WO2020073945A1 - 双环类衍生物抑制剂、其制备方法和应用 - Google Patents

双环类衍生物抑制剂、其制备方法和应用 Download PDF

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WO2020073945A1
WO2020073945A1 PCT/CN2019/110306 CN2019110306W WO2020073945A1 WO 2020073945 A1 WO2020073945 A1 WO 2020073945A1 CN 2019110306 W CN2019110306 W CN 2019110306W WO 2020073945 A1 WO2020073945 A1 WO 2020073945A1
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substituted
group
unsubstituted
alkyl
cycloalkyl
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PCT/CN2019/110306
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French (fr)
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刘世强
鲍孟
袁逸达
王永升
周远锋
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江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201980005251.XA priority Critical patent/CN111295384B/zh
Publication of WO2020073945A1 publication Critical patent/WO2020073945A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a bicyclic derivative inhibitor and a preparation method and application thereof.
  • SHP-2 (Src homology-2 domain-containing phosphatase 2), also known as PTPN11 (tyrosine-protein phosphatase non-receptor type 11), is encoded by the PTPN11 gene and belongs to protein tyrosine phosphatase (PTPs) family.
  • PTPs protein tyrosine phosphatase
  • SHP-2 As downstream signaling molecules for cytokines, growth factors and other extracellular stimulating factors, SHP-2 is widely expressed in various tissues and cells of the body, participates in cell signal transduction, regulates cell growth, differentiation, migration, metabolism, gene transcription and immune response Wait.
  • SHP-2 mainly has three components: SH-2 domain (N-SH2 and C-SH2), PTP active domain, and C-terminal (containing tyrosine phosphorylation site).
  • SH2 domain is highly conserved, is a phosphotyrosine binding site, and mediates the binding of the PTP domain to its ligand.
  • SHP-2 has two main states in the body: inactivation and activation.
  • the deactivated state the N-SH2 and PTP domains inside SHP-2 are combined with each other. Due to the occupation of the PTP domain, SHP-2 is inactivated.
  • N-SH2 specifically binds to the ligand of phosphorylated tyrosine residues
  • the PTP domain is re-exposed and SHP-2 resumes activity.
  • SHP-2 can also form dimers in the body, which can also lead to SHP-2 inactivation.
  • SHP-2 mainly functions by regulating ERK / MAPK, JAK-STAT, PI3K / AKT, Hippo, Wnt / ⁇ -catenin and other signaling pathways to maintain organism development and homeostasis.
  • SHP-2 participates in activating the ERK / MAPK pathway by directly binding to receptor tyrosine kinases (RTKs) or scaffolds.
  • RTKs receptor tyrosine kinases
  • activated SHP-2 can recruit GRB2 / SOS and indirectly promote the activation of the RAS signaling pathway.
  • SHP-2 is also involved in the suppression of immune response signaling, such as SHP-2 and SHP-1 can bind and activate immunosuppressive receptors (such as PD-1), blocking T cell activation.
  • SHP-2 mutation is closely related to various diseases. The study found that SHP-2 mutations were found in neuroblastoma, AML (4%), breast cancer, NSCLC (10%), lung cancer (30%), melanoma, and gastric cancer.
  • SHP-2 The mutation sites of SHP-2 mostly occur in the N-SH2 and PTP active regions, which relieves the mutual inhibition of the N-CH2 / PTP domain and produces highly active SHP-2. Mutations such as Cys459Sermutant and E76Kmutant will affect SHP-2 activity. Studies have shown that highly active SHP-2 is closely related to inflammation, liver cirrhosis, and the toxin CagA secreted by H. pylori, which can lead to tumor regeneration and development, which is equivalent to proto-oncogenes. With the deepening of understanding of SHP-2, SHP-2 has been used as a target for cancer treatment for drug development.
  • the object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by the general formula (I) is as follows:
  • Ring A is selected from a 6-14 membered bicyclic ring; the bicyclic ring is preferably heteroarylheteroaryl or heteroarylheterocyclyl;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 -,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-( CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from deuterium, alkyl, haloalkyl , Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 -,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-( CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,
  • two R 1 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclic group, aryl group or heteroaryl group, and the cycloalkyl, heterocyclic group, aryl group and heteroaryl group Group, optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio Group, nitro, cyano, hydroxy, ester, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted Substituted hydroxyalkyl, substituted or unsubstituted heterocyclic group, substitute
  • two R 3 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclic group, aryl group or heteroaryl group, and the cycloalkyl, heterocyclic group, aryl group and heteroaryl group
  • the group is optionally further selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio , Nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkane Group, substituted or unsubstituted heterocyclic group, substituted or unsubsti
  • R aa , R bb , R cc and R dd are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro , Hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy Group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, Oxo, nitro, cyano, substituted or unsubstituted alkenyl,
  • R aa and R bb are linked to form a cycloalkyl, heterocyclic group, aryl group and heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl group and heteroaryl group are optionally further selected from Deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, Hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted Heterocyclic group, substituted or unsubstituted aryl group
  • x is an integer of 0, 1, 2, 3 or 4;
  • y is an integer of 0, 1, 2, 3 or 4;
  • z is an integer of 0, 1, 2, 3 or 4;
  • n1 is an integer of 0, 1, or 2;
  • n1 is an integer of 0, 1, 2, 3, 4, or 5.
  • M 1 is S or NR aa ;
  • L is a bond, O, S or -CH 2- ;
  • Ring B is aryl or heteroaryl
  • R 1 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa , -(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,-(CH 2 ) n1 C (O) NR aa R bb ,-(CH 2 ) n1 NR aa C
  • two R 1 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl, heterocyclic group, aryl group or heteroaryl group, and the cycloalkyl, heterocyclic group, aryl group and heteroaryl group Group, optionally further selected from deuterium, alkyl, cycloalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, ester, alkenyl, alkynyl, alkyl Substituted by one or more substituents in oxy, haloalkoxy, hydroxyalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, aldehyde Group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group,-(CH 2 ) n1 R aa or- (CH 2 ) n1 OR aa ;
  • R 3 is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa , -(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,-(CH 2 ) n1 C (O) NR aa R bb ,-(CH 2 ) n1 NR aa C (
  • two R 3 on the same carbon atom or different carbon atoms are linked to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally further selected from hydrogen, deuterium, alkyl Group, cycloalkyl, haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, heterocyclic , One or more substituents in aryl and heteroaryl;
  • R aa and R bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, olefin Group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group;
  • x 0, 1, 2, 3 or 4;
  • z 0, 1, 2, 3 or 4;
  • q 0, 1, 2 or 3;
  • n1 0, 1, or 2;
  • n1 is 0, 1, 2, 3, 4, or 5.
  • Rings B, L, R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • Ring C is selected from aryl, cycloalkyl or heterocyclyl
  • Rings B, L, R 1 , R 2 , R 3 , x and z are as described in the general formula (II).
  • Rings B, M 1 , R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • Rings B, R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • Rings B, R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • R 1 , R 2 , R 3 , x, z and q are as described in the general formula (II).
  • M 1 is -S- or -NH-
  • M 2 is selected from CR 5 or N;
  • R 4 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered Heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,
  • two R 4 links on the same carbon atom or different carbon atoms form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group are optionally further selected from deuterium, halogen, amino, oxo, Thio, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, C 2-6 amide, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Substituted with one or more substituents in the 5-14 membered
  • R 3 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkylamino;
  • R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered Heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,
  • R 4 and R 5 are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Group, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group, optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , Hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, C 2-6 amide, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl Oxygen, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group Substituted by one or more
  • R 6 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered Heteroaryl
  • s 0, 1, 2, 3 or 4;
  • z-1 0, 1, 2 or 3.
  • M 3 is selected from CR 8 or N;
  • R 7 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered Heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,
  • two R 7 links on the same carbon atom or different carbon atoms form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group are optionally further selected from deuterium, halogen, amino, oxo, Thio, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, C 2-6 amide, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Substituted with one or more substituents in the 5-14 membered
  • R 8 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered Heteroaryl,-(CH 2 ) n1 R aa ,-(CH 2 ) n1 OR aa ,-(CH 2 ) n1 SR aa ,-(CH 2 ) n1 C (O) R aa ,-(CH 2 ) n1 C (O) OR aa ,-(CH 2 ) n1 S (O) m1 R aa ,-(CH 2 ) n1 NR aa R bb ,-
  • R 7 and R 8 are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group ,
  • the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group optionally further selected from deuterium, halogen, amino, oxo , Thio, nitro, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 ester, C 2-6 amide, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aromatic Substituted by one or more substituents in the group and
  • R 9 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered Heteroaryl
  • t 0, 1, 2, 3 or 4;
  • q 0, 1, 2 or 3;
  • z-1 0, 1, 2 or 3.
  • ring A is selected from the following groups:
  • the compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt according to any one of the features is characterized by:
  • Ring B is selected from the following groups:
  • ring B is selected from the following groups:
  • ring C is selected from the following groups:
  • ring C is selected from the following groups:
  • each of the general formulas, stereoisomers or pharmaceutically acceptable salts thereof according to any one of the claims is characterized in that
  • R 1 is selected from hydrogen, cyano, amino, halogen, C 1-6 alkyl,-(CH 2 ) n1 C (O) NR aa R bb ,-(CH 2 ) n1 C (O) OR aa or 3- 8-membered heterocyclic group;
  • R 2 is selected from hydrogen, — (CH 2 ) n1 OR aa or 5-6 heteroaryl;
  • R 3 is selected from hydrogen, C 1-6 alkyl, amino or- (CH 2 ) n1 NR aa R bb , wherein the C 1-6 alkyl is optionally further selected from hydrogen, halogen, amino, cyanide Substituted by one or more substituents in the group and the hydroxyl group.
  • a compound represented by the general formula (VI-A), its stereoisomer or a pharmaceutically acceptable salt thereof is provided:
  • the invention also relates to a method for preparing the compound represented by the general formula (V) or its stereoisomer and pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
  • Pg is an amino protecting group selected from tert-butylsulfinyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl Or phthaloyl; preferably tert-butoxycarbonyl.
  • the invention also relates to a method for preparing the compound represented by the general formula (V-a) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • a reduction reaction occurs in the general formula (V-b) to obtain the compound represented by the general formula (V-a) or its stereoisomers and pharmaceutically acceptable salts thereof.
  • the invention also relates to a method for preparing the compound represented by the general formula (V-b) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • X 1 is halogen, preferably fluorine, chlorine, bromine, iodine; more preferably chlorine.
