WO2020156494A1 - Capsid protein assembly inhibitor containing pyrrolo heterocycle - Google Patents

Capsid protein assembly inhibitor containing pyrrolo heterocycle 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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Prior art keywords
alkyl
fluorine
optionally
chlorine
oxo
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PCT/CN2020/074071
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French (fr)
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
Original Assignee
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/en
Publication of WO2020156494A1 publication Critical patent/WO2020156494A1/en

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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

The present application belongs to the field of pharmaceutical chemistry, and relates to a capsid protein assembly inhibitor containing pyrrolo heterocycle, in particular, to a compound represented by formula I, a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof, and a medical use thereof, comprising a use in treating diseases benefiting from the capsid protein assembly inhibition, in particular, diseases caused by hepatitis B viral infection.

Description

含有吡咯并杂环的衣壳蛋白装配抑制剂Capsid protein assembly inhibitor containing pyrrolo heterocycle
相关申请的交叉引用Cross references to related applications
本申请要求于2019年01月31日向中华人民共和国国家知识产权局提交的第201910096084.6号中国发明专利申请和于2019年05月28日向中华人民共和国国家知识产权局提交的第201910451689.2号中国发明专利的权益和优先权，在此将其全部内容以援引的方式整体并入本文中。This application requires the Chinese invention patent application No. 201910096084.6 filed with the State Intellectual Property Office of the People's Republic of China on January 31, 2019 and the Chinese invention patent No. 201910451689.2 filed with the State Intellectual Property Office of the People's Republic of China on May 28, 2019. Rights and priorities, the entire contents of which are incorporated herein by reference.
技术领域Technical field
本申请涉及式I所示的化合物、其立体异构体或其药学上可接受的盐、其制备方法、含有该化合物的药物组合物，及其作为治疗和预防乙型肝炎病毒感染的药物的应用。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.
背景技术Background technique
当前，针对慢性乙型病毒性肝炎不可治愈只能控制，目前主要限于两类药剂(干扰素和核苷类似物/病毒聚合酶的抑制剂)。HBV的治愈率低部分是由于受感染肝细胞的细胞核中共价闭合环状DNA(cccDNA)的存在和持续性。目前治疗方案无法将储存库中的cccDNA清除掉，而一些HBV的新靶点如核心抑制剂(Core inhibitors，例如病毒的衣壳蛋白形成或装配抑制剂和cccDNA抑制剂及干扰素刺激基因激活剂等)有望给治愈乙肝带来希望(Mayur Brahmania,et al.New therapeutic agents for chronic hepatitis B)。Currently, 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衣壳由核心蛋白装配而成，在逆转录以前，HBV逆转录酶、pgRNA需要被衣壳蛋白正确包裹。因此，阻断衣壳蛋白装配，或加快衣壳蛋白降解，都会阻断衣壳蛋白装配过程，从而影响病毒复制。本领域中需要治疗、改善或预防HBV感染的更多供选择的有效的衣壳蛋白装配抑制剂。本申请合成了一系列新型衍生物，并对其HBV蛋白组装活性进行了研究。The 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. There is a need in the art for more alternative and effective capsid protein assembly inhibitors for the treatment, improvement or prevention of HBV infection. In this application, a series of novel derivatives have been synthesized and their HBV protein assembly activity has been studied.
发明概述Summary of the invention
一方面，本申请提供式I化合物、其立体异构体或其药学上可接受的盐，In one aspect, the application provides a compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2020074071-appb-000001
Figure PCTCN2020074071-appb-000001
其中，among them,
环A选自5-10元杂环基，所述5-10元杂环基除共用N原子外任选地还含有1-3个选自N、O或S的杂原子，所述环A任选地被1-3个R 1取代；所述R 1各自独立地选自卤素或C 1-6烷基； 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选自H、卤素或C 1- 6烷基； R 2 is selected from H, halogen or C 1 - 6 alkyl;
R 3选自C 1-6烷基、C 3-8环烷基、或含有1-3个选自N、O或S的杂原子的3-8元杂环烷基； 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;
所述C 1-6烷基任选地被1-3个R 3a取代；所述R 3a各自独立地选自：卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2- 6炔基、或氧代； 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;
所述C 3-8环烷基任选地被1-3个R 3b取代；所述R 3b各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
所述3-8元杂环烷基任选地被1-3个R 3c取代；所述R 3c各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
环B选自C 6-10芳基、或含有1-3个选自N、O或S的杂原子的5-10元杂芳基，所述环B任选地被1-5个R 4取代；所述R 4各自独立地选自卤素、-CN、-OH、-NH 2、C 3-4环烷基、或任选被1-3个卤素取代的C 1-3烷基； 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;
所述R 5、R 6各自独立地选自氢、或C 1-6烷基。 The R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
另一方面，本申请提供药物组合物，其包含本申请的式I化合物、其立体异构体或其药学上可接受的盐。In another aspect, 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.
另一方面，本申请提供一种治疗受益于衣壳蛋白装配抑制的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述式I化合物、其立体异构体或其药学上可接受的盐或者上述药物组合物。On the other hand, 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.
另一方面，本申请还提供了上述式I化合物、其立体异构体或其药学上可接受的盐、或者上述药物组合物在制备治疗或预防受益于衣壳蛋白装配抑制的疾病的药物中的用途。On the other hand, 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.
另一方面，本申请还提供了上述式I化合物、其立体异构体或其药学上可接受的盐、或者上述药物组合物在治疗或预防受益于衣壳蛋白装配抑制的疾病中的用途。On the other hand, 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.
另一方面，本申请还提供了用于治疗或预防受益于衣壳蛋白装配抑制的疾病的上述式I化合物、其立体异构体或其药学上可接受的盐、或者上述药物组合物。On the other hand, 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.
发明详述Detailed description of the invention
一方面，本申请涉及式I化合物、其立体异构体或其药学上可接受的盐，In one aspect, this application relates to a compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof,
Figure PCTCN2020074071-appb-000002
Figure PCTCN2020074071-appb-000002
其中，among them,
环A选自5-10元杂环基，所述5-10元杂环基除共用N原子外任选地还含有1-3个选自N、O或S的杂原子，所述环A任选地被1-3个R 1取代；所述R 1各自独立地选自卤素、或C 1-6烷基； 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选自H、卤素或C 1-6烷基； R 2 is selected from H, halogen or C 1-6 alkyl;
R 3选自C 1-6烷基、C 3-8环烷基、或含有1-3个选自N、O或S的杂原子的3-8元杂环烷基； 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;
所述C 1-6烷基任选地被1-3个R 3a取代；所述R 3a各自独立地选自：卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2- 6炔基、或氧代； 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;
所述C 3-8环烷基任选地被1-3个R 3b取代；所述R 3b各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
所述3-8元杂环烷基任选地被1-3个R 3c取代；所述R 3c各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
环B选自C 6-10芳基、或含有1-3个选自N、O或S的杂原子的5-10元杂芳基，所述环B任选地被1-5个R 4取代；所述R 4各自独立地选自卤素、-CN、-OH、-NH 2、C 3-4环烷基、或任选被1-3个卤素取代的C 1-3烷基； 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;
所述R 5、R 6各自独立地选自氢、或C 1-6烷基。 The R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
在一些实施方案中，在上述式I化合物中，环A选自5-10元杂环基，所述5-10元杂环基除与吡咯环共用的N原子外任选地还含有1-3个选自N、O或S的杂原子，所述环A任选地被1-3个R 1取代；所述R 1各自独立地选自卤素、或C 1-6烷基； In some embodiments, in the above-mentioned compound of formula I, 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选自H、卤素或C 1-6烷基； R 2 is selected from H, halogen or C 1-6 alkyl;
R 3选自C 1-6烷基、C 3-5环烷基、或含有1-3个选自N、O或S的杂原子的3-5元杂环烷基； 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;
所述C 1-6烷基任选地被1-3个R 3a取代；所述R 3a各自独立地选自：卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选 自N、O或S的杂原子的5-8元杂芳基、C 2- 6炔基、或氧代； 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;
所述C 3-5环烷基任选地被1-3个R 3b取代；所述R 3b各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
所述3-5元杂环烷基任选地被1-3个R 3c取代；所述R 3c各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
环B选自C 6-10芳基，任选地被1-5个R 4取代；所述R 4各自独立地选自卤素、-CN、-OH、-NH 2、C 3-4环烷基、或任选被1-3个卤素取代的C 1-3烷基； 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;
所述R 5、R 6各自独立地选自氢、或C 1-6烷基。 The R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
在一些实施方案中，上述R 1各自独立地选自氟、氯、溴、或C 1-3烷基；在一些实施方案中，上述R 1各自独立地选自氟、或甲基。 In some embodiments, 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.
在一些实施方案中，上述环A选自5元杂环基、或6元杂环基；在一些实施方案中，上述环A选自5元杂环烷基、6元杂环烷基、5元杂芳基、或6元杂芳基；在一些实施方案中，上述环A选自
Figure PCTCN2020074071-appb-000003
在一些实施方案中，上述环A选自
Figure PCTCN2020074071-appb-000004
在一些实施方案中，上述环A为
Figure PCTCN2020074071-appb-000005
所述环A的取代基如前所述。在一些实施方案中，环A任选地被1个R 1取代。 In some embodiments, 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
Figure PCTCN2020074071-appb-000003
In some embodiments, the aforementioned ring A is selected from
Figure PCTCN2020074071-appb-000004
In some embodiments, the aforementioned ring A is
Figure PCTCN2020074071-appb-000005
The substituents of the ring A are as described above. In some embodiments, Ring A is optionally substituted with 1 R 1 .
在一些实施方案中，上述环A选自
Figure PCTCN2020074071-appb-000006
Figure PCTCN2020074071-appb-000007
在一些实施方案中，上述环A为
Figure PCTCN2020074071-appb-000008
In some embodiments, the aforementioned ring A is selected from
Figure PCTCN2020074071-appb-000006
Figure PCTCN2020074071-appb-000007
In some embodiments, the aforementioned ring A is
Figure PCTCN2020074071-appb-000008
在一些实施方案中，上述R 2选自H、氟、氯、溴、或C 1-3烷基；在一些实施方案中，上述R 2选自H、氯、或甲基。在一些实施方案中，上述R 2为氟、氯或溴；在一些实施方案中，上述R 2为氯。在一些实施方案中，上述R 2为C 1-3烷基，例如甲基。 In some embodiments, 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.
在一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、或氧代；在一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或氧代；在一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、或-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、或C 2-3炔基；在一些实施方案中，上述R 3a选自氟、氯、溴、-OH、-CN、C 1-4烷氧基或C 1-4烷氨基；在一些实施方案中，上述R 3a选自氟。 In some embodiments, 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; In some 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)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 alkyne In some embodiments, the above R 3a is each independently selected from fluorine, chlorine, bromine, or -C(O)NHC 1-3 alkyl, containing 1-3 selected from N, O or S heteroatom 5 or 6 membered heteroaryl, or C 2-3 alkynyl; in some embodiments, the above-mentioned R 3a is selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy Group or C 1-4 alkylamino; in some embodiments, R 3a above is selected from fluoro.
在另外一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、或氧代；在另外一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或氧代；在另外一些实施方案中，上述R 3a各自独立地选自氟、氯、溴、或-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、或C 2-3炔基；在一些实施方案中，上述R 3a选自氟、氯、溴、-OH、-CN、C 1-4烷氧基或C 1-4烷氨基；在一些实施方案中，上述R 3a选自氟。 In other embodiments, 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)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 5 or 6-membered heteroaryl, C 2-3 alkynyl, or oxo with 1-3 heteroatoms selected from N, O or S; in other embodiments, each of the above R 3a is independently selected from fluorine , Chloro, bromo, 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; In some embodiments, the above R 3a is selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy or C 1-4 alkylamino; in some embodiments, the above R 3a is selected from fluorine .
在一些实施方案中，上述R 3b各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；在一些实施方案中，上述R 3b各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基；在一些实施方案中，上述R 3b各自独立地选自氟、氯、溴、-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或任选被1-3个氟取代的C 1-3烷基；在一些实施方案中，上述R 3b选自氟、-C(O)NHCH 3、
Figure PCTCN2020074071-appb-000009
或C 2炔基；在一些实施方案中，上述R 3b各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、 C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；在一些实施方案中，上述R 3b选自氟和-C(O)NHCH 3。 In some embodiments, 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)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 from a heteroatom of N, O or S, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted with 1-3 fluorines; in some embodiments Wherein, the above R 3b are each independently selected from fluorine, chlorine, bromine, -C(O)NHC 1-3 alkyl, 5 or 6-membered heteroaromatics containing 1-3 heteroatoms selected from N, O or S Group, C 2-3 alkynyl, or C 1-3 alkyl optionally substituted by 1-3 fluorine; in some embodiments, the above-mentioned R 3b is selected from fluorine, -C(O)NHCH 3 ,
Figure PCTCN2020074071-appb-000009
Or C 2 alkynyl; in some embodiments, the above R 3b 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)OC 1-4 alkyl, -C(O) C 1-4 alkyl, -SO 2 C 1-4 alkyl, or optionally substituted with 1-3 fluoro, chloro, bromo, or hydroxy-substituted C 1-3 alkyl; in some embodiments, R 3b above It is selected from fluorine and -C(O)NHCH 3 .
在一些实施方案中，上述R 3c各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；在一些实施方案中，上述R 3c各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基；在一些实施方案中，上述R 3c各自独立地选自氟、氯、溴、-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或任选被1-3个氟取代的C 1-3烷基；在一些实施方案中，上述R 3c选自
Figure PCTCN2020074071-appb-000010
或三氟甲基；在一些实施方案中，上述R 3c各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；在一些实施方案中，上述R 3c选自甲基或三氟甲基。 In some embodiments, 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 , -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 from a heteroatom of N, O or S, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted with 1-3 fluorines; in some embodiments Wherein , the above R 3c are each independently selected from fluorine, chlorine, bromine, -C(O)NHC 1-3 alkyl, 5 or 6-membered heteroaromatics containing 1-3 heteroatoms selected from N, O or S Group, C 2-3 alkynyl, or C 1-3 alkyl optionally substituted with 1-3 fluorine; in some embodiments, the above R 3c is selected from
Figure PCTCN2020074071-appb-000010
Or trifluoromethyl; in some embodiments, each of the above R 3c is independently selected from fluorine, chlorine, bromine, -OH, -CN, C 1-4 alkoxy, C 1-4 alkylamino, or optionally C 1-3 alkyl substituted with 1-3 fluorine, chlorine, bromine or hydroxy; in some embodiments, the above-mentioned R 3c is selected from methyl or trifluoromethyl.
