WO2018171633A1 - 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用 - Google Patents

吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用 Download PDF

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WO2018171633A1
WO2018171633A1 PCT/CN2018/079866 CN2018079866W WO2018171633A1 WO 2018171633 A1 WO2018171633 A1 WO 2018171633A1 CN 2018079866 W CN2018079866 W CN 2018079866W WO 2018171633 A1 WO2018171633 A1 WO 2018171633A1
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substituted
unsubstituted
group
alkyl
compound
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PCT/CN2018/079866
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French (fr)
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赵志明
高大新
陈寿军
武志恒
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上海迪诺医药科技有限公司
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Priority to US16/496,534 priority Critical patent/US11248006B2/en
Priority to JP2019552608A priority patent/JP7140337B2/ja
Priority to EP18772694.8A priority patent/EP3604306B1/en
Publication of WO2018171633A1 publication Critical patent/WO2018171633A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention relates to a macrocyclic derivative of pyrazole[3,4-d]pyrimidin-3-one, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • Wee1 (Wee1G2 checkpoint kinase; gene number: 7465) is a member of the serine/threonine protein kinase family, which directly phosphorylates cyclin-dependent kinase 1 (CDK1) and phosphorylates the tyrosine of CDK1
  • CDK1 cyclin-dependent kinase 1
  • the acid 15 residue which is an inhibitory phosphorylation site, negatively regulates CDK1 activity.
  • Activation of the G2 checkpoint is primarily through the inhibition of mitosis, promoting the cyclin B-CDK1 complex. Normal cells repair damaged DNA during the G1 arrest period. However, cancer cell G1-S detection sites are often deleted, and it is necessary to rely on the function of G2-M detection sites for DNA repair.
  • P53-deficient tumor cells lack the function of the G1 checkpoint and thus rely on the G2 checkpoint as a response to DNA damage in cell cycle arrest. After DNA damage, the G2 checkpoint prevents damaged cells from entering mitosis, thereby protecting them from mitotic catastrophe and apoptosis.
  • Wee1 is an indispensable factor in the function of the G2 checkpoint. Abolishing the G2 detection site by Wee1 inhibitor may selectively sensitize P53-deficient cancer cells to DNA damage and avoid affecting surrounding normal tissues. Wee1 also regulates S-phase CDK activity, preventing the induction of DNA damage during normal S-phase progression. In addition, Wee1 plays an active mediating role in homologous recombination (HR) repair, and homologous recombination repair is an important pathway for DNA double-strand break repair.
  • HR homologous recombination
  • Upregulation of Wee1 can be seen in many different types of cancer, including hepatocellular carcinoma (Masaki, et al, 2003), breast cancer, cervical cancer, lung cancer (Iom, et al, 2009), squamous cell carcinoma (Magnussen, et Al, 2013), glioma DIPG (Mueller, et al, 2014), malignant glioma (Mir, et al, 2010; Music, et al, 2016), medulloblastoma (Harris, et al, 2014), leukemia (Tibas, et al, 2012; Porter, et al, 2012), melanoma (Magnussen, et al, 2012), and ovarian cancer (Slipicevic, et al, 2014).
  • Wee1 is associated with poor prognosis of many types of cancer. Inhibition of Wee1 caused apoptosis in some P53 inactivated tumor cells. Inhibition of Wee1 can be sensitive to cancer cells that are resistant to chemotherapy and radiation therapy.
  • the latest study (Pfister, et al, 2015) demonstrates the interaction between synthetic lethality and H3K36me3 deletion, epigenetic changes in some cancer cells, and Wee1 inhibition, thereby clearly defining Wee1 inhibition and more precise targeted gene changes. The relationship between cancer patients provides strong evidence.
  • Wee1 is currently a highly attractive therapeutic target in the field of cancer therapy.
  • Wee1 there are still many opportunities to expand and benefit from its application.
  • the compounds described herein, compositions and methods of use thereof will contribute to the development of Wee1 inhibitors to meet clinically unmet drug needs.
  • the technical problem to be solved by the present invention is to provide a macrocyclic derivative of a novel pyrazole [3,4-d]pyrimidin-3-one, a preparation method thereof, a pharmaceutical composition and use thereof.
  • the macrocyclic derivative of pyrazol[3,4-d]pyrimidin-3-one of the present invention has a good inhibitory effect on Wee1 and related signaling pathways, and can effectively treat and/or alleviate cancer.
  • the present invention provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt;
  • the ⁇ bond is a single bond, a double bond or a triple bond
  • L is CRR', O or NR';
  • L 1 is CRR 1 , O or C(O);
  • W is N or CR 7 ;
  • R 2 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R' and R 2 are each independently a substituent, or R 2 and R' are bonded to each other to form an A ring; the A ring is a substituted or unsubstituted C 3-15 cycloalkyl group or a substituted or unsubstituted 3-15 a heterocycloalkyl group; when the A ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, thio, halogen, -CN, -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)R e , -N(R d )C(O)OR e
  • R 3 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; said alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic When an alkyl group, an aryl group, a heteroaryl group,
  • R 4 and R 5 are each independently a substituent, or R 4 and R 5 together with the ring atom to which they are attached form a B ring which is a substituted or unsubstituted monocyclic cycloalkyl group, substituted or unsubstituted a monocyclic heterocycloalkyl group, a substituted or unsubstituted spiro group, a substituted or unsubstituted spiroheterocyclyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group;
  • the B ring When the B ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, halogen, -CN, -NO 2 , -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC
  • R 6 and R 7 are each independently hydrogen, halogen, hydroxy, decyl, cyano, nitro, carboxy, amino, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, C 2 -6 alkynyl, C 2-6 alkenyl, hydroxyalkyl, aminoalkyl, aryl, cycloalkyl, substituted or unsubstituted heterocycloalkyl, or heteroaryl; said heterocycloalkyl is substituted When optionally substituted with 1 to 3 halogens, C 1-3 alkyl, C 1-3 alkoxy and halogenated C 1-3 alkyl at any position;
  • Each R a and each R b are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • Each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6. Heteroaryl, 3-8 membered heterocycloalkyl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl;
  • Each R d and each R e are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • n' is an integer of 1-3;
  • n are each independently an integer of 0 to 5.
  • m' is preferably 1.
  • the ⁇ bond is preferably a single bond.
  • the ⁇ bond is preferably a double bond.
  • the ⁇ bond is preferably a triple bond.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I') and/or a pharmaceutically acceptable salt thereof:
  • L is CRR', O or NR';
  • L 1 is CRR 1 , O or C(O);
  • W is N or CR 7 ;
  • R 2 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R' and R 2 are each independently a substituent, or R 2 and R' are bonded to each other to form an A ring; the A ring is a substituted or unsubstituted C 3-15 cycloalkyl group or a substituted or unsubstituted 3-15 a heterocycloalkyl group; when the A ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, thio, halogen, -CN, -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)R e , -N(R d )C(O)OR e
  • R 3 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; said alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic When an alkyl group, an aryl group, a heteroaryl group,
  • R 4 and R 5 are each independently a substituent, or R 4 and R 5 together with the ring atom to which they are attached form a B ring which is a substituted or unsubstituted monocyclic cycloalkyl group, substituted or unsubstituted a monocyclic heterocycloalkyl group, a substituted or unsubstituted spiro group, a substituted or unsubstituted spiroheterocyclyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group;
  • the B ring When the B ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, halogen, -CN, -NO 2 , -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC
  • R 6 and R 7 are each independently hydrogen, halogen, hydroxy, decyl, cyano, nitro, carboxy, amino, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, C 2 -6 alkynyl, C 2-6 alkenyl, hydroxyalkyl, aminoalkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; or, in R 6 or R 7 , the heterocyclic ring
  • the alkyl group is unsubstituted or is optionally substituted at any position by 1 to 3 halogens, C 1-3 alkyl groups, C 1-3 alkoxy groups and halogenated C 1-3 alkyl groups;
  • Each R a and each R b are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • Each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6. Heteroaryl, 3-8 membered heterocycloalkyl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl;
  • Each R d and each R e are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • n are each independently an integer of 0 to 5.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I") and/or a pharmaceutically acceptable salt thereof:
  • L is CRR', O or NR';
  • L 1 is CRR 1 , O or C(O);
  • W is N or CR 7 ;
  • R 2 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R' and R 2 are each independently a substituent, or R 2 and R' are bonded to each other to form an A ring; the A ring is a substituted or unsubstituted C 3-15 cycloalkyl group or a substituted or unsubstituted 3-15 a heterocycloalkyl group; when the A ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, thio, halogen, -CN, -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)R e , -N(R d )C(O)OR e
  • R 3 is hydrogen, halogen, hydroxy, cyano, nitro, decyl, amino, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, C 2-6 alkynyl, C 2-6 alkenyl , aryl, cycloalkyl, heterocycloalkyl, heteroaryl, -OC(O)R c , -OC(O)OR c , -OC(O)N(R c ) 2 , -C(O) OR c , -C(O)R c , -C(O)N(R c ) 2 , -N(R c ) 2 , -NHC(O)R c , -NHC(O)OR c , -NHC( O) N(R c ) 2 , -NHS(O) 2 R c , -S(O) 0-2 R c or -S(O
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted Arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; said alkyl, alkoxy, alkylamino, cycloalkyl, heterocyclic When an alkyl group, an aryl group, a heteroaryl group,
  • R 4 and R 5 are each independently a substituent, or R 4 and R 5 together with the ring atom to which they are attached form a B ring which is a substituted or unsubstituted monocyclic cycloalkyl group, substituted or unsubstituted a monocyclic heterocycloalkyl group, a substituted or unsubstituted spiro group, a substituted or unsubstituted spiroheterocyclyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5-12 membered heteroaryl group;
  • the B ring When the B ring is substituted, it may be optionally substituted at any position by one or more of the following groups: oxo, halogen, -CN, -NO 2 , -SR d , -OR d , -OC(O)R d , -OC(O)OR d , -OC
  • R 6 and R 7 are each independently hydrogen, halogen, hydroxy, decyl, cyano, nitro, carboxy, amino, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, C 2 -6 alkynyl, C 2-6 alkenyl, hydroxyalkyl, aminoalkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl; said heterocycloalkyl being unsubstituted or selective Substituted in any position by 1 to 3 halogens, C 1-3 alkyl, C 1-3 alkoxy and halogenated C 1-3 alkyl;
  • Each R a and each R b are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • Each R c is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6. Heteroaryl, 3-8 membered heterocycloalkyl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl;
  • Each R d and each R e are independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 6 alkynyl, C 3 - 8 -cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkane C 1-6 alkyl group, a phenyl C 1-6 alkyl, aryl, or 5-6 membered heteroaryl C 1-6 alkyl group; a C 1-6 alkyl, C 1- 6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl is unsubstituted or selected 1 to 3 are selected from the group consist
  • n are each independently an integer of 0 to 5.
  • L is CRR'; when L 1 is 0; m is 0, 1, 2, or 3; and n is 1, or 2.
  • L is O or NR'; when L 1 is O; m is 1, 2, or 3; and n is 1, or 2.
  • L is CRR ', O, or NR'; when C (O) L 1 is a; m is 0; and n is 1, 2, or 3.
  • L is NR ', when L 1 is O; m is 1, 2 or 3; and n is 1 or 2.
  • L is NR' or O
  • L 1 is CRR 1
  • m is 1, 2, or 3
  • n is 1, 2, or 3.
  • R 1 is preferably H, F, -OH, C 1-6 alkoxy, C 1-4 alkyl (for example, methyl, ethyl, propyl or isopropyl) Or C 3-8 cycloalkyl.
  • the R 1 is more preferably hydrogen.
  • L 1 is more preferably CH 2 or O.
  • R a is preferably H or C 1-4 alkyl
  • R b is preferably H or C 1-4 alkyl
  • R is more preferably H, F, Cl, -OH, or -CH 3 .
  • R a is preferably H or C 1-4 alkyl;
  • R b is preferably H or C 1-4 alkyl. More preferably, R' is H, -CH 3 or -C(O)CH 3 .
  • the R 2 is preferably H.
  • R 2 and R' are independent substituents, or R 2 and R' are bonded to each other to form an A ring; the A ring is preferably a substituted or unsubstituted 5-8 membered heterocycloalkyl group; More preferably, it is a substituted or unsubstituted 5-6 membered heterocycloalkyl group.
  • the A ring when substituted, it is preferably substituted at any position by 1 to 4 substituents, and more preferably substituted at 1 to 3 or 1 to 2 substituents at any position.
  • the substituents are as defined above.
  • the substituent is preferably an oxo group, a thio group, a halogen, or a C 1-6 alkyl group.
  • the R 3 is preferably H, F, -OH, or a C 1-6 alkoxy group.
  • the R 3 is more preferably H.
  • the R 4 is preferably hydrogen.
  • the R 4 is preferably a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkylamino group, a substituted or unsubstituted C 3-8 cycloalkyl group, a substitution or Unsubstituted 3-9 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl C 1-6 alkane a substituted, unsubstituted 3-8 membered heterocycloalkyl C 1-6 alkyl group, substituted or unsubstituted phenyl C 1-6 alkyl group, substituted or unsubstituted 5-6 membered heteroaryl C 1 a 6 alkyl group, a substituted or unsubstituted C 2-6 alkenyl group, a substituted or un
  • the R 4 is more preferably H or a substituted or unsubstituted 3-9 membered heterocycloalkyl group.
  • the group, heteroarylalkyl group, alkenyl group or alkynyl group is substituted, it is preferably substituted at any position by 1 to 4 substituents; more preferably substituted with 1 to 3 substituents at any position; the substituent is as defined above .
  • the substituent is preferably F, Cl, C 1-6 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy C 1 -3 alkyl, amino C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, -SR d , -OR d , -OC(O)R d , -OC(O )OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)OR e , -N(R d )C(O)OR e , -N(R d )C(O)NR d R e , -NR d S(O) 2 R e ,
  • the substituent is more preferably a C 1-6 alkyl group (e.g., a methyl group).
  • the R 4 is more preferably:
  • the R 5 is preferably hydrogen.
  • the R 5 is preferably a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkylamino group, a substituted or unsubstituted C 3-8 cycloalkyl group, a substitution or Unsubstituted 3-9 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C 3-8 cycloalkyl C 1-6 alkane a substituted, unsubstituted 3-8 membered heterocycloalkyl C 1-6 alkyl group, substituted or unsubstituted phenyl C 1-6 alkyl group, substituted or unsubstituted 5-6 membered heteroaryl C 1 a 6 alkyl group, a substituted or unsubstituted C 2-6 alkenyl group, a substituted or un
  • the group, heteroarylalkyl group, alkenyl group or alkynyl group is substituted, it is preferably substituted at any position by 1 to 4 substituents; more preferably substituted with 1 to 3 substituents at any position; the substituent is as defined above .
  • the substituent is preferably F, Cl, C 1-6 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy C 1 -3 alkyl, amino C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -CN, -SR d , -OR d , -OC(O)R d , -OC(O )OR d , -OC(O)NR d R e , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -NR d R e , -NR d C(O)OR e , -N(R d )C(O)OR e , -N(R d )C(O)NR d R e , -NR d S(O) 2 R e ,
  • the substituent is more preferably a C 1-6 alkyl group (e.g., methyl group) or -NR d R e wherein R d and R e are as defined above. .
  • R 5 is:
  • R 4 and R 5 are each independently substituted, or R 4 and R 5 preferably form a B ring together with the ring atom to which they are attached, and the B ring is preferably a substituted or unsubstituted C 4-8 single Cycloalkyl, substituted or unsubstituted 4-8 membered monocyclic heterocycloalkyl, substituted or unsubstituted C 7-12 spiro group, substituted or unsubstituted 7-12 membered spirocyclyl, substituted or unsubstituted or unsubstituted Unsubstituted phenyl, substituted or unsubstituted 5-6 membered monocyclic heteroaryl, or substituted or unsubstituted 8-10 membered fused ring heteroaryl.
  • the B ring is more preferably a substituted or unsubstituted structure as follows:
  • the B ring is more preferably a substituted or unsubstituted structure as follows:
  • the B ring is more preferably a substituted or unsubstituted structure as follows:
  • the B ring when substituted, it is preferably substituted at any position by 1 to 6 substituents; more preferably substituted with 1 to 4 substituents at any position; more preferably substituted with 1 to 3 substituents. Any position; the substituents are as defined above.
  • the R 6 is preferably H, F, -CH 3 , -OCH 3 , -OCF 3 , -CH 2 OH or -CH 2 OCH 3 .
  • the R 6 is preferably a C 1-6 alkylamino group, or a substituted or unsubstituted 3-8 membered heterocycloalkyl group; wherein the 3-8 membered heterocycloalkyl group may be optionally 1 Or one or two substituents selected from the group consisting of F, Cl, -CH 3 , -OCH 3 , -OCF 3 , -CF 3 or -CHF 2 are substituted at any position.
  • the R 7 is preferably H.
  • the W is preferably N.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II) and/or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively a linkage, -CR 8 R 8a -, -NR 9 -, -O-, -C(O)-, or -S(O) 1-2 -;
  • Z is H/H, O or S
  • R 8a is independently hydrogen, halogen or alkyl
  • R 8 and R 8a together with the C atom to which they are attached together form a 3-8 membered cycloalkyl or heterocycloalkyl group;
  • the heterocycloalkyl group contains 1 or 2 selected from N, O, S ( O) a hetero atom or group of 1-2 ;
  • R 3 , R 4 , R 5 , R 6 , W, L 1 , m, n, R c , R d , and R e are as defined above.
  • the X is O, and Y is CR 8 R 8a ;
  • the X is CR 8 R 8a and Y is CR 8 R 8a ;
  • the X is a linkage and Y is CR 8 R 8a ;
  • the Z is preferably O.
  • the Z is preferably H/H.
  • R 8 is H, F or C 1-6 alkyl (eg methyl, ethyl, isopropyl).
  • R 8a is H, F or C 1-6 alkyl. (Example: methyl, ethyl, isopropyl).
  • R 3 is hydrogen
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II') and/or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively a linkage, -CR 8 R 8a -, -NR 9 -, -O-, -C(O)-, or -S(O) 1-2 -;
  • Z is H/H, O or S
  • R 8a is independently hydrogen, halogen or alkyl
  • R 8 and R 8a together with the C atom to which they are attached together form a 3-8 membered cycloalkyl or heterocycloalkyl group;
  • the heterocycloalkyl group contains 1 to 2 selected from N, O, S ( O) a hetero atom or group of 1-2 ;
  • R 3 , R 4 , R 5 , R 6 , W, L 1 , m, n, R c , R d , and R e are as defined above.
  • the X is O, and Y is CR 8 R 8a ;
  • the X is CR 8 R 8a and Y is CR 8 R 8a ;
  • the X is a linkage and Y is CR 8 R 8a ;
  • the Z is preferably O.
  • the Z is preferably H/H.
  • R 8 is H, F or C 1-6 alkyl (eg methyl, ethyl, isopropyl).
  • R 8a is H, F or C 1-6 alkyl. (Example: methyl, ethyl, isopropyl).
  • R 3 is hydrogen
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-1) and/or a pharmaceutically acceptable salt thereof:
  • M is a linkage, -CR 12 R 12a -, -NR 13 -, or -O-;
  • U is a connection key, -CR 12 R 12a -, -NR 13 -, -C(O)-, or -S(O) 1-2 -;
  • V is a connection key, -NR 13 -, -O-, or -CR 12 R 12a -;
  • R 10a , R 11a and R 12a are each independently hydrogen, hydroxy, alkoxy, halogen or alkyl;
  • R 10 and R 10a , R 11 and R 11a , R 12 and R 12a together with the C atom to which they are attached form a 3-8 membered cycloalkyl or heterocycloalkyl group; 1 to 2 hetero atoms or groups selected from N, O, S(O) 1-2 ;
  • R 10 and R 10a , R 11 and R 11a , R 12 and R 12a respectively, together with the C atom to which they are attached form a carbonyl group;
  • R 13 is hydrogen, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -S(O) 1-2 R e , -S(O 2 NR d R e , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl; said alkyl, cycl
  • R 2 , R 3 , R 6 , m, n, R c , R d , R e , L and L 1 are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-1) and/or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively a linkage, -CR 8 R 8a -, -NR 9 -, O, -C(O)-, or -S(O) 1-2 -;
  • Z is H/H, O or S
  • R 3 , R 6 , R 8a , R 8 , R 9 , R 10a , R 10 , R 11a , R 11 , m, n, U, V and M are as defined above.
  • X is a bond or O;
  • Y is -CH 2 -, - CHCH 3 - , or -C (CH 3) 2 -.
  • R 10 , R 11 and R 12 are each independently hydrogen or C 1-4 alkyl
  • R 10a , R 11a and R 12a are each independently hydrogen or C 1-4 alkyl
  • R 11 and R 11a together with the C atoms to which they are attached form a 3-membered cycloalkyl group
  • R 12 and R 12a together with the C atoms to which they are attached form a 3-membered cycloalkyl group
  • U is -CH 2 -, -CHCH 3 -, -C(CH 3 ) 2 - or
  • V is -NR 13 -, R 13 is hydrogen, substituted or unsubstituted C 1-4 alkyl; when the alkyl group is substituted, optionally 1 to 3 Fluorine substitution at any position;
  • R 10 , R 10a and the C atoms to which they are attached together form a 3-membered cycloalkyl group, U is -CH 2 -, R 11 and R 11a are H and M are linking bonds;
  • R 11 , R 11a and the C atoms to which they are attached together form a 3-membered cycloalkyl group, U is -CH 2 -, R 10 and R 10a are H and M are linking bonds;
  • R 11 and R 11a are H and U are R 10 and R 10a are H and M are linkages;
  • R 3 is H.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-2) and/or a pharmaceutically acceptable salt thereof:
  • T is N or CR 14 '
  • R 14 and R 14 ' are hydrogen, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -S(O) 1-2 R e , respectively.
  • R 2 , R 3 , R 6 , R c , R d , R e , m, n, L and L 1 are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-2) and/or a pharmaceutically acceptable salt thereof:
  • T is N or CR 14 '
  • R 3 , R 6 , R 14 , R 14 ', m, n, L and L 1 are as described above.
  • X is a bond or O;
  • Y is -CH 2 -, - CHCH 3 - , or -C (CH 3) 2 -.
  • R 3 is H
  • R 6 is H
  • T is N or CH;
  • R 14 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3- 8-membered heterocycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl C 1-6 alkyl, or substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-6 alkyl; 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3-8 membered heterocycloalkyl C 1-6 alkane
  • the group may be optionally substituted at any position by a group of 1 to 3 as follows: halogen, C 1-4 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy C 1-3 Alkyl, amino C 1-3 alky
  • T is CR 14 ';
  • R 14 ' is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3 -8 membered heterocycloalkyl, substituted or unsubstituted C 3-8 cycloalkyl C 1 - 6 alkyl, or substituted or unsubstituted 3-8 membered heterocycloalkyl C 1-6 alkyl; C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3-8 membered heterocycloalkyl C 1-6
  • the alkyl group may be optionally substituted at any position by a group of 1 to 3 as follows: halogen, C 1-4 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, hydroxy C 1- 3 alkyl
  • T is CH;
  • R 14 is hydrogen or C 1-6 alkyl;
  • R 6 is -N(CH 3 ) 2 , piperazinyl, piperidinyl, pyrrolidinyl or aza a cyclobutane group; wherein the piperazinyl, piperidinyl, pyrrolidinyl or azetidinyl group may be optionally selected from one selected from the group consisting of F, Cl, -CH 3 , -OCH 3 , -OCF 3 , a substituent of -CF 3 or -CHF 2 is substituted at any position;
  • the group Connected to the parent core through the benzene ring (2) is connected to the parent core through the benzene ring (2).
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-3) and/or a pharmaceutically acceptable salt thereof:
  • D is CR 17 or N
  • E is -CR 17 R 17a - or -NR 15 -;
  • s 0, 1 or 2;
  • t 0, 1 or 2;
  • R 15 is hydrogen, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -S(O) 1-2 R e , -S(O 2 NR d R e , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl; said alkyl, cycl
  • R 17a is hydrogen, halogen or alkyl
  • R 2 , R 3 , R 6 , m, n, R c , R d , R e , L and L 1 are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-3) and/or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively a linkage, -CR 8 R 8a -, -NR 9 -, O, -C(O)-, or -S(O) 1-2 -;
  • Z is H/H, O or S
  • R 3 , R 8a , R 8 , R 9 , R 6 , R 16 , m, n, s, t, E, D and L 1 are as defined above.
  • X is a bond or O;
  • Y is -CH 2 -, - CHCH 3 - , or -C (CH 3) 2 -.
  • R 3 is H
  • s is 1 and t is 1 or 2;
  • D is N or CH
  • R 6 is H, F, Cl, -CN, -CH 3 , -CH 2 OH, or -CH 2 OCH 3 ;
  • E is NR 15 ;
  • R 15 is H, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e ,- S(O) 1-2 R e , -S(O) 2 NR d R e , substituted or unsubstituted C 1-4 alkyl;
  • the C 1-4 alkyl group may be optionally selected as follows 1 to 3 a group substituted at any position: halogen, halogenated C 1-3 alkyl, -CN, -OR c and -N(R c ) 2 ;
  • R c , R d and R e are each independently H or C 1 -4 alkyl;
  • R 16 is H, -CH 3 , -CH 2 OH, or -CH 2 OCH 3 .
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-4) and/or a pharmaceutically acceptable salt thereof:
  • R 3 , R 6 , R 10a , R 10 , R 11a , R 11 , R 13 , L 1 , m and n are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-4) and/or a pharmaceutically acceptable salt thereof:
  • X is a linkage or O;
  • Y is -CH 2 -, -CHCH 3 -, or -C(CH 3 ) 2 -;
  • Z is H/H, O or S
  • R 3 , R 6 , R 10a , R 10 , R 11a , R 11 , m, n, U, W and L 1 are as defined above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-5) and/or a pharmaceutically acceptable salt thereof:
  • R 3 , R 6 , R 15 , R 16 , m, n, L 1 and D are as described above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-5) and/or a pharmaceutically acceptable salt thereof:
  • X is a linkage or O;
  • Y is -CH 2 -, -CHCH 3 -, or -C(CH 3 ) 2 -;
  • Z is H/H, O or S;
  • R 3 , R 6 , R 15 , R 16 , m, n, L 1 , W and D are as described above.
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (I-6) and/or a pharmaceutically acceptable salt thereof:
  • D is CR 17 or N
  • E is -CR 17 R 17a - or -NR 15 -;
  • s 0, 1 or 2;
  • t 0, 1 or 2;
  • R 15 is hydrogen, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e , -S(O) 1-2 R e , -S(O 2 NR d R e , substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl; said alkyl, cycl
  • R 17a is hydrogen, halogen or alkyl
  • the compound of formula (I) and/or a pharmaceutically acceptable salt is a compound of formula (II-6) and/or a pharmaceutically acceptable salt thereof:
  • X and Y are respectively a linkage, -CR 8 R 8a -, -NR 9 -, O, -C(O)-, or -S(O) 1-2 -;
  • Z is H/H, O or S
  • R 3 , R 6 , R 8a , R 8 , R 9 , R 16 , m, n, s, t, E, D and L 1 are as defined above.
  • X is a bond or O;
  • Y is -CH 2 -, - CHCH 3 - , or -C (CH 3) 2 -.
  • R 3 is H
  • s is 1 and t is 1 or 2;
  • D is N or CH
  • R 6 is H, F, Cl, -CN, -CH 3 , -CH 2 OH, or -CH 2 OCH 3 ;
  • E is NR 15 ;
  • R 15 is H, -OR d , -C(O)OR d , -C(O)R d , -C(O)NR d R e ,- S(O) 1-2 R e , -S(O) 2 NR d R e , substituted or unsubstituted C 1-4 alkyl;
  • the C 1-4 alkyl group may be optionally selected as follows 1 to 3 The group is substituted at any position: halogen, halogenated C 1-3 alkyl, -CN, -OR c and -N(R c ) 2 ;
  • R c , R d and R e are each independently H or C 1- 4 alkyl;
  • R 16 is H, -CH 3 , -CH 2 OH, or -CH 2 OCH 3 .
  • the compound and/or pharmaceutically acceptable salt of formula (I) is preferably any of the following compounds:
  • the compound and/or pharmaceutically acceptable salt of formula (I) is preferably any of the following compounds:
  • the compound and/or pharmaceutically acceptable salt of formula (I) is preferably any of the following compounds:
  • the present invention also provides a process for the preparation of the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, which is any of the following methods:
  • step 1) in the compound 1d
  • m-CPBA m-chloroperoxybenzoic acid
  • Step 2 Compounds 1e and 1f are reacted under basic conditions to give a compound of the formula IA.
  • the definitions of R 2 , R 4 , R 5 , R 6 , L, L 1 , m, n and W are the same as previously described; the method 2 comprises the following steps: step 3) in the compound 1d
  • the methylthio group is oxidized to the sulfone with m-chloroperoxybenzoic acid (m-CPBA) to give the compound 1g;
  • Step 4) The compound 1g and 1h are reacted under basic conditions to give the compound of the formula IA.
  • step 1) in the compound 1j
  • m-CPBA m-chloroperoxybenzoic acid
  • Step 2 The compounds 1k and 1f are reacted under basic conditions to give a compound of the formula IB.
  • the conditions and steps may be the conditions and steps of the conventional reaction in the art, and the following reaction conditions are particularly preferred in the present invention: 1) the compound is obtained by oxidizing the compound 1d with m-chloroperoxybenzoic acid in a dichloromethane solvent.
