WO2019185016A1 - 含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途 - Google Patents

含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途 Download PDF

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Publication number
WO2019185016A1
WO2019185016A1 PCT/CN2019/080412 CN2019080412W WO2019185016A1 WO 2019185016 A1 WO2019185016 A1 WO 2019185016A1 CN 2019080412 W CN2019080412 W CN 2019080412W WO 2019185016 A1 WO2019185016 A1 WO 2019185016A1
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Prior art keywords
alkyl
group
optionally
fluorine
hydrogen
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PCT/CN2019/080412
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English (en)
French (fr)
Inventor
张寅生
敖汪伟
李元
王辉
沈杭州
倪杰
张欢
吴杰
张立
曹凯
陆鹏
刘戌时
汪杰
赵天笑
葛兴枫
卢丹丹
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 CA3094022A priority Critical patent/CA3094022A1/en
Priority to SG11202009150RA priority patent/SG11202009150RA/en
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to EP19777163.7A priority patent/EP3778569A4/en
Priority to CN202211627236.9A priority patent/CN115974754A/zh
Priority to AU2019241321A priority patent/AU2019241321B2/en
Priority to KR1020207031226A priority patent/KR20200136994A/ko
Priority to JP2020552331A priority patent/JP7434166B2/ja
Priority to CN202211543931.7A priority patent/CN115974753A/zh
Priority to CN201980021317.4A priority patent/CN111868026B/zh
Priority to US17/043,593 priority patent/US11597716B2/en
Priority to EA202092159A priority patent/EA202092159A1/ru
Publication of WO2019185016A1 publication Critical patent/WO2019185016A1/zh
Priority to PH12020551616A priority patent/PH12020551616A1/en
Priority to ZA2020/06378A priority patent/ZA202006378B/en
Priority to US18/106,103 priority patent/US20230183208A1/en
Priority to AU2023204386A priority patent/AU2023204386A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to a compound of the formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, and a process for the preparation thereof , a pharmaceutical composition containing the same, and its use as a medicament for treating hepatitis B virus infection.
  • chronic hepatitis B can only be controlled without treatment, and is currently limited to two types of agents (interferons and inhibitors of nucleoside analogs/viral polymerases).
  • the lower cure rate of HBV is due in part to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.
  • Current treatment protocols are unable to remove cccDNA from the repository, and some new targets for HBV such as core inhibitors (such as viral capsid protein formation or assembly inhibitors and cccDNA inhibitors and interferon-stimulated gene activators) Etc.) is expected to bring hope to cure hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).
  • the HBV capsid is assembled from the core protein.
  • HBV reverse transcriptase and pgRNA need to be correctly encapsulated by the capsid protein. Therefore, blocking capsid protein assembly, or accelerating capsid protein degradation, blocks the assembly process of the capsid protein, thereby affecting viral replication.
  • inhibitors of capsid protein assembly such as WO2014184350, WO2015011281, WO2017156255, etc., which disclose a series of related compounds. However, most of them are in the early stage of clinical research or the research has been terminated, and there is a need in the art for more alternative effective capsid protein assembly inhibitors for treating, ameliorating or preventing HBV infection.
  • the present invention synthesizes a series of novel derivatives and studies the HBV protein assembly activity.
  • the present application relates to compounds of formula I, stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts thereof,
  • X and Y each independently represent CR 7, said R 7 are independently selected from hydrogen, C 3-4 cycloalkyl, -CN, fluoro, chloro, bromo or C 1-3 alkyl, said C 1-3 An alkyl group is optionally substituted with one or more groups selected from the group consisting of fluorine, chlorine, bromine, C 1-6 alkoxy, -OH, -NH 2 or -CN;
  • Ring A is selected from phenyl or 5-10 membered heteroaryl
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CHF 2 , -CH 2 F, -CF 3 , -CN, C 1-3 alkyl, -NH 2 , C 3 a -4 cycloalkyl group, -NHR a or -NR b R c , wherein R a , R b , R c are each independently selected from -C(O)C 1-6 alkyl, C 1-6 alkyl, - S(O) 2 C 1-6 alkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 4 is selected from the group consisting of hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl
  • R 5 is selected from C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, 3-7-membered cycloalkyl or 3-7-membered heterocycloalkyl, said C 1 - 6 alkyl
  • a C 2 -6 alkenyl group, a C 2 -6 alkynyl group, a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group is optionally substituted by a halogen group, a 3-4 membered cycloalkyl group, 3-4 membered heterocycloalkyl, -OR 8 , oxo, -CN, -C(O)OR 8 , -SO 2 R 8 , -C(O)N(R 8 ) 2 or optionally Or a plurality of C 1-3 alkyl groups substituted with fluorine, -CN or -OH;
  • R 8 is each independently selected from hydrogen or C 1-3 alkyl.
  • above X and Y each independently represent CR 7 , said R 7 being independently selected from hydrogen, fluoro, chloro, bromo or C 1-3 alkyl, said C 1-3 alkyl optionally Substituted by one or more groups selected from fluoro or C 1-3 alkoxy; in some embodiments, said R 7 is independently selected from hydrogen, fluoro, chloro, bromo or optionally by one or a plurality of methoxy-substituted C 1-3 alkyl groups; in some embodiments, the R 7 is independently selected from hydrogen, fluoro, chloro, bromo, -CH 2 OCH 3 or methyl; in some embodiments And R 7 is independently selected from hydrogen, chlorine, bromine or methyl.
  • X and Y each independently represent CR 7, said R 7 are independently selected from hydrogen, C3-4 cycloalkyl, -CN, fluorine, chlorine, bromine or optionally substituted with one or more Fluorine substituted C1-3 alkyl.
  • the above-mentioned X and Y each independently represent CR 7, said R 7 are independently selected from hydrogen, fluorine, chlorine, bromine or optionally substituted with one or more fluorine of a C 1-3 alkoxy
  • the R 7 is independently selected from hydrogen, fluoro, chloro, bromo or C 1-3 alkyl; in other embodiments, the R 7 is independently selected from hydrogen, fluoro. , chlorine, bromine or methyl.
  • the above ring A is selected from the group consisting of phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; In some embodiments, Ring A is selected from phenyl or 6-membered heteroaryl; in some embodiments, Ring A is selected from phenyl or pyridyl. In some embodiments, the heteroaryl group present in the definition of Ring A above contains 1 or 2 N atoms.
  • Ring A is selected from the group consisting of phenyl.
  • R a is selected from -C (O) C 1-3 alkyl, C 1-3 alkyl, -S (O) 2 C 1-3 alkyl, 5-6 membered heteroaryl, C 6-10 aryl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; in some embodiments, R a is selected from -C (O) C 1-3 alkyl, C 1- 3 alkyl, or -S (O) 2 C 1-3 alkyl; in some embodiments, R a is selected from -C (O) CH 3, or -S (O) 2 CH 3.
  • R b , R c are each independently selected from -C(O)C 1-3 alkyl, C 1-3 alkyl, -S(O) 2 C 1-3 alkyl, 5- a 6-membered heteroaryl, C 6-10 aryl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; in some embodiments, R b , R c are each independently selected from -C ( O) C 1-3 alkyl, C 1-3 alkyl, or -S(O) 2 C 1-3 alkyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, —CHF 2 , —CH 2 F, —CF 3 , —CN, C 1-3 alkyl. , -NH 2 , or C 3-4 cycloalkyl.
  • R 1 above is selected from hydrogen, fluoro, chloro, -CHF 2 , -CN, -CF 3 or methyl; in some embodiments, R 1 above is selected from hydrogen or fluoro.
  • the above R 2 is selected from hydrogen, fluorine, chlorine or bromine; in some embodiments, the above R 2 is selected from hydrogen or fluorine.
  • R 3 above is selected from the group consisting of hydrogen, fluoro, chloro, -CHF 2 , -CN, -CF 3 , methyl, -NH 2 or -NHR a ; in some embodiments, R 3 above is selected from Hydrogen, fluorine, chlorine, -CHF 2 , -CN, -CF 3 , methyl, -NH 2 , -NHC(O)CH 3 , or -NHS(O) 2 CH 3 ; in some embodiments, R above 3 is selected from the group consisting of hydrogen, fluorine, chlorine, -CHF 2 , -CN, -CF 3 , methyl or -NH 2 ; in some embodiments, the above R 3 is selected from the group consisting of hydrogen, fluorine, chlorine, -CN, methyl or -NH 2 .
  • R 1 is selected from hydrogen, fluoro, chloro, -CHF 2 , -CN, -CF 3 or methyl, and at least one of R 1 and R 3 is fluoro or hydrogen.
  • one of R 1 and R 3 is selected from hydrogen or fluorine, and the other is selected from the group consisting of hydrogen, fluorine, chlorine, —CHF 2 , —CN, —CF 3 , methyl or —NH 2 .
  • R 2 is selected from the group consisting of fluorine, chlorine or bromine, one of R 1 and R 3 is hydrogen, and the other is selected from the group consisting of hydrogen, fluorine, chlorine, —CHF 2 , —CN, —CF 3 or methyl;
  • R 2 above is selected from fluoro, R 1 and R 3 are each hydrogen, and the other is selected from fluoro, chloro or —CN; in some embodiments, R 2 is selected from fluoro and R 1 is hydrogen.
  • R 3 is -CN or chlorine.
  • R 2 above is selected from fluoro, R 1 is hydrogen, and R 3 is —CN.
  • one of R 1 and R 3 is hydrogen and the other is selected from the group consisting of fluorine, chlorine, —CHF 2 , —CN, —CF 3 or methyl.
  • X and Y each independently represent CR 7, said R 7 are independently selected from hydrogen, C 3-4 cycloalkyl, -CN, fluorine, chlorine, bromine or optionally substituted with one or a plurality of fluorine-substituted C 1-3 alkyl groups; R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, -CHF 2 , -CH 2 F, -CF 3 , -CN, C 1-3 alkyl or C 3-4 cycloalkyl.
  • R 4 above is selected from hydrogen or C 1-3 alkyl; in some embodiments, R 4 above is methyl or hydrogen.
  • R 4 above is methyl
  • the above R 5 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl,
  • the C 1-4 alkyl group, the C 2-4 alkenyl group, the C 2-4 alkynyl group, the 3-6 membered cycloalkyl group or the 4-6 membered heterocycloalkyl group are optionally substituted by the following groups: halogen, 3 -4 membered cycloalkyl, 3-4 membered heterocycloalkyl, -OR 8 , oxo, -CN, -C(O)OR 8 , -SO 2 R 8 , -C(O)N(R 8 ) 2 or a C 1-3 alkyl group optionally substituted by one or more fluorine, -CN or -OH; in some embodiments, the above R 5 is selected from C 1-4 alkyl, C 2-4 alkeny
  • R 5 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl
  • the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, 3-6 membered cycloalkyl group or 4-6 membered heterocycloalkyl group is optionally substituted with the following groups: halogen, -OH, -CN, -C(O)OR 8 , -C(O)N(R 8 ) 2 or a C 1-3 alkyl group optionally substituted by one or more fluorine or OH; in other embodiments
  • R 5 is selected from C 1-4 alkyl, C 2-4 alkynyl, 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, said C 1-4 alkyl, C 2 a -4 alkynyl
  • the above R 5 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4-6 membered cycloalkyl or 4-6 membered heterocycloalkyl.
  • the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, 4-6 membered cycloalkyl group or 4-6 membered heterocycloalkyl group is optionally substituted by the following group: halogen 3-4 membered cycloalkyl, 3-4 membered heterocycloalkyl, -OR 8 , oxo, -CN, -C(O)OR 8 , -SO 2 R 8 , -C(O)N(R 8) 2 or optionally substituted with one or more fluorine, -CN or -OH, C 1-3 alkyl, said R 8 are each independently selected from hydrogen or C 1-3 alkyl; in yet a further In an embodiment, the above R 5 is selected from hydrogen
  • the heterocycloalkyl group occurring in the definition of R 5 above contains 1 or 2 heteroatoms selected from N, O or S.
  • each R 8 is independently selected from hydrogen or methyl.
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • the structural unit Selected from In other embodiments, the structural unit Selected from
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • the structural unit Selected from In other specific embodiments, the structural unit Selected from
  • a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application is selected a compound of Formula II, Formula III or Formula IV, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y are as defined above;
  • R 1 , R 2 , R 3 , X, Y are as defined above; structural units Selected from
  • a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application is selected a compound of the formula II, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y are as defined above;
  • R 1 , R 2 , R 3 structural unit and The definition is as shown above.
  • a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application is selected a compound of formula III, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y are as defined above;
  • R 1 , R 2 , R 3 structural unit and The definition is as shown above.
  • a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application is selected From a compound of formula IV, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 2 , R 3 , R 5 , X, Y are as defined above;
  • R 2 , R 3 , X, Y structural unit
  • the definition is as shown above.
  • a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application is selected From the following compounds, their stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts:
  • the application provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application provides a method of treating a disease that benefits from inhibition of capsid protein assembly, comprising administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of formula I above.
  • a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of formula I above.
  • An acceptable salt or a pharmaceutical composition thereof is an acceptable salt or a pharmaceutical composition thereof.
  • the present application provides the use of a compound of formula I above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease which would benefit from inhibition of capsid protein assembly.
  • the present application provides the use of a compound of formula I above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease which benefits from inhibition of capsid protein assembly.
  • the present application provides a compound of the above formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease which benefits from inhibition of capsid protein assembly.
  • the application provides a pharmaceutical composition comprising a compound of formula I, stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs thereof, of the present application. Or a pharmaceutically acceptable salt.
  • the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
  • the present application provides a method of inhibiting capsid protein assembly comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, a stereoisomer, a tautomer thereof, a geometrical difference of the present application. A conformation, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt or pharmaceutical composition thereof.
  • the individual is a mammal; in some embodiments, the individual is a human.
  • the present application provides a method of preventing or treating a disease that benefits from inhibition of capsid protein assembly, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, a stereoisomer thereof, and a tautomer thereof of the present application.
  • the individual is a mammal; in some embodiments, the individual is a human.
  • the invention provides a compound of formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable thereof, of the present application.
  • a salt or a pharmaceutical composition thereof for inhibiting capsid protein assembly.
  • the invention provides a compound of formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable thereof, of the present application.
  • a salt or a pharmaceutical composition thereof for the preparation of a medicament for inhibiting capsid protein assembly.
  • the invention provides a compound of formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable thereof, of the present application.
  • the invention provides a compound of the above formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmaceutically acceptable salt thereof. Or the use of a pharmaceutical composition thereof for preventing or treating a disease that benefits from inhibition of capsid protein assembly.
  • the present application provides a compound of Formula I, a stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate thereof of the present application for inhibiting capsid protein assembly. , a prodrug or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the present application provides a compound of the above formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate thereof, for the prevention or treatment of a disease which benefits from inhibition of capsid protein assembly.
  • the disease that benefits from inhibition of capsid protein assembly refers to a disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the disease that benefits from inhibition of capsid protein assembly refers to a liver disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the treatment which benefits from inhibition of capsid protein assembly, refers to controlling, reducing or eliminating HBV to prevent, alleviate or cure liver disease in an infected patient.
  • Dotted line in the structural unit or group in the present application Represents a covalent bond.
  • a structural unit including but not limited to
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted and the oxo does not occur on the aryl group.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn herein is that the moiety has an integer number of carbon atoms in a given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-3 means that the group may have 1 carbon atom, 2 carbon atoms, and 3 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent.
  • each R has an independent option.
  • linking group When the number of one linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked.
  • L' represents a covalent bond in A-L'-Z, the structure is actually A-Z.
  • the substituent When a bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring.
  • a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms (eg, 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 i.e., alkyl
  • alkyl of an alkoxy group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group
  • C1-3 alkyl refers to an alkyl group containing from 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, and isopropyl).
  • alkoxy refers to -O-alkyl
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom.
  • 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) or the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 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 and the like.
  • C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, cyclohexylethane, cycloalkylethane, non-limiting examples of 4-membered heterocycloalkyl including, but not limited to, azetidinyl, acetophenan
  • Examples of a cyclic group, a thibutyl group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of the group, imidazolidinyl group, tetrahydropyrazolyl group, 6-membered heterocycloalkyl group include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothio
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an 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-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 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, fluorenyl, isodecyl and the like.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • solvate refers to a substance formed by combining a compound of the invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like.
  • Solvates include stoichiometric amounts of solvates and non-stoichiometric amounts of solvates.
  • hydrate refers to a solvate comprising a compound disclosed or claimed and a stoichiometric or non-stoichiometric amount of water.
  • the compounds of the invention may also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to increase the many desirable properties of the drug (e.g., solubility, bioavailability, preparation, etc.), the compounds of the invention can be delivered in the form of a prodrug. Accordingly, the present invention is intended to encompass prodrugs of currently claimed compounds, methods of delivery thereof, and compositions containing prodrugs.
  • prodrug is intended to include any covalently bonded carrier which, when administered to a mammalian subject, releases the active parent drug of the invention in vivo.
  • the prodrugs of the present invention are prepared by modifying a functional group present in the compound in such a manner that the modification cleaves into the parent compound in a conventional operation or in vivo.
  • the term "individual” includes humans and animals, for example, mammals (e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • mammals e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients 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 are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • Certain compounds of the present application may have asymmetric carbon atoms (stereocenters) or double bonds. Thus, racemates, diastereomers, enantiomers, geometric isomers, and individual isomers are included within the scope of the present application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present application, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, All of these are within the scope of this application. Additional asymmetric carbon atoms may be present in the substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide purity. The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes that may be incorporated into 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 respectively.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting 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.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium (ie, 2 H) can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is substituted with at least one hydrazine, and all such forms of the compound are included within the scope of the present application.
  • it can be in a structural unit Degenerate on the ground, so as to get concrete And other structures.
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the therapeutic dose of a compound of the present application can depend, for example, on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of the compounds of the present application in the pharmaceutical compositions may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration.
  • the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound.
  • Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day.
  • the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof.
  • An effective dose can be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compounds of formula (I) of the present application can be prepared by one of ordinary skill in the art of organic synthesis by general or conventional methods in the art by the following routes:
  • R 6 and R 9 are selected from methyl or ethyl.
  • NBS stands for N-bromosuccinimide
  • EA stands for ethyl acetate
  • PE stands for petroleum ether
  • NCS N-chlorosuccinimide
  • DMF stands for N,N-dimethylformamide
  • HATU stands for 2- 7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • h stands for hour
  • DCM stands for dichloromethane
  • DIPEA stands for N,N-diisopropyl
  • DMA stands for dimethylacetamide
  • THF stands for tetrahydrofuran
  • LiHDMS stands for bistrimethylsilylamine lithium
  • PO stands for oral
  • IV stands for intravenous injection
  • MRT stands for mean residence time
  • Ts stands for p-toluenesulfonyl
  • the instrument used for mass spectrometry is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.
  • Step A Under a nitrogen atmosphere, add DMF (100 mL), 2,4-dimethyl-1H-pyrrole-3-carboxylate (8.0 g), methyl iodide (8.15 g) to a 500 mL vial, under ice bath. Add sodium hydride (2.87g) in portions, add to the room temperature and react for 2.5h. After the reaction is finished, slowly pour into 400mL of ice water to quench, extract with ethyl acetate (2 * 300mL), and combine the organic layer with saturated The organic layer was washed with an aqueous solution of sodium chloride, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.
  • Step B In a 500 mL three-necked flask, under nitrogen, add THF (150 mL), 1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (15.0 g), 5-amino-2-fluoro Benzonitrile (14.08 g) was slowly added dropwise with bis(trimethylsilyl)amide lithium (27.7 g, 166 mL of THF solution) under ice-cooling, and then transferred to room temperature for 16.0 h. After the reaction was completed, it was slowly poured into 500 mL of ice water, and the mixture was evaporated. EtOAc (EtOAc m.
  • Step C Under a nitrogen atmosphere, add DCM (240 mL) to a 500 mL vial, (N-(3-cyano-4-fluorophenyl)-1,2,4-trimethyl-1H-pyrrole-3- Formamide (5.0 g), monoethyl chloroacetonate (7.55 g), add aluminum chloride (12.29 g) in portions under ice-cooling, transfer to room temperature for 15.0 h after the addition. After the reaction, slowly pour into 300 mL of ice water. The mixture was extracted with EtOAc (EtOAc m.
  • Step D In a 100 mL single-necked flask, methanol (30 mL), 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-1,3,5-trimethyl A solution of ethyl-1H-pyrrol-2-yl)-2-oxoacetate (4.00 g) and sodium hydroxide (0.862 g) in water (30 mL). Water (200 mL) and DCM (150 mL) were added to the reaction mixture, and the layers were separated, and the organic layer was evaporated. The aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (2*150 mL).
  • Step E DMF (5.0 mL), 2-(4-(3-cyano-4-fluorophenyl)carbamoyl)-1,3,5-trimethyl-1H- was added sequentially to a 50 mL vial. Pyrrol-2-yl)-2-oxoacetic acid (300 mg), HATU (399 mg), DIPEA (169 mg).
  • trans-3-aminocyclobutanol hydrochloride was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl)-5-(2-(( Trans-3-hydroxycyclobutyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide.
  • Example 1 in the step E, 2-aminoisobutyric acid methyl ester hydrochloride was used in place of propargylamine to obtain (2-(4-(3-cyano-4-fluorophenyl)carbamoyl)). Methyl-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetylamino)-2-methylpropanoate.
  • Example 1 in the step E, cis-3-amino-cyclobutane methanol was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl)-5-(2-(( 3-(Hydroxymethyl)cyclobutyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide.
  • Example 1 (R)-N-(3-cyano-4-fluorophenyl) was obtained by substituting (R)-1,1,1-trifluoroisopropylamine hydrochloride for propargylamine in step E. -1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3- Formamide.
  • Step A According to Example 1, (S)-N-(3-cyano-4-) was prepared by substituting (S)-1,1,1-trifluoroisopropylamine hydrochloride for propargylamine in step E. Fluorophenyl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole -3-carboxamide.
  • Step A In a 500 mL single-mouth bottle, under DC protection, add DCM (250 mL), ethyl 1,2,4-trimethyl-1H-pyrrole-3-carboxylate (2.0 g), monoethyl chloroacetonate (4.52) g). Under ice bath, anhydrous aluminum chloride (7.36 g) was slowly added, and after completion, it was transferred to room temperature for 5.5 h. After the completion of the reaction, the mixture was poured into 200 mL of ice water, and the mixture was evaporated.
  • Step B In a 100 mL single-mouth bottle, add methanol (10 mL), ethyl 5-(2-ethoxy-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate (1.20 g), a solution of sodium hydroxide (0.34 g) in water (10 mL) was slowly added, and the mixture was reacted for 15 minutes in an ice bath. After the completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was combined with EtOAc EtOAc. The solvent was evaporated under reduced pressure to give diethyl 2-(4-(ethoxycarbonyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (897 mg). In the next step.
  • Step D In a 50 mL single-mouth bottle, methanol (9 mL), 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3 was added in sequence. Ethyl formate (500 mg), a solution of sodium hydroxide (259 mg) in water (9 mL) was added at room temperature, and the mixture was heated to 90 ° C for 3.0 h.
  • EtOAc EtOAc (2-(tert-Butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid (260 mg) was used directly in the next step.
  • 1 H-NMR 500MHz, DMSO -d6): ⁇ 12.28 (s, 1H), 8.26s, 1H), 3.73 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H), 1.33 ( s, 9H).
  • Step E Toluene (15 mL), 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3 was added sequentially to a 50 mL single-necked flask. - Formic acid (360 mg), thionyl chloride (3.05 g), the system was heated to 115 ° C for 1.0 h under nitrogen. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was evaporated to remove the acid chloride intermediate (339 mg).
  • Step A Substituting methyl 2-methyl-1H-pyrrole-3-carboxylate for ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate according to Example 1 to obtain 1,4 Methyl dimethyl-1H-pyrrole-3-carboxylate.
  • Step B Substituting methyl 1, 4-dimethyl-1H-pyrrole-3-carboxylate for 1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid B in step A according to Example 13. Ester to give methyl 5-(2-ethoxy-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate. MS (ESI+, [M+Na] + ) m/z: 276.3.
  • Step C Substituting 5-(2-ethoxy-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid methyl ester for 5- in step B according to Example Ethyl 2-(2-ethoxy-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate to give 2-(4-(methoxycarbonyl)-1 , 3-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid.
  • Step D Substituting 2-(4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid for 2- in step C according to Example 13. (4-(ethoxycarbonyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid to give 5-(2-(tert-butylamino)-2 Methyl oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate.
  • Step E According to Example 13, methyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate was used in Step D Substituting ethyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate to give 5-(2-(uncle) Butylamino)-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid.
  • Step F Substituting 5-(2-(tert-butylamino)-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylic acid in step E according to Example 13.
  • 5-(2-(tert-Butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid to give 5-(2-(tert-butylamino) 2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1,4-dimethyl-1H-pyrrole-3-carboxamide.
  • Step A According to Example 1, in step A, ethyl 2-methyl-1H-pyrrole-3-carboxylate was used in place of ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate to obtain 1, Ethyl 2-dimethyl-1H-pyrrole-3-carboxylate.
  • Step B Substituting 1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester for 1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid in step A according to Example 13. Ethyl ester gave ethyl 5-(2-ethoxy-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate.
  • Step C According to Example 13, in step B, 5-(2-ethoxy-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester was used instead of 5- Ethyl 2-(2-ethoxy-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate to give 2-(4-(ethoxycarbonyl)-1 , 5-Dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid.
  • Step D Substituting 2-(4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid for 2- in step C according to Example 13. (4-(ethoxycarbonyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid to give 5-(2-(tert-butylamino)-2 -Oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester.
  • Step E According to Example 13, in step D, ethyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylate Substituting ethyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxylate to give 5-(2-(uncle) Butylamino)-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid. MS (ESI - , [MH] - ) m / z: 265.3.