在一些实施方案中，上述R 3选自C 1-4烷基、C 3-6环烷基、或含有1-3个选自N、O或S的杂原子的3-6元杂环烷基；在一些实施方案中，上述R 3选自C 1-3烷基、C 3-6环烷基、或含有1-3个选自N、O或S的杂原子的3、4或5元杂环烷基；在一些实施方案中，上述R 3选自甲基、乙基、丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、或氮杂环丁基；在一些实施方案中，上述R 3选自丙基、环丙基、环丁基、或氧杂环丁基；在一些实施方案中，上述R 3选自异丙基、环丁基、或氧杂环丁基；所述R 3的取代基如前所述。 In some embodiments, 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 In some embodiments, 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 In some embodiments, 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 oxetanyl; the substituent of R 3 is as described above.
在另外一些实施方案中，上述R 3选自C 1-3烷基、C 3-4环烷基、或含有1-3个选自N、O或S的杂原子的3、4或5元杂环烷基；在另外一些实施方案中，上述R 3选自C 1-3烷基、C 4环烷基、或含有1-3个选自N、O或S的杂原子的4元杂环烷基；在另外一些实施方案中，上述R 3选自甲基、乙基、丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、或氮杂环丁基；在一些实施方案中，上述R 3选自丙基、环丙基、环丁基、或氧杂环丁基；在一些实施方案中，上述R 3选自丙基、环丁基、或氧杂环丁基；所述R 3的取代基如前所述。 In other embodiments, 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 oxetanyl; in some embodiments, the above-mentioned R 3 is selected from propyl , Cyclobutyl, or oxetanyl; the substituents of R 3 are as described above.
在一些实施方案中，上述R 3为C 1-3烷基；所述C 1-3烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O 或S的杂原子的5或6元杂芳基、C 2-3炔基、或氧代。 In some embodiments, 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.
在一些实施方案中，上述R 3为C 1-3烷基；所述C 1-3烷基任选被1-3个选自以下的基团取代：氟、氯、溴、或-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、或C 2-3炔基。在一些实施方案中，上述R 3为任选被1、2或3个氟取代的丙基或异丙基。 In some embodiments, 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. In some embodiments, the above-mentioned R 3 is propyl or isopropyl optionally substituted with 1, 2 or 3 fluorines.
在一些实施方案中，上述R 3为C 3-5环烷基，所述C 3-5环烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基。在一些实施方案中，上述R 3为任选被1、2或3个选自氟和-C(O)NHCH 3的基团取代的环丁基。 In some embodiments, 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. In some embodiments, the above-mentioned R 3 is cyclobutyl optionally substituted with 1, 2 or 3 groups selected from fluorine and -C(O)NHCH 3 .
在一些实施方案中，上述R 3为含有1-3个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基。在一些实施方案中，上述R 3为含有1个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被1个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、或任选被1-3个氟取代的C 1-3烷基。在一些实施方案中，上述R 3为含有1个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被甲基或三氟甲基取代。 In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
在一些实施方案中，上述R 3选自
Figure PCTCN2020074071-appb-000011
Figure PCTCN2020074071-appb-000012
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000013
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000014
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000015
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000016
In some embodiments, the above-mentioned R 3 is selected from
Figure PCTCN2020074071-appb-000011
Figure PCTCN2020074071-appb-000012
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000013
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000014
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000015
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000016
在一些实施方案中，所述R 4各自独立地选自氟、氯、溴、-CN、任选被1-3个氟、氯、溴、取代的C 1-3烷基、-OH、或-NH 2；在一些实施方案中，所述R 4各自独立地选自氟、氯、-CN、任选被1-3个氟取代的C 1-3烷基、或-NH 2；在一些实施方案中，所述R 4各自独立地选自氟、氯、-CN、甲基、或-NH 2。 In some embodiments, 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 .
在一些具体实施方案中，所述R 4各自独立地选自氟、氯、-CN、任选被1-3个氟取代的C 1-3烷基；在一些具体实施方案中，所述R 4各自独立地选自氟、氯、-CN、二氟甲基、或三氟甲基。 In some specific embodiments, 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.
在一些实施方案中，上述环B选自5元杂芳基、6元杂芳基、或苯基；在一些实施方案中，上述环B选自吡啶基、或苯基；在一些实施方案中，上述环B选自
Figure PCTCN2020074071-appb-000017
或苯基；在一些实施方案中，上述环B为苯基；上述实施方案中所述环B的取代基如前所述，例如，上述实施方案中所述环B任选被1或2个R 4取代，R 4各自独立地选自氟、氯、-CN、任选被1-3个氟取代的C 1-3烷基、或-NH 2；或者上述实施方案中所述环B任选被2个选自氟、氯、-CN、-CH 3或-NH 2的基团取代。 In some embodiments, 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
Figure PCTCN2020074071-appb-000017
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 .
在一些实施方案中，上述环B选自
Figure PCTCN2020074071-appb-000018
Figure PCTCN2020074071-appb-000019
在一些实施方案中，上述环B为
Figure PCTCN2020074071-appb-000020
所述R 4a、R 4b、R 4c、R 4d和R 4e各自独立地如R 4所述；例如，所述R 4a为氟，且所述R 4b和R 4c为氟、氯、-CN、甲基、或-NH 2。 In some embodiments, the aforementioned ring B is selected from
Figure PCTCN2020074071-appb-000018
Figure PCTCN2020074071-appb-000019
In some embodiments, the aforementioned ring B is
Figure PCTCN2020074071-appb-000020
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 .
在一些实施方案中，上述环B选自
Figure PCTCN2020074071-appb-000021
Figure PCTCN2020074071-appb-000022
在一些实施方案中，上述环B为
Figure PCTCN2020074071-appb-000023
Figure PCTCN2020074071-appb-000024
In some embodiments, the aforementioned ring B is selected from
Figure PCTCN2020074071-appb-000021
Figure PCTCN2020074071-appb-000022
In some embodiments, the aforementioned ring B is
Figure PCTCN2020074071-appb-000023
Figure PCTCN2020074071-appb-000024
在另外一些实施方案中，上述环B选自苯基；所述环B的取代基如前所述。In other embodiments, the aforementioned ring B is selected from phenyl; the substituents of the ring B are as described above.
在另外一些实施方案中，上述环B选自
Figure PCTCN2020074071-appb-000025
所述R 4a、R 4b、R 4c、R 4d和R 4e各自独立地如R 4所述。 In other embodiments, the aforementioned ring B is selected from
Figure PCTCN2020074071-appb-000025
The R 4a , R 4b , R 4c , R 4d and R 4e are each independently as described for R 4 .
在另外一些实施方案中，上述环B选自
Figure PCTCN2020074071-appb-000026
Figure PCTCN2020074071-appb-000027
In other embodiments, the aforementioned ring B is selected from
Figure PCTCN2020074071-appb-000026
Figure PCTCN2020074071-appb-000027
在一些实施方案中，本申请的式I化合物、其立体异构体或其药学上可接受的盐选自式II化合物、其立体异构体或其药学上可接受的盐，In some embodiments, 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,
Figure PCTCN2020074071-appb-000028
Figure PCTCN2020074071-appb-000028
其中，n选自1、或2；Wherein, n is selected from 1, or 2;
R 2、R 3、R 4a、或R 4c的定义如前所示。 The definitions of R 2 , R 3 , R 4a , or R 4c are as described above.
在一些实施方案中，式II中的n为1。In some embodiments, n in Formula II is 1.
在一些实施方案中，式II中的R 2选自H、氟、氯、溴、或C 1-3烷基；在一些实施方案中，R 2选自H、氯、或甲基；在一些实施方案中，R 2为氯或甲基。 In some embodiments, 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.
在一些实施方案中，式II中的R 3为C 1-3烷基；所述C 1-3烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或氧代。 In some embodiments, 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.
在一些实施方案中，式II中的R 3为C 1-3烷基；所述C 1-3烷基任选被1-3个选自以下的基团取代：氟、氯、溴、或-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、或C 2-3炔基。在一些实施方案中，式II中的R 3为任选被1、2或3个氟取代的丙基 或异丙基。 In some embodiments, 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. In some embodiments, R 3 in Formula II is propyl or isopropyl optionally substituted with 1, 2, or 3 fluorines.
在一些实施方案中，式II中的R 3为C 3-4环烷基，所述C 3-4环烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基。在一些实施方案中，上述R 3为任选被1、2或3个选自氟和-C(O)NHCH 3的基团取代的环丁基。 In some embodiments, 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 . In some embodiments, the above-mentioned R 3 is cyclobutyl optionally substituted with 1, 2 or 3 groups selected from fluorine and -C(O)NHCH 3 .
在一些实施方案中，式II中的R 3为含有1-3个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被1-3个选自以下的基团取代：氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基。在一些实施方案中，式II中的R 3为含有1个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基或任选被1-3个氟取代的C 1-3烷基取代。在一些实施方案中，式II中的R 3为含有1个选自N、O或S的杂原子的3、4或5元杂环烷基，所述杂环烷基任选被甲基或三氟甲基取代。 In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000029
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000030
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000031
在一些实施方案中，上述R 3为
Figure PCTCN2020074071-appb-000032
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000029
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000030
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000031
In some embodiments, R 3 above is
Figure PCTCN2020074071-appb-000032
在一些实施方案中，式II中的R 4a和R 4c各自独立地选自氟、氯、溴、-CN、任选被1-3个氟、氯、溴、取代的C 1-3烷基、-OH、或-NH 2。在一些实施方案中，式II中的R 4a和R 4c各自独立地选自氟、氯、-CN、甲基、或-NH 2。在一些实施方案中，式II中的R 4a为氟，且R 4c为氟、氯、-CN、甲基、或-NH 2。上述实施方案中的各取代基之间可以彼此组合。例如，在一些实施方案中，式II中n为1；R 2选自H、氟、氯、溴、或C 1-3烷基；R 3为
Figure PCTCN2020074071-appb-000033
Figure PCTCN2020074071-appb-000034
R 4a为氟，且R 4c为氟、氯、-CN、甲基、或-NH 2。 In some embodiments, 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 . In some embodiments, R 4a and R 4c in Formula II are each independently selected from fluorine, chlorine, -CN, methyl, or -NH 2 . In some embodiments, R 4a in Formula II is fluorine, and R 4c is fluorine, chlorine, -CN, methyl, or -NH 2 . The substituents in the above embodiments can be combined with each other. For example, in some embodiments, n in formula II is 1; R 2 is selected from H, fluorine, chlorine, bromine, or C 1-3 alkyl; R 3 is
Figure PCTCN2020074071-appb-000033
Figure PCTCN2020074071-appb-000034
R 4a is fluorine, and R 4c is fluorine, chlorine, -CN, methyl, or -NH 2 .
在一些实施方案中，本申请的式I化合物、其立体异构体或其药学上可接受的盐选自以下化合物、其立体异构体或其药学上可接收的盐：In some embodiments, the compound of formula I of the present application, its stereoisomers or pharmaceutically acceptable salts thereof are selected from the following compounds, their stereoisomers or their pharmaceutically acceptable salts:
Figure PCTCN2020074071-appb-000035
Figure PCTCN2020074071-appb-000035
另一方面，本申请还提供药物组合物，其包含本申请的式I或式II化合物、或其立体异构体、或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接 受的辅料。On the other hand, 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. In some embodiments, the pharmaceutical composition of the application further includes pharmaceutically acceptable excipients.
另一方面，本申请还提供一种治疗或预防受益于衣壳蛋白装配抑制的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述式I或式II所示的化合物、其立体异构体、或其药学上可接受的盐或上述药物组合物。On the other hand, 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 The compound, its stereoisomer, or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
另一方面，本申请还提供了上述式I或式II化合物、其立体异构体、或其药学上可接受的盐、或上述药物组合物在制备治疗或预防受益于衣壳蛋白装配抑制的疾病的药物中的用途。On the other hand, 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.
另一方面，本申请还提供了上述式I或式II化合物、其立体异构体、或其药学上可接受的盐、或上述药物组合物在治疗或预防受益于衣壳蛋白装配抑制的疾病中的用途。On the other hand, 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.
另一方面，本申请还提供了用于治疗或预防受益于衣壳蛋白装配抑制的疾病的上述式I或式II化合物、其立体异构体、或其药学上可接受的盐、或上述药物组合物。On the other hand, 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.
在本申请的部分实施方式中，所述受益于衣壳蛋白装配抑制的疾病的指乙型肝炎病毒(HBV)感染引起的疾病。In some embodiments of the present application, the diseases that benefit from capsid protein assembly inhibition refer to diseases caused by hepatitis B virus (HBV) infection.
在本申请的部分实施方式中，所述受益于衣壳蛋白装配抑制的疾病的指乙型肝炎病毒(HBV)感染引起的肝脏疾病。In some embodiments of the present application, the diseases that benefit from capsid protein assembly inhibition refer to liver diseases caused by hepatitis B virus (HBV) infection.
在本申请的部分实施方式中，所述治疗受益于衣壳蛋白装配抑制的疾病指控制、降低或清除HBV以预防、缓解或治愈受感染患者的肝脏疾病。In some embodiments of the present application, 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.
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms used in this application have the following meanings. A specific term should not be regarded as uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
如本申请所用，当所述环A与吡咯形成并环结构时，如果吡咯的N原子是环A基团的成环原子，则所述N原子为共用N原子。As used in this application, when the ring A and pyrrole form a conjugated ring structure, if the N atom of the pyrrole is a ring atom of the ring A group, the N atom is a common N atom.
本申请中的结构单元或者基团中的虚线(---)表示共价键，可以是单键或双键。例如环A选自
Figure PCTCN2020074071-appb-000036
时，表示其可以通过双键或单键与相邻的原子连接，具体例如
Figure PCTCN2020074071-appb-000037
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. For example, ring A is selected from
Figure PCTCN2020074071-appb-000036
When it means that it can be connected to adjacent atoms through double bonds or single bonds, for example
Figure PCTCN2020074071-appb-000037
本申请中的某些结构单元或者基团中的共价键未与具体的原子连接时，表示该共价键可以与该结构单元或者基团中的任意原子连接，只要不违背价键连接规则。When 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 .
术语“被取代”是指特定基团上的任意一个或多个氢原子被取代基取代，只要特定基团的 价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "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. When the substituent is oxo (ie =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 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. For example, 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 ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that cannot exist in space and/or cannot be synthesized will not be introduced.
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C 1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。 C mn in this document means that the part has an integer number of carbon atoms in a given range. For example, "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. For example, C 1-3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L’-Z中L’代表共价键时表示该结构实际上是A-Z。When one of the variables is selected from a covalent bond, it means that the two connected groups are directly connected. For example, when L'in A-L'-Z represents a covalent bond, it means that the structure is actually A-Z.
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2020074071-appb-000038
表示其可在环己基或者环己二烯上的任意一个位置发生取代。 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. For example, structural unit
Figure PCTCN2020074071-appb-000038
It means that it can be substituted at any position on cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C 1-3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。 The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1 . The alkyl group may be linear or branched. For example, the term "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.). Similarly, the alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio have the same definition as above. As another example, the term "C 1-3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, and isopropyl).
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烷氨基”指-NH-烷基。The term "alkylamino" refers to -NH-alkyl.
