heterocyclic groups, and the 5-10 membered heterocyclic groups optionally contain 1-3 heteroatoms selected from N, O or S in addition to sharing N atoms, said ring A Optionally substituted by 1-3 R 1 ; each of said R 1 is independently selected from halogen or C 1-6 alkyl;
  • R 2 is selected from H, halogen or C 1 - 6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;
  • the C 1-6 alkyl group is optionally substituted with 1-3 R 3a ; each of the R 3a is independently selected from: halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1- 3 heteroatoms selected from N, 5-8 membered hetero atom O or S hetero aryl group, C 2 - 6 alkynyl, or oxo;
  • the C 3-8 cycloalkyl is optionally substituted with 1-3 R 3b ; each of the R 3b is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1- 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 alkane optionally substituted by 1-3 halogen or hydroxyl group with 3 heteroatoms selected from N, O or S base;
  • the 3-8 membered heterocycloalkyl is optionally substituted with 1-3 R 3c ; each of the R 3c is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1- 6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1 -3 heteroatoms selected from N, O or S 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 optionally substituted by 1-3 halogen or hydroxyl alkyl;
  • Ring B is selected from C 6-10 aryl groups, or 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, said ring B is optionally substituted by 1-5 R 4 Substituted; each of the R 4 is independently selected from halogen, -CN, -OH, -NH 2 , C 3-4 cycloalkyl, or C 1-3 alkyl optionally substituted with 1-3 halogens;
  • the R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
  • the present application provides a pharmaceutical composition, which comprises the compound of formula I of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for the treatment of diseases that benefit from the inhibition of capsid protein assembly, which comprises administering a therapeutically effective amount of the above-mentioned compound of formula I, its stereoisomers, or Its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
  • this application also provides the compound of the above formula I, its stereoisomer or its pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a medicine for the treatment or prevention of diseases benefiting from the inhibition of capsid protein assembly the use of.
  • this application also provides the use of the compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the treatment or prevention of diseases that benefit from capsid protein assembly inhibition.
  • this application also provides the above-mentioned compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases that benefit from capsid protein assembly inhibition.
  • this application relates to a compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof,
  • Ring A is selected from 5-10 membered heterocyclic groups, and the 5-10 membered heterocyclic groups optionally contain 1-3 heteroatoms selected from N, O or S in addition to sharing N atoms, said ring A Optionally substituted by 1-3 R 1 ; each of said R 1 is independently selected from halogen or C 1-6 alkyl;
  • R 2 is selected from H, halogen or C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;
  • the C 1-6 alkyl group is optionally substituted with 1-3 R 3a ; each of the R 3a is independently selected from: halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1- 3 heteroatoms selected from N, 5-8 membered hetero atom O or S hetero aryl group, C 2 - 6 alkynyl, or oxo;
  • the C 3-8 cycloalkyl is optionally substituted with 1-3 R 3b ; each of the R 3b is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1- 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 alkane optionally substituted by 1-3 halogen or hydroxyl group with 3 heteroatoms selected from N, O or S base;
  • the 3-8 membered heterocycloalkyl is optionally substituted with 1-3 R 3c ; each of the R 3c is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1- 6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1 -3 heteroatoms selected from N, O or S 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 optionally substituted by 1-3 halogen or hydroxyl alkyl;
  • Ring B is selected from C 6-10 aryl groups, or 5-10 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, said ring B is optionally substituted by 1-5 R 4 Substituted; each of the R 4 is independently selected from halogen, -CN, -OH, -NH 2 , C 3-4 cycloalkyl, or C 1-3 alkyl optionally substituted with 1-3 halogens;
  • the R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
  • ring A is selected from 5-10 membered heterocyclic groups, and the 5-10 membered heterocyclic groups optionally contain 1- 3 heteroatoms selected from N, O or S, said ring A is optionally substituted with 1-3 R 1 ; each of said R 1 is independently selected from halogen or C 1-6 alkyl;
  • R 2 is selected from H, halogen or C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl, C 3-5 cycloalkyl, or 3-5 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;
  • the C 1-6 alkyl group is optionally substituted with 1-3 R 3a ; each of the R 3a is independently selected from: halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C (O) N (R 5 ) (R 6 ), -C (O) R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1-3 selected from N, O or 5-8 membered heteroaryl group S aryl, C 2 - 6 alkynyl, or oxo;
  • the C 3-5 cycloalkyl group is optionally substituted with 1-3 R 3b ; each of the R 3b is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1-6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1- 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 alkane optionally substituted by 1-3 halogen or hydroxyl group with 3 heteroatoms selected from N, O or S base;
  • the 3-5 membered heterocycloalkyl group is optionally substituted with 1-3 R 3c ; each R 3c is independently selected from halogen, -OH, -CN, C 1-6 alkoxy, C 1- 6 Alkylamino, -C(O)N(R 5 )(R 6 ), -C(O)OR 6 , -C(O)R 6 , -SO 2 R 6 , C 6-10 aryl, containing 1 -3 heteroatoms selected from N, O or S 5-8 membered heteroaryl, C 2-6 alkynyl, oxo, or C 1-3 optionally substituted by 1-3 halogen or hydroxyl alkyl;
  • Ring B is selected from C 6-10 aryl groups, optionally substituted by 1-5 R 4 ; each of R 4 is independently selected from halogen, -CN, -OH, -NH 2 , C 3-4 cycloalkane Group, or C 1-3 alkyl optionally substituted by 1-3 halogens;
  • the R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
  • each of the aforementioned R 1 is independently selected from fluorine, chlorine, bromine, or a C 1-3 alkyl group; in some embodiments, each of the aforementioned R 1 is independently selected from fluorine, or methyl.