  • Step F Substituting 5-(2-(tert-butylamino)-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid in step E according to Example 13.
  • Step A To the reaction flask, 1H-pyrrole-3-carboxylic acid methyl ester (3.0 g) and 20 mL of DMF were sequentially added. After dissolving, 1.16 g of sodium hydride was added in portions at 0 ° C, and 1.67 mL of methyl iodide was added thereto. After the reaction at room temperature for 0.5 h. After the completion of the reaction, 50 mL of water and 50 mL of LDCM were added, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give methyl 1-methyl-1H-pyrrole-3-carboxylate (3.12 g) Purification was used directly in the next reaction.
  • Step C To the reaction flask, methyl 5-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylate (3.35 g), THF (4 mL) After stirring at room temperature for 10 minutes, a solution of sodium hydroxide (1.68 g) in water (4.00 ml) was slowly added thereto, and the mixture was reacted at room temperature for 1 hour. After the completion of the reaction, the pH of the solution was adjusted to 3 to 4, 50 mL of ethyl acetate and 50 mL of purified water were added, the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-(4-(methoxycarbonyl).
  • Step D To the reaction flask, 2-(4-(methoxycarbonyl)-1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid (2.46 g), ethyl acetate 2 mL), tert-butylamine (2.55 g) and 1-propylphosphoric anhydride (50% w/v ethyl acetate solution, 7.5 mL) were reacted at room temperature for 1 hour. After the reaction was completed, 100 mL of ethyl acetate and 100 mL of water were added thereto.
  • Step E To the reaction flask, methyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylate (1.17 g), methanol (5 mL), after stirring for 10 minutes, a solution of sodium hydroxide (0.53 g) in water (5.00 ml) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the pH was adjusted to 3 to 4 with 2N HCl, and 100 mL of ethyl acetate and 100 mL of water were added.
  • Step F To the reaction flask, 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylic acid (100 mg), toluene (2 mL) Sulfoxide (189 mg), under N 2 protection, heated to 110 ° C for 1 h. The solvent was removed by concentration, and N,N-dimethylacetamide (2 mL) and 5-amino-2-fluorophenylacetonitrile (108 mg) were added to the obtained crude product, and the mixture was heated to 100 ° C for 2 h.
  • Step A 100 mg of 5-(2-(tert-butylamino-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H was sequentially added to the reaction flask. - Pyrrole-3-carboxamide, 1 mL of DMF, 4 mL of acetonitrile and 48.1 mg of NBS, and reacted at 80 ° C for 24 hours. After the reaction was completed, 100 mL of ethyl acetate and 100 mL of water were added thereto, and the organic phase was separated, and brine (2*50 mL) was used. Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step A To the reaction flask was added 100 mg of 5-(2-(tert-butylamino-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H- Pyrrole-3-carboxamide, 1 mL of DMF and 4 mL of acetonitrile were added, and 144.3 mg of NBS was added thereto, and the mixture was reacted at 110 ° C for 24 hours. The stirring was stopped, and 100 mL of ethyl acetate and 100 mL of water were added to the solution. The organic phase was separated and saturated brine was used.
  • Example 1 in the step E, tetrahydro-4-methyl-2H-pyran-4-amine was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl)-1,2. 4-Trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-2-oxoacetyl)-1H-pyrrole-3-carboxamide.
  • Example 1 in the step E, 3-(trifluoromethyl)oxetan-3-amine hydrochloride was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl). -1,2,4-trimethyl-5-(2-oxo-2-((3-(trifluoromethyl)oxetan-3-yl)amino)acetyl)-1H-pyrrole -3-carboxamide.
  • Example 1 in the step E, 3(3-aminooxetan-3-yl)methanol was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl)-5-( 2-(3-(Hydroxymethyl)oxetan-3-yl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide.
  • Example 1 in the step E, (1-aminocyclopropyl)methanol was used in place of propargylamine to obtain N-(3-cyano-4-fluorophenyl)-5-(2-((1-( Hydroxymethyl)cyclopropyl)amino)-2-oxoacetyl)-1,2,4-trimethyl-1H-pyrrole-3-carboxamide.
  • Step A At 0 ° C, water (10.00 mL) and sodium hydroxide (1.416 g) were sequentially added to the reaction flask, and 1-amino-3,3-difluorocyclobutane-1-carboxylic acid (5 g) was slowly added dropwise. A solution of methanol (50 mL) was added dropwise, then di-tert-butyl dicarbonate (9.10 g) was added. After the addition, the mixture was stirred at room temperature for 16 h. After the reaction was finished, the pH was adjusted to 2 to 3 with 2N HCl and filtered.
  • Step B 1-((tert-Butoxycarbonyl)amino)-3,3-difluorocyclobutane-1-carboxylic acid (7.6 g), HATU (17.25 g), DMF (50 mL) were sequentially added to the reaction flask. ), methylamine (4.79 g) and DIPEA (42.3 mL) were reacted at room temperature for 3 h.
  • Step C To the reaction flask, t-butyl (3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)carbamate (7.38 g) and dioxane (50 mL) were added successively. 4M HCl in dioxane solution (69.8 mL) was added dropwise and stirred at room temperature for 12 h. After the reaction, the pH was adjusted to 10-11 with 2M sodium hydroxide solution, filtered, and the filter cake was dried under vacuum at 40 ° C to give 1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide salt. Acid salt (5.19 g).
  • Step D According to Example 1, in the step E, 1-amino-3,3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride was used in place of propargylamine to obtain N-(3- Cyano-4-fluorophenyl)-5-(2-((3,3-difluoro-1-(methylcarbamoyl)cyclobutyl)amino)-2-oxoacetyl)-1, 2,4-Trimethyl-1H-pyrrole-3-carboxamide.
  • Step A DMF (100 mL), 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (20 g) was added to the reaction flask, and NaH (7.83 g) was slowly added under N 2 protection. After the addition was completed, stirring for 30 min, slowly adding methyl iodide (23.17 g) to the above stirred solution, adding, stirring at room temperature for 2.0 h, pouring the reaction solution into saturated ammonium chloride solution (1000 mL) containing crushed ice, using acetic acid The ester was extracted (3*1000 mL). EtOAcjjjjjjjjjj .
  • Step B Add 1,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (10 g) and DCM (200 mL) to the reaction flask, and then add AlCl 3 (32 g) under ice bath, and add, Under N 2 protection, a solution of oxalyl chloride (24.5 g) in DCM (100 mL) was added dropwise, and the mixture was stirred at room temperature for 5.0 h. The reaction solution was poured into 500 mL of ice water and extracted with DCM (200 mL*3).
  • Step C To the reaction flask was added ethyl 5-(2-ethoxy-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate (6 g), DMF (100 mL) , NCS (4.5 g), and stirred at room temperature for 8.0 h. The reaction mixture was poured into 500 mL of water, and extracted with ethyl acetate (200 mL*3).
  • Step D To the reaction flask was added ethyl 2-chloro-5-(2-ethoxy-2-oxoacetyl)-1,4-dimethyl-1H-pyrrole-3-carboxylate (3.2 g ), methanol (30mL), NaOH (0.85g) aqueous solution (10mL) was added dropwise in an ice bath, added, stirred at room temperature, reacted for 5min, adjusted to pH 2-3 with 2N HCl, with ethyl acetate (100mL*3) The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dry to give 2-(5-chloro-4-(ethoxycarbonyl)-1,3-dimethyl-1H -pyrrol-2-yl)-2-oxoacetic acid (2.6 g). MS (ESI-, [MH] - ) m/z: 272.1.
  • Step E adding 2-(5-chloro-4-(ethoxycarbonyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (400 mg) to the reaction flask, DMF (10 mL), HATU (834 mg), DIPEA (416 mg), added, stirred at room temperature for 10 min, then added (S)-1,1,1-trifluoroisopropylamine hydrochloride (200 mg), and stirred at room temperature 2.0 h, the reaction solution was poured into 100 mL of water, and extracted with ethyl acetate (50 mL*3).
  • Step F Add (S)-2-chloro-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)) to the reaction flask
  • Ethylamino)acetyl)-1H-pyrrole-3-carboxylic acid ethyl ester 360 mg
  • methanol (20 mL) were added
  • NaOH (0.85 g) aqueous solution (5 mL) was added dropwise, and the mixture was reacted at 80 ° C for 8.0 h.
  • the pH was adjusted to 2 to 3 with 2N HCl, and extracted with ethyl acetate (100 mL*3).
  • Step G Add (S)-2-chloro-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)) to the reaction flask Amino)acetyl)-1H-pyrrole-3-carboxylic acid (320 mg), toluene (10 mL) and thionyl chloride (2.3 g), added, and reacted at 115 ° C for 2.0 h under N 2 protection. The crude product was obtained, and DMA (10 mL) and 5-amino 2-fluorobenzonitrile (256 mg) were added thereto, and the mixture was reacted at 100 ° C for 2.0 h.
  • Step A According to Example 29, in the step E, (R)-1,1,1-trifluoroisopropylamine hydrochloride was used in place of (S)-1,1,1-trifluoroisopropylamine hydrochloride. (R)-2-Chloro-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H - ethyl pyrrole-3-carboxylate.
  • Step B According to Example 29, in step F, (R)-2-chloro-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoropropane) Ethyl 2-amino)amino)acetyl)-1H-pyrrole-3-carboxylate in place of (S)-2-chloro-1,4-dimethyl-5-(2-oxo-2-(( Ethyl 1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate, (R)-2-chloro-1,4-dimethyl-5 -(2-Oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid.
  • Step C According to Example 29, in step G, ((R)-2-chloro-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoro)) Replacement of (S)-2-chloro-1,4-dimethyl-5-(2-oxo-2-(1) with propan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid ,1,1-Trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid, (R)-2-chloro-N-(3-cyano-4-fluorobenzene) ))-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-yl 1 H NMR (500 MHz, DMSO-d 6 ): ⁇ 10.58 (s, 1H), 9.51 -
  • Step A To the reaction flask were added 1,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (40 g), 5-fluoro-2-aminobenzonitrile (40.7 g), THF (200 ml), ice LiHDMS in THF (1M, 600 mL) was added to the mixture, and the mixture was stirred at room temperature for 2 h. The reaction solution was poured into ice water (1500 mL) containing saturated ammonium chloride solution, and a large amount of solid was precipitated and filtered.
  • Step B Add zinc oxide (4.11 g) to the reaction flask, add oxalyl chloride monoethyl ester (310 g) under ice bath, and then add N-(3-cyano-4-fluorophenyl)-1,4-di Methyl-1H-pyrrole-3-carboxamide (26 g), stirred in an ice bath for 20 min, stirred at room temperature for 3.0 h, added DCM (300 ml) to the reaction mixture under ice-cooling for 30 min, then poured into the ice water The mixture was extracted with EtOAc (3 mL) (EtOAc m.
  • Step C Add 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2- to the reaction flask Ethyl acetate (10 g) and DMF (400 mL) were added, and NCS (4.86 g) was dissolved in DMF (20 mL), and then added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 hours, and the reaction solution was poured into 1000 mL of water.
  • Step D Add 2-(5-chloro-4-((3-cyano-4-fluorophenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl to the reaction flask Ethyl 2-oxoacetate (4 g), THF (100 mL), EtOAc (EtOAc, EtOAc (EtOAc) 4, extracted with ethyl acetate (100 mL * 3), the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 2-(5-chloro-4-((3-cyano-4-) Fluorophenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (3.0 g).
  • Step E Add 2-(5-chloro-4-((3-cyano-4-fluorophenyl)carbamoyl)-1,3-dimethyl-1H-pyrrol-2-yl to the reaction flask 2-oxoacetic acid (150 mg), DMF (6 mL), HATU (235 mg), DIPEA (160 mg), stirring at room temperature for 5 min, then 4-methyltetrahydro-2H-pyran-4-amine (50 mg). After reacting at room temperature for 2.0 h, 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL*3).
  • Step A Substituting 3-(tetrafluoromethyl)oxetan-3-amine hydrochloride for 4-methyltetrahydro-2H-pyran-4-amine according to Example 31, Preparation of 2-chloro-N-(3-cyano-4-fluorophenyl)-1,4-dimethyl-5-(2-oxo-2-((3-(trifluoromethyl))oxy) Heterocyclobutane-3-yl)amino)acetyl)-1H-pyrrole-3-carboxamide.
  • Step A According to Example 31, in the step E, 2-amino-2-methylpropan-1-ol was used in place of 4-methyltetrahydro-2H-pyran-4-amine to give 2-chloro-N. -(3-cyano-4-fluorophenyl)-5-(2-((1-hydroxy-2-methylpropan-2-yl)amino)-2-oxoacetyl)-1,4- Dimethyl-1H-pyrrole-3-carboxamide.
  • Step A According to Example 31, in the step E, 3-methyl-aminooxetane was used instead of 4-methyltetrahydro-2H-pyran-4-amine to give 2-chloro-N- (3-cyano-4-fluorophenyl)-1,4-dimethyl-5-(2-((3-methyloxetan-3-yl)amino)-2-oxoacetyl Base)-1H-pyrrole-3-carboxamide.
  • Step A According to Example 29, in the step G, 3-chloro-4-fluoroaniline was substituted for 5-amino-2-fluorobenzonitrile to obtain (S)-2-chloro-N-(3-chloro-4). -fluorophenyl)-1,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole- 3-formamide.
  • Step A To the reaction flask, 2-(4-(ethoxycarbonyl)-1,3,5-trimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (800 mg, 3.16) was added in order. Methyl acetate (5 ml) was stirred for 10 min, then N,N-diisopropylethylamine (1225 mg, 1.66 ml, 9.48 mmol), HATU (1441 mg, 3.79 mmol). 100 mL of ethyl acetate and 100 mL of water were added to the solution, and the organic phase was separated.
  • Step B sequentially adding 1,2,4-trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-2-oxo to the reaction flask
  • Ethyl acetyl)-1H-pyrrole-3-carboxylic acid ethyl ester (954 mg, 2.72 mmol)
  • methanol 8 ml
  • water 8.00 ml
  • sodium hydroxide 0.327 g, 8.17 mmol
  • the solution was treated with N 2 and allowed to react at room temperature for 1 hour.
  • the pH of the solution was adjusted to 3 to 4, and 200 mL of ethyl acetate and 200 mL of purified water were added to the reaction.
  • Step C To the reaction flask, 1,2,4-trimethyl-5-(2-((4-methyltetrahydro-2H-pyran-4-yl)amino)-2-oxo was added sequentially.
  • Acetyl)-1H-pyrrole-3-carboxylic acid (280 mg), toluene (5 ml), thionyl chloride (0.25 ml, 3.47 mmol), and reacted at 115 ° C for 1 hour under N 2 . After concentration, 5.0 mL of toluene was added to the residue and concentrated to give 268 mg.
  • Example 37 3-chloro-4-fluoroaniline was replaced with 4-fluoroaniline to obtain (S)-N-(4-fluorophenyl)-1,2,4-trimethyl-5-(2 - Oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide.
  • Step A According to Example 37, (S)-N-(3-amino-4-fluoro) was obtained by substituting 4-fluorobenzene-1,3-diamine for 3-chloro-4-fluoroaniline in Step A. Phenyl)-1,2,4-trimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole- 3-formamide.
  • Example 1 in the step E, 1-propanolamine was replaced with 1-methylpiperazine to obtain N-(3-cyano-4-fluorophenyl)-1,2,4-trimethyl-5-. (2-(4-Methylpiperazin-1-yl)-2-oxoacetyl)-1H-pyrrole-3-carboxamide.
  • Example 1 in the step E, 3-amino-3-methylthietane 1,1-dioxide was substituted for propargylamine to obtain N-(3-cyano-4-fluorophenyl). -1,2,4-trimethyl-5-(2-((3-methyl-1,1-dithio-3-yl)amino)-2-oxoacetyl)-1H-pyrrole-3 - Formamide.
  • Step A According to Example 1, 3,4,5-trifluoroaniline in Step B was substituted for 5-amino-3-fluorobenzonitrile to obtain 1,2,4-trimethyl-N-(3, 4,5-Trifluorophenyl)-1H-pyrrole-3-carboxamide.
  • Step B Add monoethyl chloroacetonate (447 g), zinc oxide (5.28 g) to the reaction flask, and add 1,2,4-trimethyl-N-(3,4,5-three in portions under ice bath. Fluorophenyl)-1H-pyrrole-3-carboxamide (36.6 g) was added to room temperature and stirred for 2.0 h. After the reaction was completed, it was poured into 500 mL of ice water and quenched, and extracted with DCM (2*500 mL). The organic layer was evaporated.
  • Step C Under ice bath, MeOH (120 mL), 2-oxo-2-(1,3,5-trimethyl-4-) (3,4,5-trifluorophenyl) was added to the reaction flask. A solution of carbamoyl)-1H-pyrrol-2-yl)acetate (28.8 g) and sodium hydroxide (6.93 g) in water (60 mL), Water (200 mL) and DCM (150 mL) were added to the reaction mixture, and the layers were separated, and the organic layer was evaporated. The aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethyl acetate (2*500 mL).
  • Step D sequentially add DMF (5.0 mL), 2-oxo-2-(1,3,5-trimethyl-4-((3,4,5-trifluorophenyl))aminocarbamide to the reaction flask.
  • DMF 5.0 mL
  • 2-oxo-2-(1,3,5-trimethyl-4-((3,4,5-trifluorophenyl))aminocarbamide 5.0 mL
  • Acyl)-1H-pyrrol-2-yl)acetic acid 600 mg
  • DIPEA (657 mg)
  • 3-methyl-3-butylbutylamine (162 mg).
  • Step A According to Example 18, (S)-1,1,1-trifluoropropan-2-amine hydrochloride was used in step D instead of t-butylamine to give (S)-1-methyl-5- ( Methyl 2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate. MS (ESI+, [M+H] + ) m/z: 307.2.
  • Step B According to Example 18, in step E, (S)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino) Methyl acetyl)-1H-pyrrole-3-carboxylate in place of methyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylate, (S)-1-Methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate acid.
  • Step C According to Example 18, in step F, (S)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino) Acetyl)-1H-pyrrole-3-carboxylic acid in place of 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylic acid, S)-N-(3-Cyano-4-fluorophenyl)-1-methyl-5-(2-oxo-2-(1,1,1-trifluoroprop-2-yl)amino) Acetyl)-1H-pyrrole-3-carboxamide.
  • Step A According to Example 18, (R)-1,1,1-trifluoropropan-2-amine hydrochloride was used in step D instead of t-butylamine to give (R)-1-methyl-5- ( Methyl 2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate. MS (ESI-, [MH] - ) m/z: 305.3.
  • Step B According to Example 18, in step E, (R)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino) Methyl acetyl)-1H-pyrrole-3-carboxylate in place of methyl 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylate, Preparation of (R)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate acid. MS (ESI-, [MH] - ) m/z: 291.3.
  • Step C According to Example 18, in step F, (R)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino) Acetyl)-1H-pyrrole-3-carboxylic acid in place of 5-(2-(tert-butylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-3-carboxylic acid, R)-N-(3-Cyano-4-fluorophenyl)-1-methyl-5-(2-oxo-2-(1,1,1-trifluoropropan-2-yl)amino) Acetyl)-1H-pyrrole-3-carboxamide.
  • Step A In the reaction flask, methyl 1-methyl-1H-pyrrole-3-carboxylate (33 g), 2-fluoro-5-aminobenzonitrile (40.4 g), tetrahydrofuran (200 mL), Lithium bis(trimethylsilyl)amide (90 g, 538 mL of tetrahydrofuran solution) was added, and after 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into 2000 mL of ice water, stirred vigorously for 10 minutes, filtered, and the filter cake was dried overnight to give N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole-3. - formamide (51.48 g).
  • Step B Add N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole-3-carboxamide (20.0 g), dichloromethane (250 mL), and then stirred. Ethyl 2-chloro-2-oxoacetate (33.7 g), anhydrous aluminum trichloride (10.96 g) was added portionwise, and then transferred to room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into 2,000 mL of ice water, and the mixture was evaporated.
  • Step C Add 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid to the reaction flask Ethyl ester (2.16g), tetrahydrofuran (10mL), the reaction solution was placed in an ice bath, lithium hydroxide monohydrate (0.53g) was dissolved in water (5mL), and the mixture was stirred in an ice bath.
  • reaction was carried out for 30 minutes, and after completion of the reaction, it was diluted with 50 mL of water, adjusted to pH 5-6 with 2 mol/L of diluted hydrochloric acid, washed with ethyl acetate (50 mL*3), dried and concentrated to give 2-(4-((3- Cyano-4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-2-oxoacetic acid (1.03 g) was used directly in the next step.
  • Step D In the reaction flask, 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-2-oxo was added sequentially.
  • Acetic acid 0.2 g
  • 3-(trifluoromethyl)oxetan-3-amine hydrochloride (0.169 g)
  • HATU 0.362 g
  • N,N-dimethylformamide 5 mL
  • DIPEA 0.246 g
  • Example 51 5-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole- Replacement of 3-formamide with (S)-N-(3-cyano-4-fluorophenyl)-1-methyl-5-(2-oxo-2-((1,1,1-trifluoro) (2-)-N-(3-cyano-4-fluorophenyl)-2-fluoro-1-methyl 5-(2-Oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide.
  • Example 51 5-(2-(tert-butylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole- 3-formamide is replaced by (S)-N-(3-cyano-4-fluorophenyl)-1,4-dimethyl-5-(2-oxo-2-((1,1,1) -Trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide to give (S)-N-(3-cyano-4-fluorophenyl)-2-fluoro-1 4-Dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide.
  • Step A Under a nitrogen atmosphere, (1S,4S)-quinuclidin-3-ol (113 mg), tetrahydrofuran (1.5 mL), ethyl butyl-2,3-dienoate (500 mg) was added to the reaction flask.
  • Acetaldehyde (392 mg, 1.7 mL tetrahydrofuran solution) was added to the ice salt bath, and the system was reacted at -10 ° C for 5.0 h. After the addition, the mixture was transferred to room temperature for 2.5 h. After the reaction was completed, it was slowly poured into 20 mL of ice water and quenched with acetic acid.
  • Step B Under a nitrogen atmosphere, add dichloromethane (10.0 mL), ethyl 2-(1-hydroxyethyl)butane-2,3-dienoate (210 mg) to the reaction flask, and add 4- Methylbenzenesulfonyl isocyanate (292 mg), after the addition, was transferred to room temperature for 1.0 h. After the reaction was completed, it was slowly poured into 50 mL of ice water and quenched, extracted with DCM (2*50 mL). The organic layer was washed with an aqueous solution, and the organic layer was dried over anhydrous sodium sulfate.
  • Step C Under a nitrogen atmosphere, benzene (8.0 mL), ethyl 2-(1-((toluenesulfonylamino)oxy)ethyl)butane-2,3-dienoate (270 mg) was added to the reaction flask. A solution of 1,4-diazabicyclo[2.2.2]octane (83 mg) in benzene (8.0 mL) was slowly added dropwise at room temperature. The dropwise addition was continued for 5.0 h, and the reaction was carried out for 16.0 h after the completion of the reaction. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate.
  • Step D To a 250 ml single-necked flask was added diethyl ether (80 mL), ethyl 2-(1-((4-methylphenyl)sulfonylamino)ethyl)butane-2,3-dienoate, under nitrogen. (6.26 g), N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (9.57 g), silver nitrate (0.687 g), potassium carbonate (5.59 g). The reaction mixture was poured into water (100 ml), and the mixture was evaporated.
  • PE: EA 4:1
  • Step F DMF (20 mL), ethyl 4-fluoro-2-methyl-1H-pyrrole-3-carboxylate (0.2 g), iodomethane (199 mg) was added to the reaction flask, and sodium hydrogen was slowly added to the ice bath. (56mg). After the reaction was completed, the mixture was stirred at room temperature for 1.0 h. After the reaction was completed, the reaction mixture was poured into ice water (50 mL), and ethyl acetate (50 mL*2) was used to extract the organic layer, and the organic layer was washed with saturated brine. The organic phase was dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Step G To the reaction flask was added tetrahydrofuran (12 mL), ethyl 4-fluoro-1,2-dimethyl-1H-pyrrole-3-carboxylate (200 mg), 5-amino-2-fluorobenzonitrile (170 mg) Lithium bis(trimethylsilyl)amide (415 mg, 2.7 mL tetrahydrofuran solution) was slowly added under ice bath. After the reaction was completed, the mixture was stirred at room temperature for 2.0 h. After the reaction was completed, the reaction mixture was poured into ice water (50 mL), ethyl acetate (50 mL*2), and the organic layer was combined.
  • Step H Under the protection of nitrogen, zinc oxide (20 mg), monoethyl chloroacetonate (1.38 g) was added to the reaction flask, and N-(3-cyano-4-fluorophenyl)-4 was added in portions under ice bath. -Fluoro-1,2-dimethyl-1H-pyrrole-3-carboxamide (140 mg), which was reacted for 2.0 h after the addition. After the reaction was completed, it was slowly poured into 50 mL of ice water and quenched, and extracted with DCM (2*50 mL). The organic layer was evaporated.
  • Step I To a reaction flask, tetrahydrofuran (3.0 mL), 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-3-fluoro-1,5- Dimethyl-1H-pyrrol-2-yl)-2-oxoacetate (120 mg), a solution of lithium hydroxide monohydrate (19.2 mg) in water (5.0 mL) was added dropwise. Reaction for 10 minutes. Water (40 mL) and ethyl acetate (30 mL) were added to the mixture, and the layers were separated. The organic layer was evaporated.