  • the amount of the agent is preferably 1 to 50 mL / mmol of compound 1d
  • the reaction time is preferably 0-24 hours
  • the temperature is preferably 0 ° C ⁇ room temperature
  • the molar ratio of compound 1d and m-CPBA is preferably 1: 0.95 - 1:1.05 Step 2)
  • 1e and 1f are reacted to obtain a compound of the formula IA
  • the amount of the agent is preferably from 1 to 50 mL / Immol compound 1d
  • the reaction time is preferably 0-24 hours
  • the temperature is preferably room temperature to reflux of the solvent
  • the molar ratio of compound 1e, 1f and base is preferably 1:0.9:1 to 1:2.5:2.5;
  • the conditions and steps may be the conditions and steps of the conventional reaction in the art, and the following reaction conditions are particularly preferred in the present invention: 1) the compound is obtained by oxidizing the compound 1d with m-chloroperoxybenzoic acid in a dichloromethane solvent.
  • the amount of the agent is preferably 1-30mL / mmol of compound 1d, the reaction time is preferably 0-24 hours, the temperature is preferably 0 ° C ⁇ room temperature, the molar ratio of compound 1d and m-CPBA is preferably 1:2 ⁇ 1:6 Step 2)
  • the temperature is preferably 0 ° C ⁇ room temperature
  • the molar ratio of compound 1d and m-CPBA is preferably 1:2 ⁇ 1:6 Step 2
  • the temperature is preferably 0 ° C ⁇ room temperature
  • the molar ratio of compound 1d and m-CPBA is preferably 1:2 ⁇ 1:6 Step 2
  • the amount of the agent is preferably 1 to 50 mL/mmol of the compound 1 g, and the reaction time is preferably 0-24.
  • the temperature is preferably from 0 ° C to room temperature
  • the molar ratio of the compound 1 g, 1 h to the base is preferably from 1:1:1 to 1:2:120.
  • the conditions and steps may be the conditions and steps of the conventional reaction in the art, and the following reaction conditions are particularly preferred in the present invention: 1) the compound is obtained by oxidizing the compound 1j with m-chloroperoxybenzoic acid in a dichloromethane solvent.
  • the amount of the agent is preferably 1 to 50 mL / mmol of compound 1j, the reaction time is preferably 0-24 hours, the temperature is preferably 0 ° C ⁇ room temperature, the molar ratio of compound 1j and m-CPBA is preferably 1: 0.95 - 1:1.05 Step 2)
  • 1k and 1f are reacted to obtain a compound of the formula IB, and the amount of the agent is preferably 1 to 50 mL / Immol compound 1k
  • the reaction time is preferably 0-24 hours
  • the temperature is preferably room temperature to reflux of the solvent
  • the molar ratio of compound 1k, 1f and base is preferably 1:0.9:1 to 1:2.5:2.5;
  • step 1) is bromine, boric acid or boric acid ester
  • step 1) 1a and 1b are subjected to Buchwald coupling reaction to obtain compound 1c
  • step 2) two olefins in compound 1c are subjected to RCM reaction to form macrocyclic ring 1d. ;
  • step 1 under nitrogen protection, in a 1,4-dioxane solvent, in a base (1,2-N,N-dimethylethylenediamine, potassium carbonate) and cuprous chloride
  • the amount of the agent is preferably 1 to 50 mL / mmol of the compound 1a
  • the reaction time is preferably 0-24 hours
  • the temperature is preferably room temperature to the reflux of the solvent, more preferably 80 to 100 ° C
  • the compounds 1a and 1b The molar ratio is preferably 1:0.9 to 1:1.5.
  • the reaction is carried out under the action of nitrogen gas in a mixed solvent of pyridine and chloroform under the action of copper acetate.
  • the volume ratio of the pyridine to the chloroform is preferably 1:10. 50 mL / mmol of compound 1a, the reaction time is preferably 0-24 hours, the temperature is preferably room temperature to reflux of the solvent, and the molar ratio of the compound 1a and 1b is preferably 1:0.9 to 1:1.5.
  • Step 2 in the solvent of Step 1), 1 h is reacted with methanesulfonyl chloride under the action of a base to obtain Compound 1i; wherein the solvent is preferably dichloromethane, and the base is preferably triethylamine or diiso).
  • step 2) the compound 1i is reacted under basic conditions to obtain a compound 1j; wherein the solvent is preferably N,N-dimethylformamide, and the base is preferably potassium carbonate or carbonic acid. sodium.
  • the 1h can be obtained by the method shown in Reaction Scheme 3:
  • an acidic system such as p-toluenesulfonic acid, hydrochloric acid, hydrogen chloride or trifluoroacetic acid is used, or in the purification process, for example, the acidic phase exists in the mobile phase of prep-HPLC
  • the compound of the formula IA will be the corresponding p-toluenesulfonate, hydrochloride or trifluoroacetate.
  • the amino group, the hydroxyl group or the carboxyl group is preferably protected by a protecting group, Avoid any side reactions. If the above amino protecting group or hydroxy protecting group is present, a subsequent deprotection step is required to provide a compound of formula IA. Any suitable amino protecting group, for example, a tert-butoxycarbonyl (Boc) group, can be used to protect the amino group.
  • Boc is used as a protecting group
  • subsequent deprotection reactions can be carried out under standard conditions, for example, p-toluenesulfonic acid/methanol system, dichloromethane/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonate
  • the deprotection reaction can be deprotected under standard conditions, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide in tetrahydrofuran, water, and/or
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof, can be synthesized by a general chemical method.
  • the preparation of the salt can be carried out by reacting the free base or acid with an equivalent chemical equivalent or an excess of an acid (inorganic or organic acid) or a base (inorganic or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprising a compound of the formula (I), an isomer thereof, a prodrug One or more of a stable isotope derivative and a pharmaceutically acceptable salt.
  • the active ingredient may also include other therapeutic agents for cancer, viral infection or autoimmune diseases.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent, and/or excipient.
  • the pharmaceutical composition can be formulated into various types of dosage unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc., depending on the purpose of the treatment.
  • dosage unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), etc.
  • any excipient known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, dextrose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenation Oil; adsorption promoters such as quatern
  • any excipient known and widely used in the art may be used, for example, a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol, etc.; disintegrating agents such as agar and kelp powder.
  • a carrier such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
  • the solution or suspension may be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an isotonic injection with blood.
  • Any of the commonly used carriers in the art can also be used in the preparation of the injection.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan can be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited and can be selected within a wide range, and is usually from 5 to 95% by mass, preferably from 30 to 80% by mass. %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Formulations of various dosage forms can be selected depending on the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone or in combination with injectable solutions (eg, glucose solutions and amino acid solutions); suppositories are given Drug to the rectum.
  • injectable solutions eg, glucose solutions and amino acid solutions
  • suppositories are given Drug to the rectum.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the use of the pharmaceutical composition for the preparation of a Wee1 inhibitor.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a chemotherapeutic or radioactive therapy for preparing a cancer in the pharmaceutical composition
  • chemotherapeutic or radioactive therapy for preparing a cancer in the pharmaceutical composition
  • sensitizers refers to the combination of radiation therapy and/or chemotherapy using an anticancer agent, in the field of cancer therapy, additive or synergistically improving these radiotherapy and / or the therapeutic effects of chemotherapy.
  • the present invention also provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition is prepared for treatment and/or alleviation by Wee1
  • a drug mediated by a related disease the present invention preferably provides a compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the drug
  • the disease is preferably cancer.
  • the present invention preferably employs the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition for the treatment and/or alleviation of cancer Application in medicine.
  • the present invention still further provides a method of treating cancer using the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition, Included are: a compound of formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or a pharmaceutical composition, which is administered to a mammal in a dosage required for treatment.
  • Said mammal preferably a human.
  • the present invention still further provides the compound of the formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt, or the pharmaceutical composition may be combined with one or A variety of other classes of therapeutic agents and/or methods of treatment are used in combination to treat and/or ameliorate a related condition mediated by Wee1, preferably a cancer.
  • the other kind of therapeutic agent for example, other kinds of therapeutic agents for treating cancer
  • the cancers include metastatic and non-metastatic cancers, as well as familial hereditary and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • solid tumor may include, but are not limited to, eyes, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovaries (including those produced from epithelial cells).
  • the solid tumor is preferably human eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including but not limited to malignant glioma, medulloblastoma), ovarian cancer, bladder Cancer, cervical cancer, testicular cancer, kidney cancer (including but not limited to adenocarcinoma, nephroblastoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer , small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, lung cancer (including but not limited to small cell lung cancer, non-small cell lung cancer), villus epithelial cancer, flesh One or more of tumors, Ewing's tumors, soft tissue sarcomas, and skin cancers.
  • brain cancer including but not limited to malignant
  • non-solid tumors may include, but are not limited to, lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodge One or more of gold lymphoma, T cell chronic lymphocytic leukemia, B cell chronic lymphocytic leukemia, myeloid associated leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia), and AIDs-associated leukemia.
  • lymphocytic leukemia including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodge
  • T cell chronic lymphocytic leukemia B cell chronic lymphocytic leukemia
  • myeloid associated leukemia including acute myelogenous leukemia, chronic myelogenous
  • the term "optionally substituted by one or more groups at any position" means that any one or more of the hydrogen atoms of the one or more atoms specified on the group are designated by The group is substituted, provided that it does not exceed the normal valence of the specified atom, which is a reasonable substitution that is common in the art at any position.
  • alkyl refers to a saturated straight or branched hydrocarbon group containing from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 8, from 1 to 4, or from 1 to 3
  • Representative examples of carbon atoms, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, g. Base, octyl, decyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and various isomers thereof Body and so on.
  • cycloalkyl refers to a monocyclic or polycyclic group containing from 3 to 20 carbon atoms which is saturated or partially unsaturated (comprising 1 or 2 double bonds).
  • “monocyclic cycloalkyl” is preferably a 3-10 membered monocycloalkyl group, more preferably a 3-8 membered monocycloalkyl group, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ring Octyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged ring”, “fused cycloalkyl” and “spirocycloalkyl”, and representative examples of “bridged ring” include, but are not limited to, borneol, bicyclo [2.2. 1] heptenyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3. 1] nonylalkyl, bicyclo[4.2.1]nonanyl and adamantyl, and the like.
  • Fused cycloalkyl embraces a cycloalkyl ring fused to a phenyl, cycloalkyl, or heteroaryl group, including but not limited to: benzocyclobutene, 2,3-di Hydrogen-1-H-indole, 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopentyl[B]thiophene, decalin and the like.
  • “Spirocycloalkyl” refers to a bicyclic group formed by the sharing of one carbon atom by two monocyclic cycloalkyl groups, including but not limited to: spiro[2,5]octyl, spiro[2,4]g Base, snail [4,5] thiol and the like.
  • the polycyclic cycloalkyl group preferably contains from 7 to 12 carbon atoms.
  • a monocyclic cycloalkyl or polycyclic cycloalkyl group can be attached to the parent molecule through any one or two carbon atoms of the ring.
  • heterocycloalkyl refers to a non-aromatic cyclic group consisting of a carbon atom and a heteroatom consisting of a hetero atom selected from nitrogen, oxygen or sulfur, including one or two double bonds, which is a cyclic group.
  • the group may be a monocyclic or polycyclic group, and in the present invention, the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may optionally be Oxidized.
  • the nitrogen atom can optionally be further substituted with other groups to form a tertiary or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • aziridine tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholine-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl and the like.
  • Polycycloheterocycloalkyl includes “fused heterocycloalkyl”, “spiroheterocyclyl” and “bridge heterocycloalkyl”.
  • “Fused heterocycloalkyl” includes a monocyclic heterocycloalkyl ring fused to a phenyl, cycloalkyl, heterocycloalkyl or heteroaryl group, including but not limited to: 2,3 - dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indanyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopyranyl, 1, 2,3,4-tetrahydroquinolyl and the like.
  • Spiroheterocyclyl means a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing one carbon atom
  • spiroheterocyclyl groups include, but are not limited to, 5-aza [2.5 An octyl group, a 4-aza[2.5]octyl group, a 4-aza[2.4]heptyl group or the like
  • the polycyclic heterocycloalkyl group is preferably 7-15 members, more preferably 7-12 members.
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl groups can be attached to the parent molecule through any one or two ring atoms on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to a linkage between a cycloalkyl group and a parent core structure through an alkyl group.
  • cycloalkylalkyl embraces the definitions of alkyl and cycloalkyl as described above.
  • heterocycloalkylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heterocycloalkylalkyl embraces the definitions of alkyl and heterocycloalkyl as described above.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through an oxygen bridge, and includes an alkyloxy group, a cycloalkyloxy group, and a heterocycloalkyloxy group.
  • alkoxy includes the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • hydroxy means -OH
  • hydroxyalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by a hydroxy group, including but not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH.
  • alkylthio refers to a cyclic or acyclic alkyl group having the number of carbon atoms attached through a sulfur bridge, the alkylthio group comprising an alkylthio group, a cycloalkylthio group, and a heterocycloalkylsulfide group. base.
  • alkylthio embraces the definitions of alkyl, heterocycloalkyl and cycloalkyl as described above.
  • alkenyl refers to a straight, branched or cyclic non-aromatic hydrocarbon radical containing at least one carbon to carbon double bond. There may be from 1 to 3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C2-4 alkenyl refers to an alkenyl group having 2 to 4 carbon atoms
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, including vinyl, propenyl, and butyl. Alkenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
  • alkynyl refers to a straight, branched or cyclic hydrocarbon radical containing at least one carbon to carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, and includes ethynyl, propynyl, butynyl and 3-methylbutynyl.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl. Wait.
  • heteroaryl refers to an aromatic ring radical formed by the replacement of a carbon atom on at least one ring with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-7 membered monocyclic structure or 7-20.
  • a fused ring structure preferably a 5-6 membered monocyclic heteroaryl group and a 8-10 membered fused ring heteroaryl group.
  • the number of hetero atoms is preferably 1, 2 or 3, and includes: pyridyl, pyrimidinyl, piperazinyl, pyridazine-3(2H)-one, furyl, thienyl, thiazolyl, pyrrolyl , imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, fluorenyl, Isoindolyl, benzofuranyl, benzothienyl, benzo[d][1,3]dioxolanyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquino
  • arylalkyl refers to an alkyl linkage between the aryl group and the parent core structure.
  • arylalkyl embraces the definition of alkyl and aryl as defined above.
  • heteroarylalkyl refers to an alkyl linkage between a heterocycloalkyl group and a parent core structure.
  • heteroarylalkyl embraces the definitions of alkyl and heteroaryl as defined above.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group optionally substituted by halogen.
  • haloalkyl embraces the definitions of the above halo and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted by halogen.
  • haloalkoxy includes the definitions of the above halo and alkoxy.
  • amino means -NH 2
  • alkylamino refers to at least one hydrogen atom is substituted with alkyl amino group, including but not limited to: -NHCH 3, -N (CH 3 ) 2, -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 .
  • aminoalkyl means that any one of the hydrogen atoms on the alkyl group is replaced by an amino group, including but not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 .
  • aminoalkyl and alkylamino embrace the definition of alkyl and amino as defined above.
  • nitro refers to -NO 2 .
  • cyano refers to -CN.
  • mercapto refers to -SH.
  • Root temperature as used herein means 15-30 °C.
  • a double bond in the present invention Indicates a double bond configuration of a Z-type, E-type, or Z-type E mixture (cis, trans, or a mixture of cis and trans isomers). Said It is preferably cis or trans.
  • the isotope-substituted derivative includes an isotope-substituted derivative obtained by substituting any hydrogen atom of the formula I with 1-5 deuterium atoms, and an isotope obtained by substituting any carbon atom of the formula I with 1-3 carbon atoms and 14 atoms.
  • prodrug is meant that the compound is converted to the original active compound after metabolism in the body. Typically, the prodrug is inactive or less active than the active parent compound, but can provide convenient handling, administration or improved metabolic properties.
  • “Pharmaceutically acceptable salts” as described herein are discussed in Berge, et al., “Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and for pharmaceutical chemists It is apparent that the salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, and the like.
  • the compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include those prepared by reacting a compound of the present invention with an acid, for example, hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, citrate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,
  • the pharmaceutically acceptable salt thereof may further include: an alkali metal salt such as a sodium or potassium salt; an alkaline earth metal salt such as a calcium or magnesium salt; an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • an alkali metal salt such as a sodium or potassium salt
  • an alkaline earth metal salt such as a calcium or magnesium salt
  • an organic base salt such as ammonia and an alkane A salt formed from a base such as a hydroxyalkylamine, an amino acid (lysine, arginine) or N-methylglucamine.
  • “isomer” means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, all of which include Stereoisomers, geometric isomers are all included in the present invention.
  • a compound of the formula I or a salt thereof, in stereoisomeric form is a single stereoisomer (enantiomer and diastereomer). Isomers) and mixtures thereof are included within the scope of the invention.
  • the invention also includes individual isomers of the compound or salt represented by Formula I, as well as mixtures with isomers in which one or more chiral centers are inverted.
  • the scope of the invention includes: mixtures of stereoisomers, as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures.
  • the invention includes mixtures of stereoisomers of all possible different combinations of all enantiomers and diastereomers.
  • the invention includes all combinations and subsets of stereoisomers of all the specific groups defined above.
  • the invention also includes geometric isomers of a compound of formula I or a salt thereof, including cis-isomers.
  • the reagents and starting materials used in the present invention are commercially available.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • All of the compounds of the present invention can be separated by high performance liquid chromatography, silica gel column chromatography, flash column chromatography or thin layer chromatography.
  • Flash column chromatography Flash column chromatography (Flash column chromatography) (flash system / Cheetah TM) using Agela Technologies MP200, supporting the use of a separation column for Flash columm Silica-CS (80g) , Cat No.CS140080-0.
  • the thin layer chromatography is Yantai Xinnuo Chemical Co., Ltd.
  • the coating thickness is 0.2 ⁇ 0.03mm and the specification is 20 ⁇ 20cm.
  • Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • Step 1 Acetyl chloride (2.03 g, 25.9 mmol) was added dropwise to 6-bromopyridin-2-amine (3 g, 17.3 mmol) and triethylamine (4.8 mL, 34.6 mmol) in dichloromethane. In a (30 mL) solution, the reaction system was stirred for 3 hours. The reaction mixture was poured into EtOAc (EtOAc)EtOAc.
  • Step 2 Compound 2.1 (1 g, 4.65 mmol), 6-bromo-1-hexene (1.14 g, 7.0 mmol), anhydrous potassium carbonate (1.28 g, 9.3 mmol) were added to N,N-dimethyl The reaction system was stirred at 60 ° C for 16 hours in formamide (20 mL). After cooling to room temperature, the reaction mixture was poured into EtOAc EtOAc (EtOAc)EtOAc. /1) Compound 2.2 (700 mg, yield: 51%) was obtained as a colorless liquid.
  • Step 1 A solution of 6-bromopyridin-2-amine (500 mg, 2.89 mmol) and sodium hydrogen (139 mg, 3.5 mmol, 60%) in N,N-dimethylformamide (20 mL) Further, 5-bromo-1-pentene (517 mg, 3.47 mmol) was added to the reaction system, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into EtOAc (EtOAc m. %) is a colorless liquid.
  • Step 2 A solution of the compound 2.5 (270 mg, 1.12 mmol) and sodium hydrogen (45 mg, 1.12 mmol, 60%) in THF (10 mL) The reaction solution was heated to reflux for 16 hours. The reaction mixture was poured into EtOAc (EtOAc m. %) is a colorless liquid.
  • Step 1 Ethyl bromoacetate (1.66 g, 10 mmol) was added dropwise to a solution of 6-bromo-2-nitropyridin-3-ol (2.18 g, 10 mmol) in N,N-dimethylformamide (20 mL) After the reaction mixture was stirred at room temperature for 5 minutes, potassium carbonate (2.76 g, 20 mmol) was added, and the mixture was stirred for 2 hr, and the mixture was stirred with water (100 mL), and extracted with dichloromethane (20 mL ⁇ 3). The residue was purified by silica gel column chromatography (EtOAcjjjjjjjj
  • Step 3 Compound 3.2 (0.5 g, 2.2 mmol) and 5-bromo-1-pentene (0.36 g, 2.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate was added thereto. (0.45 g, 3.3 mmol). The mixture was stirred at room temperature for 2 hours. The reaction system was diluted with ethyl acetate (30 mL) and brine. The organic phase was separated and dried over anhydrous sodium The residue was purified with EtOAc EtOAcjjjjjjjjjj
  • Step 1 Compound 3.4 (600 mg, 2.03 mmol), boranoic acid pinacol ester (774 mg, 3.05 mmol), potassium acetate (396 mg, 4.03 mmol) and [1,1'-bis(diphenylphosphino)di Ferrocene]palladium dichloride (148 mg, 0.20 mmol) was added to 1,4-dioxane (20 mL). The reaction system was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water, extracted with EtOAc EtOAcjjjjjjjjj 86%) is a colorless liquid.
  • Step 2 Compound 4.1 (500 mg, 1.46 mmol) and concentrated hydrochloric acid (5 mL) were added to a mixture of acetonitrile (10 mL) and water (5 mL). The reaction system was heated to reflux for 16 hours. The reaction mixture was poured into EtOAc (EtOAc)EtOAc.
  • Step 1 Sodium hydrogen (270 mg, 6.75 mmol, 60%) was added to a solution of triethyl phosphonoacetate (1.5 g, 6.69 mmol) in N,N-dimethylformamide (30 mL). The reaction system was stirred for 0.5 hours, and 2-amino-6-bromo-nicotinic acid (900 mg, 4.48 mmol) was added to the above reaction system, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate. Rate: 33%) as a yellow solid.
  • Step 2 Sodium borohydride (112 mg, 2.95 mmol) was added to a solution of compound 5.1 (400 mg, 1.48 mmol) and lithium chloride (13 mg, 0.30 mmol) in methanol (15 mL). The reaction mixture was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to afford Compound 5.2 (400 mg, yield: 99%) as colorless liquid.
  • Step 3 To a solution of compound 5.2 (400 mg, 1.46 mmol) in tetrahydrofuran (15 mL). Ethyl acetate was extracted, dried over anhydrous sodium sulfate, filtered and evaporated to afford Compound 5.3 (300 mg, yield: 90%).
  • Step 1 To a solution of the compound 3.2 (500 mg, 2.19 mmol) in tetrahydrofuran (25 mL), br. The reaction was then quenched with EtOAc (EtOAc (EtOAc) (EtOAc) (470 mg, yield: 99%) was obtained as a white solid.
  • Step 2 4-pentenoyl chloride (160 mg, 1.35 mmol) was added dropwise to a solution of compound 23.1 (290 mg, 1.35 mmol) and triethylamine (410 mg, 4.1 mmol) in dichloromethane (20 mL) The reaction system was stirred at room temperature for 1 hour. The organic solvent was concentrated under reduced pressure.
  • Step 1 To a solution of methyl 2-fluoro-5-nitrobenzoate (2.0 g, 10 mmol) and N,N'-dimethyl-1,2-diamine (890 mg, 10 mmol) in n-butanol (30 mL) Sodium carbonate (2.1 g, 20.1 mmol) was added to the solution. The reaction system was stirred at 110 ° C for 12 hours. The reaction system was then cooled to room temperature and concentrated under reduced pressure. The residue was purified to silicagel elut elut elut elut elut elut elut elut elut
  • Step 2 A solution of borane in tetrahydrofuran (1.0 M, 8.5 mL) was slowly added dropwise to a solution of Compound 8.1 (1.0 g, 4.3 mmol) in THF (20 mL). After the addition, the reaction system was stirred at 66 ° C overnight. The reaction system was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL)EtOAc.
  • Step 3 Compound 8.2 (850 mg, 3.84 mmol) was dissolved in tetrahydrofuran (10 mL) and ethyl acetate (10 mL), and palladium carbon (50 mg, 10%). The reaction system was replaced with hydrogen three times, and then stirred at room temperature under a hydrogen atmosphere overnight. The reaction system was then filtered through celite. The filtrate was concentrated under reduced pressure to give Compound s.
  • Step 1 To a solution of (5-fluoro-2-nitrophenyl)methanol (1.0 g, 5.8 mmol) and N-methylpiperazine (0.7 g, 6.4 mmol) in dimethyl sulfoxide (20 mL) Potassium carbonate (1.2 g, 8.8 mmol) was added in portions. After the addition was completed, the reaction system was stirred at room temperature overnight. After it was diluted with ethyl acetate (50 mL), EtOAc (EtOAc m.
  • Step 2 To a solution of a mixture of compound 9.1 (1.3 g, 5.3 mmol) of THF (10 mL) and ethyl acetate (10 mL) was added palladium char (100 mg, 5%). The reaction system was replaced with hydrogen three times, and then stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.
  • Step 1 A mixed solution of the compound 10.1 (5 g, 31 mmol) and (trimethylsilane)diazomethane (3.5 g, 31 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirred at room temperature for 2 hr. The residue was concentrated, and the residue was purifiedjjjjjjjjj
  • Step 2 1,2-dibromoethane (8.05 g, 42 mmol), compound 10.2 (5.0 g, 28 mmol), tetrabutylammonium bromide (catalytic amount), aqueous sodium hydroxide (50%, 20 mL) and A mixed solution of toluene (40 mL) was stirred at room temperature for 1 hour.
  • the reaction system was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, crystalljjjjjjj .
  • Step 3 Compound 10.3 (5.4 g, 27 mmol) and Raney nickel (1.0 g) were combined in methanol (10 mL). It was replaced with a hydrogen balloon three times, and the reaction system was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction mixture was filtered over EtOAc EtOAc.
  • Step 4 Compound 10.4 (0.2 g, 1.15 mmol) was dissolved in concentrated sulfuric acid. Potassium nitrate (0.11 g, 1.15 mmol) was slowly added to the above reaction system at room temperature. Stir at room temperature for 15 minutes. Then, the reaction mixture was slowly added dropwise to ice water. After filtration, the filter cake was washed with distilled water and dried in vacuo to give a mixture of compound 10.5 and 10.5 (50/1, 0.24 g, yield: 96%) as a pale yellow solid.
  • Step 5 To a solution of sodium borohydride (52 mg, 1.37 mmol) in tetrahydrofuran (2.0 mL), EtOAc. Then, a solution of the compound 10.5 and 10.5' (100 mg, 0.46 mmol) in tetrahydrofuran was added to the above reaction system, followed by reflux for 2 hours. After cooling to room temperature, the reaction was quenched with EtOAc EtOAc (EtOAc m. The mixture (50/1, 68 mg, crude) was obtained as a pale yellow solid.
  • Step 6 A mixture of compound 10.6 and 10.6' (50 mg, 0.25 mmol), acetic acid (1 drop) and 37% formaldehyde (0.1 mL) was dissolved in dichloromethane (1.5 mL). The reaction system was stirred at room temperature for 0.5 hours. Then, sodium cyanoborohydride (104 mg, 0.5 mmol) was added to the above reaction mixture, and the mixture was stirred at room temperature for 2 hr. The combined organic phase was washed with EtOAc (EtOAc m. 94%) is a white solid.
  • Step 7 Compound 10.7 (50 mg, 0.23 mmol), ammonium formate (144 mg, 2.3 mmol) and palladium/carbon (10 mg, 10%). The reaction system was stirred at room temperature for 12 hours. After suction filtration, the filtrate was diluted with a saturated aqueous solution of sodium sulfate, and the mixture was evaporated. (10% methanolic dichloromethane) was purified to give compound 10.8 (30 mg, yield: 70%) as white solid.
  • Step 8 Compound 10.8 (30 mg) was dissolved in formic acid (5 mL), and the reaction was stirred at 100 ° C for 30 min. The solution was concentrated under reduced pressure to give Compound-1HHHHHHH
  • Step 1 Potassium carbonate (405 mg, 2.94 mmol) was added to compound 10.6 (300 mg, 1.47 mmol) and 1,1-difluoro-2-iodoethane (564 mg, 2.94 mmol) of N,N-dimethyl In a solution of formamide (5 mL), the reaction was stirred at 100 ° C overnight. The reaction mixture was cooled to room temperature, and then quenched with water. EtOAc (EtOAc) The compound 10.14 (330 mg, yield: 84%) was purified eluted elute
  • Step 2 A mixture of compound 10.14 (330 mg, 1.3 mmol) and palladium carbon (150 mg, 5%) in methanol (20 mL) was replaced with hydrogen three times and then stirred at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to yield the compound 10.15 (300 mg, crude).
  • Step 1 A solution of o-carboxyphenylacetic acid (50.0 g, 278 mmol) in methylamine (150 mL) was stirred at room temperature for 15 hours, then dichlorobenzene (300 mL) was added to the reaction mixture, and the resulting mixture was stirred at 180 ° C. 8 hours. The reaction mixture was poured into petroleum ether, filtered, and then filtered and evaporated to dryness to afford Compound 11.1 (45 g, yield:
  • Step 2 Add sodium hydrogen (10.0 g, 251 mmol, 60%) to a solution of compound 11.1 (20.0 g, 144 mmol) in ethylene glycol dimethyl ether (250 mL), stir at room temperature for 0.5 hour, then add to the reaction system Methyl iodide (35.6 g, 251 mmol) was stirred for 3 hours. The reaction solution was poured into water, the precipitate was filtered, and then filtered and evaporated to dryness to give Compound 11.2 (16 g, yield: 55%) as a pink solid.
  • Step 3 Under ice bath, concentrated nitric acid (10 mL) was slowly added dropwise to a solution of compound 11.2 (13.0 g, 64.0 mmol) in concentrated sulfuric acid (25 mL), and the reaction mixture was stirred at 0 ° C for 3 hours, then the reaction mixture was It was poured into water, the precipitate was filtered, and the cake was dried in vacuo to give compound 11.3 (10 g, yield: 63%) as white solid.