  • the invention also relates to a method for preparing the compound represented by the general formula (V-c) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • the present invention also relates to a method for preparing the compound represented by the general formula (V) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • the invention also relates to a method for preparing the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • Pg ' is an amino protecting group selected from t-butylsulfinyl, benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trityl Group or phthaloyl; preferably tert-butoxycarbonyl.
  • the invention also relates to a method for preparing the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • X 2 is selected from halogen, preferably fluorine, chlorine, bromine or iodine; more preferably bromine.
  • the invention also relates to a method for preparing the compound represented by the general formula (VI) or its stereoisomers and pharmaceutically acceptable salts thereof, which is characterized by comprising the following steps,
  • the present invention further relates to the use of any compound of the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of SHP-2 inhibitor drugs.
  • the present invention also relates to a method for the treatment of prevention and / or treatment of pre-prepared treatment of conditions mediated by SHP-2 inhibitors, which comprises administering to a patient a therapeutically effective dose of a compound represented by general formula (I) and its stereoisomerism Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the compounds and compositions of the present invention can be used to treat diseases such as Nounan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer Or use in disorders.
  • diseases such as Nounan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer Or use in disorders.
  • the compounds and compositions of the present invention can be used in the treatment of diseases or conditions such as the treatment of Nounan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer.
  • the present invention provides a method of treating a cancer condition, which comprises administering a compound or composition of the present invention to a patient suffering from a cancer condition.
  • the cancer treated by the compound or composition of the present invention is Noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer, and colon cancer thereof, wherein
  • the leukemia is preferably AML
  • the lung cancer is preferably NSCLC.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • 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-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point.
  • the substituent is preferably one or more of the following groups, which are independently selected from Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate groups, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , Deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene means that one hydrogen of the alkyl group is further substituted, for example: "methylene” means -CH 2- , "ethylene” means-(CH 2 ) 2- , “propylene” means -(CH 2 ) 3- , “butylene” means-(CH 2 ) 4 -and so on.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. The alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 Carbon atoms, most preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc .; polycyclic cycloalkyls include spiro, fused and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl Base and cyclobutyl.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (called a spiro atom) between 5- to 20-membered monocycles, which may contain one or more double bonds, but none of the rings is fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl groups are classified into monospirocycloalkyl groups, dispirocycloalkyl groups or polyspirocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably monospirocycloalkyl groups and dispirocycloalkyl groups.
  • spirocycloalkyl More preferably, it is 4 member / 4 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member, or 5 member / 6 member monospirocycloalkyl.
  • spirocycloalkyl include:
  • Spirocycloalkyl groups that also contain a monospirocycloalkyl group and a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
  • fused ring alkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or Multiple double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cyclic alkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 4 members / 4 members, 5 members / 5 members or 5 members / 6 members Bicycloalkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyls include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl, etc.
  • Cycloalkyl can be optionally substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclo
  • heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, boron, phosphorus, S (O) m (where m is an integer from 0 to 2) or P (O) n (where n is an integer from 0 to 2) heteroatom, but does not include the ring portion of -OO-, -OS- or -SS- , The remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyryl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl , Piperazinyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved are optionally connected to other groups through a single bond or through a ring Any two or more atoms in the above are further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups in parallel.
  • spiro heterocyclyl refers to a polycyclic heterocyclic group that shares an atom (called a spiro atom) between 3 and 20 membered monocycles, where one or more ring atoms are nitrogen, oxygen, boron, phosphorus, S (O) m (where m is an integer from 0 to 2) or a hetero atom of P (O) n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiro heterocyclic groups are classified into mono-spiro heterocyclic groups, di-spiro heterocyclic groups or poly-spiro heterocyclic groups according to the number of spiro atoms shared between the rings, preferably mono-spiro heterocyclic groups and di-spiro heterocyclic groups. More preferably, it is 3 member / 5 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member, or 5 member / 6 member monospiro heterocyclic group.
  • Non-limiting examples of spiro heterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings has a completely conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3 members / 5 members, 4 members / 5 members or 5 members / 6 members Bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common
  • one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridge heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged heterocyclic groups include:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate groups.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate groups.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidine Group, thiazolyl; more preferably oxazolyl, oxadiazole, tetrazole, triazoly
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate groups.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
  • alkenyl refers to alkenyl, also known as alkenyl, where the alkenyl can be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio Group, carboxyl group or carboxylate group.
  • Alkynyl refers to (CH ⁇ C-), wherein the alkynyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate groups.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH 2 .
  • Niro refers to -NO 2 .
  • Carboxy refers to -C (O) OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH refers to methanol
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • DMA refers to N, N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N, N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 means tris (dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2- (7-oxybenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi refers to methyl lithium
  • N-BuLi refers to n-butyl lithium
  • NaBH (OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • etc. The different terms all express the same Meaning, that is, X can be any one or more of A, B, and C.
  • the hydrogen described in the present invention can be replaced by its isotope deuterium, and any hydrogen in the compounds of the examples involved in the present invention can also be replaced by deuterium.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogens in the group, preferably up to 5, more preferably 1 to 3 hydrogens are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without undue effort. For example, an amino group or hydroxyl group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography separation purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized using or following methods known in the art.
  • Step 1 Preparation of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl) carbamate
  • Step 2 Preparation of 2- (5-bromo-2-((tert-butoxycarbonyl) imino) -1,3,4-thiadiazol-3 (2H) -yl) acetic acid
  • target compound 2- (5-bromo-2-((tert-butoxycarbonyl) imino) -1,3,4- Thiadiazole-3 (2H) -yl) acetic acid (467 mg, yield 46%) light yellow liquid.
  • Step 4 Preparation of 6-chloro-2- (2,3-dichlorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole
  • Step 5 Preparation of 6-chloro-2- (2,3-dichlorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole-5-carbaldehyde
  • Step 6 (1- (2- (2,3-dichlorophenyl) -5-formylimidazo [2,1-b] [1,3,4] thiadiazol-6-yl)- 4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
  • Step 7 (1- (2- (2,3-dichlorophenyl) -5- (hydroxymethyl) imidazo [2,1-b] [1,3,4] thiadiazole-6- Of 4-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
  • reaction solution was added dropwise to a saturated aqueous sodium bicarbonate solution, extracted three times with dichloromethane (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a crude product, which was purified by preparative HPLC to obtain the target product 6- (4 -Amino-4-methylpiperidin-1-yl) -2- (2,3-dichlorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole-5-carbaldehyde (3.5 mg, yield: 22%).
  • Example 6 The preparation method of Example 6 refers to the experimental scheme of Example 1.
  • Example 10 refers to the experimental scheme of Example 1.
  • Example 18 refers to the experimental scheme of Example 1.
  • Example 19 refers to the experimental scheme of Example 1.
  • Example 20 refers to the experimental scheme of Example 1.
  • the first step Preparation of ethyl 4-cyano-2- (2,3-dichlorophenyl) -6-methylnicotinate
  • Step 2 Preparation of 4- (2,3-dichlorophenyl) -6-methyl-1,2-dihydro-3H-pyrrolo [3,4-c] pyridin-3-one
  • Step 1 Preparation of 6-bromo-1-trityl-1H-pyrazolo [4,3-b] pyridine
  • 6-Bromo-1H-pyrazolo [4,3-b] pyridine (1.00g, 5mmol), triphenylchloromethane (1.67g, 6mmol), cesium carbonate (4.86g, 15mmol) in N, N-di Stir in methyl formamide (20 mL) at room temperature for 18 hours.
  • 6-Bromo-1-triphenylmethyl-1H-pyrazolo [4,3-b] pyridine (1g, 2.27mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester 728 mg, 3.4 mmol), Pd 2 (dba) 3 (208 mg, 0.023 mmol), XantPhos (262 mg, 0.45 mmol) and sodium tert-butoxide (436 mg, 4.54 mmol) were reacted in a microwave at 120 ° C. for 1 hour in dioxane.
  • reaction solution was filtered, and the filtrate was concentrated to complete column chromatography [eluent: petroleum ether ⁇ petroleum ether / ethyl acetate (50:50)] to obtain (4-methyl-1- (1-triphenylmethyl-1H -Pyrazolo [4,3-b] pyridin-6-yl) piperidin-4-amine) carbamic acid tert-butyl ester (1.3 g, yield 100%) gray solid.
  • Di-tert-butyl dicarbonate (1.2 g, 5.5 mmol) was added to the reaction solution in the previous step, and after the addition was completed, it was stirred at room temperature for 18 hours. Not completely reacted, additional di-tert-butyl dicarbonate (0.96g, 4.4mmol) was added, and stirred at room temperature for 3 hours.
  • Step 6 6- (4-((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) -3- (2,3-dichlorophenyl) -1H-pyrazole Preparation of tert-Butyl [4,3-b] pyridine-1-carboxylate
  • Step 7 1- (3- (2,3-dichlorophenyl) -1H-pyrazolo [4,3-b] pyridin-6-yl) -4-methylpiperidin-4-amine preparation
  • Example 37 For the preparation method of Example 37, refer to the experimental scheme of Example 36.
  • Example 38 refers to the experimental scheme of Example 36.
  • Example 39 For the preparation method of Example 39, refer to the experimental scheme of Example 36.
  • Example 40 For the preparation method of Example 40, refer to the experimental scheme of Example 36.
  • Example 41 For the preparation method of Example 41, refer to the experimental scheme of Example 36.
  • Example 42 For the preparation method of Example 42, refer to the experimental scheme of Example 36.
  • Example 43 For the preparation method of Example 43, refer to the experimental scheme of Example 36.
  • Example 44 For the preparation method of Example 44, refer to the experimental scheme of Example 36.
  • Example 45 For the preparation method of Example 45, refer to the experimental scheme of Example 36.
  • Example 46 For the preparation method of Example 46, refer to the experimental scheme of Example 36.
  • Example 47 For the preparation method of Example 47, refer to the experimental scheme of Example 36.
  • Example 48 For the preparation method of Example 48, refer to the experimental scheme of Example 36.
  • Example 49 refers to the experimental scheme of Example 36.
  • Example 50 For the preparation method of Example 50, refer to the experimental scheme of Example 36.
  • Example 51 For the preparation method of Example 51, refer to the experimental scheme of Example 36.
  • Example 52 For the preparation method of Example 52, refer to the experimental scheme of Example 36.
  • Example 53 For the preparation method of Example 53, refer to the experimental scheme of Example 36.
  • Example 54 refers to the experimental scheme of Example 36.
  • Example 56 For the preparation method of Example 56, refer to the experimental scheme of Example 36.
  • Example 57 refers to the experimental scheme of Example 1.