  • Step J N,N-dimethylformamide (5.0 mL), 2-(4-(3-cyano-4-fluorophenyl)carbamoyl)-3-fluoro-1 was added sequentially to the reaction flask. ,5-Dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (38.0 mg), HATU (54 mg), DIPEA (32.5 mg), then (S)-1,1,1-three Fluorin-2-amine hydrochloride (20 mg) was stirred at room temperature for 2.0 h. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated.
  • Step A To the reaction flask was added N,N-dimethylformamide (15 mL), 5-(2-ethoxy-2-oxoacetyl)-1,2-dimethyl-1H-pyrrole- 3-carboxylic acid ethyl ester (1.0 g), 1-chloropyrrolidine-2,5-dione (0.6 g), was reacted at room temperature for 24.0 h.
  • Step B Under ice bath, MeOH (9.0 mL), 2-(chloromethyl)-5-(2-ethoxy-2-oxoacetyl)-1-methyl-1H was added to the reaction flask. A solution of ethyl pyrrole-3-carboxylate (1.00 g) and lithium hydroxide monohydrate (0.143 g) in water (9.0 mL) was added and then transferred to room temperature for 10 min. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the layers were separated, the organic layer was evaporated, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (2*100 mL).
  • Step C N,N-dimethylformamide (3.0 mL), 2-(4-(ethoxycarbonyl)-5-(methoxymethyl)-1-methyl-, was added sequentially to the reaction flask.
  • 1H-pyrrol-2-yl)-2-oxoacetic acid 100 mg
  • HATU 184 mg
  • DIPEA 106 mg
  • S -1,1,1-trifluoropropan-2-amine hydrochloride
  • Step D In a reaction flask, MeOH (5.0 mL), (S)-2-(methoxymethyl)-1-methyl-5-(2-oxo-2-(1,1, Ethyl 1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylate (150 mg), a solution of sodium hydroxide (33 mg) in water (5 mL) The reaction was carried out at 80 ° C for 4.0 h.
  • Step E To the reaction flask, add toluene (10 mL), (S)-2-(methoxymethyl)-1-methyl-5-(2-oxo-2-((1,1,1) -Trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid (250 mg), thionyl chloride (1.84 g), heated to 115 ° C for 1.0 h under nitrogen, reaction After the completion, the mixture was cooled to room temperature, and the solvent was evaporated to dryness vacuo.
  • the acid chloride intermediate (297 mg) was dissolved in N,N-dimethylacetamide (5 mL) at room temperature, and 5-amino-2-fluorobenzonitrile (100 mg) was added to the system, and the mixture was heated to 100 ° C for 0.5 h. . After the reaction was completed, the mixture was cooled to room temperature, and ethyl acetate (2*50 mL) was evaporated.
  • Step A In an ice bath, under N 2 protection, 2-chloro-2-oxoacetate (40.8 g) and zinc oxide (1.22 g) were sequentially added to the reaction flask, followed by 2,4-dimethyl- Ethyl 1H-pyrrole-3-carboxylate (5 g) was added. After the addition was completed, the mixture was stirred for 10 minutes in an ice bath, and the ice bath was removed and stirred at room temperature. At the end of the reaction, the reaction mixture was slowly added dropwise to a mixture of 200 mL of ice-water mixture, EA (200 mL) was added, and the organic layer was dried over anhydrous sodium sulfate. Ethyl 2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (4.5 g). MS (ESI+, [M+Na] + ) m/z: 290.
  • Step B In the reaction flask, ethyl 5-(2-ethoxy-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (3.5 g), MeOH (40 mL), a solution of sodium hydroxide (1.05 g) in water (20 mL) was added dropwise under ice bath, and stirred at room temperature. After completion of the reaction, the pH of the aqueous phase was adjusted to 3-4 with 2N aqueous hydrochloric acid, and then extracted with EA (100 mL*2). The organic phase was washed with water (30mL) and concentrated to give 2-(4-(ethoxycarbonyl)-3. 5-Dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (2.7 g). MS (ESI-, [MH] - ) m/z: 238.1.
  • Step C Add 2-(4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (1 g) to the reaction flask at room temperature. , DMF (20 mL), HATU (2.07 g) and DIPEA (1.08 g), after the addition was completed, stirred at room temperature for 10 minutes, and (S)-1,1,1-trifluoropropane-2-hydrochloride (0.63 g) was added. ).
  • Step D In the reaction flask, (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl group was added. Ethyl-1H-pyrrole-3-carboxylate (300 mg), MeOH (2 mL), EtOAc (EtOAc) (EtOAc) The reaction was completed, concentrated, and then water (20 mL) and EA (60 mL) was added, the aqueous layer was separated, the organic phase was washed with water (30 mL), and the layers were separated, and the aqueous phase was combined, and the aqueous phase was adjusted with 2N hydrochloric acid to give a pH of about 3.
  • Step E sequentially add (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)) to the reaction flask at room temperature.
  • Amino)acetyl)-1H-pyrrole-3-carboxylic acid 230 mg
  • DMF 5 mL
  • HATU 428 mg
  • DIPEA DIPEA (194 mg)
  • Step A N,N-dimethylformamide (150 mL), 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (10.0 g), iodine was added to the reaction flask under nitrogen. Methane-d 3 (10.4 g), sodium hydrogen (2.857 g) was added portionwise in an ice bath, and then transferred to room temperature for 1.5 h. After the reaction was completed, it was poured into 500 mL of ice water, and the mixture was evaporated.
  • Step B Under nitrogen, add tetrahydrofuran (100 mL), 2,4-dimethyl-1-(methyl-d 3 )-1H-pyrrole-3-carboxylic acid ethyl ester (9.50 g). 5-Amino-2-fluorobenzonitrile (8.7g), slowly added dropwise bis(trimethylsilyl)amide lithium (21.5g, 129mL tetrahydrofuran solution) under ice bath, and then transferred to room temperature for 4.0h. . After the reaction was completed, it was slowly poured into 600 mL of ice water and quenched.
  • Step C (Compound IV) Under nitrogen atmosphere, add zinc oxide (1.48g), monoethyl chloroacetonate (100g) to the reaction flask under ice bath, stir for 5 minutes, then add N-(3-cyanide in portions). 4-fluorophenyl)-2,4-dimethyl-1-(methyl-d 3 )-1H-pyrrole-3-carboxamide (10.0 g) was added and the mixture was transferred to room temperature for 3.0 h. After the reaction was completed, it was poured into 400 mL of ice water, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated.
  • Step D To the reaction flask, 2-(4-((3-cyano-4-fluorophenyl)carbamoyl)-3,5-dimethyl-1-(methyl-d 3 )- 1H-pyrrol-2-yl)-2-oxoacetate (4.5 g), tetrahydrofuran (35 mL), and a solution of lithium hydroxide monohydrate (1.02 g) in water (50 mL). After the addition, the mixture was transferred to room temperature for 0.2 h. Water (40 mL) and dichloromethane (50 mL) were added to the mixture, and the layers were separated, and the organic layer was evaporated.
  • Step E Nitrogen protection and ice bath, adding N,N-dimethylformamide (50 mL), 2-(4-((3-cyano-4-fluorophenyl)carbamoyl) -3,5-Dimethyl-1-(methyl-d 3 )-1H-pyrrol-2-yl)-2-oxoacetic acid (3.8 g), 2-(7-oxobenzotriazole) -N,N,N',N'-tetramethyluronium hexafluorophosphate (5.4 g), (S)-1,1,1-trifluoropropan-2-amine hydrochloride (1.96 g), After stirring for 2 minutes, N,N-diisopropylethylamine (3.2 g) was added.
  • N,N-diisopropylethylamine 3.2 g
  • Each tube was first prepared with a total volume of 450 ⁇ L of substrate and enzyme mixture and NADPH preincubated at 37 ° C for 5 min, then 50 ⁇ L of NADPH + MgCl 2 mixed solution was added, and 50 ⁇ L of ice acetonitrile containing internal standard was taken out at 30 min. The reaction was stopped at 300 ⁇ L. In addition, 500 ⁇ L of each of the 2 blank groups were added in parallel, and NADPH was not added as a negative control group.
  • Sample preparation 50 ⁇ L of incubation sample, 300 ⁇ L of internal standard ice acetonitrile precipitation, vortexing for 5 min, centrifugation (12000 rpm, 4 ° C) for 10 min. Aspirate 75 ⁇ L of the supernatant, add 75 ⁇ L of ultrapure water, dilute and mix, and analyze with 1 ⁇ L of injection. The results are shown in Table 4.
  • Plasma sample preparation 495 ⁇ L of blank plasma of corresponding species (mouse, rat, dog, monkey and human) were taken, and 5 ⁇ L of the corresponding test compound solution or positive control was added to obtain a plasma sample solution, so that the plasma drug concentration of the compound was respectively It was 1 ⁇ M, 10 ⁇ M (formulated in acetonitrile).
  • Sample preparation 50 ⁇ L of plasma side sample, 450 ⁇ L of internal standard ice acetonitrile was added, vortexed for 5 min, and centrifuged (12000 rpm, 4 ° C) for 10 min.
  • Aspirate 75 ⁇ L of the supernatant add 75 ⁇ L of ultrapure water, dilute and mix, and analyze with 1 ⁇ L of the sample;
  • 50 ⁇ L of the PBS side sample add 250 ⁇ L of ice-acetonitrile precipitate containing internal standard, vortex for 5 min, and centrifuge (12000 rpm, 4 ° C) for 10 min.
  • Pipette 75 ⁇ L of the supernatant add 75 ⁇ L of ultrapure water, dilute and mix, and analyze by 2 ⁇ L. The results are shown in Table 5.
  • 300 ⁇ L of the final incubation system contained 30 ⁇ L of liver microsomes (protein concentration: 0.15 mg/mL), 30 ⁇ L of NADPH + MgCl 2 , 3 ⁇ L of substrate (acetonitrile), and 237 ⁇ L of PBS buffer. 2 copies of each species, 0.3 mL per serving.
  • Each tube was first prepared with a total volume of 270 ⁇ L of substrate and enzyme mixture, and NADPH was preincubated at 37 ° C for 5 min, then added with 30 ⁇ L of NADPH + MgCl 2 mixed solution, respectively at 0, 10, 30, 60 min. 50 ⁇ L of the reaction was stopped with 300 ⁇ L of ice-acetonitrile containing an internal standard.
  • Sample preparation 50 ⁇ L of incubation sample, 300 ⁇ L of ice-acetonitrile containing internal standard diazepam, vortexing for 5 min, centrifugation (12000 rpm, 4 ° C) for 10 min. 75 ⁇ L of the supernatant was aspirated into a 96-well plate and diluted with 75 ⁇ L of ultrapure water, and 0.5 ⁇ L was injected for LC-MS/MS analysis. The results are shown in Tables 6-1, 6-2, 6-3 below.
  • Example number 60min remaining amount (%) Example number 60min remaining amount (%) 1 69 12 78.8 6 79.1 29 99.6 7 83.8 42 102 8 70.6 45 73
  • Example number 60min remaining amount (%) Example number 60min remaining amount (%) 1 44 12 65.0 6 74.9 17 44.9 7 70.5 25 52.0 8 52.0 29 88.7 11 56.8 42 85.3 45 47
  • Example number 60min remaining amount (%)
  • Example number 60min remaining amount (%) 6 55 17 47.4 7 81.6 25 50.8 11 47.7 29 99.2 12 67.1 42 61.9
  • Example number Solubility ( ⁇ M) Example number Solubility ( ⁇ M) 2 22.1 9 9.6 6 81.8 11 7.5 7 19.8 12 8.1 8 80.9 15 4.9
  • mice Male C57BL/6 mice, 6-8 weeks old, were injected with rAAV8-1.3 HBV virus (adr subtype) into C57BL/6 mice at a dose of 1 ⁇ 10 11 vg. At the 2nd and 4th week after the injection of the virus, the mice were bled with blood, and the serum was separated. The expression levels of HBeAg and HBsAg in the serum and the copy number of HBV DNA were determined to judge whether the model was successfully constructed or not.
  • the selected HBV DNA expression levels of the mice were greater than 1 ⁇ 10 4 IU / mL, HBeAg greater than 1 ⁇ 10 3 NCU / mL and HBsAg greater than 1 ⁇ 10 3 Ng/mL.
  • the mice were divided into groups, and a blank control group, a vehicle control group, and a test group were set. Each group of mice was administered by gavage for 2-3 weeks, once a day. During the experiment, blood was collected from the eyelids every other week, serum was separated, and the DNA content was detected by fluorescent quantitative PCR.
  • mice Male C57BL/6 mice aged 6-8 weeks were used, and the purified recombinant plasmid pHBV1.3 (10 ⁇ g) was dissolved in PBS. Each mouse was injected in a volume of about 10% of its body weight through the tail vein at 3-8 s. Injection into mice. After 24 hours of injection of the plasmid, serum HBV DNA was taken from the eyelids, and the serum DNA of the model mice was selected and grouped into a blank control group, a vehicle control group, and a test group. Each group of mice was administered by intragastric administration for 6 days, once a day, at a dose of 30 mg/kg. The mouse serum was taken at 1, 3, 5, and 7 days after the injection, and the liver tissue samples were taken from the 7th day. The HBV DNA copy number in the serum and liver of the mice was detected by real-time quantitative PCR. The results are shown in Table 9.
  • ICR mice weighing 18-20 g, were adapted to 3 to 5 days, and were randomly divided into groups of 3, each of which was intragastrically administered at a dose of 30 mg/kg.
  • test animals ICR mice
  • the test animals were fasted for 12 h before administration, and given food for 4 h after administration. Drinking water was free before and after the experiment and during the experiment.
  • the time of blood collection is 0.25h, 3h, 8h
  • the time of blood collection is 0.25h, 1h, 6h
  • SD rats weighing 180-220 g, were adapted to 3 to 5 days, and were randomly divided into groups of 3, each of which was intragastrically administered at a dose of 20 mg/kg.
  • test animals SD rats
  • the test animals were fasted for 12 h before administration, and given food for 4 h after administration. Drinking water was free before and after the experiment and during the experiment.
  • test animals (Beagle dogs) were fasted for 12 h before administration, and given food for 4 h after administration. Drinking water was free before and after the experiment and during the experiment.
  • Example number 12 Mode of administration and dosage PO 5mg/kg T max (h) 1.67 C max (ng/mL) 1282 AUC (0-72h) (ng*h/mL) 61881 AUC (0- ⁇ ) (ng*h/mL) 162075 T1/2(h) 105.2 MRT(0-t)(h) 32.9

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Abstract

一种含有N杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途，具体而言，涉及式I所示的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其药物组合物及医药用途，包括用于治疗受益于衣壳蛋白装配抑制的疾病的用途，尤其是乙型肝炎病毒感染引起的疾病。

Description

含有N杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途
相关申请的交叉引用
本申请要求于2018年3月30日向中国国家知识产权局提交的第201810286111.1号、2018年7月5日向中国国家知识产权局提交的第201810730325.3号、以及2019年1月25日向中国国家知识产权局提交的第201910073465.2号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及式I所示的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其制备方法，含有该化合物的药物组合物，及其作为治疗乙型肝炎病毒感染的药物的应用。
背景技术
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)。
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。近年，研究人员开始以衣壳蛋白装配为靶点的抑制剂，例如WO2014184350、WO2015011281、WO2017156255等公开了一系列相关化合物。但是大多数处于前期临床研究阶段或者研究已终止，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。本发明合成了一系列新型衍生物，并对其HBV蛋白组装活性进行研究。
发明详述
本申请涉及式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019080412-appb-000001
其中，
X和Y各自独立地表示CR 7，所述R 7独立地选自氢、C 3-4环烷基、-CN、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自氟、氯、溴、C 1-6烷氧基、-OH、-NH 2或-CN的基团取代；
环A选自苯基或5-10元杂芳基；
R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基、-NH 2、C 3-4环烷基、-NHR a或-NR bR c，其中R a、R b、R c分别独立地选自-C(O)C 1-6烷基、C 1-6烷基、-S(O) 2C 1-6烷基、5-10元杂芳基、C 6-10芳基、C 3-6环烷基或3-6元杂环烷基；
R 4选自氢、C 1-3烷基或C 3-4环烷基；
R 5选自C 1- 6烷基、C 2- 6烯基、C 2- 6炔基、3-7元环烷基或3-7元杂环烷基，所述C 1- 6烷基、C 2- 6烯基、C 2- 6炔基、3-7元环烷基或3-7元杂环烷基任选地被以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN或-OH取代的C 1-3烷基；
R 8各自独立地选自氢或C 1-3烷基。在一些实施方案中，上述X和Y各自独立地表示CR 7，所述R 7独立地选自氢、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自氟或C 1-3烷氧基的基团取代；在一些实施方案中，所述R 7独立地选自氢、氟、氯、溴或任选地被一个或多个甲氧基取代的C 1-3烷基；在一些实施方案中，所述R 7独立地选自氢、氟、氯、溴、-CH 2OCH 3或甲基；在一些实施方案中，所述R 7独立地选自氢、氯、溴或甲基。
在另外一些实施方案中，X和Y各自独立地表示CR 7，所述R 7独立地选自氢、C3-4环烷基、-CN、氟、氯、溴或任选地被一个或多个氟取代的C1-3烷基。在另外一些实施方案中，上述X和Y各自独立地表示CR 7，所述R 7独立地选自氢、氟、氯、溴或任选地被一个或多个氟取代的C 1-3烷基；在另外一些实施方案中，所述R 7独立地选自氢、氟、氯、溴或C 1-3烷基；在另外一些实施方案中，所述R 7独立地选自氢、氟、氯、溴或甲基。
在一些实施方案中，上述环A选自苯基、5元杂芳基、6元杂芳基、7元杂芳基、8元杂芳基、9元杂芳基或10元杂芳基；在一些实施方案中，环A选自苯基或6元杂芳基；在一些实施方案中，环A选自苯基或吡啶基。在一些实施方案中，上述环A的定义中出现的杂芳基含有1或2个N原子。
在另外一些实施方案中，环A选自苯基。
在一些实施方案中，R a选自-C(O)C 1-3烷基、C 1-3烷基、-S(O) 2C 1-3烷基、5-6元杂芳基、C 6-10芳基、C 3-6环烷基、或3-6元杂环烷基；在一些实施方案中，R a选自-C(O)C 1-3烷基、C 1-3烷基、或-S(O) 2C 1-3烷基；在一些实施方案中，R a选自-C(O)CH 3、或-S(O) 2CH 3。
在一些实施方案中，R b、R c分别独立地选自-C(O)C 1-3烷基、C 1-3烷基、-S(O) 2C 1-3烷基、5-6元杂芳基、C 6-10芳基、C 3-6环烷基、或3-6元杂环烷基；在一些实施方案中，R b、R c分别独立地选自-C(O)C 1-3烷基、C 1-3烷基、或-S(O) 2C 1-3烷基。
在又一些实施方案中，R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基、-NH 2、或C 3-4环烷基。
在一些实施方案中，上述R 1选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；在一些实施方案中，上述R 1选自氢或氟。
在一些实施方案中，上述R 2选自氢、氟、氯或溴；在一些实施方案中，上述R 2选自氢或氟。
在一些实施方案中，上述R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基、-NH 2或-NHR a；在一些实施方案中，上述R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基、-NH 2、-NHC(O)CH 3、或-NHS(O) 2CH 3；在一些实施方案中，上述R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基或-NH 2；在一些实施方案中，上述R 3选自氢、氟、氯、-CN、甲基或-NH 2。
在一些实施方案中，R 1选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基，并且R 1和R 3中的至少一个是氟或氢。
在一些的实施方案中，R 1和R 3中的一个选自氢或氟，另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基或-NH 2。
在一些实施方案中，上述R 2选自氟、氯或溴，R 1和R 3一个是氢，另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；在一些实施方案中，上述R 2选自氟，R 1和R 3一个是氢，另一个选自氟、氯或-CN；在一些实施方案中，上述R 2选自氟，R 1为氢，R 3为-CN或氯。在一些实施方案中，上述R 2选自氟，R 1为氢，R 3为-CN。
在另外一些的实施方案中，R 1和R 3中的一个是氢，另一个选自氟、氯、-CHF 2、-CN、-CF 3或甲基。
在另外一些实施方案中，X和Y各自独立地表示CR 7，所述R 7独立地选自氢、C 3-4环烷基、-CN、氟、氯、溴或任选地被一个或多个氟取代的C 1-3烷基；R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基。
在一些实施方案中，上述R 4选自氢或C 1-3烷基；在一些实施方案中，上述R 4为甲基或氢。
在另外一些实施方案中，上述R 4为甲基。
在一些实施方案中，上述R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN或-OH取代的C 1-3烷基；在一些实施方案中，上述R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、氧代、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基；在一些实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、氧代、-OH、-C(O)N(R 8) 2、-C(O)OR 8或任选被一个或多个OH或氟取代的C 1-3烷基；在一些实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：卤素、-OH或-C(O)OR 8，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：氧代、-OH、氟、-C(O)N(R 8) 2或任选被一个或多个OH或氟取代的C 1-3烷基；在一些实施方案中，上述R 5选自C 1-4烷基、C 3炔基、3-6元环烷基或4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：氟、-OH或-C(O)OCH 3，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：氧代、-OH、氟、-C(O)NHCH 3或任选被一个或多个OH或氟取代的甲基。
在另外一些实施方案中，上述R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基；在另外一些实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、-OH、-C(O)N(R 8) 2、-C(O)OR 8或任选被OH或氟取代的C 1-3烷基；在另外一些实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基、4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：卤素、-OH或-C(O)OR 8，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：-OH、氟、-C(O)N(R 8) 2或任选被OH或氟取代的C 1-3烷基；在另外一些实施方案中，上述R 5选自C 1-4烷基、C 3炔基、3-6元环烷基、4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：氟、-OH或-C(O)OCH 3，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：-OH、氟、-C(O)NHCH 3或任选被OH或氟的甲基。
在又一个另外实施方案中，上述R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN或-OH取代的C 1-3烷基，所述R 8各自独立地选自氢或C 1-3烷基；在又一个另外实施方案中，上述R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，其中C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元环烷基任选地被选自以下基团取代：卤素、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基，所述R 8各自独立地选自氢或C 1-3烷基；在又一个另外实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，其中C 1-4烷基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、-OH、-C(O)OR 8或任选被OH取代的C 1-3烷基，所述R 8选自氢或C 1-3烷基；在又一个另外实施方案中，上述R 5选自C 1-4烷基、C 2-4炔基、4-6元环烷基、4-6元杂环烷基，其中 C 1-4烷基任选地被选自以下基团取代：卤素、-OH或-C(O)OR 8，其中4-6元环烷基、4-6元杂环烷基任选地被选自以下基团取代：-OH或任选被OH取代的C 1-3烷基。
在一些实施方案中，在上述R 5的定义中出现的所述杂环烷基含有1或2个选自N、O或S的杂原子。
在一些实施方案中，R 8各自独立地选自氢或甲基。
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000002
选自
Figure PCTCN2019080412-appb-000003
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000004
选自
Figure PCTCN2019080412-appb-000005
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000006
选自
Figure PCTCN2019080412-appb-000007
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000008
选自
Figure PCTCN2019080412-appb-000009
Figure PCTCN2019080412-appb-000010
Figure PCTCN2019080412-appb-000011
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000012
选自
Figure PCTCN2019080412-appb-000013
Figure PCTCN2019080412-appb-000014
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000015
选自
Figure PCTCN2019080412-appb-000016
在一些具体实施 方案中，结构单元
Figure PCTCN2019080412-appb-000017
选自
Figure PCTCN2019080412-appb-000018
在另外一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000019
选自
Figure PCTCN2019080412-appb-000020
在另外一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000021
选自
Figure PCTCN2019080412-appb-000022
在另外一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000023
选自
Figure PCTCN2019080412-appb-000024
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000025
选自
Figure PCTCN2019080412-appb-000026
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000027
选自
Figure PCTCN2019080412-appb-000028
Figure PCTCN2019080412-appb-000029
Figure PCTCN2019080412-appb-000030
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000031
选自
Figure PCTCN2019080412-appb-000032
Figure PCTCN2019080412-appb-000033
在另外一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000034
选自
Figure PCTCN2019080412-appb-000035
在另外一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000036
选自
Figure PCTCN2019080412-appb-000037
Figure PCTCN2019080412-appb-000038
Figure PCTCN2019080412-appb-000039
在另外一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000040
选自
Figure PCTCN2019080412-appb-000041
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000042
选自
Figure PCTCN2019080412-appb-000043
Figure PCTCN2019080412-appb-000044
Figure PCTCN2019080412-appb-000045
在一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000046
选自
Figure PCTCN2019080412-appb-000047
Figure PCTCN2019080412-appb-000048
在另外一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000049
选自
Figure PCTCN2019080412-appb-000050
Figure PCTCN2019080412-appb-000051
在另外一些具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000052
选自
Figure PCTCN2019080412-appb-000053
Figure PCTCN2019080412-appb-000054
Figure PCTCN2019080412-appb-000055
在又一个另外具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000056
选自
Figure PCTCN2019080412-appb-000057
Figure PCTCN2019080412-appb-000058
在又一个另外具体实施方案中，结构单元
Figure PCTCN2019080412-appb-000059
选自
Figure PCTCN2019080412-appb-000060
Figure PCTCN2019080412-appb-000061
在一些实施方案中，本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐选自式II、式III或式IV化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019080412-appb-000062
其中，R 1、R 2、R 3、R 4、R 5、X、Y的定义如前所示；
或者
R 1、R 2、R 3、X、Y的定义如前所示；结构单元
Figure PCTCN2019080412-appb-000063
选自
Figure PCTCN2019080412-appb-000064
结构单元
Figure PCTCN2019080412-appb-000065
选自
Figure PCTCN2019080412-appb-000066
Figure PCTCN2019080412-appb-000067
Figure PCTCN2019080412-appb-000068
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000069
选自
Figure PCTCN2019080412-appb-000070
Figure PCTCN2019080412-appb-000071
Figure PCTCN2019080412-appb-000072
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000073
选自
Figure PCTCN2019080412-appb-000074
Figure PCTCN2019080412-appb-000075
在一些实施方案中，结构单元
Figure PCTCN2019080412-appb-000076
选自
Figure PCTCN2019080412-appb-000077
Figure PCTCN2019080412-appb-000078
Figure PCTCN2019080412-appb-000079
在一些实施方案中，本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐选自式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019080412-appb-000080
其中，R 1、R 2、R 3、R 4、R 5、X、Y的定义如前所示；
或者
R 1、R 2、R 3、结构单元
Figure PCTCN2019080412-appb-000081
及
Figure PCTCN2019080412-appb-000082
的定义如前所示。
在一些实施方案中，本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐选自式III化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019080412-appb-000083
其中，R 1、R 2、R 3、R 4、R 5、X、Y的定义如前所示；
或者
R 1、R 2、R 3、结构单元
Figure PCTCN2019080412-appb-000084
及
Figure PCTCN2019080412-appb-000085
的定义如前所示。
在一些实施方案中，本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性 代谢物、水合物、前药或药学上可接受的盐选自式IV化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019080412-appb-000086
其中，R 2、R 3、R 5、X、Y的定义如前所示；
或者
R 2、R 3、X、Y、结构单元
Figure PCTCN2019080412-appb-000087
的定义如前所示。
在一些实施方案中，本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐选自以下化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐：
Figure PCTCN2019080412-appb-000088
Figure PCTCN2019080412-appb-000089
Figure PCTCN2019080412-appb-000090
Figure PCTCN2019080412-appb-000091
另一方面，本申请还提供药物组合物，其包含本申请的式I化合物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。
另一方面，本申请还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所示的化合物其药学上可接受的盐或其药物组合物。
另一方面，本申请还提供了上述式I化合物、其药学上可接受的盐、或其药物组合物在制备预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途。
另一方面，本申请还提供了上述式I化合物、其药学上可接受的盐、或其药物组合物在预防或者治疗受益于衣壳蛋白装配抑制的疾病中的用途。
另一方面，本申请还提供了预防或者治疗受益于衣壳蛋白装配抑制的疾病的上述式I化合物、其药学上可接受的盐、或其药物组合物。
另一方面，本申请还提供药物组合物，其包含本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包含药学上可接受的辅料。另一方面，本申请还提供一种抑制衣壳蛋白装配的方法，包括对有需要的个体给予治疗有效量的本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物。在一些实施方案中，所述个体为哺乳动物；在一些实施方案中，所述个体为人类。
另一方面，本申请还提供预防或治疗受益于衣壳蛋白装配抑制的疾病的方法，包括对有需要的个体给予治疗有效量的本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物。在一些实施方案中，所述个体为哺乳动物；在一些实施方案中，所述个体为人类。另一方面，本申请还提供了本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物在抑制衣壳蛋白装配中的用途。
另一方面，本申请还提供了本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物在制备抑制衣壳蛋白装配的药物中的用途。
另一方面，本申请还提供了本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物在制备用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途。
另一方面，本申请还提供了上述式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物在预防或者治疗受益于衣壳蛋白装配抑制的疾病中的用途。
另一方面，本申请还提供了用于抑制衣壳蛋白装配的本申请的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物。
另一方面，本申请还提供了用于预防或者治疗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、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物。
在本申请的一些实施方式中，所述受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒(HBV)感染引起的疾病。
在本申请的一些实施方式中，所述受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒(HBV)感染引起的肝脏疾病。
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。
定义
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。
本申请中的结构单元或者基团中的虚线
Figure PCTCN2019080412-appb-000092
表示共价键。
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。因此，例如，结构单元
Figure PCTCN2019080412-appb-000093
包括但不限于
Figure PCTCN2019080412-appb-000094
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子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。
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。
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。
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。
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。
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。
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 PCTCN2019080412-appb-000095
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。
术语“卤”或“卤素”是指氟、氯、溴和碘。
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)。
术语“烷氧基”指-O-烷基。
术语“烯基”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双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。
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。
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。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。
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7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、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。
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。
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。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、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：
(i)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；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”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。
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。
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。
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。
术语“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括水，乙醇，乙酸等。溶剂化物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。
术语“水合物”指的是一种溶剂化物，包括已披露或要求保护的化合物和化学计量或非化学计量数量的水。
本发明的化合物还可以被制备成前药，如药学上可接受的前药。由于已知前药可提高药物的众多期望特性(如溶解性、生物利用度、制备等)，可以以前药的形式递送本发明的化合物。因此，本发明旨在涵盖当前主张的化合物的前药，其递送方法和含有前药的组合物。
术语“前药”旨在包括任何共价结合的载体，当给予哺乳动物受试者这种前药时，该载体在体内释放本发明的活性母体药物。本发明的前药通过以这样一种方式修饰化合物中存在的官能团制备，使得该修饰物在常规操作中或在体内断裂成母体化合物。
本发明中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。术语“活性代谢物”是指当化合物被代谢时形成的化合物的生物活性衍生物。
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。
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”。
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。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些都属于本申请的范围之内。烷基等取代基中可以存在另外的不对称碳原子。所有这些异构体以及它们的混合物均包 括在本申请的范围之内。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本申请某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
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。
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。
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。例如，可以在结构单元
Figure PCTCN2019080412-appb-000096
上发生氘代，从而得到具体如
Figure PCTCN2019080412-appb-000097
Figure PCTCN2019080412-appb-000098
等结构。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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。
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：
路线1：
Figure PCTCN2019080412-appb-000099
路线2：
Figure PCTCN2019080412-appb-000100
路线3：
Figure PCTCN2019080412-appb-000101
路线4：
Figure PCTCN2019080412-appb-000102
路线5：
Figure PCTCN2019080412-appb-000103
路线6：
Figure PCTCN2019080412-appb-000104
其中R 6、R 9选自甲基或乙基。
本申请采用下述缩略词：
NBS代表N-溴代琥珀酰亚胺；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；DCM代表二氯甲烷；DIPEA代表N，N-二异丙基乙胺；DMA代表二甲基乙酰胺；THF代表四氢呋喃；LiHDMS代表双三甲基硅基胺基锂；PO代表口服；IV代表静脉注射；MRT表示平均滞留时间；Ts代表对甲苯磺酰基；selectfluor代表1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐；DMSO代表二甲基亚砜；HOBt代表1-羟基苯并三唑；DCC代表二环己基碳二亚胺；MeOH代表甲醇。
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。
具体实施方式
本发明核磁共振色谱(NMR)使用BRUKER-300和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。
实施例1 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-(丙-2-炔-1-基氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000105
步骤A：氮气保护下，向500mL单口瓶中加入DMF(100mL)，2,4-二甲基-1H-吡咯-3-甲酸乙酯(8.0g)，碘甲烷(8.15g)，冰浴下，分批加入氢化钠(2.87g)，加毕后转至室温反应2.5h，反应结束后缓慢倒入400mL冰水中淬灭，用乙酸乙酯(2*300mL)萃取，合并有机层，用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＝20:1)，制得1,2,4-三甲基-1H-吡咯-3-羧酸乙酯(4.87g)。 1H-NMR(500MHz,DMSO-d6)：δ6.44(s,1H),4.15(q,J＝7.5Hz,2H),3.44(s,3H),2.39(s,3H),2.09(s,3H),1.25(t,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d6)：δ165.63,136.13,120.78,118.91,110.56,58.76,33.58,14.85,12.93,11.60.MS(ESI+,[M+H] +)m/z:182.3.