  • the above-mentioned ring A is selected from a 5-membered heterocyclic group or a 6-membered heterocyclic group; in some embodiments, the above-mentioned ring A is selected from a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, and Membered heteroaryl, or 6-membered heteroaryl; in some embodiments, the above-mentioned ring A is selected from In some embodiments, the aforementioned ring A is selected from In some embodiments, the aforementioned ring A is The substituents of the ring A are as described above. In some embodiments, Ring A is optionally substituted with 1 R 1 .
  • the aforementioned ring A is selected from In some embodiments, the aforementioned ring A is
  • R 2 is selected from H, fluorine, chlorine, bromine, or C 1-3 alkyl; in some embodiments, R 2 is selected from H, chlorine, or methyl. In some embodiments, the aforementioned R 2 is fluorine, chlorine or bromine; in some embodiments, the aforementioned R 2 is chlorine. In some embodiments, the above-mentioned R 2 is C 1-3 alkyl, such as methyl.
  • the above-mentioned R 3a is each independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy, C 1-4 alkylamino, -C(O)NH 2 ,- C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl) 2 , -C(O)OC 1-4 alkyl, -C(O)C 1-4 alkyl , -SO 2 C 1-4 alkyl, C 6-10 aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, or Oxo;
  • the above R 3a are each independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C
  • the above R 3a are each independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy, C 1-4 alkylamino, -C(O)NH 2 , -C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl) 2 , -C(O)C 1-4 alkyl, -SO 2 C 1-4 alkyl, C 6-10 aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, or oxo; in some other embodiments, the above R 3a are each independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C (O) NH 2 , -C (O) NHC 1- 3 alkyl, -C(O)N(C 1-3 alkyl) 2 , -C(O)
  • the above-mentioned R 3b is each independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy, C 1-4 alkylamino, -C(O)NH 2 ,- C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl) 2 , -C(O)OC 1-4 alkyl, -C(O)C 1-4 alkyl , -SO 2 C 1-4 alkyl, C 6-10 aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, oxygen Substituted or optionally substituted by 1-3 fluorine, chlorine, bromine or C 1-3 alkyl groups; in some embodiments, the above R 3b are each independently selected from fluorine, chlorine, bromine, -OH,- CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)
  • each of the above R 3c is independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy, C 1-4 alkylamino, -C(O)NH 2 ,- C(O)NHC 1-4 alkyl, -C(O)N(C 1-4 alkyl) 2 , -C(O)OC 1-4 alkyl, -C(O)C 1-4 alkyl , -SO 2 C 1-4 alkyl, C 6-10 aryl, 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, oxygen Substituted or optionally substituted by 1-3 fluorine, chlorine, bromine or C 1-3 alkyl groups; in some embodiments, the above R 3c is each independently selected from fluorine, chlorine, bromine, -OH,- CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 ,
  • the above-mentioned R 3 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkanes containing 1-3 heteroatoms selected from N, O or S
  • the above-mentioned R 3 is selected from C 1-3 alkyl, C 3-6 cycloalkyl, or 3, 4 or 5 containing 1-3 heteroatoms selected from N, O or S Member heterocycloalkyl; in some embodiments, the above R 3 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, aziridine
  • the above-mentioned R 3 is selected from propyl, cyclopropyl, cyclobutyl, or oxetanyl; in some embodiments, the above-mentioned R 3 is selected from iso Propyl, cyclobutyl, or
  • the above-mentioned R 3 is selected from a C 1-3 alkyl group, a C 3-4 cycloalkyl group, or a 3, 4 or 5-membered group containing 1-3 heteroatoms selected from N, O or S Heterocycloalkyl; In other embodiments, the above-mentioned R 3 is selected from C 1-3 alkyl, C 4 cycloalkyl, or a 4- membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S Cycloalkyl; In some other embodiments, the above-mentioned R 3 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl, aziridinyl , Or azetidinyl; in some embodiments, the above-mentioned R 3 is selected from propyl, cyclopropyl, cyclobutyl, or ox
  • the above-mentioned R 3 is a C 1-3 alkyl group; the C 1-3 alkyl group is optionally substituted with 1-3 groups selected from the group consisting of fluorine, chlorine, bromine, -OH,- CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl ) 2 , -C(O)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 1-3 options A 5- or 6-membered heteroaryl group derived from a heteroatom of N, O or S, a C 2-3 alkynyl group, or an oxo group.
  • 1-3 groups selected from the group consisting of fluorine, chlorine, bromine, -OH,- CN, C 1-3 alkoxy, C 1-3 alky
  • the above-mentioned R 3 is a C 1-3 alkyl group; the C 1-3 alkyl group is optionally substituted with 1-3 groups selected from the group consisting of fluorine, chlorine, bromine, or -C( O) NHC 1-3 alkyl, 5 or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, or C 2-3 alkynyl.