  • Example 58 For the preparation method of Example 58, refer to the experimental scheme of Example 36.
  • Example 59 refers to the experimental scheme of Example 36.
  • Example 60 For the preparation method of Example 60, refer to the experimental scheme of Example 36.
  • Test Example 1 Determination of the inhibitory effect of the compound of the present invention on SHP-2 kinase activity
  • the purpose of this test is to measure the ability of compounds to inhibit the allosteric activity of SHP-2 full-length protein.
  • centrifuge (5810R) was purchased from Eppendorf company, pipette was purchased from Eppendorf or Rainin company, microplate reader was purchased from American BioTek company, model is SynergyH1 full-function microplate reader.
  • the compounds of the examples shown in the present invention showed the biological activities in Table 1 below in the SHP-2 kinase activity test
  • mice Using Balb / c mice as test animals, the pharmacokinetic behavior of Compound Example 1, Example 36 and Example 38 and oral administration in mice (plasma) was studied.
  • Example 1 Example 36 and Example 38 of the present invention, self-made
  • Balb / c mice male, purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).
  • HEC hydroxyethyl cellulose
  • Balb / c mice male; PO separately after one night of fasting, the dose is 5 mg / kg, and the administration volume is 10 mL / kg.
  • Blood was collected before and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after drug administration. Blood was placed in EDTA-2K test tubes, centrifuged at 4 °C 6000rpm for 6min to separate plasma, and stored at minus 80 °C Eat 4 hours after administration.
  • the human pancreatic cancer cell MiaPaca xenograft (CDX) model was used for in vivo drug efficacy experiments to evaluate the anti-tumor effects of the test compounds.
  • Vernier caliper (CD-6 "AX, Mitutoyo, Japan)
  • FBS Fetal bovine serum
  • Penicillin double antibody (P / S) (SV30010, GE)
  • PBS Phosphate buffer
  • mice were BALB / c nude mice, female, 6-8 weeks old, and weighed approximately 18-22 grams. The mice were kept in a special pathogen-free environment, and in a single ventilated cage, 5 mice per cage. All cages, litter and water are sterilized before use, and all animals are free to obtain standard certified commercial laboratory diets. Before the experiment, nude mice were labeled with disposable ear tags for general mice. Before inoculation, the skin of the inoculation site was disinfected with 75% medical alcohol. Each mouse was inoculated with 0.1ml (containing 8 * 10 6 cells) of MiaPaca2 tumor subcutaneously on the right back cell. When the average tumor volume reaches 100-200 mm 3 , group administration begins.
  • the test compound was administered by oral gavage daily.
  • the dosage, frequency of administration and the efficacy of each group at the end of the experiment are shown in Table 3.
  • Antitumor efficacy is determined by dividing the average tumor increase volume of the compound-treated animals by the average tumor increase volume of the untreated animals.

Abstract

公开了含双环类衍生物抑制剂、其制备方法和应用。特别地，公开了涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为蛋白质酪氨酸磷酸酶SHP-2抑制剂，在治疗白血病、神经母细胞瘤、黑色素瘤、乳腺癌、肺癌及其结肠癌等疾病或病症的用途，其中通式(I)中的各取代基与说明书中的定义相同。

Description

双环类衍生物抑制剂、其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种双环类衍生物抑制剂及其制备方法和应用。
背景技术
SHP-2(Src homology-2 domain-containing phosphatase 2)，又称PTPN11(tyrosine-protein phosphatase non-receptor type 11)，由PTPN11基因编码，隶属于蛋白酪氨酸磷酸酶(protein tyrosine phosphatase，PTPs)家族。作为细胞因子、生长因子及其他胞外刺激因素的下游信号分子，SHP-2广泛表达于机体各组织和细胞，参与细胞信号转导，调节细胞生长、分化、迁移、代谢、基因转录和免疫应答等。
SHP-2主要有3个组成部分：SH-2结构域(N-SH2和C-SH2)、PTP活性结构域、C-末端(含酪氨酸磷酸化位点)。其中SH2结构域高度保守，是磷酸酪氨酸结合位点，并介导PTP结构域与其配体的结合。
SHP-2在机体内主要有2种状态：失活与激活。在失活状态下，SHP-2内部N-SH2与PTP结构域相互结合，由于PTP结构域被占领，使SHP-2失活。而当N-SH2与磷酸化酪氨酸残基配体特异性结合时，PTP结构域重新暴露，SHP-2恢复活性。据最新研究表明，SHP-2还能在体内形成二聚体，同样也可导致SHP-2失活。
SHP-2主要通过调节ERK/MAPK、JAK-STAT、PI3K/AKT、Hippo、Wnt/β-catenin等信号通路发挥功能，以此维持生物体发育和体内动态平衡。具体研究表明，SHP-2通过直接与酪氨酸激酶受体(receptor tyrosine kinase,RTKs)或scaffold结合，参与激活ERK/MAPK通路。除此之外，活化的SHP-2还能招募GRB2/SOS，间接促进RAS信号通路的激活。此外，SHP-2还参与抑制免疫反应的信号传导，如SHP-2与SHP-1能够结合并激活免疫抑制受体(如PD-1)，阻断T细胞激活。
作为一类重要的细胞信号因子，SHP-2突变与多种疾病密切相关。研究发现：在神经母细胞瘤、AML(4％)、乳腺癌、NSCLC(10％)、肺癌(30％)、黑色素瘤和胃癌中，发现存在SHP-2突变。
SHP-2的突变位点多发生在N-SH2、PTP活性区域，解除了N-CH2/PTP结构域的相互抑制，产生高活性的SHP-2，如Cys459Ser mutant、E76K mutant等突变均会影响SHP-2活性。有研究表明，高活性的SHP-2与炎症、肝硬化、幽门螺旋杆菌所分泌的毒素CagA等密切相关，能够导致肿瘤的再生与发展，相当 于原癌基因。随着对SHP-2认识的不断深入，SHP-2已经作为肿瘤治疗靶点进行药物的开发。
目前已有多个SHP-2的变构抑制剂进入临床研究阶段，如Novartis公司开发的TNO-155，Revolution Medicine公司开发的RMC-4630，以及北京加科思的JAB-3068都已经进入临床I期研究阶段。
但还没有一款开发上市的SHP-2抑制剂用于治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、胃癌、肺癌及其结肠癌。因此迫切需要开发一类成药性好的SHP-2抑制剂药物。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2019110306-appb-000001
其中：
L选自键、-S-、-O-、-NR aa-、-(CR aaR bb) n1-或-(C＝O)-；
环A选自6-14元双环；该双环优选杂芳基并杂芳基或杂芳基并杂环基；
环B选自环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb和-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代；
环C选自环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb和-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代；
R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、 -(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 1链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
R 2选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、氧代基、醛基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，其中所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、氨基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
或者，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
R aa、R bb、R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
或者，R aa和R bb链接形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
x为0、1、2、3或4的整数；
y为0、1、2、3或4的整数；
z为0、1、2、3或4的整数；
m1为0、1或2的整数；且
n1为0、1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，提供一种通式(II)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000002
其中：
M 1为S或NR aa；
L为键、O、S或-CH 2-；
环B为芳基或杂芳基；
R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 1链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2选自氢、氘、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、醛基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa或-(CH 2) n1OR aa；
R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、氨基烯基、炔基、环烷基、杂环基、芳基、杂芳基，任选进一步被选自氢、氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基或杂环基，其中所述的环烷基和杂环基，任选进一步被选自氢、氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R aa和R bb各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、 杂环基、芳基或杂芳基；
x为0、1、2、3或4；
z为0、1、2、3或4；
q为0、1、2或3；
m1为0、1或2；且
n1为0、1、2、3、4或5。
在本发明的一个优选实施例方案中，提供一种通式(III)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000003
其中：
环B、L、R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IV)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000004
其中：
环C选自芳基、环烷基或杂环基；
环B、L、R 1、R 2、R 3、x和z如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IIA)和通式(IIB)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000005
其中：
环B、M 1、R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IIC)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000006
其中：
M 1、R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IIIA)和通式(IIIB)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000007
其中：
环B、R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IIIC)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000008
其中：
R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IVA)和通式(IVB)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000009
其中：
环B、R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(IVC)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000010
其中：
R 1、R 2、R 3、x、z和q如通式(II)所述。
在本发明的一个优选实施例方案中，提供一种通式(V)所示的化合物、其立体异构体或其药学上可接受盐，
Figure PCTCN2019110306-appb-000011
其中：
M 1为-S-或-NH-；
M 2选自CR 5或N；
R 4选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 4链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 3选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 1-6烷基或C 1-6烷基氨基；
R 5选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，R 4与R 5链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任 选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 6选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；
s为0、1、2、3或4；
z-1为0、1、2或3。
在本发明的一个优选实施例方案中，提供一种通式(VI)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000012
其中：
M 3选自CR 8或N；
R 7选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
或，相同碳原子或者不相同碳原子上的两个R 7链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 8选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
当M 3为CR 8时，任选地，R 7与R 8链接形成一个C 3-12环烷基、3-12元杂环 基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
R 9选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；
t为0、1、2、3或4；
q为0、1、2或3；且
z-1为0、1、2或3。
在本发明的一个优选实施例方案中，任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自如下基团：
Figure PCTCN2019110306-appb-000013
Figure PCTCN2019110306-appb-000014
在本发明的一个优选实施例方案中，任一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：
环B选自如下基团：
Figure PCTCN2019110306-appb-000015
在本发明进一步的一个优选实施例方案中，任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环B选自如下基团：
Figure PCTCN2019110306-appb-000016
在本发明的一个优选实施例方案中，任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环C选自如下基团：
Figure PCTCN2019110306-appb-000017
