WO2023185793A1 - 含氮杂环类化合物、其制备方法及其在医药上的应用 - Google Patents

含氮杂环类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2023185793A1
WO2023185793A1 PCT/CN2023/084265 CN2023084265W WO2023185793A1 WO 2023185793 A1 WO2023185793 A1 WO 2023185793A1 CN 2023084265 W CN2023084265 W CN 2023084265W WO 2023185793 A1 WO2023185793 A1 WO 2023185793A1
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group
alkyl
heterocyclyl
cancer
cycloalkyl
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PCT/CN2023/084265
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French (fr)
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李心
王斌
董怀德
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Publication of WO2023185793A1 publication Critical patent/WO2023185793A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine and relates to a nitrogen heterocyclic compound, its preparation method and its application in medicine. Specifically, the present disclosure relates to a nitrogen-containing heterocyclic compound represented by general formula (I), its preparation method, pharmaceutical compositions containing such compounds, and its use as a therapeutic agent, especially as a HER2 inhibitor.
  • Human epidermal growth factor receptor 2 (HER2; Neu, ERBB2) is a member of the type I receptor tyrosine kinase family, which also includes EGFR (ERBB1), HER3 (ERBB3), and HER4 (ERBB4). So far, no ligand that can directly bind to HER2 has been found in the human body. HER2 must form a homologous or heterodimer with other members of the family (such as HER3). After dimerization, the conformation of HER2 changes and activates intracellular tyrosine. amino acid kinase activity, and then reactivate the downstream pathways (MAPK signaling pathway and PI3K/AKT signaling pathway), thereby exerting corresponding physiological effects.
  • ERBB1 EGFR
  • HER3 HER3
  • HER4 HER4
  • HER2 signaling is found in a variety of human malignancies, including oncogenic mutations in the extracellular, juxtamembrane, and intracellular regions of HER2. Collectively, these mutations confer sustained activity on HER2, promoting cancer initiation, tumor maintenance, and growth. Becomes the basis of tumor transformation and tumor maintenance in various tumors including breast, gastric or lung cancer. HER2 overexpression increases HER2 signaling, particularly in breast cancer, where HER2 amplification is associated with poorer survival outcomes. HER2 mutations account for 6-7% of all human cancers. Therefore, disrupting HER2 oncogenic signaling can effectively treat tumors driven by HER2 oncogenic mutations or HER2 wild-type amplification.
  • HER2 HER2-targeted antibody-drug conjugates
  • T-DM1 T-DM1
  • ado-trastuzumab emtansine small molecules that inhibit the HER2 kinase domain
  • HER2 can inhibit wild-type HER2, such as tucatinib
  • these inhibitors are not effective against HER2 harboring exon 20 mutations.
  • Mutation of exon 20 of the HER2 gene leads to enhanced kinase activity (Wang et al. Cancer Cell, 2006, 10(1):25-38).
  • This enhanced HER2 kinase activity enters downstream signaling cascades and stimulates tumor transformation by promoting cell growth, proliferation, and survival.
  • Genetic studies in mouse models have shown that the most prevalent HER2 exon 20 mutation in non-small cell lung cancer is the insertion of the four amino acids YVMA (p.A775_G776insYVMA), which can drive oncogenic growth.
  • HER2-YVMA expression resulted in tumor shrinkage, suggesting that this oncogenic variant of HER2 is required for tumor maintenance.
  • the broad-spectrum ERBB inhibitor afatinib can effectively interfere with the oncogenic signaling of HER2-YVMA in vivo conduction.
  • ERBB-targeted tyrosine kinase inhibitors are almost ineffective in these patients, primarily due to dose-limiting toxicity mediated by EGFR wild-type.
  • Alitinib, ibrutinib, neratinib, pozitinib, and pyrotinib are known broad-spectrum ERBB inhibitors of mutated HER2 exon 20.
  • afatinib and other broad-spectrum ERBB inhibitors have only shown limited efficacy in NSCLC patients with HER2 exon 20 mutations due to limited effective doses.
  • the purpose of the present invention is to provide new inhibitors of mutant HER2 exon 20 that are selective for EGFR wild-type.
  • Ring A is aryl or heteroaryl
  • Ring B is a 7- to 10-membered fused heterocyclyl group or a 7- to 10-membered bridged heterocyclyl group;
  • G is N or C( RA );
  • R A is selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups and amino groups;
  • V 1 is C(R a ) or N;
  • V 2 and V 3 are the same or different, and are each independently C(R a ) or N; alternatively, V 2 is C(R bb ), V 3 is C(R cc ), and R bb and R cc are each the same as
  • the attached carbon atoms together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally selected from the group consisting of halogen, alkyl, haloalkyl, Substituted with one or more substituents from hydroxyalkyl, alkoxy, haloalkoxy, cyano, hydroxyl, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • L 1 is selected from O, NR b1 , C(O), S, S(O) and S(O) 2 ;
  • L 2 is selected from O, NR b2 , C(O), (CR c R d ) u , (CR c R d ) u O, O(CR c R d ) u , (CR c R d ) u NR b2 , NR b2 (CR c R d ) u , C(O)NR b2 and NR b2 C(O);
  • E is a 9- to 10-membered heteroaryl group, and the 9- to 10-membered heteroaryl group is optionally substituted by one or more R 16 ;
  • R 16 is selected from halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR 4 , -OC( O)R 4 , -C(O)NR 5 R 6 , -S(O) p R 4 , -S(O) p NR 5 R 6 , cycloalkyl, heterocyclyl, aryl and heteroaryl,
  • the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently selected from the group consisting of oxo group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, Substituted with one or more substituents from aminoalkyl, cyano, -OR 4a , -NR 5a R 6
  • R a is selected from hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, haloalkyl group, hydroxyalkyl group, -OR e , -(CH 2 ) s -NR f R g , cycloalkyl group , heterocyclyl, aryl and heteroaryl;
  • R b1 and R b2 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;
  • R c and R d are the same or different, and are each independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyl groups and hydroxyalkyl groups;
  • R 1 is selected from hydrogen atoms, alkyl groups and cycloalkyl groups
  • Each R 2 is the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, cyano, nitro, haloalkyl, hydroxyalkyl, -OR 7 , -(CH 2 ) v -NR 8 R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 3 is the same or different, and each is independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR 13 C(O)OR 10 , -NR 13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , cycloalkyl, heterocyclyl, aromatic and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of oxo, halogen,
  • R 10 is the same or different each time it appears, and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R B ;
  • R B is selected from oxo, halogen, alkyl, alkenyl, alkynyl , cyano, -OR 10b , -NR 11b R 12b , -C(O)R 10b , -C(O)NR 11b R 12b , Cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxygen Substituted with one or more substituents of substituent, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyl, cyano and amino;
  • R e , R 4 , R 4a , R 7 , R 10a and R 10b are the same or different each time they appear, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycle base, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxo, halogen, alkyl One or more of base, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, hydroxyl, alkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by substituents;
  • R f , R g , R 5 , R 6 , R 8 , R 9 , R 11 and R 12 are the same or different at each occurrence, and are each independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups, heterocycles base, aryl and heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkyne base, Substituted with one or more substituents of haloalkyl, hydroxyalkyl, aminoalkyl, cyano, hydroxyl, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl ;
  • R f and R g together with the connected nitrogen atom form a heterocyclic group
  • R 5 and R 6 together with the connected nitrogen atom form a heterocyclic group
  • R 8 , R 9 together with the connected nitrogen atom form a heterocyclic group
  • the heterocyclic group is optionally selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, and hydroxyalkyl. , substituted by one or more substituents in aminoalkyl, cyano, hydroxyl, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 13 is the same or different on each occurrence, and is each independently selected from a hydrogen atom, an alkyl group and a cycloalkyl group;
  • R 5a , R 6a , R 11a , R 12a , R 11b and R 12b are the same or different each time they appear, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a ring Alkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl;
  • s 0, 1 or 2;
  • v 0, 1 or 2;
  • u 1, 2, 3 or 4;
  • p 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • n is an integer between 0 and 10.
  • Ring A is aryl or heteroaryl
  • Ring B is a 7- to 10-membered fused heterocyclyl group or a 7- to 10-membered bridged heterocyclyl group;
  • G is N or C( RA );
  • R A is selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, hydroxyalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, hydroxyl groups and amino groups;
  • V 1 , V 2 and V 3 are the same or different, and are each independently C(R a ) or N;
  • L 1 is selected from O, NR b1 , C(O), S, S(O) and S(O) 2 ;
  • L 2 is selected from O, NR b2 , C(O), (CR c R d ) u , (CR c R d ) u O, O(CR c R d ) u , (CR c R d ) u NR b2 , NR b2 (CR c R d ) u , C(O)NR b2 and NR b2 C(O);
  • E is a 9- to 10-membered heteroaryl group, and the 9- to 10-membered heteroaryl group is optionally substituted by one or more R 16 ;
  • R 16 is selected from halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR 4 , -OC( O)R 4 , -C(O)NR 5 R 6 , -S(O) p R 4 , -S(O) p NR 5 R 6 , cycloalkyl, heterocyclyl, aryl and heteroaryl,
  • the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are each independently selected from the group consisting of oxo group, halogen, alkyl group, haloalkyl group, hydroxyalkyl group, Substituted with one or more substituents from aminoalkyl, cyano, -OR 4a , -NR 5a R 6
  • R a is selected from hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, cyano group, nitro group, haloalkyl group, hydroxyalkyl group, -OR e , -(CH 2 ) s -NR f R g , cycloalkyl group , heterocyclyl, aryl and heteroaryl;
  • R b1 and R b2 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group;
  • R c and R d are the same or different, and are each independently selected from hydrogen atoms, halogens, alkyl groups, hydroxyl groups and hydroxyalkyl groups;
  • R 1 is selected from hydrogen atoms, alkyl groups and cycloalkyl groups
  • Each R 2 is the same or different, and each is independently selected from halogen, alkyl, alkenyl, alkynyl, cyano, nitro, haloalkyl, hydroxyalkyl, -OR 7 , -(CH 2 ) v -NR 8 R 9 , cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 3 is the same or different, and each is independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, cyano, nitro, -OR 10 , -NR 11 R 12 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -C(O)NR 11 R 12 , -NR 13 C(O)R 10 , -NR 13 C(O)OR 10 , -NR 13 C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , -NR 13 S(O) p R 10 , cycloalkyl, heterocyclyl, aromatic and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently selected from the group consisting of oxo, halogen,
  • R 10 is the same or different each time it appears, and is each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R B ;
  • R B is selected from oxo, halogen, alkyl, alkenyl, alkynyl , cyano, -OR 10b , -NR 11b R 12b , -C(O)R 10b , -C(O)NR 11b R 12b , Cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxygen Substituted with one or more substituents of substituent, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyl, cyano and amino;
  • R e , R 4 , R 4a , R 7 , R 10a and R 10b are the same or different each time they appear, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocycle base, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxo, halogen, alkyl One or more of base, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, hydroxyl, alkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by substituents;
  • R f , R g , R 5 , R 6 , R 8 , R 9 , R 11 and R 12 are the same or different at each occurrence, and are each independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups, heterocycles base, aryl and heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkyne
  • R f and R g together with the connected nitrogen atom form a heterocyclic group
  • R 5 and R 6 together with the connected nitrogen atom form a heterocyclic group
  • R 8 , R 9 together with the connected nitrogen atom form a heterocyclic group
  • the heterocyclic group is optionally selected from the group consisting of oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, and hydroxyalkyl. , substituted by one or more substituents in aminoalkyl, cyano, hydroxyl, alkoxy, haloalkoxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 13 is the same or different on each occurrence, and is each independently selected from a hydrogen atom, an alkyl group and a cycloalkyl group;
  • R 5a , R 6a , R 11a , R 12a , R 11b and R 12b are the same or different each time they appear, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, a ring Alkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl;
  • s 0, 1 or 2;
  • v 0, 1 or 2;
  • u 1, 2, 3 or 4;
  • p 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • n is an integer between 0 and 10.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, Ring A is phenyl.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein R A is selected from hydrogen atoms, halogens, C 1-6 alkyl groups and cyano groups; preferably , R A is cyano group.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein L 2 is O or (CR c R d ) u O, R c , R d and u As defined in general formula (I); preferably, L 2 is O or CH 2 O; more preferably, L 2 is O.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • r is 0 or 1;
  • Rings B, E, R2 , R3 , V1 , V2 , V3 , m and n are as defined in general formula (I).
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein V 1 , V 2 and V 3 are the same or different, and each is independently C(R a ) or N; R a is as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein Selected from R 3a is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Each heteroaryl group is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, -OR 10a , -NR 11a R 12a
  • Selected from R 3a is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 11 R 12 , -S(O) p R 10 , -S(O) p NR 11 R 12 , cycloalkyl, heterocyclyl, aryl and heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Each heteroaryl group is independently optionally selected from oxo, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, aminoalkyl, cyano, -OR 10a , -NR 11a R 12a , Substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and hetero
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein each R 3 is the same or different, and each is independently selected from halogen, C 1-6 alkyl, -OR 10 and -C(O)R 10 , the C 1-6 alkyl is optionally selected from halogen, cyano, -OR 10a , -NR 11a R 12a , 3 to Substituted with one or more substituents of 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; and R 10 , R 10a , R 11a and R 12a is as defined in general formula (I); preferably, R 3 is halogen or -C(O)R 10 ; and R 10 is as defined in general formula (I); more preferably, R 3 is -C( O) R 10 ; and R 10 is as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3a is C 1-6 alkyl or -C(O) R 10 , the C 1-6 alkyl group is optionally selected from halogen, cyano group, -OR 10a , -NR 11a R 12a , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to Substituted with one or more substituents of a 10-membered aryl group and a 5- to 10-membered heteroaryl group; and R 10 , R 10a , R 11a and R 12a are as in the general formula (I) Definition;
  • R 3a is -C(O)R 10
  • R 10 is as defined in general formula (I).
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3b is selected from halogen, C 1-6 alkyl, -OR 10 and -C(O)R 10 , the C 1-6 alkyl group is optionally selected from halogen, cyano group, -OR 10a , -NR 11a R 12a , 3 to 8-membered cycloalkyl, 3 to 8 substituted with one or more substituents of a 6- to 10-membered aryl group and a 5 to 10-membered heteroaryl group; and R 10 , R 10a , R 11a and R 12a are as in the general formula (I) Definition;
  • R 3b is halogen; more preferably, R 3b is fluorine.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof wherein for R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen;
  • R 3a Selected from R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen;
  • R 3a Selected from R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen; further preferably, for R 3a is -C(O)R 10 ; R 10 is C 2-6 alkenyl (preferably vinyl); most preferably, for
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof wherein for R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen;
  • R 3a Selected from R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen;
  • R 3a Selected from R 3a is -C(O)R 10 , and R 10 is as defined in general formula (I); R 3b is halogen; further preferably, for R 3a is -C(O)R 10 ; and R 10 is C 2-6 alkenyl (preferably vinyl); most preferably, for
  • R 10 is a C 2-6 alkenyl group, and the C 2-6 alkenyl group is optionally substituted by one or more R B ;
  • R B is selected from halogen, C 1-6 alkyl, 3 to 8 yuan Cycloalkyl and 3 to 8-membered heterocyclyl, the C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently selected from oxo group, halogen , substituted by one or more substituents in C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxyl, cyano and amino;
  • R 10 is a C 2-6 alkenyl group, and the C 2-6 alkenyl group is optionally substituted by one or more substituents selected from halogen or C 1-6 alkyl;
  • R 10 is C 2-6 alkenyl
  • R 10 is vinyl.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein R 10a and R 10b are the same or different each time they appear, and Each is independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 11a , R 12a , R 11b and R 12b appear each time are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein m is 0, 1 or 2; preferably, m is 1.
  • the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof wherein R 3 is R 12c , R 12d and R 12e are the same or different, and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl groups, 3 to 8 membered cycloalkyl groups and 3 to 8 membered heterocyclyl groups, the C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently optionally selected from oxo, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Substituted with one or more substituents among alkoxy, hydroxyl, cyano and amino.