步骤B：500mL三口瓶中，氮气保护下，加入THF(150mL)，1,2,4-三甲基-1H-吡咯-3-羧酸乙酯(15.0g)，5-氨基-2-氟苯腈(14.08g)，冰浴下缓慢滴加双(三甲基甲硅烷基)氨基锂(27.7g,166mLTHF溶液)，加毕后转至室温反应16.0h。反应结束后缓慢倒至500mL冰水中淬灭，乙酸乙酯(2*400mL)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)-1,2,4-三甲基-1H-吡咯-3-甲酰胺(6.73g)。 1H-NMR(500MHz,DMSO-d6)：δ9.64(s,1H),8.18(t,J＝3.5Hz,1H),7.93-7.96(m,1H),7.48(t,J＝9.0Hz,1H),6.49(s,1H),3.47(s,3H),2.30(s,3H),2.10(s,3H). 13C-NMR(125MHz,DMSO-d6)：δ165.51,159.30,157.15,137.56,131.76,126.97,123.33,120.33,117.39,116.77,114.59,100.19,33.53,11.63.MS(ESI-,[M-H] -)m/z:270.2.
步骤C：氮气保护下，向500mL单口瓶中加入DCM(240mL)，(N-(3-氰基-4-氟苯基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺(5.0g)，氯草酸单乙酯(7.55g)，冰浴下分批加入氯化铝(12.29g)，加毕后转至室温反应15.0h。反应结束后缓慢倒入300mL冰水中淬灭，用DCM(2*300mL)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，抽滤，滤液减压旋蒸除去溶剂，得到粗品中加入乙酸乙酯(45mL)，室温下打浆1.0h，抽滤，滤饼真空干燥得2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(4.25g)。MS(ESI-,[M-H] -)m/z:370.2.
步骤D：冰浴下，向100mL单口瓶中，加入甲醇(30mL)、2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(4.00g)、氢氧化钠(0.862g)的水(30mL)溶液，加毕后转至室温反应2.0h。向反应液中加入水(200mL)及DCM(150mL)，分层，弃去有机层，水层用浓盐酸调pH至约2，用乙酸乙酯(2*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，抽滤，滤液减压 蒸除溶剂，得2-(4-(3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸(3.25g)。 1H-NMR(500MHz,DMSO-d6)：δ10.32(s,1H),8.19-8.21(m,1H),7.93-7.97(m,1H),7.52(t,J＝9.0Hz,1H),3.81(s,3H),2.36(s,3H),2.27(s,3H). 13C-NMR(125MHz,DMSO-d6)：δ178.85,167.79,163.98,159.67,157.66,141.31,136.80,130.95,127.26,123.84,117.60,114.43,100.41,60.21,33.73,21.22,14.55.
步骤E：向50mL单口瓶中依次加入DMF(5.0mL)，2-(4-(3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸(300mg)，HATU(399mg)，DIPEA(169mg)，再加入炔丙胺(52.9mg)，室温搅拌16.0h。向反应液中加入水(100mL)，用乙酸乙酯(2*100mL)萃取，合并有机层，用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)-1,2,4-三甲基-5-(2-氧代-2-(丙-2-炔-1-基氨基)乙酰基)-1H-吡咯-3-甲酰胺(142mg)。 1H-NMR(500MHz,DMSO-d6)：δ10.31(s,1H),9.19(t,J＝5.5Hz,1H),8.20-8.21(m,1H),7.93-7.97(m,1H),7.51(t,J＝9.0Hz,1H),4.01-4.02(m,2H),3.78(s,3H),3.17(t,J＝2.0Hz,1H),2.35(s,3H),2.22(s,3H). 13C-NMR(125MHz,DMSO-d6)：δ181.35,166.95,164.16,159.64,157.63,140.62,136.85,130.84,127.27,125.24,123.76,120.62,117.58,114.45,100.39,80.43,73.99,33.62,28.18,11.56.MS(ESI-,[M-H] -)m/z:379.2.
实施例2 5-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000106
根据实施例1，在步骤E中用1-双环[1,1,1]戊胺盐酸盐替代炔丙胺，制得5-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.31(s,1H),9.28(s,1H),8.20-8.22(m,1H),7.94-7.97(m,1H),7.52(t,J＝9.0Hz,1H),3.77(s,3H),2.48-2.50(m,1H),2.34(s,3H),2.22(s,3H),2.06(s,6H). 13C-NMR(125MHz,DMSO-d 6)：δ181.57,167.47,164.15,159.62,157.62,140.52,136.83,130.51,127.25,125.04,123.73,120.52,117.60,114.48,100.37,52.63,48.55,33.60,25.29,11.54.MS(ESI-,[M-H] -)m/z:407.3.
实施例3 N-(3-氰基-4-氟苯基)-5-(2-((反式-3-羟基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000107
根据实施例1，在步骤E中用反式-3-氨基环丁醇盐酸盐替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-((反式-3-羟基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.28(s,1H),8.98(d,J＝7.0Hz,1H),8.19-8.21(m,1H),7.94-7.97(m,1H),7.51(t,J＝9.0Hz,1H),5.06(d,J＝5.5Hz,1H),4.27-4.31(m,2H),3.77(s,3H),2.35(s,3H),2.14-2.24(m,7H). 13C-NMR(125MHz,DMSO-d 6)：δ182.10,166.88,164.19,159.63,157.63,140.37,136.84,130.40,127.29,125.36,123.77,120.49,117.58,114.45,100.38,63.57,33.59,11.55.MS(ESI-,[M-H] -)m/z:411.3.
实施例4 N-(3-氰基-4-氟苯基)-5-(2–((顺式-3-羟基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲 酰胺
Figure PCTCN2019080412-appb-000108
根据实施例1，在步骤E中用顺式-3-氨基环丁醇盐酸盐替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2–((顺式-3-羟基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d6)：δ10.29(s,1H),8.92(d,J＝7.0Hz,1H),8.20(d,J＝3.5Hz,1H),7.95(d,J＝3.0Hz,1H),7.52(t,J＝9.0Hz,1H),5.11(d,J＝5.5Hz,1H),3.76-3.87(m,5H),2.51-2.55(m,2H),2.35(s,3H),2.19(s,3H),1.81-1.86(m,2H)； 13C-NMR(125MHz,DMSO-d6)：δ182.07,166.64,164.20,159.63,157.63,140.32,136.84,130.40,127.25,125.32,123.77,120.50,117.50,114.45,100.32,59.78,35.81,33.58,25.27,11.43.MS(ESI-,[M-H] -)m/z：411.3.
实施例5 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-(氧杂环丁烷-3-基氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000109
根据实施例1，在步骤E中用3-氧杂环丁胺替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-(氧杂环丁烷-3-基氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.51-9.52(m,1H),8.20-8.21(m,1H),7.95-7.96(m,1H),7.50-7.53(m,1H),4.92-4.95(m,1H),4.77-4.80(t,J＝13.5Hz,2H),4.52-4.55(t,J＝12Hz,2H),3.78(s,3H),2.36(s,3H),2.19(s,3H)； 13C NMR(125MHz,DMSO-d 6):δ164.12,159.64,157.64,140.69,136.84,136.82,130.64,127.27,127.21,120.63,117.58,117.41,114.44,76.88,44.31,33.63,11.56,11.47.MS(ESI-,[M-H] -)m/z：397.3.
实施例6 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-(3-甲基氧杂环丁烷-3-基氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000110
根据实施例1，在步骤E中用3-甲基3-氨基氧杂环丁烷替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d6)：δ10.29(s,1H),9.24(s,1H),8.21(d,J＝3.5Hz,1H),7.96(s,1H),7.52(t,J＝9.0Hz,1H),4.69(d,J＝6.5Hz,2H),4.39(d,J＝6.0Hz,2H),3.78(s,3H),2.36(s,3H),2.28(s,3H),1.60(s,3H). 13C-NMR(125MHz,DMSO-d6)：δ181.41,166.23,164.14,159.64,157.64,140.70,136.85,130.46,127.26,125.41,123.78,120.51,117.50,114.45,100.32,80.79,53.55,33.62,23.38,11.64.MS(ESI-,[M-H] -)m/z：411.3.
实施例7 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000111
根据实施例1，在步骤E中用3-氨基四氢呋喃替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.29(s,1H),8.98(d,J＝6.0Hz,1H),8.20(d,J＝2.5Hz,1H),7.94-7.96(m,1H),7.51(t,J＝9.5Hz,1H),4.35(s,1H),3.69-3.83(m,6H),3.56-3.58(m,1H),2.35(s,3H),2.22(s,3H),2.12-2.20(m,1H),1.83-1.85(m,1H). 13C-NMR(125MHz,DMSO-d 6):δ181.80,167.32,164.18,159.64,157.63,140.44,136.86,130.42,127.28,125.29,123.77,120.52,117.58,114.45,100.39,72.28,66.83,50.00,33.61,32.04,11.55.MS(ESI-,[M-H] -)m/z:411.3.
实施例8 N-(3-氰基-4-氟苯基)-5-(2-((1-羟基-2-甲基丙烷-2-基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000112
根据实施例1，在步骤E中用2-氨基-2-甲基-1-丙醇替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-((1-羟基-2-甲基丙烷-2-基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.26(s,1H),8.20-8.21(m,1H),8.08(m,1H),7.95-7.97(m,1H),7.51(t,J＝9.0Hz,1H),4.85(t,J＝5.5Hz,1H),3.76(s,3H),3.45(d,J＝5.5Hz,2H),2.35(s,3H),2.28(s,3H),1.29(s,6H). 13C-NMR(125MHz,DMSO-d 6)：δ181.94,167.14,164.28,159.61,157.60,140.04,136.91,130.12,127.25,125.44,123.74,120.28,117.56,114.46,100.37,67.75,55.38,33.56,23.52,11.61.MS(ESI-,[M-H] -)m/z:413.4.
实施例9 (2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酰氨基)-2-甲基丙酸甲酯
Figure PCTCN2019080412-appb-000113
根据实施例1，在步骤E中用2-氨基异丁酸甲酯盐酸盐替代炔丙胺，制得(2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酰氨基)-2-甲基丙酸甲酯。 1H-NMR(500MHz,DMSO-d6)：δ10.28(s,1H),9.07(s,1H),8.21(d,J＝3.5Hz,1H),7.96(s,1H),7.52(t,J＝9.0Hz,1H),3.76(s,3H),3.62(s,3H),2.36(s,3H),2.26(s,3H),1.44(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ174.12,166.24,164.24,162.77,157.62,140.51,136.89,130.67,127.25,125.57,123.76,120.40,117.49,114.46,100.31,55.67,52.41,36.24,33.60,25.06,11.58.MS(ESI-,[M-H] -)m/z：441.4.
实施例10 N-(3-氰基-4-氟苯基)-5-(2-((顺式-3-(羟甲基)环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000114
根据实施例1，在步骤E中用顺式-3-氨基-环丁烷甲醇替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-((顺式-3-(羟甲基)环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.28(s,1H),8.90(d,J＝7.5Hz,1H),8.20(s,1H),7.95(t,J＝4.0Hz,1H),7.52(t,J＝9.5Hz,1H),4.48(t,J＝5.0Hz,1H),4.17(m,1H),3.77(s,3H),3.35(t,J＝5.5Hz,2H),2.35(s,3H),2.25(m,2H),2.10(s,3H),1.75(m,2H). 13C-NMR(125MHz,DMSO-d 6)：δ182.14,166.41,164.21,159.63,157.62,140.27,136.85,130.35,127.24,125.35,123.76,120.48,117.50,114.45,100.31,65.26,60.21,33.58,32.66,31.00,11.44.MS(ESI-,[M-H] -)m/z：425.3.
实施例11 (R)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000115
根据实施例1，在步骤E中用(R)-1,1,1-三氟异丙胺盐酸盐替代炔丙胺，制得(R)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.31(s,1H),9.38(d,J＝8.5Hz,1H),8.19(d,J＝4.0Hz,1H),7.95(t,J＝4.5Hz,1H),7.52(t,J＝9.0Hz,1H),4.67-4.75(m,1H),3.79(s,3H),2.36(s,3H),2.12(s,3H),1.31(d,J＝6.5Hz,3H). 13C-NMR(125MHz,DMSO-d 6)：δ180.80,167.24,164.08,140.92,136.82,130.81,127.32,125.02,123.82,120.71,117.59,114.44,100.27,33.66,13.76,11.58.MS(ESI-,[M-H] -)m/z:437.3.
实施例12 (S)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000116
步骤A：根据实施例1，在步骤E中用(S)-1,1,1-三氟异丙胺盐酸盐替代炔丙胺，制得(S)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.31(s,1H),9.38(d,J＝9.0Hz,1H),8.19-8.21(m,1H),7.93-7.97(m,1H),7.51(t,J＝9.5Hz,1H),4.68-4.75(m,1H),3.79(s,3H),2.36(s,3H),2.21(s,3H),1.31(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6)：δ180.80,167.24,164.08,159.66,157.65,140.92,136.82,130.81,127.31,125.02,123.81,120.71,117.58,114.44,100.40,46.04,33.66,13.75,11.57.MS(ESI-,[M-H] -)m/z:437.3.
实施例13 5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000117
步骤A：500mL单口瓶中，氮气保护下，加入DCM(250mL)，1,2,4-三甲基-1H-吡咯-3-羧酸乙酯(2.0g)，氯草酸单乙酯(4.52g)。冰浴下，缓慢加入无水氯化铝(7.36g)，加毕后转至室温反应5.5h。反应结束后缓慢倒入200mL冰水中淬灭，用DCM(2*200mL)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＝10：1)洗脱，得到5-(2-乙氧基-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯(2.14g)。 1H-NMR(500MHz,DMSO-d6)：δ4.35(q,J＝7.0Hz,2H),4.24(q,J＝7.0Hz,2H),3.77(s,3H),2.50(s,3H),2.30(s,3H),1.27-1.32(m,6H). 13C-NMR(125MHz,DMSO-d6)：δ177.03,165.34,164.38,146.14,134.75,124.72,113.85,62.66,60.09,33.76,14.59,14.12,12.06,11.59.
步骤B:100mL单口瓶中，加入甲醇(10mL)，5-(2-乙氧基-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯(1.20g)，冰浴下，缓慢加入氢氧化钠(0.34g)的水(10mL)溶液，冰浴下反应15分钟。反应结束后，向反应体系中加入水(30mL)，浓盐酸调pH至2，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，得到2-(4-(乙氧基羰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸(897mg)粗品，直接用于下一步反应。
MS(ESI-,[M-H] -)m/z:252.1.
步骤C:室温下，向25mL单口瓶中，依次加入DMF(15mL)，2-(4-(乙氧基羰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸(700mg)，HATU(1366mg)，DIPEA(464mg)，室温搅拌10分钟，加入叔丁胺(202mg)，室温搅拌反应0.5h。反应结束后，向反应体系中加入100mL水，用乙酸乙酯(2*100mL)萃取，合并有机层，用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5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯(719mg)。 1H-NMR(500MHz,DMSO-d6)：δ8.28(s,1H),4.23(q,J＝7.0Hz,2H),3.73(s,3H),2.51(s,3H),2.37(s,3H),1.34(s,9H),1.29(t,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d6)：δ182.55,166.89,164.78,144.19,132.84,126.23,113.01,59.86,51.26,33.55,28.59,14.67,12.05.MS(ESI+,[M+H] +)m/z:309.4.
步骤D:50mL单口瓶中，依次加入甲醇(9mL)，5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯(500mg)，室温下加入氢氧化钠(259mg)的水(9mL)溶液，将混合物加热至90℃反应3.0h。反应结束后，用浓盐酸调pH至2，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，得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸(260mg)粗品，直接用于下一步反应。 1H-NMR(500MHz,DMSO-d6)：δ12.28(s,1H),8.26s,1H),3.73(s,3H), 2.50(s,3H),2.38(s,3H),1.33(s,9H). 13C-NMR(125MHz,DMSO-d6)：δ182.50,167.00,166.39,144.35,133.30,126.12,113.61,51.23,33.50,28.61,12.04.MS(ESI+,[M+H] +)m/z:281.3.
步骤E:50mL单口瓶中，依次加入甲苯(15mL)，5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸(360mg)，氯化亚砜(3.05g)，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，收酰氯中间体(339mg)。在室温下，将酰氯中间体(339mg)溶于N,N-二甲基乙酰胺(12mL)，向体系中加入5-氨基-2-氟苯腈(309mg)，升温至100℃反应0.5h。反应结束后降至室温，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5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺(280mg)。 1H-NMR(500MHz,DMSO-d6)：δ10.26(s,1H),8.29(s,1H),8.20-8.21(m,1H),7.95-7.98(m,1H),7.51(t,J＝9.0Hz,1H),3.77(s,3H),2.35(s,3H),2.88(s,3H),1.35(s,9H). 13C-NMR(125MHz,DMSO-d6)：δ182.06,167.12,164.27,159.61,157.61,140.07,136.90,130.03,127.27,125.36,123.75,120.27,117.56,114.46,100.37,51.23,33.57,28.66,11.57.MS(ESI-,[M-H] -)m/z:397.3.
实施例14 5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000118
步骤A：根据实施例1在步骤A中用4-甲基-1H-吡咯-3-甲酸甲酯替代2,4-二甲基-1H-吡咯-3-甲酸乙酯，制得1,4-二甲基-1H-吡咯-3-甲酸甲酯。 1H-NMR(500MHz,DMSO-d 6):δ7.30-7.31(d,J＝2Hz,1H),6.56(s,1H),3.66(s,3H),23.57(s,3H),2.13(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ165.14,128.24,122.40,120.50,113.04,50.72,36.34,11.96.
步骤B：根据实施例13，在步骤A中用1,4-二甲基-1H-吡咯-3-甲酸甲酯替代1,2,4-三甲基-1H-吡咯-3-羧酸乙酯，制得5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酸甲酯。MS(ESI+,[M+Na] +)m/z：276.3.
步骤C：根据实施例13，在步骤B中用5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酸甲酯替代5-(2-乙氧基-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯，制得2-(4-(甲氧基羰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸。 1H-NMR(500MHz,DMSO-d 6):δ7.91(s,1H),3.87(s,3H),3.74(s,3H),2.43(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ179.71,167.42,164.00,137.43,134.14,125.72,113.93,51.43,38.52,10.81.
步骤D：根据实施例13，在步骤C中用2-(4-(甲氧基羰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸替代2-(4-(乙氧基羰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸，制得5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酸甲酯。MS(ESI+,[M+Na] +)m/z：303.3.