在本发明进一步的一个优选实施例方案中，任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环C选自如下基团：
Figure PCTCN2019110306-appb-000018
在本发明的一个优选实施例方案中，任一项所述的各通式、其立体异构体或其药学上可接受的盐，其特征在于，
R 1选自氢、氰基、氨基、卤素、C 1-6烷基、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1C(O)OR aa或3-8元杂环基；
R 2选自氢、-(CH 2) n1OR aa或5-6杂芳基；
R 3选自氢、C 1-6烷基、氨基或-(CH 2) n1NR aaR bb，其中所述的C 1-6烷基，任选进一步被选自氢、卤素、氨基、氰基和羟基中的一个或多个取代基所取代。
在本发明的一个优选实施例方案中，提供一种通式(VI-A)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019110306-appb-000019
本发明还涉及一种制备所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：
Figure PCTCN2019110306-appb-000020
通式(V-a)脱保护，得到通式(V)所示化合物或其立体异构体及其药学上可接受盐；
其中：
Pg为氨基保护基，选自叔丁基亚磺酰基、苄氧羰基、叔丁氧羰基、9-芴甲氧羰基、苄基、对甲氧基苄基、烯丙氧羰基、三苯甲基或邻苯二甲酰基；优选叔丁氧羰基。
本发明还涉及一种制备所述的通式(V-a)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000021
通式(V-b)发生还原反应，得到通式(V-a)所示化合物或其立体异构体及其药学上可接受盐。
本发明还涉及一种制备所述的通式(V-b)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000022
通式(V-c)与通式(V-d)反应，得到通式(V-b)所示化合物或其立体异构体及其药学上可接受盐；
其中：
X 1为卤素，优选氟、氯、溴、碘；更优选氯。
本发明还涉及一种制备所述的通式(V-c)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000023
通式(V-e)反应，得到通式(V-c)所示化合物或其立体异构体及其药学上可接受盐。
本发明还涉及一种制备所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000024
本发明还涉及一种制备所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000025
通式(VI-a)脱保护，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；
其中：
Pg’为氨基保护基，选自叔丁基亚磺酰基、苄氧羰基、叔丁氧羰基、9-芴甲氧羰基、苄基、对甲氧基苄基、烯丙氧羰基、三苯甲基或邻苯二甲酰基；优选叔 丁氧羰基。
本发明还涉及一种制备所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000026
通式(VI-b)与通式(VI-c)发生偶联反应，得到通式(VI-a)所示化合物或其立体异构体及其药学上可接受盐；
其中：
X 2选自卤素，优选氟、氯、溴或碘；更优选溴。
本发明还涉及一种制备所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于包含以下步骤，
Figure PCTCN2019110306-appb-000027
本发明进一步涉及任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备SHP-2抑制剂药物中的应用。
本发明还涉及一种治疗预防和/或治疗预制备治疗由SHP-2抑制剂介导的病症的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。
在一些实施例中，本发明的化合物和组合物可用于治疗在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、胃癌、肺癌及其结肠癌等疾病或病症中的用途。
本发明的化合物和组合物可用于治疗在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳癌、肺癌及其结肠癌等疾病或病症中的方法。
在一些实施例中，本发明提供一种治疗癌症病症的方法，其包含将本发明的化合物或组合物给予患有癌症病症的患者。
在一些实施例中，由本发明的化合物或组合物治疗的癌症为努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、胃癌、肺癌及其结肠 癌，其中所述的白血病优选AML，肺癌优选NSCLC。
发明的详细说明
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”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、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。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、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、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“亚烷基”是指烷基的一个氢进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫 基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、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、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基，更优选环丙基和环丁基、。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2019110306-appb-000028
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
Figure PCTCN2019110306-appb-000029
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为4元/4元、5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2019110306-appb-000030
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2019110306-appb-000031
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧、硼、磷、S(O) m(其中m是整数0至2)或P(O) n(其中n是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括氧杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选氧杂环丁基、四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。更优选氧杂环丁基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“螺杂环基”指3至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为氮、氧、硼、磷、S(O) m(其中m是整数0至2)或P(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2019110306-appb-000032
Figure PCTCN2019110306-appb-000033
Figure PCTCN2019110306-appb-000034
等。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/5元、4元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2019110306-appb-000035
等。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2019110306-appb-000036
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接 在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2019110306-appb-000037
Figure PCTCN2019110306-appb-000038
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2019110306-appb-000039
Figure PCTCN2019110306-appb-000040
等。
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、噁二唑、吡嗪基等，优选为噁唑基、噁二唑、四氮唑、三氮唑基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选噁唑基、 噁二唑、四氮唑、三氮唑基、噻吩基、噻唑基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2019110306-appb-000041
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“EtOAc”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N、N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et 2O”指乙醚。
“DCE”指1,2二氯乙烷。
“DIPEA”指N，N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“Cbz-Cl”指氯甲酸苄酯。
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢也均可被氘取代。
“任选”或“任选地”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，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢，优选为最多5个，更优选为1～3个氢彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)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生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。
“可药用盐”是指本发明化合物的盐，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。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
实施例1
(6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000042
第一步：叔-丁基(5-溴-1,3,4-噻二唑-2-基)氨基甲酸酯的制备
Figure PCTCN2019110306-appb-000043
将5-溴-1,3,4-噻二唑-2-胺(5.0g，27.78mmol)，二-叔-丁基二碳酸酯(7.3g，33.34mmol)和DMAP(339mg,2.78mmol)溶于150mL二氯甲烷中，室温搅拌，直至反应完全。浓缩有机相得粗品，柱层析(PE/EA＝10：1)纯化得到目标产物叔-丁基(5-溴-1,3,4-噻二唑-2-基)氨基甲酸酯(6.6g，产率83％)白色固体。
1H NMR(400MHz,CDCl 3)δ1.56(s,9H).
MS m/z(ESI):280.1[M+H] +，282.3[M+2+H] +
第二步：2-(5-溴-2-((叔-丁氧基羰基)亚氨基)-1,3,4-噻二唑-3(2H)-基)乙酸的制备
Figure PCTCN2019110306-appb-000044
将叔-丁基(5-溴-1,3,4-噻二唑-2-基)氨基甲酸酯(840mg，3.00mmol)，溴乙酸(2.1g，0.14mmol)溶解于无水四氢呋喃(150mL)中，冰水浴中，氮气保护下，加入氢化钠(1.2g,30.00mmol,60％in oil，分三批，每半个小时加一批)。加料完毕，室温搅拌约72小时。反应结束后，将反应液滴加进100mL水中,搅拌30分钟，乙酸乙酯萃取(200mL),水层用稀盐酸调节至pH＝3-4，二氯甲烷(150mL)萃取有机相，合并有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，无需纯化，得到目标化合物2-(5-溴-2-((叔-丁氧基羰基)亚氨基)-1,3,4-噻二唑-3(2H)-基)乙酸(467mg，产率46％)淡黄色液体。
MS m/z(ESI):337.9[M+H] +，340.0[M+2+H] +。
第三步：2-溴-6-氯咪唑并[2,1-b][1,3,4]噻二唑的制备
Figure PCTCN2019110306-appb-000045
将2-(5-溴-2-((叔-丁氧基羰基)亚氨基)-1,3,4-噻二唑-3(2H)-基)乙酸(467mg，1.38mmol)溶解于无水乙腈(50mL)中，冰水浴中，氮气保护下，滴加三乙胺(0.80mL,5.52mmol,d＝0.726g/mL)，加料完毕室温加拌10分钟，后滴加氧氯化磷(0.77mL,8.28mmol,d＝1.65g/mL)，将反应液加热到80℃，搅拌3小时直至反应完全。反应结束后，将反应液冷却至室温，滴加到搅动的水(100mL)中,饱和碳酸钠溶液调节pH＝9-10,用乙酸乙酯(100mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，柱层析(PE/EA＝5：1)纯化得到目标产物2-溴-6-氯咪唑并[2,1-b][1,3,4]噻二唑(143mg，产率43％)白色固体。
1H NMR(400MHz,CDCl3)δ7.69(s,1H).
MS m/z(ESI):237.9[M+H] +，239.8[M+2+H] +。
第四步：6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑的制备
Figure PCTCN2019110306-appb-000046
将2-溴-6-氯咪唑并[2,1-b][1,3,4]噻二唑(121mg，0.51mmol)，(2,3-二氯苯基)硼酸(243mg，1.28mmol)，碳酸钠(162mg,1.53mmol)和氟化铯(87mg,0.51mmol)溶解于二氧六环(15mL)和水中(5mL)中，氮气保护下，加入Pd(dppf)Cl 2(73mg,0.1mmol)。加热到60℃，搅拌1小时。反应结束后，除去溶剂，用乙酸乙酯(50mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，柱层析(PE/EA＝3：1)纯化得到目标产物6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑(46mg，产率30％)白色固体。
MS m/z(ESI):303.9[M+H] +，305.9[M+2+H] +
第五步：6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛的制备
Figure PCTCN2019110306-appb-000047
冰水浴下，将氧氯化磷(1mL)滴加到无水DMF(5mL)中,后加热到60℃搅拌30分钟，加入底物6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑(46mg,0.15mmol)，继续搅拌，TLC监测，直至原料消耗完全。将反应液冷却至室温，滴加进水中，用饱和碳酸钠溶液调节至pH＝9-10，用乙酸乙酯(80mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，柱层析(PE/EA＝2：1)纯化得到目标产物6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛(28mg，产率56％)白色固体。
1H NMR(400MHz,CDCl 3)δ10.01(s,1H),8.07(dd,J＝8.0,1.5Hz,1H),7.71(dd,J＝8.0,1.5Hz,1H),7.42(t,J＝8.0Hz,1H).
MS m/z(ESI):331.9[M+H] +，333.9[M+2+H] +。
第六步：(1-(2-(2,3-二氯苯基)-5-甲酰基咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯
Figure PCTCN2019110306-appb-000048
将6-氯-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛(28mg，0.08mmol)，(4-甲基哌啶-4-基)氨基甲酸叔丁酯(180mg，0.80mmol)和二异丙基乙胺(20mg,0.16mmol)溶解于二氧六环(3mL)中，氮气保护下，加热到120℃，搅拌20小时。反应结束后，将反应液倒入水中，用乙酸乙酯(50mL)萃取三次， 有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，制备HPLC纯化得到目标产物(1-(2-(2,3-二氯苯基)-5-甲酰基咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(10mg，产率23％)白色固体。
MS m/z(ESI):510.1[M+H] +，512.1[M+2+H] +。
第七步：(1-(2-(2,3-二氯苯基)-5-(羟甲基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯的制备
Figure PCTCN2019110306-appb-000049
(1-(2-(2,3-二氯苯基)-5-甲酰基咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(10mg，0.02mmol)溶解于乙醇(3.0mL),冰水浴条件下，氮气保护下，加入硼氢化钠(0.4mg,0.10mmol)。室温搅拌30分钟。反应结束后，将反应液滴加到饱和氯化铵溶液中，用二氯甲烷(50mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，制备HPLC纯化得到目标产物(1-(2-(2,3-二氯苯基)-5-(羟甲基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(7.2mg，产率70％)白色固体。
MS m/z(ESI):512.0[M+H] +，514.1[M+2+H] +。
第八步：(6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000050
将(1-(2-(2,3-二氯苯基)-5-(羟甲基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(7.2mg，0.01mmol)溶解于二氯甲烷(3mL)中，加入三氟乙酸(1mL)，室温搅拌2小时。除去溶剂，得到粗品，制备HPLC纯化得到目标化合物(6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇(1.8mg，产率33％)。
1H NMR(500MHz,CDCl 3)δ7.78(s,1H),7.59(s,1H),7.33(s,1H),5.37(s,2H),4.43(s,2H),3.89(s,2H),2.41(s,1H),1.83(s,2H),1.61(s,2H),1.22(s,2H),1.12(s,2H).