术语“氧代”指＝O。The term "oxo" refers to =O.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙 炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。 The term "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. Non-limiting examples of 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.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环、3至8元环或3至5元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、二环[1.1.1]戊-1-基等。例如，C 3-4环烷基包括环丙基和环丁基。 The term "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. For example, C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
术语“杂环基”是指完全饱和的或不饱和的并且可以以单环、桥环或螺环存在的环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至8元环、3至7元环或3至5元环。杂环基的非限制性实例包括但不限于环氧乙烷基、氧杂环丁烷、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基、吡啶基、嘧啶基、吡嗪基、噁唑基或吡唑基等。The term "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. Non-limiting examples of 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.
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至8元环、3至7元环或3至5元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基(氧杂环丁烷)、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。优选为具有4或5个环原子的单环杂环烷基。The term "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. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfiethane, and azaethylenyl groups, and non-limiting examples of 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, Examples of isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl , Piperazinyl, 1,4-thiaoxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, 7 member Examples of heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thieppanyl. Preferably, it is a monocyclic heterocycloalkyl group having 5 or 6 ring atoms. Preferably, it is a monocyclic heterocycloalkyl group having 4 or 5 ring atoms.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, 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.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。The term "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. Non-limiting examples of 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.
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相 关的一个或多个症状，且包括：The term "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:
(i)抑制疾病或疾病状态，即遏制其发展；(i) Suppress the disease or disease state, that is, curb its development;
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) Alleviate the disease or disease state, even if the disease or disease state subsides.
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "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.
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。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 dosage of the compound of the present application for the onset of one or more symptoms of a specific disease, condition, or disorder described in. 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.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "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.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As pharmaceutically acceptable 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. .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "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.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "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.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood as an open, non-exclusive meaning, that is, "including but not limited to".
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions via 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.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 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. Examples of 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.
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。 Certain isotope-labeled compounds of the application (such as those labeled with 3 H and 14 C) 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. 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.
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。 In addition, substitution with heavier isotopes (such as deuterium (ie 2 H)) 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.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。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.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。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.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。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.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。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.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, 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.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。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.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产 品。The pharmaceutical composition is also suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。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. For example, 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 μg/kg to about 1 g/kg body weight/day. In certain embodiments, 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.
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。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.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction in the specific embodiment of the application is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the application and the required reagents and materials. In order to obtain the compound of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。An important consideration in the planning of synthetic routes in this field is to select suitable protective groups for reactive functional groups (such as amino groups in this application). For example, refer to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited in this application are incorporated into this application as a whole.
在一些实施方案中，本申请通式I的化合物可以由有机合成领域技术人员通过以下路线，用本领域的通用或常规方法来制备：In some embodiments, 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:
路线1：Route 1:
Figure PCTCN2020074071-appb-000039
Figure PCTCN2020074071-appb-000039
路线2：Route 2:
Figure PCTCN2020074071-appb-000040
Figure PCTCN2020074071-appb-000040
环B、R 2、R 3和n如前文所定义，R 7、R 8分别独立地选自C 1-6烷基。 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.
本申请采用下述缩略词：This application uses the following acronyms:
EA代表乙酸乙酯；PE代表石油醚；NCS代表N-氯代琥珀酰亚胺；DMF代表N,N-二甲基甲酰胺；HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；h代表小时；THF代表四氢呋喃。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.
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。For clarity, examples are further used to illustrate the present invention, but the examples do not limit the scope of the application. All reagents used in this application are commercially available and can be used without further purification.
具体实施方式detailed description
本申请核磁共振色谱(NMR)使用BRUKER-500核磁共振仪测定，化学位移以四甲基硅烷(TMS＝δ0.00)为内标，核磁共振氢谱数据记录的格式为：质子数，峰型(s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰)，耦合常数(以赫兹Hz为单位)。质谱使用的仪器为AB SCIEX Triple TOF 4600或AB SCIEX 3200QTRAP。The nuclear magnetic resonance chromatography (NMR) of this application is measured by BRUKER-500 nuclear magnetic resonance instrument, the chemical shift is measured with tetramethylsilane (TMS=δ0.00) as the internal standard, and 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.
实施例1(R)-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 1 (R)-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino) Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000041
Figure PCTCN2020074071-appb-000041
步骤A：反应瓶中加入DL-脯氨酸(3.0g)、甲酸(67.2g)，加毕，在冰浴下缓慢滴加醋酸酐(19.95g)，加毕，撤去冰浴，室温搅拌反应5.0h，向反应液中加入100mL冰水，浓缩反应液得到N-甲酰基-脯氨酸(3.5g)。MS(ESI-,[M-H] -)m/z:142.2. 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
步骤B：反应瓶中加入醋酸酐(50mL)、N-甲酰基-脯氨酸(3.0g)和丙炔酸乙酯(10.28g)，加毕，加热至135℃反应5h，冷却至室温，向其中加入300mL冰水，用乙酸乙酯(3*100mL)萃取，合并有机层，饱和碳酸氢钠溶液洗涤有机层、饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝50:1)，制得2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.2g)。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. Add 300 mL of ice water to it, extract with ethyl acetate (3*100 mL), combine the organic layers, wash the organic layer with saturated sodium bicarbonate solution, wash the organic layer with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, and reduce pressure The solvent was evaporated, and the obtained crude product was separated by silica gel column chromatography (PE:EA=50:1) to obtain 2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (1.2g).
1H-NMR(500MHz,DMSO-d 6)：δ6.71(d,J＝2.5Hz,1H),6.41(s,1H),4.13(q,J＝7.5Hz,2H),3.95(s,J＝7.0Hz,1H),2.93(t,J＝7.5Hz,1H),2.42-2.44(m,2H),1.24(s,J＝7.5Hz,6H).MS(ESI+,[M+H] +)m/z:180.1. 1 H-NMR (500MHz, DMSO-d 6 ): δ 6.71 (d, J = 2.5 Hz, 1H), 6.41 (s, 1H), 4.13 (q, J = 7.5 Hz, 2H), 3.95 (s, J=7.0Hz,1H),2.93(t,J=7.5Hz,1H),2.42-2.44(m,2H),1.24(s,J=7.5Hz,6H).MS(ESI+,[M+H] + )m/z:180.1.
步骤C：反应瓶中加入2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.1g)、二氯甲烷(40mL)，冰浴下滴加草酰氯单乙酯(2.51g)，加毕，分批加入三氯化铝(2.86g)，加毕，撤去冰浴室温搅拌反应2.0h，将反应液倒入200mL冰水中，用二氯甲烷(3*100mL)萃取，合并有机层，饱和碳酸氢钠溶液洗涤有机层、饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝50:1)制得5-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.1g)。Step C: Add 2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (1.1g) and dichloromethane (40mL) into the reaction flask, add oxalyl chloride monoethyl ester (2.51g) dropwise under ice bath ), after the addition, add aluminum trichloride (2.86g) in batches, after the addition, remove the ice bath and stir the reaction for 2.0h, pour the reaction solution into 200mL ice water, extract with dichloromethane (3*100mL), and combine The organic layer was washed with saturated sodium bicarbonate solution, the organic layer was washed with saturated sodium chloride aqueous solution, the organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography (PE:EA=50: 1) Ethyl 5-(2-ethoxy-2-oxoacetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylate (1.1 g) was prepared.
1H-NMR(500MHz,DMSO-d 6)：δ7.52(s,1H),4.35(q,J＝7.0Hz,2H),4.27(m,2H),4.21(q,J＝7.0Hz,2H),3.04(t,J＝7.5Hz,2H),2.48-2.52(m,2H),1.26-1.29(m,6H).MS(ESI+,[M+Na] +)m/z:302.1. 1 H-NMR (500MHz, DMSO-d 6 ): δ7.52 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 4.27 (m, 2H), 4.21 (q, J = 7.0 Hz, 2H),3.04(t,J=7.5Hz,2H),2.48-2.52(m,2H),1.26-1.29(m,6H).MS(ESI+,[M+Na] + )m/z: 302.1.
步骤D：反应瓶中加入5-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.1g)、甲醇(10mL)，冰浴下缓慢滴加NaOH(315mg)的水(5mL)溶液，加毕室温搅拌10min，用2N的稀盐酸调pH至2-3，用乙酸乙酯(3*50mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，抽滤，滤液浓缩旋干得到2-(7-(乙氧基羰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸(880mg)。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).
1H-NMR(500MHz,DMSO-d 6)：δ7.49(s,1H),4.26-4.29(m,2H),4.20(q,J＝7.0Hz,2H),3.03(t,J＝7.5Hz,2H),2.48-2.52(m,2H),1.25-1.28(m,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:250.2. 1 H-NMR (500MHz, DMSO-d 6 ): δ7.49 (s, 1H), 4.26-4.29 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.03 (t, J = 7.5 Hz,2H),2.48-2.52(m,2H),1.25-1.28(m,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z: 250.2.
步骤E:反应瓶中加入N,N-二甲基甲酰胺(15mL)、2-(7-(乙氧基羰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸(400mg)、HATU(1.5g)、(R)-1,1,1-三氟丙-2-胺盐酸盐(262mg)和N,N-二异丙基乙胺(617mg)，加毕，室温搅拌2.0h，将反应液倒入200mL水中， 用乙酸乙酯(3*50mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝4:1)制得(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(340mg)。Step E: Add N,N-dimethylformamide (15mL), 2-(7-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2 to the reaction flask -Oxoacetic acid (400mg), HATU (1.5g), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (262mg) and N,N-diisopropylethylamine (617mg) ), after the addition, stir at room temperature for 2.0h, pour the reaction solution into 200mL water, 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, The solvent was evaporated under reduced pressure, and the crude product obtained was separated by silica gel column chromatography (PE:EA=4:1) to obtain (R)-5-(2-oxo-2-((1,1,1-trifluoropropane) -2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (340 mg).
MS(ESI+,[M+H] +)m/z:347.3. MS(ESI+,[M+H] + )m/z:347.3.
步骤F：反应瓶中依次加入(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(340mg)、甲醇(10mL)和NaOH(79mg)的水(5mL)溶液，加毕，加热反应温度至80℃反应12h，用1N的稀盐酸调pH至2～3后，乙酸乙酯(3*50mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥有机相，抽滤，滤液浓缩旋干得(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸(280mg)。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 ℃ 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-dihydro-1H-pyrrolazine-7-carboxylic acid (280mg ).
1H-NMR(500MHz,DMSO-d 6)：δ12.25(s,1H),9.33(d,J＝9.0Hz,1H),7.62(s,1H),4.70(q,J＝7.5Hz,1H),4.29(t,J＝7.5Hz,2H),3.01-3.03(m,J＝7.5Hz,2H),2.54(t,J＝7.5Hz,2H),1.35(s,3H).MS(ESI-,[M-H] -)m/z:317.3. 1 H-NMR (500MHz, DMSO-d 6 ): δ 12.25 (s, 1H), 9.33 (d, J = 9.0 Hz, 1H), 7.62 (s, 1H), 4.70 (q, J = 7.5 Hz, 1H), 4.29(t,J=7.5Hz,2H),3.01-3.03(m,J=7.5Hz,2H),2.54(t,J=7.5Hz,2H),1.35(s,3H).MS( ESI-,[MH] - )m/z:317.3.
步骤G：反应瓶中，依次加入甲苯(15mL)、(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸(260mg)和氯化亚砜(1.9g)，加毕氮气保护下，加热反应至115℃反应1.0h，反应结束后降至室温，减压旋蒸除去溶剂，得到酰氯中间体(335mg)。室温下，将酰氯中间体(335mg)溶于N,N-二甲基乙酰胺(12mL)，加入5-氨基-2-氟苯腈(222mg)，加毕100℃下反应1.0h。反应结束后降至室温，将反应液倒入100mL水中，用乙酸乙酯(3*50mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经柱层析(PE：EA＝3：1)洗脱，得到(R)-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(130mg)。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). At room temperature, the acid chloride intermediate (335 mg) was dissolved in N,N-dimethylacetamide (12 mL), 5-amino-2-fluorobenzonitrile (222 mg) was added, and the reaction was completed at 100° C. for 1.0 h. After the reaction, it was cooled to room temperature, the reaction solution was poured into 100 mL of water, extracted with ethyl acetate (3*50 mL), the organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure , The obtained crude product was eluted by column chromatography (PE:EA=3:1) to obtain (R)-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-( (1,1,1-Trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide (130 mg).
1H-NMR(500MHz,DMSO-d 6)：δ10.23(s,1H),9.37(d,J＝9.0Hz,1H),8.27(m,1H),8.16(s,1H),8.05(m,1H),7.50(t,J＝9.5Hz,1H),4.71-4.73(m,1H),4.30(t,J＝8.0Hz,2H),3.07-3.10(m,J＝7.5Hz,2H),2.55(t,J＝7.5Hz,2H),1.40(d,J＝7.0Hz,3H).MS(ESI+,[M+H] +)m/z:437.3. 1 H-NMR (500MHz, DMSO-d 6 ): δ10.23 (s, 1H), 9.37 (d, J = 9.0 Hz, 1H), 8.27 (m, 1H), 8.16 (s, 1H), 8.05 ( m,1H),7.50(t,J=9.5Hz,1H),4.71-4.73(m,1H),4.30(t,J=8.0Hz,2H),3.07-3.10(m,J=7.5Hz,2H ),2.55(t,J=7.5Hz,2H),1.40(d,J=7.0Hz,3H).MS(ESI+,[M+H] + )m/z: 437.3
实施例2(S)-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 2 (S)-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino) Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000042
Figure PCTCN2020074071-appb-000042
步骤A：参照实施例1步骤E用(S)-1,1,1-三氟丙-2-胺盐酸盐替代(R)-1,1,1-三氟丙-2-胺盐酸盐制得(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯。MS(ESI+,M+H] +)m/z:347.3. 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.
步骤B：参照实施例1的步骤用(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替代(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯制得(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸。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.
1H-NMR(500MHz,DMSO-d 6)：δ12.20(s,1H),9.33(d,J＝8.5Hz,1H),7.62(s,1H),4.69(q,J＝7.5Hz,1H),4.29(t,J＝7.5Hz,2H),3.03(t,J＝7.5Hz,2H),2.54(t,J＝7.5Hz,2H),1.35(s,3H).MS(ESI-,[M-H] -)m/z:317.3. 1 H-NMR (500MHz, DMSO-d 6 ): δ12.20 (s, 1H), 9.33 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 4.69 (q, J = 7.5 Hz, 1H), 4.29(t,J=7.5Hz,2H),3.03(t,J=7.5Hz,2H),2.54(t,J=7.5Hz,2H),1.35(s,3H).MS(ESI- ,[MH] - )m/z:317.3.
步骤C：参照实施例1中的步骤G用(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替代(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸制得(S)-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。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.