  • R 3 is R 12c , R 12d and R 12e are the same or different, and are each independently selected from hydrogen atoms, halogens, C 1-6 alkyl groups, 3 to 8 membered cycloalkyl groups and 3
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:
  • Ring B is a 7- to 10-membered nitrogen-containing fused heterocyclic group or a 7- to 10-membered nitrogen-containing bridged heterocyclic group;
  • R 12c , R 12d and R 12e are the same or different, and are each independently selected from hydrogen atom, halogen, C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl, the C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently selected from the group consisting of oxo Substituted with one or more substituents of base, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxyl, cyano and amino; and
  • R 2 , L 2 , V 1 , V 2 , V 3 and n are as defined in general formula (I).
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein for Preferably, for
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein E is selected from X is N or CR 16a ; X 1 , X 2 and X 3 are each independently N or CR 16b ; and NR 16d ; X 7 , X 8 , X 9 and X 10 are the same or different, and each is independently N or CR 16e , and at least one of X 7 , , R 16b , R 16c and R 16e are the same or different, and are each independently selected from hydrogen atoms, halogens, alkyl groups, alkenyl groups, alkynyl groups, cyano groups, nitro groups, -OR 4 , -NR 5 R 6 , -C(O)R 4 , -C(O)OR 4 , -OC(O)R 4 , -C(O)NR 5 R 6 , -S(O)
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein R 16 is selected from halogen, C 1- 6 alkyl, cyano, -OR 4 and 3 to 8 membered cycloalkyl, the C 1-6 alkyl is optionally substituted by one or more halogens, R 4 is as defined in general formula (I) ;
  • R 16 is halogen or C 1-6 alkyl; more preferably, R 16 is C 1-6 alkyl; most preferably, R 16 is methyl.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 appear each time are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein R 5a and R 6a appear each time are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein R 16a , R 16b , R 16c and R 16e is the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl group; preferably, R 16a , R 16b , R 16c and R 16e are each independently a hydrogen atom.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein E is selected from Preferably X is N or CR 16a ; R 16a , R 16b and R 16c are the same or different, and are each independently selected from hydrogen atom, halogen and C 1-6 alkyl group; R 16d is selected from hydrogen atom, C 1-6 alkyl group and 3 to 8-membered cycloalkyl; R 16 is halogen or C 1-6 alkyl; q is 0, 1, 2 or 3.
  • each R 2 is the same or different, and each is independently C 1-6 alkyl or halogen; preferably, R 2 is C 1-6 alkyl; more preferably, R 2 is methyl.
  • the compound represented by general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 2a is a hydrogen atom or halogen; E and R 2 are as defined in general formula (I); preferably, for E and R are as defined in general formula (I); more preferably, for E is as defined in general formula (I).
  • the compound represented by general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 2a is a hydrogen atom or halogen; R 2 is a C 1-6 alkyl group; E is as defined in general formula (I); preferably E is as defined in general formula (I); more preferably E is as defined in general formula (I).
  • the compound represented by the general formula (II), the general formula (III) or a pharmaceutically acceptable compound thereof salt used which Selected from Preferably
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein R a is selected from hydrogen atom, halogen, C 1-6 alkyl group, cyano group and -OR e , R e is as defined in general formula (I); preferably, R a is a hydrogen atom or C 1-6 alkoxy group; further preferably, R a is selected from From a hydrogen atom, a methoxy group and an ethoxy group; more preferably, R a is a hydrogen atom or a methoxy group.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein V 1 is C (R a ) or N; V 2 and V 3 are the same or different, and are each independently C(R a ) or N; or V 2 is C(R bb ), V 3 is C(R cc ), and R bb and R cc Together with the carbon atoms connected to each other, a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group is formed; R a is a hydrogen atom or a C 1-6 alkoxy group; preferably, V 1 , V 2 and V 3 are the same or different, and each is independently C(R a ) or N; R a is a hydrogen atom or a C 1-6 alkoxy group; more preferably, V 1 is N or CH; V 2 is C(R a ) or N, R a is
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein V 1 , V 2 and V 3 each independently be C(R a ), R a is as defined in general formula (I); or V 1 and V 2 are both N, V 3 is C(R a ), R a is as defined in general formula (I) definition;
  • V 1 , V 2 and V 3 are each independently C(R a ), R a is a hydrogen atom or a C 1-6 alkoxy group; or V 1 and V 2 are both N, and V 3 is C ( R a ), R a is a hydrogen atom or C 1-6 alkoxy group;
  • V 1 , V 2 and V 3 are all CH; or V 1 and V 3 are both CH, and V 2 is CC 1-6 alkoxy; or V 1 and V 2 are both N, and V 3 is CH;
  • V 1 , V 2 and V 3 are all CH.
  • the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof wherein V 1 is C (R a ); V 2 and V 3 are the same or different, and each is independently C(R a ) or N; R a is as defined in general formula (I); preferably, V 1 , V 2 and V 3 are the same or different, and Each is independently C(R a ); R a is as defined in general formula (I); more preferably, V 1 , V 2 and V 3 are all CH.
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein R 12c , R 12d and R 12e are the same or different, and each is independently selected from a hydrogen atom, Halogen and C 1-6 alkyl; preferably, R 12c , R 12d and R 12e are all hydrogen atoms.
  • the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof B is an 8-membered fused heterocyclyl group or a 7- to 8-membered bridged heterocyclyl group;
  • R 2 is a C 1-6 alkyl group or halogen; n is 1 or 2;
  • R 3 is a halogen or -C(O)R 10 ;
  • R 10 is C 2-6 alkenyl, and the C 2-6 alkenyl is optionally substituted by one or more substituents selected from halogen or C 1-6 alkyl;
  • m is 1;
  • E is selected from r is 0 or 1;
  • V 1 is C(R a ) or N;
  • V 2 and V 3 are the same or different, and each independently is C(R a ) or N; or,
  • V 2 is C(R bb ),
  • V 3 is C (R cc ), and R bb and R cc together with the carbon atoms
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein B is an 8-membered fused heterocyclyl group or a 7- to 8-membered bridged heterocyclyl group; R 2 is C 1-6 alkyl or halogen; n is 1; R 3 is halogen or -C(O)R 10 ; R 10 is C 2-6 alkenyl, and the C 2-6 alkenyl is optionally replaced by one or Substituted with multiple substituents selected from halogen or C 1-6 alkyl; m is 1; E is selected from r is 0 or 1; V 1 , V 2 and V 3 are each independently C(R a ), R a is a hydrogen atom or a C 1-6 alkoxy group; or V 1 and V 2 are both N, V 3 is C(R a ), and R a is a hydrogen atom or a C 1-6 alkoxy group.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein B is a 7- to 8-membered bridged heterocyclyl group; R 2 is a C 1-6 alkyl group or Halogen; n is 1 or 2; R 3 is -C(O)R 10 ; R 10 is C 2-6 alkenyl; m is 1; E is selected from r is 0; V 1 , V 2 and V 3 are all CH.
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 2 is C 1-6 alkyl or halogen; n is 1 or 2; R 12c , R 12d and R 12e are all hydrogen atoms; E is selected from V 1 , V 2 and V 3 are the same or different, and each is independently C(R a ) or N; R a is a hydrogen atom or a C 1-6 alkoxy group.
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 2 is C 1-6 alkyl or halogen; n is 1; R 12c , R 12d and R 12e is the same or different, and each is independently selected from hydrogen atom, halogen and C 1-6 alkyl; E is selected from V 1 , V 2 and V 3 are each independently C(R a ), and R a is a hydrogen atom or a C 1-6 alkoxy group; or V 1 and V 2 are both N, and V 3 is C(R a ) , R a is a hydrogen atom or C 1-6 alkoxy group.
  • the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 2 is C 1-6 alkyl or halogen; n is 1 or 2; R 12c , R 12d and R 12e are all hydrogen atoms; E is selected from V 1 , V 2 and V 3 are all CH.
  • Typical compounds of the present disclosure include, but are not limited to:
  • E, ring B, R 2 , L 2 , V 1 , V 2 , V 3 and n are as defined in general formula (III).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound represented by the general formula (IIa) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IIb) or a salt thereof, to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound represented by the general formula (IIIa) or a salt thereof undergoes a condensation reaction with the compound represented by the general formula (IIIb) or a salt thereof to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • X L is halogen; preferably, X L is chlorine;
  • Ring B, R 2 , L 2 , V 1 , V 2 , V 3 , R 12c , R 12d , R 12e and n are as defined in general formula (III).
  • compositions which contains compounds shown in the general formula (I), general formula (II), general formula (III) of the present disclosure and table A or pharmaceutically acceptable compounds thereof. salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the use of compounds shown in Formula (I), Formula (II), Formula (III) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them in the preparation of type I receptor tyrosine. Use in acid kinase inhibitors.
  • the present disclosure further relates to the use of compounds shown in Formula (I), Formula (II), Formula (III) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them in the preparation of HER2 inhibitors. .
  • the present disclosure further relates to the use of compounds shown in general formula (I), general formula (II), general formula (III) and table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same in the preparation of drugs for inhibiting HER2. uses in.
  • the present disclosure further relates to the compounds shown in general formula (I), general formula (II), general formula (III) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same for the preparation of treatments and/or Use in drugs to prevent HER2-mediated diseases or conditions.
  • the present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III) and Table A or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the same in the preparation of HER2-inhibiting treatments and/or or use in medicines to prevent disease or condition.
  • the present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III) or table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same for use in the treatment and / Or use in cancer prevention drugs;
  • the cancer is preferably selected from brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, uterine cancer Endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell cancer, renal pelvis cancer, ureteral cancer, small bowel cancer, Pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethra cancer, penile cancer, testicular cancer, bone cancer, osteos
  • the present disclosure also relates to a method for inhibiting HER2, which includes administering to a patient in need a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (III) and Table A or a pharmaceutically acceptable amount thereof salts, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method of treating and/or preventing a disease or condition by inhibiting HER2, comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table A
  • a method of treating and/or preventing a disease or condition by inhibiting HER2 comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table A
  • the indicated compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table A
  • the indicated compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same comprising administering to a patient in need thereof a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table A
  • the indicated compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same comprising administering
  • the present disclosure also relates to a method of treating and/or preventing a HER2-mediated disease or disorder, which comprises administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (III) and Table 1
  • the present disclosure further relates to a method for treating and/or preventing cancer, which includes administering to a patient in need a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (III) and Table A, or Its pharmaceutically acceptable salts, or pharmaceutical compositions including them;
  • the cancer is preferably selected from brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, and cervical cancer , fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell carcinoma, renal pelvis cancer, ureter Cancer, small bowel cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethra cancer, penile cancer
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III) and table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine .
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) and table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used as HER2 inhibitors .
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used to inhibit HER2.
  • the present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which treat and /or prevent disease or illness.
  • the present disclosure further relates to compounds represented by general formula (I), general formula (II), general formula (III) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, which are used for the treatment and/or or prevent HER2-mediated diseases or conditions.
  • the present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used for treatment and/or prevent cancer;
  • the cancer is preferably selected from brain cancer, breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, Prostate cancer, stomach cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell cancer, renal pelvis cancer, ureteral cancer, small intestine cancer, pancreatic cancer, thyroid Cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal cancer, urethra cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma
  • the diseases or conditions described in this disclosure are those that are treated and/or prevented by inhibiting HER2.
  • the disease or condition is cancer; the cancer is preferably selected from brain cancer, Breast cancer, ovarian cancer, lung cancer, anal cancer, melanoma, neuroblastoma, colorectal cancer, cervical cancer, fallopian tube cancer, endometrial cancer, prostate cancer, gastric cancer, head and neck cancer, nasopharyngeal cancer, oral cancer, bile duct Cancer, esophageal cancer, liver cancer, skin cancer, mesothelioma, bladder cancer, renal cell carcinoma, renal pelvis cancer, ureteral cancer, small bowel cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, vaginal cancer, vulvar cancer, leukemia, adrenal gland Cancer, urethral cancer, penile cancer, testicular cancer, bone cancer, osteosarcoma, myeloma, soft tissue sarcoma, pituitary adenoma, brainstem glioma, spinal tumor and lymphoma; more preferably, the cancer
  • the HER2 is a mutant HER2, preferably a HER2 mutated in exon 20.
  • the exon 20 mutation is preferably an insertion mutation of 4 amino acids YVMA (p.A775_G776insYVMA).
  • the active compounds of the present disclosure are preferably in unit dosage form, or in such form that a patient may self-administer a single dose.
  • the unit dosage form of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • compositions containing the active ingredients may be in forms suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, to provide medicinal preparations that are pleasing to the eye and palatable.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations may also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredient in vegetable or mineral oil.
  • Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oil phase can be vegetable oil, mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles or solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion may be injected into the patient's bloodstream by local mass injection.
  • solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the present disclosure.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent.
  • sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used.
  • fatty acids are also prepared as injectables.
  • the compounds of the present disclosure may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
  • the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, and the patient's behavior. , patient's diet, administration time, administration method, excretion rate, combination of drugs, severity of disease, etc.; in addition, the best treatment method such as treatment mode, daily dosage of compounds or pharmaceutically acceptable salts Types can be verified based on traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e. C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, C 1-6 alkyl group).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl
  • the alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where the alkyl group is as defined above and has 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e. C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cyclic One or more of alkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group), and further preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group). ), more preferably a cycloalkyl group with 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), and most preferably a cycloalkyl group with 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group).
  • Non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic system in which one carbon atom (called a spiro atom) is shared between the rings.
  • the ring may contain one or more double bonds, or the ring may contain one or more atoms selected from nitrogen, Heteroatoms of oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxoated, that is, to form sulfoxide or sulfone, but does not include -O-O-, -O-S - or -S-S-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, which has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spirocycloalkyl group), and more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spirocycloalkyl group). membered spirocycloalkyl).
  • the spirocycloalkyl group includes a single spirocycloalkyl group and a multi-spirocycloalkyl group (such as a double spirocycloalkyl group, etc.), preferably a single spirocycloalkyl group or a double spirocycloalkyl group, and more preferably a 3-membered/4-membered, 3-membered or 3-membered spirocycloalkyl group.
  • Non-limiting examples include:
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with a heterocyclic cycloalkyl group.
  • One or more of the cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on a single-ring cycloalkyl group, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the fused ring alkyl group is preferably a fused ring alkyl group having 6 to 14 ring atoms (ie, a 6 to 14-membered fused ring alkyl group), and more preferably a fused ring alkyl group having 7 to 10 ring atoms (ie, a 7 to 10 membered ring alkyl group). fused ring alkyl group).
  • the fused cycloalkyl group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e., a 6- to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl group). bridged cycloalkyl).
  • the bridged cycloalkyl group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment.
  • the substituents are preferably selected from the group consisting of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic system (i.e., polycyclic heterocyclyl), which contains at least one ring (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxogenated, that is, to form sulfoxide or sulfone, but not including -O-O-, -O-S- or -S-S-), and having 3 to 20 (e.g.
  • the heterocyclyl group is preferably a heterocyclyl group with 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclyl group), such as a 4 to 12-membered heterocyclyl group containing at least one nitrogen atom; further preferably, it has 3 to 8 ring atoms.
  • Heterocyclyl with ring atoms ie, 3 to 8 membered heterocyclyl
  • more preferably heterocyclyl with 3 to 6 ring atoms ie, 3 to 6 membered heterocyclyl
  • Non-limiting examples of the monocyclic heterocyclyl include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl and homopiperazinyl, etc.
  • the polycyclic heterocyclyl group includes spiroheterocyclyl group, fused heterocyclyl group and bridged heterocyclyl group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic system in which the rings share one atom (called a spiro atom).
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., forming nitrogen oxides; the sulfur Can be optionally oxoated, i.e.
  • a sulfoxide or sulfone but not -OO-, -OS- or -SS-), provided it contains at least one monocyclic heterocyclyl group and the point of attachment is at the monocyclic heterocyclyl group , which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 1-membered spiroheterocyclyl).
  • the spiroheterocyclyl group is preferably a spiroheterocyclyl group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclyl group), and more preferably a spiroheterocyclyl group having 7 to 11 ring atoms (i.e., a 7 to 11 membered spiroheterocyclyl group).
  • 1-membered spiroheterocyclyl 1-membered spiroheterocyclyl
  • the spiroheterocyclyl group includes a single spiroheterocyclyl group and a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group, etc.), preferably a single spiroheterocyclyl group or a double spiroheterocyclyl group, more preferably 3-membered/4-membered, 3-membered or 3-membered spiroheterocyclyl.