  • the above-mentioned R 3 is propyl or isopropyl optionally substituted with 1, 2 or 3 fluorines.
  • the above R 3 is a C 3-5 cycloalkyl group, and the C 3-5 cycloalkyl group is optionally substituted by 1-3 groups selected from the group consisting of fluorine, chlorine, bromine, -OH , -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 Alkyl) 2 , -C(O)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 1-3 A 5- or 6-membered heteroaryl group selected from N, O or S heteroatoms, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted with 1-3 fluorines.
  • the above-mentioned R 3 is cyclobutyl optionally substituted with 1,
  • the above-mentioned R 3 is a 3, 4 or 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S, and the heterocycloalkyl group is optionally substituted by 1-3 Substitution selected from the following groups: fluorine, chlorine, bromine, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1 -3 alkyl, -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1 -3 alkyl, C 6-10 aryl, 5 or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, oxo, or optionally 1-3 fluorine substituted C 1-3 alkyl groups.
  • the above-mentioned R 3 is a 3-, 4- or 5-membered heterocycloalkyl group containing one heteroatom selected from N, O or S, and the heterocycloalkyl group is optionally selected from the following substituted: fluoro, chloro, bromo, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, or optionally fluorine-substituted 1-3 C 1-3 alkyl.
  • the above-mentioned R 3 is a 3-, 4- or 5-membered heterocycloalkyl group containing 1 heteroatom selected from N, O or S, and the heterocycloalkyl group is optionally methyl or trifluoromethyl. Substitution.
  • the above-mentioned R 3 is selected from In some embodiments, R 3 above is In some embodiments, R 3 above is In some embodiments, R 3 above is In some embodiments, R 3 above is
  • each R 4 is independently selected from fluorine, chlorine, bromine, -CN, optionally substituted by 1-3 fluorine, chlorine, bromine, substituted C 1-3 alkyl, -OH, or -NH 2 ; In some embodiments, the R 4 is each independently selected from fluorine, chlorine, -CN, C 1-3 alkyl optionally substituted with 1-3 fluorines, or -NH 2 ; in some In an embodiment, each of the R 4 is independently selected from fluorine, chlorine, -CN, methyl, or -NH 2 .
  • each R 4 is independently selected from fluorine, chlorine, -CN, and C 1-3 alkyl optionally substituted with 1-3 fluorines; in some specific embodiments, the R 4 are each independently selected from fluorine, chlorine, -CN, difluoromethyl, or trifluoromethyl.
  • the aforementioned ring B is selected from 5-membered heteroaryl, 6-membered heteroaryl, or phenyl; in some embodiments, the aforementioned ring B is selected from pyridyl, or phenyl; in some embodiments , The above ring B is selected from Or phenyl; in some embodiments, the above-mentioned ring B is phenyl; the substituents of the above-mentioned ring B in the above-mentioned embodiments are as described above, for example, in the above-mentioned embodiment, the above-mentioned ring B is optionally composed of 1 or 2 R 4 is substituted, R 4 is each independently selected from fluorine, chlorine, -CN, C 1-3 alkyl optionally substituted with 1-3 fluorines, or -NH 2 ; or the ring B in the above embodiment is any It is optionally substituted by 2 groups selected from fluorine, chlorine, -CN, -CH 3 or -NH 2
  • the aforementioned ring B is selected from In some embodiments, the aforementioned ring B is The R 4a , R 4b , R 4c , R 4d and R 4e are each independently as described in R 4 ; for example, R 4a is fluorine, and R 4b and R 4c are fluorine, chlorine, -CN, Methyl, or -NH 2 .
  • the aforementioned ring B is selected from In some embodiments, the aforementioned ring B is
  • the aforementioned ring B is selected from phenyl; the substituents of the ring B are as described above.
  • the aforementioned ring B is selected from The R 4a , R 4b , R 4c , R 4d and R 4e are each independently as described for R 4 .
  • the aforementioned ring B is selected from
  • the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof of the present application is selected from a compound of formula II, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • n is selected from 1, or 2;
  • R 2 , R 3 , R 4a , or R 4c are as described above.
  • n in Formula II is 1.
  • R 2 in formula II is selected from H, fluorine, chlorine, bromine, or C 1-3 alkyl; in some embodiments, R 2 is selected from H, chlorine, or methyl; in some In an embodiment, R 2 is chloro or methyl.
  • R 3 in formula II is a C 1-3 alkyl group; the C 1-3 alkyl group is optionally substituted with 1-3 groups selected from the group consisting of fluorine, chlorine, bromine,- OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1- 3 alkyl) 2 , -C (O) OC 1-3 alkyl, -C (O) C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 1- A 5- or 6-membered heteroaryl group with 3 heteroatoms selected from N, O or S, C 2-3 alkynyl, or oxo.
  • 1-3 groups selected from the group consisting of fluorine, chlorine, bromine,- OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2
  • R 3 in Formula II is a C 1-3 alkyl group; the C 1-3 alkyl group is optionally substituted with 1-3 groups selected from the group consisting of fluorine, chlorine, bromine, or -C(O)NHC 1-3 alkyl, 5 or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, or C 2-3 alkynyl.