  • Step 4 Compound 11.3 (10.0 g, 40.3 mmol) and palladium on carbon (2.0 g, 10%) were added to methanol (150 mL), and the reaction system was replaced with hydrogen three times, and then stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • Step 5 The borane dimethyl sulfide complex (8 mL, 82.4 mmol) was slowly added to a solution of compound 11.4 (4.0 g, 18.3 mmol) in tetrahydrofuran (50 mL). To 0 ° C, methanol (20 mL) was added, and the mixture was stirred and evaporated, evaporated, evaporated, evaporated. The mixed solution of 1) was extracted, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuo to give compound 11.5 (3 g, yield: 86%) as a brown liquid.
  • Step 1 Add octahydropyrrole [1,2-a]pyrazine (447 mg, 3.55 mmol) to potassium carbonate (978 mg, 7.1 mmol) and 4-fluoronitrobenzene (500 mg, 3.55 mmol) of N,N- In a solution of dimethylformamide (5 mL). Potassium carbonate (1.2 g, 8.8 mmol) was added portionwise to the mixture at room temperature. After the addition was completed, the reaction system was stirred at room temperature overnight.
  • Step 2 Palladium on carbon (200 mg, 5%) was added to a solution of compound 12.1 (580 mg, 2.3 mmol) in methanol (20 mL). After the system was replaced with hydrogen three times, the reaction system was stirred under a hydrogen atmosphere (hydrogen balloon) for 16 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc.
  • Step 1 5-Nitroindole (1.0 g, 6.2 mmol), dimethylaminochloroethane hydrochloride (1.3 g, 9.3 mmol) and anhydrous potassium carbonate (3.4 g, 25 mmol) of N, N
  • the mixture of dimethylformamide (15 mL) was stirred at 70 ° C for 3 hours.
  • the reaction mixture was cooled to room temperature, poured into ice water (50 mL), and the mixture was evaporated, evaporated, evaporated, evaporated.
  • the residue was purified by silica gel column chromatography eluting eluting
  • Step 2 Compound 13.1 (700 mg, 3 mmol) was added to a solution of palladium carbon (100 mg, 10%) in methanol (20 mL). After the system was replaced with hydrogen three times, the reaction was stirred overnight under a hydrogen atmosphere (hydrogen balloon). The reaction mixture was filtered through Celite (EtOAc)EtOAc.
  • Step 1 5-Nitroindole (1.0 g, 6.2 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and sodium hydrogen (0.5 g, 12.4 mmol) was slowly added to the system. 60%). The reaction system was stirred at 20 ° C for 30 minutes, and then 1-Boc-4-methanesulfonyloxypiperidine (1.72 g, 6.2 mmol) was added to the above reaction system, and stirred at 100 ° C for 12 hours. Then, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. : 75%) is a yellow oil.
  • Step 2 A mixed solution of the compound 14.1 (0.85 g, 2.4 mmol) of trifluoroacetic acid (2.0 mL) and dichloromethane (4.0 mL) was stirred at room temperature for 1 hour, and concentrated directly to give compound 14.2 (0.55 g, crude) It is yellow oily.
  • Step 3 Compound 14.2 (0.50 g, 2.0 mmol), 37% formaldehyde (0.33 g, 4.0 mmol), triethylamine (0.1 mL) and acetic acid (two drops) of 1,2-dichloroethane (10 mL) The solution was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.39 g, 6.0 mmol) was then added to the reaction system, and the reaction mixture was further stirred at room temperature for 2 hours. The reaction was then quenched with aqueous EtOAc (EtOAc)EtOAc. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. 66%) is a yellow solid.
  • Step 4 Compound 14.3 (0.35 g, 1.3 mmol) was dissolved in methanol (10 mL) and palladium carbon (0.05 g, 5%) was added. After the system was replaced with hydrogen three times, the reaction was stirred under a hydrogen atmosphere (hydrogen balloon). hour. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc.
  • Step 1 Methyl chloroformate (57.8 mg, 0.61 mmol) was added to a solution of compound 14.2 (100 mg, 0.41 mmol) and triethylamine (82.8 mg, 0.82 mmol) in dichloromethane. The reaction mixture was concentrated and purified mjjjjlilililililililili
  • Step 2 Compound 16.1 (57 mg, 0.19 mmol) was added to a solution of palladium carbon (20 mg, 5%) in methanol. After the system was replaced with hydrogen three times, the reaction mixture was stirred under a hydrogen atmosphere (hydrogen balloon) for 12 hours. The reaction mixture was filtered with EtOAc m.
  • Step 1 A solution of compound 14.2 (110 mg, 0.45 mmol), bromoethanol (168 mg, 1.35 mmol) and potassium carbonate (186 mg, 1.35 mmol) in N,N-dimethylformamide (5 mL) .
  • Step 2 Compound 16.3 (82 mg, 0.28 mmol) and palladium on carbon (40 mg, 10%) were combined in methanol (10.0 mL). The reaction system was replaced with hydrogen three times, and then stirred at room temperature for 2 hours under a hydrogen atmosphere (hydrogen balloon). The reaction solution was filtered through Celite, and then evaporated to ethylamine.
  • Step 1 Add sodium hydrogen (73.4 mg, 1.83 mmol, 60%) to a solution of compound 14.2 (150 mg, 0.61 mmol) in anhydrous N,N-dimethylformamide (5 mL). The reaction system was stirred at room temperature for 0.5 hour, then 1-bromo-2-(methylsulfonyl)ethane (343 mg, 1.83 mmol) was added to the above reaction system and the mixture was stirred at room temperature overnight. The reaction system was then warmed to 50 ° C and the stirring was continued for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (10 mL ⁇ 3). The organic layer was purified by EtOAc (EtOAc:EtOAc)
  • Step 2 Compound 16.5 (200 mg, 0.57 mmol) and palladium/carbon (100 mg, 10%) were combined in methanol (10.0 mL). The reaction system was replaced with hydrogen three times, and then stirred at room temperature for 2 hours under a hydrogen atmosphere (hydrogen balloon). Filtration over celite and EtOAc (EtOAc)
  • Step 1 To a solution of 5-nitrosalicylaldehyde (1.67 g, 10.0 mmol) and N-methyl-2-hydroxyethylamine (1.13 g, 15.0 mmol) in methanol (60 mL) Zinc (1.36 g, 10.0 mmol) was stirred and the reaction was stirred at room temperature for 2 hours. Sodium cyanoborohydride (1.24 g, 20.0 mmol) was then added to the above reaction system and stirred at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. Yellow solid.
  • EtOAc EtOAc
  • Step 2 Add azodicarboxylic acid II to a mixture of compound 17.1 (732 mg, 3.2 mmol) and triphenylsulfonium (1.27 g, 4.9 mmol) in tetrahydrofuran (20 mL) and dichloromethane (8 mL). Ethyl ester (DEAD) (845 mg, 4.9 mmol), and the reaction was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj
  • Step 3 Compound 17.2 (569 mg, 2.7 mmol) was dissolved in methanol (10.0 mL), and palladium carbon (171 mg) was added. After the system was replaced with hydrogen three times, the reaction mixture was stirred under a hydrogen atmosphere (hydrogen balloon) for 12 hours. The reaction mixture was filtered over EtOAc (EtOAc m.
  • Step 1 Add sodium hydrogen (600 mg, 15.0) to a solution of ethyl 5-nitroindole-2-carboxylate (2.34 g, 10.0 mmol) in N,N-dimethylformamide (50 mL). The reaction system was stirred at room temperature for 0.5 hour, then N-Boc-bromoethylamine (2.92 g, 13.0 mmol) was added, and the reaction was stirred at 70 ° C overnight. It was then diluted with ethyl acetate (100 mL) and washed with brine. The organic phase was separated and dried over anhydrous sodium The residue was purified to silicagel elut elut elut elut elut elut elut elut elut elut elut elut elut elut
  • Step 2 A mixture of compound 18.1 (3.05 g, 8.1 mmol) in trifluoroacetic acid (4 mL) and dichloromethane (20 mL) was stirred at room temperature for 2 hr then quenched with saturated aqueous sodium hydrogen carbonate Extract with dichloromethane. The organic phase was combined and washed with EtOAc EtOAc (EtOAc m. Rate: 49%) as a pale yellow solid.
  • Step 3 Compound 18.2 (1.1 g, 4.0 mmol), EtOAc (EtOAc (EtOAc) Then, saturated brine was added to the reaction system, and the mixture was extracted with dichloromethane. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated.
  • Step 4 To a solution of the compound 18.3 (310 mg, 1.3 mmol) in N,N-dimethylformamide (20 mL), sodium hydrogen (81 mg, 2.0 mmol, 60%) After stirring for 15 minutes, methyl iodide (285 mg, 2.0 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. It was then diluted with ethyl acetate (100 mL) and washed with brine. The organic phase was separated and dried over anhydrous sodium sulfate.
  • Step 5 Compound 18.4 (358 mg, 1.5 mmol) was dissolved in methanol (15 mL), and palladium carbon (180 mg) was added. After the system was replaced with hydrogen three times, the reaction was stirred under a hydrogen atmosphere (hydrogen balloon) for 0.5 hour. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • Step 6 A solution of lithium tetrahydroaluminum in tetrahydrofuran (1.95 mL, 4.9 mmol, 2.5 M) was added dropwise to a solution of the compound 18.5 (275 mg, 1.3 mmol) in methyl t-butyl ether (30 mL). The system was stirred at 60 ° C for 5 hours. The reaction was then quenched with EtOAc EtOAc (EtOAc) The organic phase was separated and dried over anhydrous sodium sulfate.
  • EtOAc EtOAc
  • Step 1 Isobutyl chloroformate (10.2 mL, 78 mmol) was added dropwise to monomethyl 1,1-cyclopropyldicarboxylate (10.0 g, 69.4 mmol) and triethylamine (10.8 mL) at -10 °C. , 78 mmol) in tetrahydrofuran (200 mL), and stirred at this temperature for 1 hour, then the reaction system was warmed to 0 ° C, the solid in the reaction mixture was filtered, and the filtrate was used.
  • Step 2 Methanesulfonyl chloride (7.4 g, 64.5 mmol) was added dropwise to a solution of compound 19.1 (5.6 g, 43 mmol) and triethylamine (8.7 mL, 86 mmol) in dichloromethane (100 mL) Stir at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride, washed with EtOAc EtOAc (EtOAc)EtOAc. solid.
  • Step 3 Compound 19.2 (10.7 g, 51.5 mmol) was added to 5-nitroindole (5.56 g, 34.3 mmol) and cesium carbonate (33.5 g, 103 mmol) of N,N-dimethylformamide (60 mL) In the solution, the reaction system was then warmed to 100 ° C and stirred overnight, then the reaction solution was cooled to room temperature and poured into water, the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined, followed by water, saturated brine The organic layer was purified by silica gel chromatography chromatography chromatography eluting elut elut
  • Step 4 Aqueous solution of lithium hydroxide monohydrate (475 mg, 11.3 mmol) (10 mL) was added dropwise to a solution of compound 19.3 (1.24 g, 4.5 mmol) in tetrahydrofuran (30 mL). The aqueous phase was washed with a petroleum ether/ethyl acetate (1/1) mixed solvent, then adjusted to pH 3 with a saturated aqueous solution of citric acid, and then extracted with ethyl acetate (10 mL ⁇ 3). The mixture was washed with brine, dried over anhydrous sodium sulfate.
  • Step 6 Compound 19.5 (460 mg, 1.39 mmol) and palladium on carbon (100 mg, 10%) were combined in methanol (30.0 mL). After the system was replaced with hydrogen three times, the reaction system was stirred under a hydrogen atmosphere (hydrogen balloon) for 2 hours. The reaction mixture was filtered through Celite (EtOAc)EtOAc.
  • Step 1 Under ice bath, sodium hydrogen (121 mg, 3.0 mmol, 60%) was added to a solution of compound 19.5 (500 mg, 1.5 mmol) in N,N-dimethylformamide (10 mL). After the lapse, the iodomethane (639 mg, 4.5 mmol) was added to the above reaction system, and the mixture was stirred at room temperature for 2 hours, then the mixture was poured into ice water, and the aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined. The organic layer was washed with EtOAc (EtOAc m.).
  • Step 2 Compound 19.7 (362 mg, 1.0 mmol) and palladium on carbon (100 mg, 10%) were combined in methanol (15.0 mL). The reaction system was replaced with hydrogen for 3 times, and then stirred at room temperature for 2 hours under a hydrogen atmosphere (hydrogen balloon), and then the reaction mixture was filtered through Celite, and filtrate was concentrated to give compound 19.8 (315 mg, yield: 100%) brown. solid.
  • Step 2 Palladium carbon (50 mg) was added to a solution of the compound 20.1 (760 mg, 2.9 mmol) in methanol (30 mL). The reaction system was stirred for three times with a hydrogen balloon and stirred under a hydrogen atmosphere (hydrogen balloon) for 30 minutes. The mixture was filtered through EtOAc (EtOAc)EtOAc.
  • 6-Bromo-2-aminonaphthalene 500 mg, 2.25 mmol
  • N-methylpiperazine 270 mg, 2.7 mmol
  • cesium hydroxide hydrate 760 mg, 4.5 mmol
  • the solution was stirred at 120 ° C for 20 hours, then the reaction system was cooled to room temperature, diluted with ice water (10 mL), and the aqueous phase was extracted with dichloromethane (20 mL ⁇ 2). The organic layer was dried (MgSO4).
  • Step 1 A solution of phenylacetonitrile (10 g, 96.9 mmol) in polyphosphoric acid (120 g) was heated to 140 ° C. At this temperature, acetone (14.9 g, 257 mmol) was added dropwise, and the mixture was added over 1 hour, and then the temperature was kept stirring. hour. The reaction mixture was cooled and poured into ice water and quenched. EtOAc was evaporated. EtOAc (EtOAc) Filtration and concentration of the filtrate gave Compound 22.1 (6.7 g, yield: 40%) as an oily liquid.
  • Step 2 Potassium nitrate (4.30 g, 42.0 mmol) was slowly added to a solution of the compound 22.1 (6.7 g, 40.0 mmol) of sulfuric acid (80.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (200 mL), EtOAc (EtOAc) , yield: 56%) as a brown solid.
  • Step 3 Boron trifluoride etherate (772 mg, 5.44 mmol) and sodium borohydride (155 mg, 4.08 mmol) were added to tetrahydrofuran (10 mL) under ice-cooling, and the reaction was stirred at 0 ° C for 2 hours. Compound 22.2 (300 mg, 1.36 mmol) was added to the reaction, and the reaction was heated to reflux for 3 hr. The reaction system was then concentrated under reduced pressure to dryness.
  • Step 4 A solution of compound 22.3 (250 mg, 1.21 mmol), EtOAc (2 mL) 2.42 mmol). The reaction system was further stirred for 2 hours. The solvent was then concentrated under reduced pressure. EtOAc was evaporated.
  • Step 5 Compound 22.4 (200 mg, 0.91 mmol) and palladium on carbon (50 mg, 10%) were added to methanol (15 mL), and the reaction mixture was stirred under a hydrogen atmosphere (hydrogen balloon) for 0.5 hr. Filtration and rinsing of the filter cake with methanol, and the filtrate was concentrated under reduced pressure to afford compound 22.5 (170 mg, yield: 98%) as brown oil.
  • Step 3 A mixture of compound 24.2 (210 mg, 0.77 mmol) and palladium/carbon (60 mg, 5%) in methanol (15 mL) was replaced with hydrogen three times. The reaction system was then stirred at room temperature for 1 hour under a hydrogen atmosphere. The solution was filtered and concentrated to give compound 24.3 (205 mg, yield: 100%).
  • Step 2 Raney nickel (20 mg) was added to a solution of the compound 25.1 (150 mg, 0.60 mmol) in methanol (5.0 mL). The reaction system was replaced with hydrogen three times, and then stirred at room temperature for 1 hour under a hydrogen atmosphere. Filtration and concentration under reduced pressure gave Compound 25.2 (90 mg, yield: 68%) as a yellow solid.
  • Step 1 N-Bromosuccinimide (2.12 g, 12.0 mmol) was added to a solution of 5-nitrosalicylaldehyde (2.0 g, 11.9 mmol) in acetonitrile (60 mL). Then, ethyl acetate was added, and the organic phase was washed successively with water, brine, and water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated, and then the mixture was added to the residue and heated to reflux, and then water was added to the reaction system. After the solid was precipitated, the mixture was cooled to 0 ° C and stirred for half an hour, filtered, and filtered and dried in vacuo to give compound 26.1 (2.4 g, yield: 82%) as a yellow solid.
  • Step 2 To a solution of the compound 26.1 (1 g, 4.06 mmol) and diethyl bromomalonate (1.16 g, 4. After stirring for 6 hours, the reaction solution was cooled to room temperature and poured into ice water and stirred, filtered, and then filtered and evaporated to dryness.
  • Step 3 An aqueous solution (5 mL) of sodium hydroxide (361 mg, 9.0 mmol) was added dropwise to a mixture of compound 26.2 (945 mg, 3.0 mmol) of methanol and tetrahydrofuran (10 mL, 1/1). . After the reaction was quenched with water, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. Concentration gave Compound 26.3 (858 mg, yield: 100%) as a brown solid.
  • Step 4 Copper powder (44.8 mg, 1.4 mmol) was added to a solution of compound 26.3 (200 mg, 0.7 mmol) in quinoline (2mL), and the mixture was heated to 200 ° C in a sealed tube and stirred for 0.5 hour.
  • the reaction system was cooled to room temperature, and poured into concentrated hydrochloric acid (15 mL), and the aqueous layer was extracted with ethyl acetate (5 mL ⁇ 3). The residue was purified by silica gel column chromatography eluting elut elut elut elut elut
  • Step 5 Adding tris(dibenzylideneacetone)dipalladium (Pd(dba) 3 ) (4.6 mg, 5.0 ⁇ mol) to compound 26.4 (130 mg, 0.50 mmol), 1,1'-binaphthyl-2,2 '-Diphenylenephosphine (BINAP) (9.3 mg, 15 ⁇ mol), cesium carbonate (488 mg, 1.5 mmol) and N-methylpiperazine (49.9 mg, 0.50 mmol) of 1,4-dioxane (15 mL) In the solution, the reaction system was replaced with nitrogen three times, and the temperature was raised to 110 ° C under a nitrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, EtOAc (EtOAc m.)
  • Step 6 Raney nickel (30 mg) was added to a mixed solution of compound 26.5 (68 mg, 0.26 mmol) and hydrazine hydrate (65 mg, 1.3 mmol) in ethanol and tetrahydrofuran (15 mL, 3/1). Filtration, the filtrate was concentrated, and the residue was purified mjjjjjjj
  • Step 1 N-bromosuccinimide (1.96 g, 11.0 mmol) was added to a solution of 2-methoxy-4-nitroaniline (1.68 g, 10.0 mmol) in acetonitrile (20 mL). After stirring at room temperature for two hours, the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was separated by dropwise addition of water and then cooled to 0 ° C and stirred for half an hour, filtered, and the filter cake was dried in vacuo to give compound 27.1 (2.2 g, yield: 89%) as a brown solid.
  • Step 2 Acetic anhydride (10 mL) was added to a solution of the compound 27.1 (2.2 g, 8.9 mmol) in acetic acid (10 mL), and the mixture was stirred under reflux for 3 hours, then the reaction mixture was cooled to room temperature and poured into ice water and stirred. The mixture was filtered, washed with water, and the residue was added to ethanol and stirred under reflux for 15 minutes to dissolve completely. Then, aqueous ammonia (1 mL) was added to the above clear solution, and the mixture was stirred and cooled to room temperature, filtered, and the cake was washed with ethanol and dried in vacuo. Compound 27.2 (2.1 g, yield: 82%) was obtained as a white solid.
  • Step 3 Boron tribromide (4.33 g, 17.3 mmol) was added to a solution of compound 27.2 (1.0 g, 3.46 mmol) in dichloromethane (60 mL), and the reaction system was slowly warmed to room temperature and continued. Stir overnight. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. /1) Purification gave Compound 27.3 (890 mg, yield: 93%) as a white solid.
  • Step 4 4-Dimethylaminopyridine (26 mg, 0.21 mmol) was added to compound 27.3 (1.15 g, 4.18 mmol) and p-toluenesulfonic acid (79.5 mg, 0.418 mmol) of 1,3-dichlorobenzene (25 mL) In the solution, the reaction system was heated to 170 ° C and stirred for 4 hours. The reaction solution was cooled to room temperature, and the organic solvent was evaporated to ethyl ether.
  • Step 5 Pd(dba) 3 (29.6 mg, 0.032 mmol) was added to compound 27.4 (830 mg, 3.23 mmol), BINAP (60.4 mg, 0.097 mmol), cesium carbonate (3.16 g, 9.69 mmol) and N-methyl
  • piperazine 323.0 mg, 3.23 mmol
  • 1,4-dioxane 30 mL
  • Step 6 Palladium carbon (30 mg, 10%) was added to a mixed solution of compound 27.5 (60 mg, 0.22 mmol) methanol and ethyl acetate (10 mL, 1/1), and the system was replaced with hydrogen three times, then under hydrogen atmosphere After stirring at room temperature for 2 hours, the reaction mixture was filtered over EtOAcjjjjjjjjjjjj It is a brown solid.
  • Step 1 Compound 1.1 (255 mg, 1 mmol), 2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (222 mg, 1 mmol), cuprous iodide (191 mg, 1 mmol), anhydrous potassium carbonate (276 mg, 2 mmol) and N,N-dimethylethylenediamine (88 mg, 1 mmol) were added to 1,4-dioxane (20 mL) The reaction system was stirred at 100 ° C overnight. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjjjj .
  • Step 2 Hoveyda-Grubbs reagent (2 mg) was added to a solution of compound 1-1 (205 mg, 0.52 mmol) in dichloromethane (20 mL), and the mixture was stirred at 40 ° C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure to dryness crystals crystals crystals crystals .
  • Step 3 m-Chloroperoxybenzoic acid (31 mg, 0.154 mmol) was added to a solution of Compound 1-2 (57 mg, 0.154 mmol) in dichloromethane (10 mL). The liquid was concentrated under reduced pressure and the organic solvent was evaporated to give Compound 1-3 (yield:
  • Step 4 Compound 1-3 (59 mg, 0.154 mmol), N,N-diisopropylethylamine (40 mg, 0.308 mmol) and 4-(N-methylpiperazine) phenylamine (30 mg, 0.154 mmol)
  • the toluene (10 mL) solution was stirred at 70 ° C overnight. EtOAc was evaporated.
  • the compound 1-1-2 (cis) was synthesized using the compound 1.2 as a starting material.
  • the compound 1-1-3 (cis) was synthesized using the compound 1.3 as a starting material.
  • the compound 1-1-4 (trans) was synthesized using the compound 1.4 as a starting material.
  • the compound 1.1 in the step 1 is replaced with the compound 1.3, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 9.2 to obtain the compound 1-1-5. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 1.4, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 1-3-2. (trans).
  • the compound 1.1 in the step 1 is replaced with the compound 23.4, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 8-3-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 1.3, and the 4-(N-methylpiperazine)aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 1-2-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 1.3, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 1-3-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 1.4, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 1-3-2. (trans).
  • Step 1 Compound 2.2 (200 mg, 0.67 mmol), 2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (179 mg) , 0.81 mmol), anhydrous potassium carbonate (186 mg, 1.35 mmol)), cuprous iodide (128 mg, 0.67 mmol), N,N-dimethylethylenediamine (59 mg, 0.67 mmol) were added to 1,4- The reaction system was stirred at 100 ° C for 16 hours in dioxane (20 mL). After cooling to room temperature, the reaction mixture was evaporated to purified crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
  • Step 2 Hoveyda-Grubbs reagent (30 mg) was added to a solution of compound 2-1 (160 mg, 0.365 mmol) in dichloromethane (30 mL), and the mixture was stirred at 45 ° C for 4 hours. The reaction solution was cooled, and the methylene chloride was evaporated, evaporated, mjjjjjjjjjjjjj Larger) and 2-3 (trans, 60mg, yield: 40%, less polar), all white solids.
  • Step 3 m-Chloroperoxybenzoic acid (17 mg, 0.097 mmol) was added to a solution of Compound 2-2 (40 mg, 0.097 mmol) in dichloromethane (10 mL). Methyl chloride gave Compound 2-4 (43 mg, yield: 100%) as a white solid.
  • Step 4 Compound 2-4 (43 mg, 0.097 mmol), N,N-diisopropylethylamine (0.3 mL) and 4-(N-methylpiperazine) phenylamine (19 mg, 0.097 mmol) Intoluene (10 mL), the reaction mixture was stirred at EtOAc (EtOAc).
  • the compound 2.2 in the step 1 is replaced with the compound 2.3, and the 4-(N-methylpiperazine)aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 2-2-1. (cis).
  • the compound 2.2 in the step 1 is replaced with the compound 2.4, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 2-3-1. (cis).
  • the compound 2.2 in the step 1 is replaced with the compound 2.3, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound compound 11.5 to obtain the compound 2-3- 2 (cis).
  • Step 1 Compound 3.2 (1.9 g, 8.29 mmol), 2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( 1.84 g, 8.29 mmol), cuprous iodide (1.5 g, 8.29 mmol), anhydrous potassium carbonate (2.35 g, 17 mmol) and N,N-dimethylethylenediamine (0.73 g, 8.29 mmol).
  • 4-dioxane (30 mL) the reaction was stirred at 100 ° C overnight. The mixture was cooled to room temperature, and the mixture was evaporated toluiserjjjjjjjjjjjjjjjjjjj .
  • Step 2 6-Bromo-1-hexene (0.25 g, 1.5 mmol) was added to a solution of compound 3-1 (0.37 g, 1 mmol) in N,N-dimethylformamide (8 mL). After a few minutes, potassium carbonate (0.28 g, 2 mmol) was added, and the mixture was stirred at 50 ° C for 3 hours. After cooling to room temperature, water (20 mL) was added to quench the reaction, which was extracted with dichloromethane (100 mL ⁇ 3) It was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut
  • Step 4 To a solution of compound 3-3 (0.11 g, 0.26 mmol) in dichloromethane (10 mL), m. The solvent obtained Compound 3-4 (0.155 g, crude) was taken directly to the next step.
  • Step 5 Compound 3-4 (0.155 g, crude), N,N-diisopropylethylamine (34 mg, 0.26 mmol) and 4-(N-methylpiperazine) aniline (38 mg, 0.2). Ment) was dissolved in toluene (5 mL), and the reaction was stirred at 70 ° C for 1 hour. The solvent was concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound 3-1-1 (trans, 13.5 mg, Rate: 9.1%) as a yellow solid.
  • the compound 3-2-1 (trans) was obtained by substituting the 4-(N-methylpiperazine)aniline in the step 5 to the compound 10.8 by the synthesis method of the compound 3-1-1.
  • Step 1 Compound 3.3 (53 g, 0.18 mol) and 2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (35.7 g, 0.61 mol) was dissolved in 1,4-dioxane (530 mL) and N,N-dimethylformamide (53 mL), and cuprous iodide (34 g, 178 mmol) and cesium carbonate (116 g, 356 mmol) were added thereto. ). After 5 minutes, N,N'-dimethylethylenediamine (15.7 g, 178 mmol) was added. The mixture was stirred at 100 ° C overnight under a nitrogen atmosphere. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut elut
  • Step 2 To a solution of compound 4-1 (42.0 g, 950 mmol) in dichloromethane (420 mL) was added 4 times to Hoveyda-Grubbs catalyst (2.3 g). After 4 hours, the reaction was stirred at 40 ° C overnight. .
  • Step 3 To a solution of compound 4-2 (700 mg, 1.7 mmol) in dichloromethane (20 mL) After the addition, the reaction system was stirred at 0 ° C for 30 minutes. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen sulfate (10 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to afford compound 4-4 (730 mg, yield: 100%) as a yellow solid.
  • Step 4 Compound 4-4 (300 mg, 0.7 mmol), Compound 10.8 (146 mg, 0.77 mmol) and N,N-diisopropylethylamine (136 mg, 1.1 mmol) dissolved in toluene (20 mL) Stir at 70 ° C overnight. The mixture was washed with brine (20 mL ⁇ 2), dried over anhydrous The residue was purified by silica gel chromatography chromatography eluting
  • Step 1 To a solution of compound 4-2 (700 mg, 1.7 mmol) in dichloromethane (20 mL) After the addition, the reaction system was further stirred at 0 ° C for 30 minutes. The mixture was washed successively with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 2 Compound 5-1 (250 mg, 0.59 mmol), Compound 9.2 (143 mg, 0.64 mmol) and N,N-diisopropylethylamine (114 mg, 0.88 mmol) dissolved in toluene (10 mL) Stir at 70 ° C for 16 hours. The reaction mixture was concentrated under reduced vacuo. The residue was purified by silica gel chromatography eluting eluting
  • the compound 1.1 in the step 1 is replaced with the compound 3.5, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 3-2-3 ( Cis).
  • step 2 Using the synthesis of compound 3-3-1, compound 9.2 in step 2 was replaced with compound 10.11, and the final step was purified by prep-HPLC to give compound 3-2-6 (cis) and 3-2-7 (cis).
  • Trifluoroacetic acid (2 mL) was added dropwise to Compound 6.1 (51 mg, ⁇ The residue was purified by prep-HPLC to yield Compound 3-7-3 (23.5mg, yield: 39%) as white solid.
  • step 2 compound 9.2 in step 2 was replaced with compound 19.8 to give compound 3-8 (cis).
  • compound 3-7-12 is reacted with the compound 3-7-11 to give the compound 3-7-12 (cis).