MS m/z(ESI):412.1[M+H] +，414.1[M+2+H] +。
实施例2
6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛的制备
Figure PCTCN2019110306-appb-000051
第一步：6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛的制备
Figure PCTCN2019110306-appb-000052
(1-(2-(2,3-二氯苯基)-5-甲酰基咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(20mg，0.04mmol)溶解于二氯甲烷(10mL)中,冰水浴条件下，加入三氟乙酸(1mL)，搅拌30分钟。将反应液滴加到饱和碳酸氢钠水溶液中，用二氯甲烷(20mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，制备HPLC纯化得到目标产物6-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-甲醛(3.5mg，产率：22％)。
1H NMR(400MHz,CDCl 3)δ9.75(s,1H),7.78(s,1H),7.59(s,1H),7.33(s,1H),4.31(s,2H),4.17(s,2H),1.87(s,2H),1.54(s,2H),1.22(s,3H),1.06(s,2H).
MS m/z(ESI):409.1[M+H] +，411.1[M+2+H] +。
实施例3
(5-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)-3-甲基-3H-咪唑并[1,2-b][1,2,4]三唑-6-基)甲醇的制备
Figure PCTCN2019110306-appb-000053
实施例3的制备方法参考实施例1实验方案。
MS m/z(ESI):409.1[M+H] +，411.1[M+2+H] +。
实施例4
(6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000054
实施例4的制备方法参考实施例1实验方案。
MS m/z(ESI):468.1[M+H] +，470.1[M+2+H] +。
实施例5
(R)-(6-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000055
实施例5的制备方法参考实施例1实验方案。
MS m/z(ESI):452.1[M+H] +，454.1[M+2+H] +。
实施例6
(6-(6-氨基-3-氮杂二环[3.1.0]己烷-3-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000056
实施例6的制备方法参考实施例1实验方案。
MS m/z(ESI):396.1[M+H] +，398.1[M+2+H] +。
实施例7
(6-(5-氨基六氢环戊二烯并[c]吡咯-2(1H)-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000057
实施例7的制备方法参考实施例1实验方案。
MS m/z(ESI):424.1[M+H] +，426.1[M+2+H] +。
实施例8
(6-(3-氨基哌啶-1-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000058
实施例8的制备方法参考实施例1实验方案。
MS m/z(ESI):398.1[M+H] +，400.1[M+2+H] +。
实施例9
(6-((2R)-2-氨基螺[二环[3.1.0]己烷-3,4'-哌啶]-1'-基)-2-(2,3-二氯苯基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000059
实施例9的制备方法参考实施例1实验方案。
MS m/z(ESI):464.1[M+H] +，466.1[M+2+H] +。
实施例10
1-(2-(2,3-二氯苯基)-5-(1,3,4-噁二唑-2-基)咪唑并[2,1-b][1,3,4]噻二唑-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000060
实施例10的制备方法参考实施例1实验方案。
MS m/z(ESI):450.1[M+H] +，452.1[M+2+H] +。
实施例11
(6-(4-氨基-4-甲基哌啶-1-基)-2-(1-甲基-1H-苯并[d]咪唑-6-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000061
实施例11的制备方法参考实施例1实验方案。
MS m/z(ESI):398.1[M+H] +。
实施例12
(6-(4-氨基-4-甲基哌啶-1-基)-2-(苯并[d][1,3]二噁唑-5-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000062
实施例12的制备方法参考实施例1实验方案。
MS m/z(ESI):388.1[M+H] +。
实施例13
(6-(4-氨基-4-甲基哌啶-1-基)-2-(喹啉-7-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000063
实施例13的制备方法参考实施例1实验方案。
MS m/z(ESI):395.1[M+H] +。
实施例14
乙基6-(6-(4-氨基-4-甲基哌啶-1-基)-5-(羟甲基)咪唑并[2,1-b][1,3,4]噻二唑-2-基)-2-萘酸酯的制备
Figure PCTCN2019110306-appb-000064
实施例14的制备方法参考实施例1实验方案。
MS m/z(ESI):466.1[M+H] +。
实施例15
3-(6-(4-氨基-4-甲基哌啶-1-基)-5-(羟甲基)咪唑并[2,1-b][1,3,4]噻二唑-2-基)-N-甲基苯酰胺的制备
Figure PCTCN2019110306-appb-000065
实施例15的制备方法参考实施例1实验方案。
MS m/z(ESI):401.1[M+H] +。
实施例16
(2-((2-氨基-3-氯吡啶-4-基)硫代)-6-(4-氨基-4-甲基哌啶-1-基)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000066
实施例16的制备方法参考实施例1实验方案。
MS m/z(ESI):426.1[M+H] +，428.1[M+2+H] +。
实施例17
(6-(4-氨基-4-甲基哌啶-1-基)-2-((2,3-二氯吡啶-4-基)硫代)咪唑并[2,1-b][1,3,4]噻 二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000067
实施例17的制备方法参考实施例1实验方案。
MS m/z(ESI):445.1[M+H] +，447.1[M+2+H] +。
实施例18
(6-(4-氨基-4-甲基哌啶-1-基)-2-((2,3-二氯苯基)硫代)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000068
实施例18的制备方法参考实施例1实验方案。
MS m/z(ESI):444.1[M+H] +，446.1[M+2+H] +。
实施例19
(6-(4-氨基-4-甲基哌啶-1-基)-2-((3-氯-2-吗啉代吡啶-4-基)硫代)咪唑并[2,1-b][1,3,4]噻二唑-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000069
实施例19的制备方法参考实施例1实验方案。
MS m/z(ESI):496.1[M+H] +，498.1[M+2+H] +。
实施例20
(5-(4-氨基-4-甲基哌啶-1-基)-2-(2,3-二氯苯基)-3-甲基-3H-咪唑并[1,2-b][1,2,4]三唑-6-基)甲醇的制备
Figure PCTCN2019110306-appb-000070
实施例20的制备方法参考实施例1实验方案。
MS m/z(ESI):409.1[M+H] +，411.1[M+2+H] +。
实施例21
7-(4-氨基-4-甲基哌啶-1-基)-4-(2,3-二氯苯基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000071
第一步：乙基4-氰基-2-(2,3-二氯苯基)-6-甲基尼古丁酸酯的制备
Figure PCTCN2019110306-appb-000072
将乙基2-氯-4-氰基-6-甲基尼古丁酸酯(5.0g，22.32mmol)，2,3-二氯苯硼酸(5.1g，26.84mmol)和碳酸钾(9.2g,66.67mmol)溶于100ml四氢呋喃和10mL水中，加入Pd(dppf)Cl 2(7.27g，2.23mmol)，氮气置换。90℃微波反应13小时。浓缩除去溶剂，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩有机相得粗品，柱层析纯化得到目标产物乙基乙基4-氰基-2-(2,3-二氯苯基)-6-甲基尼古丁酸酯(5.6g，产率75％)。
MS m/z(ESI):335.1[M+H] +，337.1[M+2+H] +。
第二步：4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000073
在干燥的圆底烧瓶中加入无水InCl 3(2.0g，9.05mmol)，NaBH 4(1.02g，26.94mmol)，加入无水THF(50mL)溶解，反应液室温搅拌1小时。室温下滴加入乙基4-氰基-2-(2,3-二氯苯基)-6-甲基尼古丁酸酯(3.0g，8.98mmol)的无水THF溶液(20mL)，室温搅拌过夜。加3M盐酸(10mL)淬灭，室温搅拌30分钟，用NaOH水溶液调节至中性，加入水和乙酸乙酯萃取，有机相用水和食盐水洗涤，用无水硫酸钠干燥，过滤，浓缩得粗品，用柱层析纯化得到产物4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮(1.1g，产率42％)。
MS m/z(ESI):293.1[M+H] +，295.1[M+2+H] +。
第三步：7-溴-4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000074
4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮(1.0g，3.42mmol)，溶于DMF(30mL)中，加入NBS(730mg，4.11mmol)，然后加入KOH(383mg，6.84mmol)，室温搅拌13小时。加水(100mL)，搅拌30分钟，过滤，水洗，烘干得固体粗品。滤液用二氯甲烷提取，无水硫酸钠干燥，浓缩所得固体和烘干的固体一起柱层析纯化得到产物7-溴-4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮(510mg，产率40％)。
MS m/z(ESI):371.1[M+H] +，373.1[M+2+H] +。
第四步：(1-(4-(2,3-二氯苯基)-6-甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯的制备
Figure PCTCN2019110306-appb-000075
7-溴-4-(2,3-二氯苯基)-6-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮(500mg，1.35mmol)，叔-丁基(4-甲基哌啶-4-基)氨基甲酸酯(578mg，2.70mmol)，Pd 2(dba) 3(247mg，0.27mmol)，XantPhos(185mg，0.32mmol)和碳酸铯(1.3g，4.05mmol)溶解于无水二氧六环(50mL)中，氮气置换，加热到100℃反应13小时。冷却至室温，浓缩除去溶剂，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，浓缩有机相得到粗品，柱层析纯化得到产物(1-(4-(2,3-二氯苯基)-6-甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(150mg,产率22％)。
MS m/z(ESI):505.1[M+H] +，507.1[M+2+H] +。
第五步：(1-(4-(2,3-二氯苯基)-6-溴甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯的制备
Figure PCTCN2019110306-appb-000076
(1-(4-(2,3-二氯苯基)-6-甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(140mg，0.28mmol)加入CCl 4(20mL)中，加入NBS(54 mg，0.31mmol)，AIBN(10mg，0.06mmol)，氮气置换，加热回流2小时，降至室温，过滤反应液，滤渣用四氯化碳洗两次，浓缩滤液得到粗品，柱层析纯化得到产物(1-(4-(2,3-二氯苯基)-6-溴甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(45mg,产率28％)。
MS m/z(ESI):583.1[M+H] +，585.1[M+2+H] +。
第六步：7-(4-氨基-4-甲基哌啶-1-基)-4-(2,3-二氯苯基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000077
(1-(4-(2,3-二氯苯基)-6-溴甲基-3-氧-2,3-二氢-1H-吡咯[3,4-c]吡啶-7-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(45mg,0.08mmol)溶解于THF(10mL)中，室温下加入稀盐酸(2M,5mL)，搅拌3h，加水，用NaOH溶液调节至pH＝10，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩滤液，粗品用制备HPLC纯化得到产物7-(4-氨基-4-甲基哌啶-1-基)-4-(2,3-二氯苯基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮(7mg,产率22％)。
1H NMR(400MHz,d-DMSO)δ：8.43(s,1H),7.85(d,J＝8Hz,1H),7.80(d,J＝7.6Hz,1H),7.35(t,J＝7.2Hz,1H),5.54(s,2H),4.42(s,1H),3.51(m,2H),3.44(s,2H),3.16(m,2H),3.04(m,2H),1.85(m,2H),1.76(m,2H),1.23(s,3H).