  • R 3 in Formula II is propyl or isopropyl optionally substituted with 1, 2, or 3 fluorines.
  • R 3 in formula II is a C 3-4 cycloalkyl group, the C 3-4 cycloalkyl is optionally substituted with 1-3 groups selected from: fluoro, chloro, bromo , -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 5 or 6-membered heteroaryl groups with 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted by 1-3 fluorine .
  • the above-mentioned R 3 is cyclobutyl optionally substituted with 1, 2 or
  • R 3 in Formula II is a 3 , 4, or 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O, or S, and the heterocycloalkyl group is optionally substituted by 1 -3 substitutions selected from the following groups: fluorine, chlorine, bromine, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino, -C (O) NH 2 , -C (O )NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, 5 or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted with 1-3 fluorines.
  • R 3 in formula II is a 3- , 4- or 5-membered heterocycloalkyl group containing 1 heteroatom selected from N, O, or S, and the heterocycloalkyl group is optionally substituted by fluorine or chlorine. , Bromine, -OH, -CN, C 1-3 alkoxy, C 1-3 alkylamino or C 1-3 alkyl optionally substituted with 1-3 fluorine.
  • R 3 in formula II is a 3- , 4- or 5-membered heterocycloalkyl group containing 1 heteroatom selected from N, O or S, and the heterocycloalkyl group is optionally methyl or Trifluoromethyl substitution.
  • R 3 above is In some embodiments, R 3 above is In some embodiments, R 3 above is In some embodiments, R 3 above is In some embodiments, R 3 above is
  • R 4a and R 4c in formula II are each independently selected from fluorine, chlorine, bromine, -CN, optionally substituted with 1-3 fluorine, chlorine, bromine, C 1-3 alkyl , -OH, or -NH 2 .
  • R 4a and R 4c in Formula II are each independently selected from fluorine, chlorine, -CN, methyl, or -NH 2 .
  • R 4a in Formula II is fluorine
  • R 4c is fluorine, chlorine, -CN, methyl, or -NH 2 .
  • the substituents in the above embodiments can be combined with each other.
  • n in formula II is 1;
  • R 2 is selected from H, fluorine, chlorine, bromine, or C 1-3 alkyl;
  • R 3 is R 4a is fluorine, and
  • R 4c is fluorine, chlorine, -CN, methyl, or -NH 2 .
  • the compound of formula I of the present application is selected from the following compounds, their stereoisomers or their pharmaceutically acceptable salts:
  • the application also provides a pharmaceutical composition, which comprises the compound of formula I or formula II of the application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the application further includes pharmaceutically acceptable excipients.
  • this application also provides a method for the treatment or prevention of diseases that benefit from capsid protein assembly inhibition, including administering a therapeutically effective amount of the above formula I or formula II to a mammal in need of the treatment, preferably a human
  • a mammal in need of the treatment, preferably a human
  • the compound, its stereoisomer, or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition preferably a human
  • the present application also provides the compound of formula I or formula II, its stereoisomers, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of treatment or prevention benefiting from capsid protein assembly inhibition Use in medicine for diseases.
  • this application also provides the compound of formula I or formula II, its stereoisomers, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition in the treatment or prevention of diseases that benefit from capsid protein assembly inhibition. Use in.
  • this application also provides the compound of formula I or formula II, its stereoisomers, or pharmaceutically acceptable salts thereof, or the above-mentioned drugs for the treatment or prevention of diseases that benefit from capsid protein assembly inhibition combination.
  • the diseases that benefit from capsid protein assembly inhibition refer to diseases caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the diseases that benefit from capsid protein assembly inhibition refer to liver diseases caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the treatment of diseases that benefit from capsid protein assembly inhibition refers to the control, reduction or elimination of HBV to prevent, alleviate or cure liver diseases in infected patients.
  • the N atom of the pyrrole is a ring atom of the ring A group, the N atom is a common N atom.
  • the dotted line (---) in the structural unit or group in this application represents a covalent bond, which can be a single bond or a double bond.
  • ring A is selected from When it means that it can be connected to adjacent atoms through double bonds or single bonds, for example
  • the covalent bond in some structural unit or group in this application is not connected to a specific atom, it means that the covalent bond can be connected to any atom in the structural unit or group, as long as it does not violate the valence bond connection rules .
  • substituted means that any one or more hydrogen atoms on a specific group are replaced by a substituent, as long as the valence of the specific group is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
  • the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • CH 2 CH 3 unsubstituted
  • monosubstituted such as CH 2 CH 2 F
  • polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
  • CF 2 CF 3 completely substituted
  • C mn in this document means that the part has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
  • any variable such as R
  • its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • the substituent When the bond of a substituent is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • structural unit It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1 .
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety ie, alkyl
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio have the same definition as above.
  • C 1-3 alkyl refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH) and so on.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring, a 3 to 8 membered ring, or a 3 to 5 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, bicyclo[1.1.1]pent-1-yl, etc.
  • C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • heterocyclyl refers to a ring that is fully saturated or unsaturated and may exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is usually a 3 to 8 membered ring, 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen Or 3 to 5 membered ring.