步骤E：根据实施例13，在步骤D中用5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酸甲酯替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯，制得5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸。 1H-NMR(500MHz,DMSO-d 6):δ8.32(s,1H),7.75(s,1H),3.83(s,3H),2.43(s,3H),1.34(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ182.74,166.86,165.41,136.65,133.37,127.10, 114.68,51.28,38.24,28.63,11.25.
步骤F：根据实施例13，在步骤E中用5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸，制得5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.11(s,1H),8.36(s,1H),8.21(s,1H),7.96-7.97(m,1H),7.84(s,1H),7.50-7.53(m,1H),3.87(s,3H),2.43(s,3H),1.35(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ166.83,163.09,159.48,157.47,137.01,133.74,132.59,127.41,127.35,127.00,123.87,117.82,117.50,117.34,114.49,51.31,38.34,28.64,11.32.MS(ESI-,[M-H] -)m/z：383.3.
实施例15 2-溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000119
100mL单口瓶中，加入5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(0.3g)、DMF(8mL)、乙腈(4mL)，冰浴下加入NBS(0.153g)，升至室温反应3小时。反应结束后加入乙酸乙酯(100mL)，水(3*100mL)洗三次，干燥，浓缩，用PE：EA＝3:1混合溶剂(2mL)打浆，过滤，烘干得到2-溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(79mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.56(s,1H),8.41(s,1H),8.20(s,1H),7.96-7.97(m,1H),7.52-7.56(m,1H),3.87(s,3H),2.28(s,3H),1.35(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ162.45,159.83,157.82,136.55,130.30,129.13,127.16,123.67,122.42,117.59,116.05,114.36,51.40,35.97,28.60,11.50.MS(ESI-,[M-H] -)m/z：461.3.
实施例16 5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000120
步骤A：根据实施例1在步骤A中用2-甲基-1H-吡咯-3-羧酸乙酯替代2,4-二甲基-1H-吡咯-3-甲酸乙酯，制得1,2-二甲基-1H-吡咯-3-羧酸乙酯。
步骤B：根据实施例13，在步骤A中用1,2-二甲基-1H-吡咯-3-羧酸乙酯替代1,2,4-三甲基-1H-吡咯-3- 羧酸乙酯，制得5-(2-乙氧基-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-甲酸乙酯。 1H-NMR(500MHz,DMSO-d 6):δ7.44(s,1H),4.36(q,J＝7.0Hz,2H),4.22(q,J＝7.0Hz,2H),3.86(s,3H),2.56(s,3H),1.30(m,6H)； 13C-NMR(125MHz,DMSO-d 6):δ175.07,163.61,163.53,147.08,126.13,125.73,113.98,62.52,60.12,33.53,14.67,14.29,11.45.
步骤C：根据实施例13，在步骤B中用5-(2-乙氧基-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-甲酸乙酯替代5-(2-乙氧基-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯，制得2-(4-(乙氧基羰基)-1,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸。MS(ESI -,[M-H] -)m/z：238.2.
步骤D：根据实施例13，在步骤C中用2-(4-(乙氧基羰基)-1,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸替代2-(4-(乙氧基羰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸，制得5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-甲酸乙酯。MS(ESI +,[M+Na] +)m/z：317.3.
步骤E：根据实施例13，在步骤D中用5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-甲酸乙酯替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸乙酯，制得5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-羧酸。MS(ESI -,[M-H] -)m/z：265.3.
步骤F：根据实施例13，在步骤E中用5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-羧酸替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酸，制得5-(2-(叔丁基氨基-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,2-二甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.28(s,1H),8.25(m,1H),8.11(s,1H),8.05(m,1H),7.91(s,1H),7.50(t,J＝9.0Hz,1H),3.88(s,3H),2.59(s,3H),1.38(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ179.71,164.45,163.28,159.51,157.51,145.38,136.99,127.97,126.33,124.49,123.28,117.29,116.54,114.51,100.51,51.32,33.32,28.77.MS(ESI -,[M-H] -)m/z：383.3.
实施例17 5-(2-(叔丁基氨基)-2-氧代乙酰基)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000121
50mL单口瓶中，加入5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(0.1g)、NCS(52mg)、冰醋酸(5mL)、三氟乙酸酐(42μL)，室温反应10小时。反应结束将反应液倒入50mL饱和碳酸氢钠水溶液中，用50mL*3乙酸乙酯萃取，分离有机层，干燥，浓缩，用石油醚：乙酸乙酯＝1:1混合溶剂(2ml)打浆，过滤，烘干得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(16.9mg)。 1H NMR(500MHz,DMSO-d 6):δ10.55(s,1H),8.42(s,1H),8.20(m,1H),7.96(s,1H),7.52-7.56(t,J＝18Hz,1H),3.85(s,3H),2.29(s,3H),1.35(s,9H). 13C NMR(125MHz,DMSO-d 6):δ181.83,166.43,161.78,136.45,130.14,127.32,126.14,125.90,123.80,118.99,117.73,117.56,114.36,100.30,51.41,34.17,28.60,11.45.MS(ESI-,[M-H]-)m/z：417.4.
实施例18 5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000122
步骤A：向反应瓶中，依次加入1H-吡咯-3-羧酸甲酯(3.0g)、20mL DMF，溶解后，0℃下分批加入1.16g氢化钠，加入1.67mL碘甲烷，加完后室温反应0.5h。反应结束后向其中加入50mL水以及50mLDCM，分离有机层，用无水硫酸钠干燥，过滤，将滤液浓缩，得到1-甲基-1H-吡咯-3-甲酸甲酯(3.12g)，不经纯化直接用于下一步反应。 1H-NMR(500MHz,DMSO-d 6):δ7.40(s,1H),6.77(s,1H),6.41(s,1H),3.69(s,3H),3.66(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ162.69,127.59,123.74,115.01,109.71,50.88,31.09.
步骤B：向反应瓶中，依次加入DCM(2mL)、200mg 1-甲基-1H-吡咯-3-甲酸甲酯，降温至0℃，加入0.52mL氯草酸单乙酯，再分批加人958mg三氯化铝，加完后室温下反应3小时。反应结束后向反应液中加入50mL乙酸乙酯和50mL纯化水，分离有机层，用无水硫酸钠干燥，过滤，滤液浓缩，粗品经柱层析分离纯化(PE:EA＝5:1)，得5-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯(104mg)。 1H-NMR(500MHz,DMSO-d6):δ8.02(s,1H),7.50(s,1H),4.36(m,2H),3.94(s,3H),3.76(s,3H),1.32(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d6):δ175.50,163.36,163.09,137.81,127.88,124.63,115.80,62.67,51.78,28.12,14.29.
步骤C：向反应瓶中，依次加入5-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯(3.35g)、THF(4mL)，室温搅拌10分钟，缓慢加入溶有氢氧化钠(1.68g)的水(4.00ml)溶液，室温下反应1小时。反应结束后将溶液pH调至3～4，加入50mL乙酸乙酯和50mL纯化水，分离有机层，用无水硫酸钠干燥，过滤，滤液浓缩，得到2-(4-(甲氧基羰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸2.46g。 1H-NMR(500MHz,DMSO-d6):δ7.97(s,1H),7.45(s,1H),3.94(s,3H),3.76(s,3H)； 13C-NMR(125MHz,DMSO-d6):δ177.66,165.22,163.43,137.45,127.84,124.11,115.57,51.74,38.06.MS(ESI-,[M-H] -)m/z：210.2.
步骤D：向反应瓶中，依次加入2-(4-(甲氧基羰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸(2.46g)、乙酸乙酯(2mL)、叔丁胺(2.55g)及1-丙基磷酸酐(50％w/v乙酸乙酯溶液,7.5mL)，室温下反应1小时。反应结束后向其中加入乙酸乙酯100mL和水100mL。分离有机相，用饱和食盐水(2*50mL)洗，无水硫酸钠干燥，过滤，浓缩，粗品经通过柱层析分离纯化(PE:EA＝3:1)，得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯(2.60g)。 1H-NMR(500MHz,DMSO-d 6):δ8.17(s,1H),7.94(s,1H),7.49(s,1H),3.93(s,3H),3.76(s,3H),1.36(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ180.44,164.20,157.50,136.63,128.32,123.93,115.26,51.40,38.02,29.83,28.6.MS(ESI +,[M+Na] +)m/z：289.3.
步骤E：向反应瓶中，依次加入5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯(1.17g)、甲醇(5mL)，搅拌10分钟后，再加入氢氧化钠(0.53g)的水(5.00ml)溶液，室温下反应1小时。反应结束后用2N HCl调节pH＝3～4，加入乙酸乙酯100mL和水100mL。分离有机相，分别用饱和食盐水(2*50mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干，得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸(1.11g)。MS(ESI -,[M-H] -)m/z：251.2.
步骤F：向反应瓶中，加入5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸(100mg)、甲苯(2mL)、氯化亚砜(189mg)，N 2保护下，加热至110℃反应1h。浓缩除去溶剂，向所得粗品中加入N,N-二甲基乙酰胺(2mL)、5-氨基-2-氟苯乙腈(108mg)，加热至100℃反应2h。反应结束后加入乙酸乙酯60mL和水60mL，分离有机相，用饱和食盐水(2*50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析(PE:EA＝1:1)得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺(118mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.29(s,1H),8.25(d,J＝4.0Hz 1H),8.15(s,1H),8.05(t,J＝4.0Hz 1H),7.96(s,1H),7.89(s,1H),7.52(t,J＝9.0Hz 1H),3.96(s,3H),1.39(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ180.31,164.12,161.83,159.58,157.58,136.87,128.07,124.30,122.66,119.46,117.44,114.48,100.27,51.38,38.14,28.72.MS(ESI -,[M-H] -)m/z：369.3.
实施例19 2-溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000123
步骤A：向反应瓶中依次加入100mg 5-(2-(叔丁基氨基-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺、1mL DMF、4mL乙腈及NBS 48.1mg，80℃反应24小时。反应结束后向其中加入乙酸乙酯100mL和水100mL，分离有机相，用饱和食盐水(2*50mL)洗涤，无水硫酸钠干燥，过滤，将滤液浓缩，所得粗品经柱层析纯化(PE:EA＝1:1)，得2-溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺(81mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.44(s,1H),8.23(m,2H),8.03(m,1H),7.94(s,1H),7.53(t,J＝9.0Hz 1H),3.97(s,3H),1.38(s,9H)； 13C-NMR(125MHz,DMSO-d6):δ179.52,163.76,161.11,159.72,157.71,136.65,128.62,124.58,123.08,120.55,118.44,117.43,117.27,114.42,100.29,51.51,35.74,28.73；MS(ESI -,[M-H] -)m/z：447.3.
实施例20 2,4-二溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000124
Figure PCTCN2019080412-appb-000125
步骤A：向反应瓶中加入100mg 5-(2-(叔丁基氨基-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺、1mL DMF及4mL乙腈，搅拌下，加入NBS 144.3mg，110℃反应24小时。停止搅拌，向溶液中加入乙酸乙酯100mL和水100mL。分离有机相，用饱和食盐水(2×50mL)洗涤，无水硫酸钠干燥，过滤，将滤液浓缩后，通过柱层析纯化(PE/EA＝1/1)得到2,4-二溴-5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺19.4mg。 1H-NMR(500MHz,DMSO-d 6):δ10.80(s,1H),8.42(s,1H),8.19(s,1H),7.96(s,1H),7.56(t,J＝8.5Hz,1H),3.86(s,3H),1.37(s,9H)； 13C-NMR(125MHz,DMSO-d 6):δ181.55,179.82,164.62,160.93,139.18,136.31,127.96,127.09,123.56,117.92,115.79,114.29,105.28,100.87,51.45,36.46,28.67；MS(ESI -,[M-H] -)m/z：525.2.
实施例21 (R)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000126
根据实施例1，在步骤E中用(R)-3-氨基四氢呋喃替代炔丙胺，制备(R)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),8.99(s,1H),8.20-8.21(m,1H),7.95-7.97(m,1H),7.50-7.54(m,1H),4.35-4.36(m,1H),3.80-3.84(m,2H),3.78(s,3H),3.71-3.74(m,1H),3.56-3.59(m,1H),2.36(s,3H),2.22(s,3H),2.16-2.19(m,1H),1.84-2.15(m,1H)； 13C-NMR(125MHz,DMSO-d 6):δ164.18,159.64,157.63,140.44,136.85,136.83,130.43,127.28,125.29,123.77,120.51,117.58,117.41,114.45,72.28,66.82,50.00,33.61,32.04,11.55,11.40.MS(ESI-,[M-H]-)m/z：411.4.
实施例22 (S)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000127
根据实施例1，在步骤E中用(S)-3-氨基四氢呋喃替代炔丙胺，制得(S)-N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((四氢呋喃-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.30(s,1H),8.98(d,J＝6.5Hz,1H),8.20(s,1H),7.96(d,J＝7.0Hz,1H),7.52(t,J＝9.0Hz,1H),4.35(d,J＝2.5Hz,1H),3.83(t,J＝6.5Hz,2H),3.74(s,3H),3.71(m,1H),3.57(m,1H),2.51(s,3H),2.36(s,3H),2.17(m,1H),1.85(m,1H)； 13C-NMR(125MHz,DMSO-d 6)：δ181.80,167.33,164.18,159.64,157.63,140.44,136.86,130.43,127.25,125.30,123.77,120.52,117.50,100.32,72.28,66.83,50.00,33.61,32.04,11.55.MS(ESI-,[M-H] -)m/z： 411.4.
实施例23 N-(3-氰基-4-氟苯基)-1，2，4-三甲基-5-(2-((3-甲基四氢呋喃-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000128
根据实施例1，在步骤E中用3-氨基-3-甲基四氢呋喃替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1，2，4-三甲基-5-(2-((3-甲基四氢呋喃-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d6):δ10.28(s,1H),8.76(s,1H),8.20-8.21(m,1H),7.95-7.98(m,1H),7.52(t,J＝9.0Hz,1H),3.99(d,J＝9.0Hz,1H),3.78-3.82(m,5H),3.54(d,J＝8.5Hz,1H),2.36(s,3H),2.31-2.33(m,1H),2.27(s,3H),1.86-1.91(m,1H),1.46(s,3H)； 13C-NMR(125MHz,DMSO-d6):δ181.80,167.41,164.20,159.62,157.63,140.42,136.85,130.30,127.26,125.29,123.78,120.41,117.50,114.45,100.32,76.77,66.85,59.96,38.70,33.60,22.80,11.53.MS(ESI-,[M-H] -)m/z：425.4.
实施例24 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000129
根据实施例1，在步骤E中用四氢-4-甲基-2H-吡喃-4-胺替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.26(s,1H),8.33(s,1H),8.21(s,1H),7.96(d,J＝4.5Hz,1H),7.51(t,J＝9.0Hz,1H),3.78(s,3H),3.58-3.60(m,4H),2.35(s,3H),2.29(s,3H),2.07-2.10(m,2H),1.55-1.59(m,2H),1.40(s,3H). 13C-NMR(125MHz,DMSO-d 6)：δ181.94,167.53,164.40,140.26,136.84,130.12,127.30,125.28,123.79,120.30,117.40,114.43,100.51,93.69,63.46,60.42,51.33,36.40,33.60,25.76,11.72.MS(ESI-,[M-H] -)m/z:439.5.
实施例25 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000130
根据实施例1，在步骤E中用3-(三氟甲基)氧杂环丁烷-3-胺盐酸盐替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6)：δ10.32(s,1H),9.93(s,1H),8.20-8.22(m,1H),7.95-7.98(m,1H),7.50-7.54(m,1H),4.82(q,J＝8.0Hz,4H),3.79(s,3H),2.37(s,3H),2.28(s,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ180.07, 166.20,164.00,159.68,157.67,141.38,136.80,131.00,127.31,125.10,123.85,120.80,117.51,114.44,100.33,73.37,57.28,57.03,33.70,11.62,11.55.MS(ESI-,[M-H] -)m/z：465.4.
实施例26 N-(3-氰基-4-氟苯基)-5-(2-(3-(羟甲基)氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000131
根据实施例1，在步骤E中用3(3-氨基氧杂环丁烷-3-基)甲醇替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-(3-(羟甲基)氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.23(s,1H),8.21(d,J＝3.5Hz,1H),7.96(t,J＝3.5Hz,1H),7.52(t,J＝9.0Hz,1H),5.23(t,J＝5.0Hz,1H),4.61(d,J＝6.0Hz,2H),4.56(d,J＝6.0Hz,2H),3.77(s,3H),3.72(t,J＝5.0Hz,2H),2.36(s,3H),2.29(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ181.31,170.78,166.50,164.17,159.64,157.63,140.57,136.84,130.52,127.27,125.44,123.77,120.50,117.57,114.45,100.39,76.45,57.63,33.61,21.22,11.61.MS(ESI -,[M-H] -)m/z：427.4.
实施例27 N-(3-氰基-4-氟苯基)-5-(2-((1-(羟甲基)环丙基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000132
根据实施例1，在步骤E中用(1-氨基环丙基)甲醇替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-((1-(羟甲基)环丙基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.28(s,1H),8.92(s,1H),8.20-8.21(m,1H),7.94-7.97(m,1H),7.50-7.53(m,1H),4.71-4.73(t,J＝11Hz,1H),3.75(s,3H),3.53(s,3H),2.35(s,3H),2.32(s,3H),0.77-0.70(t,J＝11Hz,1H),0.65-0.67(t,J＝11Hz,1H)； 13C-NMR(125MHz,DMSO-d 6):δ168.07,164.23,159.62,157.62,140.25,136.88,130.31,127.26,127.19,125.44,123.74,120.38,117.57,117.41,114.45,63.83,34.49,33.55,11.55,11.42,10.45.MS(ESI-,[M-H]-)m/z：411.4.
实施例28 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)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000133
Figure PCTCN2019080412-appb-000134
步骤A：0℃下，向反应瓶中依次加入水(10.00mL)、氢氧化钠(1.416g)，缓慢滴加1-氨基-3,3-二氟环丁烷-1-羧酸(5g)的甲醇(50mL)溶液，滴加完毕，再加入二碳酸二叔丁酯(9.10g)，加完后升至室温搅拌16h，反应结束后用2N HCl调节pH至2～3，过滤，所得滤饼，干燥后得到1-((叔丁氧基羰基)氨基)-3,3-二氟环丁烷-1-羧酸(7.80g)。 1H NMR(500MHz,DMSO-d 6):δ12.81(s,1H),7.82(s,1H),3.08-3.16(m,2H),2.72-2.79(m,2H),1.39(s,9H)； 13C NMR(125MHz,DMSO-d 6):δ174.03,155.49,79.05,47.73,44.84,44.66,44.48,28.61,28.33.
步骤B：向反应瓶中依次加入1-((叔丁氧基羰基)氨基)-3,3-二氟环丁烷-1-羧酸(7.6g)、HATU(17.25g)、DMF(50mL)、甲胺(4.79g)和DIPEA(42.3mL)，室温反应3h。反应结束后向反应液中加入300mL水，用乙酸乙酯(200mL*3)萃取，合并有机相，干燥，过滤、浓缩，得到(3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基甲酸叔丁酯(7.88g)。 1H NMR(500MHz,DMSO-d 6):δ7.65-7.73(m,2H),3.08-3.09(m,2H),2.89(s,3H),2.60-2.61(m,2H),1.40(s,9H)； 13C NMR(125MHz,DMSO-d 6):δ172.41,154.97,79.32,48.55,43.98,28.57,26.81.
步骤C：向反应瓶中，依次加入(3,3-二氟-1-(甲基氨基甲酰基)环丁基)氨基甲酸叔丁酯(7.38g)、二氧六环(50mL)，缓缓滴加4M HCl的二氧六环溶液(69.8mL)，室温搅拌12h。反应结束后用2M氢氧化钠溶液调节pH至10～11，过滤，滤饼40℃真空干燥，得到1-氨基-3,3-二氟-N-甲基环丁烷-1-甲酰胺盐酸盐(5.19g)。 1H NMR(500MHz,DMSO-d 6):δ 1H NMR(500MHz,DMSO-d 6):δ9.32(s,3H),8.72(s,1H),3.23-3.32(m,2H),3.11-3.19(m,2H),2.69-2.70(d,J＝4.5Hz,3H)； 13C NMR(125MHz,DMSO-d 6):δ168.26,117.74,48.12,48.05,43.73,26.78.
步骤D：根据实施例1，在步骤E中用1-氨基-3,3-二氟-N-甲基环丁烷-1-甲酰胺盐酸盐替代炔丙胺，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)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.57(s,1H),8.20-8.22(m,1H),7.94-7.97(m,1H),7.68(s,1H),7.50-7.54(m,1H),3.75(s,3H),3.22-3.30(m,2H),2.90-2.97(m,2H),2.63(s,3H),2.36(s,3H),2.22(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ180.49,170.89,166.39,164.16,159.64,157.64,140.67,136.83,130.92,127.23,125.76,123.80,120.60,119.47,117.41,114.45,100.39,48.92,43.91,33.68,26.72,11.65.MS(ESI+,[M+Na] +)m/z：512.4.
实施例29 (S)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000135
Figure PCTCN2019080412-appb-000136
步骤A：向反应瓶中依次加入DMF(100mL)，4-甲基-1H-吡咯-3-羧酸乙酯(20g)，冰浴中，且N 2保护下缓慢加入NaH(7.83g)，加毕，搅拌30min，缓慢将碘甲烷(23.17g)加入上述搅拌液中，加毕，室温搅拌2.0h，将反应液倒入含有碎冰的饱和氯化铵溶液(1000mL)中，使用乙酸乙酯(3*1000mL)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到1,4-二甲基-1H-吡咯-3-羧酸乙酯(21.34g)。 1H-NMR(500MHz,DMSO-d 6):δ7.28(s,1H),6.54(s,1H),4.12-4.16(q,J＝21Hz,2H),3.57(s,3H),2.14(s,3H),1.23-1.26(t,J＝14.5Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ164.73,128.16,122.34,120.49,113.43,58.91,36.29,14.88,11.95.
步骤B：向反应瓶中依次加入1,4-二甲基-1H-吡咯-3-羧酸乙酯(10g)、DCM(200mL)，冰浴下再加入AlCl 3(32g)，加毕，N 2保护下，滴加草酰氯单乙酯(24.5g)的DCM溶液(100mL)，加毕室温搅拌反应5.0h，将反应液倒入500mL冰水中，用DCM(200mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液经柱层析纯化(PE:EA＝12:1)得到5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸乙酯(11.5g)。 1H-NMR(500MHz,DMSO-d 6)：δ7.92(s,1H),4.37(q,J＝7.0Hz,1H),4.21(q,J＝7.0Hz,1H),8.16(s,1H),3.87(s,3H),2.36(s,2H),1.32(t,J＝7.5Hz,3H),1.27(t,J＝7.5Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ177.54,165.14,163.47,138.01,134.82,125.79,114.52,62.83,59.98,38.48,14.71,14.14,10.86.MS(ESI+,[M+Na] +)m/z：290.4.
步骤C：向反应瓶中加入5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸乙酯(6g)、DMF(100mL)、NCS(4.5g)，加毕室温搅拌8.0h，将反应液倒入500mL水中，用乙酸乙酯(200mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干，经柱层析纯化(PE:EA＝50:1)得到2-氯-5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸乙酯(3.5g)。 1H-NMR(500MHz,DMSO-d 6)：δ4.38(q,J＝7.0Hz,2H),4.26(q,J＝7.0Hz,2H),3.84(s,3H),2.33(s,3H),1.32(t,J＝7.0Hz,3H),1.30(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ176.88,164.71,162.33,134.29,132.17,125.12,112.75,63.06,60.64,34.52,14.50,14.10,11.60.
步骤D：向反应瓶中加入2-氯-5-(2-乙氧基-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-羧酸乙酯(3.2g)、甲醇(30mL)，冰浴下滴加NaOH(0.85g)水溶液(10mL)，加毕，室温搅拌反应，反应5min，使用2N HCl调节pH至2～3，用乙酸乙酯(100mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干得到2-(5-氯-4-(乙氧基羰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸(2.6g)。MS(ESI-,[M-H] -)m/z：272.1.
步骤E：向反应瓶中加入2-(5-氯-4-(乙氧基羰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸(400mg)、DMF(10mL)、HATU(834mg)、DIPEA(416mg)，加毕，室温搅拌10min，再加入(S)-1,1,1-三氟异丙胺盐酸盐(200mg)，加毕室温搅拌2.0h，将反应液倒入100mL水中，用乙酸乙酯(50mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩至干，经柱层析纯化(PE:EA＝9:1)得到(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(380mg)。 1H-NMR(500MHz,DMSO-d 6)：δ9.49(s,1H),4.72(q,J＝7.5Hz,1H),4.26(q,J＝7.0Hz,2H),3.83(s,3H),2.34(s,3H),1.32(t,J＝7.0Hz,3H),1.30(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ181.10,166.38,162.55,133.17,130.95,126.29,112.45,60.56,,46.21,45.97,34.38,14.56,13.69,11.72.MS(ESI-,[M-H] -)m/z：367.3.
步骤F：向反应瓶中加入(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(360mg)和甲醇(20mL)，加毕，滴加NaOH(0.85g)的水溶液(5mL)，80℃反应8.0h。使用2N HCl调节pH至2～3，用乙酸乙酯(100mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干得到(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(320mg)。MS(ESI-,[M-H] -)m/z：339.3.
步骤G：向反应瓶中加入(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(320mg)、甲苯(10mL)和二氯亚砜(2.3g)，加毕，N 2保护下115℃反应2.0h，将反应液浓缩干得到粗品，向其中加入DMA(10mL)、5-氨基2-氟苯腈(256mg)，100℃反应2.0h，将反应液倒入100mL水中，使用乙酸乙酯(50mL*3)萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干，经柱层析纯化(PE:EA＝4:1)得到(S)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(125mg)。 1H-NMR(500MHz,DMSO-d 6)：δ10.57(s,1H),9.51(d,J＝9.0Hz,1H),8.20(m,1H),7.96(m,1H),7.54(t,J＝9.0Hz,1H),4.72(m,1H),3.86(s,3H),2.23(s,3H),1.33(d,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ180.70,166.56,161.60,159.87,157.87,136.42,134.88,127.28,125.53,124.90,123.84,119.35,117.67,114.34,100.51,46.17,34.28,13.75,11.19.MS(ESI-,[M-H] -)m/z：457.3.