MS m/z(ESI):421.1[M+H] +，423.1[M+2+H] +。
实施例22
(R)-7-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)-4-(2,3-二氯苯基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000078
实施例22的制备方法参考实施例21实验方案。
MS m/z(ESI):461.1[M+H] +，463.1[M+2+H] +。
实施例23
7-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-4-(2,3-二氯苯基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000079
实施例23的制备方法参考实施例21实验方案。
MS m/z(ESI):447.1[M+H] +，449.1[M+2+H] +。
实施例24
7-(3-氨基哌啶-1-基)-4-(2,3-二氯苯基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000080
实施例24的制备方法参考实施例21实验方案。
MS m/z(ESI):377.1[M+H] +，379.1[M+2+H] +。
实施例25
7-(5-氨基六氢环戊二烯并[c]吡咯-2(1H)-基)-4-(2,3-二氯苯基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000081
实施例25的制备方法参考实施例21实验方案。
MS m/z(ESI):403.1[M+H] +，405.1[M+2+H] +。
实施例26
7-(6-氨基-3-氮杂二环[3.1.0]己烷-3-基)-4-(2,3-二氯苯基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000082
实施例26的制备方法参考实施例21实验方案。
MS m/z(ESI):375.1[M+H] +，377.1[M+2+H] +。
实施例27
4-(2,3-二氯苯基)-7-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000083
实施例27的制备方法参考实施例21实验方案。
MS m/z(ESI):389.1[M+H] +，391.1[M+2+H] +。
实施例28
7-(4-氨基-4-甲基哌啶-1-基)-4-(1-甲基-1H-苯并[d]咪唑-6-基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000084
实施例28的制备方法参考实施例21实验方案。
MS m/z(ESI):377.1[M+H] +。
实施例29
7-(4-氨基-4-甲基哌啶-1-基)-4-(苯并[d][1,3]二噁唑-5-基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000085
实施例29的制备方法参考实施例21实验方案。
MS m/z(ESI):367.1[M+H] +。
实施例30
7-(4-氨基-4-甲基哌啶-1-基)-4-(喹啉-7-基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000086
实施例30的制备方法参考实施例21实验方案。
MS m/z(ESI):374.1[M+H] +。
实施例31
3-(7-(4-氨基-4-甲基哌啶-1-基)-3-羰基-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)-N-甲基苯酰胺的制备
Figure PCTCN2019110306-appb-000087
实施例31的制备方法参考实施例21实验方案。
MS m/z(ESI):380.1[M+H] +。
实施例32
4-((2-氨基-3-氯吡啶-4-基)硫代)-7-(4-氨基-4-甲基哌啶-1-基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000088
实施例32的制备方法参考实施例21实验方案。
MS m/z(ESI):405.1[M+H] +，407.1[M+2+H] +。
实施例33
7-(4-氨基-4-甲基哌啶-1-基)-4-((3-氯-2-吗啉代吡啶-4-基)硫代)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000089
实施例33的制备方法参考实施例21实验方案。
MS m/z(ESI):475.1[M+H] +，477.1[M+2+H] +。
实施例34
7-(4-氨基-4-甲基哌啶-1-基)-4-(2,3-二氯苯基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000090
实施例34的制备方法参考实施例21实验方案。
MS m/z(ESI):421.1[M+H] +，423.1[M+2+H] +。
实施例35
4-((2-氨基-3-氯吡啶-4-基)硫代)-7-(4-氨基-4-甲基哌啶-1-基)-6-(羟甲基)-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮的制备
Figure PCTCN2019110306-appb-000091
实施例35的制备方法参考实施例21实验方案。
MS m/z(ESI):435.1[M+H] +，437.1[M+2+H] +。
实施例36
1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺制备
Figure PCTCN2019110306-appb-000092
第一步：6-溴-1-三苯代甲基-1H-吡唑并[4,3-b]吡啶的制备
Figure PCTCN2019110306-appb-000093
6-溴-1H-吡唑并[4,3-b]吡啶(1.00g,5mmol)，三苯基氯甲烷(1.67g,6mmol)，碳酸铯(4.86g,15mmol)在N，N-二甲基甲酰胺(20mL)中室温搅拌18小时。往反应液里加乙酸乙酯(100mL)，用水(50mL*2)洗涤，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩得粗品，用乙醇(8mL)打浆，过滤得到叔-丁基(4-甲基-1-(1-三苯代甲基-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺)氨基甲酸酯(2.00g，产率90％)白色固体。
MS m/z(ESI):440.1[M+H] +，442.1[M+2+H] +
第二步：(4-甲基-1-(1-三苯代甲基-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺)氨基甲酸叔丁酯的制备
Figure PCTCN2019110306-appb-000094
6-溴-1-三苯代甲基-1H-吡唑并[4,3-b]吡啶(1g,2.27mmol)，(4-甲基哌啶-4-基)氨基甲酸叔丁酯(728mg,3.4mmol)，Pd 2(dba) 3(208mg，0.023mmol)，XantPhos(262mg，0.45mmol)和叔丁醇钠(436mg,4.54mmol)在二氧六环中微波120℃反应1小时。过滤反应液，滤液浓缩完柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(50:50)]纯化得到(4-甲基-1-(1-三苯代甲基-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺)氨基甲酸叔丁酯(1.3g,产率100％)灰色固体。
MS m/z(ESI):574.3[M+H] +
第三步：4-甲基-1-(1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000095
往(4-甲基-1-(1-三苯代甲基-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺)氨基甲酸叔丁酯(1.3g,2.26mmol)和三乙基硅烷(394mg,3.4mmol)的二氯甲烷(5mL)溶液里加三氟乙酸(6mL)，室温搅拌18小时。浓缩反应液得4-甲基-1-(1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺粗品(1.9g)红黑色固体。
MS m/z(ESI):232.1[M+H] +
第四步：1-(3-溴-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000096
往4-甲基-1-(1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺(1.8g,2.2mmol)和氢氧化钾(1.2g,22mmol)的DMF(20mL)里慢慢滴加N-溴代琥珀酰亚胺(392mg,2.2mmol)的DMF(5mL)溶液，加完搅拌10分钟，LCMS检测还剩10％原料，直接用于下一步反应。
MS m/z(ESI):310.0[M+H] +，312.1[M+2+H] +
第五步：3-溴-6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯的制备
Figure PCTCN2019110306-appb-000097
往上一步的反应液里加二碳酸二叔丁酯(1.2g,5.5mmol)，加完，室温搅拌18小时。没反应完全，补加二碳酸二叔丁酯(0.96g,4.4mmol)，室温搅拌3小时。往反应液里加入水(100mL)，用乙酸乙酯(80mL*2)萃取，有机相浓缩后柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(75:25)]纯化得到3-溴-6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯(300mg,三步产率26％)淡黄色固体。
MS m/z(ESI):510.1[M+H] +，512.1[M+2+H] +
第六步：6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯的制备
Figure PCTCN2019110306-appb-000098
3-溴-6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯(200mg，0.39mmol)，(2,3-二氯苯基)硼酸(112mg，0.59mmol)，碳酸钠(124mg,1.17mmol)，四三苯基磷钯(45mg,0.039mmol)在二氧六环(15mL)和水(1mL)中100℃搅拌16小时后，将反应液浓缩得粗品，柱层析[洗脱剂:石油醚～石油醚/乙酸乙酯(70:30)]纯化得到6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯(50mg,产率22％)白色固体。
MS m/z(ESI):576.2[M+H] +，578.2[M+2+H] +
第七步：1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000099
往6-(4-((叔-丁氧基羰基)氨基)-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-1-羧酸叔丁酯(15mg，0.026mmol)的二氯甲烷(10mL)溶液里加入三氟乙酸(2mL)，室温搅拌4小时后，将反应液浓缩，制备HPLC纯化得到1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺(10mg,产率 100％)黄色油状物。
1H NMR(400MHz,MeOD)δ8.80(s,1H),8.18(s,1H),8.05-7.95(m,1H),7.79(d,J＝8Hz,1H),7.66-7.58(m,1H),7.56-7.47(m,1H),3.94-3.83(m,2H),3.50-3.43(m,2H),2.10-1.96(m,4H),1.53(s,3H).
MS m/z(ESI):376.1[M+H] +，378.1[M+2+H] +。
实施例37-60参考以上实验方案制备。
实施例37
1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-N,4-二甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000100
实施例37的制备方法参考实施例36实验方案。
MS m/z(ESI):390.1[M+H] +，392.1[M+2+H] +。
实施例38
1-(3-(3-氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000101
实施例38的制备方法参考实施例36实验方案。
1H NMR(500MHz,CDCl 3)δ8.04(d,J＝2.9Hz,1H),7.97(dd,J＝3.5,1.9Hz,1H),7.77–7.68(m,1H),7.48–7.42(m,2H),7.36(d,J＝2.9Hz,1H),3.44(dt,J＝24.7,11.1Hz,2H),3.23(dt,J＝24.7,11.1Hz,2H),1.88(dt,J＝24.8,11.1Hz,2H),1.66(dt,J＝24.8,11.1Hz,2H),1.22(s,3H),1.15(s,2H).