  • heterocyclic groups include, but are not limited to, oxirane, oxetane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperyl Ridinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl or pyrazolyl Wait.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is usually a 3 to 8 membered ring, 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen Or 3 to 5 membered ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfiethane, and azaethylenyl groups
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetane
  • Examples of cyclic groups (oxetane), thibutane, and 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl
  • 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
  • heteroaryl refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • treatment means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying this article
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. It is determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, where protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from those generally found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotope-labeled compound of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing the non-isotopically-labeled reagent with an isotope-labeled reagent.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • the following may be preferred, where the deuterium substitution may be partial or complete.
  • Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included in the scope of the present application.
  • the compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition is also suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (such as hydrophobicity) and route of administration.
  • the compound of the present application can be provided by a physiological buffer aqueous solution containing about 0.1-10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration.
  • the effective dose can be obtained by extrapolating the dose-response curve derived from the in vitro or animal model test system.
  • 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, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the examples of the present application.
  • the compound of general formula I of the present application can be prepared by a person skilled in the art of organic synthesis through the following route, using general or conventional methods in the art:
  • Ring B, R 2 , R 3 and n are as defined above, and R 7 and R 8 are each independently selected from a C 1-6 alkyl group.
  • EA stands for ethyl acetate
  • PE stands for petroleum ether
  • NCS stands for N-chlorosuccinimide
  • DMF stands for N,N-dimethylformamide
  • HATU stands for 2-(7-oxybenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate
  • h stands for hour
  • THF stands for tetrahydrofuran.
  • NMR nuclear magnetic resonance chromatography
  • TMS tetramethylsilane
  • the format of the data recording of the proton spectrum is: proton number, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in Hz).
  • the instrument used for mass spectrometry is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.
  • Step A Add DL-proline (3.0g) and formic acid (67.2g) to the reaction flask. After the addition, slowly add acetic anhydride (19.95g) dropwise under an ice bath. After the addition, remove the ice bath and stir at room temperature for reaction For 5.0 h, 100 mL of ice water was added to the reaction solution, and the reaction solution was concentrated to obtain N-formyl-proline (3.5 g). MS(ESI-,[MH] - )m/z: 142.2
  • Step B Add acetic anhydride (50mL), N-formyl-proline (3.0g) and ethyl propiolate (10.28g) into the reaction flask. After the addition, heat to 135°C to react for 5h, then cool to room temperature.
  • Step D Add 5-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (1.1g), methanol (10mL) to the reaction flask ), slowly add NaOH (315mg) in water (5mL) solution dropwise in an ice bath, stir at room temperature for 10min after addition, adjust the pH to 2-3 with 2N dilute hydrochloric acid, extract with ethyl acetate (3*50mL), combine the organic Wash the organic layer with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter with suction, concentrate the filtrate and spin dry to obtain 2-(7-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolazine -5-yl)-2-oxoacetic acid (880 mg).
  • Step F Add (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro in the reaction flask successively -1H-pyrrolazine-7-carboxylic acid ethyl ester (340mg), methanol (10mL) and NaOH (79mg) in water (5mL) solution, after the addition, heat the reaction temperature to 80 °C for 12h, adjust with 1N dilute hydrochloric acid After the pH reaches 2 to 3, extract with ethyl acetate (3*50mL), combine the organic layers, wash the organic layer with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate by spin-drying to obtain (R)- 5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-d
  • Step G Into the reaction flask, add toluene (15mL), (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)- 2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid (260mg) and thionyl chloride (1.9g), under nitrogen protection, heat the reaction to 115°C and react for 1.0h, and then cool to room temperature after the reaction is complete The solvent was removed by rotary evaporation under reduced pressure to obtain the acid chloride intermediate (335 mg).
  • Step A Refer to Step E of Example 1 and replace (R)-1,1,1-trifluoropropan-2-amine hydrochloride with (S)-1,1,1-trifluoropropan-2-amine hydrochloride (S)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine prepared from salt -7-Ethyl carboxylate. MS(ESI+,M+H) + )m/z:347.3.
  • Step B Refer to the step of Example 1 with (S)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3- Dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester instead of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) (S)-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl) prepared from ethyl-2,3-dihydro-1H-pyrrolazine-7-carboxylate )Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid.
  • Step C Refer to Step G in Example 1 with (S)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2, 3-Dihydro-1H-pyrrolazine-7-carboxylic acid instead of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid to produce (S)-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-(( 1,1,1-Trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide.
  • Step A Add (S)-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoropropane-2 -Yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide (80mg, 0.183mmol), N,N-dimethylformamide (3mL) and N-chlorobutane After the addition of diimide (49mg, 0.366mmol), microwave reaction at 120°C for 2.0h, pour the reaction solution into 50mL water, extract with ethyl acetate (2*40mL), combine the organic layers, and wash with saturated sodium chloride aqueous solution The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step A In the reaction flask, under the protection of nitrogen, add THF (50mL), 2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (1.5g), 5-amino-2-fluorobenzonitrile in sequence (1.36g), slowly dropwise add lithium bis(trimethylsilyl)amide (2.80g, 1.0M in THF) under ice bath, and then transfer to room temperature to react for 2.0h after addition.