  • Non-limiting examples include:
  • fused heterocyclyl refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between the rings.
  • the ring may contain one or more double bonds, and the ring may contain at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not Including -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused with one or more monocyclic heterocyclyl groups, or a monocyclic heterocyclyl group with a cycloalkyl, aryl or heteroaryl group.
  • One or more of the radicals are fused, wherein the point of attachment is on the monocyclic heterocyclyl radical, and there are 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) ring atoms (i.e. 5 to 20 membered fused heterocyclyl).
  • the fused heterocyclyl group is preferably a fused heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused heterocyclyl group), and more preferably a fused heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclyl group).
  • the fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl group, tetracyclic fused heterocyclyl group, etc.), preferably bicyclic fused heterocyclyl group or tricyclic fused heterocyclyl group, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuanuan, 6 yuanuan, 6 yuan/5 yuan, 6 yuan
  • bridged heterocyclyl refers to a polycyclic heterocyclic system that shares two atoms that are not directly connected between the rings.
  • the ring may contain one or more double bonds, and the ring contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen can be optionally oxidized, that is, to form nitrogen oxides; the sulfur can be optionally oxo-substituted, that is, to form sulfoxide or sulfone, but not including -OO-, -OS- or -SS-), which have 5 to 20 (e.g. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e.
  • the bridged heterocyclyl group is preferably a bridged heterocyclyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl group), and more preferably a bridged heterocyclyl group having 7 to 10 ring atoms (i.e., a 7 to 10-membered bridged heterocyclyl group).
  • bridged heterocyclyl group further preferably a bridged heterocyclyl group having 7 to 8 ring atoms (i.e., 7 to 8 membered bridged heterocyclyl group).
  • bicyclic bridged heterocyclyl and polycyclic bridged heterocyclyl such as tricyclic bridged heterocyclyl, tetracyclic bridged heterocyclyl, etc.
  • bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl.
  • base preferably bicyclic bridged heterocyclyl or tricyclic bridged heterocyclyl.
  • Non-limiting examples include: wait.
  • Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • the substituent is preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkyl.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ electron system, having 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e. 6 to 14 membered aryl group).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, 6 to 10 membered aryl group).
  • the monocyclic aryl group is, for example, phenyl.
  • Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc.
  • the polycyclic aryl group also includes a phenyl group condensed with one or more of a heterocyclyl group or a cycloalkyl group, or a naphthyl group condensed with one or more of a heterocyclyl group or a cycloalkyl group, wherein The point of attachment is on the phenyl or naphthyl group, and in this case the number of ring atoms continues to mean the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:
  • Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups. or Multiple.
  • heteroaryl refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) with a conjugated ⁇ electron system, which contains at least one (For example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo-substituted, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and more preferably a monocyclic heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered monocyclic heteroaryl group).
  • Cyclic heteroaryl or bicyclic heteroaryl having 9 to 10 ring atoms (i.e. 9 to 10 membered bicyclic heteroaryl), most preferably containing 1, 2 or 3 heteroaryls selected from nitrogen, oxygen and sulfur in the ring.
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • Non-limiting examples of the polycyclic heteroaryl include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene base, quinazolinyl, benzothiazolyl, carbazolyl, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent a polycyclic heteroaryl ring The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused to one or more of cycloalkyl or heterocyclyl, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the ring
  • the number of atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include: wait.
  • Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment.
  • the substituents are preferably selected from D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkyl groups.
  • amino protecting group refers to an easily removable group introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), watmethoxycarbonyl (Fmoc), allyl Oxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthalyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), Trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.
  • hydroxyl protecting group refers to an easily removable group introduced on a hydroxyl group to block or protect the hydroxyl group for reactions on other functional groups of the compound.
  • Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyl Diphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), methyl Acyl, acetyl, benzoyl, p-nitrobenzoyl, etc.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, where aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, where heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • stereoisomer refers to the structure Isomers with the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers and their mixtures (e.g. racemates, mixtures of diastereomers) . Additional asymmetric atoms may be present for substituents in the compounds of the present disclosure.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains basic functional groups (such as amino) or acidic functional groups (such as carboxyl), and appropriate optical Reactive acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.
  • tautomer or tautomeric form
  • tautomer refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, either as single isomers or as mixtures of said tautomers in any proportion.
  • Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like.
  • An example of a lactam-lactam equilibrium is shown below:
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, such as 2 H (deuterium, D), respectively.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of the drug. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete.
  • the replacement of partial deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • a position when a position is specifically designated as “deuterium” or “D", that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. At least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).
  • C 1-6 alkyl optionally (optionally) substituted by halogen or cyano group means that halogen or cyano group may but does not have to be present. This description includes the case where the alkyl group is substituted by halogen or cyano group and the alkyl group. The group is not substituted by halogen and cyano group.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents.
  • a person skilled in the art will be able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically). example For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. They can be prepared individually during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • therapeutically effective amount refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of a therapeutically effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective amount in an individual case can be determined by those skilled in the art based on routine experiments.
  • the present disclosure discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • R is C 1-6 alkyl; preferably, R is methyl;
  • the present disclosure discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • X L is halogen; preferably, X L is chlorine;
  • Ring B, R 2 , L 2 , V 1 , V 2 , V 3 , R 12c , R 12d , R 12e and n are as defined in general formula (III).
  • the bases include organic bases and inorganic bases
  • the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamino Lithium, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide
  • the inorganic base includes but is not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, anhydrous potassium carbonate, cesium carbonate, Sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the base described in Scheme 1 is potassium tert-butoxide; the base described in Scheme 2 is N,N-diisopropyl ethylamine.
  • the above synthesis scheme is preferably carried out in a solvent.
  • the solvents used include but are not limited to: glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, glacial acetic acid and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR is measured using Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M.
  • the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS); waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model : waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High-performance liquid phase preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm ⁇ 0.2mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200 ⁇ 300 mesh silica gel as the carrier.
  • the average kinase inhibition rate and IC 50 value were measured using NovoStar microplate reader (BMG Company, Germany).
  • the known starting materials of the present disclosure can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals, WuXi AppTec and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenator and Clear Blue QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent used in the reaction, the column chromatography eluent system and the thin layer chromatography developing agent system used to purify the compound include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and Adjust with alkaline or acidic reagents such as acetic acid.
  • reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 1 (15 mg, yield: 16.6%).
  • the residue is purified by high performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: water phase (10mmol/L Ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min), to obtain the title compound 3 (5.3 mg, yield: 10.4%).
  • reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min), to obtain the title compound 4 (10 mg, yield: 11.9%). MS m/z(ESI):591.2[M+1].
  • the crude compound 7c (60 mg, 101 ⁇ mol) was dissolved in 1 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added at 0°C, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7d (62 mg). The product was not purified. used directly for the next reaction.
  • reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to obtain the title compound 7.
  • Example 7 The synthetic route in Example 7 was adopted, and the starting material compound 1a in the first step was replaced by compound 6a to obtain the title compound 8 (30 mg, yield: 27%).
  • Example 1 The synthetic route in Example 1 was adopted, and the starting material compound 1a in the first step was replaced by compound 6a to obtain the title compound 9 (100 mg, yield: 44%).
  • reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L hydrogen carbonate) ammonium) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min), to obtain the title compound 10 (110 mg, yield: 39.7%).
  • the crude compound 12a (40 mg, 64 ⁇ mol) was dissolved in 1 mL of methylene chloride, 0.5 mL of trifluoroacetic acid was added under an ice bath, and the reaction was allowed to return to room temperature with stirring for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 12b (40 mg), the product It was used directly in the next reaction without purification.
  • Adopt the synthetic route in Example 12 and replace the first step raw material 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline with 2-Fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline (implemented using the intermediate on page 75 of the specification in the patent application "WO2022003575A1" Prepared by the method disclosed in Example G), the title compound 15 (20 mg, yield: 45%) was obtained.
  • reaction solution was concentrated under reduced pressure, and the residue was subjected to high-performance liquid phase preparative chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) was purified to obtain the title compound 16 (110 mg, yield: 39.7%).
  • high-performance liquid phase preparative chromatography Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5 ⁇ m; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and Acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min
  • Adopt the synthetic route in Example 22, and replace the first step raw material compound 22a with N-(3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy) )phenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine prepared by the method disclosed for compound K on page 41 of the specification in the patent application "WO2021156178A1").
  • Title compound 25 (15 mg, yield: 20%).
  • Adopt the synthetic route in Example 26 replace the first step raw material compound 1d with 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy base) aniline to obtain the title compound 27 (50 mg, yield: 45.3%).
  • Test example 1 Ba/F3 cell proliferation experiment
  • EGFR wild-type Ba/F3 cells Take logarithmic growth EGFR wild-type Ba/F3 cells (Cobioer, Cat. No.: CBP73110) and inoculate them into a 96-well plate with 2.5 ⁇ 10 3 cells/100uL growth medium.
  • HER2 wild-type Ba/F3 cells in the logarithmic growth phase (Cobioer, Catalog No.: CBP73110) or HER2A775_G776insYVMA mutant Ba/F3 (Cobioer, Catalog No.: CBP73184) was inoculated into a 96-well plate with 5 ⁇ 10 3 cells/100uL growth medium, and placed in a 37°C cell culture incubator overnight. 100uL/well compound diluted 3-fold in culture medium was added every day, and all treatments were performed in triplicate. Continue culturing in a 37°C cell culture incubator for 72 hours. Perform Celltiter-Glo Luminescent cell viability assay.
  • Proliferation % (average G3-G0 average of test compound wells)/(average G3-G0 average of DMSO control wells)*100.
  • Proliferation % (average G3-G0 average of test compound wells)/(average G3-G0 average of DMSO control wells)*100.
  • Prism Graphpad software to fit the gradient curve of cell proliferation, and calculate the GI 50 of the compound (GI 50 is defined as the concentration of the compound corresponding to the cell proliferation inhibition rate of 50%) .
  • HER2 selective inhibitor tucatinib (synthesized with reference to Example 11 in patent WO2007059257A2) is as follows:
  • the disclosed compound has a strong inhibitory effect on the proliferation of HER2 exon 20YVMA insertion mutation and HER2 wild-type dependent Ba/F3 cells, and has strong selectivity relative to EGFR wild-type dependent Ba/F3 cells; Moreover, the compound of the present disclosure has significantly better inhibitory activity than tucatinib on the proliferation of Ba/F3 cells with HER2 exon 20YVMA insertion mutation.
  • TPGS D-alpha-vitamin E polyethylene glycol succinate
  • HPMC Hydroxypropyl methylcellulose
  • PEG400 polyethylene glycol 400
  • the LC/MS/MS method was used to measure the drug concentrations in the plasma of SD rats at different times after the compounds of the examples were administered intragastrically (i.g.). Study the pharmacokinetic behavior of the disclosed compound in SD rats and evaluate its pharmacokinetic characteristics.
  • the dosage is 50 mg/kg, and the dosage volume is 10.0 mL/kg.
  • 0.2 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10000 rpm for 1 minute (4°C) , separate the plasma within 1 hour and store it on dry ice for testing.
  • the process from blood collection to centrifugation is operated under ice bath conditions. Eat 2 hours after dosing.
  • the disclosed compound has high exposure in SD rats and has obvious pharmacokinetic advantages.
  • the LC/MS/MS method was used to determine the drug concentration in the plasma of C57 mice at different times after the compounds of the examples were administered intragastrically (i.g.). Study the pharmacokinetic behavior of the disclosed compound in C57 mice and evaluate its pharmacokinetic characteristics.
  • the dosage is 50 mg/kg, and the dosage volume is 20.0 mL/kg.
  • 0.1 mL of blood was collected from the orbit, placed in an EDTA-K2 anticoagulant test tube, and centrifuged at 10000 rpm for 2 minutes (4°C) , separate plasma within 1 hour, and store at -20°C for testing.
  • the process from blood collection to centrifugation is operated under ice bath conditions. Eat 2 hours after dosing.
  • the disclosed compound has high exposure in C57 mice and has obvious pharmacokinetic advantages.