MS m/z(ESI):342.1[M+H] +，344.1[M+2+H] +。
实施例39
(R)-8-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-8-氮杂螺[4.5]癸烷-1-胺的制备
Figure PCTCN2019110306-appb-000102
实施例39的制备方法参考实施例36实验方案。
MS m/z(ESI):416.1[M+H] +，418.1[M+2+H] +。
实施例40
(3S,4S)-8-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺的制备
Figure PCTCN2019110306-appb-000103
实施例40的制备方法参考实施例36实验方案。
MS m/z(ESI):432.1[M+H] +，434.1[M+2+H] +。
实施例41
3-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-3-氮杂二环[3.1.0]己烷-6-胺的制备
Figure PCTCN2019110306-appb-000104
实施例41的制备方法参考实施例36实验方案。
MS m/z(ESI):360.1[M+H] +，362.1[M+2+H] +。
实施例42
2-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)八氢环戊二烯并[c]吡咯-5-胺的制备
Figure PCTCN2019110306-appb-000105
实施例42的制备方法参考实施例36实验方案。
MS m/z(ESI):388.1[M+H] +，390.1[M+2+H] +。
实施例43
(1R)-2-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)环戊烷-1-胺的制备
Figure PCTCN2019110306-appb-000106
实施例43的制备方法参考实施例36实验方案。
MS m/z(ESI):347.1[M+H] +，349.1[M+2+H] +。
实施例44
(1R)-3-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)环戊烷-1-胺的制备
Figure PCTCN2019110306-appb-000107
实施例44的制备方法参考实施例36实验方案。
MS m/z(ESI):347.1[M+H] +，349.1[M+2+H] +。
实施例45
(R)-1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-3-胺的制备
Figure PCTCN2019110306-appb-000108
实施例45的制备方法参考实施例36实验方案。
MS m/z(ESI):362.1[M+H] +，364.1[M+2+H] +。
实施例46
N-环丙基-1-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000109
实施例46的制备方法参考实施例36实验方案。
MS m/z(ESI):416.1[M+H] +，418.1[M+2+H] +。
实施例47
4-甲基-1-(3-(1-甲基-1H-苯并[d]咪唑-6-基)-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000110
实施例47的制备方法参考实施例36实验方案。
MS m/z(ESI):362.1[M+H] +。
实施例48
1-(3-(苯并[d][1,3]二噁唑-5-基)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000111
实施例48的制备方法参考实施例36实验方案。
MS m/z(ESI):352.1[M+H] +。
实施例49
4-甲基-1-(3-(喹啉-7-基)-1H-吡唑并[4,3-b]吡啶-6-基)哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000112
实施例49的制备方法参考实施例36实验方案。
MS m/z(ESI):359.1[M+H] +。
实施例50
3-(6-(4-氨基-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-3-基)-N,N-二甲基苯酰胺的制备
Figure PCTCN2019110306-appb-000113
实施例50的制备方法参考实施例36实验方案。
MS m/z(ESI):379.1[M+H] +。
实施例51
4-((6-(4-氨基-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-3-基)硫代)-3-氯吡啶-2-胺的制备
Figure PCTCN2019110306-appb-000114
实施例51的制备方法参考实施例36实验方案。
MS m/z(ESI):390.1[M+H] +，392.1[M+2+H] +。
实施例52
1-(3-((2,3-二氯吡啶-4-基)硫代)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000115
实施例52的制备方法参考实施例36实验方案。
MS m/z(ESI):409.1[M+H] +，411.1[M+2+H] +。
实施例53
4-((6-(4-氨基-4-甲基哌啶-1-基)-1H-吡唑并[4,3-b]吡啶-3-基)硫代)-3-氯氰基吡啶的制备
Figure PCTCN2019110306-appb-000116
实施例53的制备方法参考实施例36实验方案。
MS m/z(ESI):400.1[M+H] +，402.1[M+2+H] +。
实施例54
1-(3-((2,3-二氯苯基)硫代)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000117
实施例54的制备方法参考实施例36实验方案。
MS m/z(ESI):408.1[M+H] +，410.1[M+2+H] +。
实施例55
1-(3-((3-氯-2-吗啉代吡啶-4-基)硫代)-1H-吡唑并[4,3-b]吡啶-6-基)-4-甲基哌啶-4-胺的制备
Figure PCTCN2019110306-appb-000118
实施例55的制备方法参考实施例36实验方案。
MS m/z(ESI):460.1[M+H] +，462.1[M+2+H] +。
实施例56
(3-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)苯基)甲胺的制备
Figure PCTCN2019110306-appb-000119
实施例56的制备方法参考实施例36实验方案。
MS m/z(ESI):369.1[M+H] +，371.1[M+2+H] +。
实施例57
1-(3-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)苯基)乙烷-1-胺的制备
Figure PCTCN2019110306-appb-000120
实施例57的制备方法参考实施例1实验方案。
MS m/z(ESI):383.1[M+H] +，385.1[M+2+H] +。
实施例58
3-(2,3-二氯苯基)-6-(异二氢吲哚-5-基)-1H-吡唑并[4,3-b]吡啶的制备
Figure PCTCN2019110306-appb-000121
实施例58的制备方法参考实施例36实验方案。
MS m/z(ESI):381.1[M+H] +，383.1[M+2+H] +。
实施例59
5-(3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-6-基)-2-甲基-2,3-二氢-1H-茚-2-胺的制备
Figure PCTCN2019110306-appb-000122
实施例59的制备方法参考实施例36实验方案。
MS m/z(ESI):409.1[M+H] +，411.1[M+2+H] +。
实施例60
(6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)-1H-吡唑并[4,3-b]吡啶-5-基)甲醇的制备
Figure PCTCN2019110306-appb-000123
实施例60的制备方法参考实施例36实验方案。
MS m/z(ESI):406.1[M+H] +，408.1[M+2+H] +。
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、本发明化合物对SHP-2激酶活性抑制作用的测定
本测试的目的是测量化合物对SHP-2全长蛋白变构活性的抑制能力。
实验仪器：离心机(5810R)购自Eppendorf公司，移液器购自Eppendorf或Rainin公司，酶标仪购自美国BioTek公司，型号为SynergyH1全功能酶标仪。
实验方法：使用Homogeneous Full Length SHP-2 Assay Kit(BPS Bioscience，#79330)进行体外SHP-2活性检测。首先在96孔低吸附微孔板(NUNC，#267342)中加入18μL的Master Mix，即在终浓度为1×的反应缓冲液中包含0.5μM的SHP-2 activating Peptide和5mM的DTT，离心后再加入每孔5μL的待测化合物/DMSO(终DMSO含量为1％，V/V，将待测化合物在DMSO中溶解成1mM，进行三倍系列稀释，10个浓度，反应体系终浓度范围从1μM至0.05nM)，将SHP-2在1×的反应缓冲液中稀释至终浓度为0.06nM后，加入反应微孔板中，每孔2μL，在反应板上设置全活性对照(化合物只加DMSO)和全抑制对照(不加SHP-2)离心后在室温下孵育该反应混合物60分钟。
孵育结束后，加入每孔25μL的Substrate solution，包含终浓度为10μM的Substrate和5mM的DTT，离心后室温继续孵育30分钟。反应结束后，在Synergy H1全功能酶标仪(Biotek)酶标仪上设置激发波长340nm，发射波长455nM，增益值75进行读数。
实验数据处理方法：
根据全活性对照和全抑制对照作为Max和Min的数值，通过反应板上阳性对照孔(DMSO对照孔)和阴性对照孔(不添加激酶)计算使用化合物处理的孔的百分比抑制比率数据{％抑制率＝100-[(测试化合物-Min平均值)/(Max平均值-Min平均值)]×100}。使用GraphPad prism拟合百分比抑制率和十点浓度数据至4参数非线性逻辑公式计算出测试化合物的IC 50值。
实验结论：
通过以上方案得出本发明所示的实施例化合物在SHP-2激酶活性试验中显示出如下表1的生物活性，
表1：化合物对SHP-2激酶活性抑制相对IC 50值
Figure PCTCN2019110306-appb-000124
测试例2、小鼠药代动力学测定
2.1.研究目的：
以Balb/c小鼠为受试动物，研究化合物实施例1、实施例36和实施例38，口服给药在小鼠体内(血浆)的药代动力学行为。
2.2.试验方案
2.2.1试验药品：
本发明实施例1、实施例36和实施例38，自制；
2.2.2试验动物：
Balb/c小鼠，雄性，购自上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006 N0.311620400001794)。
2.2.3药物配制：
称取5g羟乙基纤维素(HEC，CMC-Na，粘度：800-1200Cps)，溶于1000mL纯净水，加入10g Tween80。混合均匀成澄清溶液。
分别称取样品1.2mg，加入4-mL玻璃瓶，加入2.4mL该溶液，超声10分钟，得到无色澄清溶液，浓度为0.5mg/mL。
2.2.4给药：
Balb/c小鼠，雄性；禁食一夜后分别PO，剂量为5mg/kg，给药体积10mL/kg。
2.2.5样品采集：
于给药前和给药后0.25h、0.5h、1h、2h、4h、6h、8h、24h采血，血液置于EDTA-2K试管中，4℃6000rpm离心6min分离血浆，于负80℃保存；给药后4h进食。
2.2.6测定结果：
应用LCMS/MS方法得到最后测定结果见表2
表2：化合物的小鼠药代动力学参数
Figure PCTCN2019110306-appb-000125
Figure PCTCN2019110306-appb-000126
以上数据显示：5mg/kg剂量下，本发明实施例化合物显示出良好的代谢活性。
测试例3、MiaPaca 2移植瘤模型上对肿瘤的抑制实验
3.1实验目的：
以BALB/c裸小鼠为受试动物，采用人胰腺癌细胞MiaPaca 2异种移植瘤(CDX)模型进行体内药效实验，评价受试化合物抗肿瘤作用。
3.2实验仪器与试剂：
3.2.1仪器：
超净工作台(BSC-1300II A2，上海博讯实业有限公司医疗设备厂)
CO 2培养箱(Thermo-311，Thermo)
离心机(Centrifuge 5720R，Eppendorf)
全自动细胞计数仪(Countess II，Life Technologies)
移液器(10-20μL，Eppendorf)
显微镜(Ts 2，尼康)
游标卡尺(CD-6”AX，日本三丰)
细胞培养瓶(T25/T75/T225，Corning)
恒温水槽(HWS12，上海一恒科学)
3.2.2试剂：
DMEM(11995-065，Gibco)
胎牛血清(FBS)(10091-148，Gibco)
0.25％胰蛋白酶(25200-056，Gibco)
青链霉素双抗(P/S)(SV30010，GE)
磷酸盐缓冲液(PBS)(10010-023，Gibco)
Matrigel(356234，Corning)
Gln(25030-081，Gibco)
3.3实验操作：
从细胞库中取出MiaPaca 2细胞，复苏后加入DMEM培养基(含10％FBS、1％Glu、1％P/S)置于CO 2培养箱中培养(培养箱温度为37℃，CO 2浓度为5％)。待细胞铺满培养瓶底部80-90％后传代，传代后细胞继续置于CO 2培养箱中培养。重复该过程直到细胞数满足体内药效接种需求量，开始收集对数生长期的细胞，用全自动细胞计数仪计数，根据计数结果用PBS和Matrigel(体积比为1：1)重悬细胞，制成细胞悬液(密度8×10 7/ml)，置于冰盒中待用。
使用动物为BALB/c裸小鼠，雌性，6-8周龄，体重约为18-22克。将小鼠 保持在一个无特殊病原体的环境中，且在单个通风笼中，每笼5只小鼠。所有的笼子、垫料和水在使用前进行消毒，所有动物可以自由获取标准认证的商业实验室饮食。实验开始前用一次性大小鼠通用耳标标记裸鼠，接种前用75％医用酒精消毒接种部位皮肤，每只小鼠在右后背皮下接种0.1ml(含8*10 6个细胞)MiaPaca2肿瘤细胞。当平均肿瘤体积达到100-200mm 3时开始分组给药。受试化合物每日经口灌胃给药，给药剂量、给药频次及实验结束时各组药效情况见表3。每周两次用游标卡尺测量肿瘤体积(mm 3)，计算公式为：V＝0.5*D*d*d，其中D和d分别是肿瘤的长径和短径。抗肿瘤药效是通过化合物处理过的动物的平均肿瘤增加体积除以未处理过动物的平均肿瘤增加体积来确定。抑瘤率计算公式为：TGI(％)＝1-[(Vt-V0)给药组/(Vt-V0)溶剂对照组]*100％。实验结束后将所有动物安乐死。
3.4实验结果：
表3：化合物的移植瘤小鼠药效参数
Figure PCTCN2019110306-appb-000127
实验结论：以上数据显示，口服连续给药21天后，本发明实施例化合物能显著抑制MiaPaca 2裸小鼠移植瘤生长。

Claims (23)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019110306-appb-100001
    其中：
    L选自键、-S-、-O-、-NR aa-、-(CR aaR bb) n1-或-(C＝O)-；
    环A选自6-14元双环；该双环优选杂芳基并杂芳基或杂芳基并杂环基；
    环B选自环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb和-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代；