  • THF 50mL
  • 2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester 1.5g
  • 5-amino-2-fluorobenzonitrile in sequence (1.36g)
  • lithium bis(trimethylsilyl)amide 2.80g, 1.0M in THF
  • Step B Add zinc oxide (181mg) and monoethyl oxalyl chloride (12.17g) to the reaction flask in sequence. After the addition, add N-(3-cyano-4-fluoro) in batches under the protection of N 2 and ice bath. Phenyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide (1.2g), after the addition, remove the ice bath and stir for 4.0h. After the reaction is over, pour the reaction solution into 200ml ice water for quenching.
  • Step C Add DMF (15mL), 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5- Ethyl)-2-oxoacetate (450mg), NCS (325mg), after the addition, transfer to a microwave reactor for 100 watts and heat to 110°C for 2h.
  • Step D Add (2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5-
  • An aqueous solution (5.00 mL) of ethyl)-2-oxoethyl acetate (240 mg), tetrahydrofuran (10 mL) and lithium hydroxide (50 mg). After the addition, stir at room temperature for 20 min. Adjust the pH of the solution to 3 with 2N dilute hydrochloric acid. 4.
  • Extract with ethyl acetate (30mL*2) combine the organic layers, wash the organic layers with saturated brine, dry the organic phase with anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain 2-(6-chloro-7-(( 3-cyano-4-fluorophenyl) carbamoyl) -2,3-dihydro -1H- pyrrol-5-yl) -2-oxo acetic acid (120mg) .MS (ESI -, [MH] - )m/z:374.0.
  • Step A Add DMF (35mL), (S)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino-)acetyl)- 2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (3.31g), N-chlorosuccinimide (2.55g), add microwave 110°C and react for 2h.
  • Step B Add (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2 in sequence to the reaction flask, An aqueous solution (10.00 mL) of ethyl 3-dihydro-1H-pyrrolazine-7-carboxylate (1.7 g), methanol (30 mL) and sodium hydroxide (0.357 g), after the addition, was stirred at 80° C. for 3 h.
  • Step C Into the reaction flask, add toluene (15mL), (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino) in sequence Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid (200mg) and thionyl chloride (1.349g), under the protection of nitrogen, the system was heated to 115°C for 1.0h, and the temperature dropped after the reaction At room temperature, the solvent was removed by rotary evaporation under reduced pressure to obtain the acid chloride intermediate (220 mg).
  • the acid chloride intermediate (220 mg) was dissolved in N,N-dimethylacetamide (10 mL), 3,4-difluoroaniline (110 mg) was added, and the reaction was completed at 100° C. for 0.5 h. After the reaction, it was cooled to room temperature and extracted with ethyl acetate (2*50mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • step D replaces 3,4-difluoroaniline with 3-chloro-4-fluoroaniline to obtain (S)-6-chloro-N-(3-chloro-4-fluorophenyl)-5- (2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide.
  • Step A According to Example 5, (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino-)acetyl)- Replacement of (S)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino) with ethyl 2,3-dihydro-1H-pyrrolazine-7-carboxylate -) Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to prepare (R)-6-chloro-5-(2-oxo-2-((1,1 ,1-Trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester.
  • Step B According to Example 5, (R)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoro)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester Propan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to produce (R)-6-chloro-5-(2-oxo-2) -((1,1,1-Trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid.
  • Step C According to Example 5, (R)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl was used in step C (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoropropyl-)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid 2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid, substituting 5-amino-2-fluorobenzonitrile for 3,4-difluoroaniline to prepare (R )-6-chloro-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl Yl)-2,3-dihydro-1H-pyrrolazine-7-car
  • Step A Add 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (8.0g), dimethyl sulfoxide (60mL), and KOH (3.52g) to the reaction flask in sequence. After the addition, add dropwise under ice bath 1,3-Dibromopropane (15.82g), after the addition, stir at room temperature for 15h, pour the reaction solution into 600mL water, extract with ether (3*150mL), combine the organic layers, and wash the organic layer with saturated sodium chloride aqueous solution.
  • 1,3-Dibromopropane 15.82g
  • Step C Add 1-(3-iodopropyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.1g), dimethyl sulfoxide (60mL) and ferrous sulfate heptahydrate into the reaction flask (1.82g), after the addition, slowly add hydrogen peroxide (7.41g) dropwise under the ice-salt bath.
  • Step D Refer to Step C of Example 1 and replace 2,3-dihydro-1H-pyrrolazine-7-carboxylic acid with ethyl 6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid The ethyl ester is reacted to obtain 5-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester.
  • Step E Refer to Example 1 Step D with 5-(2-ethoxy-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester Substitute 5-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to produce 2-(7-(ethoxycarbonyl) -6-Methyl-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxoacetic acid.
  • Step F Refer to Example 1 Step E and replace with 2-(7-(ethoxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxoacetic acid 2-(7-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxoacetic acid, with (S)-1,1,1-trifluoropropane- 2-amine hydrochloride replaces (R)-1,1,1-trifluoropropan-2-amine hydrochloride to prepare (S)-6-methyl-5-(2-oxo-2-(( 1,1,1-Trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester.
  • Step G Refer to Example 1 Step F with (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester instead of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester is reacted to produce (S)-6-methyl-5-(2-oxo-2-((1, 1,1-Trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid.