  • Step 2 Hoveyda-Grubbs reagent (30 mg) was added to a solution of compound 5-1 (150 mg, 0.343 mmol) in dichloromethane (30 mL), and the mixture was stirred at 40 ° C for 16 hours. After cooling, the residue was evaporated to dryness crystals crystals crystals
  • Step 3 m-Chloroperoxybenzoic acid (25 mg, 0.122 mmol) was added to a solution of compound 5-2 (50 mg, 0.122 mmol) in dichloromethane (10 mL). The dichloromethane was removed to give compound 5-3 (78 mg, crude)
  • Step 4 A solution of compound 5-3 (78 mg, crude), N,N-diisopropylethylamine (0.5 mL) and Compound 10.8 (25 mg, 0.134 mmol) in toluene (10 mL) The solvent was concentrated under reduced pressure and the residue was crystallijjjjjjjj
  • the compound 1.1 in the step 1 is replaced with the compound 6.1, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 13.2 to obtain the compound 6-1-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 7.2, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 7-1-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 23.2, and the 4-(N-methylpiperazine)aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 8-1-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 23.2, and the 4-(N-methylpiperazine)aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 8-1-2. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 23.3, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 8-2-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 23.4, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 10.8 to obtain the compound 8-3-1. (cis).
  • the compound 1.1 in the step 1 is replaced with the compound 2.6, and the 4-(N-methylpiperazine) aniline in the step 4 is replaced with the compound 11.5 to obtain the compound 9-1-1. (cis).
  • n-butyl lithium (12.6 mL) was added dropwise to a solution of piperane (4 g, 28.5 mmol) in anhydrous tetrahydrofuran (40 mL) at -78 ° C under dry ice acetone bath.
  • the internal temperature of the system did not exceed -70 ° C. This temperature was stirred for 45 minutes, and then a solution of 1,4-dibromobutane (18.5 g, 85.6 mmol) and hexamethylphosphoric triamide (8 mL) in anhydrous tetrahydrofuran (40 mL) was added dropwise to the above reaction mixture.
  • Step 1 Compound 3-1 (430 mg, 1.16 mmol) was added to 2-((6-bromohex-2-yn-1-yl)oxy)tetrahydro-2H-pyran (303 mg, 1.16 mmol). Potassium carbonate (481 mg, 3.48 mmol) in N,N-dimethylformamide (15 mL), EtOAc. The organic phase was combined and washed with water and brine, EtOAc EtOAcjjjjjjjjj %) is an oily liquid.
  • Step 2 A dichloromethane complex of Pd(dppf)Cl 2 (10.4 mg, 0.013 mmol) was added to compound -6 (140 mg, 0.25 mmol) and formic acid (32 mg, 0.51 mmol).
  • a dioxane (5 mL) solution the reaction system was replaced with nitrogen three times, then warmed to 100 ° C under a nitrogen atmosphere and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, and then evaporated tolululululululululululululululululululululu
  • Step 3 p-Toluenesulfonic acid (3 mg, 0.016 mmol) was added to a solution of compound 6-3 (40 mg, 0.078 mmol) in methanol (5 mL), and the mixture was warmed to 50 ° C and stirred for 2 hours. After the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated,jjjjjjjj
  • Step 4 Methanesulfonyl chloride (31.1 mg, 0.27 mmol) was added to compound 6-4 (77 mg, 0.18 mmol) and triethylamine (36.5 mg, 0.36 mmol) in dichloromethane (10 mL) In the solution, the reaction system was stirred at room temperature for 1 hour, and the reaction was quenched with water. The aqueous phase was extracted with dichloromethane (5 mL ⁇ 3). (91 mg, crude) was used in the next step without purification.
  • Step 5 Potassium carbonate (74.5 mg, 0.54 mmol) was added to a solution of compound 6-5 (91 mg, 0.18 mmol) in N, N-dimethylformamide (15 mL). The reaction mixture was extracted with ethyl acetate (15 mL ⁇ 3). Compound 6-6 (20 mg, yield: 27%) was obtained as a brown solid.
  • Step 6 m-Chloroperoxybenzoic acid (10 mg, 0.05 mmol) was added to a solution of compound 6-6 (20 mg, 0.05 mmol) in dichloromethane (10 mL). 6-7 (21.2 mg, crude) was used in the next step without purification.
  • Step 7 Compound 6-7 (21.2 mg, 0.05 mmol) was added to 3-methoxy-4-(4-methylpiperazin-1-yl)phenylamine (11.1 mg, 0.05 mmol) and N,N- In a solution of diisopropylethylamine (12.9 mg, 0.1 mmol) in toluene (10 mL), the reaction mixture was warmed to 75 ° C and stirred overnight, then the reaction system was directly concentrated, and the residue was purified by prep-HPLC to give compound 10- 1-1 (9.3 mg, yield: 27%) was a yellow solid.
  • Step 1 n-Butyllithium (22 mL) was added dropwise to dryness (7 g, 50 mmol) and N,N-dimethylpropenyl urea (640 mg, 5.0 mmol) in a dry ice acetone bath at -78 °C.
  • the internal temperature did not exceed -70 ° C
  • the reaction system was stirred at this temperature for 30 minutes, and then propylene oxide (8.8 g, 200 mmol) was added dropwise to the above reaction solution, and the temperature was continued at this temperature. After stirring for 1 hour, the reaction system was slowly warmed to room temperature and stirred overnight. The reaction system was quenched with aq.
  • Step 2 Diisopropyl azodicarboxylate (883 mg, 4.37 mmol) was added to triphenylphosphine (1.15 g, 4.37 mmol) in anhydrous tetrahydrofuran (10 mL) under ice-bath.
  • Step 3 Compound 7-1 (1.7 g, 4.37 mmol), 2-allyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (971.3 mg, 4.37 mmol), cuprous iodide (835 mg, 4.37 mmol), N,N-dimethylethylenediamine (385 mg, 4.37 mmol) and potassium carbonate (1.21 g, 8.74 mmol) were dissolved in 1, In a mixed solution of 4-dioxane (40 mL) and N,N-dimethylformamide (4 mL), the reaction mixture was stirred at 100 ° C overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. mjjjjjjjj
  • the compound 6-2 in the step 3 is replaced with the compound 7-2 to obtain the compound 10-1-5.
  • the Wee1 enzyme catalysis test is carried out using the ATP-Glo Max luminescence detection kinase kit (Promega). Kinase activity was assessed by quantitative detection of the amount of ATP retained in the solution following the kinase reaction. The luminescent signal in the test is proportional to the amount of ATP and inversely proportional to the kinase activity.
  • the concentration of the compound in the test ranged from 0.5 nM to 30 ⁇ M. The compound was dissolved in 10% DMSO, and 5 ⁇ L of the solution was added to 50 ⁇ L of the reaction, and the concentration of DMSO in the final reaction was 1%. The reaction was carried out at 30 ° C for 50 minutes.
  • the 50 ⁇ L reaction mixture contained 40 mM Tris, pH 7.4, 10 mM MgCl 2 , 0.1 mg/ml BSA, 2 mM DTT, 0.1 mg/ml Poly(Lys, Tyr) substrate, 10 ⁇ M ATP and Wee1.
  • 50 ⁇ L of ATP-Glo Max luminescence assay kinase assay solution (Promega) was added and incubated for 15 minutes at room temperature. The luminescent signal was measured using a microplate reader.
  • a known Wee1 inhibitor was added as a positive control. Luminance data was analyzed using Graphpad software.
  • Non-linear regression analysis was used to plot the % activity value and the corresponding series compound concentration dose-effect curve.
  • IC 50 values determined by the concentration causing half-maximal percentage activity.
  • cellular assays are used to assess the biological activity of a compound. This trial was conducted using the human colon adenocarcinoma cell line WiDr. The activity of a specific Wee1 inhibitor was evaluated using the p-CDK1Y15 ELISA assay. The detailed test method is described as follows:
  • WiDr cells were cultured in Dulbecco's Modified Eagle's medium containing 10% FBS at 37 ° C and 5% CO 2 .
  • the compound concentration ranged from 0.5 nM to 30 ⁇ M.
  • the compound was diluted and added to a 24-well plate and incubated with the cells for 24 hours.
  • DMSO was used as a negative control.
  • a known Wee1 inhibitor was added as a positive control in some experiments.
  • the manufacturer's instructions in the p-CDK1Y15 assay, cells were lysed and subjected to a colorimetric ELISA kit test to determine the amount of p-CDK1Y15. The optical density is measured using a spectrophotometer. OD data analysis using Graphpad Software, curve fitting to obtain IC 50 values of the compounds.
  • the biological activity of the compound is evaluated using a cell test method.
  • MG63 ATCC CRL-1427
  • a human osteosarcoma cell line cultured in a 96-well plate of Dulbecco's Modified Eagle's medium, supplemented with 10% fetal bovine serum and 1% (v/v) L-glutamine, cultured at 37 °C and 5% CO 2 .
  • Compound concentrations ranged from 4.5 nM to 30 [mu]M.
  • the Wee1 inhibitor stock solution was dissolved in DMSO and added to the indicated concentration medium and incubated for 72 hours. Negative control cells were treated only with vehicle. In some experiments, a known Wee1 inhibitor was added as a positive control.
  • Cell viability was measured using Cell Counting Kit-8 (CCK-8, Sigma-Aldrich) under the direction of the product specification. Using Graphpad software for data analysis, and IC 50 values obtained compound and the fitted curve.
  • the positive control in Biological Examples 1, 2 and 3 is AZD1775, chemical name: 2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6- ((4-(4-Methylpiperazin-1-yl)phenyl)amino)-1H-pyrazole[3,4-d]pyrimidin-3(2H)-one (2-allyl-1-(6) -(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3 (2H)-one).

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Abstract

一种如式(I)所示的吡唑[3,4-d]嘧啶-3-酮的大环衍生物和/或其药学上可接受的盐，以及含有如式(I)所示化合物的组合物和/或其药学上可接受的盐，制备方法和其作为Wee1抑制剂的用途及其作为癌症的化学疗法或放射性疗法的增敏剂中的用途；所述的吡唑[3,4-d]嘧啶-3-酮的大环衍生物可以有效的抑制Wee1及相关信号通路，具有良好的治疗和/或缓解癌症的作用。

Description

吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用
本申请要求申请日为2017年3月23日的中国专利申请CN201710179860.X、申请日为2017年8月25日的中国专利申请CN201710741306.6、申请日为2017年9月20日的中国专利申请CN201710853561.X、申请日为2018年1月5日的中国专利申请CN201810012312.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
发明涉及一种吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其制备方法、药物组合物及应用。
背景技术
Wee1(Wee1G2检测点激酶；基因编号：7465)是丝氨酸/苏氨酸蛋白激酶家族中的一员，可直接磷酸化细胞周期蛋白依赖性激酶1(CDK1)，磷酸化位点为CDK1的酪氨酸15残基，该位点是一个抑制性磷酸化位点，对CDK1活性起消极调节作用。G2检测点的激活主要是通过抑制有丝分裂，促进细胞周期蛋白B-CDK1复合物。正常细胞在G1逮捕期内对损伤的DNA进行修复，然而癌细胞G1-S检测点常常缺失，需要依靠G2-M检测点的功能来进行DNA修复。例如，P53缺陷肿瘤细胞缺乏G1检测点的功能，因而依赖G2检测点作为细胞周期停滞对DNA损伤进行应答反应。DNA受损后，G2检测点阻止受损细胞进入有丝分裂，进而保护其免受有丝分裂灾难及细胞凋亡。Wee1是G2检测点功能发挥中必不可少的因素。通过Wee1抑制剂来废除G2检测点可能选择性的使P53缺陷性癌细胞对DNA损伤敏感，避免对周围正常组织产生影响。Wee1也调节S期的CDK活性，阻止正常的S期进程中DNA损伤的诱导。此外，Wee1在同源重组(HR)修复中起积极调解作用，同源重组修复是DNA双链断裂修复的重要路径。
在多种不同类型的癌症中可见Wee1的上调，包括肝细胞癌(Masaki,et al,2003)，乳腺癌，宫颈癌，肺癌(Iom,et al,2009)，鳞状细胞癌(Magnussen,et al,2013)，神经胶质瘤DIPG(Mueller,et al,2014)，恶性胶质瘤(Mir,et al,2010；Music,et al,2016)，成神经管细胞瘤(Harris,et al,2014)，白血病(Tibas,et al,2012；Porter,et al,2012)，黑色素瘤(Magnussen,et al,2012)，及卵巢癌(Slipicevic,et al,2014)。此外，Wee1的高度表达与多种类型癌症的不良预后有关。抑制Wee1可引起一些P53失活肿瘤细胞的凋亡。抑制Wee1可使对化疗及放疗产生抵抗的癌细胞变的敏感。最新的研究(Pfister,et al,2015)展示了合成致死与H3K36me3缺失、部分癌细胞表观遗传学改变及Wee1抑制之间的相互作用，从而对Wee1抑制和更精确的靶向基因改变明确的癌症患者之间的关系提供了强有力的证据。
因而，目前Wee1成为癌症治疗领域高度引人注目的治疗靶点。除了已有的对Wee1的研究外，仍然还有很多机遇去扩展它的应用并从中获益。目前尚无以Wee1作为治疗靶点的药物上市。本发明所描述的化合物、其组合物和应用方法将有助于Wee1抑制剂的发展，满足临床未满足的用药需求。
发明内容
本发明所要解决的技术问题在于，提供了一种新型吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其制备方法、药物组合物及应用。本发明的吡唑[3,4-d]嘧啶-3-酮的大环衍生物对Wee1及相关信号通路具有良好的抑制作用，可以有效治疗和/或缓解癌症。
本发明提供了一种如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
Figure PCTCN2018079866-appb-000001
其中，α键为单键、双键或三键；
L为CRR’、O或NR’；L 1为CRR 1、O或C(O)；W为N或CR 7；
R和R 1分别为氢、卤素、-OR a、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；或者R和R 1与它们共同连接的C原子一起形成3-8元环烷基；
R’为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；
R 2为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R’和R 2各自为独立取代基，或者，R 2和R’相互连接形成A环；所述A环为取代或未取代的C 3-15环烷基或取代或未取代的3-15元杂环烷基；所述A环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、硫代基、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、- NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 3为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R 4和R 5分别独立地为氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷氨基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、烷氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；
R 4和R 5各自为独立取代基，或者，R 4和R 5与其所连接的环原子一起形成B环，所述B环为取代或未取代的单环环烷基、取代或未取代的单环杂环烷基、取代或未取代的螺环基、取代或未取代的螺杂环基、取代或未取代的苯基、或取代或未取代的5-12元杂芳基；所述B环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、卤素、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、 -C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 6和R 7分别独立地为氢、卤素、羟基、巯基、氰基、硝基、羧基、氨基、烷基、烷氧基、烷硫基、烷氨基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、羟基烷基、氨基烷基、芳基、环烷基、取代或未取代的杂环烷基、或杂芳基；所述杂环烷基被取代时，可选择性被1～3个卤素、C 1-3烷基、C 1-3烷氧基和卤代C 1-3烷基取代在任意位置；
每个R a和每个R b分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
每个R c独立地选自氢、C 1-6烷基、卤代C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、3-8元杂环烷基C 1-6烷基、C 3-8环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；
每个R d和每个R e分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
m’为1～3的整数；
m和n分别独立地为0～5的整数。
本发明中，m’优选为1。
本发明中，所述α键优选为单键。
本发明中，所述α键优选为双键。
本发明中，所述α键优选为三键。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I’)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000002
其中，L为CRR’、O或NR’；L 1为CRR 1、O或C(O)；W为N或CR 7；
R和R 1分别为氢、卤素、-OR a、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、 -S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；或者R和R 1与它们共同连接的C原子一起形成3-8元环烷基；
R’为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；
R 2为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R’和R 2各自为独立取代基，或者，R 2和R’相互连接形成A环；所述A环为取代或未取代的C 3-15环烷基或取代或未取代的3-15元杂环烷基；所述A环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、硫代基、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 3为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R 4和R 5分别独立地为氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷氨基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代 或未取代的炔基；所述烷基、烷氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；
R 4和R 5各自为独立取代基，或者，R 4和R 5与其所连接的环原子一起形成B环，所述B环为取代或未取代的单环环烷基、取代或未取代的单环杂环烷基、取代或未取代的螺环基、取代或未取代的螺杂环基、取代或未取代的苯基、或取代或未取代的5-12元杂芳基；所述B环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、卤素、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 6和R 7分别独立地为氢、卤素、羟基、巯基、氰基、硝基、羧基、氨基、烷基、烷氧基、烷硫基、烷氨基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、羟基烷基、氨基烷基、芳基、环烷基、杂环烷基、或杂芳基；或者，R 6或R 7中，所述杂环烷基为未取代，或者选择性被1～3个卤素、C 1-3烷基、C 1-3烷氧基和卤代C 1-3烷基取代在任意位置；
每个R a和每个R b分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
每个R c独立地选自氢、C 1-6烷基、卤代C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、3-8元杂环烷基C 1-6烷基、C 3-8环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；
每个R d和每个R e分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
m和n分别独立地为0～5的整数。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I”)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000003
其中，L为CRR’、O或NR’；L 1为CRR 1、O或C(O)；W为N或CR 7；
R和R 1分别为氢、卤素、-OR a、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；或者R和R 1与它们共同连接的C原子一起形成3-8元环烷基；
R’为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置；
R 2为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R’和R 2各自为独立取代基，或者，R 2和R’相互连接形成A环；所述A环为取代或未取代的C 3-15环烷基或取代或未取代的3-15元杂环烷基；所述A环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、硫代基、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、- NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 3为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
R 4和R 5分别独立地为氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷氨基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、烷氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；
R 4和R 5各自为独立取代基，或者，R 4和R 5与其所连接的环原子一起形成B环，所述B环为取代或未取代的单环环烷基、取代或未取代的单环杂环烷基、取代或未取代的螺环基、取代或未取代的螺杂环基、取代或未取代的苯基、或取代或未取代的5-12元杂芳基；所述B环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、卤素、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、 -C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 6和R 7分别独立地为氢、卤素、羟基、巯基、氰基、硝基、羧基、氨基、烷基、烷氧基、烷硫基、烷氨基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、羟基烷基、氨基烷基、芳基、环烷基、杂环烷基、或杂芳基；所述杂环烷基为未取代，或者选择性被1～3个卤素、C 1-3烷基、C 1-3烷氧基和卤代C 1-3烷基取代在任意位置；
每个R a和每个R b分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
每个R c独立地选自氢、C 1-6烷基、卤代C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、3-8元杂环烷基C 1-6烷基、C 3-8环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；
每个R d和每个R e分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
m和n分别独立地为0～5的整数。
本发明中，优选L为CRR’；L 1为O时；m为0、1、2、或3；和n为1、或2。
本发明中，优选L为O、或NR’；L 1为O时；m为1、2、或3；和n为1、或2。
本发明中，优选L为CRR’、O、或NR’；L 1为C(O)时；m为0；和n为1、2、或3。
本发明中，优选L为NR’、L 1为O时；m为1、2、或3；和n为1、或2。
本发明中，优选L为NR’或O、L 1为CRR 1时；m为1、2、或3；和n为1、2、或3。
本发明中，L 1中，所述R 1优选为H、F、-OH、C 1-6烷氧基、C 1-4烷基(例如，甲基、乙基、丙基或异丙基)或C 3-8环烷基。
本发明中，L 1中，所述R 1更优选为氢。
本发明中，L 1更优选为CH 2或O。
本发明中，所述R优选为氢、卤素、-OR a、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NHS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2NHC(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NH)R a、C 1-6烷基、或C 3-8环烷基；R a和R b的定义如前所述。R a优选为H或C 1-4烷基；R b优选为H或C 1-4烷基；所述R更优选为H、F、Cl、-OH、或-CH 3。