Abstract

本公开涉及含氮杂环类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的含氮杂环类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为HER2抑制剂的用途和在制备通过抑制HER2治疗和/或预防疾病或病症的药物中的用途。

Description

含氮杂环类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种氮杂环类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的含氮杂环类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为HER2抑制剂的用途和在制备通过抑制HER2治疗和/或预防疾病或病症的药物中的用途。
背景技术
人表皮生长因子受体2(HER2；Neu,ERBB2)是I型受体酪氨酸激酶家族的成员，其还包括EGFR(ERBB1)、HER3(ERBB3)和HER4(ERBB4)。迄今为止，人体内尚未发现能与HER2直接结合的配体，HER2必须与家族其他成员(如HER3)组成同源或异源二聚体，HER2二聚化后构象发生改变，激活胞内的酪氨酸激酶活性，继而再激活下游通路(MAPK信号通路和PI3K/AKT信号通路)，从而发挥相应的生理作用。
异常HER2信号传导在多种人类恶性肿瘤中都有发现，包括HER2胞外区、近膜区和胞内区域都会发生致癌突变。总的来说，这些突变使HER2具有持续的活性，促进了癌症的发生、肿瘤的维持和生长。在包括乳腺癌、胃癌或肺癌在内的各种肿瘤中成为肿瘤转化和肿瘤维持的基础。HER2过表达增加了HER2信号传导，特别是在乳腺癌中，HER2扩增与较差的存活结果相关。HER2突变占人类所有癌症的6-7％。因此，破坏HER2致癌信号可以有效的治疗HER2致癌突变或HER2野生型扩增驱动的肿瘤。目前已有多种针对HER2的药物获得FDA批准用于乳腺癌治疗，包括抗HER2的抗体(曲妥珠单抗和帕妥珠单抗)、针对HER2的抗体-药物偶联物(曲妥珠单抗-DM1(T-DM1、ado-trastuzumab emtansine)和抑制HER2激酶结构域的小分子(阿法替尼、来那替尼、拉帕替尼、图卡替尼、吡咯替尼)。
尽管这些药物可以抑制HER2野生型，例如图卡替尼，但这些抑制剂对携带外显子20突变的HER2无效。HER2基因20号外显子突变导致激酶活性增强(Wang等人Cancer Cell,2006,10(1):25-38)。这种增强的HER2激酶活性进入下游信号级联，通过促进细胞的生长、增殖和存活来刺激肿瘤转化。小鼠模型的遗传学研究表明，非小细胞肺癌是最普遍的HER2外显子20突变，是4个氨基酸YVMA(p.A775_G776insYVMA)的***，它可以驱动致癌生长。降低HER2-YVMA表达可以使肿瘤缩小，这表明HER2的这种致癌变体是肿瘤维持所必需的。此外，广谱ERBB抑制剂阿法替尼在体内可以有效的可以干扰HER2-YVMA的致癌信号 传导。
据统计约有2-4％的肺癌患者在HER2外显子20中携带激活突变。目前临床批准的ERBB靶向酪氨酸激酶抑制剂对这些患者几乎无效，这主要是因为EGFR野生型介导的剂量限制毒性。阿利替尼、依鲁替尼、来那替尼、波齐替尼和吡咯替尼是已知的突变HER2外显子20的广谱ERBB抑制剂。但在临床上，受到有效剂量的限制，阿法替尼和其他广谱ERBB抑制剂在HER2外显子20突变的NSCLC患者中仅显示出有限的疗效。
因此开发一款特异性抑制HER2外显子20突变蛋白而对EGFR野生型无效，从而克服EGFR野生型介导的剂量限制毒性的缺点的分子成为一项迫切的医疗需求。本发明的目的是提供对EGFR野生型具有选择性的突变HER2外显子20的新抑制剂。
目前公开了一系列的HER2抑制剂的专利申请，其中包括WO2007059257A1、WO2017148391A1、WO2021213800A1和WO2021156178A1。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为芳基或杂芳基；
环B为7至10元稠杂环基或7至10元桥杂环基；
G为N或C(RA)；
RA选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基和氨基；
V1为C(Ra)或N；
V2和V3相同或不同，且各自独立地为C(Ra)或N；或者，V2为C(Rbb)，V3为C(Rcc)，且Rbb与Rcc与各自相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被选自卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
L1选自O、NRb1、C(O)、S、S(O)和S(O)2；
L2选自O、NRb2、C(O)、(CRcRd)u、(CRcRd)uO、O(CRcRd)u、(CRcRd)uNRb2、NRb2(CRcRd)u、C(O)NRb2和NRb2C(O)；
E为9至10元杂芳基，所述9至10元杂芳基任选被一个或多个R16取代；
R16选自卤素、烷基、烯基、炔基、氰基、硝基、-OR4、-NR5R6、-C(O)R4、-C(O)OR4、-OC(O)R4、-C(O)NR5R6、-S(O)pR4、-S(O)pNR5R6、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、氨基烷基、氰基、-OR4a、-NR5aR6a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
Ra选自氢原子、卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-ORe、-(CH2)s-NRfRg、环烷基、杂环基、芳基和杂芳基；
Rb1和Rb2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、烷基、羟基和羟烷基；
R1选自氢原子、烷基和环烷基；
各个R2相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-OR7、-(CH2)v-NR8R9、环烷基、杂环基、芳基和杂芳基；
各个R3相同或不同，且各自独立地选自氧代基、卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RB取代；
RB选自氧代基、卤素、烷基、烯基、炔基、氰基、-OR10b、-NR11bR12b、-C(O)R10b、-C(O)NR11bR12b、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；
Re、R4、R4a、R7、R10a和R10b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
Rf、Rg、R5、R6、R8、R9、R11和R12在每次出现时相同或不同，且各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、 卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者Rf、Rg与相连的氮原子一起形成杂环基，或者R5、R6与相连的氮原子一起形成杂环基，或者R8、R9与相连的氮原子一起形成杂环基，或者R11、R12与相连的氮原子一起形成杂环基，所述的杂环基任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R13在每次出现时相同或不同，且各自独立地选自氢原子、烷基和环烷基；
R5a、R6a、R11a、R12a、R11b和R12b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、氨基烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
s为0、1或2；
v为0、1或2；
u为1、2、3或4；
p为0、1或2；
n为0、1、2、3或4；且
m为0至10之间的整数。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，
其中：
环A为芳基或杂芳基；
环B为7至10元稠杂环基或7至10元桥杂环基；
G为N或C(RA)；
RA选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基和氨基；
V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；
L1选自O、NRb1、C(O)、S、S(O)和S(O)2；
L2选自O、NRb2、C(O)、(CRcRd)u、(CRcRd)uO、O(CRcRd)u、(CRcRd)uNRb2、NRb2(CRcRd)u、C(O)NRb2和NRb2C(O)；
E为9至10元杂芳基，所述9至10元杂芳基任选被一个或多个R16取代；
R16选自卤素、烷基、烯基、炔基、氰基、硝基、-OR4、-NR5R6、-C(O)R4、-C(O)OR4、-OC(O)R4、-C(O)NR5R6、-S(O)pR4、-S(O)pNR5R6、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、氨基烷基、氰基、-OR4a、-NR5aR6a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
Ra选自氢原子、卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-ORe、-(CH2)s-NRfRg、环烷基、杂环基、芳基和杂芳基；
Rb1和Rb2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、烷基、羟基和羟烷基；
R1选自氢原子、烷基和环烷基；
各个R2相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-OR7、-(CH2)v-NR8R9、环烷基、杂环基、芳基和杂芳基；
各个R3相同或不同，且各自独立地选自氧代基、卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RB取代；
RB选自氧代基、卤素、烷基、烯基、炔基、氰基、-OR10b、-NR11bR12b、-C(O)R10b、-C(O)NR11bR12b、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；
Re、R4、R4a、R7、R10a和R10b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
Rf、Rg、R5、R6、R8、R9、R11和R12在每次出现时相同或不同，且各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者Rf、Rg与相连的氮原子一起形成杂环基，或者R5、R6与相连的氮原子一起形成杂环基，或者R8、R9与相连的氮原子一起形成杂环基，或者R11、R12与相连的氮原子一起形成杂环基，所述的杂环基任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R13在每次出现时相同或不同，且各自独立地选自氢原子、烷基和环烷基；
R5a、R6a、R11a、R12a、R11b和R12b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、氨基烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
s为0、1或2；
v为0、1或2；
u为1、2、3或4；
p为0、1或2；
n为0、1、2、3或4；且
m为0至10之间的整数。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中L1为O。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选地，环A为苯基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中RA选自氢原子、卤素、C1-6烷基和氰基；优选地，RA为氰基。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中G为N或C-CN；优选地，G为N。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中R1为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中Rc和Rd均为氢原子。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中u为1或2；优选地，u为1。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中L2为O或(CRcRd)uO，Rc、Rd和u如通式(I)中所定义；优选地，L2为O或CH2O；更优选地，L2为O。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
其中：
r为0或1；
环B、E、R2、R3、V1、V2、V3、m和n如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中环B为8元稠杂环基或7至8元桥杂环基；优选地，环B为R3可取代在所述环B任意可取代位置。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中选自 R3可取代在所述环B任意可取代位置；优选地，选自 R3可取代在所述环B任意可取代位置；更优选地，为
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中选自 R3a选自氢原子、烷基、烯基、炔基、-C(O)R10、-C(O)OR10、-C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R3b选自氢原子、氧代基、卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、 炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R10、R11、R12、R10a、R11a、R12a和p如通式通式(I)中所定义；
优选地，选自 R3a选自氢原子、烷基、烯基、炔基、-C(O)R10、-C(O)OR10、-C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R3b选自卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R10、R11、R12、R10a、R11a、R12a和p如通式通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、-OR10和-C(O)R10，所述的C1-6烷基任选被选自卤素、氰基、-OR10a、-NR11aR12a、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；且R10、R10a、R11a和R12a如通式(I)中所定义；优选地，R3为卤素或-C(O)R10；且R10如通式(I)中所定义；更优选地，R3为-C(O)R10；且R10如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R3a为C1-6烷基或-C(O)R10，所述的C1-6烷基任选被选自卤素、氰基、-OR10a、-NR11aR12a、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；且R10、R10a、R11a和R12a如通式(I)中所 定义；优选地，R3a为-C(O)R10，R10如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R3b选自卤素、C1-6烷基、-OR10和-C(O)R10，所述的C1-6烷基任选被选自卤素、氰基、-OR10a、-NR11aR12a、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；且R10、R10a、R11a和R12a如通式(I)中所定义；优选地，R3b为卤素；更优选地，R3b为氟。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中为R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；
优选地，选自 R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；
更优选地，选自 R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；进一步优选地，为R3a为-C(O)R10；R10为C2-6烯基(优选为乙烯基)；最优选地，为
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其 中r为0。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中为R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；
优选地，选自 R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；
更优选地，选自 R3a为-C(O)R10，且R10如通式(I)中所定义；R3b为卤素；进一步优选地，为R3a为-C(O)R10；且R10为C2-6烯基(优选为乙烯基)；最优选地，为
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R10在每次出现时相同或不同，且各自独立地选自氢原子、C1-6烷基、C2-6烯基、C2-6炔基、3至8元环烷基和3至8元杂环基，所述的C1-6烷基、C2-6烯基、C2-6炔基、3至8元环烷基和3至8元杂环基各自独立地任选被一个或多个RB取代；RB选自氧代基、卤素、C1-6烷基、-OR10b、-NR11bR12b、-C(O)R10b、-C(O)NR11bR12b、3至8元环烷基和3至8元杂环基，所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6卤代 烷基、C1-6羟烷基、C1-6烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；R10b、R11b和R12b如通式(I)中所定义；
优选地，R10为C2-6烯基，所述的C2-6烯基任选被一个或多个RB取代；RB选自卤素、C1-6烷基、3至8元环烷基和3至8元杂环基，所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；
更优选地，R10为C2-6烯基，所述的C2-6烯基任选被一个或多个选自卤素或C1-6烷基的取代基所取代；
进一步优选地，R10为C2-6烯基；
最优选地，R10为乙烯基。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R10a和R10b在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R11a、R12a、R11b和R12b在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中m为0、1或2；优选地，m为1。
在本公开一些实施方案中，所述的通式(I)、通式(II)所示的化合物或其可药用的盐，其中R3为R12c、R12d和R12e相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、3至8元环烷基和3至8元杂环基，所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
其中：
环B为7至10元含氮稠杂环基或7至10元含氮桥杂环基；
R12c、R12d和R12e相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、3 至8元环烷基和3至8元杂环基，所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；且
E、R2、L2、V1、V2、V3和n如通式(I)中所定义。在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中L2为O。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中环B为8元含氮稠杂环基或7至8元含氮桥杂环基；优选地，环B为7至8元含氮桥杂环基；更优选地，环B为R3可取代在所述环B任意可取代位置。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中为优选地，为
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中E选自 X为N或CR16a；X1、X2和X3各自独立地为N或CR16b；X4和X5相同或不同，且各自独立地为N或CR16c；X6选自O、S和NR16d；X7、X8、X9和X10相同或不同，且各自独立地为N或CR16e，且X7、X8、X9和X10中至少有一个为N；R16a、R16b、R16c和R16e相同或不同，且各自独立地选自选自氢原子、卤素、烷基、烯基、炔基、氰基、硝基、-OR4、-NR5R6、-C(O)R4、-C(O)OR4、-OC(O)R4、-C(O)NR5R6、-S(O)pR4、-S(O)pNR5R6、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、氨基烷基、氰基、-OR4a、-NR5aR6a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R16d选自氢原子、烷基和环烷基，所 述的烷基和环烷基各自独立地任选被选自氧代基、卤素、烷基、氰基、-OR4a和-NR5aR6a中的一个或多个取代基所取代；q为0、1、2或3；且R4、R4a、R5、R6、R5a、R6a、R16和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R16选自卤素、C1-6烷基、氰基、-OR4和3至8元环烷基，所述的C1-6烷基任选被一个或多个卤素所取代，R4如通式(I)中所定义；优选地，R16为卤素或C1-6烷基；更优选地，R16为C1-6烷基；最优选地，R16为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R4为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R4a为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R5和R6在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R5a和R6a在每次出现时相同或不同，且各自独立地为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R16a、R16b、R16c和R16e相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；优选地，R16a、R16b、R16c和R16e各自独立地为氢原子。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中R16d选自氢原子、C1-6烷基和3至8元环烷基；优选地，R16d为C1-6烷基；更优选地，R16d为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中E选自 优选为 X为N或CR16a；R16a、R16b和R16c相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；R16d选自氢原子、C1-6烷基和3至8元环烷基；R16为卤素或C1-6烷基；q为0、1、2或3。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中q为0或1；优选地，q为0。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中E选自
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中各个R2相同或不同，且各自独立地为C1-6烷基或卤素；优选地，R2为C1-6烷基；更优选地，R2为甲基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中各个R2相同或不同，且各自独立地为甲基或氟。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中n为0、1或2；优选地，n为1或2；更优选地，n为1。
在本公开一些实施方案中，所述的通式(II)、通式(III)所示的化合物或其可药用的盐，其中为R2a为氢原子或卤素；E和R2如通式(I)中所定义；优选地，为E和R2如通式(I)中所定义；更优选地，为E如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(II)、通式(III)所示的化合物或其可药用的盐，其中为R2a为氢原子或卤素；R2为C1-6烷基；E如通式(I)中所定义；优选为E如通式(I)中所定义；更优选为E如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(II)、通式(III)所示的化合物或其可药 用的盐，其中选自 优选为