  • Step H Refer to Example 1 Step G with (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid instead of (R)-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino) Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid to prepare (S)-N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2 -Oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide.
  • Step A According to Example 8, in Step A, methyl 3-pyrrolecarboxylate was used to replace ethyl 4-methyl-1H-pyrrole-3-carboxylate, and 1,4-dibromobutane was used to replace 1,3-di Bromopropane was used to prepare 1-(4-bromobutyl)-1H-pyrrole-3-carboxylic acid methyl ester.
  • Step B According to Example 8, in Step B, 1-(4-bromobutyl)-1H-pyrrole-3-carboxylic acid methyl ester was used to replace 1-(3-bromopropyl)-4-methyl-1H -Pyrrole-3-carboxylic acid ethyl ester to prepare 1-(4-iodobutyl)-1H-pyrrole-3-carboxylic acid methyl ester.
  • Step C According to Example 8, in Step C, 1-(4-iodobutyl)-1H-pyrrole-3-carboxylic acid methyl ester was used to replace 1-(3-iodopropyl)-4-methyl-1H -Ethyl pyrrole-3-carboxylate to prepare methyl 5,6,7,8-tetrahydroindoleazine-1-carboxylate.
  • Step D According to Example 1, in Step C, 2,3-dihydro-1H-pyrrolazine-7-carboxy is replaced with methyl 5,6,7,8-tetrahydroindolazine-1-carboxylate Ethyl acid to obtain methyl 3-(2-ethoxy-2-oxoacetyl)-5,6,7,8-tetrahydroindolazine-1-carboxylate.
  • Step E According to Example 1, in Step D, 3-(2-ethoxy-2-oxoacetyl)-5,6,7,8-tetrahydroindoleazine-1-carboxylic acid methyl Ester replaces 5-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to produce 2-(1-(methoxycarbonyl) )-5,6,7,8-Tetrahydroindolazin-3-yl)-2-oxoacetic acid.
  • Step F According to Example 1, replace with 2-(1-(methoxycarbonyl)-5,6,7,8-tetrahydroindolazin-3-yl)-2-oxoacetic acid in step E 2-(7-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetic acid, with (S)-1,1,1-trifluoropropane- 2-amine hydrochloride replaces (R)-1,1,1-trifluoropropan-2-amine hydrochloride to produce (S)-3-(2-oxo-2-((1,1, 1-Trifluoropropan-2-yl)amino)acetyl)-5,6,7,8-tetrahydroindolazine-1-carboxylic acid methyl ester.
  • Step G According to Example 1, in Step F, (S)-3-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)- Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl) with methyl 5,6,7,8-tetrahydroindolazine-1-carboxylate )Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to prepare (S)-3-(2-oxo-2-((1,1,1-tri Fluoropropan-2-yl)amino)acetyl)-5,6,7,8-tetrahydroindoleazine-1-carboxylic acid.
  • Step H According to Example 1, in Step G, (S)-3-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)- Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino) with 5,6,7,8-tetrahydroindolazine-1-carboxylic acid )Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid to produce (S)-N-(3-cyano-4-fluorophenyl)-3-(2-oxo -2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-5,6,7,8-tetrahydroindoleazine-1-carboxamide.
  • step E of Example 4 3-(trifluoromethyl)oxetane-3-amine was replaced with 3-methyloxetane-3-amine to prepare 6-chloro-N-(3-cyano 4-fluorophenyl)-5-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3-dihydro-1H- Pyrrolazine-7-carboxamide.
  • Step A Replace with 2-(7-(ethoxycarbonyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-5-yl)-2-oxoacetic acid according to step E of Example 1
  • Cyclobutane-1-carboxamide replaces (R)-1,1,1-trifluoropropan-2-amine hydrochloride to produce 5-(2-((3,3-difluoro-1-(form Cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester.
  • Step B Using 5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6- Methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester replaces (R)-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester to produce 5-(2-((3,3-difluoro-1-(methylcarbamoyl) )Cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid.
  • Step C Use 5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6- Methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid replaces (R)-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl) Amino) acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid to prepare N-(3-cyano-4-fluorophenyl)-5-(2-((3,3- Difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxamide.
  • Step A Under N 2 protection, add tetrahydrofuran (15mL), 6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (700mg), 5-amino-2 to the reaction flask -Fluorobenzonitrile (616 mg), lithium bis(trimethylsilyl)amide (1.52 g, 9.05 mL tetrahydrofuran solution) was slowly added at room temperature, and the reaction solution was stirred and reacted for 17.0 h.
  • Step B Replace nitrogen, add zinc oxide (111mg) and ethyl oxalyl chloride (7.4g) to the reaction flask under ice bath, add N-(3-cyano-4-fluorophenyl)-6-methyl in batches Hydroxy-2,3-dihydro-1H-pyrrolazine-7-carboxamide (770mg), stir for 5 minutes after the addition, and then turn to room temperature and stir for 3.5h.
  • the reaction solution was slowly poured into stirring ice and quenched. After quenching, it was extracted with dichloromethane (2*100 mL). The organic layers were combined, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. .