本发明中，所述R’优选为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NHS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2NHC(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NH)R a、C 1-6烷基、或C 3-8环烷基；R a和R b的定义如前所述。R a优选为H或C 1-4烷基；R b优选为H或C 1-4烷基。所述R’更优选为H、-CH 3、或-C(O)CH 3。
本发明中，所述R 2优选为H。
本发明中，R 2和R’为独立取代基，或者R 2和R’相互连接形成A环；所述A环优选为取代或未取代的5-8元杂环烷基；所述A环更优选为取代或未取代的5-6元杂环烷基。
本发明中，所述A环被取代时，优选被1～4个取代基取代在任意位置；更优选被1～3个或1～2个取代基取代在任意位置。所述取代基定义如上。
本发明中，所述A环被取代时，所述取代基优选为氧代基、硫代基、卤素、或C 1-6烷基。
本发明中，所述R 3优选为H、F、-OH、或C 1-6烷氧基。
本发明中，所述R 3更优选为H。
本发明中，所述R 4优选为：氢。
本发明中，所述R 4优选为取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷胺基、取代或未取代的C 3-8环烷基、取代或未取代的3-9元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的C 3-8环烷基C 1-6烷基、取代或未取代的3-8元杂环烷基C 1-6烷基、取代或未取代的苯基C 1-6烷基、取代或未取代的5-6元杂芳基C 1- 6烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基。
本发明中，所述R 4更优选为H或取代或未取代的3-9元杂环烷基。
本发明中，所述R 4中，所述烷基、烷胺基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，优选被1～4个取代基取代在任意位置；更优选被1～3个取代基取代在任意位置；所述取代基定义如上。
本发明中，所述R 4被取代时，所述取代基优选F、Cl、C 1-6烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、C 2-6烯基、C 2-6炔基、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、或-NR dS(O) 2NR dR e；其中，R d和R e的定义如前所述。R d优选为H或C 1-4烷基；R e优选为H或C 1-4烷基。
本发明中，所述R 4被取代时，所述取代基更优选为C 1-6烷基(例如：甲基)。
本发明中，所述R 4更优选为：
Figure PCTCN2018079866-appb-000004
本发明中，所述R 5优选为：氢。
本发明中，所述R 5优选为取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷胺基、取代或未取代的C 3-8环烷基、取代或未取代的3-9元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的C 3-8环烷基C 1-6烷基、取代或未取代的3-8元杂环烷基C 1-6烷基、取代或未取代的苯基C 1-6烷基、取代或未取代的5-6元杂芳基C 1- 6烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基。
本发明中，所述R 5中，所述烷基、烷胺基、环烷基、杂环基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，优选被1～4个取代基取代在任意位置；更优选被1～3个取代基取代在任意位置；所述取代基定义如上。
本发明中，所述R 5被取代时，所述取代基优选F、Cl、C 1-6烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、C 2-6烯基、C 2-6炔基、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、或-NR dS(O) 2NR dR e；其中，R d和R e的定义如前所述。R d优选为H或C 1-4烷基；R e优选为H或C 1-4烷基。
本发明中，所述R 5被取代时，所述取代基更优选为C 1-6烷基(例如：甲基)或-NR dR e其中，R d和R e的定义如前所述。
所述R 5更优选为：
Figure PCTCN2018079866-appb-000005
Figure PCTCN2018079866-appb-000006
本发明中，所述R 4和R 5为独立取代基，或者R 4和R 5优选与其所连接的环原子一起形成B环，所述B环优选为取代或未取代的C 4-8单环环烷基、取代或未取代的4-8元单环杂环烷基、取代或未取代的C 7-12螺环基、取代或未取代的7-12元螺杂环基、取代或未取代的苯基、取代或未取代的5-6元单环杂芳基、或取代或未取代的8-10元稠环杂芳基。
本发明中，所述B环更优选为取代或未取代的如下任一结构：
Figure PCTCN2018079866-appb-000007
本发明中，所述B环更优选为取代或未取代的如下任一结构：
Figure PCTCN2018079866-appb-000008
本发明中，所述B环更优选为取代或未取代的如下任一结构：
Figure PCTCN2018079866-appb-000009
本发明中，所述B环被取代时，优选被1～6个取代基取代在任意位置；更优选被1～4个取代基取代在任意位置；更优选被1～3个取代基取代在任意位置；所述取代基定义如上。
本发明中，所述R 6优选为H、F、-CH 3、-OCH 3、-OCF 3、-CH 2OH或-CH 2OCH 3。
本发明中，所述R 6优选为C 1-6烷胺基、或取代或未取代的3-8元杂环烷基；其中所述3-8元杂环烷基可以选择性被1个、或1～2个选自F、Cl、-CH 3、-OCH 3、-OCF 3、-CF 3、或-CHF 2的取代基取代在任意位置。
本发明中，所述基团
Figure PCTCN2018079866-appb-000010
更优选为：
Figure PCTCN2018079866-appb-000011
Figure PCTCN2018079866-appb-000012
Figure PCTCN2018079866-appb-000013
本发明中，所述R 7优选为H。
本发明中，所述W优选为N。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000014
X和Y分别为连接键、-CR 8R 8a-、-NR 9-、-O-、-C(O)-、或-S(O) 1-2-；
Z为H/H、O或S；
R 8和R 9分别独立地为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1- 2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 8a分别独立地为氢、卤素或烷基；
或者，R 8和R 8a分别与它们共同连接的C原子一起形成3-8元环烷基或杂环烷基； 所述杂环烷基包含有1～2个选自N、O、S(O) 1-2的杂原子或基团；
R 3、R 4、R 5、R 6、W、L 1、m、n、R c、R d、R e的定义如前所述。
以下各种情况均包括在结构式(II)的定义中：
在其中一种优选实施方案中，所述X为O、Y为CR 8R 8a；
在其中一种优选实施方案中，所述X为CR 8R 8a、Y为CR 8R 8a；
在其中一种优选实施方案中，所述X为连接键、Y为CR 8R 8a；
在其中一种优选实施方案中，所述Z优选为O。
在其中一种优选实施方案中，所述Z优选为H/H。
在其中一种优选实施方案中，R 8为H、F或C 1-6烷基(例如：甲基、乙基、异丙基)。
在其中一种优选实施方案中，R 8a为H、F或C 1-6烷基。(例如：甲基、乙基、异丙基)。
在其中一种优选实施方案中，R 3为氢。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II’)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000015
X和Y分别为连接键、-CR 8R 8a-、-NR 9-、-O-、-C(O)-、或-S(O) 1-2-；
Z为H/H、O或S；
R 8和R 9分别独立地为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1- 2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 8a分别独立地为氢、卤素或烷基；
或者，R 8和R 8a分别与它们共同连接的C原子一起形成3-8元环烷基或杂环烷基；所述杂环烷基包含有1～2个选自N、O、S(O) 1-2的杂原子或基团；
R 3、R 4、R 5、R 6、W、L 1、m、n、R c、R d、R e的定义如前所述。
以下各种情况均包括在结构式(II’)的定义中：
在其中一种优选实施方案中，所述X为O、Y为CR 8R 8a；
在其中一种优选实施方案中，所述X为CR 8R 8a、Y为CR 8R 8a；
在其中一种优选实施方案中，所述X为连接键、Y为CR 8R 8a；
在其中一种优选实施方案中，所述Z优选为O。
在其中一种优选实施方案中，所述Z优选为H/H。
在其中一种优选实施方案中，R 8为H、F或C 1-6烷基(例如：甲基、乙基、异丙基)。
在其中一种优选实施方案中，R 8a为H、F或C 1-6烷基。(例如：甲基、乙基、异丙基)。
在其中一种优选实施方案中，R 3为氢。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-1)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000016
其中，M为连接键、-CR 12R 12a-、-NR 13-、或-O-；
U为连接键、-CR 12R 12a-、-NR 13-、-C(O)-、或-S(O) 1-2-；
V为连接键、-NR 13-、-O-、或-CR 12R 12a-；
R 10、R 11和R 12分别独立地为氢、卤素、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 10a、R 11a和R 12a分别独立地为氢、羟基、烷氧基、卤素或烷基；
或者，R 10和R 10a、R 11和R 11a、R 12和R 12a分别与它们共同连接的C原子一起形成3-8元环烷基或杂环烷基；所述杂环烷基包含有1～2个选自N、O、S(O) 1-2的杂原子或基团；
或者，R 10和R 10a、R 11和R 11a、R 12和R 12a分别与它们共同连接的C原子一起形成羰基；
R 13为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代 或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 2、R 3、R 6、m、n、R c、R d、R e、L和L 1的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-1)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000017
其中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
Z为H/H、O或S；
R 3、R 6、R 8a、R 8、R 9、R 10a、R 10、R 11a、R 11、m、n、U、V和M的定义如前所述。
以下各种情况均包括在结构式(II-1)的定义中：
在其中一种优选实施方案中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-。
以下各种情况均包括在结构式(I-I)、或(II-1)的定义中：
在其中一种优选实施方案中，R 10、R 11和R 12分别独立地为氢、或C 1-4烷基；
在其中一种优选实施方案中，R 10a、R 11a和R 12a分别独立地为氢、或C 1-4烷基；
在其中一种优选实施方案中，R 10和R 10a与它们共同连接的C原子一起形成3元环烷基；
在其中一种优选实施方案中，R 11和R 11a与它们共同连接的C原子一起形成3元环烷基；
在其中一种优选实施方案中，R 12和R 12a与它们共同连接的C原子一起形成3元环烷基；
在其中一种优选实施方案中，U为-CH 2-、-CHCH 3-、-C(CH 3) 2-或
Figure PCTCN2018079866-appb-000018
在其中一种优选实施方案中，V为-NR 13-、R 13为氢、取代或未取代的C 1-4烷基；所述烷基被取代时，可选择性地被1～3个氟取代在任意位置；
在其中一种优选实施方案中，R 10、R 10a和它们共同连接的C原子一起形成3元环烷基、U为-CH 2-、R 11和R 11a为H和M为连接键；
在其中一种优选实施方案中，R 11、R 11a和它们共同连接的C原子一起形成3元环烷 基、U为-CH 2-、R 10和R 10a为H和M为连接键；
在其中一种优选实施方案中，R 11和R 11a为H、U为
Figure PCTCN2018079866-appb-000019
R 10和R 10a为H和M为连接键；
在其中一种优选实施方案中，R 3为H。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-2)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000020
其中，T为N或CR 14’；
R 14和R 14’分别为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 2、R 3、R 6、R c、R d、R e、m、n、L和L 1的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-2)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000021
其中，T为N或CR 14’；
R 3、R 6、R 14、R 14’、m、n、L和L 1的定义如前所述。
以下各种情况均包括在结构式(II-2)的定义中：
在其中一种优选实施方案中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-。
以下各种情况均包括在结构式(I-2)、或(II-2)的定义中：
在其中一种优选实施方案中，R 3为H；
在其中一种优选实施方案中，R 6为H；
在其中一种优选实施方案中，T为N或CH；R 14为取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 3-8环烷基C 1-6烷基、或取代或未取代的3-8元杂环烷基C 1-6烷基；所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基可选择性地被如下1～3基团取代在任意位置：卤素、C 1-4烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、-CN、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；R d和R e分别独立地为H或C 1-4烷基；
在其中一种优选实施方案中，T为CR 14’；R 14’为取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 3-8环烷基C 1- 6烷基、或取代或未取代的3-8元杂环烷基C 1-6烷基；所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基可选择性地被如下1～3基团取代在任意位置：卤素、C 1-4烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、-CN、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；R d和R e分别独立地为H或C 1-4烷基；R 14为氢；
在其中一种优选实施方案中，T为CH；R 14为氢或C 1-6烷基；R 6为-N(CH 3) 2、哌嗪基、哌啶基、吡咯烷基或氮杂环丁烷基；其中所述哌嗪基、哌啶基、吡咯烷基或氮杂环丁烷基可以选择性被1个选自F、Cl、-CH 3、-OCH 3、-OCF 3、-CF 3、或-CHF 2的取代基取代在任意位置；
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000022
通过苯环(1)位和母核连接；
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000023
通过苯环(2)位和母核连接。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-3)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000024
D为CR 17、或N；
E为-CR 17R 17a-或-NR 15-；
s为0、1或2；
t为0、1或2；
R 15为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代 或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 16为氢、卤素、氧代基、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 17为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 17a为氢、卤素或烷基；
R 2、R 3、R 6、m、n、R c、R d、R e、L和L 1的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-3)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000025
其中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
Z为H/H、O或S；
R 3、R 8a、R 8、R 9、R 6、R 16、m、n、s、t、E、D和L 1的定义如前所述。
以下各种情况均包括在结构式(II-3)的定义中：
在其中一种优选实施方案中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-。
以下各种情况均包括在结构式(I-3)、或(II-3)的定义中：
在其中一种优选实施方案中，R 3为H；
在其中一种优选实施方案中，s为1和t为1或2；
在其中一种优选实施方案中，D为N或CH；
在其中一种优选实施方案中，R 6为H、F、Cl、-CN、-CH 3、-CH 2OH、或-CH 2OCH 3；
在其中一种优选实施方案中，E为NR 15；R 15为H、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的C 1-4烷基；所述C 1-4烷基可选择性地被如下1～3个基团取代在任意位置：卤素、卤代C 1-3烷基、-CN、-OR c和-N(R c) 2；R c、R d和R e分别独立地为H或C 1-4烷基；
在其中一种优选实施方案中，R 16为H、-CH 3、-CH 2OH、或-CH 2OCH 3。
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000026
为
Figure PCTCN2018079866-appb-000027
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000028
为
Figure PCTCN2018079866-appb-000029
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-4)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000030
其中，L为O、或NR’；R’为氢、C 1-6烷基、-C(O)-C 1-6烷基；R 2为H；
R 3、R 6、R 10a、R 10、R 11a、R 11、R 13、L 1、m和n的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-4)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000031
其中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-；
Z为H/H、O或S；
R 3、R 6、R 10a、R 10、R 11a、R 11、m、n、U、W和L 1的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-5)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000032
其中，L为O、或NR’；R’为氢、C 1-6烷基、-C(O)-C 1-6烷基；R 2为H；
R 3、R 6、R 15、R 16、m、n、L 1和D的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-5)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000033
其中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-；Z为H/H、O或S；
R 3、R 6、R 15、R 16、m、n、L 1、W和D的定义如前所述。
在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(I-6)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000034
D为CR 17、或N；
E为-CR 17R 17a-或-NR 15-；
s为0、1或2；
t为0、1或2；
R 15为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 16为氢、卤素、氧代基、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 17为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、 -NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
R 17a为氢、卤素或烷基；
R 2、R 3、R 6、m、n、R c、R d、R e、L和L 1的定义如前所述。在一些实施方案中，如式(I)所示化合物和/或药学上可接受的盐为如式(II-6)所示化合物和/或其药学上可接受的盐：
Figure PCTCN2018079866-appb-000035
其中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
Z为H/H、O或S；
R 3、R 6、R 8a、R 8、R 9、R 16、m、n、s、t、E、D和L 1的定义如前所述。
以下各种情况均包括在结构式(II-3)的定义中：
在其中一种优选实施方案中，X为连接键或O；Y为-CH 2-、-CHCH 3-、或-C(CH 3) 2-。
以下各种情况均包括在结构式(I-6)、或(II-6)的定义中：
在其中一种优选实施方案中，R 3为H；
在其中一种优选实施方案中，s为1和t为1或2；
在其中一种优选实施方案中，D为N或CH；
在其中一种优选实施方案中，R 6为H、F、Cl、-CN、-CH 3、-CH 2OH、或-CH 2OCH 3；
在其中一种优选实施方案中，E为NR 15；R 15为H、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的C 1-4烷基；所述C 1-4烷基可选择性地被如下1～3基团取代在任意位置：卤素、卤代C 1-3烷基、-CN、-OR c和-N(R c) 2；R c、R d和R e分别独立地为H或C 1-4烷基；
在其中一种优选实施方案中，R 16为H、-CH 3、-CH 2OH、或-CH 2OCH 3。
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000036
为
Figure PCTCN2018079866-appb-000037
在其中一种优选实施方案中，基团
Figure PCTCN2018079866-appb-000038
为
Figure PCTCN2018079866-appb-000039
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐优选为以下任一化合物：
Figure PCTCN2018079866-appb-000040
Figure PCTCN2018079866-appb-000041
Figure PCTCN2018079866-appb-000042
Figure PCTCN2018079866-appb-000043
Figure PCTCN2018079866-appb-000044
Figure PCTCN2018079866-appb-000045
Figure PCTCN2018079866-appb-000046
其中，
Figure PCTCN2018079866-appb-000047
表示双键构型为顺式、反式，或者顺反异构的混合物。
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐优选为以下任一化合物：
Figure PCTCN2018079866-appb-000048
Figure PCTCN2018079866-appb-000049
其中，
Figure PCTCN2018079866-appb-000050
表示双键构型为顺式、反式，或者顺反异构的混合物。
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐优选为以下任一化合物：
Figure PCTCN2018079866-appb-000051
本发明还提供了所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐的制备方法，其为如下任一方法：
方法1：
Figure PCTCN2018079866-appb-000052
方法1中，所述R 2、R 4、R 5、R 6、L、L 1、m、n和W的定义均同前所述；方法1包括如下步骤：步骤1)将化合物1d中的甲硫基用间氯过氧苯甲酸(m-CPBA)氧化为亚砜得到化合物1e；步骤2)将化合物1e和1f在碱性条件下反应得到通式IA所示化合物。
方法2：
Figure PCTCN2018079866-appb-000053
方法2中，所述R 2、R 4、R 5、R 6、L、L 1、m、n和W的定义均同前所述；方法2包括如下步骤：步骤3)将化合物1d中的甲硫基用间氯过氧苯甲酸(m-CPBA)氧化为砜得到化合物1g；步骤4)将化合物1g和1h在碱性条件下反应得到通式IA所示化合物。
方法3：
Figure PCTCN2018079866-appb-000054
方法1中，所述R 2、R 4、R 5、R 6、L、L 1、m、n和W的定义均同前所述；方法1包括如下步骤：步骤1)将化合物1j中的甲硫基用间氯过氧苯甲酸(m-CPBA)氧化为亚砜得到化合物1k；步骤2)将化合物1k和1f在碱性条件下反应得到通式IB所示化合物。
方法1中，所述的条件和步骤可为本领域常规的反应的条件和步骤，本发明特别优选以下反应条件：1)二氯甲烷溶剂中，用间氯过氧苯甲酸氧化化合物1d得到化合物1e；所述剂的用量优选1～50mL/mmol化合物1d，所述反应时间优选0-24小时，温度优选0℃～室温，化合物1d和m-CPBA的摩尔比优选1:0.95～1:1.05；步骤2)甲苯中，碱性条件下(N,N-二异丙基乙胺或三乙胺)，1e和1f反应得到通式IA所示化合物，所述剂的用量优选1～50mL/mmol化合物1d，所述反应时间优选0-24小时，温度优选室温到溶剂回流，化合物1e、1f和碱的摩尔比优选1:0.9:1～1:2.5:2.5；
方法2中，所述的条件和步骤可为本领域常规的反应的条件和步骤，本发明特别优选以下反应条件：1)二氯甲烷溶剂中，用间氯过氧苯甲酸氧化化合物1d得到化合物1g；所述剂的用量优选1～30mL/mmol化合物1d，所述反应时间优选0-24小时，温度优选0℃～室温，化合物1d和m-CPBA的摩尔比优选1：2～1：6；步骤2)四氢呋喃中，碱性条件下(钠氢)，1g和1h反应得到通式IA所示化合物，所述剂的用量优选1～50mL/mmol化合物1g，所述反应时间优选0-24小时，温度优选0℃到室温，化合物1g、1h和碱的摩尔比优选1:1:1～1:2:120。
方法3中，所述的条件和步骤可为本领域常规的反应的条件和步骤，本发明特别优选以下反应条件：1)二氯甲烷溶剂中，用间氯过氧苯甲酸氧化化合物1j得到化合物1k；所述剂的用量优选1～50mL/mmol化合物1j，所述反应时间优选0-24小时，温度优选0℃～室温，化合物1j和m-CPBA的摩尔比优选1:0.95～1:1.05；步骤2)甲苯中，碱性条 件下(N,N-二异丙基乙胺或三乙胺)，1k和1f反应得到通式IB所示化合物，所述剂的用量优选1～50mL/mmol化合物1k，所述反应时间优选0-24小时，温度优选室温到溶剂回流，化合物1k、1f和碱的摩尔比优选1:0.9:1～1:2.5:2.5；
方法1或2中，所述化合物1d由如下反应式1所示方法得到：
Figure PCTCN2018079866-appb-000055
反应式1中，P为溴、硼酸或硼酸酯，步骤1)将1a与1b通过Buchwald偶联反应得到化合物1c；步骤2)将化合物1c中的两个烯烃通过RCM反应行成大环1d；
P为溴时，步骤1)氮气保护下，在1,4-二氧六环溶剂中，在碱(1,2-N,N-二甲基乙二胺、碳酸钾)和氯化亚铜的作用下反应得到，所述剂的用量优选1～50mL/mmol化合物1a，所述反应时间优选0-24小时，温度优选室温到溶剂回流，更优选为80～100℃，化合物1a和1b的摩尔比优选1:0.9～1:1.5。P为硼酸或硼酸酯时，步骤1)氮气保护下，在吡啶和氯仿混合溶剂中，在醋酸铜的作用下反应得到，所述剂吡啶和氯仿体积比优选1:10的用量优选1～50mL/mmol化合物1a，所述反应时间优选0-24小时，温度优选室温到溶剂回流，化合物1a和1b的摩尔比优选1:0.9～1:1.5。步骤2)二氯甲烷溶剂中用Hoveyda-Grubbs催化剂回流反应可得1d，催化剂的用量优选10％摩尔比；
方法3中，所述化合物1j由如下反应式2所示方法得到：
Figure PCTCN2018079866-appb-000056
反应式2中，步骤1)溶剂中，在碱的作用下，将1h与甲磺酰氯反应得到化合物1i；其中，所述溶剂优选为二氯甲烷，所述碱优选为三乙胺或二异丙基乙胺；步骤2)溶剂中，将化合物1i在碱性条件下反应得到化合物1j；其中，所述溶剂优选为N,N-二甲基甲酰胺，所述碱优选为碳酸钾或碳酸钠。所述1h可以通过反应式3所示方法得到：
Figure PCTCN2018079866-appb-000057
在上述方法1、2或3中最后的合成步骤中使用对甲苯磺酸、盐酸、氯化氢、或三氟乙酸等酸性体系，或在纯化过程中，例如：prep-HPLC的流动相中存在上述酸性体系时，则所述的如式IA所示的化合物将会是相应的对甲苯磺酸盐、盐酸盐或三氟乙酸盐等。
在上述方法中，在1a、1b、1f或1h中存在不参与反应的氨基基团、羟基基团或羧基基团时，该氨基基团、羟基基团或羧基基团优选通过保护基保护，避免有任何副反应发生。如果存在上述氨基保护基团或羟基保护基团则需要经过后续的脱保护步骤后，得到如式IA所示化合物。任何合适的氨基保护基团，例如：叔丁氧羰基(Boc)基团，均可以用于保护氨基基团。如果使用Boc作为保护基，后续的脱保护反应可以在标准条件，例如，对甲苯磺酸/甲醇体系，二氯甲烷/三氟乙酸体系、饱和的氯化氢乙醚溶液、或三氟甲磺酸三甲基硅酯/2,6-二甲基吡啶/二氯甲烷体系中进行；任何合适的羟基保护基团，例如：苄基，均可以用于保护氨基基团，后续的脱保护反应可以在标准条件，例如，钯碳/氢气；任何合适的羧基保护基团，例如：形成羧酸酯基团(例如，羧酸甲酯，羧酸乙酯)，均可以用于保护羧基基团，后续的脱保护反应可以在标准条件，例如，氢氧化钠、氢氧化钾、氢氧化锂在四氢呋喃、水和/或甲醇溶剂中脱保护。上述脱保护反应优选在最后一步进行。
所述如式(I)所示化合物，其药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明还提供了一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物和药学上可接受的盐中的一种或多种。
所述药物组合物中，所述活性组分还可包括癌症、病毒感染或自身免疫疾病的其它治疗剂。
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉 伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备Wee1抑制剂中的应用。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备癌症的化学疗法或放射性疗法的增敏剂中的应用。其中，所述化学疗法或放射线疗法的增敏剂是指在癌症治疗领域中个，通过与放射线疗法和/或使用抗癌剂的化学疗法组合使用，相加地或协同地提高这些放射线疗法和/或化学疗法的治疗效果的药物。
本发明还提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗和/或缓解由Wee1介导的相关疾病的药物中的应用；本发明优选提供了如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗和/或预防由Wee1介导的相关疾病的药物中的应用；所述疾病包括肿瘤和非肿瘤性疾病。所述疾病优选为癌症。
本发明优选用所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗和/或缓解癌症药物中的应用。
本发明还进一步提供了用所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物治疗癌症的方法，包括：给予哺乳动物治疗所需剂量的如式(I)所述化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或药物组合物。
所述哺乳动物，优选人。
本发明还进一步提供了所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物还可和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗和/或缓解由Wee1介导的相关疾病，所述的疾病优选为癌症。
所述其它种类的治疗剂(例如：用于治疗癌症的其它种类的治疗剂)可以和所述的如式(I)所示化合物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
所述的癌症包括转移性的和非转移性的癌症，也包括家族遗传性的和偶发性的癌症，还可包括固体肿瘤和非固体肿瘤。
所述固体肿瘤的具体例子可包括但不限于：眼、骨、肺、胃、胰腺、乳腺、前列腺、脑(包括胶质母细胞瘤和髓母细胞瘤)、卵巢(包括那些从上皮细胞产生的基质细胞，生殖细胞和间质细胞)、膀胱、睾丸、脊髓、肾脏(包括腺癌、肾母细胞瘤)、口、唇、咽喉、口腔(包括鳞状细胞癌)、鼻腔、小肠、结肠、直肠、甲状旁腺、胆囊、胆管、宫颈、心、咽下腺、支气管、肝、输尿管、阴道、肛门、喉腺、甲状腺(包括甲状腺癌和髓样癌)，食道、鼻咽腺垂体、唾液腺、肾上腺、头颈部上皮内瘤样病变(包括Bowen病和Paget氏病)，肉瘤(包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤、骨肉瘤)、皮肤(包括黑色素瘤、卡波氏肉瘤、basocellular癌和鳞状细胞癌)等相关的肿瘤。
所述固体肿瘤优选为人的眼癌、骨癌、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、脑癌(包括但不限于噁性胶质瘤、成神经管细胞瘤)、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌(包括但不限于腺癌、肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、宫颈癌、肝癌、肺癌(包括但不限于小细胞肺癌、非小细胞肺癌)、绒毛上皮癌、骨肉瘤、尤文瘤、软组织肉瘤和皮肤癌中的一种或多种。
所述非固体肿瘤(包括血液学肿瘤)的具体例子可包括但不限于：淋巴性白血病(包括急性淋巴细胞白血病、淋巴瘤、骨髓瘤、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)、髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)和AIDs相关的白血病中的一种或多种。
本发明中，除非另有说明，术语“选择性地被一个或多个基团取代在任意位置”是指基团上所指定的一个或多个原子的任何一个或者多个氢原子用所指定的基团取代，条件是不超过指定原子的正常化合价，所述取代在任意位置均为本领域常见的合理取代。
本发明中，当与取代基的键合显示与连接环中两个原子的键合相交时，那么这样的取代基可键合在环上的任何可键合的环原子。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基，优选1-10个碳原子，更优选1-8，1-6，1-4，或1-3个碳原子，烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的单环或多环基团。“单环环烷基”优选3-10元单环烷基，更优选3-8元单环烷基，例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基。“多环环烷基”包括“桥环基”、“稠合环烷基”和“螺环烷基”，“桥环基”的代表性例子包括但不限于：冰片基、双环[2.2.1]庚烯基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基、双环[4.2.1]壬烷基和金刚烷基等。“稠合环烷基”包含稠合到苯基、环烷基、或杂芳基上的环烷基环，稠合环烷基包括但不限于： 苯并环丁烯、2,3-二氢-1-H-茚、2,3-环戊烯并吡啶、5,6-二氢-4H-环戊基[B]噻吩、十氢萘等。“螺环烷基”是指两个单环环烷基共用一个碳原子形成的双环基团，螺环烷基包括但不限于：螺[2,5]辛基、螺[2,4]庚基、螺[4,5]癸基等。所述多环环烷基优选包含7～12个碳原子。单环环烷基或多环环烷基可以通过环上任意的1个或2个碳原子链接到母体分子上。