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中Re为氢原子或C1-6烷基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中Ra选自氢原子、卤素、C1-6烷基、氰基和-ORe，Re如通式(I)中所定义；优选地，Ra为氢原子或C1-6烷氧基；进一步优选地，Ra选自氢原子、甲氧基和乙氧基；更优选地，Ra为氢原子或甲氧基。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中V1为C(Ra)或N；V2和V3相同或不同，且各自独立地为C(Ra)或N；或者，V2为C(Rbb)，V3为C(Rcc)，且Rbb与Rcc与各自相连的碳原子一起形成5或6元环烷基或5或6元杂环基；Ra为氢原子或C1-6烷氧基；优选地，V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra为氢原子或C1-6烷氧基；更优选地，V1为N或CH；V2为C(Ra)或N，Ra为氢原子或C1-6烷氧基；V3为CH。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中V1、V2和V3各自独立地为C(Ra)，Ra如通式(I)中所定义；或者V1和V2均为N，V3为C(Ra)，Ra如通式(I)中所定义；
优选地，V1、V2和V3各自独立地为C(Ra)，Ra为氢原子或C1-6烷氧基；或者V1和V2均为N，V3为C(Ra)，Ra为氢原子或C1-6烷氧基；
更优选地，V1、V2和V3均为CH；或者V1和V3均为CH，V2为C-C1-6烷氧基；或者V1和V2均为N，V3为CH；
最优选地，V1、V2和V3均为CH。
在本公开一些实施方案中，所述的通式(I)、通式(II)、通式(III)所示的化合物或其可药用的盐，其中V1为C(Ra)；V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra如通式(I)中所定义；优选地，V1、V2和V3相同或不同，且各自独立地为C(Ra)；Ra如通式(I)中所定义；更优选地，V1、V2和V3均为CH。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中R12c、R12d和R12e相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；优选地，R12c、R12d和R12e均为氢原子。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其 中B为8元稠杂环基或7至8元桥杂环基；R2为C1-6烷基或卤素；n为1或2；R3为卤素或-C(O)R10；R10为C2-6烯基，所述的C2-6烯基任选被一个或多个选自卤素或C1-6烷基的取代基所取代；m为1；E选自 r为0或1；V1为C(Ra)或N；V2和V3相同或不同，且各自独立地为C(Ra)或N；或者，V2为C(Rbb)，V3为C(Rcc)，且Rbb与Rcc与各自相连的碳原子一起形成5或6元环烷基或5或6元杂环基；Ra为氢原子或C1-6烷氧基。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中B为8元稠杂环基或7至8元桥杂环基；R2为C1-6烷基或卤素；n为1；R3为卤素或-C(O)R10；R10为C2-6烯基，所述的C2-6烯基任选被一个或多个选自卤素或C1-6烷基的取代基所取代；m为1；E选自 r为0或1；V1、V2和V3各自独立地为C(Ra)，Ra为氢原子或C1-6烷氧基；或者V1和V2均为N，V3为C(Ra)，Ra为氢原子或C1-6烷氧基。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中B为7至8元桥杂环基；R2为C1-6烷基或卤素；n为1或2；R3为-C(O)R10；R10为C2-6烯基；m为1；E选自r为0；V1、V2和V3均为CH。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中为R2为C1-6烷基或卤素；n为1或2；R12c、R12d和R12e均为氢原子；E选自V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra为氢原子或C1-6烷氧基。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中为R2为C1-6烷基或卤素；n为1；R12c、R12d和 R12e相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；E选自 V1、V2和V3各自独立地为C(Ra)，Ra为氢原子或C1-6烷氧基；或者V1和V2均为N，V3为C(Ra)，Ra为氢原子或C1-6烷氧基。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中为R2为C1-6烷基或卤素；n为1或2；R12c、R12d和R12e均为氢原子；E选自V1、V2和V3均为CH。
表A本公开的典型化合物包括但不限于：









本公开的另一方面涉及通式(IIIa)所示的化合物或其盐：
其中：
E、环B、R2、L2、V1、V2、V3和n如通式(III)中所定义。
在本公开一些实施方案中，所述的通式(IIIa)所示的化合物或其盐，其中V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；Ra如通式(I)中所定义。
表B本公开的典型中间体化合物包括但不限于：












本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，其包括以下步骤：
通式(IIa)所示的化合物或其盐与通式(IIb)所示的化合物或其盐发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
E、环B、R2、R3、V1、V2、V3、r、m和n如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，其包括以下步骤：
通式(IIIa)所示的化合物或其盐与通式(IIIb)所示的化合物或其盐发生缩合反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
XL为卤素；优选地，XL为氯；
E、环B、R2、L2、V1、V2、V3、R12c、R12d、R12e和n如通式(III)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备I型受体酪氨酸激酶抑制剂中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备HER2抑制剂中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备用于抑制HER2的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备用于治疗和/或预防HER2介导的疾病或病症的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐或包含其的药物组合物在制备通过抑制HER2治疗和/或预防疾病或病症的药物中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防癌症的药物中的用途；所述的癌症优选选自脑癌、乳腺癌、卵巢癌、肺癌、***癌、黑色素瘤、神经母细胞瘤、结直肠癌、***、输卵管癌、子宫内膜癌、***癌、胃癌、头颈癌、鼻咽癌、口腔癌、胆管癌、食道癌、肝癌、皮肤癌、间皮瘤、膀胱癌、肾细胞癌、肾盂癌、输尿管癌、小肠癌、胰腺癌、甲状腺癌、甲状旁腺癌、***癌、外阴癌、白血病、肾上腺癌、尿道癌、***癌、睾丸癌、骨癌、骨肉瘤、骨髓瘤、软组织肉瘤、垂体腺瘤、脑干神经胶质瘤、脊柱肿瘤和淋巴瘤；更优选地，所述的癌症选自乳腺癌、胃癌、肺癌、结直肠癌、胰腺癌、***癌、膀胱癌和卵巢癌；进一步优选地，所述的肺癌为非小细胞肺癌。
本公开还涉及一种抑制HER2的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种通过抑制HER2治疗和/或预防疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开还涉及一种治疗和/或预防HER2介导的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物。
本公开进一步涉及一种治疗和/或预防癌症的方法，其包括给予所需患者治疗有效量的通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物；所述的癌症优选选自脑癌、乳腺癌、卵巢癌、肺癌、***癌、黑色素瘤、神经母细胞瘤、结直肠癌、***、输卵管癌、子宫内膜癌、***癌、胃癌、头颈癌、鼻咽癌、口腔癌、胆管癌、食道癌、肝癌、皮肤癌、间皮瘤、膀胱癌、肾细胞癌、肾盂癌、输尿管癌、小肠癌、胰腺癌、甲状腺癌、甲状旁腺癌、***癌、外阴癌、白血病、肾上腺癌、尿道癌、***癌、睾丸癌、骨癌、骨肉瘤、骨髓瘤、软组织肉瘤、垂体腺瘤、脑干神经胶质瘤、脊柱肿瘤和淋巴瘤；更优选地，所述的癌症选自乳腺癌、胃癌、肺癌、结直肠癌、胰腺癌、***癌、膀胱癌和卵巢癌；进一步优选地，所述的肺癌为非小细胞肺癌。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作药物。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用作HER2抑制剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于抑制HER2。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其通过抑制HER2治疗和/或预防疾病或病症。
本公开进一步涉及通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物，其用于治疗和/或预防HER2介导的疾病或病症。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防癌症；所述的癌症优选选自脑癌、乳腺癌、卵巢癌、肺癌、***癌、黑色素瘤、神经母细胞瘤、结直肠癌、***、输卵管癌、子宫内膜癌、***癌、胃癌、头颈癌、鼻咽癌、口腔癌、胆管癌、食道癌、肝癌、皮肤癌、间皮瘤、膀胱癌、肾细胞癌、肾盂癌、输尿管癌、小肠癌、胰腺癌、甲状腺癌、甲状旁腺癌、***癌、外阴癌、白血病、肾上腺癌、尿道癌、***癌、睾丸癌、骨癌、骨肉瘤、骨髓瘤、软组织肉瘤、垂体腺瘤、脑干神经胶质瘤、脊柱肿瘤和淋巴瘤；更优选地，所述的癌症选自乳腺癌、胃癌、肺癌、结直肠癌、胰腺癌、***癌、膀胱癌和卵巢癌；进一步优选地，所述的肺癌为非小细胞肺癌。
本公开所述的疾病或病症是通过抑制HER2来治疗和/或预防的疾病或病症。
在本公开一些方案中，所述的疾病或病症为癌症；所述癌症优选选自脑癌、 乳腺癌、卵巢癌、肺癌、***癌、黑色素瘤、神经母细胞瘤、结直肠癌、***、输卵管癌、子宫内膜癌、***癌、胃癌、头颈癌、鼻咽癌、口腔癌、胆管癌、食道癌、肝癌、皮肤癌、间皮瘤、膀胱癌、肾细胞癌、肾盂癌、输尿管癌、小肠癌、胰腺癌、甲状腺癌、甲状旁腺癌、***癌、外阴癌、白血病、肾上腺癌、尿道癌、***癌、睾丸癌、骨癌、骨肉瘤、骨髓瘤、软组织肉瘤、垂体腺瘤、脑干神经胶质瘤、脊柱肿瘤和淋巴瘤；更优选地，所述的癌症选自乳腺癌、胃癌、肺癌、结直肠癌、胰腺癌、***癌、膀胱癌和卵巢癌；进一步优选地，所述的肺癌为非小细胞肺癌。
在本公开一些方案中，所述的HER2为突变型HER2，优选为外显子20突变的HER2。其中外显子20突变优选为4个氨基酸YVMA(p.A775_G776insYVMA)的***突变。
作为一般性指导，本公开活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5- 二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，进一步优选具有3至8个环原子的环烷基(即3至8元环烷基)，更优选具有3至6个环原子的环烷基(即3至6元环烷基)，最优选具有5或6个环原子的环烷基(即5或6元环烷基)。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括： 其连接点可在任意位置；
等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)，例如至少含有一个氮原子的4至12元杂环基；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫 可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至11个环原子的螺杂环基(即7至11元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)，进一步优选具有8个环原子的稠杂环基(即8元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：
等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)，进一步优选具有7至8个环原子的桥杂环基(即7至8元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中 连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括：
等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的单环杂芳基(即5或6元单环杂芳基)或具有9至10个环原子的双环杂芳基(即9至10元双环杂芳基)，最优选环内含有1、2或3个选自氮、氧和硫的杂原子的5或6元单环杂芳基或环内含有1、2、3或4个选自氮、氧和硫的杂原子的9至10元双环杂芳基。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括：
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“氨基保护基”是指为了使分子其它部位进行反应时氨基保持不变，在氨基上引入的易于脱去的基团。非限制性的实例包括：(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基(Boc)、苄氧羰基(Cbz)、笏甲氧羰基(Fmoc)、烯丙氧羰基(Alloc)、三甲基硅乙氧羰基(Teoc)、甲氧羰基、乙氧羰基、邻苯二甲酰基(Pht)、对甲苯磺酰基(Tos)、三氟乙酰基(Tfa)、三苯甲基(Trt)、2,4-二甲氧基苄基(DMB)、乙酰基、苄基、烯丙基、对甲氧苄基等。
术语“羟基保护基”是指在羟基上引入的易于脱去的基团，用于阻断或保护羟基而在化合物的其它官能团上进行反应。非限制性的实例包括：三甲基硅基(TMS)、三乙基硅基(TES)、三异丙基硅基(TIPS)、叔丁基二甲基硅基(TBS)、叔丁基二苯基硅基(TBDPS)、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“氨基烷基”指烷基被一个或多个氨基取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结 构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，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，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物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在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺的平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、 11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
本公开的化合物，当其一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6633.3倍(即至少99.5％的氘掺入)。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选地(任选)被卤素或者氰基取代的C1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选为1至6个，更优选为1至3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例 如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(II)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
通式(IIa)所示的化合物或其盐与通式(IIb)所示的化合物或其盐，在碱性条件下，发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
E、环B、R2、R3、V1、V2、V3、r、m和n如通式(II)中所定义。
方案二
本公开通式(III)所示的化合物或其可药用的盐的制备方法，其包括以下步骤：
通式(IIIa)所示的化合物或其盐与通式(IIIb)所示的化合物或其盐，在碱性条件下，发生缩合反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
XL为卤素；优选地，XL为氯；
E、环B、R2、L2、V1、V2、V3、R12c、R12d、R12e和n如通式(III)中所定义。
上述合成方案中，所述的碱包括有机碱和无机碱，所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、乙酸钠、乙醇钠、叔丁醇钠或叔丁醇钾；所述的无机碱包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、无水碳酸钾、碳酸铯、氢氧化钠、氢氧化锂一水合物、氢氧化锂和氢氧化钾；优选地，方案一中所述的碱为叔丁醇钾；方案二中所述的碱为N,N-二异丙基乙胺。
上述合成方案优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、冰乙酸及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪或Bruker AVANCE NEO 500M，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)；waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)；THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC  1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品、药明康德等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮1

第一步
外-3-(对甲苯磺酰氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯1b
将外-3-羟基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯1a(1g，4.4mmol，上海韶远)，对甲苯磺酰氯(1g，5.24mmol)，4-二甲氨基吡啶(542mg，4.4mmol)溶于20mL二氯甲烷中，加入N,N-二异丙基乙胺(853mg，6.6mmol)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1b(1g，产率：59.5％)。
第二步
4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基乙酸酯1e
将4-氯喹唑啉-6-乙酸酯1c(200mg，898μmol，采用文献“Bioorganic&Medicinal Chemistry Letters,2009,19(19):5531–5538”公开的方法制备而得)溶于异丙醇(5mL)，加入4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯胺1d(216mg，898μmol，采用专利申请“WO2021156180A1”中说明书第33页方法1公开的方法制备而得)，80℃反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1e(200mg，产率：52.2％)。
MS m/z(ESI)：427.2[M+1]。
第三步
内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯1f
将化合物1e(200mg，469μmol)溶于N,N-二甲基甲酰胺(15mL)，加入化合物1b(197mg，516μmol)，碳酸铯(229mg，703μmol)，80℃反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1f(150mg，产率：53.8％)。
MS m/z(ESI)：594.2[M+1]。
第四步
6-((内-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3- 甲基苯基)喹唑啉-4-胺2,2,2-三氟乙酸盐1g
将化合物1f(100mg，168μmol)溶于2mL二氯甲烷中，0℃下加入1mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物1g(100mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：494.2[M+1]。
第五步
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮1
将粗品化合物1g(100mg，168μmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(42mg，329μmol)，冰浴下加入丙烯酰氯(18mg，197μmol)，搅拌反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物1(15mg，产率：16.6％)。
MS m/z(ESI)：548.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.72(s,1H),8.61(s,1H),8.52(d,1H),8.24(s,1H),7.90(d,1H),7.70(s,1H),7.67(d,1H),7.63(d,1H),7.44(d,1H),7.08(d,1H),6.93(d,1H),6.83(s,1H),6.58-6.53(m,1H),6.41-6.37(m,1H),5.74(d,1H),4.90-4.88(m,1H),4.83-4.81(m,1H),4.44-4.42(m,1H),2.42-2.40(m,1H),2.37-2.31(m,3H),2.29(s,3H),2.28-2.26(m,2H),2.09-2.02(m,2H)。
实施例2
1-(内-3-((4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮2
采用实施例1中的合成路线，将第二步原料化合物1d替换为3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(采用专利申请“WO2021156178A1”中说明书第34页方法1公开的方法制备而得)得到标题化合物2(10mg，11％)。
MS m/z(ESI)：561.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.68(s,1H),8.00(s,1H),7.90-7.87(m,2H),7.54(s,1H),7.42-7.35(m,5H),7.11(d,1H),6.89(d,1H),6.56-6.51(m,1H),6.42-6.39(m,1H),5.74(d,1H),4.83-4.78(m,2H),4.39(s,1H),3.87(s,3H),2.38-2.36(m,1H),2.34(s,3H),2.30-2.27(m,3H),2.24-2.08(m,4H)。
实施例3
6-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)嘧啶并[5,4-d]嘧啶-4-胺3
第一步
N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-6-(甲磺酰基)嘧啶并[5,4-d]嘧啶-4-胺3b
将N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-6-(甲硫基)嘧啶并[5,4-d]嘧啶-4-胺3a(1g，3.32mmol，采用专利申请“WO2021156178A1”中说明书第40页化合物J公开的方法制备而得)溶于二氯甲烷(25mL)，加入间氯过氧苯甲酸(482mg，2.8mmol)，搅拌反应0.5小时，反应液中加入饱和碳酸氢钠水溶液淬灭，用二氯甲烷萃取(20mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物3b(650mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：462.1[M+1]。