1H-NMR(500MHz,DMSO-d 6)：δ10.23(s,1H),9.37(d,J＝9.0Hz,1H),8.24-8.26(m,1H),8.16(s,1H),8.02-8.05(m,1H),7.50(t,J＝9.5Hz,1H),4.70-4.74(m,1H),4.29-4.31(m,2H),3.07-3.09(m,J＝8.0Hz,2H),2.55(q,J＝7.5Hz,2H),1.37(d,J＝7.5Hz,3H).MS(ESI+,[M+H] +)m/z:437.3. 1 H-NMR (500MHz, DMSO-d 6 ): δ 10.23 (s, 1H), 9.37 (d, J = 9.0 Hz, 1H), 8.24-8.26 (m, 1H), 8.16 (s, 1H), 8.02-8.05(m,1H),7.50(t,J=9.5Hz,1H),4.70-4.74(m,1H),4.29-4.31(m,2H),3.07-3.09(m,J=8.0Hz, 2H),2.55(q,J=7.5Hz,2H),1.37(d,J=7.5Hz,3H).MS(ESI+,[M+H] + )m/z: 437.3
实施例3(S)-6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,-1,3-二氢-1H-吡咯嗪-7-甲酰胺Example 3 (S)-6-chloro-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,-1,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000043
Figure PCTCN2020074071-appb-000043
步骤A：微波管中依次加入(S)-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(80mg,0.183mmol)、N,N-二甲基甲酰胺(3mL)和N-氯代丁二酰亚胺(49mg,0.366mmol)加毕，120℃下微波反应2.0h，将反应液倒入50mL水中，用乙酸乙酯(2*40mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经柱层析(PE:EA＝4:1)洗脱，得到(S)-6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(28mg)。 1H-NMR(500MHz,DMSO-d 6)：δ10.08(s,1H),9.46(s,1H),8.19(s,1H),7.97(s,1H),7.52-7.55(m,1H),4.70-4.74(m,1H),4.30-4.33(m,2H),3.10-3.13(m,2H),2.51(s,2H),1.32(s,3H).MS(ESI-,[M-H] -)m/z:469.1. 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℃ 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. The crude product was eluted by column chromatography (PE:EA=4:1) to obtain (S)-6-chloro-N-(3-cyano- 4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine -7-Carboxamide (28mg). 1 H-NMR (500MHz, DMSO-d 6 ): δ10.08 (s, 1H), 9.46 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.52-7.55 (m, 1H) ),4.70-4.74(m,1H),4.30-4.33(m,2H),3.10-3.13(m,2H),2.51(s,2H),1.32(s,3H).MS(ESI-,(MH ] - )m/z:469.1.
实施例4 6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-2,3-二氢-1H-吡咯-7-甲酰胺Example 4 6-Chloro-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((3-(trifluoromethyl)oxetane-3- (Amino)acetyl)-2,3-dihydro-1H-pyrrole-7-carboxamide
Figure PCTCN2020074071-appb-000044
Figure PCTCN2020074071-appb-000044
步骤A：反应瓶中，氮气保护下，依次加入THF(50mL)、2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.5g)、5-氨基-2-氟苯腈(1.36g)，冰浴下缓慢滴加双(三甲基甲硅烷基)氨基锂(2.80g,1.0M in THF)，加毕后转至室温反应2.0h。反应结束后缓慢倒至100mL冰水中淬灭，乙酸乙酯(2*100mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝1:1)制得N-(3-氰基-4-氟苯基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(1.3g)。MS(ESI-,[M-H] -)m/z:268.3. 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. After the reaction, it was slowly poured into 100 mL ice water for quenching, extracted with ethyl acetate (2*100 mL), combined the organic layers, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. Separated by silica gel column chromatography (PE:EA=1:1) to obtain N-(3-cyano-4-fluorophenyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide (1.3g ). MS(ESI-,[MH] - )m/z: 268.3
步骤B：反应瓶中依次加入氧化锌(181mg)、草酰氯单乙酯(12.17g)，加毕，冰浴下且在N 2保护下分批加入N-(3-氰基-4-氟苯基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(1.2g)，加毕，撤去冰浴室温搅拌4.0h，反应结束后向反应液倒入200ml冰水中淬灭，二氯甲烷(2*100mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝1:1)，制得2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸乙酯(480mg)。MS(ESI-,[M-H] -)m/z:368.3. 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. Extraction with dichloromethane (2*100mL), combine the organic layers, wash the organic layer with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate the crude product by silica gel column chromatography (PE:EA=1: 1) to obtain 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5-yl)-2-oxoacetic acid Ethyl ester (480 mg). MS(ESI-,[MH] - )m/z:368.3.
步骤C：封管中依次加入DMF(15mL)、2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸乙酯(450mg)、NCS(325mg)，加完后转移至微波反应器中100瓦加热至110℃反应2h。反应结束后将反应液倒入100mL水中，用乙酸乙酯(30mL*2)进行萃取，合并有机层，饱和食盐水洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝3：2)，制得2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸乙酯(240mg)。MS(ESI -,[M-H] -)m/z:402.3. 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. After the reaction, the reaction solution was poured into 100 mL of water, extracted with ethyl acetate (30 mL*2), combined the organic layers, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, evaporated the solvent under reduced pressure, and obtained crude product Separated by silica gel column chromatography (PE:EA=3:2) to obtain 2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-di Hydrogen-1H-pyrrolizin-5-yl)-2-oxoacetate (240 mg). MS(ESI - ,[MH] - )m/z: 402.3
步骤D：反应瓶中，加入(2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸乙酯(240mg)、四氢呋喃(10mL)和氢氧化锂(50mg)的水溶液(5.00mL)，加毕，室温搅拌20min，用2N稀盐酸将溶液pH调至3-4，用乙酸乙酯(30mL*2)进行萃取，合并有机层，饱和食盐水洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂得到2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸(120mg)。MS(ESI -,[M-H] -)m/z:374.0. 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.
步骤E：反应瓶中依次加入2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸(60mg)、N,N-二甲基甲酰胺(6mL)、HATU(79mg)、3-(三氟甲基)氧杂环丁烷-3-胺(27mg)和N,N-二异丙基乙胺(47.5mg)，加毕，室温搅拌2.0h，向反应液中加入50mL水，用乙酸乙酯(50mL*2)进行萃取，合并有机层，饱和食盐水洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝3：2)，制得6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3- 基)氨基)乙酰基)-2,3-二氢-1H-吡咯-7-甲酰胺(30mg)。 1H-NMR(DMSO-d 6,500MHz):δ10.11(s,1H),10.01(s,1H),8.19(s,1H),7.98(d,J＝5.0Hz,1H),7.54(t,J＝10.0Hz,1H),4.85(d,J＝5.0Hz,2H),4.80(d,J＝5.0Hz,2H),4.33(t,J＝5.0Hz,2H),3.12(t,J＝5.0Hz,2H),2.48(t,J＝5.0Hz,2H).MS(ESI -,[M-H] -)m/z:497.4. Step E: Add 2-(6-chloro-7-((3-cyano-4-fluorophenyl)carbamoyl)-2,3-dihydro-1H-pyrrolazine-5-yl into the reaction flask in sequence )-2-oxoacetic acid (60mg), N,N-dimethylformamide (6mL), HATU (79mg), 3-(trifluoromethyl)oxetane-3-amine (27mg) and N,N-Diisopropylethylamine (47.5mg), after the addition, stir for 2.0h at room temperature, add 50mL water to the reaction solution, extract with ethyl acetate (50mL*2), combine the organic layers, and saturated brine Wash the organic layer, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate the crude product by silica gel column chromatography (PE:EA=3:2) to obtain 6-chloro-N-(3-cyano- 4-fluorophenyl)-5-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-2,3-dihydro- 1H-pyrrole-7-carboxamide (30 mg). 1 H-NMR(DMSO-d 6 ,500MHz): δ10.11(s,1H),10.01(s,1H),8.19(s,1H),7.98(d,J=5.0Hz,1H),7.54( t,J=10.0Hz,1H), 4.85(d,J=5.0Hz,2H), 4.80(d,J=5.0Hz,2H),4.33(t,J=5.0Hz,2H), 3.12(t, J=5.0Hz,2H),2.48(t,J=5.0Hz,2H).MS(ESI - ,[MH] - )m/z:497.4.
实施例5(S)-6-氯-N-(3,4-二氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 5 (S)-6-chloro-N-(3,4-difluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000045
Figure PCTCN2020074071-appb-000045
步骤A：封管中依次加入DMF(35mL)、(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基-)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(3.31g)、N-氯代丁二酰亚胺(2.55g)，加毕微波110℃反应2h。反应结束后将反应液倒入50mL水中，用乙酸乙酯(30mL*2)进行萃取，合并有机层，饱和食盐水洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，所得粗品经硅胶柱层析分离(PE：EA＝3：2)，制得(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.74g)。MS(ESI-,[M-H] -)m/z:379.1. 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. After the reaction, the reaction solution was poured into 50 mL of water, extracted with ethyl acetate (30 mL*2), the organic layers were combined, the organic layer was washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product Separated by silica gel column chromatography (PE:EA=3:2) to obtain (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxylic acid ethyl ester (1.74 g). MS(ESI-,[MH] - )m/z:379.1.
步骤B：反应瓶中依次加入(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(1.7g)、甲醇(30mL)和氢氧化钠(0.357g)的水溶液(10.00mL)，加毕，80℃下搅拌3h。反应结束后用2N的稀盐酸将溶液pH调至3-4，用乙酸乙酯(100mL*2)进行萃取，合并有机层，饱和食盐水洗涤有机层，无水硫酸钠干燥有机相，减压蒸除溶剂，得到(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸(1.17g)。MS(ESI-,[M-H] -)m/z:351.4. 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. After the reaction, the pH of the solution was adjusted to 3-4 with 2N dilute hydrochloric acid, extracted with ethyl acetate (100mL*2), combined the organic layers, washed with saturated brine, dried the organic phase with anhydrous sodium sulfate, and reduced pressure The solvent was evaporated to obtain (S)-6-chloro-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-di Hydrogen-1H-pyrrolazine-7-carboxylic acid (1.17 g). MS(ESI-,[MH] - )m/z:351.4.
步骤C：反应瓶中，依次加入甲苯(15mL)、(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸(200mg)及氯化亚砜(1.349g)，氮气保护下，体系加热至115℃反应1.0h，反应结束后降至室温，减压旋蒸除去溶剂，得到酰氯中间体(220mg)。在室温下，将酰氯中间体(220mg)溶于N,N-二甲基乙酰胺(10mL)， 加入3,4-二氟苯胺(110mg)，加毕100℃下反应0.5h。反应结束后降至室温，用乙酸乙酯(2*50mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经柱层析(PE：EA＝2：1)洗脱，得到(S)-6-氯-N-(3,4-二氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺(77mg)。 1H NMR(500MHz,DMSO)δ9.97(s,1H),9.44(d,J＝8.7Hz,1H),7.84(dd,J＝12.9,7.5Hz,1H),7.42(t,J＝7.0Hz,2H),4.72(dd,J＝15.1,7.5Hz,1H),4.31(t,J＝7.2Hz,2H),3.10(t,J＝7.4Hz,2H),2.48(d,J＝7.3Hz,2H),1.32(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:462.4. 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). At room temperature, 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. PE:EA=2:1) eluted to obtain (S)-6-chloro-N-(3,4-difluorophenyl)-5-(2-oxo-2-((1,1,1 -Trifluoropropan-2-yl)amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide (77 mg). 1 H NMR(500MHz,DMSO)δ9.97(s,1H), 9.44(d,J=8.7Hz,1H), 7.84(dd,J=12.9,7.5Hz,1H),7.42(t,J=7.0 Hz, 2H), 4.72 (dd, J = 15.1, 7.5 Hz, 1H), 4.31 (t, J = 7.2 Hz, 2H), 3.10 (t, J = 7.4 Hz, 2H), 2.48 (d, J = 7.3 Hz,2H),1.32(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z:462.4.
实施例6(S)-6-氯-N-(3-氯-4-氟苯基)-5-(2-氧代-2-((1，1，1-三氟丙-2-基)氨基)乙酰基)-2,-1,3-二氢-1H-吡咯嗪-7-甲酰胺Example 6 (S)-6-chloro-N-(3-chloro-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) )Amino)acetyl)-2,-1,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000046
Figure PCTCN2020074071-appb-000046
参照实施例5，步骤D用3-氯-4-氟苯胺替换3,4-二氟苯胺制得(S)-6-氯-N-(3-氯-4-氟苯基)-5-(2-氧代-2-((1，1，1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ9.94(s,1H),9.44(d,J＝8.5Hz,1H),7.97(d,J＝7.0Hz,1H),7.60(t,J＝5.0Hz,1H),7.40(t,J＝9.0Hz,1H),4.73-4.69(m,1H),4.30(t,J＝7.5Hz,2H),3.10(t,J＝7.5Hz,2H),2.48-2.47(m,2H),1.32(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:478.4. Referring to Example 5, 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. 1 H-NMR (500MHz, DMSO-d 6 ): δ9.94 (s, 1H), 9.44 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.60 (t, J=5.0Hz,1H),7.40(t,J=9.0Hz,1H),4.73-4.69(m,1H),4.30(t,J=7.5Hz,2H),3.10(t,J=7.5Hz, 2H),2.48-2.47(m,2H),1.32(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z:478.4.
实施例7(R)-6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,-1,3-二氢-1H-吡咯嗪-7-甲酰胺Example 7 (R)-6-chloro-N-(3-cyano-4-fluorophenyl)-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,-1,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000047
Figure PCTCN2020074071-appb-000047
Figure PCTCN2020074071-appb-000048
Figure PCTCN2020074071-appb-000048
步骤A：根据实施例5，在步骤A中用(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基-)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替换(S)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基-)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯，制得(R)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯。MS(ESI-,[M-H] -)m/z:379.1. 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. MS(ESI-,[MH] - )m/z:379.1.
步骤B：根据实施例5，在步骤B中用(R)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替换(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯，制得(R)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸。MS(ESI-,[M-H] -)m/z:351.4. 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. MS(ESI-,[MH] - )m/z:351.4.
步骤C：根据实施例5，在步骤C中用(R)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替换(S)-6-氯-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，用5-氨基-2-氟苯腈替换3,4-二氟苯胺，制得(R)-6-氯-N-(3-氰基-4-氟苯基)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.08(s,1H),9.45(d,J＝9.0Hz,1H),8.18(dd,J＝6.0Hz,1H),7.98(m,1H),7.53(t,J＝9.0Hz,1H),4.71(m,1H),4.31(m,2H),3.12(t,J＝7.5Hz,2H),2.47(t,J＝7.5Hz,2H),1.33(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:469.3. 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-carboxamide. 1 H-NMR (500MHz, DMSO-d 6 ): δ10.08 (s, 1H), 9.45 (d, J = 9.0 Hz, 1H), 8.18 (dd, J = 6.0 Hz, 1H), 7.98 (m, 1H), 7.53(t,J=9.0Hz,1H),4.71(m,1H),4.31(m,2H),3.12(t,J=7.5Hz,2H),2.47(t,J=7.5Hz, 2H),1.33(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z:469.3.