术语“杂环烷基”指由碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分不饱和(包含1或2个双键)的非芳香环状基团，此环状基团可为单环或多环基团，在本发明中，杂环烷基中杂原子个数优选1、2、3或4，杂环烷基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。“单环杂环烷基”优选3-10元单环杂环烷基，更优选3-8元单环杂环烷基。例如：氮丙啶基、四氢呋喃-2-基、吗啉-4-基、硫代吗啉-4-基、硫代吗啉-S-氧化物-4-基、哌啶-1-基、N-烷基哌啶-4-基、吡咯烷-1-基、N-烷基吡咯烷-2-基、哌嗪-1-基、4-烷基哌嗪-1-基等。“多环杂环烷基”包括“稠合杂环烷基”、“螺杂环基”和“桥杂环烷基”。“稠合杂环烷基”包含稠合到苯基、环烷基、杂环烷基或杂芳基的单环杂环烷基环，稠合杂环烷基包括但不限于：2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、二氢吲哚基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基等。“螺杂环基”是指两个杂环烷基或一个环烷基和一个杂环烷基共用一个碳原子形成的双环基团，螺杂环基包括但不限于：5-氮杂[2.5]辛基、4-氮杂[2.5]辛基、4-氮杂[2.4]庚基等，所述多环杂环烷基优选7-15元，更优选7-12元。单环杂环烷基和多环杂环烷基可以通过环上任意的1个或2个环原子链接到母体分子上。上述环原子特指组成环骨架的碳原子和/或氮原子。
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此，“环烷基烷基”包含上述烷基和环烷基的定义。
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂环烷基烷基”包含上述烷基和杂环烷基的定义。
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，包含烷基氧基、环烷基氧基和杂环烷基氧基。由此，“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。
术语“羟基”是指-OH，术语“羟基烷基”是指烷基上任意一个氢原子被羟基所取代，包括但不限于：-CH 2OH、-CH 2CH 2OH、-CH 2CH 2C(CH 3) 2OH。
术语“烷硫基”指通过硫桥连接的具有所述碳原子数目的环状或者非环状烷基，所述烷硫基包含烷基硫基、环烷基硫基和杂环烷基硫基。由此，“烷硫基”包含上述烷基、杂环烷基和环烷基的定义。
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。术语“C2-4烯基”是指具有2-4个碳原子的烯基，术语“C2-6烯基”是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。所述的烯基可以被取代。
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3个碳碳三键，优选存在1个碳碳三键。术语“C2-6炔基”是指具有2-6个碳原子的炔 基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。
术语“芳基”是指任何稳定的6-20元单环或多环芳香族基团，例如：苯基、萘基、四氢萘基、2,3-二氢化茚基、或联苯基等。
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，其可为5-7元单环结构或7-20稠合环结构，优选5-6元单环杂芳基和8-10元稠环杂芳基。在本发明中，杂原子个数优选1、2或3，包括:吡啶基、嘧啶基、哌嗪基、哒嗪-3(2H)-酮基、呋喃基、噻吩基、噻唑基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,3,4-噻二唑、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基、吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并[d][1,3]二氧戊环基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、异喹啉酮基、喹唑啉基、4-羟基噻吩并[3,2-c]吡啶基、4,5-二氢-4-氧代呋喃[3,2]吡啶基、4-羟基-5-氮杂吲哚基、呋喃[2,3-c]并吡啶-7(6H)-酮基、噻吩[2,3-c]并吡啶-7(6H)-酮基、1,2,3,4-四氢吡咯并[1,2-a]吡嗪等。
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此，“芳基烷基”包含上述烷基和芳基的定义。
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂芳基烷基”包含上述烷基和杂芳基的定义。
术语“卤素”表示氟、氯、溴或碘。
术语“卤代烷基”是指被卤素任意取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此，“卤代烷氧基”包含以上卤素和烷氧基的定义。
术语“氨基”是指-NH 2，术语“烷氨基”是指氨基上至少一个氢原子被烷基所取代，包括但不限于：-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2。术语“氨基烷基”是指烷基上任意一个氢原子被氨基所取代，包括但不限于：-CH 2NH 2、-CH 2CH 2NH 2。由此，“氨基烷基”和“烷氨基”包含上述烷基和氨基的定义。
术语“硝基”是指-NO 2。
术语“氰基”是指-CN。
术语“巯基”是指-SH。
本发明所述“室温”是指15-30℃。
本发明中与双键连接的
Figure PCTCN2018079866-appb-000058
表示双键构型为Z型、E型，或者Z型E型的混合物(顺式、反式，或者顺反异构体的混合物)。所述
Figure PCTCN2018079866-appb-000059
优选为顺式或反式。
所述的同位素取代衍生物包括：式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
所述的“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲，前药为非活性物质，或者比活性母体化合物活性小，但可以提供方便的操作、给药或者改善代 谢特性。
本发明所述的“药学上可接受的盐”在Berge,et al.,“Pharmaceutically acceptable salts”,J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团，典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐，例如：盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D，L)-酒石酸，柠檬酸，马来酸，(D，L)-苹果酸，富马酸，丁二酸、琥珀酸盐、乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合物含有酸性基团时，其药学上可接受的盐还可以包括：碱金属盐，例如钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。
本发明所述“异构体”是指本发明的式(I)化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。在本发明中，式I化合物或其盐以立体异构的形式(例如，其含有一个或多个不对称碳原子)存在时，单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式I表示的化合物或盐的单独异构体，以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括：立体异构体的混合物，以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。本发明还包括式I化合物或其盐的几何异构体，所述几何异构体包括顺反异构体。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代二甲亚砜(DMSO-d 6)，四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Agilent 1200HPLC/6120质谱仪测定，使用XBridge C18，4.6×50mm，3.5μm，ESI源，梯度洗脱条件一：80-5％溶剂A 1和20-95％溶剂B 1(1.8分钟)，然后95％溶剂B 1和5％溶剂A 1(3分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 1：0.01％三氟乙酸(TFA)的水溶液；溶剂B 1：0.01％三氟乙酸的乙腈溶液；百分数为溶质占溶液的体积百分数。梯度洗脱条件二：80-5％溶剂A 2和20-95％溶剂B 2(1.5分钟)，然后95％溶剂B 2和5％溶剂A 2(2分钟以上)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A 2：10mM的碳酸氢铵的水溶液；溶剂B 2：乙腈。
本发明所有化合物可通过高效液相色谱仪、硅胶柱层析色谱、快速柱层析色谱或薄层层析色谱进行分离。
高效液相色谱仪(prep-HPLC)使用岛津LC-20制备液相色谱，色谱柱为：waters xbridge Pre C18，10um，19mmx250mm。分离条件1：流动相A：0.05％三氟乙酸水溶液，流动相B：乙腈；流动相B为40％，洗脱时间：20分钟。分离条件2：流动相A：10mmol/L碳酸氢铵水溶液，流动相B：乙腈；梯度洗脱流动相B从25％到80％，洗脱时间30分钟。检测波长：214nm&254nm；流速：15.0mL/分钟。
快速柱层析(Flash柱层析)(flash system/Cheetah TM)使用的是Agela Technologies MP200，配套使用的分离柱为Flash columm Silica-CS(80g)，Cat No.CS140080-0。
薄层层析色谱是烟台新诺化工，涂层厚度0.2±0.03mm，规格20×20cm。柱层析一般使用烟台黄海200-300目硅胶作为载体。
实施例1：化合物1.1～1.4的合成
Figure PCTCN2018079866-appb-000060
冰浴条件下，将偶氮二甲酸二异丙酯(580mg，2.87mmol)滴加到三苯基磷(753mg，2.87mmol)的四氢呋喃(6mL)溶液中，反应体系搅拌5分钟后，分别加入2-羟基6-溴吡啶(500mg，2.87mmol)和5-己烯-1-醇(287mg，2.87mmol)，继续搅拌2小时，减压浓缩除去溶剂，向残留物中加入石油醚打浆半小时，过滤，滤液浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝30/1)得化合物1.1(600mg，产率：82％)为红色液体。
利用化合物1.1的合成方法，将5-己烯-1-醇替换为4-戊烯-1-醇、3-丁烯-1-醇、或烯丙基羟乙基醚得到化合物1.2(2-溴-6-(4-戊烯-1-氧基)吡啶)、化合物1.3(2-溴-6-(3-丁烯-1-氧基)吡啶)和化合物1.4(2-(2-(烯丙氧基)乙氧基)-6-溴吡啶)。
实施例2：化合物2.2～2.4的合成
Figure PCTCN2018079866-appb-000061
步骤1：冰浴条件下，将乙酰氯(2.03g，25.9mmol)滴加到6-溴吡啶-2-胺(3g，17.3mmol)和三乙胺(4.8mL，34.6mmol)的二氯甲烷(30mL)溶液中，反应体系搅拌3小时。将反应液倒入水中，用乙酸乙酯萃取，有机相用无水硫酸钠干燥后，过滤、 浓缩得化合物2.1(2.5g，产率：68％)为白色固体。
步骤2：依次将化合物2.1(1g，4.65mmol)、6-溴-1-己烯(1.14g，7.0mmol)、无水碳酸钾(1.28g，9.3mmol)加入到N,N-二甲基甲酰胺(20mL)中，反应体系在60℃下搅拌16小时。冷却至室温，将反应液倒入水中，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，残留物用prep-TLC(石油醚/乙酸乙酯＝4/1)纯化得化合物2.2(700mg，产率：51％)为无色液体。
m/z:[M+H] +297.1
利用化合物2.2的合成方法，将6-溴-1-己烯替换为5-溴-1-戊烯或4-溴-1-丁烯得到化合物2.3(N-(6-溴吡啶-2-基)-N-(4-戊烯-1-基)乙酰胺)或化合物2.4(N-(6-溴吡啶-2-基)-N-(3-丁烯-1-基)乙酰胺)。
实施例3：化合物2.6的合成
Figure PCTCN2018079866-appb-000062
步骤1：将6-溴吡啶-2-胺(500mg，2.89mmol)和钠氢(139mg，3.5mmol，60％)的N,N-二甲基甲酰胺(20mL)溶液在室温下搅拌15分钟，再将5-溴-1-戊烯(517mg，3.47mmol)加入到反应体系中，反应液室温搅拌16小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥后，减压浓缩并用prep-TLC(石油醚/乙酸乙酯＝1/1)纯化得化合物2.5(270mg，产率：39％)为无色液体。
步骤2：将化合物2.5(270mg，1.12mmol)和钠氢(45mg，1.12mmol，60％)的四氢呋喃(10mL)溶液加热回流2小时，再将碘甲烷(159mg，1.12mmol)加入到反应体系中，反应液加热回流16小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥后，减压浓缩并用prep-TLC(石油醚/乙酸乙酯＝1/1)纯化得化合物2.6(100mg，产率：35％)为无色液体。
实施例4：化合物3.2～3.5的合成
Figure PCTCN2018079866-appb-000063
步骤1：将溴乙酸乙酯(1.66g，10mmol)滴加到6-溴-2-硝基吡啶-3-醇(2.18g，10mmol)的N,N二甲基甲酰胺(20mL)溶液中，反应体系室温搅拌5分钟后，加入碳酸钾(2.76g，20mmol)，继续搅拌2小时，加水(100mL)淬灭反应，用二氯甲烷萃取(20mL×3)，合并有机相，用无水硫酸钠干燥、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得化合物3.1(2.7g，产率：89％)为淡黄色液体。
m/z:[M+H] +305.0
步骤2：将化合物3.1(2.7g，8.85mmol)和铁粉(2.48g，44.3mmol)加入到醋酸(40mL)中，反应体系在100℃下搅拌2小时。冷却至室温，将反应液用硅藻土过滤、 滤液中加水(100mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用无水硫酸钠干燥、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得化合物3.2(1.9g，产率：95％)为淡黄色液体。
m/z:[M+H] +229.0
步骤3:将化合物3.2(0.5g，2.2mmol)和5-溴-1-戊烯(0.36g，2.4mmol)溶于N,N-二甲基甲酰胺(10mL)中，向其中加入碳酸钾(0.45g，3.3mmol)。混合物在室温下搅拌2小时。反应体系用乙酸乙酯(30mL)稀释，并用饱和食盐水洗涤。分离有机相并用无水硫酸钠干燥，过滤、浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物3.3(0.51g，产率：79％)为无色油状物。
利用化合物3.3的合成方法，将6-溴-2-硝基吡啶-3-醇替换为4-溴-2-硝基苯酚得到化合物3.4(6-溴-4-(4-戊烯-1-基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮)。
利用化合物3.3的合成方法，将5-溴-1-戊烯替换为4-溴-1-丁烯得到化合物3.5(6-溴-4-(3-丁烯-1-基)-2H-吡啶并[b][1,4]恶嗪-3(4H)-酮)。
实施例5：化合物4.2的合成
Figure PCTCN2018079866-appb-000064
步骤1:将化合物3.4(600mg，2.03mmol)，联硼酸频那醇酯(774mg，3.05mmol)，乙酸钾(396mg，4.03mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(148mg，0.20mmol)加入到1,4-二氧六环(20mL)中。反应体系在氮气保护下，在80℃下搅拌16小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝8/1)纯化得到化合物4.1(600mg，产率：86％)为无色液体。
步骤2:将化合物4.1(500mg，1.46mmol)和浓盐酸(5mL)加入到乙腈(10mL)和水(5mL)的混合物溶液中。反应体系加热回流16小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩得到化合物4.2(400mg，粗品)为黄色液体。
实施例6：化合物5.4的合成
Figure PCTCN2018079866-appb-000065
步骤1：在0℃下将钠氢(270mg，6.75mmol，60％)加入到膦酰基乙酸三乙酯(1.5g，6.69mmol)的N,N-二甲基甲酰胺(30mL)溶液中，反应体系搅拌0.5小时，将2-氨基-6-溴烟醛(900mg，4.48mmol)加入到上述反应体系中，并在室温下搅拌1小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝8/1)得化合物5.1(400mg，产率：33％)为黄色固体。
步骤2：将硼氢化钠(112mg，2.95mmol)加入到化合物5.1(400mg，1.48mmol) 和氯化锂(13mg，0.30mmol)的甲醇(15mL)溶液中，反应体系室温搅拌2小时，然后将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、浓缩得到化合物5.2(400mg，产率：99％)为无色液体。
步骤3：将叔丁醇钾(246mg，2.2mmol)加入到化合物5.2(400mg，1.46mmol)的四氢呋喃(15mL)溶液中，该反应体系在室温下搅拌2小时，反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、浓缩得化合物5.3(300mg，产率：90％)为类白色固体。
步骤4：将化合物5.3(300mg，1.32mmol)，5-溴-1-戊烯(525mg，3.52mmol)和碳酸钾(486mg，352mmol)加入到N,N-二甲基甲酰胺(15mL)中，反应体系在100℃下搅拌16小时，然后将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得化合物5.4(300mg，产率：77％)为无色液体。
实施例7：化合物6.1的合成
Figure PCTCN2018079866-appb-000066
将5-溴-1-戊烯(1.0g，6.71mmol)和镁屑(179mg，7.38mmol)加入四氢呋喃(10mL)中，然后加入碘单质(20mg，0.08mmol)，反应引发后，将反应体系加热回流45分钟，等到镁屑全部溶解后，将反应液冷却0℃，然后冰浴条件下，将上述反应液滴加6-溴-2-乙酰基吡啶(1.48g，7.38mmol)的四氢呋喃(10mL)溶液中，得到的混合物在室温下搅拌3小时，将反应液倒入饱和的氯化铵水溶液中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝20/1)纯化得到化合物6.1(520mg，产率：30％)为黄色液体。
实施例8：化合物7.2的合成
Figure PCTCN2018079866-appb-000067
步骤1：将碳酸钾(6.33g，45.9mmol)加入到2-氨基-6-溴-3-羟基吡啶(2.83g，9.17mmol)和2-溴异丁酸乙酯(2.7g，13.8mmol)的丙酮(30mL)溶液中，将反应液加热回流并搅拌过夜，减压浓缩除去丙酮，所得固体溶于二氯甲烷中，分别用水和饱和食盐水洗涤，有机相减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物7.1(690mg，产率：23％)为白色固体。
步骤2：将5-溴-1-戊烯(600mg，4.0mmol)加入到化合物7.1(690mg，2.68mmol)和碳酸钾(740mg，5.36mmol)的N,N-二甲基甲酰胺(5mL)混合物中，反应体系室温搅拌过夜，加水(20mL)淬灭反应，水相用乙酸乙酯萃取(15mL×3)，合并有机相，依次用水和饱和食盐水洗涤，过滤、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物7.2(790mg，产率：91％)为白色固体。
实施例9：化合物23.2的合成
Figure PCTCN2018079866-appb-000068
步骤1：冰浴条件下，将硼烷四氢呋喃溶液(5.5mL，5.5mmol，1.0M)滴加到化合物3.2(500mg，2.19mmol)的四氢呋喃(25mL)溶液中，反应体系加热回流搅拌1小时。然后在回流的状态小心用甲醇(10滴)淬灭反应，混合物冷却至室温后减压浓缩除去溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物23.1(470mg，产率：99％)为白色固体。
m/z:[M+H] +215.1
步骤2：冰浴条件下，将4-戊烯酰氯(160mg，1.35mmol)滴加到化合物23.1(290mg，1.35mmol)和三乙胺(410mg，4.1mmol)的二氯甲烷(20mL)的溶液中，反应体系在室温下搅拌1小时。然后减压浓缩除去有机溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物23.2(380mg，产率：95％)为无色液体。
m/z:[M+H] +297.1
实施例10：化合物23.3的合成
Figure PCTCN2018079866-appb-000069
将钠氢(186mg，4.66mmol，60％)加入到化合物23.1(500mg，2.33mmoL)的N,N-二甲基甲酰胺(20mL)溶液中，反应体系在室温下搅拌0.5小时后，将5-溴-1-戊烯(381mg，2.56mmol)加入到上述反应体系中，然后再在120℃下搅拌16小时。将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤、减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物23.3(450mg，产率：68％)为无色液体。
m/z:[M+H] +283.0
实施例11：化合物23.4的合成
Figure PCTCN2018079866-appb-000070
将化合物23.1(320mg，1.49mmol)和钠氢(179mg，4.48mmol，60％)的四氢呋喃(20mL)溶液加热回流2小时，再将氯甲酸烯丙酯(540mg，4.48mmol)加入到上述反应体系中，得到的反应液继续加热回流16小时。将反应液倒入水中，用乙酸乙酯萃取，分离有机相并用无水硫酸钠干燥，过滤、浓缩，残留物用prep-TLC(石油醚/乙酸乙酯＝1/1)纯化得到化合物23.4(440mg，产率：67％)为无色液体。
实施例12：化合物8.3的合成
Figure PCTCN2018079866-appb-000071
步骤1：向2-氟-5-硝基苯甲酸甲酯(2.0g，10mmol)和N,N'-二甲基-1,2-二胺(890mg，10mmol)的正丁醇(30mL)溶液中加入碳酸钠(2.1g，20.1mmol)。反应体系在110℃下搅拌12小时。然后将反应体系冷却至室温，减压浓缩。残留物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化得化合物8.1(2.0g，产率：85％)为黄色固体。
m/z:[M+H] +236.0
步骤2：向化合物8.1(1.0g，4.3mmol)的四氢呋喃(20mL)溶液中缓慢滴加硼烷四氢呋喃溶液(1.0M，8.5mL)。加毕，反应体系在66℃下搅拌过夜。然后将反应体系冷却至室温，减压浓缩。残留物溶于二氯甲烷(20mL)中并用饱和食盐水洗涤，无水硫酸钠干燥，过滤、减压浓缩得化合物8.2(850mg，产率：90％)为黄色固体。
m/z:[M+H] +222.1
步骤3：将化合物8.2(850mg，3.84mmol)溶于四氢呋喃(10mL)和乙酸乙酯(10mL)的混合溶液中，向其中加钯碳(50mg，10％)。反应体系用氢气置换3次，然后在氢气氛下室温搅拌过夜。然后将反应体系用硅藻土过滤。滤液减压浓缩得化合物8.3(650mg，产率：88％)为黄色固体。
实施例13：化合物9.2的合成
Figure PCTCN2018079866-appb-000072
步骤1：向(5-氟-2-硝基苯基)甲醇(1.0g，5.8mmol)和N-甲基哌嗪(0.7g，6.4mmol)的二甲基亚砜(20mL)溶液中分批加入碳酸钾(1.2g，8.8mmol)。加毕，反应体系室温搅拌过夜。然后用乙酸乙酯(50mL)稀释，用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤、减压浓缩得到化合物9.1(1.4g，产率：92％)为黄色固体。
m/z:[M+H] +252.0
步骤2：向化合物9.1(1.3g，5.3mmol)的四氢呋喃(10mL)和乙酸乙酯(10mL)混合物溶液中加入钯炭(100mg，5％)。反应体系用氢气置换三次，然后在氢气氛下室温搅拌16小时。反应液用硅藻土过滤，滤液减压浓缩得化合物9.2(1.0g，产率：84％)为黄色固体。
m/z:[M+H] +221.9
实施例14：化合物10.8～10.11的合成
Figure PCTCN2018079866-appb-000073
步骤1：将化合物10.1(5g，31mmol)和(三甲基硅烷)重氮甲烷(3.5g，31mmol)的四氢呋喃(20mL)和甲醇(20mL)混合溶液在室温下搅拌2小时，然后将反应体系直接浓缩，残留物用硅胶柱层析(30％的乙酸乙酯石油醚溶液)纯化得到化合物10.2(5.1g，产率：95％)为无色油状物。
步骤2：将1,2-二溴乙烷(8.05g，42mmol)、化合物10.2(5.0g，28mmol)、四丁基溴化铵(催化量)、氢氧化钠水溶液(50％，20mL)和甲苯(40mL)的混合溶液在室温下搅拌1小时。反应体系用水稀释，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤。有机相用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(20％的乙酸乙酯石油醚溶液)纯化得到化合物10.3(5.5g，产率：96％)为无色油状物。
步骤3：将化合物10.3(5.4g，27mmol)和雷尼镍(1.0g)混于甲醇(10mL)中。用氢气球置换三次，将反应体系在氢气氛下室温搅拌12小时。反应液用硅藻土过滤，滤液用无水硫酸钠干燥、过滤、浓缩得到化合物10.4(4.4g，粗品)为白色固体。
m/z:[M+H] +174.0
步骤4：将化合物10.4(0.2g，1.15mmol)溶于浓硫酸中。在室温条件下，将硝酸钾(0.11g，1.15mmol)缓慢加入到上述反应体系中。室温下搅拌15分钟。然后，把反应混合物缓慢的滴加到冰水中。过滤，滤饼用蒸馏水洗涤，真空干燥后得到化合物10.5和10.5’的混合物(50/1，0.24g，产率：96％)为淡黄色固体。
步骤5：冰浴条件下，把三氟化硼乙醚(260mg，1.83mmol)缓慢的加入到硼氢化钠(52mg，1.37mmol)的四氢呋喃溶液(2.0mL)中，室温下搅拌1小时。然后把化合物10.5和10.5’混合物(100mg，0.46mmol)的四氢呋喃溶液加入到上述反应体系，回流2小时。冷却到室温，用饱和氯化铵水溶液淬灭反应，混合物用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，分离有机相用无水硫酸钠干燥，过滤、浓缩得到化合物10.6和10.6’的混合物(50/1，68mg，粗品)为淡黄色固体。
步骤6：将化合物10.6和10.6’的混合物(50mg，0.25mmol)、醋酸(1滴)和37％甲醛(0.1mL)溶于二氯甲烷(1.5mL)中。反应体系在室温下搅拌0.5小时。然后将氰基硼氢化钠(104mg，0.5mmol)加到上述反应体系中，室温下搅拌2小时，加水淬灭反应，并用乙酸乙酯萃取。合并有机相用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(50％的乙酸乙酯石油醚)纯化得到化合物10.7(50mg，产率：94％)为白色固体。
m/z:[M+H] +219.0
步骤7：将化合物10.7(50mg，0.23mmol)、甲酸铵(144mg，2.3mmol)和钯/碳(10mg，10％)混于甲醇(2.0mL)中。反应体系在室温条件下搅拌12小时。抽滤，滤液加饱和碳酸钠水溶液稀释，用乙酸乙酯萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥、过滤、浓缩，残留物用硅胶柱层析(10％的甲醇二氯甲烷)纯化得到化合物10.8(30mg，产率：70％)为白色固体。
m/z:[M+H] +189.0
步骤8：将化合物10.8(30mg)溶于甲酸(5mL)中，反应体系100℃下搅拌30分 钟。溶液减压浓缩得到化合物10.9(35mg，粗品)为棕色油状物。
利用化合物10.8的合成方法，将步骤6中的37％甲醛替换为乙醛得到化合物10.10(2'-乙基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-胺)。
利用化合物10.8的合成方法，将步骤6中的37％甲醛替换为丙酮得到化合物10.11(2'-异丙基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-胺(主要)和2'-异丙基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-6'-胺(次要)的混合物)。
实施例15：化合物10.15的合成
Figure PCTCN2018079866-appb-000074
步骤1：将碳酸钾(405mg，2.94mmol)加入到化合物10.6(300mg，1.47mmol)和1,1-二氟-2-碘代乙烷(564mg，2.94mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应体系在100℃下搅拌过夜。然后将反应液冷至室温，加水淬灭，水相用乙酸乙酯萃取(15mL×3)，合并有机相并依次用水、饱和食盐水洗涤，有机相浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得化合物10.14(330mg，产率：84％)为白色固体。
m/z:[M+H] +269.1
步骤2：将化合物10.14(330mg，1.3mmol)和钯碳(150mg，5％)的甲醇(20mL)混合物用氢气置换三次，然后在氢气氛下室温搅拌16小时。反应液用硅藻土过滤，滤液减压浓缩所得化合物10.15(300mg，粗品)，可直接用于下一步反应。
实施例16：化合物11.5的合成
Figure PCTCN2018079866-appb-000075
步骤1:将邻羧基苯乙酸(50.0g，278mmol)的甲胺醇溶液(150mL)在室温下搅拌15小时，然后向反应体系中加入二氯苯(300mL)，得到的混合物在180℃下搅拌8小时。反应液倒入石油醚中，过滤，滤饼真空干燥得到化合物11.1(45g，产率：92％)为类白色固体。
步骤2:将钠氢(10.0g，251mmol，60％)加入到化合物11.1(20.0g，144mmol)的乙二醇二甲醚(250mL)溶液中，室温搅拌0.5小时后，然后向反应体系中加入碘甲烷(35.6g，251mmol)，继续搅拌3小时。将反应液倒入水中，过滤沉淀，滤饼真空干燥得到化合物11.2(16g，产率：55％)为粉色固体。
步骤3:冰浴条件下，将浓硝酸(10mL)缓慢滴加到化合物11.2(13.0g，64.0mmol)的浓硫酸(25mL)溶液中，反应体系在0℃下搅拌3小时后，将反应液倒入水中，过滤沉淀，滤饼真空干燥得到化合物11.3(10g，产率：63％)为白色固体。
步骤4:化合物11.3(10.0g，40.3mmol)和钯碳(2.0g，10％)加入到甲醇(150 mL)中，反应体系用氢气置换3次，然后在氢气氛下室温搅拌16小时。然后将反应液用硅藻土过滤，滤液减压浓缩得到化合物11.4(8g，产率：91％)为棕色固体。
步骤5:将硼烷二甲硫醚络合物(8mL，82.4mmol)缓慢加入化合物11.4(4.0g，18.3mmol)的四氢呋喃(50mL)溶液中，反应液加热回流3小时后，将反应液冷却到0℃，加入甲醇(20mL)，混合物搅拌半小时后减压浓缩，残留物加入盐酸(6M)并且加热回流1小时，混合物用氢氧化钠固体中和，用二氯甲烷和甲醇(10/1)的混合溶液萃取，分离有机相用无水硫酸钠干燥，过滤、减压浓缩得到化合物11.5(3g，产率：86％)为棕色液体。
实施例17：化合物12.2的合成
Figure PCTCN2018079866-appb-000076
步骤1:将八氢吡咯[1,2-a]吡嗪(447mg，3.55mmol)加入到碳酸钾(978mg，7.1mmol)和4-氟硝基苯(500mg，3.55mmol)的N,N-二甲基甲酰胺(5mL)溶液中。室温条件下，向混合体系中分批加入碳酸钾(1.2g，8.8mmol)。加毕，反应体系室温搅拌过夜。将反应液倒入冰水中，水相用乙酸乙酯(10mL×3)萃取，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩。残留物经硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到化合物12.1(580mg，产率:66％)为黄色液体。
m/z:[M+H] +248.1
步骤2:向化合物12.1(580mg，2.3mmol)的甲醇(20mL)溶液中加入的钯碳(200mg，5％)。体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌16小时。反应液用硅藻土过滤，滤液浓缩，残留物经硅柱胶层析纯化(二氯甲烷/甲醇＝15/1)得化合物12.2(424mg，产率:85％)为棕色固体。
m/z:[M+H] +218.0
实施例18：化合物13.2的合成
Figure PCTCN2018079866-appb-000077
步骤1：将5-硝基吲哚(1.0g，6.2mmol)、二甲胺基氯乙烷盐酸盐(1.3g，9.3mmol)和无水碳酸钾(3.4g，25mmol)的N,N-二甲基甲酰胺(15mL)混合物在70℃下搅拌3小时。反应液冷却至室温，倒入冰水中(50mL)搅拌，溶液用乙酸乙酯(20mL×3)萃取，合并有机相，依次用水、饱和食盐水洗涤，有机相用无水硫酸钠干燥、过滤、浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化得化合物13.1(700mg，产率：32％)为无色油状液体。
步骤2:将化合物13.1(700mg，3mmol)加入到钯碳(100mg，10％)的甲醇(20mL)溶液中，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌过夜。反应液用硅藻土过滤，滤液浓缩得化合物13.2(600mg，产率：98％)为棕色油状液体。
m/z:[M+H] +204.1
实施例19：化合物14.4～14.9的合成
Figure PCTCN2018079866-appb-000078
步骤1：将5-硝基吲哚(1.0g，6.2mmol)溶于N,N-二甲基甲酰胺(10.0mL)中，并向该体系中缓慢加入钠氢(0.5g，12.4mmol，60％)。反应体系在20℃下搅拌30分钟，接着把1-Boc-4-甲磺酰氧基哌啶(1.72g，6.2mmol)加到上述反应体系中，100℃下搅拌12小时。然后，用水淬灭反应，乙酸乙酯萃取。合并有机相并用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(35％的乙酸乙酯石油醚)纯化得到化合物14.1(0.85g，产率：75％)为黄色油状物。
步骤2：将化合物14.1(0.85g，2.4mmol)的三氟乙酸(2.0mL)和二氯甲烷(4.0mL)的混合溶液在室温下搅拌1小时，直接浓缩得到化合物14.2(0.55g，粗品)为黄色油状。
步骤3：将化合物14.2(0.50g，2.0mmol)、37％甲醛(0.33g，4.0mmol)、三乙胺(0.1mL)和醋酸(两滴)的1,2-二氯乙烷(10mL)溶液在室温下搅拌1小时。然后把氰基硼氢化钠(0.39g，6.0mmol)加入到反应体系内，反应体系再在室温下搅拌2小时。然后用氢氧化钠水溶液(1.0M)淬灭反应，加水稀释并用乙酸乙酯萃取。合并有机相并用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(5％的甲醇二氯甲烷)纯化得到化合物14.3(0.35g，产率：66％)为黄色固体。
步骤4：将化合物14.3(0.35g，1.3mmol)溶于甲醇(10mL)，加入钯碳(0.05g，5％)，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌12小时。反应液用硅藻土过滤，滤液浓缩得化合物14.4(100mg，粗品)为淡黄色固体。