第二步
6-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)嘧啶并[5,4-d]嘧啶-4-胺3
将粗品化合物3b(35mg，75.8μmol)，((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(15mg，94μmol，药明康德)溶于二氯甲烷(2mL)，加入叔丁醇钾(16mg，142μmol)，60℃下搅拌反应1小时，反应液中加入水，用二氯甲烷萃取(5mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物3(5.3mg，产率：10.4％)。
MS m/z(ESI)：541.1[M+1]。
1H NMR(500MHz,CDCl3):δ9.28(s,1H),8.73(s,1H),8.59(s,1H),7.88(s,1H),7.77(s,1H),7.69(d,1H),7.38-7.34(m,2H),7.10(d,1H),6.95(d,1H),5.42-5.35(m,1H),4.37(d,1H),4.27(d,1H),3.88(s,3H),3.37-3.22(m,3H),3.05(s,1H),2.39(s, 3H),2.26-2.19(m,2H),2.08-2.00(m,3H),1.95(s,1H)。
实施例4
1-(内-3-((7-甲氧基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮4
第一步
内-3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯4b
将4-氯-7-甲氧基喹唑啉-6-酚4a(140mg，664μmol，江苏艾康)，化合物1a(181mg，797μmol)，三苯基膦(262mg，997μmol)溶于四氢呋喃(5mL)中，冰浴下滴加偶氮二甲酸二异丙酯(269mg，1.33mmol，上海韶远)，自然恢复至室温反应16小时，反应液减压浓缩后，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物4b(270mg，产率：96％)。
MS m/z(ESI)：420.2[M+1]。
第二步
6-((内-8-氮杂双环[3.2.1]辛-3-基)氧基)-7-甲氧基-N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)喹唑啉-4-胺盐酸盐4c
将化合物4b(60mg，142μmol)，3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(36.2mg，142μmol)溶于异丙醇(5mL)，加入2滴4M氯化氢异丙醇溶液，80℃反应1小时，反应液减压浓缩即得到粗品标题化合物4c(90mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI)：537.2[M+1]。
第三步
1-(内-3-((7-甲氧基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮4
将粗品化合物4c(76mg，140μmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(55mg，424μmol)，冰浴下加入丙烯酰氯(15mg，169μmol)，反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物4(10mg，产率：11.9％)。MS m/z(ESI):591.2[M+1]。
1H NMR(500MHz,CDCl3)：δ8.64(s,1H),7.96(s,1H),7.86(s,1H),7.50(s,1H),7.41-7.31(m,4H),7.09(dd,1H),6.87(d,1H),6.53(dd,1H),6.39(d,1H),5.74-5.68(m,1H),4.82(d,1H),4.78(d,1H),4.38(d,1H),4.01(s,3H),3.87(s,3H),2.45(d,1H),2.41-2.32(m,1H),2.29(s,3H),2.27-2.20(m,2H),2.16(d,1H),2.12(d,1H),2.07-2.01(m,3H)。
实施例5
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮5
采用实施例4中的合成路线，将第二步原料化合物3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺替换为化合物1d得到标题化合物5(20mg，18.3％)。
MS m/z(ESI)：578.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.69(s,1H),8.51(d,1H),8.24(s,1H),8.16(s,1H),7.68(s,1H),7.65(d,1H),7.44(s,1H),7.30(s,1H),7.08(d,1H),6.95-6.89(m,1H),6.86(s,1H),6.56(dd,1H),6.39(d,1H),5.72(d,1H),4.89(s,1H),4.80(d,1H),4.42(s,1H),4.03(s,3H),2.49(d,1H),2.39(t,1H),2.30(d,1H),2.25(d,1H),2.23(s,3H),2.21-2.11(m,1H),2.06(d,3H)。
实施例6
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮6

第一步
外-3-((4-氯-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯6b
将化合物4a(100mg，474μmol，江苏艾康)，内-3-羟基-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯6a(130mg，570μmol，上海毕得)，三苯基膦(186mg，712μmol)溶于四氢呋喃(5mL)中，冰浴下滴加偶氮二甲酸二异丙酯(192mg，949μmol)，自然恢复室温反应16小时，反应液减压浓缩后，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物6b(180mg，产率：90.3％)。
MS m/z(ESI)：420.2[M+1]。
第二步
6-((外-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-7-甲氧基喹唑啉-4-胺盐酸盐6c
将化合物6b(180mg，428μmol)，化合物1d(103mg，428μmol)溶于异丙醇(3mL)，加入0.1mL 4M氯化氢异丙醇溶液，80℃反应1小时，反应液减压浓缩即得到粗品标题化合物6c(220mg)，不经纯化，直接用于下一步反应。
MS m/z(ESI)：524.2[M+1]。
第三步
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮6
将粗品化合物6c(220mg，393μmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(152mg，1.2mmol)，冰浴下加入丙烯酰氯(45.6mg，504μmol)，反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物6(100mg，产率：41.2％)。
MS m/z(ESI):578.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.70(s,1H),8.52(d,1H),8.25(s,1H),7.85(s,1H),7.67(d,1H),7.64-7.58(m,1H),7.51(s,1H),7.29(s,1H),7.09(d,1H),6.93(dd,1H),6.82(d,1H),6.55(dd,1H),6.47-6.40(m,1H),5.79-5.73(m,1H),4.86(d,1H),4.80(dt,1H),4.47(d,1H),4.00(s,3H),2.31(dd,1H),2.23(s,4H),2.12(dd,1H),2.02(td,2H),1.91-1.78(m,2H),1.72(td,1H)。
实施例7
1-(内-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮7
第一步
内-3-((4-氯喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯7b
将4-氯喹唑啉-6-酚7a(20mg，110μmol，采用文献“European Journal of Medicinal Chemistry,2018,vol.147,p.130-149”公开的方法制备而得)，化合物1a(30mg，133μmol)，三苯基膦(58mg，221μmol)溶于四氢呋喃(5mL)中，冰浴下滴加偶氮二甲酸二异丙酯(34mg，166μmol)，自然恢复至室温后反应16小时。反应液减压浓缩后，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物7b(40mg，产率：92.6％)。
MS m/z(ESI：390.2[M+1]。
第二步
内-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯7c
将化合物7b(40mg，102μmol)溶于异丙醇(2mL)，加入4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺(25mg，102μmol，采用专利申请“WO2020057511A1”中说明书第95页example 1公开的方法制备而得)，80℃反应1小时，反应液减压 浓缩得到粗品标题化合物7c(60mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：595.2[M+1]。
第三步
6-((内-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)喹唑啉-4-胺2,2,2-三氟乙酸盐7d
将粗品化合物7c(60mg，101μmol)溶于1mL二氯甲烷中，0℃下加入0.5mL三氟乙酸，搅拌反应2小时，反应液减压浓缩得到粗品标题化合物7d(62mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：495.2[M+1]。
第四步
1-(内-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮7
将粗品化合物7d(62mg，101μmol)溶于2mL二氯甲烷中，加入N,N-二异丙基乙胺(39mg，303μmol)，冰浴下加入丙烯酰氯(14mg，152μmol)，搅拌反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物7。
MS m/z(ESI)：549.2[M+1]。
实施例8
1-(外-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮8
采用实施例7中的合成路线，将第一步原料化合物1a替换为化合物6a得到标题化合物8(30mg，产率：27％)。
MS m/z(ESI)：549.2[M+1]。
1H NMR(500MHz,CDCl3):δ9.22(s,1H),8.73(s,1H),8.35(s,1H),7.91(d,1H),7.74(s,1H),7.69(d,1H),7.62(s,1H),7.49(d,1H),7.37(s,1H),7.16(d,1H),6.92(s,1H),6.56(dd,1H),6.46(d,1H),5.78(d,1H),4.93-4.86(m,2H),4.50(d,1H),2.35-2.31(m,1H),2.28(s,3H),2.26-2.23(m,1H),2.19(m,1H),2.09-2.04(m,1H),2.01-1.90(m,2H),1.85-1.77(m,2H)。
实施例9
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮9
采用实施例1中的合成路线，将第一步原料化合物1a替换为化合物6a得到标题化合物9(100mg，产率：44％)。
MS m/z(ESI):548.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.72(s,1H),8.52(d,1H),8.25(s,1H),8.21(s,1H),7.89(d,1H),7.65(d,1H),7.59(dd,2H),7.46(dd,1H),7.07(d,1H),6.93(dd,1H),6.78(d,1H),6.55(dd,1H),6.47-6.40(m,1H),5.79-5.73(m,1H),4.89(dt,2H),4.47(d,1H),2.36-2.28(m,1H),2.21(s,4H),2.14(q,1H),2.05-1.92(m,2H),1.91-1.83(m,1H),1.82-1.75(m,2H)。
实施例10
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮10
第一步
内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯10a
将化合物7b(1.2g，3mmol)溶于异丙醇(5mL)，加入4-([1,2,4]***并[1,5-a] 吡啶-7-基氧基)-2-氟-3-甲基苯胺(845mg，3.27mmol，采用专利申请“WO2022003575A1”中说明书第143页Example 95公开的方法制备而得)，80℃反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物10a(1.05g，产率：55.7％)。
MS m/z(ESI)：612.2[M+1]。
第二步
6-((内-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)喹唑啉-4-胺盐酸盐10b
将化合物10a(1.05g，1.7mmol)溶于甲醇(10mL)，加入0.1mL 4M氯化氢1,4-二氧六环溶液，搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物10b(940mg)，粗产品不经纯化，直接用于下一步反应。
MS m/z(ESI)：512.2[M+1]。
第三步
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮10
将粗品化合物10b(250mg，488.7μmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(126mg，974μmol)，冰浴下加入丙烯酰氯(50mg，552.4μmol)，搅拌反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物10(110mg，产率：39.7％)。
MS m/z(ESI)：566.2[M+1]。
1H NMR(500MHz,MeOD):δ8.80-8.78(d,1H),8.41(s,1H),8.33(s,1H),7.84-7.82(m,1H),7.77(s,1H),7.60-7.56(m,2H),7.14-7.10(m,2H),7.02-7.01(m,1H),6.79-6.74(m,1H),6.35(dd,1H),5.81(dd,1H),4.97-4.93(m,1H),4.76-4.73(m,1H),4.61-4.59(m,1H),2.44-2.17(m,10H),2.06-2.02(m,1H)。
实施例11
1-(内-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮11
采用实施例4中的合成路线将第二步原料3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺替换为4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺得到标题 化合物11(6mg，产率：15.5％)。
MS m/z(ESI)：579.2[M+1]。
1H NMR(500MHz,CDCl3):δ9.22(s,1H),8.69(s,1H),8.35(s,1H),8.10(s,1H),7.70(s,1H),7.68(d,1H),7.39(s,1H),7.31(s,1H),7.12(d,1H),6.89(s,1H),6.56(dd,1H),6.46-6.34(m,1H),5.73(d,1H),4.86(s,1H),4.84-4.77(m,1H),4.42(s,2H),4.03(s,3H),2.52-2.47(m,1H),2.40-2.35(m,1H),2.31-2.26(m,1H),2.25(s,3H),2.23-2.12(m,2H),2.08-2.03(m,2H)。
实施例12
1-(外-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮12
第一步
外-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯12a
将化合物6b(30mg，71μmol)，4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺(20mg，83μmol)溶于异丙醇(4mL)，80℃反应14小时，反应液减压浓缩即得到粗品标题化合物12a(44mg)，粗产品不经纯化，直接用于下一步反应。
MS m/z(ESI)：625.2[M+1]。
第二步
6-(外-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)-7-甲氧基喹唑啉-4-胺2,2,2-三氟乙酸盐12b
将粗品化合物12a(40mg，64μmol)溶于1mL二氯甲烷中，冰浴下加入0.5mL三氟乙酸，自然恢复室温搅拌反应2小时，反应液减压浓缩得到粗品标题化合物12b(40mg)，产品不经纯化，直接用于下一步反应。
MS m/z(ESI)：525.2[M+1]。
第三步
1-(外-3-((4-((4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮12
将粗品化合物12b(40mg，62μmol)溶于2mL二氯甲烷中，加入N,N-二异丙基乙胺(22mg，170μmol)，冰浴下加入丙烯酰氯(5.6mg，62μmol)，搅拌反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)，得到标题化合物12(10mg，产率：30％)。
MS m/z(ESI)：579.2[M+1]。
1H NMR(500MHz,CDCl3):δ9.22(d,1H),8.70(s,1H),8.35(s,1H),7.71(d,1H),7.66(dd,1H),7.49(d,1H),7.37(s,1H),7.16(d,1H),6.92(d,1H),6.56(dd,1H),6.44(dd,1H),5.77(dd,1H),4.88(d,1H),4.80(tt,1H),4.56-4.42(m,1H),4.02(s,3H),2.32-2.29(m,1H),2.28(s,3H),2.27-2.10(m,2H),2.04(t,3H),1.86(q,3H)。
实施例13
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮13
采用实施例12中的合成路线，将第一步原料4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺替换为4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯胺得到标题化合物13(15mg，36％)。
MS m/z(ESI):596.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.73(d,1H),8.54(dd,1H),8.49(d,1H),8.26(d,1H),7.45(s,1H),7.32(d,1H),7.01(d,1H),6.93(dt,1H),6.88(d,1H),6.62-6.34(m,2H),5.77(dt,1H),4.98-4.79(m,2H),4.50(s,1H),4.03(d,3H),2.36(d,1H),2.25(s,1H),2.17(s,3H),2.05(d,3H),1.91(s,2H),1.79(t,2H)。
实施例14
1-(外-3-((7-甲氧基-4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮14
采用实施例12中的合成路线，将第一步原料4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺替换为3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺得到标题化合物14(12mg，产率：29％)。
MS m/z(ESI):591.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.63(d,1H),8.37(s,1H),7.83(d,1H),7.69-7.64(m,1H),7.45(s,1H),7.37-7.33(m,1H),7.31(s,1H),7.24(d,1H),7.18(s,1H),7.13-7.07(m,1H),6.84(dt,1H),6.50(dq,1H),6.40(d,1H),5.76-5.70(m,1H),4.77(dd,2H),4.40(s,1H),3.96(d,3H),3.85(d,3H),2.25(d,4H),2.17(dd,2H),2.07-1.97(m,2H),1.80(s,1H),1.72(s,1H),1.61(s,1H)。
实施例15
1-(外-3-((4-((2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮15
采用实施例12中的合成路线，将第一步原料4-([1,2,4]***并[1,5-c]嘧啶-7-基氧基)-3-甲基苯胺替换为2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(采用专利申请“WO2022003575A1”中说明书第75页中间体实施例G公开的方法制备而得)得到标题化合物15(20mg，产率：45％)。
MS m/z(ESI):609.2[M+1]。
1H NMR(500MHz,MeOD):δ8.33(t,1H),8.16(d,1H),7.80(d,1H),7.60(t,1H),7.33(s,1H),7.27(d,1H),7.20(d,1H),7.15(d,1H),6.82-6.70(m,2H),6.36(d,1H),5.81(d,1H),5.08(s,2H),4.65(s,1H),4.07-3.90(m,6H),2.42(s,1H),2.34(s,1H),2.30(s,3H),2.06(d,4H),1.89(d,1H),1.76(s,1H)。
实施例16
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮16
第一步
内-3-((4-(甲氧基羰基)-5-硝基吡啶-2-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯16b
将化合物6a(1g，4.6mmol)溶于N,N-二甲基甲酰胺(20mL)，冰浴下加入氢化钠(212mg，5.54mmol，60％purity)，保持温度反应20分钟后加入2-氯-5-硝基异烟酸甲酯16a(1.26g，5.54mmol，上海毕得)，35℃反应30分钟后继续室温搅拌16小时，反应液中加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物16b(600mg，产率：31.8％)。
MS m/z(ESI):408.2[M+1]。
第二步
内-3-((5-氨基-4-(甲氧基羰基)吡啶-2-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯16c
将化合物16b(500mg，1.2mmol)溶于甲醇(20mL)，加入10％钯碳催化剂(湿)(50mg)，氢气氛围下，搅拌反应14小时，反应液过滤，滤液减压浓缩即得粗品标题化合物16c(360mg)，产物不经纯化，直接用于下步反应。
MS m/z(ESI)：378.2[M+1]。
第三步
内-3-((4-羟基吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯16d
将粗品化合物16c(200mg，529.9μmol)溶于乙醇(20mL)，加入醋酸甲脒(276mg，2.6mmol，上海韶远)，80℃搅拌反应14小时，反应液冷却至室温后减压浓 缩，残余物中加入水，用二氯甲烷萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得粗品标题化合物16d(160mg)，产物不经纯化，直接用于下步反应。
MS m/z(ESI):373.2[M+1]。
第四步
内-3-((4-氯吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯16e