实施例8(S)-N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 8 (S)-N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoropropane-2 -Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000049
Figure PCTCN2020074071-appb-000049
步骤A：反应瓶中依次加入4-甲基-1H-吡咯-3-羧酸乙酯(8.0g)、二甲亚砜(60mL)、KOH(3.52g)，加毕，冰浴下滴加1,3-二溴丙烷(15.82g)，加毕，室温搅拌15h，将反应液倒入600mL水中，用乙醚(3*150mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经柱层析(PE:EA＝50:1)洗脱，得到1-(3-溴丙基)-4-甲基-1H-吡咯-3-羧酸乙酯(5.6g)。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. After drying with sodium sulfate and evaporating the solvent under reduced pressure, the crude product was eluted by column chromatography (PE:EA=50:1) to obtain 1-(3-bromopropyl)-4-methyl-1H-pyrrole-3 -Ethyl carboxylate (5.6 g).
1H-NMR(500MHz,DMSO-d 6)：δ7.35(s,1H),6.63(s,1H),4.12-4.16(m,2H),3.96-3.99(m,2H),3.37-3.40(m,2H),2.19-2.25(m,2H),2.15(s,3H),1.23-1.26(m,3H).MS(ESI+,[M+Na] +)m/z:296.4. 1 H-NMR (500MHz, DMSO-d 6 ): δ 7.35 (s, 1H), 6.63 (s, 1H), 4.12-4.16 (m, 2H), 3.96-3.99 (m, 2H), 3.37-3.40 (m,2H),2.19-2.25(m,2H),2.15(s,3H),1.23-1.26(m,3H).MS(ESI+,[M+Na] + )m/z:296.4.
步骤B：反应瓶中依次加入1-(3-溴丙基)-4-甲基-1H-吡咯-3-羧酸乙酯(5.6g)、乙腈(50mL)和碘化钠(4.84g)，加毕，加热反应温度至90℃反应10h，冷却反应液，直接经柱层析(PE：EA＝4：1)纯化，得到1-(3-碘丙基)-4-甲基-1H-吡咯-3-羧酸乙酯(6.3g)。MS(ESI+,[M+Na] +)m/z:344.1. Step B: Add 1-(3-bromopropyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.6g), acetonitrile (50mL) and sodium iodide (4.84g) to the reaction flask in sequence After the addition, heat the reaction temperature to 90°C and react for 10 hours. Cool the reaction solution and directly purify by column chromatography (PE:EA=4:1) to obtain 1-(3-iodopropyl)-4-methyl-1H -Ethyl pyrrole-3-carboxylate (6.3 g). MS(ESI+,[M+Na] + )m/z:344.1.
步骤C：反应瓶中加入1-(3-碘丙基)-4-甲基-1H-吡咯-3-羧酸乙酯(2.1g)、二甲亚砜(60mL)和七水合硫酸亚铁(1.82g)，加毕，冰盐浴下缓慢滴加双氧水(7.41g)，加毕，室温搅拌反应5.0h，将反应液倒入200mL冰水中，加入10％的亚硫酸钠溶液500mL，用二氯甲烷(3*100mL)萃取，合并有机层，饱和氯化钠水溶液洗涤有机层，无水硫酸钠干燥，减压蒸除溶剂，所得粗品经柱层析(PE：EA＝20：1)洗脱，得到6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(360mg)。MS(ESI+,[M+Na] +)m/z:216.1. 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. After the addition, stir the reaction at room temperature for 5.0h, pour the reaction solution into 200mL ice water, add 500mL 10% sodium sulfite solution, and use dichloride Methane (3*100mL) was extracted, the organic layers were combined, the organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was eluted by column chromatography (PE:EA=20:1) To obtain ethyl 6-methyl-2,3-dihydro-1H-pyrrolazine-7-carboxylate (360 mg). MS(ESI+,[M+Na] + )m/z: 216.1.
步骤D：参照实施例1步骤C用6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替代2,3-二氢-1H-吡咯嗪-7-羧酸乙酯反应得到5-(2-乙氧基-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯。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.
1H-NMR(500MHz,DMSO-d 6)：δ4.34-4.38(m,2H),4.17-4.24(m,4H),3.01-3.103(m,2H),2.47-2.49(m,2H),2.39(s,3H),1.24-1.34(m,6H). 1 H-NMR (500MHz, DMSO-d 6 ): δ4.34-4.38 (m, 2H), 4.17-4.24 (m, 4H), 3.01-3.103 (m, 2H), 2.47-2.49 (m, 2H) , 2.39 (s, 3H), 1.24-1.34 (m, 6H).
步骤E：参照实施例1步骤D用5-(2-乙氧基-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替代5-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯反应制得2-(7-(乙氧基羰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸。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.
1H-NMR(500MHz,DMSO-d 6)：δ4.17-4.27(m,4H),3.00-3.03(m,2H),2.42-2.48(m,5H),1.29(s,3H). 1 H-NMR (500MHz, DMSO-d 6 ): δ 4.17-4.27 (m, 4H), 3.00-3.03 (m, 2H), 2.42-2.48 (m, 5H), 1.29 (s, 3H).
步骤F：参照实施例1步骤E用2-(7-(乙氧基羰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸替代2-(7-(乙氧基羰基)-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸、用(S)-1,1,1-三氟丙-2-胺盐酸盐替代(R)-1,1,1-三氟丙-2-胺盐酸盐制得(S)-6-甲基-5-(2-氧代-2-((1,1,1- 三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯。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.
1H-NMR(500MHz,DMSO-d 6)：δ9.44(s,1H),4.69-4.76(m,1H),4.17-4.23(m,4H),3.01-3.04(m,2H),2.44-2.49(m,2H),2.39(s,3H),1.26-1.32(m,6H).MS(ESI-,[M-H] -)m/z:359.4. 1 H-NMR (500MHz, DMSO-d 6 ): δ9.44 (s, 1H), 4.69-4.76 (m, 1H), 4.17-4.23 (m, 4H), 3.01-3.04 (m, 2H), 2.44 -2.49(m,2H),2.39(s,3H),1.26-1.32(m,6H).MS(ESI-,[MH] - )m/z:359.4.
步骤G：参照实施例1步骤F用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替代(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯反应制得(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸。MS(ESI-,[M-H] -)m/z:331.4.。 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. MS (ESI-, [MH] - ) m/z: 331.4.
步骤H：参照实施例1步骤G用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替代(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸制得(S)-N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。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.
1H-NMR(500MHz,DMSO-d 6)：δ9.90(s,1H),9.46(d,J＝8.5Hz,1H),8.16-8.18(m,1H),7.93-7.97(m,1H),7.52(t,J＝9.0Hz,1H),4.69-4.77(m,1H),4.24(t,J＝7.0Hz,2H),3.08(t,J＝7.5Hz,2H),2.46-2.49(m,2H),2.34(s,3H),1.33(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:449.5. 1 H-NMR (500MHz, DMSO-d 6 ): δ9.90(s,1H), 9.46(d,J=8.5Hz,1H), 8.16-8.18(m,1H),7.93-7.97(m,1H ), 7.52(t,J=9.0Hz,1H),4.69-4.77(m,1H),4.24(t,J=7.0Hz,2H),3.08(t,J=7.5Hz,2H),2.46-2.49 (m,2H),2.34(s,3H),1.33(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z:449.5.
实施例9(S)-N-(3-氰基-4-氟苯基)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-甲酰胺Example 9 (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
Figure PCTCN2020074071-appb-000050
Figure PCTCN2020074071-appb-000050
步骤A：根据实施例8,在步骤A中用3-吡咯甲酸甲酯替换4-甲基-1H-吡咯-3-羧酸乙酯，1,4-二溴丁烷替换1,3-二溴丙烷制得1-(4-溴丁基)-1H-吡咯-3-羧酸甲酯。 1H-NMR(500MHz, DMSO-d 6)：δ7.48(s,1H),6.85(s,1H),6.41(s,1H),3.97(t,J＝7.0Hz,2H),3.69(s,3H),3.53(t,J＝7.0Hz,2H),1.81-1.85(m,2H),1.68-1.80(m,2H). 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. 1 H-NMR(500MHz, DMSO-d 6 ): δ7.48(s,1H), 6.85(s,1H), 6.41(s,1H), 3.97(t,J=7.0Hz,2H), 3.69( s, 3H), 3.53 (t, J = 7.0 Hz, 2H), 1.81-1.85 (m, 2H), 1.68-1.80 (m, 2H).
步骤B：根据实施例8,在步骤B中用1-(4-溴丁基)-1H-吡咯-3-羧酸甲酯替换1-(3-溴丙基)-4-甲基-1H-吡咯-3-羧酸乙酯，制得1-(4-碘丁基)-1H-吡咯-3-羧酸甲酯。MS(ESI+,[M+H] +)m/z:308.2. 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. MS(ESI+,[M+H] + )m/z: 308.2
步骤C：根据实施例8，在步骤C中用1-(4-碘丁基)-1H-吡咯-3-羧酸甲酯替换1-(3-碘丙基)-4-甲基-1H-吡咯-3-羧酸乙酯，制得5,6,7,8-四氢吲哚嗪-1-羧酸甲酯。 1H-NMR(500MHz,DMSO-d 6)：δ6.62(d,J＝3.0Hz,1H),6.37(s,J＝3.0Hz,1H),3.92(t,J＝7.0Hz,2H),3.67(s,3H),2.93(t,J＝6.5Hz,2H),1.84-1.88(m,2H),1.74-1.80(m,2H).MS(ESI+,[M+H] +)m/z:180.4. 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. 1 H-NMR (500MHz, DMSO-d 6 ): δ6.62(d,J=3.0Hz,1H), 6.37(s,J=3.0Hz,1H), 3.92(t,J=7.0Hz,2H) ,3.67(s,3H),2.93(t,J=6.5Hz,2H),1.84-1.88(m,2H),1.74-1.80(m,2H).MS(ESI+,[M+H] + )m /z:180.4.
步骤D：根据实施例1，在步骤C中，用5,6,7,8-四氢吲哚嗪-1-羧酸甲酯替换2,3-二氢-1H-吡咯嗪-7-羧酸乙酯，制得3-(2-乙氧基-2-氧代乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸甲酯。 1H-NMR(500MHz,DMSO-d 6)：δ7.47(s,1H),4.28-4.37(m,4H),3.75(s,3H),3.06(t,J＝7.0Hz,2H),1.91-1.93(m,2H),1.76-1.81(m,2H),1.31(t,J＝7.0Hz,3H).MS(ESI+,[M+H] +)m/z:280.5. 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. 1 H-NMR (500MHz, DMSO-d 6 ): δ7.47 (s, 1H), 4.28-4.37 (m, 4H), 3.75 (s, 3H), 3.06 (t, J = 7.0 Hz, 2H), 1.91-1.93(m,2H),1.76-1.81(m,2H),1.31(t,J=7.0Hz,3H).MS(ESI+,[M+H] + )m/z:280.5.
步骤E：根据实施例1，在步骤D中，用3-(2-乙氧基-2-氧代乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸甲酯替换5-(2-乙氧基-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯，制得2-(1-(甲氧基羰基)-5,6,7,8-四氢吲哚嗪-3-基)-2-氧代乙酸。 1H-NMR(500MHz,DMSO-d 6)：δ7.45(s,1H),4.30(t,J＝7.0Hz,2H),3.74(s,3H),3.06(t,J＝7.0Hz,2H),1.90-1.92(m,2H),1.78-1.80(m,2H).MS(ESI-,[M-H] -)m/z:250.2. 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. 1 H-NMR (500MHz, DMSO-d 6 ): δ7.45 (s, 1H), 4.30 (t, J = 7.0 Hz, 2H), 3.74 (s, 3H), 3.06 (t, J = 7.0 Hz, 2H),1.90-1.92(m,2H),1.78-1.80(m,2H).MS(ESI-,[MH] - )m/z: 250.2.
步骤F：根据实施例1，在步骤E中用2-(1-(甲氧基羰基)-5,6,7,8-四氢吲哚嗪-3-基)-2-氧代乙酸替换2-(7-(乙氧基羰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸，用(S)-1,1,1-三氟丙-2-胺盐酸盐替换(R)-1,1,1-三氟丙-2-胺盐酸盐，制得(S)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸甲酯。 1H NMR(500MHz,DMSO-d 6)δ9.34(s,1H),7.59(s,1H),4.71(dq,J＝15.2,7.5Hz,1H),4.32(t,J＝5.9Hz,2H),3.74(s,3H),3.07(t,J＝6.3Hz,2H),1.96-1.89(m,2H),1.83-1.76(m,2H),1.33(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:345.4. 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. 1 H NMR(500MHz,DMSO-d 6 )δ9.34(s,1H),7.59(s,1H),4.71(dq,J=15.2,7.5Hz,1H), 4.32(t,J=5.9Hz, 2H),3.74(s,3H),3.07(t,J=6.3Hz,2H),1.96-1.89(m,2H),1.83-1.76(m,2H),1.33(d,J=7.0Hz,3H ).MS(ESI-,[MH] - )m/z:345.4.
步骤G：根据实施例1，在步骤F中，用(S)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸甲酯替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯制得(S)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨 基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸。 1H NMR(500MHz,DMSO-d 6)δ12.26(s,1H),9.30(s,1H),7.54(s,1H),4.77-4.65(m,1H),4.31(t,J＝5.6Hz,2H),3.07(t,J＝6.0Hz,2H),1.98-1.87(m,2H),1.84-1.73(m,2H),1.33(d,J＝6.9Hz,3H).MS(ESI-,[M-H] -)m/z:331.4. 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. 1 H NMR(500MHz,DMSO-d 6 )δ12.26(s,1H),9.30(s,1H),7.54(s,1H),4.77-4.65(m,1H),4.31(t,J=5.6 Hz,2H),3.07(t,J=6.0Hz,2H),1.98-1.87(m,2H),1.84-1.73(m,2H),1.33(d,J=6.9Hz,3H).MS(ESI -,[MH] - )m/z:331.4.
步骤H：根据实施例1，在步骤G中，用(S)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，制得(S)-N-(3-氰基-4-氟苯基)-3-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-5,6,7,8-四氢吲哚嗪-1-甲酰胺。1H NMR(500MHz,DMSO-d6)δ10.21(s,1H),9.35(d,J＝8.7Hz,1H),8.24(d,J＝3.1Hz,1H),8.06(s,2H),7.50(t,J＝9.1Hz,1H),4.82-4.62(m,1H),4.34(s,2H),3.15(t,J＝5.8Hz,2H),1.94(s,2H),1.79(s,2H),1.36(d,J＝6.9Hz,3H).MS(ESI-,[M-H] -)m/z:449.4. 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. 1H NMR(500MHz,DMSO-d6)δ10.21(s,1H), 9.35(d,J=8.7Hz,1H), 8.24(d,J=3.1Hz,1H), 8.06(s,2H), 7.50 (t,J=9.1Hz,1H),4.82-4.62(m,1H),4.34(s,2H),3.15(t,J=5.8Hz,2H),1.94(s,2H),1.79(s, 2H),1.36(d,J=6.9Hz,3H).MS(ESI-,[MH] - )m/z:449.4.