    环C选自环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1-、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb和-(CH 2) n1NR aaS(O) m1R bb中的一个或多个取代基所取代；
    R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 1链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、 -(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多个取代基所取代；
    R 2选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、氧代基、醛基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、氨基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、氧代杂环基、硫代杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-NR aaC(O)(CH 2) n1OR aa、-NR aaC(＝S)(CH 2) n1OR bb、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-N＝S＝O(R aaR bb)、-P(O)R aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    或者，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R cc、-(CH 2) n1OR cc、-(CH 2) n1SR cc、-(CH 2) n1C(O)R cc、-(CH 2) n1C(O)OR cc、-(CH 2) n1S(O) m1R cc、-(CH 2) n1NR ccR dd、-(CH 2) n1C(O)NR ccR dd、-(CH 2) n1C(O)NHR cc、-(CH 2) n1NR ccC(O)R dd和-(CH 2) n1NR ccS(O) m1R dd中的一个或多 个取代基所取代；
    R aa、R bb、R cc和R dd各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    或者，R aa和R bb链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的卤代烷基、卤素、取代或未取代的氨基、氧代基、硫代基、硝基、氰基、羟基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的烷氧基、取代或未取代的卤代烷氧基、取代或未取代的羟烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    x为0、1、2、3或4；
    y为0、1、2、3或4；
    z为0、1、2、3或4；
    m1为0、1或2；且
    n1为0、1、2、3、4或5。
  2. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(II)所示：
    Figure PCTCN2019110306-appb-100002
    其中：
    M 1为S或NR aa；
    L为键、O、S或-CH 2-；
    环B为芳基或杂芳基；
    R 1选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或 -(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 1链接形成一个环烷基、杂环基、芳基或杂芳基，所述的环烷基、杂环基、芳基和杂芳基，任选进一步被选自氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、酯基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2选自氢、氘、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、醛基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa或-(CH 2) n1OR aa；
    R 3选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb，所述的烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、氨基烯基、炔基、环烷基、杂环基、芳基、杂芳基，任选进一步被选自氢、氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或，相同碳原子或者不相同碳原子上的两个R 3链接形成一个环烷基或杂环基，所述的环烷基和杂环基，任选进一步被选自氢、氘、烷基、环烷基、卤代烷基、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R aa和R bb各自独立地选自氢、氘、烷基、氘代烷基、卤代烷基、烷氧基、羟烷基、卤代烷氧基、卤素、氰基、硝基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；
    x为0、1、2、3或4；
    z为0、1、2、3或4；
    q为0、1、2或3；
    m1为0、1或2；且
    n1为0、1、2、3、4或5。
  3. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(III)所示：
    Figure PCTCN2019110306-appb-100003
    其中：
    环B、L、R 1、R 2、R 3、x、z和q如权利要求2所述。
  4. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IV)所示：
    Figure PCTCN2019110306-appb-100004
    其中：
    环C选自芳基、环烷基或杂环基；
    环B、L、R 1、R 2、R 3、x和z如权利要求2所述。
  5. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IIA)和通式(IIB)所示：
    Figure PCTCN2019110306-appb-100005
    其中：
    环B、M 1、R 1、R 2、R 3、x、z和q如权利要求2所述。
  6. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IIC)所示：
    Figure PCTCN2019110306-appb-100006
    其中：
    M 1、R 1、R 2、R 3、x、z和q如权利要求2所述。
  7. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IIIA)和通式(IIIB)所示：
    Figure PCTCN2019110306-appb-100007
    其中：
    环B、R 1、R 2、R 3、x、z和q如权利要求2所述。
  8. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IIIC)所示：
    Figure PCTCN2019110306-appb-100008
    其中：
    R 1、R 2、R 3、x、z和q如权利要求2所述。
  9. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IVA)和通式(IVB)所示：
    Figure PCTCN2019110306-appb-100009
    其中：
    环B、R 1、R 2、R 3、x、z和q如权利要求2所述。
  10. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(IVC)所示：
    Figure PCTCN2019110306-appb-100010
    其中：
    R 1、R 2、R 3、x、z和q如权利要求2所述。
  11. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(VI)所示：
    Figure PCTCN2019110306-appb-100011
    其中：
    M 3选自CR 8或N；
    R 7选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 7链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 8选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    当M 3为CR 8时，任选地，R 7与R 8链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基 和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 9选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；
    t为0、1、2、3或4；
    q为0、1、2或3；且
    z-1为0、1、2或3。
  12. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，环A选自如下基团：
    Figure PCTCN2019110306-appb-100012
    Figure PCTCN2019110306-appb-100013
  13. 根据权利要求2、3、4、5、7和9中任一项所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：
    环B选自如下基团：
    Figure PCTCN2019110306-appb-100014
    环B进一步选自如下基团：
    Figure PCTCN2019110306-appb-100015
  14. 根据权利要求1或4所述的各通式所示的化合物、其立体异构体或其药学上可接受盐，其特征在于：
    环C选自如下基团：
    Figure PCTCN2019110306-appb-100016
    环C进一步选自如下基团：
    Figure PCTCN2019110306-appb-100017
  15. 根据权利要求1～10中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，
    R 1选自氢、氰基、氨基、卤素、C 1-6烷基、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1C(O)OR aa或3-8元杂环基；
    R 2选自氢、-(CH 2) n1OR aa或5-6杂芳基；
    R 3选自氢、C 1-6烷基、氨基或-(CH 2) n1NR aaR bb，所述的C 1-6烷基和氨基，任选进一步被选自氢、卤素、氨基、氰基和羟基中的一个或多个取代基所取代。
  16. 根据权利要求11所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(VI-A)所示：
    Figure PCTCN2019110306-appb-100018
  17. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，通式(I)进一步如通式(V)所示：
    Figure PCTCN2019110306-appb-100019
    其中：
    M 1为-S-或-NH-；
    M 2选自CR 5或N；
    R 4选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，相同碳原子或者不相同碳原子上的两个R 4链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 5选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-(CH 2) n1R aa、-(CH 2) n1OR aa、-(CH 2) n1SR aa、-(CH 2) n1C(O)R aa、-(CH 2) n1C(O)OR aa、-(CH 2) n1S(O) m1R aa、-(CH 2) n1NR aaR bb、-(CH 2) n1C(O)NR aaR bb、-(CH 2) n1NR aaC(O)R bb或-(CH 2) n1NR aaS(O) m1R bb；
    或，R 4与R 5链接形成一个C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基，所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基，任 选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 2-6酯基、C 2-6酰胺基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；
    R 3选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 1-6烷基或C 1-6烷基氨基；
    R 6选自氢、氘、卤素、氨基、硝基、羟基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基；
    s为0、1、2、3或4；
    z-1为0、1、2或3。
  18. 根据权利要求1～17中任一项所述的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：
    Figure PCTCN2019110306-appb-100020
    Figure PCTCN2019110306-appb-100021
  19. 一种制备权利要求17所述的通式(V)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：
    Figure PCTCN2019110306-appb-100022
    其中：
    X 1为卤素，优选氟、氯、溴、碘；更优选氯；
    Pg为氨基保护基，选自叔丁基亚磺酰基、苄氧羰基、叔丁氧羰基、9-芴甲氧羰基、苄基、对甲氧基苄基、烯丙氧羰基、三苯甲基或邻苯二甲酰基；优选叔丁氧羰基。
  20. 一种制备权利要求11所述的通式(VI)所示的化合物或其立体异构体及其药学上可接受盐的方法，其特征在于，包含以下步骤：
    Figure PCTCN2019110306-appb-100023
    通式偶联和脱保护反应，得到通式(VI)所示化合物或其立体异构体及其药学上可接受盐；
    其中：
    X 2选自卤素，优选氟、氯、溴或碘；更优选溴；
    Pg’为氨基保护基，选自叔丁基亚磺酰基、苄氧羰基、叔丁氧羰基、9-芴甲氧羰基、苄基、对甲氧基苄基、烯丙氧羰基、三苯甲基或邻苯二甲酰基；优选叔丁氧羰基。
  21. 一种药用组合物，其包括治疗有效剂量的权利要求1～18中任一项所示的通式(I)化合物、其立体异构体或其药学上可接受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。
  22. 根据权利要求1～18中任一项所述的化合物、其立体异构体或其药学上 可接受的盐，或权利要求21所述的药物组合物在制备SHP-2抑制剂药物中的应用。
  23. 根据权利要求1～18中任一项所述的化合物、其立体异构体或其药学上可接受的盐，或权利要求21所述的药物组合物在制备治疗努南氏症候群、豹皮症候群、白血病、神经母细胞瘤、黑色素瘤、乳腺癌、胃癌、肺癌及其结肠癌等疾病或病症中的用途。
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