将粗品化合物16d(160mg，429.66μmol)溶于甲苯(10mL)，加入三氯氧磷(329.4mg，2.15mmol)，N,N-二异丙基乙胺(55.42mg，429.6μmol)，80℃搅拌2小时，反应液减压浓缩，残余物经乙酸乙酯溶解后倒入冰水中，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物16e(100mg)，产品不经纯化直接用于下一步反应。
MS m/z(ESI)：391.1[M+1]。
第五步
内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯16f
将粗品化合物16e(100mg，255.8μmol)溶于异丙醇(10mL)，加入化合物1d(61.5mg，255.8μmol)，80℃搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物16f(150mg)，产品不经纯化直接用于下步反应。
MS m/z(ESI)：595.2[M+1]。
第六步
6-((内-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)吡啶并[3,4-d]嘧啶-4-胺盐酸盐16g
将粗品化合物16f(150mg，252.2μmol)溶于二氯甲烷(3mL)，加入4M氯化氢1,4-二氧六环溶液(1mL)，搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物16g(130mg)，粗产物不经纯化，直接用于下一步反应。
MS m/z(ESI)：495.2[M+1]。
第七步
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮16
将粗品化合物16g(130mg，245μmol)溶于5mL二氯甲烷中，加入N,N-二异丙基乙胺(63mg，490mmol)，冰浴下加入丙烯酰氯(24.4mg，269μmol)，反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物16(110mg，产率：39.7％)。
MS m/z(ESI)：549.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.97(s,1H),8.97-8.91(m,2H),8.58(s,1H),8.39(s,1H),7.92(s,2H),7.90(d,1H),7.25(d,1H),7.04(dd,1H),6.82(d,1H),6.75(dd,2H),6.20(dd,1H),5.71(dd,1H),5.45(s,1H),4.60-4.55(m,2H),2.32-2.24(m,2H),2.22(s,3H),2.18(d,2H),2.04-1.91(m,3H)。
实施例17
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮17
第一步
4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-酚17b
将4-氯-7-乙氧基喹唑啉-6-酚17a(140mg，623μmol，采用专利申请“WO2021231400A1”中说明书第54页Example 3公开的方法制备而得)溶于异丙醇(2mL)，加入4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯胺(160mg，623μmol)，110℃下搅拌反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物17b(92mg，产率：33％)。
MS m/z(ESI)：447.2[M+1]。
第二步
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)-7-乙氧基喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮17
采用实施例1中的合成路线第三步至第五步，将第三步原料化合物1e替换为化合物17b得到标题化合物17(1.6mg，产率：1.4％)。
MS m/z(ESI)：610.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.43(s,1H),8.98(d,1H),8.42(s,1H),8.38(s,1H),7.81(s,1H),7.49(t,1H),7.21(s,1H),7.12-7.08(m,1H),6.95(d,1H),6.79-6.74(m,1H),6.66(s,1H),6.19(dd,1H),5.70(dd,1H),4.89(t,1H),4.55(dd,2H),4.21(q,2H),2.16(d,3H),2.14-1.96(m,7H),1.88(t,1H),1.43(t,3H)。
实施例18
1-(内-3-((4-((2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮18
采用实施例1中的合成路线，将第二步原料化合物1d替换为2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺得到标题化合物18(15mg，产率：25％)。
MS m/z(ESI)：579.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.70(s,1H),8.09(t,1H),7.96-7.79(m,2H),7.49(s,1H),7.44(dd,1H),7.40-7.33(m,2H),7.16(d,1H),7.10(dd,1H),6.73(dd,1H),6.55(dd,1H),6.44(dd,1H),5.75(dd,1H),4.86-4.81(m,2H),4.41(d,1H),3.88(s,3H),2.39-2.34(m,2H),2.30(s,3H),2.29-2.21(m,2H),2.19-2.14(m,2H),2.10-1.99(m,2H)。
实施例19
1-(外-3-((4-((2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮19
第一步
1-(外-3-((4-氯喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮19a
将化合物7a(27mg，149μmol)，化合物6a(34mg，149μmol)，三苯基膦(80mg，305μmol)溶于四氢呋喃(5mL)中，冰浴下滴加偶氮二甲酸二异丙酯(60mg，296 μmol)，自然恢复室温反应16小时，反应液减压浓缩后，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物19a(34mg，产率：58.3％)。
MS m/z(ESI)：390.2[M+1]。
第二步
6-((外-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)喹唑啉-4-胺盐酸盐19b
将化合物19a(34mg，87.2μmol)，2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺(25mg，92.1μmol)溶于异丙醇(3mL)，加入0.1mL 4M盐酸异丙醇溶液，80℃反应1小时，反应液减压浓缩即得到粗品标题化合物19b(45mg)，粗产物不经纯化，直接用于下一步反应。
MS m/z(ESI)：525.2[M+1]。
第三步
1-(外-3-((4-((2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮19
将粗品化合物19b(45mg，80.3μmol)溶于3mL二氯甲烷中，加入N,N-二异丙基乙胺(33mg，255.3mmol)，冰浴下加入丙烯酰氯(10mg，110μmol)，反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物19(15mg，产率：30％)。
MS m/z(ESI)：579.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.70(s,1H),8.17(t,1H),7.96-7.77(m,2H),7.54-7.44(m,2H),7.41-7.33(m,2H),7.10(dd,1H),6.74(dd,1H),6.55(dd,1H),6.45(dd,1H),5.77(dd,1H),4.92(tq,2H),4.65-4.36(m,1H),3.88(s,3H),2.42-2.32(m,1H),2.31(s,3H),2.30-2.14(m,3H),2.13-2.06(m,1H),2.05-1.88(m,2H),1.88-1.76(m,2H)。
实施例20
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮20
采用实施例16中的合成路线，将第五步原料化合物1d替换为4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯胺得到标题化合物20(10mg，产率：6.4％)。
MS m/z(ESI)：567.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.70(s,1H),8.09(t,1H),7.96-7.79(m,2H),7.49(s,1H),7.44(dd,1H),7.40-7.33(m,2H),7.16(d,1H),7.10(dd,1H),6.73(dd,1H),6.55(dd,1H),6.44(dd,1H),5.75(dd,1H),4.83(dt,2H),4.41(d,1H),2.39-2.34(td,2H),2.30(s,3H),2.28-2.23(m,1H),2.19-2.14(m,2H),2.08-2.02(m,2H)。
实施例21
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮21
第一步
外-3-((4-氯吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯21a
采用实施例16中的合成路线第一步至第四步，将第一步原料化合物6a替换为化合物1a得到标题化合物21a(200mg，产率：21.2％)。
MS m/z(ESI):391.2[M+1]。
第二步
外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯21b
将化合物21a(15mg，38.3μmol)溶于异丙醇(2mL)，加入4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯胺(10mg，38.7μmol)，80℃反应1小时，反应液减压浓缩得到粗品标题化合物21b(23mg)，产品不经纯化，直接用于下步反应。
MS m/z(ESI):613.2[M+1]。
第三步
6-((外-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)吡啶并[3,4-d]嘧啶-4-胺2,2,2-三氟乙酸盐21c
将化合物21b(23mg，37.5μmol)溶于二氯甲烷(3mL)，加入0.5mL三氟醋酸(1mL)，搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物21c(24mg)，粗产物不经纯化，直接用于下一步反应。
MS m/z(ESI)：513.2[M+1]。
第四步
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-2-氟-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮21
将粗品化合物21c(24mg，37μmol)溶于2mL二氯甲烷中，加入N,N-二异丙基乙胺(48mg，371μmol)，冰浴下加入丙烯酰氯(3.5mg，38μmol)，反应1小时，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物21(15mg，产率：71％)。MS m/z(ESI)：567.2[M+1]。
1H NMR(500MHz,CDCl3):δ9.04(s,1H),8.74(s,1H),8.55(dd,2H),8.26(s,1H),7.69(s,1H),7.06(s,1H),7.02(dd,1H),6.95-6.89(m,2H),6.57(dd,1H),6.44(dd,1H),5.79-5.71(m,2H),4.91(d,1H),4.49(s,1H),2.42(s,1H),2.27(s,1H),2.22(d,3H),2.21-2.14(m,1H),1.99(h,4H),1.77(t,1H)。
实施例22
1-(内-3-((8-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)嘧啶并[5,4-d]嘧啶-2-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮22
第一步
内-3-((8-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)嘧啶并[5,4-d]嘧啶-2-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯22b
将化合物6a(78.8mg，346μmol)溶于N,N-二甲基甲酰胺(20mL)，冰浴下加入氢化钠(18.5mg，462μmol，60％purity)，保持温度反应20分钟后加入N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-6-(甲基亚磺酰基)嘧啶并[5,4-d]嘧啶-4-胺22a(100mg，231μmol，采用专利申请“WO2021156180A1”中说明书第38页“化 合物K的合成”公开的方法制备而得)，60℃反应1小时后降至室温，反应液中加入水淬灭，用乙酸乙酯萃取(10mL×2)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物22b(80mg，产率：58％)。
MS m/z(ESI)：596.2[M+1]。
第二步
1-(内-3-((8-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)嘧啶并[5,4-d]嘧啶-2-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮22
采用实施例1中的合成路线第四步至第五步，将第四步原料化合物1f替换为化合物22b得到标题化合物22(15mg，产率：20％)。
MS m/z(ESI):550.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.81(s,1H),9.36(s,1H),8.95(d,1H),8.65(s,1H),8.39(s,1H),7.98-7.91(m,2H),7.26(d,1H),7.04(dd,1H),6.82-6.73(m,2H),6.21(dd,1H),5.80(d,1H),5.72(dd,1H),4.57(d,2H),2.22(s,5H),2.13-1.96(m,6H)。
实施例23
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-8,9-二氢呋喃并[2,3-h]喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮23

第一步
内-3-(对甲苯磺酰基氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯23a
将化合物6a(4g，17.6mmol)，对甲苯磺酰氯(4g，21.1mmol)，4-二甲氨基吡啶(2.17g，17.6mmol)溶于50mL二氯甲烷中，加入N,N-二异丙基乙胺(2.27mg，17.6mmol)，搅拌反应16小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物23a(4.5g，产率：67％)。
第二步
6-碘-8,9-二氢呋喃并[2,3-h]喹唑啉-4-酚23c
将4-氨基-7-碘-2,3-二氢苯并呋喃-5-羧酸甲酯23b(1g，3.13mmol，采用专利申请“WO2021249475A1”中说明书第93页实施例11公开的方法制备而得)溶于乙醇(50mL)，加入醋酸甲脒(1.6g，15.3mmol，上海韶远)，回流搅拌反应14小时，反应液冷却至室温后，减压浓缩除去大部分溶剂，残余物中加入水，搅拌0.5小时，过滤，滤饼用水洗涤，干燥后即得粗品标题化合物23c(1g)，产物不经纯化，直接用于下步反应。
MS m/z(ESI)：315.2[M+1]。
第三步
4-氯-6-碘-8,9-二氢呋喃并[2,3-h]喹唑啉23d
将粗品化合物23c(500mg，1.59mmol)溶于三氯氧磷(20mL)，加入N,N-二异 丙基乙胺(41mg，317μmol)，100℃搅拌反应2小时，反应液减压浓缩，残余物溶于乙酸乙酯后倒入冰水中，用乙酸乙酯萃取(15mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得到粗品标题化合物23d(529mg)，产品不经纯化，直接用于下一步反应。
MS m/z(ESI)：333.1[M+1]。
第四步
N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)-6-碘-8,9-二氢呋喃并[2,3-h]喹唑啉-4-胺23e
将粗品化合物23d(300mg，902μmol)溶于异丙醇(20mL)，加入化合物1d(216mg，898μmol)，80℃反应2小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物23e(380mg，产率：78％)。
MS m/z(ESI)：537.2[M+1]。
第五步
4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-8,9-二氢呋喃并[2,3-h]喹唑啉-6-酚23f
将化合物23e(300mg，559.3μmol)溶于二甲亚砜(3mL)和水(1mL)，加入氢氧化钾(94mg，1.67mmol)，乙酰丙酮酸铜(15mg，57.3μmol，J&K)，N1,N2-双(4-羟基-2,6-二甲基苯基)草酰胺(18.4mg，56μmol，上海毕得)，氮气置换，95℃下反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物23f(60mg，产率：25％)。
MS m/z(ESI)：427.2[M+1]。
第六步
外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-8,9-二氢呋喃并[2,3-h]喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯23g
将化合物23f(60mg，140μmol)溶于N,N-二甲基甲酰胺(10mL)，加入化合物23b(86mg，281μmol)，碳酸铯(82mg，281μmol)，80℃反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物23g(75mg，产率：83％)。
MS m/z(ESI)：636.2[M+1]。
第七步
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)-8,9-二氢呋喃并[2,3-h]喹唑啉-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮23
采用实施例12中的合成路线第二步至第三步，将第二步原料化合物12a替换为化合物23g得到标题化合物23(40mg，产率：60％)。
MS m/z(ESI)：590.2[M+1]。
1H NMR(500MHz,MeOD):δ8.76(t,1H),8.43(s,1H),8.30(s,1H),7.80(d,1H),7.71 (s,1H),7.68-7.62(m,1H),7.21(d,1H),7.10(dd,1H),6.86(s,1H),6.76(dq,1H),6.36(d,1H),5.82(d,1H),5.15(s,1H),4.90(s,2H),4.78(s,1H),4.65(d,1H),3.56(m,2H),2.39(s,1H),2.33(d,1H),2.26(d,3H),2.17(s,1H),2.09-1.96(m,3H),1.85(t,1H),1.74(t,1H)。
实施例24
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮24
第一步
6-氯-3-硝基吡啶甲酰胺24b
将6-氯-2-氰基-3-硝基吡啶24a(5g，27.2mmol，上海乐研)分批加入90％的硫酸(50mL)中，70℃下搅拌反应3小时，反应液冷却至室温，倒入冰水中，有固体析出，过滤，滤饼用水洗涤，干燥后即得到粗品标题化合物24b(3g)，产品不经纯化，直接用于下一步反应。
MS m/z(ESI)：202.2[M+1]。
第二步
内-3-((6-甲酰氨基-5-硝基吡啶-2-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯24c
将化合物6a(676.6mg，3mmol)溶于二甲亚砜(10mL)，冰浴下加入叔丁醇钾(835mg，7.4mmol)，自然恢复室温搅拌反应30分钟后加入化合物24b(500mg，2.5mmol)的二甲亚砜(5mL)溶液，搅拌反应2小时，反应液中加入水淬灭，用乙酸乙酯萃取(10mL×3)，合并有机相，用无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，残余物用硅胶柱色谱法以洗脱体系A纯化得到标题化合物24c(500mg，产率：51.3％)。
MS m/z(ESI)：393.2[M+1]。
第三步
内-3-((5-氨基-6-甲酰氨基吡啶-2-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯24d
将化合物24c(500mg，1.27mmol)溶于甲醇(10mL)，加入雷尼镍(150mg)，氢气氛下搅拌反应12小时，反应液过滤，滤液减压浓缩即得粗品标题化合物24d(320mg)，产物不经纯化，直接用于下步反应。
MS m/z(ESI)：363.2[M+1]。
第四步
内-3-((4-羟基吡啶并[3,2-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯24e
将粗品化合物24d(320mg，882.9μmol)与乙酸二乙氧基甲酯(5mL，J&K)混合，100℃下搅拌16小时，反应液冷却至室温后减压浓缩，残余物用硅胶柱色谱法以洗脱体系C纯化得到标题化合物24e(110mg，产率：33％)。
MS m/z(ESI)：373.2[M+1]。
第五步
1-(内-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,2-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮24
采用实施例16中的合成路线第四步至第七步，将第四步原料化合物16d替换为化合物24e得到标题化合物24(5mg，产率：10.8％)。
MS m/z(ESI)：549.2[M+1]。
1H NMR(500MHz,MeOD):δ8.76(d,1H),8.57(s,1H),8.30(s,1H),8.11(d,1H),7.95-7.88(m,2H),7.40(d,1H),7.21(d,1H),7.09(dd,1H),6.83-6.73(m,2H),6.35(dd,1H),5.91(t,1H),5.81(dd,1H),5.36(dd,1H),4.79-4.73(m,1H),4.63-4.58(m,1H),2.46-2.33(m,3H),2.27(s,3H),2.26-2.15(m,3H),2.05(q,2H)。
实施例25
1-(内-3-((8-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)嘧啶并[5,4-d]嘧啶-2-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮25
采用实施例22中的合成路线，将第一步原料化合物22a替换为N-(3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)-6-(甲基亚磺酰基)嘧啶并[5,4-d]嘧啶-4-胺(采用专利申请“WO2021156178A1”中说明书第41页化合物K公开的方法制备而得)得到标题化合物25(15mg，产率：20％)。
MS m/z(ESI)：563.2[M+1]。
1H NMR(500MHz,MeOD):δ9.25(t,1H),8.58(d,1H),8.14(d,1H),7.83(s,1H),7.73(d,1H),7.60-7.54(m,1H),7.15(s,1H),7.12-7.08(m,1H),6.92(t,1H),6.77(t,1H),6.35(d,1H),5.84-5.75(m,2H),4.75(m,1H),4.60(m,1H),3.93(t,3H),2.44(t,3H),2.33(m,3H),2.28(s,1H),2.24-2.16(m,3H),2.05(m,1H)。
实施例26
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮26
第一步
外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯26a
将粗品化合物21a(1.7g，4.86mmol)溶于异丙醇(50mL)，加入化合物1d(1.17g，4.87mmol)，80℃下搅拌反应5小时，反应液减压浓缩即得到粗品标题化合物26a(2.8g)，产品不经纯化，直接用于下一步反应。