实施例10(S)-N-(4-氟-3-甲基苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 10 (S)-N-(4-fluoro-3-methylphenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoropropane-2 -Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000051
Figure PCTCN2020074071-appb-000051
根据实施例1步骤G用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，用4-氟-3-甲基苯胺替换5-氨基-2-氟苯氰制得(S)-N-(4-氟-3-甲基苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。Use (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2, Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) with 3-dihydro-1H-pyrrolazine-7-carboxylic acid -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid, substituted with 4-fluoro-3-methylaniline for 5-amino-2-fluorobenzene cyanide to produce (S)-N-(4-fluoro -3-methylphenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3- Dihydro-1H-pyrrolazine-7-carboxamide.
1H-NMR(500MHz,DMSO-d 6):δ9.54(s,1H),9.44(d,J＝8.5Hz,1H),7.58(d,J＝6.5Hz,1H),7.47(t,J＝4.0Hz,1H),7.09(t,J＝9.0Hz,1H),4.73(m,1H),4.23(t,J＝7.0Hz,2H),3.07(t,J＝7.0Hz,2H),2.47(t,J＝7.0Hz,2H),2.33(s,3H),2.23(s,3H),1.32(d,J＝7.0Hz,3H).MS(ESI-,[M-H]-)m/z：438.4。 1 H-NMR (500MHz, DMSO-d 6 ): δ9.54 (s, 1H), 9.44 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 6.5 Hz, 1H), 7.47 (t, J = 4.0Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 4.73 (m, 1H), 4.23 (t, J = 7.0 Hz, 2H), 3.07 (t, J = 7.0 Hz, 2H) ,2.47(t,J=7.0Hz,2H),2.33(s,3H),2.23(s,3H),1.32(d,J=7.0Hz,3H).MS(ESI-,[MH]-)m /z: 438.4.
实施例11(S)-N-(3-氨基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 11 (S)-N-(3-amino-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000052
Figure PCTCN2020074071-appb-000052
根据实施例1步骤G用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，用4-氟苯-1,3-二胺替换5-氨基-2-氟苯氰制得(S)-N-(3-氨基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。Use (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2, Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) with 3-dihydro-1H-pyrrolazine-7-carboxylic acid -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid, replacing 5-amino-2-fluorobenzocyanide with 4-fluorobenzene-1,3-diamine to prepare (S)-N-(3 -Amino-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3 -Dihydro-1H-pyrrolazine-7-carboxamide.
1H NMR(500MHz,DMSO-d 6):δ9.43(d,J＝9.0Hz,1H),9.35(s,1H),7.20(d,J＝8.0Hz,1H),6.93-6.85(m,1H),6.75-6.70(m,1H),5.12(s,2H),4.72(dq,J＝15.0,7.5Hz,1H),4.21(t,J＝7.0Hz,2H),3.04(t,J＝7.4Hz,2H),2.49-2.43(m,2H),2.31(s,3H),1.32(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z：439.4. 1 H NMR (500MHz, DMSO-d 6 ): δ9.43 (d, J = 9.0Hz, 1H), 9.35 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.93-6.85 (m ,1H),6.75-6.70(m,1H),5.12(s,2H),4.72(dq,J=15.0,7.5Hz,1H),4.21(t,J=7.0Hz,2H),3.04(t, J=7.4Hz,2H),2.49-2.43(m,2H),2.31(s,3H),1.32(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z: 439.4.
实施例12 6-氯-N-(3-氰基-4-氟苯基)-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 12 6-Chloro-N-(3-cyano-4-fluorophenyl)-5-(2-((3-methyloxetan-3-yl)amino)-2-oxo Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000053
Figure PCTCN2020074071-appb-000053
根据实施例4步骤E用3-甲基氧杂环丁烷-3-胺替换3-(三氟甲基)氧杂环丁烷-3-胺制得6-氯-N-(3-氰基-4-氟苯基)-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。According to 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.
1H NMR(500MHz,DMSO-d 6):δ10.06(s,1H),9.30(s,1H),8.20-8.16(m,1H),7.97(dd,J＝8.5Hz,1H),7.53(t,J＝9.0Hz,1H),4.71(d,J＝6.5Hz,2H),4.38(d,J＝6.0Hz,2H),4.30(t,J＝7.0Hz,2H),3.10(t,J＝7.5Hz,2H),2.47(d,J＝7.5Hz,2H),1.60(s,3H).MS(ESI-,[M-H] -)m/z：443.4. 1 H NMR (500MHz, DMSO-d 6 ): δ10.06(s,1H),9.30(s,1H),8.20-8.16(m,1H),7.97(dd,J=8.5Hz,1H),7.53 (t,J=9.0Hz,1H), 4.71(d,J=6.5Hz,2H), 4.38(d,J=6.0Hz,2H), 4.30(t,J=7.0Hz,2H), 3.10(t ,J=7.5Hz,2H),2.47(d,J=7.5Hz,2H),1.60(s,3H).MS(ESI-,[MH] - )m/z: 443.4.
实施例13(S)-N-(3-氯-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 13 (S)-N-(3-chloro-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2- (Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000054
Figure PCTCN2020074071-appb-000054
根据实施例1步骤G用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，用3-氯-4-氟苯胺替换5-氨基-2-氟苯氰制得(S)-N-(3-氯-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7- 甲酰胺。Use (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2, Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) with 3-dihydro-1H-pyrrolazine-7-carboxylic acid -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid, using 3-chloro-4-fluoroaniline to replace 5-amino-2-fluorobenzonitrile to produce (S)-N-(3-chloro- 4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro -1H-pyrrolazine-7-carboxamide.
1H NMR(500MHz,DMSO-d 6)δ9.76(s,1H),9.45(d,J＝8.8Hz,1H),7.97(dd,J＝7.0,2.4Hz,1H),7.59(dt,J＝9.5,3.3Hz,1H),7.39(t,J＝9.1Hz,1H),4.69-4.77(m,J＝7.5Hz,1H),4.23(t,J＝7.3Hz,2H),3.08(t,J＝7.5Hz,2H),2.48(d,J＝7.4Hz,2H),2.33(s,3H),1.33(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z：458.3. 1 H NMR(500MHz,DMSO-d 6 )δ9.76(s,1H), 9.45(d,J=8.8Hz,1H), 7.97(dd,J=7.0,2.4Hz,1H), 7.59(dt, J = 9.5, 3.3 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H), 4.69-4.77 (m, J = 7.5 Hz, 1H), 4.23 (t, J = 7.3 Hz, 2H), 3.08 ( t,J=7.5Hz,2H),2.48(d,J=7.4Hz,2H),2.33(s,3H),1.33(d,J=7.0Hz,3H).MS(ESI-,[MH] - )m/z: 458.3
实施例14(S)-N-(3,4-二氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 14 (S)-N-(3,4-Difluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl )Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000055
Figure PCTCN2020074071-appb-000055
根据实施例1步骤G用(S)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸，用3,4-二氟苯胺替换5-氨基-2-氟苯氰制得(S)-N-(3,4-二氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。MS(ESI-,[M-H] -)m/z：442.4. Use (S)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2, Replacement of (R)-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) with 3-dihydro-1H-pyrrolazine-7-carboxylic acid -2,3-Dihydro-1H-pyrrolazine-7-carboxylic acid, replacing 5-amino-2-fluorobenzonitrile with 3,4-difluoroaniline to produce (S)-N-(3,4-di Fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-2,3-dihydro-1H -Pyrrolazine-7-carboxamide. MS(ESI-,[MH] - )m/z: 442.4.
1H NMR(500MHz,DMSO-d 6)δ9.80(s,1H),9.46(d,J＝8.7Hz,1H),7.84(dd,J＝13.0,7.4Hz,1H),7.40(d,J＝2.8Hz,2H),4.74(dd,J＝14.9,7.4Hz,1H),4.24(t,J＝7.0Hz,2H),3.08(t,J＝7.3Hz,2H),2.51(s,2H),2.34(s,3H),1.33(d,J＝6.9Hz,3H). 1 H NMR (500MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 9.46 (d, J = 8.7 Hz, 1H), 7.84 (dd, J = 13.0, 7.4 Hz, 1H), 7.40 (d, J = 2.8Hz, 2H), 4.74 (dd, J = 14.9, 7.4 Hz, 1H), 4.24 (t, J = 7.0Hz, 2H), 3.08 (t, J = 7.3Hz, 2H), 2.51 (s, 2H), 2.34 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H).
实施例15 N-(3-氰基-4-氟苯基)-5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 15 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
Figure PCTCN2020074071-appb-000056
Figure PCTCN2020074071-appb-000056
步骤A：根据实施例1步骤E用2-(7-(乙氧基羰基)-6-甲基-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸替换2-(7-(乙氧基羰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸，用1-氨基-3,3-二氟-N-甲基环丁烷-1-甲酰胺替换(R)-1,1,1-三氟丙-2-胺盐酸盐制得5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯。 1H NMR(500MHz,DMSO-d 6)δ9.60(s,1H),7.77(s,1H),4.20(s,4H),3.32(s,2H),3.24(q,J＝13.5Hz,2H),3.03(t,J＝7.0Hz,2H),2.99-2.88(m,2H),2.62(s,3H),2.43(s,3H),1.27(t,J＝7.0Hz,3H).MS(ESI+,[M-H] +)m/z：412.3. 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 2-(7-(ethoxycarbonyl)-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetic acid, with 1-amino-3,3-difluoro-N-methyl 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. 1 H NMR(500MHz,DMSO-d 6 )δ9.60(s,1H),7.77(s,1H), 4.20(s,4H), 3.32(s,2H), 3.24(q,J=13.5Hz, 2H), 3.03(t, J=7.0Hz, 2H), 2.99-2.88(m, 2H), 2.62(s, 3H), 2.43(s, 3H), 1.27(t, J=7.0Hz, 3H). MS(ESI+,[MH] + )m/z: 412.3
步骤B：根据实施例1步骤F用5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯制得5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸。MS(ESI-,[M-H] -)m/z：382.3. 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. MS(ESI-,[MH] - )m/z: 382.3
步骤C：根据实施例1步骤G用5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸替换(R)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-羧酸制得N-(3-氰基-4-氟苯基)-5-(2-((3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基)-2-氧代乙酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-甲酰胺。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.
1H NMR(500MHz,DMSO-d 6)δ9.89(s,1H),9.62(s,1H),8.18(dd,J＝5.9,2.6Hz,1H),7.99-7.92(m,1H),7.77(q,J＝4.5Hz,1H),7.52(t,J＝9.1Hz,1H),4.22(t,J＝7.3Hz,2H),3.25(d,J＝13.4Hz,2H),3.09(t,J＝7.5Hz,2H),2.93(td,J＝14.2,7.1Hz,2H),2.63(d,J＝4.5Hz,3H),2.47(q,J＝7.4Hz,2H),2.37(s,3H).MS(ESI-,[M-H] -)m/z：500.4. 1 H NMR (500MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.62 (s, 1H), 8.18 (dd, J = 5.9, 2.6 Hz, 1H), 7.99-7.92 (m, 1H), 7.77 (q, J = 4.5 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.25 (d, J = 13.4 Hz, 2H), 3.09 ( t,J=7.5Hz,2H), 2.93(td,J=14.2,7.1Hz,2H), 2.63(d,J=4.5Hz,3H), 2.47(q,J=7.4Hz,2H), 2.37( s,3H).MS(ESI-,[MH] - )m/z: 500.4.
实施例16 N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-2,3-二氢-1H-吡咯-7-甲酰胺Example 16 N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((3-(trifluoromethyl)oxetane-3 -Amino)acetyl)-2,3-dihydro-1H-pyrrole-7-carboxamide
Figure PCTCN2020074071-appb-000057
Figure PCTCN2020074071-appb-000057
步骤A：N 2保护下，在反应瓶中加入四氢呋喃(15mL)，6-甲基-2,3-二氢-1H-吡咯嗪-7-羧酸乙酯(700mg)，5-氨基-2-氟苯腈(616mg)，室温下缓慢加入双(三甲基甲硅烷基)氨基化锂(1.52g,9.05mL四氢呋喃溶液)，反应液搅拌反应17.0h。反应液缓慢倒至150mL冰水中淬灭，乙酸乙酯(2*150mL)萃取，合并有机层，饱和氯化钠水洗，无水硫酸钠干燥，减压蒸除溶剂。得到粗品用石油醚(9.0mL)和乙酸乙酯(6.0mL)打浆0.5h，抽滤，滤饼真空干燥得到N-(3-氰基-4-氟苯基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-甲酰胺(0.77g)。MS(ESI-,[M-H] -)m/z:282.2. 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. The reaction solution was slowly poured into 150 mL ice water for quenching, extracted with ethyl acetate (2*150 mL), the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was slurried with petroleum ether (9.0 mL) and ethyl acetate (6.0 mL) for 0.5 h, filtered with suction, and the filter cake was dried in vacuo to obtain N-(3-cyano-4-fluorophenyl)-6-methyl-2 ,3-Dihydro-1H-pyrrolazine-7-carboxamide (0.77g). MS(ESI-,[MH] - )m/z: 282.2
步骤B：置换氮气，冰浴下在反应瓶加入氧化锌(111mg)，草酰氯单乙酯(7.4g)，分批加入N-(3-氰基-4-氟苯基)-6-甲基-2,3-二氢-1H-吡咯嗪-7-甲酰胺(770mg)，加毕后搅拌5 分钟，再转至室温搅拌反应3.5h。反应液缓慢倒至搅拌的冰中淬灭，淬灭完毕后，用二氯甲烷(2*100mL)萃取，合并有机层，用饱和氯化钠水洗，无水硫酸钠干燥，减压蒸除溶剂。反应混合物经硅胶柱色谱分离，以V(二氯甲烷)：V(甲醇)＝50：1混合溶剂洗脱，得到2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸乙酯(0.28g)。MS(ESI-,[M-H] -)m/z:382.3. 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. . The reaction mixture was separated by silica gel column chromatography and eluted with a mixed solvent of V (dichloromethane): V (methanol) = 50:1 to obtain 2-(7-((3-cyano-4-fluorophenyl)aminomethyl) Acyl)-6-methyl-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxoacetate (0.28 g). MS(ESI-,[MH] - )m/z:382.3.
步骤C：向反应瓶中，加入2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸乙酯(280mg)，四氢呋喃(5mL)，冰浴下缓慢滴加氢氧化锂一水合物(61mg)的水(10mL)溶液，加毕后转至室温反应10分钟。向反应液中加入50mL水和50mL二氯甲烷，分层，弃去有机层，水层用2M盐酸溶液调pH至3，再用乙酸乙酯(2*50mL)萃取，合并有机层，饱和氯化钠水洗，无水硫酸钠干燥，抽滤，滤液减压旋蒸除去溶剂，真空干燥得到2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸(0.19g)。MS(ESI-,[M-H] -)m/z:354.2.。 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. Add 50 mL of water and 50 mL of dichloromethane to the reaction solution, separate the layers, discard the organic layer, adjust the pH of the aqueous layer to 3 with 2M hydrochloric acid solution, and extract with ethyl acetate (2*50 mL). Combine the organic layers. Washed with sodium chloride, dried with anhydrous sodium sulfate, filtered with suction, the filtrate was evaporated under reduced pressure to remove the solvent, and dried under vacuum to obtain 2-(7-((3-cyano-4-fluorophenyl)carbamoyl)-6-methyl Yl-2,3-dihydro-1H-pyrrolin-5-yl)-2-oxoacetic acid (0.19 g). MS (ESI-, [MH] - ) m/z: 354.2.