实施例30 (R)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000137
步骤A：根据实施例29，在步骤E中用(R)-1,1,1-三氟异丙胺盐酸盐替代(S)-1,1,1-三氟异丙胺盐酸盐，制得(R)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯。 1H NMR(500MHz,DMSO-d 6):δ9.47-9.49(d,J＝8.5Hz,1H),4.70-7.75(m,1H),4.24-4.28(q,J＝21Hz,2H),3.83(s,3H),2.34(s,3H),1.28-1.36(m,6H)； 13C NMR(125MHz,DMSO-d 6):δ181.11,166.38,162.55,133.17,130.95,127.13,126.29,124.89,112.45,60.56,34.38,14.56,13.69,11.72.MS(ESI-,[M-H] -)m/z：367.3.
步骤B：根据实施例29，在步骤F中用(R)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯替代(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯，制得(R)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸。 1H NMR(500MHz,DMSO-d 6):δ12.79(s,1H),9.45-9.47(m,1H),4.68-4.76(m,1H),3.82(s,3H),2.35(s,3H),1.32(s,3H)； 13C NMR(125MHz,DMSO-d 6):δ181.09,166.50,164.11,133.54,131.09,127.13,126.19,124.90,113.17,34.31,13.69,11.70.MS(ESI-,[M-H] -)m/z：339.3.
步骤C：根据实施例29，在步骤G中用((R)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸替代(S)-2-氯-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸，制得(R)-2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H NMR(500MHz,DMSO-d 6):δ10.58(s,1H),9.51-9.52(d,J＝8.5Hz,1H),8.19-8.20(m,1H),7.94-7.97(m,1H),7.52-7.56 3.82(m,1H),4.70-4.77(m,1H),3.86(s,3H),2.23(s,3H),1.34(s,3H)； 13C NMR (125MHz,DMSO-d 6):δ166.57,161.61,159.88,157.87,136.43,136.41,130.89,127.07,125.54,124.90,123.84,119.35,117.74,117.58,114.34,34.27,13.73,11.18.MS(ESI-,[M-H] -)m/z：457.4.
实施例31 2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000138
步骤A：向反应瓶中加入1,4-二甲基-1H-吡咯-3-羧酸乙酯(40g)、5-氟-2-氨基苯氰(40.7g)，THF(200ml)，冰浴下加入LiHDMS的THF溶液(1M,600mL)，加毕，室温搅拌2h，将反应液倒入含有饱和氯化铵溶液的冰水(1500mL)中，析出大量固体，过滤，滤饼用PE:EA＝1:1的混合溶剂200mL打浆得到N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(52.01g)。 1H NMR(500MHz,DMSO-d 6):δ9.73(s,1H),8.22-8.23(m,1H),7.95-7.98(m,1H),7.45-7.49(m,1H),6.58(s,1H),3.62(s,3H),2.18(s,3H)； 13C NMR(125MHz,DMSO-d 6):δ164.07,127.07,127.00,125.22,123.46,122.48,120.45,117.31,117.15,116.95,114.61,36.43,11.98.MS(ESI-,[M-H] -)m/z：256.3.
步骤B:向反应瓶中加入氧化锌(4.11g)，冰浴下加入草酰氯单乙酯(310g)，后加入N-(3-氰基-4-氟苯基)-1,4-二甲基-1H-吡咯-3-甲酰胺(26g)，冰浴搅拌20min，室温搅拌3.0h，在冰浴下向反应液中加入DCM(300ml)搅拌30min后将反应液倒入冰水中，用DCM(300ml*3)萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩至干得到2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(16.31g)。 1H-NMR(500MHz,DMSO-d 6)：δ10.20(s,1H),8.20(q,J＝2.5Hz,1H),7.94(m,2H),7.52(t,J＝9.0Hz,1H),4.38(q,J＝7.0Hz,2H),3.91(s,3H),2.36(s,3H),1.33(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ177.50,165.22,162.71,159.57,157.57,136.84,135.49,134.22,127.45,125.56,123.95,117.47,114.46,100.28,62.82,38.61,14.18,10.88.MS(ESI-,[M-H]-)m/z：356.4.
步骤C：向反应瓶中加入2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(10g)、DMF(400mL)，加毕，将NCS(4.86g)用DMF(20mL)溶解后，滴加至反应液中，室温搅拌30h，将反应液倒入1000mL水中，用乙酸乙酯(300mL*3)萃取，合并有机层，用饱和食盐水洗，无水硫酸钠干燥，过滤，滤液用柱层析纯化，得到2-(5-氯-4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(4.6g)。 1H-NMR(500MHz,DMSO-d 6)：δ10.62(s,1H),8.19(q,J＝2.5Hz,1H),7.94(m,1H),7.55(t,J＝8.0Hz,1H),4.39(q,J＝7.0Hz,2H),3.89(s,3H),2.22(s,3H),1.33(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ176.51,164.91,161.34,159.91,157.90,136.34,131.82,128.43,127.28,124.36,123.82,119.77,114.34,100.53,63.07,34.48,14.16,11.14.MS(ESI-,[M-H]-)m/z：390.3.
步骤D：向反应瓶中加入2-(5-氯-4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙 酸乙酯(4g)、THF(100mL)，冰浴下缓慢加入LiOH的水溶液(0.857g,15mL)，冰浴搅拌反应10min，用2N稀盐酸调节反应液pH至3～4，用乙酸乙酯(100mL*3)萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液浓缩得到2-(5-氯-4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸(3.0g)。 1H-NMR(500MHz,DMSO-d 6)：δ10.59(s,1H),8.19(q,J＝2.5Hz,1H),7.95(m,2H),7.54(t,J＝9.0Hz,1H),3.87(s,2H),2.29(s,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ178.90,167.25,161.52,159.88,157.87,136.40,131.05,127.29,124.39,123.78,119.48,117.68,114.35,100.61,34.36,11.08.
步骤E：向反应瓶中加入2-(5-氯-4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸(150mg)、DMF(6mL)、HATU(235mg)，DIPEA(160mg)，室温搅拌5min后加入4-甲基四氢-2H-吡喃-4-胺(50mg)，室温反应2.0h，向反应液中加入50mL水，用乙酸乙酯(60mL*3)萃取，合并有机层，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液中经柱层析纯化得到2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺(43mg)。 1H-NMR(500MHz,DMSO-d 6)：δ10.58(s,1H),8.46(s,1H),8.21(q,J＝2.5Hz,1H),7.98(m,1H),7.54(t,J＝9.0Hz,1H),3.86(s,3H),3.59(m,4H),2.31(s,3H),2.08(m,2H),1.61(m,2H),1.41(s,3H)； 13C-NMR(125MHz,DMSO-d 6)：δ181.53,166.82,161.75,159.84,157.83,136.52,130.24,127.32,126.31,125.81,123.83,119.03,117.72,117.56,114.37,100.46,63.44,51.50,36.35,34.20,25.66,11.61.MS(ESI-,[M-H] -)m/z：459.5.
实施例32 2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000139
步骤A：根据实施例31，在步骤E中用3-(三氟甲基)氧杂环丁烷-3-胺盐酸盐替代4-甲基四氢-2H-吡喃-4-胺，制得2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.58(s,1H),10.06(s,1H),8.20(s,1H),7.96(s,1H),7.55(s,1H),4.93(s,4H),3.85(s,3H),2.29(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ179.98,165.34,161.56,160.05,142.91,136.41,131.06,127.32,123.87,119.41,117.76,117.59,114.36,100.58,96.90,73.33,57.37,34.33,11.53.MS(ESI +,[M+Na] +)m/z：485.4.
实施例33 2-氯-N-(3-氰基-4-氟苯基)-5-(2-((1-羟基-2-甲基丙烷-2-基)氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000140
步骤A：根据实施例31，在步骤E中用2-氨基-2-甲基丙-1-醇替代4-甲基四氢-2H-吡喃-4-胺，制得2-氯-N-(3-氰基-4-氟苯基)-5-(2-((1-羟基-2-甲基丙烷-2-基)氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d6):δ10.55(s,1H),8.23(s,1H),8.20-8.21(m,1H),7.94-7.97(m,1H),7.54(t,J＝9.0Hz,1H),4.89(t,J＝5.5Hz,1H),3.83(s,3H),3.47(d,J＝5.5Hz,2H),2.29(s,3H),1.29(s, 6H)； 13C-NMR(125MHz,DMSO-d6):δ181.74,166.45,161.79,159.83,157.82,136.50,130.20,127.25,126.02,123.76,118.97,117.66,114.37,100.49,67.54,55.49,34.17,23.48,11.48.MS(ESI-,[M-H] -)m/z：433.4.
实施例34 2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000141
步骤A：根据实施例31，在步骤E中用3-甲基3-氨基氧杂环丁烷替代4-甲基四氢-2H-吡喃-4-胺，制得2-氯-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H NMR(500MHz,DMSO-d 6):δ10.57(s,1H),9.38(s,1H),8.19-8.20(m,1H),7.94-7.97(m,1H),7.52-7.56(m,1H),4.68-4.70(t,J＝6.5Hz,2H),4.39-4.41(t,J＝6.5Hz,2H),3.86(s,3H),2.29(s,3H),1.60(s,3H)； 13C NMR(125MHz,DMSO-d 6):δ181.26,165.40,161.66,159.85,157.84,136.46,130.55,127.30,126.70,125.94,123.79,119.17,117.74,114.36,100.56,80.72,53.62,34.25,23.30,11.65.MS(ESI-,[M-H] -)m/z：431.4.
实施例35 (S)-2-氯-N-(3-氯-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000142
步骤A：根据实施例29，在步骤G中用3-氯-4-氟苯胺替代5-氨基-2-氟苯腈，制得(S)-2-氯-N-(3-氯-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.42(s,1H),9.50(d,J＝8.5Hz,1H),7.99(m,1H),7.59(m,1H),7.41(t,J＝9.0Hz,1H),4.73(m,1H),3.86(s,3H),2.22(s,3H),1.33(d,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ180.68,166.60,161.42,154.81,152.88,136.57,136.55,130.85,126.98,125.47,121.38,120.34,119.66,117.57,46.16,34.25,13.73,11.17；MS(ESI -,[M-H] -)m/z：466.3.
实施例36 N-(3-氯-4-氟苯基)-1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000143
步骤A：向反应瓶中，依次加入2-(4-(乙氧基羰基)-1,3,5-三甲基-1H-吡咯-2-基)-2-氧代乙酸(800mg,3.16 mmol)、DMF(5ml)，搅拌10分钟，加入N,N-二异丙基乙基胺(1225mg,1.66ml,9.48mmol)、HATU(1441mg,3.79mmol)，室温反应3小时。向溶液中加入乙酸乙酯100mL和水100mL，分离有机相，将有机相用饱和食盐水(2×50mL)洗涤，后无水硫酸钠干燥，过滤，将滤液浓缩，通过柱层析(PE/EA＝1/1)得到化合物1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-羧酸乙酯817.5mg。MS(ESI +,[M+Na] +)m/z：373.4.
步骤B：向反应瓶中，依次加入1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-羧酸乙酯(954mg,2.72mmol)、甲醇(8ml)，室温搅拌10分钟，加入溶有氢氧化钠(0.327g,8.17mmol)的水(8.00ml)溶液，N 2保护下，室温下反应1小时。将溶液PH调至3～4，再向反应中加入200mL乙酸乙酯和200mL纯化水，分离有机层，用无水硫酸钠干燥，过滤，将滤液浓缩，得到1,2,4-三甲基-5-(2–((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-羧酸0.508mg。MS(ESI -,[M-H] -)m/z：321.6.
步骤C：向反应瓶中，依次加入1,2,4-三甲基-5-(2–((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-羧酸(280mg)、甲苯(5ml)、氯化亚砜(0.25ml,3.47mmol)，N 2保护下，115℃反应1小时。浓缩，向残留物中加入5.0mL甲苯，浓缩，得到固体268mg。向反应瓶中，依次加入上述固体、N,N-二甲基乙酰胺(10ml)、3-氯-4-氟苯胺(160mg,1.101mmol)，N 2保护下，100℃反应2小时。向溶液中加入乙酸乙酯300mL和水300mL。分离有机相，用饱和食盐水(2×50mL)洗涤，后无水硫酸钠干燥，过滤，将滤液浓缩，通过柱层析(PE/EA＝1/1)纯化得到N-(3-氯-4-氟苯基)-1,2,4-三甲基-5-(2-((4-甲基四氢-2H-吡喃-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺69mg。 1H-NMR(500MHz,DMSO-d 6):δ10.13(s,1H),8.34(s,1H),8.01(d,J＝5.0Hz,1H),7.60(m,1H),7.39(t,J＝9.0Hz,1H),3.78(s,3H),3.60(m,4H),2.35(s,3H),2.29(s,3H),2.09(m,2H),1.58(m,2H),1.40(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ181.71,167.58,164.06,154.55,152.62,140.13,137.01,130.12,125.18,121.31,120.62,120.24,119.58,117.41,63.46,51.31,36.38,33.59,25.76,11.71,11.56.MS(ESI+,[M+Na]+)m/z：472.4.
实施例37 (S)-N-(3-氯-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000144
向反应瓶中，加入(S)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(0.3g)、甲苯(10ml)、氯化亚砜(0.68mL)，115℃反应2h。结束后浓缩，加入3-氯-4-氟苯胺(0.27g)、N，N-二甲基乙酰胺(10ml)，100℃反应3h。反应结束后加入乙酸乙酯(30mL)，水(3*20mL)洗三次，干燥，浓缩，用石油醚：乙酸乙酯＝3:1混合溶剂(5ml)打浆，过滤，干燥得(S)-N-(3-氯-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(0.19g)。 1H NMR(500MHz,DMSO-d 6):δ10.18(s,1H),9.39-9.41(m,1H),8.00-8.02(m,1H),7.58-7.61(m,1H),7.37-7.41(m,1H),4.69-4.76(m,1H),3.79(s,3H),2.36(s,3H),2.21(s,3H),1.32-1.33(d,J＝7Hz,3H)； 13C NMR(125MHz,DMSO-d 6):δ180.76,167.27,163.90,154.58,152.65,140.80,136.95,127.20,124.93,121.33,120.25,119.60,117.42,46.01,33.65,13.75,11.57.MS(ESI-,[M-H] -)m/z：446.4.
实施例38 (S)-N-(3,4-二氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000145
根据实施例37，用3,4-二氟苯胺替换3-氯-4-氟苯胺，制得(S)-N-(3,4-二氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(DMSO-d 6,500MHz):δ10.20(s,1H),9.39(d,J＝8.5Hz,1H),7.86(q,J＝8.0Hz,1H),7.40(q,J＝6.5Hz,2H),4.75-4.68(m,1H),3.79(s,3H),2.35(s,3H),2.20(s,3H),1.31(d,J＝7.0Hz,3H).MS(ESI -,[M-H] -)m/z:430.4.
实施例39 (S)-N-(4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000146
根据实施例37，用4-氟苯胺替换3-氯-4-氟苯胺，制得(S)-N-(4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(DMSO-d 6,500MHz):δ10.03(s,1H),9.38(d,J＝8.0Hz,1H),7.70(s,2H),7.16(t,J＝8.0Hz,2H),4.71(d,J＝6.5Hz,1H),3.78(s,3H),2.35(s,3H),2.20(s,3H),1.31(d,J＝6.0Hz,3H). 13C-NMR(DMSO-d 6,125MHz):δ180.70,167.33,163.65,159.50,157.60,140.62,136.10,130.76,124.97,124.84,121.77,121.71,121.47,115.77,115.59,33.63,13.75,11.57,11.24.MS(ESI +,[M+Na] +)m/z:436.2.
实施例40 (S)-N-(4-氟-3-甲基苯基)-1,2,4-三甲基-5-(2-氧代-2–((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000147
根据实施例37，用2-氟-5-氨基甲苯替换3-氯-4-氟苯胺，制得(S)-N-(4-氟-3-甲基苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(DMSO-d 6,500MHz):δ9.95(s,1H),9.36(s,1H),8.85(s,1H),7.66(d,J＝3.95Hz,1H),7.51(d,J＝4.0Hz,1H),4.75-4.66(m,1H),3.84(s,3H),3.74(s,3H),2.67(s,3H),2.45(s,3H),2.32(s,3H). 13C-NMR(DMSO-d 6,125MHz):δ181.26,167.16,166.26,153.10,145.19,140.09,134.25,134.12,130.31,129.28,125.77,121.14,114.00,106.94,33.58,13.17,12.75,12.18,12.05,11.76.MS(ESI +,[M+Na] +)m/z:450.1.
实施例41 (S)-N-(2-氯吡啶-4-基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000148
根据实施例37，用2-氯-4-氨基吡啶替代3-氯-4-氟苯胺，制得(S)-N-(2-氯吡啶-4-基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。
1H-NMR(500MHz,DMSO-d 6):δ9.55(d,J＝8.3Hz,1H),8.85(s,1H),8.74(d,J＝8.0Hz,1H),7.72-7.62(m,1H),4.80-4.67(m,1H),3.84(s,3H),3.75(s,1H),2.68(s,3H),2.45(s,3H),1.34(d,J＝6.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6):δ181.75,166.41,160.75,153.08,147.73,140.60,134.91,134.24,130.30,122.17,106.93,34.23,33.58,13.70,12.75,12.18,12.05.
实施例42 (S)-N-(3-氨基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000149
步骤A:根据实施例37，在步骤A中用4-氟苯-1,3-二胺替代3-氯-4-氟苯胺，制得(S)-N-(3-氨基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。
1H-NMR(500MHz,DMSO-d 6):δ9.76(s,1H),9.37(d,J＝9.0Hz,1H),7.25(d,J＝8.0Hz,1H),6.92-6.88(m,1H),6.75(d,J＝8.5Hz,1H),5.13(s,2H),4.71(q,J＝7.5Hz,1H),3.78(s,3H),2.34(s,3H),2.19(s,3H),1.32(d,J＝7.0Hz,3H).MS(ESI-,[M-H] -)m/z:427.4.
实施例43 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-(4-甲基哌嗪-1-基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000150
根据实施例1，在步骤E中用1-甲基哌嗪替换丙炔胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-(4-甲基哌嗪-1-基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(DMSO-d 6,500MHz)：δ10.35(s,1H),8.20(q,J＝2.5Hz,1H),7.96-7.93(m,1H),7.53(t,J＝9.0Hz,1H),3.85(s,3H),3.56(s,2H),3.33(s,2H),2.36(d,J＝9.0Hz,5H),2.32(d,J＝4.0Hz,2H),2.22(d,J＝5.5Hz,6H). 13C-NMR(DMSO-d 6,125MHz)：δ181.14,166.00,164.05,141.17,136.77,131.02,127.27,127.20,124.84,123.75,120.96,117.63,117.46,114.44,54.59,54.12,46.06,45.67,40.78,33.92,11.56,11.33.MS(ESI -,[M-H] -)m/z:424.4.
实施例44 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-((1-甲基哌啶-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000151
根据实施例1，在步骤E中用1-甲基哌啶-4-胺替代炔丙胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2-((1-甲基哌啶-4-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),8.69(d,J＝8.0Hz,1H),8.19-8.21(m,1H),7.93-7.97(m,1H),7.51(t,J＝9.0Hz,1H),3.77(s,3H),3.60-3.66(br,1H),2.74-2.77(m,2H),2.35(s,3H),2.22(s,3H),2.18(s,3H),2.01(t,J＝10.5Hz,2H),1.762-1.782(m,2H),1.50-1.55(m,2H). 13C-NMR(125MHz,DMSO-d 6):δ182.06,166.78,164.20,159.62,157.62,140.31,136.87,130.33,127.26,125.32,123.73,120.45,117.58,114.46,100.37,54.42,46.22,33.60,31.41,11.56.MS(ESI-,[M-H] -)m/z:438.5.
实施例45 N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2–((3-甲基-1,1-二氧化硫-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000152
根据实施例1，在步骤E中用3-氨基-3-甲基硫杂环丁烷1,1-二氧化物替换丙炔胺，制得N-(3-氰基-4-氟苯基)-1,2,4-三甲基-5-(2–((3-甲基-1,1-二氧化硫-3-基)氨基)-2-氧代乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(DMSO-d 6,500MHz):δ10.32(s,1H),9.52(s,1H),8.20(s,1H),7.95(d,J＝8.5Hz,1H),7.52(d,J＝9.0Hz,1H),4.45(d,J＝14.5Hz,2H),4.35(d,J＝14.5Hz,2H),3.78(s,3H),2.36(s,3H),2.26(s,3H),1.70(s,3H). 13C-NMR(DMSO-d 6,125MHz):δ180.75,166.98,164.06,159.65,157.64,141.04,136.82,130.81,127.28,125.16,123.78,120.65,117.59,117.43,114.45,100.39,74.66,41.80,33.68,26.10,11.71。MS(ESI -,[M-H] -)m/z:459.4.
实施例46 N-(3-氰基-4-氟苯基)-5-(2-((3-羟基-1-甲基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000153
根据实施例1，在步骤E中用3-甲基-3-氨基1-环丁醇替代炔丙胺，制得N-(3-氰基-4-氟苯基)-5-(2-((3-羟基-1-甲基环丁基)氨基)-2-氧代乙酰基)-1,2,4-三甲基-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.29(s,1H),8.84(s,1H),8.21～8.20(m,1H),7.96(t,J＝4.0Hz,1H),7.52(t,J＝4.0Hz,1H),5.06(d,J＝7.0Hz,1H),4.01(t,J＝7.0Hz,1H),3.77(s,3H),2.40～2.35(m,5H),2.28(s,3H),2.09(t,J＝9.5Hz,2H),1.37(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ182.14,166.00,164.24,159.62,157.61,140.25,136.88,130.18,127.26,125.47,123.74,120.31,117.58,114.47,100.37,100.24,60.88,45.70,33.58,25.98,11.68.MS(ESI -,[M-H] -)m/z：425.4.
实施例47 1,2,4-三甲基-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-N-(3,4,5-三氟苯基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000154
步骤A:根据实施例1，将步骤B中的3,4,5-三氟苯胺替代5-氨基-3-氟苯腈，制得1,2,4-三甲基-N-(3,4,5-三氟苯基)-1H-吡咯-3-甲酰胺。
步骤B:向反应瓶中加入氯草酸单乙酯(447g)，氧化锌(5.28g)，冰浴下分批加入1,2,4-三甲基-N-(3,4,5-三氟苯基)-1H-吡咯-3-甲酰胺(36.6g)，加毕后转至室温，搅拌反应2.0h。反应结束后缓慢倒入500mL冰水中淬灭，用DCM(2*500mL)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，抽滤，滤液经过减压浓缩，除去溶剂，得到粗品加入乙酸乙酯(100mL)，室温下打浆1.0h，抽滤，滤饼真空干燥得2-氧代-2-(1,3,5-三甲基-4-((3,4,5-三氟苯基)氨基甲酰基)-1H-吡咯-2-基)乙酸乙酯(28.8g)。MS(ESI-,[M-H] -)m/z:381.3.
步骤C：冰浴下，向反应瓶中加入MeOH(120mL)、2-氧代-2-(1,3,5-三甲基-4-((3,4,5-三氟苯基)氨基甲酰基)-1H-吡咯-2-基)乙酸乙酯(28.8g)、氢氧化钠(6.93g)的水(60mL)溶液，加毕后转至室温反应2.0h。向反应液中加入水(200mL)及DCM(150mL)，分层，弃去有机层，水层用浓盐酸调pH至约3，用乙酸乙酯(2*500mL)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，抽滤，滤液减压蒸除溶剂，得2-氧代-2-(1,3,5-三甲基-4-((3,4,5-三氟苯基)氨基甲酰基)-1H-吡咯-2-基)乙酸(22.77g)。 1H-NMR(500MHz,DMSO-d 6):δ14.35(s,1H),10.33(s,1H),7.62(dd,J＝10Hz,2H),3.82(s,3H),2.35(s,3H),2.26(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ178.69,167.72,164.04,151.51,149.61,149.49,141.38,136.27,134.32,130.95,123.79,120.90,104.19,60.21,33.74,11.47.MS(ESI-,[M-H] -)m/z:353.5.
步骤D：向反应瓶中依次加入DMF(5.0mL)、2-氧代-2-(1,3,5-三甲基-4-((3,4,5-三氟苯基)氨基甲酰基)-1H-吡咯-2-基)乙酸(600mg)，HATU(773mg)，DIPEA(657mg)，再加入3-甲基-3-环氧丁胺(162mg)，室温搅拌16.0h。向反应液中加入水(200mL)，用乙酸乙酯(2*200mL)萃取，合并有机层，用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1,2,4-三甲基-5-(2-((3-甲基氧杂环丁烷-3-基)氨基)-2-氧代乙酰基)-N-(3,4,5-三氟苯基)-1H-吡咯-3-甲酰胺(700mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.26(s,1H),7.63～7.60(m,2H),4.68(d,J＝6Hz,2H),4.39(d,J＝6Hz,2H),3.77(s,3H),2.35(s,3H),2.27(s,3H),1.60(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ181.42, 166.19,164.22,151.47,151.43,149.61,149.53,140.70,136.10,136.03,134.15,130.40,125.41,120.50,104.19,80.79,53.53,33.63,23.37,11.68.MS(ESI -,[M-H] -)m/z：422.3。
实施例48 (S)-N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-(1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000155
步骤A:根据实施例18，在步骤D中用(S)-1,1,1-三氟丙-2-胺盐酸盐替代叔丁胺，制得(S)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸甲酯。MS(ESI+,[M+H] +)m/z:307.2.