MS m/z(ESI):595.2[M+1]。
第二步
6-((外-8-氮杂双环[3.2.1]辛-3-基)氧基)-N-(4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)吡啶并[3,4-d]嘧啶-4-胺盐酸盐26b
将粗品化合物26a(2.8g，4.7mmol)溶于二氯甲烷(20mL)，加入20mL 4M氯化氢1,4-二氧六环溶液(20mL)，搅拌反应1小时，反应液减压浓缩即得到粗品标题化合物26b(2.5g)，产物不经纯化，直接用于下一步反应。
MS m/z(ESI):495.2[M+1]。
第三步
1-(外-3-((4-((4-([1,2,4]***并[1,5-a]吡啶-7-基氧基)-3-甲基苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮26
将粗品化合物26b(2.5g，4.7mmol)溶于20mL二氯甲烷中，加入N,N-二异丙基乙胺(1.8g，14mmol)，冰浴下加入丙烯酰氯(469mg，5.18mmol)，反应10分钟，反应液减压浓缩，残余物用高效液相制备色谱法纯化(Waters-2545，色谱柱：YMC Triart-Exrs C18,30*150mm,5μm；流动相：水相(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)得到标题化合物26(1.5g，产率：58％)。MS m/z(ESI):549.2[M+1]。
1H NMR(500MHz,DMSO-d6):δ9.86(s,1H),8.94(d,2H),8.58(s,1H),8.39(s,1H),7.95(d,1H),7.93-7.85(m,2H),7.23(d,1H),7.03(dd,1H),6.83-6.79(m,1H),6.78-6.73(m,1H),6.22(dd,1H),5.72(dd,1H),5.61(tt,1H),4.64(dt,2H),2.38-2.35(m,1H),2.27(dd,1H),2.20(s,3H),2.09-2.01(m,1H),1.97-1.84(m,3H),1.69(t,1H),1.55(t,1H)。
实施例27
1-(外-3-((4-((2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮27
采用实施例26中的合成路线，将第一步原料化合物1d替换为2-氟-3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺得到标题化合物27(50mg，产率：45.3％)。
MS m/z(ESI):580.2[M+1]。
1H NMR(500MHz,CDCl3):δ9.00(s,1H),8.68(s,1H),8.20(t,1H),7.89(s,1H),7.57(d,1H),7.40-7.35(m,2H),7.09(dd,1H),7.04(s,1H),6.73(dd,1H),6.57(dd,1H),6.44(dd,1H),5.78-5.68(m,2H),4.93-4.88(m,1H),4.48(d,1H),3.88(s,3H),2.41(dd,1H),2.31(d,4H),2.17(dt,1H),2.05(q,2H),1.96-1.91(m,1H),1.76(t,1H)。
实施例28
1-(外-3-((4-((3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯基)氨基)吡啶并[3,4-d]嘧啶-6-基)氧基)-8-氮杂双环[3.2.1]辛-8-基)丙-2-烯-1-酮28
采用实施例26中的合成路线，将第一步原料化合物1d替换为3-甲基-4-((1-甲基-1H-苯并[d]咪唑-5-基)氧基)苯胺得到标题化合物28(50mg，产率：47％)。
MS m/z(ESI):562.2[M+1]。
1H NMR(500MHz,CDCl3):δ8.96(s,1H),8.67(s,1H),8.12(s,1H),7.87(s,1H),7.67(d,1H),7.51(dd,1H),7.38-7.31(m,2H),7.09(dd,1H),6.89(d,1H),6.58(dd,1H),6.43(dd,1H),5.79-5.70(m,2H),4.89(d,1H),4.48(d,1H),3.87(s,3H),2.45(dd,1H),2.35(s,3H),2.25-2.15(m,2H),2.05(q,3H),1.93(s,1H),1.72(t,1H)。
生物学评价
以下结合测试例进一步描述解释本公开，但这些测试例并非意味着限制本公开的范围。
测试例1：Ba/F3细胞增值实验
取对数生长EGFR野生型Ba/F3细胞(Cobioer,货号:CBP73110)以2.5×103个细胞/100uL的生长培养基接种到96孔板中，对数生长期的HER2野生型Ba/F3细胞(Cobioer,货号:CBP73110)或HER2A775_G776insYVMA突变Ba/F3(Cobioer,货号:CBP73184)以5×103个细胞/100uL的生长培养基接种到96孔板中，放置37℃细胞培养箱过夜，第二天加入用培养基3倍梯度稀释的100uL/孔化合物，所有处理均以一式三份进行。继续在37℃细胞培养箱中培养72小时。进行Celltiter-Glo Luminescent细胞活力测定。
根据以下公式计算每个孔对应的细胞增殖率：增殖％＝(待测化合物孔G3-G0平均值)/(DMSO对照孔G3平均值-G0平均值)*100。根据每个梯度浓度孔对应的增殖率和其浓度，利用Prism Graphpad软件拟合细胞增殖的梯度曲线，并且计算化合物的GI50(GI50定义为细胞增殖抑制率为50％时对应的化合物浓度)。
HER2选择性抑制剂图卡替尼(tucatinib，参照专利WO2007059257A2中实施例11合成)结构如下：
表1本公开化合物对Ba/F3细胞增殖的抑制活性的GI50值
结论：本公开化合物对HER2外显子20YVMA***突变及HER2野生型依赖的Ba/F3细胞具有强效抑制增值的作用，并且相对于EGFR野生型依赖的Ba/F3细胞具有较强的选择性；并且，本公开化合物对HER2外显子20YVMA***突变的Ba/F3细胞增值抑制活性显著优于图卡替尼。
测试例2：药代动力学评价
TPGS：D-α-维生素E聚乙二醇琥珀酸酯
HPMC：羟丙基甲基纤维素
PEG400：聚乙二醇400
一、SD大鼠试验
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠灌胃(i.g.)给予实施例化合物后不同时刻血浆中的药物浓度。研究本公开化合物在SD大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例10化合物。
2.2试验动物
SD大鼠4只，雌雄各半，由维通利华实验动物技术有限公司提供。禁食一夜后分别灌胃给药。
2.3药物配制
分别称取一定量的实施例化合物，加5％DMSO+20％PEG400+70％(10％TPGS)+5％(1％HPMC K100LV)，配制成5mg/mL无色澄明溶液。
2.4给药
给药剂量为50mg/kg，给药体积为10.0mL/kg。
3、操作
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.2mL，置EDTA-K2抗凝试管中，10000rpm离心1分钟(4℃)，1小时内分离血浆，干冰保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。
测定不同浓度的药物给药后SD大鼠血浆中的待测化合物含量：取给药后各时刻的SD大鼠血浆样品50μL，25μL喜树碱(1μg/mL)和450μL乙腈，涡旋混合，并在3700rpm下离心10分钟。取上清液0.1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表2本公开化合物在SD大鼠体内的药代动力学参数
结论：本公开化合物在SD大鼠体内暴露量高，具有明显的药代动力学优势。
二、C57小鼠试验
1、摘要
以C57小鼠为受试动物，应用LC/MS/MS法测定了C57小鼠灌胃(i.g.)给予实施例化合物后不同时刻血浆中的药物浓度。研究本公开化合物在C57小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例10化合物、实施例18化合物和实施例26化合物。
2.2试验动物
C57小鼠27只，雌性，平均分成3组，由北京华阜康生物科技股份有限公司提供。分别灌胃给药。
2.3药物配制
分别称取一定量的实施例化合物，加5％DMSO+20％PEG400+70％(10％TPGS)+5％(1％HPMC K100LV)，配制成2.5mg/mL无色澄明溶液。
2.4给药
给药剂量为50mg/kg，给药体积为20.0mL/kg。
3、操作
于给药前及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时，由眼眶采血0.1mL，置EDTA-K2抗凝试管中，10000rpm离心2分钟(4℃)，1小时内分离血浆，-20℃保存待测。采血至离心过程在冰浴条件下操作。给药后2小时进食。
测定不同浓度的药物给药后C57小鼠血浆中的待测化合物含量：取给药后各时刻的C57小鼠血浆样品50μL，25μL拉贝洛尔(1μg/mL)和450μL乙腈，涡旋混合，并在3700rpm下离心10分钟。取上清液0.1μL进行LC/MS/MS分析。
4、药代动力学参数结果
表3本公开化合物在C57小鼠体内的药代动力学参数
结论：本公开化合物在C57小鼠体内暴露量高，具有明显的药代动力学优势。

Claims (23)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    环A为芳基或杂芳基；
    环B为7至10元稠杂环基或7至10元桥杂环基；
    G为N或C(RA)；
    RA选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基和氨基；
    V1为C(Ra)或N；
    V2和V3相同或不同，且各自独立地为C(Ra)或N；或者，V2为C(Rbb)，V3为C(Rcc)，且Rbb与Rcc与各自相连的碳原子一起形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基或杂芳基任选被选自卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    L1选自O、NRb1、C(O)、S、S(O)和S(O)2；
    L2选自O、NRb2、C(O)、(CRcRd)u、(CRcRd)uO、O(CRcRd)u、(CRcRd)uNRb2、NRb2(CRcRd)u、C(O)NRb2和NRb2C(O)；
    E为9至10元杂芳基，所述9至10元杂芳基任选被一个或多个R16取代；
    R16选自卤素、烷基、烯基、炔基、氰基、硝基、-OR4、-NR5R6、-C(O)R4、-C(O)OR4、-OC(O)R4、-C(O)NR5R6、-S(O)pR4、-S(O)pNR5R6、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、氨基烷基、氰基、-OR4a、-NR5aR6a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    Ra选自氢原子、卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-ORe、-(CH2)s-NRfRg、环烷基、杂环基、芳基和杂芳基；
    Rb1和Rb2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
    Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、烷基、羟基和羟烷基；
    R1选自氢原子、烷基和环烷基；
    各个R2相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-OR7、-(CH2)v-NR8R9、环烷基、杂环基、芳基和杂芳基；
    各个R3相同或不同，且各自独立地选自氧代基、卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RB取代；
    RB选自氧代基、卤素、烷基、烯基、炔基、氰基、-OR10b、-NR11bR12b、-C(O)R10b、-C(O)NR11bR12b、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；
    Re、R4、R4a、R7、R10a和R10b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    Rf、Rg、R5、R6、R8、R9、R11和R12在每次出现时相同或不同，且各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者Rf、Rg与相连的氮原子一起形成杂环基，或者R5、R6与相连的氮原子一起形成杂环基，或者R8、R9与相连的氮原子一起形成杂环基，或者R11、R12与相连的氮原子一起形成杂环基，所述的杂环基任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R13在每次出现时相同或不同，且各自独立地选自氢原子、烷基和环烷基；
    R5a、R6a、R11a、R12a、R11b和R12b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、氨基烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
    s为0、1或2；
    v为0、1或2；
    u为1、2、3或4；
    p为0、1或2；
    n为0、1、2、3或4；且
    m为0至10之间的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，
    其中：
    环A为芳基或杂芳基；
    环B为7至10元稠杂环基或7至10元桥杂环基；
    G为N或C(RA)；
    RA选自氢原子、卤素、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、氰基、羟基和氨基；
    V1、V2和V3相同或不同，且各自独立地为C(Ra)或N；
    L1选自O、NRb1、C(O)、S、S(O)和S(O)2；
    L2选自O、NRb2、C(O)、(CRcRd)u、(CRcRd)uO、O(CRcRd)u、(CRcRd)uNRb2、NRb2(CRcRd)u、C(O)NRb2和NRb2C(O)；
    E为9至10元杂芳基，所述9至10元杂芳基任选被一个或多个R16取代；
    R16选自卤素、烷基、烯基、炔基、氰基、硝基、-OR4、-NR5R6、-C(O)R4、-C(O)OR4、-OC(O)R4、-C(O)NR5R6、-S(O)pR4、-S(O)pNR5R6、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、氨基烷基、氰基、-OR4a、-NR5aR6a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    Ra选自氢原子、卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-ORe、-(CH2)s-NRfRg、环烷基、杂环基、芳基和杂芳基；
    Rb1和Rb2相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基和杂环基；
    Rc和Rd相同或不同，且各自独立地选自氢原子、卤素、烷基、羟基和羟烷基；
    R1选自氢原子、烷基和环烷基；
    各个R2相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、氰基、硝基、卤代烷基、羟烷基、-OR7、-(CH2)v-NR8R9、环烷基、杂环基、芳基和杂芳基；
    各个R3相同或不同，且各自独立地选自氧代基、卤素、烷基、烯基、炔基、氰基、硝基、-OR10、-NR11R12、-C(O)R10、-C(O)OR10、-OC(O)R10、-C(O)NR11R12、-NR13C(O)R10、-NR13C(O)OR10、-NR13C(O)NR11R12、-S(O)pR10、-S(O)pNR11R12、-NR13S(O)pR10、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、 炔基、卤代烷基、羟烷基、氨基烷基、氰基、-OR10a、-NR11aR12a、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R10在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被一个或多个RB取代；
    RB选自氧代基、卤素、烷基、烯基、炔基、氰基、-OR10b、-NR11bR12b、-C(O)R10b、-C(O)NR11bR12b、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、卤代烷基、羟烷基、烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；
    Re、R4、R4a、R7、R10a和R10b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    Rf、Rg、R5、R6、R8、R9、R11和R12在每次出现时相同或不同，且各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基，所述的烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者Rf、Rg与相连的氮原子一起形成杂环基，或者R5、R6与相连的氮原子一起形成杂环基，或者R8、R9与相连的氮原子一起形成杂环基，或者R11、R12与相连的氮原子一起形成杂环基，所述的杂环基任选被选自氧代基、卤素、烷基、烯基、炔基、卤代烷基、羟烷基、氨基烷基、氰基、羟基、烷氧基、卤代烷氧基、氨基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R13在每次出现时相同或不同，且各自独立地选自氢原子、烷基和环烷基；
    R5a、R6a、R11a、R12a、R11b和R12b在每次出现时相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、氨基烷基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环基烷基、芳基烷基和杂芳基烷基；
    s为0、1或2；
    v为0、1或2；
    u为1、2、3或4；
    p为0、1或2；
    n为0、1、2、3或4；且
    m为0至10之间的整数。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其中L1 为O。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中环A为6至10元芳基或5至10元杂芳基；优选地，环A为苯基。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中G为N。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R1为氢原子。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其中L2为O或(CRcRd)uO，Rc、Rd和u如利要求1中所定义；优选地，L2为O或CH2O。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    其中：
    r为0或1；
    环B、E、R2、R3、V1、V2、V3、m和n如利要求1中所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中环B为8元稠杂环基或7至8元桥杂环基；优选地，环B为R3可取代在所述环B任意可取代位置。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、-OR10和-C(O)R10，所述的C1-6烷基任选被选自卤素、氰基、-OR10a、-NR11aR12a、3至8元环烷基、3至8元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代； 且R10、R10a、R11a和R12a如权利要求1中所定义；优选地，R3为卤素或-C(O)R10；且R10如权利要求1中所定义。
  11. 根据权利要求1至7、9、10中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    其中：环B为7至10元含氮稠杂环基或7至10元含氮桥杂环基；
    R12c、R12d和R12e相同或不同，且各自独立地选自氢原子、卤素、C1-6烷基、3至8元环烷基和3至8元杂环基，所述的C1-6烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自氧代基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、羟基、氰基和氨基中的一个或多个取代基所取代；优选地，R12c、R12d和R12e相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；更优选地，R12c、R12d和R12e均为氢原子；且
    E、R2、L2、V1、V2、V3和n如权利要求1中所定义。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，其中E选自 X为N或CR16a；R16a、R16b和R16c相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；R16d选自氢原子、C1-6烷基和3至8元环烷基；R16为卤素或C1-6烷基；q为0、1、2或3。
  13. 根据权利要求1至12中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R2相同或不同，且各自独立地为C1-6烷基或卤素。
  14. 根据权利要求1、3至13中任一项所述的通式(I)所示的化合物或其可药用的盐，其中V1为C(Ra)或N；V2和V3相同或不同，且各自独立地为C(Ra)或N， 或者，V2为C(Rbb)，V3为C(Rcc)，且Rbb与Rcc与各自相连的碳原子一起形成5或6元环烷基或5或6元杂环基；Ra为氢原子或C1-6烷氧基。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下化合物：




  16. 一种通式(IIIa)所示的化合物或其盐：
    其中：
    E、环B、R2、L2、V1、V2、V3和n如权利要求11中所定义。
  17. 根据权利要求16所述的化合物或其盐，其选自以下化合物：




  18. 一种制备通式(II)所示的化合物或其可药用的盐的方法，其包括以下步骤：
    通式(IIa)所示的化合物或其盐与通式(IIb)所示的化合物或其盐发生亲核取代反应，得到通式(II)所示的化合物或其可药用的盐；
    其中：
    R为C1-6烷基；优选地，R为甲基；
    E、环B、R2、R3、V1、V2、V3、r、m和n如权利要求8中所定义。
  19. 一种制备通式(III)所示的化合物或其可药用的盐的方法，其包括以下步骤：
    通式(IIIa)所示的化合物或其盐与通式(IIIb)所示的化合物或其盐发生缩合反应，得到通式(III)所示的化合物或其可药用的盐；
    其中：
    XL为卤素；优选地，XL为氯；
    E、环B、R2、L2、V1、V2、V3、R12c、R12d、R12e和n如权利要求11中所定义。
  20. 一种药物组合物，所述药物组合物含有根据权利要求1至15中任一项所述的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  21. 根据权利要求1至15中任一项所述的化合物或其可药用的盐或根据权利要求20所述的药物组合物在制备HER2抑制剂中的用途。
  22. 根据权利要求1至15中任一项所述的化合物或其可药用的盐或根据权利要求20所述的药物组合物在制备通过抑制HER2治疗和/或预防疾病或病症的药物中的用途；优选地，所述的疾病或病症为癌症。
  23. 根据权利要求1至15中任一项所述的化合物或其可药用的盐或根据权利要求20所述的药物组合物在制备用于治疗和/或预防癌症的药物中的用途；所述的癌症优选选自脑癌、乳腺癌、卵巢癌、肺癌、***癌、黑色素瘤、神经母细胞瘤、结直肠癌、***、输卵管癌、子宫内膜癌、***癌、胃癌、头颈癌、鼻咽癌、口腔癌、胆管癌、食道癌、肝癌、皮肤癌、间皮瘤、膀胱癌、肾细胞癌、肾盂癌、输尿管癌、小肠癌、胰腺癌、甲状腺癌、甲状旁腺癌、***癌、外阴癌、白血病、肾上腺癌、尿道癌、***癌、睾丸癌、骨癌、骨肉瘤、骨髓瘤、软组织肉瘤、垂体腺瘤、脑干神经胶质瘤、脊柱肿瘤和淋巴瘤；更优选地，所述的癌症选自乳腺癌、胃癌、肺癌、结直肠癌、胰腺癌、***癌、膀胱癌和卵巢癌。
PCT/CN2023/084265 2022-03-28 2023-03-28 含氮杂环类化合物、其制备方法及其在医药上的应用 WO2023185793A1 (zh)

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