步骤D：根据实施例4步骤E用2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸替换2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸制得N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-2,3-二氢-1H-吡咯-7-甲酰胺。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.
1H-NMR(500MHz,DMSO-d 6):δ9.99(s,1H),9.93(s,1H),8.21-8.12(m,1H),8.00-7.89(m,1H),7.53(t,J＝9.1Hz,1H),4.82(q,J＝8.0Hz,4H),4.25(t,J＝7.0Hz,2H),3.09(t,J＝7.4Hz,2H),2.48(d,J＝7.3Hz,2H),2.40(s,3H).MS(ESI-,[M-H] -)m/z:477.3. 1 H-NMR (500MHz, DMSO-d 6 ): δ9.99 (s, 1H), 9.93 (s, 1H), 8.21-8.12 (m, 1H), 8.00-7.89 (m, 1H), 7.53 (t ,J=9.1Hz,1H), 4.82(q,J=8.0Hz,4H), 4.25(t,J=7.0Hz,2H), 3.09(t,J=7.4Hz,2H), 2.48(d,J ＝7.3Hz,2H),2.40(s,3H).MS(ESI-,[MH] - )m/z:477.3.
实施例17 N-(3-氰基-4-氟苯基)-6-甲基-5-(2-((3-甲基氧杂环丁基-3-基)氨基)-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 17 N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-((3-methyloxetan-3-yl)amino)-2-oxo Acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000058
Figure PCTCN2020074071-appb-000058
根据实施例4步骤E中用2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯啉-5-基)-2-氧代乙酸替换2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸，用3-甲基氧杂环丁烷-3-胺替换3-(三氟甲基)氧杂环丁烷-3-胺制得N-(3-氰基-4-氟苯基)-6-甲基-5-(2-((3-甲基氧杂环丁基-3-基)氨基)-2-氧代乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。According to Example 4, 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.
1H NMR(500MHz,DMSO-d 6)δ9.89(s,1H),9.31(s,1H),8.17(s,1H),7.95(s,1H),7.52(t, J＝9.1Hz,1H),4.69(d,J＝6.3Hz,2H),4.40(d,J＝6.3Hz,2H),4.24(t,J＝7.1Hz,2H),3.09(t,J＝7.4Hz,2H),2.48(d,J＝7.3Hz,2H),2.40(s,3H),1.61(s,3H).MS(ESI-,[M-H] -)m/z：423.4. 1 H NMR(500MHz,DMSO-d 6 )δ9.89(s,1H),9.31(s,1H),8.17(s,1H),7.95(s,1H),7.52(t, J=9.1Hz, 1H), 4.69 (d, J = 6.3 Hz, 2H), 4.40 (d, J = 6.3 Hz, 2H), 4.24 (t, J = 7.1 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H) ,2.48(d,J=7.3Hz,2H),2.40(s,3H),1.61(s,3H).MS(ESI-,[MH] - )m/z: 423.4.
实施例18(R)-N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺Example 18 (R)-N-(3-cyano-4-fluorophenyl)-6-methyl-5-(2-oxo-2-((1,1,1-trifluoropropane-2 -Amino)acetyl)-2,3-dihydro-1H-pyrrolazine-7-carboxamide
Figure PCTCN2020074071-appb-000059
Figure PCTCN2020074071-appb-000059
根据实施例4步骤E中用2-(7-((3-氰基-4-氟苯基)氨基甲酰基)-6-甲基-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸替换2-(6-氯-7-((3-氰基-4-氟苯基)氨基甲酰基)-2,3-二氢-1H-吡咯嗪-5-基)-2-氧代乙酸，用(R)-1,1,1-三氟-2-甲基丙烷盐酸盐替换3-(三氟甲基)氧杂环丁烷-3-胺制得(R)-N-(3-氰基-4-氟苯基)-6-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-2,3-二氢-1H-吡咯嗪-7-甲酰胺。MS(ESI-,[M-H] -)m/z:449.4. According to Example 4, 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. MS(ESI-,[MH] - )m/z:449.4.
1H-NMR(500MHz,DMSO-d 6):δ9.89(s,1H),9.45(d,J＝8.7Hz,1H),8.17(dd,J＝5.4,2.1Hz,1H),8.01–7.91(m,1H),7.52(t,J＝9.1Hz,1H),4.73(dq,J＝15.1,7.5Hz,1H),4.24(t,J＝7.1Hz,2H),3.09(t,J＝7.4Hz,2H),2.50-2.43(m,2H),2.34(s,3H),1.33(d,J＝7.0Hz,3H). 1 H-NMR (500MHz, DMSO-d 6 ): δ9.89 (s, 1H), 9.45 (d, J=8.7Hz, 1H), 8.17 (dd, J=5.4, 2.1Hz, 1H), 8.01– 7.91(m,1H),7.52(t,J=9.1Hz,1H), 4.73(dq,J=15.1,7.5Hz,1H), 4.24(t,J=7.1Hz,2H), 3.09(t,J ＝7.4Hz, 2H), 2.50-2.43(m, 2H), 2.34(s, 3H), 1.33(d, J=7.0Hz, 3H).
实验例1.体外活性研究Experimental example 1. In vitro activity study
1.1体外细胞HBV DNA抑制活性1.1 In vitro cell HBV DNA inhibitory activity
取处于指数生长期状态良好的HepG2.2.15或HepAD38细胞一瓶，加入5mL PBS清洗一遍，加入3mL胰酶。室温消化5min，弃掉2mL胰酶后再放入细胞培养箱中消化10min，不时取出显微镜下观察(是否为单个圆形，细胞间无粘连)，加入10mL完全培养基终止消化。吹打成单细胞悬液后，取10μL细胞悬液使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至1*10 5个/mL。使用排枪接种于24孔板上(24孔板提前使用50μg/mL CollagenⅠ溶液包被)，1mL/孔，置恒温CO 2培养箱中培养48h。 Take a bottle of HepG2.2.15 or HepAD38 cells in good condition in the exponential growth phase, add 5mL PBS to wash it again, and add 3mL pancreatin. Digest at room temperature for 5 minutes, discard 2 mL of trypsin, and then put it in a cell incubator for 10 minutes. Take it out from time to time to observe under the microscope (whether it is a single round shape and no adhesion between cells), and add 10 mL of complete medium to terminate the digestion. After pipetting into a single cell suspension, take 10μL of the cell suspension and count it with a cell counter. Dilute with complete medium and adjust the cell density to 1*10 5 cells/mL. Use a row gun to inoculate on a 24-well plate (the 24-well plate was coated with 50μg/mL CollagenI solution in advance), 1mL/well, and placed in a constant temperature CO 2 incubator for 48h.
使用完全培养基将DMSO溶解的不同化合物稀释，2倍梯度，共10个浓度，进行化合物加样，每72h更换含化合物的新鲜培养基，化合物处理细胞6天。吸去上清后，每孔加入300μL裂解液(10mM Tris-HCl，1mM EDTA，1％NP-40)，室温放置裂解10min后，提取DNA，用实时荧光定量PCR仪测定胞内病毒衣壳中HBV DNA，根据Ct值计算抑制率，四参数法计算EC50值。结果见表1。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. After aspirating the supernatant, add 300μL of lysis buffer (10mM Tris-HCl, 1mM EDTA, 1% NP-40) to each well. After lysis at room temperature for 10 minutes, DNA is extracted, and the intracellular viral capsid is determined by real-time fluorescent quantitative PCR instrument For HBV DNA, 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.
1.2体外细胞毒性1.2 In vitro cytotoxicity
取处于指数生长期状态良好的HepG2.2.15或HepAD38细胞一瓶，加入5mL PBS清洗一 遍，加入2mL胰酶。放入细胞培养箱中进行消化，不时取出显微镜下观察，待细胞刚脱落时，弃掉1mL胰酶，仅仅留下残液，放入37℃培养箱中消化8-15min，取出在显微镜下观察细胞(是否为单个圆形，细胞间无粘连)，加入5mL MEM培养基进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至2*10 5个/mL。使用排枪接种于96孔板上(96孔板提前使用50μg/mL CollagenⅠ溶液包被)，100μL/孔，置恒温CO 2培养箱中培养24h，给药处理，每隔3天，更换含化合物的新鲜培养基，对照孔加不含药物的DMSO浓度为0.5％的培养基，并设普通培养基的对照孔，给药处理6天后，加CCK-8，10μL/孔，1-2h后酶标仪450nm处检测其吸光值，计算抑制率，并计算CC50。结果见表1-1。 Take a bottle of HepG2.2.15 or HepAD38 cells that are in good condition in the exponential growth phase, add 5mL PBS to wash it again, and add 2mL pancreatin. Put it in a cell incubator for digestion, take it out from time to time for observation under the microscope, when the cells just fall off, discard 1mL of trypsin, leaving only the residual liquid, put it in a 37℃ incubator for digestion for 8-15 minutes, take it out and observe under the microscope Cells (whether they are single round, no adhesion between cells), add 5mL MEM medium to resuspend the cells. Count using a cell counter, dilute the complete medium, and adjust the cell density to 2*10 5 cells/mL. Use a row gun to inoculate a 96-well plate (the 96-well plate was coated with 50μg/mL CollagenI solution in advance), 100μL/well, placed in a constant temperature CO 2 incubator for 24 hours, dosing treatment, every 3 days, replace the compound containing Fresh medium, control wells with 0.5% DMSO medium without drug, and control wells with normal medium. After 6 days of administration, add CCK-8, 10μL/well, 1-2h later The absorbance at 450nm was detected by the instrument, the inhibition rate was calculated, and the CC50 was calculated. The results are shown in Table 1-1.
表1 HepAD38细胞中抗HBV活性实验结果Table 1 Experimental results of anti-HBV activity in HepAD38 cells
实施例编号Example number EC50(nM)EC50(nM) 实施例编号Example number EC50(nM)EC50(nM) 实施例编号Example number EC50(nM)EC50(nM)
33 1919 66 27.927.9 1414 1414
44 11.311.3 77 29.729.7 1515 6666
55 15.815.8 88 22.522.5 1616 1414
1010 1010 1212 2525 1717 3434
1111 3131 1313 1313 1818 1414
。.
表1-1Table 1-1
Figure PCTCN2020074071-appb-000060
Figure PCTCN2020074071-appb-000060
实验例2体外肝微粒体稳定性Experimental example 2 in vitro liver microsome stability
300μL最终的温孵体系中，含30μL肝微粒体(蛋白浓度：0.15mg/mL)，30μL NADPH+MgCl 2，3μL底物(乙腈配制)，237μL PBS缓冲液。每个种属做2份，每份0.3mL。每管先配好总体积为270μL的底物及酶的混匀液，和NADPH分别在37℃预温孵5min后，加入30μL NADPH+MgCl 2混合溶液反应，分别于0、10、30、60min取出50μL用含内标的冰乙腈300μL终止反应。 300μL final incubation system containing 30 L liver microsomes (protein concentration: 0.15mg / mL), 30μL NADPH + MgCl 2, 3μL substrate (formulated acetonitrile), 237μL PBS buffer. Make 2 servings for each species, 0.3mL each. Prepare each tube with a total volume of 270μL of substrate and enzyme mixing solution. After pre-incubating with NADPH for 5 minutes at 37°C, add 30μL of NADPH+MgCl 2 mixed solution for reaction at 0, 10, 30, and 60 minutes. Take out 50 μL and terminate the reaction with 300 μL ice acetonitrile containing internal standard.
样品前处理：50μL温孵样品，加入300μL含内标地西泮的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL至96孔板中用75μL超纯水稀释混匀，进样0.5μL，进行LC-MS/MS分析。具体结果见表2.Sample pretreatment: 50μL of incubation sample, adding 300μL of ice acetonitrile precipitation containing internal standard diazepam, vortexing for 5min, centrifuging (12000rpm, 4℃) for 10min. Pipette 75μL of the supernatant into a 96-well plate and dilute and mix with 75μL ultrapure water, inject 0.5μL, and perform LC-MS/MS analysis. The specific results are shown in Table 2.
表2 体外肝微粒体稳定性Table 2 Stability of liver microsomes in vitro
Figure PCTCN2020074071-appb-000061
Figure PCTCN2020074071-appb-000061
Figure PCTCN2020074071-appb-000062
Figure PCTCN2020074071-appb-000062
实验例3体内动物药效Experimental example 3 in vivo animal efficacy
HDI小鼠模型评价抗病毒效果HDI mouse model to evaluate antiviral effects
取6-8周龄雄性C57BL/6小鼠，将纯化的重组质粒pHBVl.3(10μg)溶解在PBS中，每只小鼠注射体积约为其体重的10％，通过尾静脉在3-8s内注射到小鼠体内。注射质粒24h后眼眶取血检测血清HBV DNA，挑选出模型小鼠血清DNA均一的进行分组，设空白对照组、溶媒对照组、受试物组。每组小鼠以灌胃方式连续给药6天，每日1次，剂量为30mg/kg。分别于注射后的1、3、5、7天取小鼠血清，第7天处死小鼠取肝组织样本，荧光定量PCR方法检测小鼠血清和肝脏中HBV DNA拷贝数。结果见表3。Take 6-8 week old male C57BL/6 mice, and dissolve the purified recombinant plasmid pHBV1.3 (10μg) 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.
表3table 3
Figure PCTCN2020074071-appb-000063
Figure PCTCN2020074071-appb-000063
实验例4体内药物代谢动力学Experimental Example 4 Pharmacokinetics in vivo
4.1小鼠体内药物代谢动力学(PK)研究4.1 Pharmacokinetics (PK) study in mice
ICR小鼠，体重18～20g，适应3～5天后，随机分组，每组3只，按10mg/kg剂量分别灌胃系列化合物。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.
受试动物(ICR小鼠)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。The 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.
灌胃给药后，于眼眶取血0.1mL左右，EDTA-K 2抗凝后，30min内于4℃，4000rpm条件下离心10min分离血浆。收集全部血浆后立即于-20℃保存待测。 After intragastric administration, about 0.1 mL of blood was taken from the orbit, and after EDTA-K 2 anticoagulation, the plasma was separated by centrifugation at 4°C and 4000 rpm within 30 minutes for 10 minutes. After collecting all plasma, store it at -20°C for testing.
吸取20μL待测血浆样品和标曲样品，加入200μL含内标(地西泮20mg/mL)的乙腈溶液，振荡混匀5min，12000rpm离心10min，取上清75μL，加入75μL超纯水稀释，混匀，吸取1μL用于LC/MS/MS测定。结果见表4。Aspirate 20μL of plasma sample to be tested and standard curve sample, add 200μL of acetonitrile solution containing internal standard (diazepam 20mg/mL), shake and mix for 5min, centrifuge at 12000rpm for 10min, take 75μL of supernatant, add 75μL of ultrapure water to dilute and mix Evenly, draw 1μL for LC/MS/MS determination. The results are shown in Table 4.