步骤B:根据实施例18，在步骤E中用(S)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸甲酯替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯，制得(S)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸。
MS(ESI+,[M+H] +)m/z:293.3.
步骤C:根据实施例18，在步骤F中用(S)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸，制得(S)-N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-(1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.41(d,J＝9.0Hz,1H),8.25(q,J＝3.0Hz,1H),8.03-8.05(m,2H),7.94(d,J＝2.0Hz,1H),7.53(t,J＝9.0Hz,1H),4.69-4.77(m,1H),3.98(s,3H),1.36(d,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ178.70,164.31,161.68,159.60,157.60,136.80,127.70,127.17,124.93,124.26,123.21,119.71,117.40,114.49,100.23,46.24,38.23,13.56.
MS(ESI-,[M-H] -)m/z:409.3.
实施例49(R)-N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000156
Figure PCTCN2019080412-appb-000157
步骤A:根据实施例18，在步骤D中用(R)-1,1,1-三氟丙-2-胺盐酸盐替代叔丁胺，制得(R)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸甲酯。MS(ESI-,[M-H] -)m/z:305.3.
步骤B:根据实施例18，在步骤E中用(R)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸甲酯替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-甲酸甲酯，制得(R)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸。MS(ESI-,[M-H] -)m/z:291.3.
步骤C:根据实施例18，在步骤F中用(R)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸替代5-(2-(叔丁基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸，制得(R)-N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-(1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.41(d,J＝9.0Hz,1H),8.25(q,J＝2.5Hz,1H),8.02-8.05(m,2H),7.94(d,J＝1.5Hz,1H),7.52(t,J＝9.0Hz,1H),4.69-4.77(m,1H),3.98(s,3H),1.36(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6):δ178.69,164.31,161.68,159.60,157.59,136.80,127.70,127.17,124.92,124.26,123.22,119.72,117.39,114.48,100.23,45.99,38.23,13.56.MS(ESI-,[M-H] -)m/z:409.3.
实施例50 N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000158
步骤A：反应瓶中，依次加入1-甲基-1H-吡咯-3-羧酸甲酯(33g)，2-氟-5-氨基苯腈(40.4g)，四氢呋喃(200mL)，冰浴下加入二(三甲基硅基)氨基锂(90g,538mL四氢呋喃溶液)，30分钟后加完，反应液升至室温继续搅拌1小时。反应结束后将反应液倒入2000mL冰水中，剧烈搅拌10分钟后过滤，滤饼干燥过夜，得到N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺(51.48g)。
步骤B：反应瓶中加入N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺(20.0g)，二氯甲烷(250mL)，搅拌下加入2-氯-2-氧代乙酸乙酯(33.7g)，分批加入无水三氯化铝(10.96g)，加毕后转至室温反应2小时。反应结束后将反应液缓慢倒至2000mL冰水中淬灭，用二氯甲烷(1000mL*2)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＝3:1)，得到2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(7.16g)。 1H NMR(500MHz,DMSO-d 6):δ10.26(s,1H),8.22-8.23(m,1H),8.01-8.06(m,2H),7.80(s,1H),7.52-7.55(m,1H),4.39(q,J＝21.0Hz,2H),3.97(s,3H),1.34(t,J＝14.0Hz,3H)； 13C NMR(125MHz,DMSO-d 6):δ175.60,163.46,161.48,159.66,157.66,137.25,136.68,127.77,124.33,123.20,120.00,117.53,114.46,100.34,62.64,38.15,14.36.
步骤C：反应瓶中，加入2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(2.16g)，四氢呋喃(10mL)，将反应液置于冰浴下，将氢氧化锂一水合物(0.53g)溶于水(5mL)滴入反应液中，混合物在冰浴下搅拌反应30分钟，反应结束后加入50mL水稀释，用2mol/L稀盐酸调节pH至5～6，用乙酸乙酯(50mL*3)洗涤，干燥，浓缩，得到2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸(1.03g)，直接用于下一步反应。
步骤D：反应瓶中，依次加入2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸(0.2g)、3-(三氟甲基)氧杂环丁烷-3-胺盐酸盐(0.169g)、HATU(0.362g)、N，N-二甲基甲酰胺(5mL)，N 2保护下，加入DIPEA(0.246g)，将混合物室温搅拌反应2小时。反应结束后向反应液中加入100mL乙酸乙酯，用100mL*2水洗涤两次。干燥，浓缩，以5mL石油醚：乙酸乙酯＝3:1混合溶剂打浆3小时。过滤，滤饼经真空干燥4h，得到N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-((3-(三氟甲基)氧杂环丁烷-3-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(115mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.30(s,1H),9.98(s,1H),8.24-8.26(m,1H),8.13(m,1H),8.04-8.06(m,2H),7.52(t,J＝18.0Hz,1H),4.92(d,J＝8.0Hz,2H),4.77(d,J＝8.0Hz,2H),3.99(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ176.97,162.91,161.70,159.60,157.60,137.07,127.75,124.67,123.90,119.76,117.28,114.49,100.28,73.51,57.09,38.41.MS(ESI-,[M-H] -)m/z：437.4.
实施例51 5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-2-氟-1-甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000159
反应瓶中，加入5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺(100mg)、selectfluor(115mg)、乙腈(2mL)、DMF(0.5mL)，油浴65℃反应过夜。反应结束将反应液倒入50mL饱和氯化钠水溶液中，用乙酸乙酯(50mL*2)萃取，分离有机层，干燥，浓缩，通过柱层析(PE:EA＝3：1)分离得到5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-2-氟-1-甲基-1H-吡咯-3-甲酰胺(38.1mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.35(s,1H),8.22(t,J＝3.0Hz,1H),8.15(s,1H),8.05～8.02(m,1H),7.98(d,J＝6.5Hz,1H),7.52(t,J＝9.0Hz,1H),3.81(s,3H),1.83(s,9H). 13C-NMR(125MHz,DMSO-d 6):δ179.54,163.36,159.97,157.72,153.45,151.19,136.50,128.01,124.60,121.35,119.46,117.45,117.29,114.42,100.68, 100.29,51.42,31.97,28.70.MS(ESI -,[M-H] -)m/z：387.3.
实施例52 (S)-N-(3-氰基-4-氟苯基)-2-氟-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000160
根据实施例51，将5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺替换成(S)-N-(3-氰基-4-氟苯基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺，制得(S)-N-(3-氰基-4-氟苯基)-2-氟-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.34(s,1H),9.43(d,J＝9.0Hz,1H),8.21(q,J＝3.0Hz,1H),8.05-8.00(m,2H),7.53(t,J＝9.0Hz,1H),4.76-4.70(m,1H),3.83(s,3H),1.36(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6):δ177.83,163.62,159.88,157.74,153.80,151.54,136.47,127.89,124.56,121.96,119.33,117.49,114.42,101.06,100.19,46.04,32.08,13.53.MS(ESI -,[M-H] -)m/z：427.3.
实施例53 (S)-N-(3-氰基-4-氟苯基)-2-氟-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000161
根据实施例51，将5-(2-(叔丁基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-3-甲酰胺替换成(S)-N-(3-氰基-4-氟苯基)-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺，制得(S)-N-(3-氰基-4-氟苯基)-2-氟-1,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d 6):δ10.34(s,1H),9.49(d,J＝9.0Hz,1H),8.16(q,J＝3.0Hz,1H),7.93-7.90(m,1H),7.53(t,J＝9.0Hz,1H),4.77-4.69(m,1H),3.76(s,3H),2.30(s,3H),1.33(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6):δ181.09,166.79,160.33,157.80,151.02,148.81,136.43,131.67,127.57,124.10,118.58,117.66,114.37,101.62,100.49,45.86,32.01,13.72,11.16.MS(ESI -,[M-H] -)m/z：440.9.
实施例54 (S)-N-(3-氰基-4-氟苯基)-4-氟-1,2-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000162
Figure PCTCN2019080412-appb-000163
步骤A：氮气保护下，向反应瓶中加入(1S，4S)-奎宁环-3-醇(113mg)，四氢呋喃(1.5mL)，丁基-2,3-二烯酸乙酯(500mg)，冰盐浴下加入乙醛(392mg,1.7mL四氢呋喃溶液)，体系在-10℃反应5.0h，加毕后转至室温反应2.5h，反应结束后缓慢倒至20mL冰水中淬灭，用乙酸乙酯(2*20mL)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＝10:1)，制得2-(1-羟乙基)丁-2,3-二烯酸乙酯(210mg)。 1H-NMR(500MHz,DMSO-d 6)：δ5.42(d,J＝1.5Hz,2H),4.94(d,J＝5.0Hz,1H),4.48(q,J＝5.5Hz,1H),4.15-4.10(m,2H),1.20(dd,J 1＝5.5Hz,J 2＝7.0Hz,6H). 13C-NMR(125MHz,DMSO-d 6)：δ212.31,166.11,105.77,81.94,63.23,60.78,22.99,14.59.
步骤B：氮气保护下，向反应瓶中加入二氯甲烷(10.0mL),2-(1-羟乙基)丁-2,3-二烯酸乙酯(210mg)，冰浴下加入4-甲基苯磺酰基异氰酸酯(292mg)，加毕后转至室温反应1.0h，反应结束后缓慢倒入50mL冰水中淬灭，用DCM(2*50mL)萃取，合并有机层，用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2-(1-((甲苯磺酰基氨基)氧基)乙基)丁-2，3-二烯酸乙酯(270mg)。 1H-NMR(500MHz,CDCl 3):δ7.92(d,J＝8.5Hz,2H),7.70(br,1H),7.33(d,J＝8.0Hz,2H),5.55-5.58(m,1H),5.22-5.30(m,2H),4.12(q,J＝7.5Hz,2H),2.44(s,3H),1.37(d,J＝6.5Hz,3H),1.20(t,J＝7.0Hz,3H). 13C-NMR(125MHz,CDCl 3):δ212.95,164.70,149.52,144.97,135.60,129.54,128.44,102.01,82.23,69.79,61.32,21.66,19.10,14.06.MS(ESI+,[M+H] +)m/z:354.3.
步骤C：氮气保护下，向反应瓶中加入苯(8.0mL)，2-(1-((甲苯磺酰基氨基)氧基)乙基)丁-2,3-二烯酸乙酯(270mg)，室温下缓慢滴加1,4-二氮杂双环[2.2.2]辛烷(83mg)的苯(8.0mL)溶液，滴加过程持续5.0h，滴毕后反应16.0h，反应结束后缓慢倒入50mL冰水中淬灭，用乙酸乙酯(2*50mL)萃取，合并有机层，用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＝5:1)，制得2-(1-((4-甲基苯基)磺酰氨基)乙基)丁-2,3-二烯酸乙酯(110mg)。 1H-NMR(500MHz,DMSO-d 6):δ7.70(d,J＝8.0Hz,2H),7.26(t,J＝4.0Hz,2H),5.28(d,J＝10.0Hz,1H),5.05(dd,J 1＝14.5Hz,17.0Hz,2H),4.26-4.20(m,1H),4.08(dd,J 1＝7.0Hz,14.0Hz,2H),2.41(s,3H),1.35(d,J＝7.0Hz,3H),1.20(t,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6):δ212.14,165.46,143.17,138.08,129.42,127.23,101.44,80.60,61.15,49.86,22.09,21.51,14.09.MS(ESI+,[M+Na] +)m/z:332.3.
步骤D：氮气保护下，向250ml单口瓶中加入乙醚(80mL)，2-(1-((4-甲基苯基)磺酰氨基)乙基)丁-2,3-二烯酸乙酯(6.26g)，N-氟-N-(苯磺酰基)苯磺酰胺(9.57g)，硝酸银(0.687g)，碳酸钾(5.59g)，体系遮光，在室温下搅拌反应过夜。反应结束将反应物倒入水(100ml)中，用乙酸乙酯(100ml*2)进行萃取，合并有机层， 用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，所得粗品通过硅胶柱层析分离(PE:EA＝10:1)，制得4-氟-2-甲基-1-甲苯磺酰基-2,5-二氢-1H-吡咯-3-羧酸乙酯(4.1g)。 1H-NMR(500MHz,DMSO-d 6):δ7.72(d,J＝8.0Hz,2H),7.33(d,J＝7.5Hz,2H),4.68(d,J＝4.5Hz,1H),4.28-4.15(m,4H),2.44(s,3H),1.56(d,J＝6.0Hz,3H),1.27(t,J＝6.5Hz,3H). 13C-NMR(125MHz,DMSO-d 6,):δ161.09,160.62,158.70,144.24,134.01,130.08,129.86,127.50,110.60,60.97,50.48,50.26,22.37,21.57,14.09.MS(ESI+,[M+Na] +)m/z:350.08.
步骤E：向反应瓶中加入二甲亚砜(70mL)，4-氟-2-甲基-1-甲苯磺酰基-2,5-二氢-1H-吡咯-3-羧酸乙酯(3.52g)，叔丁醇钾(3.62g)，将反应体系加热至50℃反应1h。反应结束后将反应液加入水(100mL)中，二氯甲烷(100mL*2)萃取，合并有机层，用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，所得粗品通过硅胶柱层析分离(PE:EA＝4:1)，制得4-氟-2-甲基-1H-吡咯-3-羧酸乙酯(0.2g)。 1H-NMR(500MHz,DMSO-d 6):δ11.40(s,1H),7.28(s,1H),4.45(s,2H),2.80(s,3H),1.49(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ168.09,137.93,124.48,109.14,103.49,60.01,15.26,14.60.MS(ESI+,[M+Na] +)m/z:194.04.
步骤F：向反应瓶中加入DMF(20mL)，4-氟-2-甲基-1H-吡咯-3-羧酸乙酯(0.2g)，碘甲烷(199mg)，冰浴下缓慢加入钠氢(56mg)。加毕转至室温反应1.0h，反应结束后将反应液加入冰水(50mL)中，用乙酸乙酯(50mL*2)进行萃取，合并有机层，用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，所得粗品通过硅胶柱层析分离(PE:EA＝20:1)，制得4-氟-1,2-二甲基-1H-吡咯-3-羧酸乙酯(169mg)。 1H-NMR(500MHz,CDCl 3)：δ6.27(s,1H),4.30(d,J＝6.5Hz,2H),3.47(s,3H),2.46(s,3H),1.35(d,J＝6.5Hz,3H). 13C-NMR(125MHz,CDCl 3)：δ164.04,151.11,149.14,132.92,104.86,59.46,33.67,14.46,10.94.MS(ESI+,[M+Na] +)m/z:208.7.
步骤G：向反应瓶中加入四氢呋喃(12mL)，4-氟-1,2-二甲基-1H-吡咯-3-羧酸乙酯(200mg)，5-氨基-2-氟苯腈(170mg)，冰浴下缓慢加入双(三甲基甲硅烷基)氨基化锂(415mg,2.7mL四氢呋喃溶液)。加毕转至室温反应2.0h，反应结束后将反应液加入冰水(50mL)中，用乙酸乙酯(50mL*2)进行萃取，合并有机层，用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，所得粗品通过硅胶柱层析分离(PE：EA＝1:1)，制得N-(3-氰基-4-氟苯基)-4-氟-1,2-二甲基-1H-吡咯-3-甲酰胺(200mg)。 1H-NMR(500MHz,DMSO-d 6)：δ9.53(s,1H),8.19(d,J＝3.0Hz,1H),7.97(d,J＝4.0Hz,1H),7.49(t,J＝9.0Hz,1H),6.74(s,1H),3.49(s,3H),2.36(s,3H). 13C-NMR(125MHz,DMSO-d 6)：δ148.76,146.25,136.94,131.34,127.72,124.14,117.36,114.53,105.51,104.07,33.84,10.89.MS(ESI+,[M+H] +)m/z:276.03.
步骤H：氮气保护下，向反应瓶中加入氧化锌(20mg)，氯草酸单乙酯(1.38g)，冰浴下分批加入N-(3-氰基-4-氟苯基)-4-氟-1,2-二甲基-1H-吡咯-3-甲酰胺(140mg)，加毕后反应2.0h。反应结束后缓慢倒入50mL冰水中淬灭，用DCM(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，抽滤，滤液减压旋蒸除去溶剂，所得粗品通过硅胶柱层析分离(DCM:MeOH＝10:1)，制得2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3-氟-1,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(120mg)。MS(ESI+,[M+Na] +)m/z:398.10.
步骤I：冰浴下，向反应瓶中，加入四氢呋喃(3.0mL)，2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3-氟-1，5-二甲基-1H-吡咯-2-基)-2-氧代乙酸乙酯(120mg)，滴加氢氧化锂一水合物(19.2mg)的水(5.0mL)溶液，加毕后转至室温反应10分钟。向反应液中加入水(40mL)及乙酸乙酯(30mL)，分层，弃去有机层，水层用浓盐酸调pH至约2，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，抽滤，滤液减压蒸除溶剂，得2-(4-(3-氰基-4-氟苯基)氨基甲酰基)-3-氟-1,5-二甲基-1H-吡咯-2-基)-2-氧 代乙酸(38.0mg)。MS(ESI-,[M-H] -)m/z:346.3.
步骤J：向反应瓶中依次加入N,N-二甲基甲酰胺(5.0mL)，2-(4-(3-氰基-4-氟苯基)氨基甲酰基)-3-氟-1,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸(38.0mg)，HATU(54mg)，DIPEA(32.5mg)，再加入(S)-1,1,1-三氟丙-2-胺盐酸盐(20mg)，室温搅拌2.0h。向反应液中加入水(50mL)，用乙酸乙酯(2*50mL)萃取，合并有机层，用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(S)-N-(3-氰基-4-氟苯基)-4-氟-1,2-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(21mg)。 1H-NMR(500MHz,DMSO-d 6)：δ10.25(s,1H),9.36(d,J＝8.5Hz,1H),8.17(d,J＝3.0Hz,1H),7.95(d,J＝4.5Hz,1H),7.52(t,J＝9.0Hz,1H),4.67(d,J＝6.5Hz,1H),3.83(s,3H),2.47(s,3H),1.30(d,J＝6.5Hz,3H). 13C-NMR(125MHz,DMSO-d 6)：δ165.87,160.43,159.84,142.17,136.38,128.03,124.58,117.55,114.40,112.50,105.68,100.33,93.06,88.16,45.75,33.16,13.78,11.38.MS(ESI-,[M-H] -)m/z:441.4.
实施例55 2-氯-N-(3-氰基-4-氟苯基)-5-(2-((3-羟基-1-甲基环丁基)氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000164
室温下，反应瓶中，依次加入2-(5-氯-4-((3-氰基-4-氟苯基)氨基甲酰基)-1,3-二甲基-1H-吡咯-2-基)-2-氧代乙酸(500mg)、DCM(25mL)及HOBt(211mg)，加料完毕，继续室温搅拌30分钟。然后向反应液中加入DMAP(16.79mg)、3-氨基-3-甲基环丁-1-醇盐酸盐(189mg)及DIPEA(0.24mL)，冰浴降温搅拌20分钟，向上述反应液中，加入DCC(312mg)的DCM(20mL)溶液，撤去冰浴，室温搅拌过夜。反应结束，浓缩除去溶剂，向剩余物加入EA(150mL)和水(30mL)，分离有机层，有机相分别用1N盐酸(30mL*2)和水(30mL*3)洗涤，无水硫酸钠干燥，抽滤，浓缩，柱层析纯化得到2-氯-N-(3-氰基-4-氟苯基)-5-(2-((3-羟基-1-甲基环丁基)氨基)-2-氧代乙酰基)-1,4-二甲基-1H-吡咯-3-甲酰胺(201mg)。 1H-NMR(500MHz,DMSO-d 6):δ10.56(s,1H),8.97(s,1H),8.20-8.19(m,1H),7.95-7.94(m,1H),7.54(t,J＝9.5Hz,1H),5.58-5.57(d,J＝8.0Hz,1H),5.10-5.08(m,1H),3.84(s,3H),2.29(s,3H),1.73-1.71(m,2H),1.63-1.61(m,2H),1.37(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ181.94,165.27,161.76,159.85,157.84,157.11,136.47,130.28,127.26,126.33,123.79,119.01,117.75,114.37,100.55,61.49,45.82,34.18,25.90,24.92,11.58.MS(ESI+,[M+H] +)m/z：447.1.
实施例56 ((S)-N-(3-氰基-4-氟苯基)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-(1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000165
步骤A：向反应瓶中加入N,N-二甲基甲酰胺(15mL)，5-(2-乙氧基-2-氧代乙酰基)-1,2-二甲基-1H-吡咯-3-羧酸乙酯(1.0g)，1-氯吡咯烷-2,5-二酮(0.6g)，室温下反应24.0h。反应结束后将反应液加入冰水(50mL)中，用乙酸乙酯(50mL*2)进行萃取，合并有机层，用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，所得粗品通过硅胶柱层析分离(PE：EA＝20:1)，制得2-(氯甲基)-5-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸乙酯(350mg)。
1H-NMR(500MHz,DMSO-d 6)：δ7.52(s,1H),5.22(s,2H),4.36(q,J＝7.0Hz,2H),4.27(q,J＝7.0Hz,2H),3.96(s,3H),1.29-1.33(m,6H). 13C-NMR(125MHz,DMSO-d 6)：δ175.76,162.87,142.45,127.70,124.76,114.78,62.79,60.70,34.23,14.59.
步骤B：冰浴下，向反应瓶中，加入MeOH(9.0mL)，2-(氯甲基)-5-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-3-羧酸乙酯(1.00g)，氢氧化锂一水合物(0.143g)的水(9.0mL)溶液，加毕后转至室温反应10分钟。向反应液中加入水(100mL)及乙酸乙酯(100mL)，分层，弃去有机层，水层用浓盐酸调pH至约2，用乙酸乙酯(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，抽滤，滤液减压蒸除溶剂，得2-(4-(乙氧基羰基)-5-(甲氧基甲基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸(684mg)。MS(ESI-,[M-H] -)m/z:268.3.
步骤C：向反应瓶中依次加入N,N-二甲基甲酰胺(3.0mL)，2-(4-(乙氧基羰基)-5-(甲氧基甲基)-1-甲基-1H-吡咯-2-基)-2-氧代乙酸(100mg)，HATU(184mg)，DIPEA(106mg)，再加入(S)-1,1,1-三氟丙-2-胺盐酸盐(66mg)，室温搅拌2.0h。向反应液中加入水(50mL)，用乙酸乙酯(2*50mL)萃取，合并有机层，用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＝5:1)，制得(S)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯。 1H-NMR(500MHz,DMSO-d 6)：δ9.38(d,J＝9.0Hz,1H),7.54(s,1H),4.86(s,2H),4.69-4.76(m,1H),4.22-4.26(m,2H),3.93(s,3H),3.29(s,3H),1.33(d,J＝7.0Hz,3H),1.28(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d6)：δ179.38,164.51,163.30,143.21,129.44,127.52,124.96,122.71,115.32,62.15,60.39,58.07,64.44,34.21,14.60.MS(ESI-,[M-H] -)m/z:363.4.
步骤D:反应瓶中，依次加入MeOH(5.0mL)，(S)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(150mg)，室温下加入氢氧化钠(33mg)的水(5mL)溶液，将混合物加热至80℃反应4.0h。反应结束后，用浓盐酸调pH至2，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，得到(S)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(256mg)。 1H-NMR(500MHz,DMSO-d 6)：δ12.57(s,1H),9.37(d,J＝9.0Hz,1H),7.48(s,1H),4.87(s,2H),4.70-4.74(m,1H),3.29(s,3H),3.28(s,3H),1.33(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d 6)：δ179.59,164.89,143.21,127.34,125.17,116.24,62.13,58.03,46.15,34.17,13.50.MS(ESI-,[M-H] -)m/z:335.3.
步骤E:反应瓶中，依次加入甲苯(10mL)，(S)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(250mg)，氯化亚砜(1.84g)，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，收酰氯中间体(297mg)。在室温下，将酰氯中间体(297mg)溶于N,N-二甲基乙酰胺(5mL)，向体系中加入5-氨基-2-氟苯腈(100mg)，升温至100℃反应0.5h。反应结束后降至室温，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＝3：1)洗脱，得到(S)-N-(3-氰基-4-氟苯基)-2-(甲氧基甲基)-1-甲基-5-(2-氧代-2-(1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(280mg)。 1H-NMR(500MHz,DMSO-d 6)：δ10.37(s,1H),9.40(d,J＝9.0Hz,1H),8.23-8.24(m,1H),8.01-8.04(m,1H),7.92(s,1H),7.52(t,J＝9.5Hz,1H),4.90-4.95(m,2H),4.70-4.76(m,1H),3.95(s,3H),3.29(s,3H),1.36(d,J＝7.0Hz,3H). 13C-NMR(125MHz,DMSO-d6):δ179.16,164.49,162.69,159.69,157.69,143.05,136.68,128.12,127.18,124.70,122.77,118.66,117.40,114.45,100.26,62.28,58.10,46.27,34.21,13.63.MS(ESI-,[M-H] -)m/z:453.4.
实施例57 (S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)--1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000166
步骤A：冰浴中，N 2保护下，反应瓶中依次加入2-氯-2-氧代乙酸乙酯(40.8g)和氧化锌(1.22g)，然后加入2,4-二甲基-1H-吡咯-3-羧酸乙酯(5g)，加料完毕，混合物在冰浴下搅拌10分钟，撤去冰浴，室温搅拌。反应结束，将反应液缓慢滴加到200mL冰水混合物中，加入EA(200mL)，分层，有机相用无水硫酸钠干燥，浓缩，柱层析制备得到5-(2-乙氧基-2-氧代乙酰基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯(4.5g)。MS(ESI+,[M+Na] +)m/z：290.07。
步骤B:反应瓶中，依次加入5-(2-乙氧基-2-氧代乙酰基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯(3.5g)、MeOH(40mL)，冰浴下滴加氢氧化钠(1.05g)的水(20mL)溶液，室温下搅拌。反应结束，用2N盐酸水溶液调节水相pH为3-4，加入EA(100mL*2)萃取，有机相用水(30mL)洗涤，浓缩，得到2-(4-(乙氧基羰基)-3,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸(2.7g)。MS(ESI-,[M-H] -)m/z：238.1.