m/z:[M+H] +230.1
利用化合物14.4的合成方法，将步骤1中的1-Boc-4-甲磺酰氧基哌啶替换为1-Boc-3-甲磺酰氧基哌啶得到化合物14.5(1-(1-甲基哌啶-3-基)-1H-吲哚-5-胺)。
利用化合物14.4的合成方法，将步骤1中的1-Boc-4-甲磺酰氧基哌啶替换为1-Boc-3-甲磺酰氧基吡咯烷得到化合物14.6(1-(1-甲基吡咯烷-3-基)-1H-吲哚-5-胺)。
利用化合物14.4的合成方法，将步骤3中的37％甲醛替换为丙酮得到化合物14.7(1-(1-异丙基哌啶-4-基)-1H-吲哚-5-胺)。
利用化合物14.4的合成方法，将步骤1中的5-硝基吲哚替换为5-硝基-1H-吡咯并[2,3-]吡啶、步骤3中的37％甲醛替换为丙酮得到化合物14.8(1-(1-异丙基哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-5-胺)。
利用化合物14.4的合成方法，将步骤1中的5-硝基吲哚替换为5-硝基-1H-吲唑、步骤3中的37％甲醛替换为丙酮得到化合物14.9(1-(1-异丙基哌啶-4-基)-1H-吲唑-5-胺)。
实施例20：化合物15.1的合成
Figure PCTCN2018079866-appb-000079
将化合物14.1(287mg，0.83mmol)加入到钯碳(100mg，5％)的甲醇溶液中，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌12小时。反应液用硅藻土过滤，滤液浓缩得化合物15.1(197mg，产率：75％)为棕色固体。
实施例21：化合物16.2的合成
Figure PCTCN2018079866-appb-000080
步骤1：将氯甲酸甲酯(57.8mg，0.61mmol)加入到化合物14.2(100mg，0.41mmol)和三乙胺(82.8mg，0.82mmol)的二氯甲烷溶液中，室温搅拌过夜。反应液浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得化合物16.1(57mg，产率：46％)为黄色固体。
步骤2：将化合物16.1(57mg，0.19mmol)加入到钯碳(20mg，5％)的甲醇溶液中，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌12小时。反应液用硅藻土过滤，滤液浓缩得化合物16.2(43mg，粗品)为棕色固体。
实施例22：化合物16.4的合成
Figure PCTCN2018079866-appb-000081
步骤1：将化合物14.2(110mg，0.45mmol)、溴乙醇(168mg，1.35mmol)和碳酸钾(186mg，1.35mmol)的N,N-二甲基甲酰胺(5mL)溶液在100℃下搅拌过夜。反应液冷却至室温，加水淬灭，水相用乙酸乙酯萃取(15mL×3)，合并有机相，依次用水、饱和食盐水洗涤，有机相用无水硫酸钠干燥、过滤、浓缩，残留物用prep-TLC纯化(二氯甲烷/甲醇＝10/1)得到化合物16.3(82mg,产率：60％)为棕色油状物。
m/z:[M+H] +290.2
步骤2：将化合物16.3(82mg，0.28mmol)和钯碳(40mg，10％)混于甲醇(10.0mL)溶液中。反应体系用氢气置换3次，然后在氢气氛(氢气球)作用下室温搅拌2小时。反应液用硅藻土过滤，所得滤液浓缩得到化合物16.4(74mg，产率：100％)为棕色固体。
实施例23：化合物16.6的合成
Figure PCTCN2018079866-appb-000082
步骤1：冰浴条件下，将钠氢(73.4mg，1.83mmol，60％)加入到化合物14.2(150mg，0.61mmol)的无水N,N-二甲基甲酰胺(5mL)溶液中，该反应体系在室温下搅拌0.5小时，然后将1-溴2-(甲基磺酰基)乙烷(343mg，1.83mmol)加入到上述反应体系中并继续室温搅拌过夜。然后将反应体系升温至50℃并继续搅拌2小时，将反应液倒入到冰水中，用乙酸乙酯萃取(10mL×3)，合并有机相并用水和饱和食盐水洗涤，用无水硫酸钠干燥、过滤、浓缩，残留物prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物16.5(200mg，产率:93％)为黄色固体。
m/z:[M+H] +352.2
步骤2：将化合物16.5(200mg，0.57mmol)和钯/碳(100mg，10％)混于甲醇(10.0mL)溶液中。反应体系用氢气置换3次，然后在氢气氛(氢气球)作用下室温搅拌2小时。用硅藻土过滤，所得滤液浓缩得到化合物16.6(130mg，产率：74％)为黄色固体。
m/z:[M+H] +322.2
实施例24：化合物17.3的合成
Figure PCTCN2018079866-appb-000083
步骤1：冰浴条件下，向5-硝基水杨醛(1.67g，10.0mmol)和N-甲基-2-羟基乙胺(1.13g，15.0mmol)的甲醇(60mL)溶液中加入氯化锌(1.36g，10.0mmol)，反应体系在室温下搅拌2小时。然后将氰基硼氢化钠(1.24g，20.0mmol)加入到上述反应体系中，室温搅拌1小时。加水淬灭反应，水相用二氯甲烷(200mL)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤、减压浓缩得化合物17.1(1.2g，产率：53％)为淡黄色固体。
m/z:[M+H] +227.1
步骤2：冰浴条件下，向化合物17.1(732mg，3.2mmol)和三苯基瞵(1.27g，4.9mmol)的四氢呋喃(20mL)和二氯甲烷(8mL)混合物溶液中加入偶氮二甲酸二乙酯(DEAD)(845mg，4.9mmol)，反应体系在室温下搅拌2小时。然后将反应混合物减压浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得化合物17.2(569mg，含少量三苯基氧膦)为淡黄色固体。
m/z:[M+H] +209.1
步骤3：将化合物17.2(569mg，2.7mmol)溶于甲醇(10.0mL)中，加入钯碳(171mg)，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌12小时。反应液用 硅藻土过滤，滤液浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得化合物17.3(199mg，两步产率：34％)为棕红色固体。
m/z:[M+H] +179.1
实施例25：化合物18.6的合成
Figure PCTCN2018079866-appb-000084
步骤1：冰浴条件下，向5-硝基吲哚-2-甲酸乙酯(2.34g，10.0mmol)的N,N-二甲基甲酰胺(50mL)溶液中加入钠氢(600mg，15.0mmol，60％)，反应体系在室温下搅拌0.5小时，然后加入N-Boc-溴乙胺(2.92g，13.0mmol)，反应体系在70℃下搅拌过夜。然后用乙酸乙酯(100mL)稀释，用饱和食盐水洗涤。分离有机相并用无水硫酸钠干燥，过滤、浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物18.1(3.05g，产率：81％)为淡黄色固体。
步骤2：将化合物18.1(3.05g，8.1mmol)的三氟乙酸(4mL)和二氯甲烷(20mL)混合溶液在室温下搅拌2小时，然后用饱和的碳酸氢钠水溶液淬灭反应，水相用二氯甲烷萃取。合并有机相并用饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥，过滤、浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物18.2(1.1g，产率：49％)为淡黄色固体。
m/z:[M+H] +278.4
步骤3：化合物18.2(1.1g，4.0mmol)、甲醇钠(643mg，11.9mmol)的乙醇溶液(20mL)在55℃下搅拌2小时。然后向反应体系中加入饱和食盐水，用二氯甲烷萃取。合并有机相，并用无水硫酸钠干燥，过滤、浓缩得化合物18.3(361mg，产率：39％)为黄色固体。
m/z:[M+H] +232.4
步骤4：冰浴条件下，向化合物18.3(310mg，1.3mmol)的N,N-二甲基甲酰胺(20mL)溶液中，加入钠氢(81mg，2.0mmol，60％)，反应体系在室温下搅拌15分钟，然后加入碘甲烷(285mg，2.0mmol)，反应体系在室温下继续搅拌30分钟。然后用乙酸乙酯(100mL)稀释，并用饱和食盐水洗涤。分离有机相并用无水硫酸钠干燥，过滤、浓缩得化合物18.4(358mg，粗品)为黄色固体。
m/z:[M+H] +246.0
步骤5：将化合物18.4(358mg，1.5mmol)溶于甲醇(15mL)，加入钯碳(180mg)，体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌0.5小时。反应液用硅藻土过滤，滤液浓缩，得到化合物18.5(277mg，产率：109％)为红色固体。
m/z:[M+H] +216.1
步骤6：冰浴条件下，向化合物18.5(275mg，1.3mmol)的甲基叔丁基醚(30mL)溶液中滴加四氢铝锂的四氢呋喃溶液(1.95mL，4.9mmol，2.5M)，反应体系在60℃搅拌5小时。然后用饱和的酒石酸钾钠水溶液淬灭反应，乙酸乙酯(100mL)稀释，并用饱和食盐水洗涤。分离有机相并用无水硫酸钠干燥，过滤、浓缩得化合物18.6(248mg，产率：96％)为红色固体。
m/z:[M+H] +202.3
实施例26：化合物19.6的合成
Figure PCTCN2018079866-appb-000085
步骤1：在-10℃下，将氯甲酸异丁酯(10.2mL，78mmol)滴加到1,1-环丙基二甲酸单甲酯(10.0g，69.4mmol)和三乙胺(10.8mL，78mmol)的四氢呋喃(200mL)溶液中，并在此温度下搅拌1小时，然后将反应体系升温至0℃，过滤掉反应液中固体，滤液待用。在冰浴条件下将硼氢化钠(7.87g，208mmol)的四氢呋喃(100mL)和水(25mL)的混合溶液滴加到上述滤液中，滴加时间1小时，加毕，得到的反应液继续在冰浴条件下搅拌1小时。将反应液倒入到20％的柠檬酸冰水溶液中，搅拌5分钟，浓缩除掉有机溶液，水相用乙酸乙酯萃取，有机相合并，依次用水和饱和食盐用洗涤，无水硫酸钠干燥、过滤，浓缩得到化合物19.1(6.9g，产率：77％)为油状液体。
步骤2：冰浴条件下，将甲基磺酰氯(7.4g，64.5mmol)滴加到化合物19.1(5.6g，43mmol)和三乙胺(8.7mL，86mmol)的二氯甲烷(100mL)溶液中，室温搅拌3小时。反应液用二氯甲烷稀释，依次用盐酸(1.0M)、水和饱和食盐水洗涤，有机相用无水硫酸钠干燥、过滤、浓缩得到化合物19.2(8.9g，产率：100％)为白色固体。
步骤3：将化合物19.2(10.7g，51.5mmol)加入到5-硝基吲哚(5.56g，34.3mmol)和碳酸铯(33.5g，103mmol)的N,N-二甲基甲酰胺(60mL)溶液中，然后将反应体系升温至100℃并搅拌过夜，然后将反应液冷却至室温并倒入到水中，水相用乙酸乙酯萃取(20mL×3)，合并有机相，依次用水、饱和食盐水洗涤、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物19.3(8g，产率：72％)为黄色固体。
m/z:[M+H] +275.2
步骤4：将一水合氢氧化锂(475mg，11.3mmol)的水溶液(10mL)滴加到化合物19.3(1.24g，4.5mmol)的四氢呋喃(30mL)溶液中，室温搅拌过夜，减压浓缩除去四氢呋喃，水相先用石油醚/乙酸乙酯(1/1)混合溶剂洗涤，然后用饱和的柠檬酸水溶液调pH＝3，再用乙酸乙酯萃取(10mL×3)，合并有机相并用水和饱和食盐水洗涤，无水硫酸钠干燥、过滤，浓缩得到化合物19.4(920mg，产率：79％)为黄色固体。
步骤5：冰浴条件下，将叠氮磷酸二苯酯(605mg，2.2mmol)滴加到化合物19.4(520mg)和三乙胺(607mg,6.0mmol)的甲苯(15mL)溶液中，反应体系在此温度下搅拌2小时，然后升至室温继续搅拌4小时，将叔丁醇(10mL)加入到反应体系中，得到的混合物回流搅拌过夜。然后冷至室温，减压浓缩，向得到的残留物中加入二氯甲烷(20mL)，并依次用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤，浓缩有机相，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物19.5(460mg，产率：69％)为黄色固体。
步骤6：将化合物19.5(460mg，1.39mmol)和钯碳(100mg，10％)混于甲醇(30.0mL)溶液中。体系用氢气置换三次后，反应体系在氢气氛(氢气球)下搅拌2小时。反应液用硅藻土过滤，滤液浓缩得到化合物19.6(308mg，产率：74％)为棕色固体。
m/z:[M+H] +302.2
实施例27：化合物19.8的合成
Figure PCTCN2018079866-appb-000086
步骤1：冰浴条件下，将钠氢(121mg，3.0mmol，60％)加入到化合物19.5(500mg，1.5mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应体系搅拌半小时后，将碘甲烷(639mg，4.5mmol)加入到上述反应体系中，室温搅拌2小时后将反应液倒入到冰水中，水相用乙酸乙酯萃取(20mL×3)，合并有机相，依次用水、饱和食盐水洗涤，浓缩有机相，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)得到化合物19.7(362mg，产率：70％)为油状液体。
步骤2：将化合物19.7(362mg，1.0mmol)和钯碳(100mg，10％)混于甲醇(15.0mL)溶液中。反应体系用氢气置换3次，然后在氢气氛(氢气球)作用下室温搅拌2小时，然后将反应液用硅藻土过滤，所得滤液浓缩得到化合物19.8(315mg，产率：100％)为棕色固体。
m/z:[M+H] +316.2
实施例28：化合物20.2的合成
Figure PCTCN2018079866-appb-000087
步骤1：将6-硝基吲哚(1.62g，10.0mmol)和1-甲基-4-哌啶酮(2.26g，20.0mmol)溶解于甲醇(20mL)中，然后加入氢氧化钾(1.12g，20.0mmol)。反应体系加热至90℃搅拌过夜，冷却室温后用水(100mL)淬灭反应，用乙酸乙酯萃取，分离有机相并用无水硫酸钠干燥、过滤、减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物20.1(760mg，产率：30％)为淡黄色固体。
m/z:[M+H] +258.1
步骤2：向化合物20.1(760mg，2.9mmol)的甲醇(30mL)溶液中加入钯碳(50mg)，反应体系用氢气球中置换三次气体后在氢气氛(氢气球)下搅拌30分钟。将混合物经硅藻土过滤，滤液经浓缩后得到化合物20.2(510mg，产率：77％)为棕色油状物。
m/z:[M+H] +230.1
实施例29：化合物21.1的合成
Figure PCTCN2018079866-appb-000088
将6-溴-2-氨基萘(500mg，2.25mmol)、N-甲基哌嗪(270mg，2.7mmol)、氢氧化铯水合物(760mg，4.5mmol)的二甲基亚砜(5.0mL)溶液在120℃下搅拌20小时，然后将反应体系冷却至室温，加入冰水(10mL)稀释，水相用二氯甲烷(20mL×2)萃取，有机相依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤、浓缩，残留物用Flash柱层析纯化(石油醚/乙酸乙酯＝1/3)得到化合物21.1(70mg，产率：13％)为棕色固体。
实施例30：化合物22.5的合成
Figure PCTCN2018079866-appb-000089
步骤1：将苯乙腈(10g，96.9mmol)的多聚磷酸(120g)溶液加热到140℃，在此温度下滴加丙酮(14.9g，257mmol)，1小时加毕，然后保持温度继续搅拌1小时。反应液冷却并倒入到冰水中淬灭，加入石油醚搅拌，分层除去有机相，水相用氯仿萃取，分离有机相并用饱和碳酸氢钠水溶液洗涤，分离有机相并用无水硫酸钠干燥、过滤、滤液浓缩得到化合物22.1(6.7g，产率：40％)为油状液体。
步骤2：向化合物22.1(6.7g，40.0mmol)的硫酸(80.0mL)溶液中缓慢加入硝酸钾(4.30g，42.0mmol)，反应体系室温下搅拌1小时。将反应液倒入冰水(200mL)中，用二氯甲烷(200mL×2)萃取，合并有机相后用饱和食盐水洗涤、无水硫酸钠干燥，过滤、减压浓缩得到化合物22.2(5.0g，产率：56％)为棕色固体。
步骤3：冰浴条件下，将三氟化硼乙醚(772mg，5.44mmol)和硼氢化钠(155mg，4.08mmol)加入到四氢呋喃(10mL)中，反应体系在0℃下搅拌2小时后，将化合物22.2(300mg，1.36mmol)加入到反应中，反应体系加热回流3小时。然后将反应体系减压浓缩除去有机溶剂，向得到的残留物中加入盐酸(20mL，5M)，并加热回流1小时，得到的混合物用饱和的碳酸钠水溶液中和后，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤、浓缩得到化合物22.3(250mg，产率：67％)为黄色固体。
步骤4：将化合物22.3(250mg，1.21mmol)，甲醛水溶液(2mL)和乙酸(0.3mL) 的甲醇(10mL)溶液在室温下搅拌2小时，然后向体系中加入氰基硼氢化钠(152mg，2.42mmol)。反应体系继续搅拌2小时。然后减压浓缩除去溶剂，得到的残留物中加入水，用乙酸乙酯萃取，分离有机相并用无水硫酸钠干燥，过滤、浓缩得到化合物22.4(200mg，产率：75％)为黄色固体。
步骤5：将化合物22.4(200mg，0.91mmol)和钯碳(50mg，10％)加入到甲醇(15mL)中，反应体系在氢气氛(氢气球)下搅拌0.5小时，将反应液用硅藻土过滤，并用甲醇冲洗滤饼，滤液减压浓缩得到化合物22.5(170mg，产率：98％)为棕色油状物。
m/z:[M+H] +191.0
实施例31：化合物24.3的合成
Figure PCTCN2018079866-appb-000090
步骤1：冰浴条件下，将钠氢(229mg，5.73mmol，60％)加入到4-溴-6-硝基-1H-吲哚(690mg，2.86mmol)的无水N,N-二甲基甲酰胺(15mL)溶液中，得到的混合物在室温下搅拌0.5小时，然后将碘甲烷(1.22g，8.59mmol)加入到上述混合物中，将反应体系继续搅拌2小时。然后将反应液缓慢倒入搅拌的冰水中，水相用乙酸乙酯萃取(10mL×2)，合并有机相，依次用水、饱和食盐水洗涤，浓缩有机相，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物24.1(529mg，产率：73％)为黄色固体。
步骤2：将三(二亚苄基丙酮)钯(7.2mg，7.8μmol)加入到化合物24.1(200mg，0.78mmol)、N-甲基哌嗪(78.4mg，0.78mmol)、碳酸铯(767mg，2.35mmol)和(±)-2,2'-双-(二苯膦基)-1,1'-联萘(14.7mg，24μmol)的1,4-二氧六环(15mL)溶液中，用氮气将反应体系置换3次，反应体系在氮气氛下在110℃下搅拌过夜，然后冷却至室温加硅藻土过滤，用乙酸乙酯洗涤滤饼，滤液浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物24.2(210mg，产率：98％)为黄色固体。
步骤3：将化合物24.2(210mg，0.77mmol)和钯/碳(60mg，5％)的甲醇(15mL)混合物用氢气置换三次。然后将反应体系在氢气氛下室温搅拌1小时。溶液过滤，浓缩得到化合物24.3(205mg，产率：100％)为棕色固体。
实施例32：化合物25.2和25.3的合成
Figure PCTCN2018079866-appb-000091
步骤1：氮气保护下，向化合物1-溴-3-甲氧基-5-硝基苯(1.00g，4.31mmol)的四氢呋喃(30.0mL)溶液中，依次加入醋酸钯(100mg，0.43mmol)、碳酸铯(2.15g，6.60mmol)、2,2’-双(二苯基膦)-1,1’-联萘(400mg，0.65mmol)、N-甲基哌嗪(1.29g，12.9mmol)，反应体系在80℃下搅拌16小时。反应体系减压浓缩，经过Flash柱层析(石油 醚/乙酸乙酯＝4/1)纯化得到化合物25.1(1.15g，产率：106％)为棕色固体。
m/z:[M+H] +252.2
步骤2：向化合物25.1(150mg，0.60mmol)的甲醇(5.0mL)溶液中加入雷尼镍(20mg)，反应体系用氢气置换三次，然后室温下在氢气氛中搅拌1小时。过滤、减压浓缩得到化合物25.2(90mg，产率：68％)为黄色固体。
m/z:[M+H] +222.2
利用化合物25.2的合成方法，将步骤1中的1-溴-3-甲氧基-5-硝基苯替换为2-溴-1-甲氧基-4-硝基苯得到化合物25.3(4-甲氧基-3-(4-甲基哌嗪-1-基)苯胺)。
实施例33：化合物26.6的合成
Figure PCTCN2018079866-appb-000092
步骤1：将N-溴代丁二酰亚胺(2.12g，12.0mmol)加入到5-硝基水杨醛(2.0g，11.9mmol)的乙腈(60mL)溶液中，反应体系室温搅拌过夜，然后加入乙酸乙酯，有机相依次用水、饱和食盐水、水洗涤，分离有机相并用无水硫酸钠干燥、过滤、浓缩，然后向残留物中加入甲醇并加热回流，然后向反应体系中滴加水析出固体后将混合物冷却至0℃搅拌半小时，过滤、滤饼真空干燥得到化合物26.1(2.4g，产率：82％)为黄色固体。
步骤2：将碳酸钾(1.12g，8.12mmol)加入到化合物26.1(1g，4.06mmol)和溴代丙二酸二乙酯(1.16g，4.87mmol)的丙酮(15mL)溶液中，反应体系回流搅拌6小时，然后将反应液冷却至室温并倒入到冰水中搅拌，过滤、滤饼真空干燥后得到化合物26.2(945mg，产率：74％)为黄色固体。
步骤3：将氢氧化钠(361mg，9.0mmol)的水溶液(5mL)滴加到化合物26.2(945mg，3.0mmol)的甲醇和四氢呋喃(10mL，1/1)的混合溶液中，反应体系室温搅拌过夜。然后加水淬灭反应，减压浓缩除去有机溶剂，水相用柠檬酸酸化后用乙酸乙酯萃取(20mL)，有机相依次用水、饱和食盐水洗涤，分离有机相并用无水硫酸钠干燥、过滤、浓缩得到化合物26.3(858mg，产率：100％)为棕色固体。
m/z:[M+H] +286.0
步骤4：将铜粉(44.8mg，1.4mmol)加入到化合物26.3(200mg，0.7mmol)的喹啉(2mL)溶液中,在封管内加热至200℃并搅拌0.5小时。反应体系冷却至室温，并倒入到浓盐酸(15mL)中，水相用乙酸乙酯萃取(5mL×3)，合并有机相并依次用水、饱和食盐水洗涤，有机相用无水硫酸钠干燥、过滤、浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物26.4(130mg，产率：71％)为白色固体。
步骤5：将三(二亚苄基丙酮)二钯(Pd(dba) 3)(4.6mg，5.0μmol)加入到化合物26.4 (130mg，0.50mmol)、1,1'-联萘-2,2'-双二苯膦(BINAP)(9.3mg，15μmol)、碳酸铯(488mg，1.5mmol)和N-甲基哌嗪(49.9mg，0.50mmol)的1,4-二氧六环(15mL)溶液中，反应体系用氮气置换3次，在氮气保护下升温至110℃并搅拌过夜。将反应液冷至室温，用硅藻土过滤，滤液浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物26.5(68mg，产率：52％)为棕色固体。
m/z:[M+H] +262.2
步骤6：将兰尼镍(30mg)加入到化合物26.5(68mg，0.26mmol)和水合肼(65mg，1.3mmol)的乙醇和四氢呋喃(15mL，3/1)混合溶液中，反应体系室温搅拌过夜，过滤，滤液浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝8/1)纯化得到化合物26.6(28mg，产率：47％)为棕色固体。
m/z:[M+H] +232.1
实施例34：化合物27.6的合成
Figure PCTCN2018079866-appb-000093
步骤1：将N-溴代丁二酰亚胺(1.96g，11.0mmol)加入到2-甲氧基-4-硝基苯胺(1.68g，10.0mmol)的乙腈(20mL)溶液中，反应体系在室温下搅拌两个小时，然后将反应液用乙酸乙酯稀释，有机相依次用水、饱和食盐水洗涤，并用无水硫酸钠干燥、过滤、浓缩，残留物溶入到回流中的甲醇溶液中，滴加水析出固体后冷至0℃搅拌半小时，过滤，滤饼真空干燥得到化合物27.1(2.2g，产率：89％)为棕色固体。
步骤2：将乙酸酐(10mL)加入到化合物27.1(2.2g，8.9mmol)的醋酸(10mL)溶液中，反应体系回流搅拌3小时，然后将反应液冷至室温并倒入到冰水中搅拌，过滤、滤饼用水洗涤，残留物加入到乙醇中并回流搅拌15分钟至全部溶解，然后向上述澄清溶液中加入氨水(1mL)，搅拌冷却至室温，过滤、滤饼用乙醇洗涤，真空干燥得到化合物27.2(2.1g，产率：82％)为白色固体。
m/z:[M+H] +289.0
步骤3：冰浴条件下，将三溴化硼(4.33g，17.3mmol)加入到化合物27.2(1.0g，3.46mmol)的二氯甲烷(60mL)溶液中，反应体系慢慢升至室温并继续搅拌过夜。用盐酸(1M)淬灭反应，水相用二氯甲烷萃取，合并有机相，依次用水、饱和食盐水洗涤，有机相减压浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝50/1)纯化得到化合物27.3(890mg，产率：93％)为白色固体。
m/z:[M+H] +275.0
步骤4：将4-二甲氨基吡啶(26mg，0.21mmol)加入到化合物27.3(1.15g，4.18 mmol)和对甲苯磺酸(79.5mg，0.418mmol)的1,3-二氯苯(25mL)溶液中，反应体系升温至170℃并搅拌4小时。反应液冷至室温，用真空泵除去有机溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物27.4(700mg，产率：65％)为棕色固体。
m/z:[M+H] +257.0
步骤5：将Pd(dba) 3(29.6mg，0.032mmol)加入到化合物27.4(830mg，3.23mmol)、BINAP(60.4mg，0.097mmol)、碳酸铯(3.16g，9.69mmol)和N-甲基哌嗪(323.0mg，3.23mmol)的1,4-二氧六环(30mL)溶液中，反应体系用氮气置换三次,在氮气保护下升温至110℃并搅拌3小时。将反应液冷至室温，过滤、将滤液浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物27.5(60mg，产率：7％)为棕色固体。
m/z:[M+H] +277.2
步骤6：将钯碳(30mg，10％)加入到化合物27.5(60mg，0.22mmol)甲醇和乙酸乙酯(10mL，1/1)的混合溶液中，体系用氢气置换三次，然后在氢气氛下室温搅拌2小时，然后将反应液用硅藻土过滤，滤液减压浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝8/1)纯化得到化合物27.6(23mg，产率：42％)为棕色固体。
m/z:[M+H] +247.2
实施例35：化合物1-1-1的合成
Figure PCTCN2018079866-appb-000094
步骤1：依次将化合物1.1(255mg，1mmol)、2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(222mg，1mmol)、碘化亚铜(191mg，1mmol)、无水碳酸钾(276mg，2mmol)和N,N-二甲基乙二胺(88mg，1mmol)加入到1,4-二氧六环(20mL)中，反应体系在100℃下搅拌过夜。然后将反应液冷却至室温，过滤，滤液浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得化合物1-1(205mg，产率：52％)为红色液体。
m/z:[M+H] +398.1
步骤2：将Hoveyda-Grubbs试剂(2mg)加入到化合物1-1(205mg，0.52mmol)的二氯甲烷(20mL)溶液中，将反应体系在40℃下搅拌16小时。冷却，将反应液直接减压浓缩除去有机溶剂，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得化合物1-2(57mg，产率：30％)为白色固体。
m/z:[M+H] +370.1
步骤3：将间氯过氧苯甲酸(31mg，0.154mmol)加入到化合物1-2(57mg，0.154 mmol)的二氯甲烷(10mL)溶液中，反应体系在室温下搅拌1小时，然后将反应液直接减压浓缩除去有机溶剂得到化合物1-3(59mg，产率：100％)为白色固体。
m/z:[M+H] +385.9
步骤4：将化合物1-3(59mg，0.154mmol)、N,N-二异丙基乙胺(40mg,0.308mmol)和4-(N-甲基哌嗪)苯胺(30mg，0.154mmol)的甲苯(10mL)溶液在70℃下搅拌过夜，减压浓缩除去有机溶剂，残留物用prep-HPLC纯化得到化合物1-1-1(trans，16.2mg，产率：21％)为白色固体。
m/z:[M+H] +512.9； 1H NMR(400MHz,CD 3OD):δ8.78(s,1H),7.88(t,J＝7.8Hz,1H),7.57(d,J＝8.8Hz,2H),7.39(d,J＝7.6Hz,1H),6.95(d,J＝7.2Hz,2H),6.73(d,J＝8.0Hz,1H),5.75(dt,J＝8.0,15.6Hz,1H),5.39(dt,J＝8.0,16.0Hz,1H),4.59(t,J＝6.8Hz,2H),4.30(d,J＝5.6Hz,2H),3.19(t,J＝5.2Hz,4H),2.65(t,J＝4.8Hz,4H),2.38(s,3H),2.22-2.19(m,2H),1.85-1.82(m,2H),1.58-1.56(m,2H)。
实施例36：化合物1-1-2的合成
Figure PCTCN2018079866-appb-000095
利用化合物1-1-1的合成方法，用化合物1.2为起始原料合成化合物1-1-2(cis)。
m/z:[M+H] +498.8； 1H NMR(400MHz,CD 3OD):δ8.79(s,1H),7.86(t,J＝8.0Hz,1H),7.64(d,J＝8.8Hz,2H),7.50(d,J＝8.0Hz,1H),7.02(d,J＝8.8Hz,2H),6.70(d,J＝8.0Hz,1H),6.07(dt,J＝7.6,10.8Hz,1H),5.55(dt,J＝7.2,10.8Hz,1H),4.57(s,2H),4.34(d,J＝8.0Hz,2H),3.82(d,J＝13.6Hz,2H),3.63(d,J＝12.0Hz,2H),3.30(d,J＝16.0Hz,2H),3.07(d,J＝12.4Hz,2H),3.00(s,3H),2.20(br.s,2H),1.91(br.s,2H)。
实施例37：化合物1-1-3的合成
Figure PCTCN2018079866-appb-000096
利用化合物1-1-1的合成方法，用化合物1.3为起始原料合成化合物1-1-3(cis)。
m/z:[M+H] +484.9； 1H NMR(400MHz,CD 3OD):δ8.82(s,1H),7.89(t,J＝7.6Hz,1H),7.71(d,J＝8.4Hz,1H),7.66(d,J＝8.8Hz,2H),7.07(d,J＝8.8Hz,2H),6.75(d,J＝8.0Hz,1H),6.10(dt,J＝8.0,11.2Hz,1H),5.86(dt,J＝8.8,11.2Hz,1H),4.46-4.31(m,4H),3.85(d,J＝13.2Hz,2H),3.64(d,J＝10.4Hz,2H),3.34-3.32(m,2H),3.07(d,J＝11.6Hz,2H),3.01(s,3H),2.56-2.51(m,2H)。
实施例38：化合物1-1-4的合成
Figure PCTCN2018079866-appb-000097
利用化合物1-1-1的合成方法，用化合物1.4为起始原料合成化合物1-1-4(trans)。
m/z:[M+H] +515.4； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.69(d,J＝8.0Hz,1H),7.42-7.39(m,2H),7.22(d,J＝7.6Hz,1H),6.82(d,J＝6.8Hz,2H),6.64(d,J＝7.6Hz,1H),5.87(dt,J＝5.6,15.6Hz,1H),5.58(dt,J＝7.2,15.2Hz,1H),4.61(t,J＝5.6Hz,2H),4.25(d,J＝5.2Hz,2H),4.03(d,J＝7.2Hz,2H),3.78(t,J＝5.6Hz,2H),3.13(t,J＝4.8Hz,4H),2.54(t,J＝4.8Hz,4H),2.30(s,3H)。
实施例39：化合物1-1-5的合成
Figure PCTCN2018079866-appb-000098
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物1.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物9.2得到化合物1-1-5(cis)。
m/z:[M+H] +515.4； 1H NMR(400MHz,CD 3OD):δ8.72(s,1H),7.91(s,1H),7.82(t,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.48(dd,J＝2.4,8.4Hz,1H),7.09(d,J＝8.8Hz,1H),6.64(d,J＝8.0Hz,1H),6.01-5.96(m,1H),5.70(dt,J＝8.8,10.8Hz,1H),4.65(s,2H),4.34(br.s,2H),4.22(s,2H),3.49(d,J＝11.2Hz,2H),3.28-3.20(m,4H),3.05-2.98(m,2H),2.90(s,3H),2.44-2.39(m,2H)。
实施例40：化合物1-1-6的合成
Figure PCTCN2018079866-appb-000099
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物1.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物1-3-2(trans)。用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物12.2得到化合物3-3-10(cis)。利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物8-3-1(cis)。
m/z:[M+H] +514.9； 1H NMR(400MHz,DMSO-d 6):δ10.10(s,1H),8.84(s,1H),7.94(t,J＝8.0Hz,1H),7.69-7.67(m,1H),7.34(d,J＝2.0Hz,1H),7.29(dd,J＝2.0,8.4Hz,1H),6.88(d,J＝8.8Hz,1H),6.77(d,J＝8.4Hz,1H),5.95(dt,J＝8.0,10.8Hz,1H),5.76(dt,J＝8.8,10.4Hz,1H),4.30(s,2H),4.26(s,2H),3.72(s,3H),2.94(s,4H),2.46(s,6H),2.22(s,3H)。
实施例41：化合物1-2-1的合成
Figure PCTCN2018079866-appb-000100
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物1.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物1-2-1(cis)。
m/z:[M+H] +482.4； 1H NMR(400MHz,CDCl 3):δ8.87(s,1H),7.79(t,J＝8.0Hz,1H),7.69(d,J＝7.6Hz,1H),7.52(s,1H),7.49(s,1H),7.26(d,J＝2.0Hz,1H),6.70(t,J＝8.4Hz,2H),6.24(dt,J＝8.0,10.8Hz,1H),5.81(dt,J＝9.2,10.4Hz,1H),4.45(s,2H),4.36(s,2H),3.77(s,2H),2.61(s,2H),2.56-2.51(m,5H),1.07-0.90(m,4H)。
实施例42：化合物1-2-2的合成
Figure PCTCN2018079866-appb-000101
利用化合物1-1-1的合成方法，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物1-2-2(cis)。
m/z:[M+H] +510.4； 1H NMR(400MHz,DMSO-d 6):δ10.17(s,1H),8.85(s,1H),7.95(t,J＝8.0Hz,1H),7.59(s,1H),7.41(d,J＝7.6Hz,1H),7.34(dd,J＝1.6,8.4Hz,1H),6.79(d,J＝8.4Hz,1H),6.65(d,J＝8.8Hz,1H),5.67(dt,J＝5.2,15.2Hz,1H),5.37(dt,J＝7.2,15.2Hz,1H),4.51(t,J＝6.8Hz,2H),4.21(d,J＝8.0Hz,2H),3.53(s,2H),2.43(s,2H),2.33(s,3H),2.13(s,2H),1.74(dd,J＝6.0,12.0Hz,2H),1.47(t,J＝3.2Hz,2H),0.91-0.81(m,4H)。
实施例43：化合物1-3-1的合成
Figure PCTCN2018079866-appb-000102
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物1.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物1-3-1(cis)。