  • Step C Add 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrroline-5 to the reaction flask -Yl)-2-oxoacetate (280mg), tetrahydrofuran (5mL), slowly dropwise add lithium hydroxide monohydrate (61mg) in water (10mL) solution under ice bath, after the addition, turn to room temperature and react 10 minute.
  • Step D Use 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrroline- 5-yl)-2-oxoacetic acid replaces 2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine- 5-yl)-2-oxoacetic acid produces N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((3-(trifluoromethyl) Group)oxetan-3-yl)amino)acetyl)-2,3-dihydro-1H-pyrrole-7-carboxamide.
  • step E used 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrroline-5- Yl)-2-oxoacetic acid replaces 2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5- Yl)-2-oxoacetic acid, replacing 3-(trifluoromethyl)oxetane-3-amine with 3-methyloxetane-3-amine to produce N-(3-cyano -4-fluorophenyl)-6-methyl-5-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl)-2,3-di Hydrogen-1H-pyrrolazine-7-carboxamide.
  • step E with 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl-2,3-dihydro-1H-pyrrolazine-5- Yl)-2-oxoacetic acid replaces 2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5- Yl)-2-oxoacetic acid, using (R)-1,1,1-trifluoro-2-methylpropane hydrochloride instead of 3-(trifluoromethyl)oxetane-3-amine (R)-N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) )Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide.
  • the complete medium was used to dilute the different compounds dissolved in DMSO with a 2-fold gradient, a total of 10 concentrations, and the compound was added.
  • the fresh medium containing the compound was replaced every 72 h, and the cells were treated with the compound for 6 days.
  • 300 ⁇ L of lysis buffer (10mM Tris-HCl, 1mM EDTA, 1% NP-40) to each well.
  • DNA is extracted, and the intracellular viral capsid is determined by real-time fluorescent quantitative PCR instrument
  • the inhibition rate is calculated based on the Ct value, and the EC50 value is calculated by the four-parameter method. The results are shown in Table 1.
  • Example number EC50(nM) Example number EC50(nM) Example number EC50(nM) Example number EC50(nM) 3 19 6 27.9 14 14 4 11.3 7 29.7 15 66 5 15.8 8 22.5 16 14 10 10 12 25 17 34 11 31 13 13 18 14
  • Sample pretreatment 50 ⁇ L of incubation sample, adding 300 ⁇ L of ice acetonitrile precipitation containing internal standard diazepam, vortexing for 5min, centrifuging (12000rpm, 4°C) for 10min. Pipette 75 ⁇ L of the supernatant into a 96-well plate and dilute and mix with 75 ⁇ L ultrapure water, inject 0.5 ⁇ L, and perform LC-MS/MS analysis. The specific results are shown in Table 2.
  • mice Take 6-8 week old male C57BL/6 mice, and dissolve the purified recombinant plasmid pHBV1.3 (10 ⁇ g) in PBS.
  • the injection volume of each mouse is about 10% of its body weight. Injected into mice. After 24 hours of plasmid injection, blood was taken from the orbit to detect serum HBV DNA, and the model mice were selected for uniform serum DNA and grouped. A blank control group, a vehicle control group, and a test substance group were set up. Each group of mice was given intragastric administration for 6 consecutive days, once a day, at a dose of 30 mg/kg. Mice serum was collected 1, 3, 5, and 7 days after injection, and liver tissue samples were sacrificed on the 7th day. Fluorescence quantitative PCR method was used to detect HBV DNA copy numbers in mouse serum and liver. The results are shown in Table 3.
  • ICR mice weighing 18-20g, were adapted for 3 to 5 days, and then randomly divided into groups, 3 mice in each group, and were given a series of compounds at a dose of 10mg/kg.
  • test animals ICR mice were fasted for 12 hours before the administration, and were given food 4 hours after the administration. They were free to drink water before and after the experiment and during the experiment.
  • po oral; time points for blood collection are 0.25h, 1h, 3h, 8h.
  • SD rats weighing 180-220g, were adapted for 3 to 5 days, and then randomly divided into groups, 3 rats in each group, and administered a series of compounds at a dose of 10 mg/kg.
  • test animals SD rats were fasted for 12 hours before the administration, and were given food 4 hours after the administration. They were free to drink water before and after the experiment and during the experiment.
  • po oral; time points for blood collection are 0.25h, 4h, 10h.

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Abstract

La présente invention se rapporte au domaine de la chimie pharmaceutique, et concerne un pyrrolo-hétérocycle contenant un inhibiteur d'assemblage de protéines capsidiques, et en particulier un composé représenté par la formule I, un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, une composition pharmaceutique correspondante, et une utilisation médicale de ceux-ci, notamment une utilisation dans le traitement de maladies sur lesquelles l'inhibition d'assemblage de protéines capsidiques a un effet bénéfique, et en particulier, des maladies provoquées par une infection par le virus de l'hépatite B.
PCT/CN2020/074071 2019-01-31 2020-01-30 Pyrrolo-hétérocycle contenant un inhibiteur d'assemblage de protéines capsidiques WO2020156494A1 (fr)

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WO2023056933A1 (fr) 2021-10-08 2023-04-13 正大天晴药业集团股份有限公司 Combinaison pharmaceutique contenant un inhibiteur de protéine capsidique et un inhibiteur de la transcriptase inverse

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