步骤C:室温下，向反应瓶中,依次加入2-(4-(乙氧基羰基)-3,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸(1g)、DMF(20mL)、HATU(2.07g)及DIPEA(1.08g)，加料完毕，室温下搅拌10分钟，加入(S)-1,1,1-三氟丙-2-盐酸盐(0.63g)。反应结束，将反应液倒入50mL水中，EA(50mL*3)萃取，有机相用饱和硫酸钠水溶液(50mL*3)洗涤，无水硫酸钠干燥，过滤，收集滤液，浓缩、经柱层析纯化，得到(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(0.5g)。MS(ESI-,[M-H] -)m/z：333.4.
步骤D:反应瓶中，加入(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(300mg)、MeOH(2mL)、加入NaOH(72mg)的水(1mL)溶液，加毕，加热反应温度至80℃反应过夜。反应结束，浓缩，然后加入水(20mL)及EA(60mL)，分离水层，有机相加水(30mL)洗涤，分层，合并水相，用2N盐酸调节水相，使pH为3左右，然后加入EA(100mL*2)萃取，分层，浓缩有机相，得到(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(230mg)。MS(ESI-,[M-H] -)m/z：305.4.
步骤E:室温下，向反应瓶中依次加入(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(230mg)、DMF(5mL)、HATU(428mg)及DIPEA(194mg)，加料完毕，搅拌10分钟，再加入5-氨基-2-氟苄腈(123mg)，加热40℃搅拌反应20小时。反应结束，加入水(20mL)及EA(60mL)，分层，无水硫酸钠干燥，过滤，收集滤液，旋干，拌样，柱层析纯化得到(S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)--1H-吡咯-3-甲酰胺(180mg)。MS(ESI-,[M-H] -)m/z：423.0。
实施例58 (S)-N-(4-氟-3-(甲基磺酰氨基)苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000167
向反应瓶中加入(S)-N-(3-氨基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(实施例42化合物，150mg)，DMF(5mL)，甲基磺酰氯(50mg)，室温搅拌过夜，反应结束后缓慢倒入20mL水中，用乙酸乙酯(3*20mL)萃取，合并有机层，用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(DCM：MeOH＝20:1)，制得(S)-N-(4-氟-3-(甲基磺酰氨基)苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(45mg)。MS(ESI-,[M-H] -)m/z:505.3.
实施例59 (S)-N-(3-乙酰氨基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000168
参考实施例58，用乙酰氯替代甲基磺酰氯，制得(S)-N-(3-乙酰氨基-4-氟苯基)-1,2,4-三甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。MS(ESI-,[M-H] -)m/z:469.3.
实施例60 (S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-1-(甲基–d3)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019080412-appb-000169
步骤A:氮气保护下，向反应瓶中，加入N,N-二甲基甲酰胺(150mL)，2,4-二甲基-1H-吡咯-3-羧酸乙酯(10.0g)，碘甲烷-d 3(10.4g)，冰浴下分批加入钠氢(2.857g)，加毕后转至室温反应1.5h。反应结束后缓慢倒至500mL冰水中淬灭，乙酸乙酯(2*300mL)萃取，合并有机层，饱和氯化钠水溶液洗，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(石油醚:乙酸乙酯＝50:1)，制备得到2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-羧酸乙酯(9.7g)。
1H-NMR(500MHz,DMSO-d6)：δ6.44(s,1H),4.19(q,J＝7.0Hz,2H),2.39(s,3H),2.09(s,3H),1.25(t,J＝7.0Hz,3H).MS(ESI+,[M+H] +)m/z:185.1.
步骤B:氮气保护下，向反应瓶中，加入四氢呋喃(100mL)，2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-羧酸乙酯(9.50g)，5-氨基-2-氟苯腈(8.7g)，冰浴下缓慢滴加双(三甲基甲硅烷基)氨基锂(21.5g,129mL四氢呋喃溶液)，加毕后转至室温反应4.0h。反应结束后缓慢倒至600mL冰水中淬灭，过滤，滤饼用石油醚(50mL)和乙酸乙酯(50mL)混合溶剂打浆16.0h，过滤，滤饼真空干燥得到N-(3-氰基-4-氟苯基)-2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-甲酰胺(10.2g)。
1H-NMR(500MHz,DMSO-d 6)：δ9.65(s,1H),8.18(t,J＝3.5Hz,1H),7.93-7.96(m,1H),7.48(t,J＝9.0Hz,1H),6.49(s,1H),2.29(s,3H),2.10(s,3H).MS(ESI-,[M-H] -)m/z:273.3.
步骤C:(化合物IV)氮气保护下，冰浴下，向反应瓶中，加入氧化锌(1.48g)，氯草酸单乙酯(100g)，搅拌5分钟后分批加入N-(3-氰基-4-氟苯基)-2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-甲酰胺(10.0g)，加毕后转至室温反应3.0h。反应结束后缓慢倒入400mL冰水中淬灭，用二氯甲烷(2*300mL)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。反应混合物经硅胶柱色谱(二氯甲烷:甲醇＝100:1)分离，得到2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-基)-2-氧代乙酸乙酯(4.5g)。
1H-NMR(500MHz,DMSO-d 6)：δ10.37(s,1H),8.21-8.20(m,1H),7.93(s,1H),7.53(t,J＝9.0Hz,1H),4.35(d,J＝7.5Hz,2H),2.36(s,3H),2.19(s,3H),1.32(t,J＝7.0Hz,3H).MS(ESI+,[M+Na] +)m/z:397.2.
步骤D:向反应瓶中，加入2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-基)-2-氧代乙酸乙酯(4.5g)，四氢呋喃(35mL)，冰浴下，缓慢滴加氢氧化锂一水合物(1.02g)的水(50mL)溶液，加毕后转至室温反应0.2h。向反应液中加入水(40mL)，二氯甲烷(50mL)，分层，弃去有机层，水层用浓盐酸调pH至约4，过滤，滤饼真空干燥，得到2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-基)-2-氧代乙酸(3.8g)。
1H-NMR(500MHz,DMSO-d 6)：δ10.34(s,1H),8.21-8.19(m,1H),7.96-7.94(m,1H),7.52(t,J＝9.0Hz,1H),2.35(s,3H),2.27(s,3H).MS(ESI+,[M+H] +)m/z:347.1.
步骤E:氮气保护及冰浴下，向反应瓶中，加入N，N-二甲基甲酰胺(50mL)，2-(4-((3-氰基-4-氟苯基)氨基甲酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-基)-2-氧代乙酸(3.8g)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.4g)，(S)-1,1,1-三氟丙-2-胺盐酸盐(1.96g)，搅拌2分钟，加入N,N-二异丙基乙胺(3.2g)，加毕后转至室温搅拌4.0h。向反应液中加入水(150mL)，用乙酸乙酯(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(二氯甲烷:甲醇＝20:1)分离，得到(S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-1-(甲基–d3)-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(3.95g)。
1H-NMR(500MHz,DMSO-d 6)：δ10.32(s,1H),9.40(d,J＝9.0Hz,1H),8.20(t,J＝3.0Hz,1H),7.94(s,1H),7.52(t,J＝9.5Hz,1H),4.74-4.79(m,1H),2.36(s,3H),2.21(s,3H),1.31(d,J＝7.0Hz,3H).MS(ESI +,[M+H] +)m/z:442.1.
实验例1.体外活性研究
1.1体外细胞HBV DNA抑制活性
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。
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。结果如表1及表2所示。
1.2体外细胞毒性
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。结果如表3所示。
表1及表2，其中A表示EC50≤10nM，B表示10nM＜EC50≤50nM，C表示50nM＜EC50≤100nM。
表1.HepAD38细胞中抗HBV活性实验结果
实施例编号 EC50 实施例编号 EC50 实施例编号 EC50
1 B 6 B 11 A
2 A 7 A 12 A
3 C 8 A 13 A
4 B 9 A 14 B
5 B 10 B 15 A
20 B 26 C 32 A
21 B 27 B 34 B
22 B 28 B 35 A
23 A 29 A 36 A
24 A 30 B 37 A
25 A 31 A 50 C
38 A 45 B 54 B
39 A 46 B 55 B
42 B 47 A 60 A
表2.HepG2.2.15细胞中抗HBV活性实验结果
实施例编号 EC50 实施例编号 EC50 实施例编号 EC50
1 B 12 A 23 A
2 A 15 B 24 A
6 B 16 A 25 A
7 B 17 B 26 C
8 A 20 C 27 B
9 B 21 C 29 B
11 A 22 B 30 A
38 A 45 A 54 A
39 A 46 A 55 B
42 A 47 A    
表3
Figure PCTCN2019080412-appb-000170
Figure PCTCN2019080412-appb-000171
1.3CYP450酶诱导研究
500μL最终的温孵体系中，含50μL肝微粒体(蛋白浓度：0.2mg/mL)，1μL混合的CYP450特异性底物(CYP1A2、CYP 2B6、CYP 2C9、CYP2C19、CYP 2D6、CYP 3A4)，398μL PBS缓冲液(PH7.4)，1μL特异性阳性抑制剂(阳性对照组)或受试化合物(乙腈配制)，50μL NADPH+MgCl 2。每个CYP450亚型做2份，每份0.5mL。每管先配好总体积为450μL的底物和酶的混匀液及NADPH分别在37℃预温孵5min后，加入50μL NADPH+MgCl 2混合溶液反应，于30min取出50μL用含内标的冰乙腈300μL终止反应。另外平行做2份空白组各500μL，不加NADPH，作为阴性对照组。
样品前处理：50μL温孵样品，加入300μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水，稀释混匀，1μL进样分析。结果见表4。
表4
Figure PCTCN2019080412-appb-000172
1.4血浆蛋白结合试验
血浆样品配制：分别吸取495μL相应种属(小鼠、大鼠、犬、猴及人)的空白血浆，加入5μL相应受试化合物溶液或阳性对照，即得血浆样品溶液，使化合物血浆药物浓度分别为1μM、10μM(乙腈配制)。
预处理好的透析膜置于高通量平衡透析装置中，吸取100μL血浆样品溶液及PBS缓冲液，分别加到透析膜的两侧(样品侧及缓冲液侧)(n＝3)，用贴膜将平衡装置封好后，放入37℃温孵过夜(100rpm)，达到透析平衡后，分别从样品侧及缓冲液侧吸取50μL样品，用含内标的冰乙腈终止反应。
样品前处理：50μL血浆侧样品，加入450μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水稀释混匀，1μL进样分析；50μLPBS侧样品，加入250μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水稀释混匀，2μL进样分析。结果见表5。
表5
Figure PCTCN2019080412-appb-000173
实验例2 体外肝微粒体稳定性
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。
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。结果见下表6-1、6-2、6-3。
表6-1体外人肝微粒体稳定性
实施例编号 60min剩余量(％) 实施例编号 60min剩余量(％)
1 69 12 78.8
6 79.1 29 99.6
7 83.8 42 102
8 70.6 45 73
表6-2体外大鼠肝微粒体稳定性
实施例编号 60min剩余量(％) 实施例编号 60min剩余量(％)
1 44 12 65.0
6 74.9 17 44.9
7 70.5 25 52.0
8 52.0 29 88.7
11 56.8 42 85.3
45 47    
表6-3体外小鼠肝微粒体稳定性
实施例编号 60min剩余量(％) 实施例编号 60min剩余量(％)
6 55 17 47.4
7 81.6 25 50.8
11 47.7 29 99.2
12 67.1 42 61.9
实验例3 在pH 7.4的PBS缓冲液中溶解度
1000μL最终的体系中，含990μL pH7.4的PBS缓冲液，10μL受试化合物(乙腈配制)。放入25℃静置16h后离心(12000rpm，室温)10min，取出20μL上清液，用含内标(地西泮20ng/mL)的乙腈400μL终止反应。吸取上清液30μL，加入150μL50％乙腈水稀释混匀，0.5μL进样分析。结果见表7。
表7
实施例编号 溶解度(μM) 实施例编号 溶解度(μM)
2 22.1 9 9.6
6 81.8 11 7.5
7 19.8 12 8.1
8 80.9 15 4.9
实验例4：体内动物药效
4.1AAV小鼠模型评价抗病毒效果
取6-8周龄雄性C57BL/6小鼠，按照1×10 11vg剂量，尾静脉注射rAAV8-1.3HBV病毒(adr亚型)至C57BL/6小鼠体内。注射病毒第2、4周，小鼠眼眶采血，分离血清，测定血清中HBeAg和HBsAg表达水平以及HBV DNA拷贝数，判断模型构建成功与否。结合血清学HBeAg、HBsAg和HBV DNA的定量检测结果，挑选出的小鼠各自HBV DNA表达水平都大于1×10 4IU/mL，HBeAg大于1×10 3NCU/mL和HBsAg大于1×10 3ng/mL。小鼠进行分组，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2-3周，每日1次。实验过程中，隔周分别眼眶采血，分离血清，荧光定量PCR方法检测DNA含量。
表8 血清中HBV DNA下降水平(log10)(给药24天，给药剂量30mpk)
实施例编号 第7天 第14天 第21天 第28天
12 2.42 3.46 5.08 2.48
25 1.16 1.76 2.89 1.28
4.2HDI小鼠模型评价抗病毒效果
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9。
表9
实施例编号 第5天血清中HBV DNA下降水平(log10)
12 2.17
25 1.73
实验例5 体内药物代谢动力学
5.1小鼠体内药物代谢动力学(PK)研究
ICR小鼠，体重18～20g，适应3～5天后，随机分组，每组3只，按30mg/kg剂量分别灌胃系列化合物。
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。
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。
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10及表11。
表10
Figure PCTCN2019080412-appb-000174
注：取血时间点为0.25h、3h、8h
表11
Figure PCTCN2019080412-appb-000175
注：取血时间点为0.25h、1h、6h
5.2大鼠体内药物代谢动力学(PK)研究
SD大鼠，体重180～220g，适应3～5天后，随机分组，每组3只，按20mg/kg剂量分别灌胃系列化合物。
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。
给药后，于0min、15min、30min、1h、2h、4h、6h、8h、10h、24h、30h、48h于眼眶取血0.2mL左右，EDTA-K2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。
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12。
表12
Figure PCTCN2019080412-appb-000176
Figure PCTCN2019080412-appb-000177
NA表示未检测
5.3比格犬体内药物代谢动力学(PK)研究
比格犬，体重9～11Kg，随机分为两组，每组3只，按5mg/kg剂量分别灌胃化合物12。
受试动物(比格犬)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。
灌胃给药后，于0min、15min、30min、1h、2h、4h、6h、8h、10h、24h、48、72h于左前肢静脉采集全血0.5mL左右于EDTA-K2抗凝的真空采血管内，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。收集全部血浆后立即于-20℃保存待测。
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13。
表13
实施例编号 12
给药方式及剂量 PO 5mg/kg
T max(h) 1.67
C max(ng/mL) 1282
AUC (0-72h)(ng*h/mL) 61881
AUC (0-∞)(ng*h/mL) 162075
T1/2(h) 105.2
MRT(0-t)(h) 32.9

Claims (21)

  1. 式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019080412-appb-100001
    其中，
    X和Y各自独立地表示CR 7，所述R 7独立地选自氢、C 3-4环烷基、-CN、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自氟、氯、溴、C 1-6烷氧基、-OH、-NH 2或-CN的基团取代；
    环A选自苯基或5-10元杂芳基；
    R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基、-NH 2、C 3-4环烷基、-NHR a或-NR bR c，其中R a、R b、R c分别独立地选自-C(O)C 1-6烷基、C 1-6烷基、-S(O) 2C 1-6烷基、5-10元杂芳基、C 6-10芳基、C 3-6环烷基或3-6元杂环烷基；
    R 4选自氢、C 1-3烷基或C 3-4环烷基；
    R 5选自C 1-6烷基、C 2-6烯基、C 2-6炔基、3-7元环烷基或3-7元杂环烷基，所述C 1-6烷基、C 2-6烯基、C 2-6炔基、3-7元环烷基或3-7元杂环烷基任选地被以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN或-OH取代的C 1-3烷基；
    R 8各自独立地选自氢或C 1-3烷基。
  2. 如权利要求1所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中:
    R a选自-C(O)C 1-3烷基、C 1-3烷基、-S(O) 2C 1-3烷基、5-6元杂芳基、C 6-10芳基、C 3-6环烷基、或3-6元杂环烷基；
    任选地，R a选自-C(O)C 1-3烷基、C 1-3烷基、或-S(O) 2C 1-3烷基；
    任选地，R a选自-C(O)CH 3、或-S(O) 2CH 3。
  3. 如权利要求1或2所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R b、R c各自独立地选自-C(O)C 1-3烷基、C 1-3烷基、-S(O) 2C 1-3烷基、5-6元杂芳基、C 6-10芳基、C 3-6环烷基、或3-6元杂环烷基；
    任选地，R b、R c各自独立地选自-C(O)C 1-3烷基、C 1-3烷基、或-S(O) 2C 1-3烷基。
  4. 如权利要求1-3中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    X和Y各自独立地表示CR 7，所述R 7独立地选自氢、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个选自氟或C 1-3烷氧基的基团取代；
    任选地，R 7独立地选自氢、氟、氯、溴或任选地被一个或多个甲氧基取代的C 1-3烷基；
    任选地，R 7独立地选自氢、氟、氯、溴、-CH 2OCH 3或甲基；
    任选地，R 7独立地选自氢、氯、溴或甲基。
  5. 如权利要求1-3中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中X和Y各自独立地表示CR 7，所述R 7独立地选自氢、C3-4环烷基、-CN、氟、氯、溴或任选地被一个或多个氟取代的C1-3烷基；
    任选地，R 7独立地选自氢、氟、氯、溴或任选地被一个或多个氟取代的C 1-3烷基；
    任选地，R 7独立地选自氢、氟、氯、溴或C 1-3烷基；
    任选地，R 7独立地选自氢、氟、氯、溴或甲基。
  6. 如权利要求1-5中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中:
    环A选自苯基、5元杂芳基、6元杂芳基、7元杂芳基、8元杂芳基、9元杂芳基或10元杂芳基；
    任选地，环A选自苯基或6元杂芳基；
    任选地，环A选自苯基或吡啶基；
    任选地，环A选自苯基；
    任选地，环A的定义中出现的所述杂芳基含有1或2个N原子。
  7. 如权利要求1-6中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中:
    R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基、-NH 2或C 3-4环烷基；
    任选地，R 1、R 2和R 3各自独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基；
    任选地，R 1选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；
    任选地，R 1选自氢或氟。
  8. 如权利要求1-7中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中:
    R 2选自氢、氟、氯或溴；
    任选地，R 2选自氢或氟。
  9. 如权利要求1-8中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基、-NH 2或-NHR a；
    任选地，R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基、-NH 2、-NHC(O)CH 3、或-NHS(O) 2CH 3；
    任选地，R 3选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基或-NH 2；
    任选地，R 3选自氢、氟、氯、-CN、甲基或-NH 2。
  10. 如权利要求1-9中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R 1选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基，并且R 1和R 3中的至少一个是氟或氢。
  11. 如权利要求1-9中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R 1和R 3中的一个选自氢或氟，另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3、甲基或-NH 2；
    任选地，R 1和R 3中的一个是氢，另一个选自氟、氯、-CHF 2、-CN、-CF 3或甲基；
    任选地，R 2选自氟、氯或溴，R 1和R 3中的一个是氢，另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；
    任选地，R 2为氟，R 1和R 3中的一个是氢，另一个选自氟、氯或-CN；
    任选地，R 2为氟，R 1为氢，R 3为-CN或氯；
    任选地，R 2选自氟，R 1为氢，R 3为-CN。
  12. 如权利要求1-11中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R 4选自氢或C 1-3烷基；
    任选地，R 4为甲基或氢；
    任选地，R 4为甲基。
  13. 如权利要求1-12中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN或-OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，其中所述C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、3-4元环烷基、3-4元杂环烷基、-OR 8、氧代、-CN、-C(O)OR 8、-SO 2R 8、-C(O)N(R 8) 2或任选地被一个或多个氟、-CN、-OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、氧代、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：卤素、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，其中C 1-4烷基、C 2-4烯基、C 2-4炔基、4-6元环烷基或4-6元环烷基任选地被选自以下基团取代：卤素、-OH、-CN、-C(O)OR 8、-C(O)N(R 8) 2或任选地被一个或多个氟或OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、氧代、-OH、-C(O)N(R 8) 2、-C(O)OR 8或任选被一个或多个OH或氟取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，所述C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、-OH、-C(O)N(R 8) 2、-C(O)OR 8或任选被OH或氟取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基，其中C 1-4烷基、C 2-4炔基、4-6元环烷基或4-6元杂环烷基任选地被选自以下基团取代：卤素、-OH、-C(O)OR 8或任选被OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基或4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：卤素、-OH或-C(O)OR 8，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：氧代、-OH、氟、-C(O)N(R 8) 2或任选被一个或多个OH或氟取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、3-6元环烷基、4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：卤素、-OH或-C(O)OR 8，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：-OH、氟、-C(O)N(R 8) 2或任选被OH或氟取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 2-4炔基、4-6元环烷基、4-6元杂环烷基，其中C 1-4烷基任选地被选自以下基团取代：卤素、-OH或-C(O)OR 8，其中4-6元环烷基、4-6元杂环烷基任选地被选自以下基团取代：-OH或任选被OH取代的C 1-3烷基；
    任选地，R 5选自C 1-4烷基、C 3炔基、3-6元环烷基或4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：氟、-OH或-C(O)OCH 3，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：氧代、-OH、氟、-C(O)NHCH 3或任选被一个或多个OH或氟取代的甲基；
    任选地，R 5选自C 1-4烷基、C 3炔基、3-6元环烷基、4-6元杂环烷基，其中所述C 1-4烷基任选地被以下基团取代：氟、-OH或-C(O)OCH 3，其中所述3-6元环烷基或4-6元杂环烷基任选地被以下基团取代：-OH、氟、-C(O)NHCH 3或任选被OH或氟取代的甲基；
    任选地，R 5的定义中出现的所述杂环烷基含有1或2个选自N、O或S的杂原子。
  14. 如权利要求1-13中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中R 8选自氢或甲基。
  15. 如权利要求1-14中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    结构单元
    Figure PCTCN2019080412-appb-100002
    选自
    Figure PCTCN2019080412-appb-100003
    任选地，结构单元
    Figure PCTCN2019080412-appb-100004
    选自
    Figure PCTCN2019080412-appb-100005
    任选地，结构单元
    Figure PCTCN2019080412-appb-100006
    选自
    Figure PCTCN2019080412-appb-100007
    任选地，结构单元
    Figure PCTCN2019080412-appb-100008
    选自
    Figure PCTCN2019080412-appb-100009
    任选地，结构单元
    Figure PCTCN2019080412-appb-100010
    选自
    Figure PCTCN2019080412-appb-100011
    Figure PCTCN2019080412-appb-100012
  16. 如权利要求1-15中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    结构单元
    Figure PCTCN2019080412-appb-100013
    选自
    Figure PCTCN2019080412-appb-100014
    任选地，结构单元
    Figure PCTCN2019080412-appb-100015
    选自
    Figure PCTCN2019080412-appb-100016
    Figure PCTCN2019080412-appb-100017
  17. 如权利要求1-16中任一项所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中：
    结构单元
    Figure PCTCN2019080412-appb-100018
    选自
    Figure PCTCN2019080412-appb-100019
    Figure PCTCN2019080412-appb-100020
    Figure PCTCN2019080412-appb-100021
    任选地，结构单元
    Figure PCTCN2019080412-appb-100022
    选自
    Figure PCTCN2019080412-appb-100023
    Figure PCTCN2019080412-appb-100024
  18. 如权利要求1所述的式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其中所述式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐选自式II、式III或式IV化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019080412-appb-100025
    其中，R 1、R 2、R 3、R 4、R 5、X、Y的定义如权利要求1所述。
  19. 以下化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐：
    Figure PCTCN2019080412-appb-100026
    Figure PCTCN2019080412-appb-100027
    Figure PCTCN2019080412-appb-100028
  20. 药物组合物，其包含如权利要求1-19中任一项所述的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐；任选地，所述药物组合物还包含药学上可接受的辅料。
  21. 如权利要求1-19中任一项所述的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者如权利要求20所述的药物组合物在制备用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途。
PCT/CN2019/080412 2018-03-30 2019-03-29 含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途 WO2019185016A1 (zh)

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KR1020207031226A KR20200136994A (ko) 2018-03-30 2019-03-29 N-헤테로시클릭 5-원 고리-함유 캡시드 단백질 조립 억제제, 그의 약학적 조성물, 및 그의 용도
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JP2020552331A JP7434166B2 (ja) 2018-03-30 2019-03-29 Ｎ－複素環式５員環含有カプシドタンパク質のアセンブリの阻害剤、その医薬組成物および使用
EA202092159A EA202092159A1 (ru) 2019-01-25 2019-03-29 Содержащий n-гетероциклическое пятичленное кольцо ингибитор сборки капсидного белка, его фармацевтическая композиция и их применение
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CN113493441A (zh) * 2020-04-03 2021-10-12 广东东阳光药业有限公司 新型螺环类化合物及其在药物中的应用
WO2021197486A1 (zh) * 2020-04-03 2021-10-07 东莞市东阳光新药研发有限公司 新型螺环类化合物及其在药物中的应用
WO2023056933A1 (zh) * 2021-10-08 2023-04-13 正大天晴药业集团股份有限公司 包含衣壳蛋白抑制剂和逆转录酶抑制剂的药物组合

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