表4Table 4
Figure PCTCN2020074071-appb-000064
Figure PCTCN2020074071-appb-000064
注：po：口服；取血时间点为0.25h、1h、3h、8h。Note: po: oral; time points for blood collection are 0.25h, 1h, 3h, 8h.
4.2大鼠体内药物代谢动力学(PK)研究4.2 Pharmacokinetics (PK) study in rats
SD大鼠，体重180～220g，适应3～5天后，随机分组，每组3只，按10mg/kg剂量分别灌胃系列化合物。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.
受试动物(SD大鼠)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。The 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.
灌胃给药后，于眼眶取血0.1mL左右，EDTA-K 2抗凝后，30min内于4℃，4000rpm条件下离心10min分离血浆。收集全部血浆后立即于-20℃保存待测。 After intragastric administration, about 0.1 mL of blood was taken from the orbit. After EDTA-K 2 anticoagulation, the plasma was separated by centrifugation at 4°C and 4000 rpm within 30 minutes for 10 minutes. After collecting all plasma, store it at -20°C for testing.
吸取50μL待测血浆样品和标曲样品，加入500μL含内标(地西泮20mg/mL)的乙腈溶液，振荡混匀5min，12000rpm离心10min，取上清75μL，加入75μL超纯水稀释，混匀，吸取1μL用于LC/MS/MS测定。结果见表5。Take 50μL of the plasma sample to be tested and the standard curve sample, add 500μL of acetonitrile solution containing the internal standard (diazepam 20mg/mL), shake and mix for 5min, centrifuge at 12000rpm for 10min, take 75μL of supernatant, add 75μL of ultrapure water to dilute and mix Evenly, draw 1μL for LC/MS/MS determination. The results are shown in Table 5.
表5table 5
Figure PCTCN2020074071-appb-000065
Figure PCTCN2020074071-appb-000065
注：po：口服；取血时间点为0.25h、4h、10h。Note: po: oral; time points for blood collection are 0.25h, 4h, 10h.

Claims (15)

  1. 式I化合物、其立体异构体或其药学上可接受的盐，The compound of formula I, its stereoisomer or its pharmaceutically acceptable salt,
    Figure PCTCN2020074071-appb-100001
    Figure PCTCN2020074071-appb-100001
    其中，among them,
    环A选自5-10元杂环基，所述5-10元杂环基除与吡咯环共用的N原子外任选地还含有1-3个选自N、O或S的杂原子，所述环A任选地被1-3个R 1取代；所述R 1各自独立地选自卤素、或C 1-6烷基； 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 the N atom shared with the pyrrole ring, The ring A is optionally substituted with 1 to 3 R 1 ; each of the R 1 is independently selected from halogen or C 1-6 alkyl;
    R 2选自H、卤素或C 1- 6烷基； R 2 is selected from H, halogen or C 1 - 6 alkyl;
    R 3选自C 1-6烷基、C 3-8环烷基、或含有1-3个选自N、O或S的杂原子的3-8元杂环烷基； 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;
    所述C 1-6烷基任选地被1-3个R 3a取代；所述R 3a各自独立地选自：卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2- 6炔基、或氧代； 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;
    所述C 3-8环烷基任选地被1-3个R 3b取代；所述R 3b各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
    所述3-8元杂环烷基任选地被1-3个R 3c取代；所述R 3c各自独立地选自卤素、-OH、-CN、C 1-6烷氧基、C 1-6烷氨基、-C(O)N(R 5)(R 6)、-C(O)OR 6、-C(O)R 6、-SO 2R 6、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-6炔基、氧代、或任选地被1-3个卤素或羟基取代的C 1-3烷基； 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;
    环B选自C 6-10芳基、或含有1-3个选自N、O或S的杂原子的5-10元杂芳基，所述环B任选地被1-5个R 4取代；所述R 4各自独立地选自卤素、-CN、-OH、-NH 2、C 3-4环烷基、或任选被1-3个卤素取代的C 1-3烷基； 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;
    所述R 5、R 6各自独立地选自氢、或C 1-6烷基。 The R 5 and R 6 are each independently selected from hydrogen or C 1-6 alkyl.
  2. 如权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 1各自独立地选自氟、氯、溴、或C 1-3烷基；任选地，上述R 1各自独立地选自氟、或甲基。 The compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 1 is independently selected from fluorine, chlorine, bromine, or C 1-3 alkyl; optionally , The aforementioned R 1 is each independently selected from fluorine or methyl.
  3. 如权利要求1-2任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中环A 选自5元杂环基、或6元杂环基；任选地，上述环A选自5元杂环烷基、6元杂环烷基、5元杂芳基、或6元杂芳基；任选地，上述环A选自
    Figure PCTCN2020074071-appb-100002
    Figure PCTCN2020074071-appb-100003
    任选地，上述环A选自
    Figure PCTCN2020074071-appb-100004
    所述环A的取代基如权利要求1所述。     The compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1-2, wherein ring A is selected from a 5-membered heterocyclic group or a 6-membered heterocyclic group; optionally Alternatively, the aforementioned ring A is selected from a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, a 5-membered heteroaryl group, or a 6-membered heteroaryl group; optionally, the aforementioned ring A is selected from
    Figure PCTCN2020074071-appb-100002
    Figure PCTCN2020074071-appb-100003
    Optionally, the aforementioned ring A is selected from
    Figure PCTCN2020074071-appb-100004
    The substituent of the ring A is as described in claim 1.
  4. 如权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 2选自H、氟、氯、溴、或C 1-3烷基；任选地，上述R 2选自H、氯、或甲基。 The compound of formula I according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, fluorine, chlorine, bromine, or C 1-3 alkyl ; Optionally, the above R 2 is selected from H, chlorine, or methyl.
  5. 如权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、或氧代；任选地，R 3a各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或氧代；任选地，上述R 3a各自独立地选自氟、氯、溴、或-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、或C 2-3炔基；任选地，上述R 3a选自氟。 The compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, wherein 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, containing 1-3 selected from N , O or S heteroatom 5-8 membered heteroaryl, C 2-3 alkynyl, or oxo; optionally, R 3a is 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)OC 1-3 alkyl, -C(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, C 6-10 aryl, containing 1-3 selected from N , O or S heteroatom of 5 or 6 membered heteroaryl, C 2-3 alkynyl, or oxo; optionally, the above R 3a is each independently selected from 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; optionally, the above R 3a is selected from fluorine .
  6. 如权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 3b各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；任选地，上述R 3b各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基；任选地，上述R 3b各自独立地选自氟、氯、溴、-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或任选被1-3个氟取代的C 1-3烷基；任选地，上述R 3b选自氟、-C(O)NHCH 3、
    Figure PCTCN2020074071-appb-100005
    Figure PCTCN2020074071-appb-100006
    或C 2炔基。     The compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5, wherein 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, containing 1-3 selected from N , O or S heteroatom of 5-8 membered heteroaryl, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted by 1-3 fluorine, chlorine, bromine or hydroxy; Optionally, the above R 3b 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)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 a C 1-3 alkyl group optionally substituted by 1-3 fluorines; optionally, the above R 3b are each independently selected from fluorine, chlorine, bromine, -C(O)NHC 1-3 alkyl, containing 1 -5 or 6-membered heteroaryl groups with 3 heteroatoms selected from N, O or S, C 2-3 alkynyl groups, or C 1-3 alkyl groups optionally substituted by 1-3 fluorines; optionally , The above R 3b is selected from fluorine, -C(O)NHCH 3 ,
    Figure PCTCN2020074071-appb-100005
    Figure PCTCN2020074071-appb-100006
    Or C 2 alkynyl.
  7. 如权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 3c各自独立地选自氟、氯、溴、-OH、-CN、C 1-4烷氧基、C 1-4烷氨基、-C(O)NH 2、-C(O)NHC 1-4烷基、-C(O)N(C 1-4烷基) 2、-C(O)OC 1-4烷基、-C(O)C 1-4烷基、-SO 2C 1-4烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5-8元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟、氯、溴或羟基取代的C 1-3烷基；任选地，上述R 3c各自独立地选自氟、氯、溴、-OH、-CN、C 1-3烷氧基、C 1-3烷氨基、-C(O)NH 2、-C(O)NHC 1-3烷基、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、C 6-10芳基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、氧代、或任选被1-3个氟取代的C 1-3烷基；任选地，上述R 3c各自独立地选自氟、氯、溴、-C(O)NHC 1-3烷基、含有1-3个选自N、O或S的杂原子的5或6元杂芳基、C 2-3炔基、或任选被1-3个氟取代的C 1-3烷基；任选地，上述R 3c选自
    Figure PCTCN2020074071-appb-100007
    甲基或三氟甲基。     The compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6, wherein R 3c 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, containing 1-3 selected from N , O or S heteroatom of 5-8 membered heteroaryl, C 2-3 alkynyl, oxo, or C 1-3 alkyl optionally substituted by 1-3 fluorine, chlorine, bromine or hydroxy; Optionally, the above R 3c 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)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 a C 1-3 alkyl group optionally substituted by 1-3 fluorines; optionally, the above R 3c are each independently selected from fluorine, chlorine, bromine, -C(O)NHC 1-3 alkyl, containing 1 -5 or 6-membered heteroaryl groups with 3 heteroatoms selected from N, O or S, C 2-3 alkynyl groups, or C 1-3 alkyl groups optionally substituted by 1-3 fluorines; optionally , The above R 3c is selected from
    Figure PCTCN2020074071-appb-100007
    Methyl or trifluoromethyl.
  8. 如权利要求1-7任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 3选自C 1-3烷基、C 3-4环烷基、或含有1-3个选自N、O或S的杂原子的3、4或5元杂环烷基；任选地，上述R 3选自C 1-3烷基、C 4环烷基、或含有1-3个选自N、O或S的杂原子的4元杂环烷基；任选地，上述R 3选自甲基、乙基、丙基、环丙基、环丁基、氧杂环丙基、氧杂环丁基、氮杂环丙基、或氮杂环丁基；任选地，上述R 3选自异丙基、环丙基、环丁基、或氧杂环丁基；所述R 3的取代基如权利要求1所述。 The compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof according to any one of claims 1-7, wherein R 3 is selected from C 1-3 alkyl, C 3-4 cycloalkyl, Or a 3-, 4- or 5-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; optionally, the above-mentioned R 3 is selected from C 1-3 alkyl, C 4 cycloalkyl, Or a 4-membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; optionally, the above-mentioned R 3 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, Oxecyclopropyl, oxetanyl, aziridinyl, or azetidine; optionally, the above R 3 is selected from isopropyl, cyclopropyl, cyclobutyl, or oxetanyl Butyl; the substituent of R 3 is as described in claim 1.
  9. 如权利要求1-8任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中R 4各自独立地选自氟、氯、溴、-CN、任选被1-3个氟、氯、溴、取代的C 1-3烷基、-OH、或-NH 2；任选地，所述R 4各自独立地选自氟、氯、-CN、任选被1-3个氟取代的C 1-3烷基、或-NH 2；任选地，R 4各自独立地选自氟、氯、-CN、甲基、或-NH 2。 The compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof according to any one of claims 1-8, wherein R 4 is each independently selected from fluorine, chlorine, bromine, -CN, optionally 1-3 fluorine, chlorine, bromine, substituted C 1-3 alkyl, -OH, or -NH 2 ; optionally, the R 4 is each independently selected from fluorine, chlorine, -CN, optionally 1-3 fluorine-substituted C 1-3 alkyl, or -NH 2 ; optionally, R 4 is each independently selected from fluorine, chlorine, -CN, methyl, or -NH 2 .
  10. 如权利要求1-9任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中环B选自苯基；所述环B的取代基如权利要求1所述。The compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof according to any one of claims 1-9, wherein ring B is selected from phenyl; the substituents of ring B are as defined in claim 1. Narrated.
  11. 如权利要求1-10任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中环B选自
    Figure PCTCN2020074071-appb-100008
    所述R 4a、R 4b、R 4c、R 4d和R 4e各自独 立地如权利要求1中R 4所述；任选地，R 4a和R 4c各自独立地选自氟、氯、溴、-CN、任选被1-3个氟、氯、溴、取代的C 1-3烷基、-OH、或-NH 2。     The compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1-10, wherein ring B is selected from
    Figure PCTCN2020074071-appb-100008
    The R 4a , R 4b , R 4c , R 4d and R 4e are each independently as described in R 4 in claim 1; optionally, R 4a and R 4c are each independently selected from fluorine, chlorine, bromine,- CN, optionally substituted by 1-3 fluorine, chlorine, bromine, C 1-3 alkyl, -OH, or -NH 2 .
  12. 如权利要求1-11任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，选自式II化合物、其立体异构体或其药学上可接受的盐，The compound of formula I, its stereoisomers or pharmaceutically acceptable salts thereof according to any one of claims 1-11, selected from the group consisting of compounds of formula II, its stereoisomers or pharmaceutically acceptable salts thereof,
    Figure PCTCN2020074071-appb-100009
    Figure PCTCN2020074071-appb-100009
    其中，n选自1、或2；Wherein, n is selected from 1, or 2;
    R 2或R 3的定义如权利要求1～11所述；R 4a或R 4c的定义如权利要求1中R 4所述。 The definition of R 2 or R 3 is as described in claims 1 to 11; the definition of R 4a or R 4c is as described in R 4 in claim 1.
  13. 以下化合物、其立体异构体或其药学上可接受的盐：The following compounds, their stereoisomers or their pharmaceutically acceptable salts:
    Figure PCTCN2020074071-appb-100010
    Figure PCTCN2020074071-appb-100010
    Figure PCTCN2020074071-appb-100011
    Figure PCTCN2020074071-appb-100011
  14. 药物组合物，其包含权利要求1-13任一项所述化合物、其立体异构体或其药学上可接受的盐，任选地还包括药学上可接受的辅料。A pharmaceutical composition comprising the compound according to any one of claims 1-13, its stereoisomer or a pharmaceutically acceptable salt thereof, and optionally pharmaceutically acceptable excipients.
  15. 用于预防或治疗受益于衣壳蛋白装配抑制的疾病的权利要求1-13任一项所述化合物、其立体异构体、其药学上可接受的盐、或权利要求14所述药物组合物；任选地，其中所述受益于衣壳蛋白装配抑制的疾病的指乙型肝炎病毒感染引起的疾病；任选地，所述受益于衣壳蛋白装配抑制的疾病的指乙型肝炎病毒感染引起的肝脏疾病。The compound according to any one of claims 1-13, its stereoisomer, its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14 for preventing or treating diseases benefiting from capsid protein assembly inhibition Optionally, wherein said disease that benefits from capsid protein assembly inhibition refers to a disease caused by hepatitis B virus infection; optionally, said disease that benefits from capsid protein assembly inhibition refers to hepatitis B virus infection Caused by liver disease.
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