m/z:[M+H] +484.4； 1H NMR(400MHz,CDCl 3):δ8.88(s,1H),7.80(t,J＝8.0Hz,1H),7.71(d,J＝7.6Hz,1H),7.51(s,1H),7.48(s,1H),7.35-7.29(m,1H),6.71(d,J＝8.0Hz,1H),6.23(ddd,J＝8.0,12.4,20.0Hz,1H),5.81(dd,J＝8.8,20.0Hz,1H),4.45(s,2H),4.36(s,2H),3.58(s,2H),2.56-2.51(m,2H),2.47(s,3H),2.45(s,2H),1.35(s,6H)。
实施例44：化合物1-3-2的合成
Figure PCTCN2018079866-appb-000103
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物1.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物1-3-2(trans)。
m/z:[M+H] +514.4； 1H NMR(400MHz,DMSO-d 6):δ10.33(s,1H),9.72(t,J＝2.0Hz,1H),8.91(s,1H),8.05(t,J＝8.0Hz,1H),7.69(s,1H),7.58(dd,J＝2.0,8.8Hz,1H),7.44(d,J＝8.8Hz,1H),7.41(d,J＝7.2Hz,1H),6.85(d,J＝8.0Hz,1H),5.89-5.83(m,1H),5.52-5.48(m,1H),4.63-4.56(m,2H),4.32(s,2H),4.28(s,2H),4.03(d,J＝6.8Hz,2H),3.74(t,J＝5.2Hz,2H),3.50-3.5(m,1H),3.27-3.21(m,1H),3.01(s,3H),1.38(s,3H),1.33(s,3H)。
实施例45：化合物2-1-1和2-1-2的合成
Figure PCTCN2018079866-appb-000104
步骤1：依次将化合物2.2(200mg，0.67mmol)、2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(179mg，0.81mmol)、无水碳酸钾(186mg，1.35mmol))、碘化亚铜(128mg，0.67mmol)、N,N-二甲基乙二胺(59mg，0.67mmol)加入到1,4-二氧六环(20mL)中，反应体系在100℃下搅拌16小时。冷至室温，将反应液浓缩，用prep-TLC(石油醚/乙酸乙酯＝1/1)纯化得化合物2-1(160mg，产率：54％)为棕色固体。
m/z:[M+H] +439.0
步骤2：将Hoveyda-Grubbs试剂(30mg)加入到化合物2-1(160mg，0.365mmol)的二氯甲烷(30mL)溶液中，反应体系在45℃下搅拌4小时。将反应液冷却，减压浓缩除去二氯甲烷，残留物用prep-TLC纯化(石油醚/乙酸乙酯＝1/1)得化合物2-2(顺式，40mg，产率：27％，极性较大)和2-3(反式，60mg，产率：40％，极性较小)，均为为白色固体。
m/z:[M+H] +410.9
步骤3：将间氯过氧苯甲酸(17mg，0.097mmol)加入到化合物2-2(40mg，0.097mmol)的二氯甲烷(10mL)溶液中，反应体系室温搅拌1小时，减压浓缩除去二氯甲烷得到化合物2-4(43mg，产率：100％)为白色固体。
m/z:[M+H] +427.0
步骤4:将化合物2-4(43mg，0.097mmol)、N,N-二异丙基乙胺(0.3mL)和4-(N-甲基哌嗪)苯胺(19mg，0.097mmol)溶入到甲苯(10mL)中，反应体系在90℃下搅拌过夜，减压浓缩除去溶剂，残留物用prep-HPLC分离得到化合物2-1-1(cis，29mg，产率：54％)为白色固体。
m/z:[M+H] +553.8； 1H NMR(400MHz,CD 3OD):δ8.85(s,1H),8.00-8.25(m,2H),7.65(dd,J＝2.4,6.8Hz,2H),7.35-7.40(m,1H),7.06(dd,J＝2.4,6.8Hz,2H),5.25-5.50(m,2H),5.05-5.15(m,1H),4.09(t,J＝7.6Hz,2H),3.86(d,J＝13.2Hz,2H),3.65(d,J＝12.4Hz,2H),2.95-3.20(m,5H),2.05-2.25(m,5H),1.30-1.75(m,6H)。
用化合物2-1-1的合成方法，用化合物2-2为起始原料合成得到化合物2-1-2(trans,57mg)为白色固体。
m/z:[M+H] +553.8； 1H NMR(400MHz,CD 3OD):δ8.83(s,1H),8.15(t,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.51-7.60(m,3H),6.97(d,J＝8.4Hz,2H),5.45-5.50(m,1H),5.30-5.48(m,1H),4.43(d,J＝5.6Hz,2H),3.85-4.00(m,2H),3.80(d,J＝13.6Hz,2 H),3.63(d,J＝12.4Hz,2H),2.80-3.20(m,5H),1.85-2.25(m,5H),1.25-1.75(m,6H)。
实施例46：化合物2-2-1的合成
Figure PCTCN2018079866-appb-000105
利用化合物2-1-1的合成方法，将步骤1中的化合物2.2替换为化合物2.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物2-2-1(cis)。
m/z:[M+H] +536.6； 1H NMR(400MHz,CDCl 3):δ8.82(s,1H),7.94(d,J＝8.0Hz,1H),7.77(t,J＝8.0Hz,1H),7.38(s,1H),7.32(s,1H),7.20(d,J＝6.4Hz,1H),6.59(d,J＝8.4Hz,1H),5.47-5.32(m,2H),4.86(d,J＝6.8Hz,2H),3.86(t,J＝5.2Hz,2H),3.64(s,2H),2.50(s,2H),2.41(s,3H),2.20(dd,J＝6.4,13.2Hz,2H),2.11(s,3H),1.56-1.45(m,2H),0.95-0.85(m,4H)。
实施例47：化合物2-3-1的合成
Figure PCTCN2018079866-appb-000106
利用化合物2-1-1的合成方法，将步骤1中的化合物2.2替换为化合物2.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物2-3-1(cis)。
m/z:[M+H] +524.9； 1H NMR(400MHz,CDCl 3):δ8.80(s,1H),8.02(d,J＝8.4Hz,1H),7.86(t,J＝8.0Hz,1H),7.43(s,1H),7.34(s,1H),7.30-7.21(m,2H),5.86-5.77(m,1H),5.61-5.52(m,1H),4.47(d,J＝7.6Hz,2H),3.90(s,2H),3.58(s,2H),2.45-2.32(m,7H),2.00(s,3H),1.28(s,6H)。
实施例48：化合物2-3-2的合成
Figure PCTCN2018079866-appb-000107
利用化合物2-1-1的合成方法，将步骤1中的化合物2.2替换为化合物2.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物化合物11.5得到化合物2-3-2(cis)。
m/z:[M+H] +538.9； 1H NMR(400MHz,CDCl 3):δ8.81(s,1H),7.95(d,J＝8.0Hz,1H),7.77(t,J＝7.6Hz,1H),7.40(t,J＝8.0Hz,1H),7.27-7.19(m,3H),5.45-5.33(m,2H),4.86(d,J＝6.8Hz,2H),3.86(t,J＝5.6Hz,2H),3.46(s,3H),2.36(s,3H),2.35(d,J＝2.0Hz,2H),2.23-2.18(m,2H),2.11(s,3H),1.59-1.55(m,2H),1.25(s,6H)。
实施例49：化合物3-1-1的合成
Figure PCTCN2018079866-appb-000108
步骤1：依次将化合物3.2(1.9g，8.29mmol)、2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(1.84g，8.29mmol)、碘化亚铜(1.5g，8.29mmol)、无水碳酸钾(2.35g，17mmol)和N,N-二甲基乙二胺(0.73g，8.29mmol)加入到1,4-二氧六环(30mL)中，反应体系在100℃下搅拌过夜。冷至室温，将反应液过滤，滤液浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝1/1)得化合物3-1(1.56g，产率：51％)为黄色固体。
步骤2：将6-溴-1-己烯(0.25g,1.5mmol)加入到化合物3-1(0.37g，1mmol)的N,N-二甲基甲酰胺(8mL)溶液中，室温搅拌5分钟后，加入碳酸钾(0.28g，2mmol)，反应体系在50℃下继续搅拌3小时，冷却至室温后加水(20mL)淬灭反应，用二氯甲烷萃取(100mL×3)，合并有机相并用无水硫酸钠干燥，过滤、浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得化合物3-2(0.35g，产率：77％)为淡黄色固体。
步骤3：向化合物3-2(0.35g，0.77mmol)的二氯甲烷(10mL)溶液中加入Hoveyda-Grubbs催化剂(20mg，0.032mmol)，反应体系室温搅拌过夜，然后减压浓缩除去溶剂，残留物用prep-TLC(石油醚/乙酸乙酯＝2/1)分离得到化合物3-3(110mg，产率：33％)为黄色油状物。
m/z:[M+H] +424.8
步骤4：向化合物3-3(0.11g，0.26mmol)的二氯甲烷(10mL)溶液中加入间氯过氧苯甲酸(47mg，0.30mmol)，反应体系室温下搅拌30分钟，减压浓缩除去溶剂得到化合物3-4(0.155g，粗品)直接进行下一步反应。
m/z:[M+H] +440.9
步骤5：将步骤4所得化合物3-4(0.155g，粗品)、N,N-二异丙基乙胺(34mg，0.26mmol)和4-(N-甲基哌嗪)苯胺(38mg，0.2mmol)溶入到甲苯(5mL)中，反应体系在70℃下搅拌1小时，减压浓缩除去溶剂，残留物用prep-HPLC分离得到化合物3-1-1(trans，13.5mg，两步产率：9.1％)为黄色固体。
m/z:[M+H] +567.9； 1H NMR(400MHz,CD 3OD):δ8.81(s,1H),7.62(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,2H),5.72-5.61(m,2H),4.73(s,2H),4.39(s,2H),4.04(t,J＝8.0Hz,2H),3.81(br.s,2H),3.62(br.s,2H),3.10-3.03(m,2H),3.00(s,3H),2.24-2.19(m,3H),2.08-2.03(m,1H),1.69-1.65(m,2H),1.55-1.51(m,2H)。
实施例50：化合物3-2-1的合成
Figure PCTCN2018079866-appb-000109
用化合物3-1-1的合成方法，将步骤5中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物3-2-1(trans)。
m/z:[M+H] +565.1； 1H NMR(400MHz,CD 3OD):δ8.81(s,1H),7.66(d,J＝1.6Hz,1H),7.64(d,J＝8.4Hz,1H),7.59(dd,J＝2.0,8.4Hz,1H),7.49(d,J＝8.4Hz,1H),6.85(d,J＝8.4Hz,1H),5.72-5.58(m,2H),4.74(s,2H),4.60,4.48(two q,J＝14.8Hz,2H),4.36(s,2H),3.99(dd,J＝8.0,8.4Hz,2H),3.64,3.28(two q,J＝12.4Hz,2H),3.10(s,3H),2.20(dt,J＝6.4,12.8Hz,2H),1.70-1.66(m,2H),1.54-1.49(m,2H),1.30-1.05(m,4H)。
实施例51：化合物3-2-2的合成
Figure PCTCN2018079866-appb-000110
步骤1：化合物3.3(53g，0.18mol)和2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(35.7g，0.61mol)溶于1,4-二氧六环(530mL)和N,N-二甲基甲酰胺(53mL)中，向其中加入碘化亚铜(34g，178mmol)和碳酸铯(116g，356mmol)。5分钟后加入N,N’-二甲基乙二胺(15.7g，178mmol)。氮气保护下，将混合物在100℃下搅拌过夜。混合物用乙酸乙酯稀释后水洗，分离有机相并用无水硫酸钠干燥、过滤、浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物4-1(42g，产率：54％)为类白色固体。
m/z:[M+H] +438.9
步骤2：向化合物4-1(42.0g，950mmol)的二氯甲烷(420mL)溶液中分4次加入Hoveyda-Grubbs催化剂(2.3g)，4小时加毕，将反应体系在40℃下搅拌过夜。然后将反应液浓缩，残留物用硅胶柱层析纯化，用洗脱剂石油醚/乙酸乙酯＝5/1～1/1洗脱45分钟先收集得到化合物4-3(600mg，产率：1.5％)，然后用洗脱剂石油醚/乙酸乙酯＝1/1继续洗脱45分钟得到化合物4-2(25.2g，产率：64％)，均为白色固体。
m/z:[M+H] +411.2
步骤3：冰水浴条件下，向化合物4-2(700mg，1.7mmol)的二氯甲烷(20mL)溶液中分批加入间氯过氧苯甲酸(355mg，1.8mmol)。加毕，反应体系在0℃下搅拌30分钟。反应溶液依次用饱和碳酸氢钠水溶液(10mL)和饱和食盐水(20mL)洗涤。有机相用无水硫酸钠干燥，过滤、浓缩得到化合物4-4(730mg，产率:100％)为黄色固体.
步骤4：化合物4-4(300mg，0.7mmol)，化合物10.8(146mg，0.77mmol)和N,N- 二异丙基乙胺(136mg，1.1mmol)溶于甲苯(20mL)中，反应体系在70℃下搅拌过夜。然后将混合物用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥、过滤、浓缩。残留物经硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到的化合物用甲醇重结晶得化合物3-2-2(137mg，产率：35％)为黄色固体。
m/z:[M+H] +550.9； 1H NMR(400MHz,CD 3OD):δ8.81(s,1H),7.65(d,J＝2.0Hz,1H),7.60-7.56(m,2H),7.48(d,J＝8.4Hz,1H),6.84(d,J＝8.8Hz,1H),5.91(dt,J＝7.2,11.2Hz,1H),5.55(dt,J＝7.2,11.2Hz,1H),4.82(s,2H),4.60,4.47(two q,J＝16.0Hz,2H),4.37(d,J＝7.2Hz,2H),4.09(t,J＝4.4Hz,2H),3.63,3.27(two q,J＝12.4Hz,2H),3.09(s,3H),2.14(br.s,2H),1.87(br.s,2H),1.31-1.05(m,4H)。
实施例52：化合物3-3-1的合成
Figure PCTCN2018079866-appb-000111
步骤1：冰水浴条件下，向化合物4-2(700mg，1.7mmol)的二氯甲烷(20mL)溶液中分批加入间氯过氧苯甲酸(355mg，1.8mmol)。加毕，反应体系在0℃下继续搅拌30分钟。然后将混合物依次用饱和碳酸氢钠水溶液(10mL)和饱和食盐水(20mL)洗涤。有机相用无水硫酸钠干燥，过滤、浓缩得到化合物5-1(730mg，产率:100％)为黄色固体。
m/z:[M+H] +427.0
步骤2:化合物5-1(250mg，0.59mmol)，化合物9.2(143mg，0.64mmol)和N,N-二异丙基乙胺(114mg，0.88mmol)溶于甲苯(10mL)中，反应体系在70℃下搅拌16小时。然后将反应体系减压浓缩，残留物溶于二氯甲烷(30mL)中，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、浓缩。残留物用硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化后得到的产物再用甲醇重结晶得化合物3-3-1(50mg，产率：15％)为黄色固体。
m/z:[M+H] +583.9； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.50(br.s,1H),7.42(d,J＝7.2Hz,1H),7.40(s,1H),7.30(d,J＝6.8Hz,1H),7.12(d,J＝8.8Hz,1H),5.98-6.07(m,1H),5.47(dt,J＝10.8,7.2Hz,1H),4.68(s,4H),4.27(d,J＝7.6Hz,2H),4.08-4.11(m,2H),2.95(t,J＝4.8Hz,4H),2.57(br.s,4H),2.32(s,3H),2.05(br.s,2H),1.85(br.s,2H),1.58(br.s,2H)。
实施例53：化合物3-3-2的合成
Figure PCTCN2018079866-appb-000112
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺得到化合物3-3-2(cis)。
m/z:[M+H] +583.9； 1H NMR(400MHz,CD 3OD):δ8.76(s,1H),7.42(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.27(d,J＝2.4Hz,1H),7.06(dd,J＝8.4,2.4Hz,1H),6.88(d,J＝8.8Hz,1H),5.70-5.77(m,1H),5.44-5.55(m,1H),4.73(s,2H),4.32(d,J＝7.2Hz,2H),4.05(t,J＝4.8Hz,2H),3.69(s,3H),3.47(d,J＝10.4Hz,4H),3.22-3.26(m,2H),2.92-2.98m,2H),2.87(s,3H),2.05(br.s,2H),1.81(br.s,2H)。
实施例54：化合物3-3-3的合成
Figure PCTCN2018079866-appb-000113
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为3-甲基-4-(4-甲基哌嗪-1-基)苯胺得到化合物3-3-3(cis)。
m/z:[M+H] +567.9； 1H NMR(400MHz,CDCl 3):δ8.70(s,1H),7.50(d,J＝9.2Hz,2H),7.44(d,J＝8.8Hz,1H),7.38(d,J＝8.8Hz,1H),6.89(d,J＝9.2Hz,2H),5.79-5.87(m,1H),5.44-5.51(m,1H),4.70(s,2H),4.29(d,J＝7.6Hz,2H),4.00-4.07(m,2H),3.72(t,J＝14.8Hz,2H),3.53(d,J＝12.8Hz,1H),3.24-3.40(m,2H),2.86-2.97(m,4H),2.67(dd,J＝13.2,10.8Hz,1H),2.05(d,J＝4.4Hz,2H),1.75-1.84(m,2H),1.36(d,J＝6.4Hz,3H)。
实施例55：化合物3-3-4的合成
Figure PCTCN2018079866-appb-000114
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为4-(1S,4S)-5-甲基-2,5-二氮杂二环[2,2,1]环庚烷-2-基)苯胺得到化合物3-3-4(cis)。
m/z:[M+H] +565.8； 1H NMR(400MHz,DMSO-d 6):δ10.47(br.s,1H),8.81(s,1H),7.69(br.s,1H),7.53(d,J＝8.0Hz,2H),7.47(d,J＝8.4Hz,1H),6.65(dd,J＝12.0,9.2Hz,2H),5.86(s,1H),5.47-5.57(m,1H),4.85(s,2H),4.52-4.64(m,1H),4.31-4.43(m,1H),4.22(d,J＝7.4Hz,2H),3.96-4.03(m,2H),3.45-3.63(m,3H),3.04(d,J＝11.6Hz,1H),2.67-2.86(m,3H),2.37(d,J＝11.2Hz,1H),2.03-2.21(m,3H),1.81(br.s,2H)。
实施例56：化合物3-3-5的合成
Figure PCTCN2018079866-appb-000115
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为4-(3,4-二甲基哌嗪-1-基)-3-甲氧基苯胺得到化合物3-3-5(cis)。
m/z:[M+H] +598.0； 1H NMR(400MHz,DMSO-d 6):δ10.85(s,1H),10.12(br.s,1H), 8.85(s,1H),7.64(dd,J＝8.4,2.8Hz,1H),(m,1H),7.43(d,J＝8.0Hz,2H),7.25(d,J＝6.8Hz,1H),6.88(d,J＝8.8Hz,1H),5.68-5.80(m,1H),5.47-5.57(m,1H),4.86(m,2H),4.23(d,J＝7.2Hz,2H),3.96-4.00(m,3H),3.63(br.s,3H),3.34-3.49(m,3H),3.17-3.29(m,1H),2.97-3.07(m,1H),2.80(d,J＝4.4Hz,4H),2.07(br.s,2H),1.80(br.s,2H),1.33(d,J＝6.4Hz,3H)。
实施例57：化合物3-3-6的合成
Figure PCTCN2018079866-appb-000116
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为4-((4-甲基哌嗪-1-基)甲基)苯胺得到化合物3-3-6(cis)。
m/z:[M+H] +567.9； 1H NMR(400MHz,CDCl 3):δ8.79(s,1H),7.46(d,J＝8.4Hz,2H),7.40(d,J＝3.2Hz,1H),7.37(dd,J＝8.4,2.8Hz,2H),7.21(s,1H),5.95-6.03(m,1H),5.46(dt,J＝10.8,7.2Hz,1H),4.70(s,2H),4.27(d,J＝7.2Hz,2H),4.08(dd,J＝5.2,4.4Hz,2H),3.42(s,2H),2.44(br.s,4H),2.25(s,3H),2.05(br.s,2H),1.84(br.s,2H),1.60(br.s,4H)。
实施例58：化合物3-3-7的合成
Figure PCTCN2018079866-appb-000117
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为4-(N-甲基哌嗪)苯胺得到化合物3-3-7(cis)。
m/z:[M+H] +553.7； 1H NMR(400MHz,DMSO-d 6):δ10.76(s,1H),8.83(s,1H),7.69(d,J＝8.0Hz,1H),7.61(d,J＝8.8Hz,2H),7.48(d,J＝8.4Hz,1H),6.98(d,J＝9.2Hz,2H),5.90-5.79(m,1H),5.51-5.55(m,1H),4.85(s,2H),4.23(d,J＝7.2Hz,2H),4.00(t,J＝4.0Hz,2H),3.76(d,J＝12.8Hz,2H),3.49(d,J＝11.6Hz,2H),3.05-3.16(m,4H),2.81(d,J＝4.4Hz,3H),2.15(br.s,2H),1.94(br.s,2H)。
实施例59：化合物3-3-8的合成
Figure PCTCN2018079866-appb-000118
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为3-氟-4-甲基哌嗪-1-苯胺得到化合物3-3-8(cis)。
m/z:[M+H] +571.9； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.66(d,J＝10.8Hz,1 H),7.45-7.37(m,3H),6.96-6.93(m,1H),6.84(t,J＝8.8Hz,1H),6.03(dd,J＝8.0,10.0Hz,1H),5.47(dt,J＝7.2,11.2Hz,1H),4.69(s,2H),4.28(d,J＝7.6Hz,2H),4.09(t,J＝4.8Hz,2H),3.05(t,J＝4.8Hz,4H),2.60(s,4H),2.33(s,3H),2.06(s,2H),1.85(s,2H)。
实施例60：化合物3-3-9的合成
Figure PCTCN2018079866-appb-000119
用化合物3-3-1的合成方法，将步骤1中的化合物4-2替换为4-2和4-3的混合物，步骤2中的化合物9.2替换为3-甲基-4-甲基哌嗪-1-苯胺得到化合物3-3-9(cis和trans混合物)。
m/z:[M+H] +567.9； 1H NMR(400MHz,CDCl 3):δ8.76(s,1H),7.55(s,1H),7.43-7.25(m,2H),7.23(d,J＝2.8Hz,1H),6.92(d,J＝8.4Hz,1H),6.07-5.95(m,1H),5.49-5.43(m,1H),4.70(s,2H),4.27(d,J＝1.2Hz,2H),4.10-4.07(m,2H),2.88-2.85(m,4H),2.55-2.46(m,4H),2.31(s,3H),2.23(s,3H),2.07(s,2H),1.82(s,2H)(major rotamer 4:1)。
实施例61：化合物3-3-10的合成
Figure PCTCN2018079866-appb-000120
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物12.2得到化合物3-3-10(cis)。
m/z:[M+H] +580.0； 1H NMR(400MHz,DMSO-d 6):δ10.03(d,J＝3.6Hz,1H),8.80(s,1H),7.72-7.71(m,1H),7.54(d,J＝9.2Hz,2H),7.47(d,J＝8.4Hz,1H),6.91(d,J＝8.8Hz,2H),5.88-5.83(m,1H),5.55-5.48(m,1H),4.84(s,2H),4.21(d,J＝7.2Hz,2H),3.99(s,2H),3.72(d,J＝10.4Hz,1H),3.43(d,J＝3.6Hz,1H),3.06-2.99(m,2H),2.71-2.65(m,1H),2.35(t,J＝10.4Hz,1H),2.25-2.20(m,1H),2.09-1.99(m,4H),1.85-1.72(m,5H),1.40-1.32(m,1H)。
实施例62：化合物3-3-11的合成
Figure PCTCN2018079866-appb-000121
用化合物3-3-1的合成方法，将步骤1中的化合物4.2替换为4.3，步骤2中的化合物9.2替换为3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺得到化合物3-3-11(trans)。
m/z:[M+H] +584.3； 1H NMR(400MHz,CDCl 3):δ8.76(s,1H),7.37(s,1H),7.36(d,J＝8.4Hz,1H),7.29(d,J＝8.0Hz,1H),7.07(s,1H),6.99(d,J＝9.2Hz,1H),6.81(d,J＝8.8 Hz,1H),5.43-5.31(m,2H),4.61(s,2H),4.30(s,2H),4.12(s,2H),3.73(s,3H),3.01(s,4H),2.56(s,4H),2.29(s,3H),1.98(dd,J＝6.0,11.6Hz,2H),1.82(s,2H)。
实施例63：化合物3-3-12的合成
Figure PCTCN2018079866-appb-000122
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为3-(4-甲基哌嗪-1-基)苯胺得到化合物3-3-12(cis)。
m/z:[M+H] +554.2； 1H NMR(400MHz,DMSO-d 6):δ10.13(s,1H),9.66(s,1H),8.89(s,1H),7.65(d,J＝8.0Hz,1H),7.48-7.37(m,2H),7.25-7.15(m,2H),6.74-6.64(m,1H),5.79-5.69(m,1H),5.58-5.48(m,1H),4.89(s,2H),4.29-4.19(m,2H),4.41-3.97(m,2H),3.66(d,J＝12.4Hz,2H),3.59-3.45(m,2H),3.19-3.07(m,2H),2.95-2.78(m,5H),2.08(s,2H),1.82(s.2H)。
实施例64：化合物3-3-13的合成
Figure PCTCN2018079866-appb-000123
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物25.2得到化合物3-3-13(cis)。
m/z:[M+H] +584.3； 1H NMR(400MHz,CDCl 3):δ8.86(s,1H),7.45-7.38(m,2H),6.79(s,1H),6.74(s,1H),6.21(t,J＝2.0Hz,1H),6.05-5.99(m,1H),5.58-5.51(m,1H),4.76(s,2H),4.35(d,J＝7.2Hz,2H),4.19-4.14(m,2H),3.74(s,3H),3.21-3.13(m,4H),2.66-2.58(s,4H),2.40(s,3H),2.15-2.07(m,2H),1.96-1.88(m,2H)。
实施例65：化合物3-3-14的合成
Figure PCTCN2018079866-appb-000124
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物25.3得到化合物3-3-14(cis)。
m/z:[M+H] +584.3； 1H NMR(400MHz,DMSO-d 6):δ10.01(br.s,1H),8.82(s,1H),7.65-7.61(m,1H),7.35-7.29(m,2H),7.17(s,1H),6.85(d，J＝8.8Hz，1H),5.73-5.68(m, 1H),5.57-5.52(m,1H)，4.86(s，2H)，4.21(d,J＝7.2Hz,2H)，4.02-4.01(m,2H),3.73(s,3H),2.80-2.70(m,4H),2.39-2.36(m,4H),2.19(s,3H),2.20-2.10(m,2H),1.83-1.79(m,2H)。
实施例66：化合物3-4-1的合成
Figure PCTCN2018079866-appb-000125
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物8.3得到化合物3-4-1(cis)。
m/z:[M+H] +554.1； 1H NMR(400MHz,DMSO-d 6):δ11.11(br.s,1H),10.23(br.s,1H),8.85(s,1H),7.70-7.75(m,2H),7.60(dd,J＝8.8,2.8Hz,1H),7.48(d,J＝8.0Hz,1H),6.99(d,J＝8.8Hz,1H),5.83-5.80(m,1H),5.48-5.52(m,1H),4.91(s,2H),4.23(d,J＝7.3Hz,4H),3.98(t,J＝4.4Hz,2H),3.34-3.45(m,1H),3.08-3.31(m,3H),2.86(s,3H),2.75(d,J＝4.0Hz,3H),2.06(br.s,2H),1.79(br.s,2H)。
实施例67：化合物3-4-2的合成
Figure PCTCN2018079866-appb-000126
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物17.3得到化合物3-4-2(cis)。
m/z:[M+H] +540.9； 1H NMR(400MHz,CDCl 3):δ8.87(s,1H),7.50-7.41(m,4H),7.35(dd,J＝2.8Hz,8.8Hz,1H),6.98(d,J＝8.8Hz,1H),6.12(dd,J＝7.2,18.4Hz,1H),5.54(dt,J＝7.2,11.2Hz,1H),4.78(s,2H),4.36(d,J＝7.6Hz,2H),4.22-4.15(m,2H),4.11-4.06(m,2H),3.72(s,2H),3.06-2.98(m,2H),2.43(s,3H),2.19-2.11(m,2H),1.98-1.89(m,2H)。
实施例68：化合物3-2-3的合成
Figure PCTCN2018079866-appb-000127
用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物3.5，步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物3-2-3(cis)。
m/z:[M+H] +536.6； 1H NMR(400MHz,CDCl 3):δ8.87(s,1H),7.73(d,J＝8.8Hz,1H),7.43(d,J＝8.8Hz,2H),7.30(d,J＝2.0Hz,1H),6.69(d,J＝8.4Hz,1H),6.22(dt,J＝8.0,11.2Hz,1H),5.88(dd,J＝8.8,20Hz,1H),4.80(s,2H),4.44(d,J＝8.0Hz,2H),4.15-4.02(m,2H),3.77(s,2H),2.62(s,2H),2.53(s,3H),2.44(dd,J＝6.4,10.8Hz,2H),1.07-0.83 (m,4H)。
实施例69：化合物3-2-5的合成
Figure PCTCN2018079866-appb-000128
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物10.10得到化合物3-2-5(cis)。
m/z:[M+H] +565.4； 1H NMR(400MHz,CD 3OD):δ8.74(s,1H),7.61(s,1H),7.49(d,J＝8.4Hz,1H),7.43(dd,J＝2.4,8.8Hz,1H),7.39(d,J＝8.4Hz,1H),6.73(d,J＝8.8Hz,1H),5.81(dt,J＝7.2,10.8Hz,1H),5.50-5.44(m,1H),4.71(s,2H),4.47(d,J＝14.8Hz,1H),4.33(d,J＝14.8Hz,1H),4.30(d,J＝7.2Hz,2H),4.01(d,J＝4.4Hz,2H),3.51(d,J＝12.4Hz,1H),3.30-3.22(m,2H),3.15(d,J＝12.4Hz,1H),2.05(s,2H),1.79(s,2H),1.35(t,J＝7.2Hz,3H),1.19-1.04(m,4H)。
实施例70：化合物3-2-6和3-2-7的合成
Figure PCTCN2018079866-appb-000129
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物10.11，最后一步用prep-HPLC纯化得到化合物3-2-6(cis)和3-2-7(cis)。
3-2-6：m/z:[M+H] +579.4； 1H NMR(400MHz,CD 3OD):δ8.74(d,J＝3.2Hz,1H),7.64(s,1H),7.49(d,J＝8.4Hz,1H),7.42(dd,J＝2.0,8.8Hz,1H),7.39(d,J＝8.4Hz,1H),6.74(d,J＝8.8Hz,1H),5.82-5.78(m,1H),5.49-5.46(m,1H),4.72(s,2H),4.50(d,J＝15.2Hz,1H),4.31(d,J＝7.2Hz,2H),4.28(d,J＝15.6Hz,1H),4.03(d,J＝4.4Hz,2H),3.59(dd,J＝6.4,12.8Hz,2H),3.00(d,J＝12.0Hz,1H),2.06(br.s,2H),1.80(br.s,2H),1.36(d,J＝6.4Hz,6H),1.19-0.90(m,4H)。
3-2-7：m/z:[M+H] +579.4； 1H NMR(400MHz,CD 3OD):δ8.74(d,J＝3.2Hz,1H),7.64(s,1H),7.49(d,J＝8.4Hz,1H),7.42(dd,J＝2.0,8.8Hz,1H),7.39(d,J＝8.4Hz,1H),6.74(d,J＝8.8Hz,1H),5.82-5.78(m,1H),5.46-5.49(m,1H),4.75(s,2H),4.50(d,J＝15.2Hz,1H),4.32-4.27(m,3H),4.04-4.03(m,2H),3.62-3.57(m,2H),3.01(d,J＝12.0Hz,1H),2.06(br.s,2H),1.80(br.s,2H),1.36(d,J＝6.4Hz,6H),1.11-0.90(m,4H)。
实施例71：化合物3-2-8的合成
Figure PCTCN2018079866-appb-000130
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物10.15得到化合物3-2-8(cis)。
m/z:[M+H] +601.0； 1H NMR(400MHz,CD 3OD):δ8.90(s,1H),7.71(d,J＝2.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.57(dd,J＝2.4,8.8Hz,1H),7.50(d,J＝8.4Hz,1H),6.89(d,J＝8.8Hz,1H),6.54(tt,J＝3.6,12.0Hz,1H),5.93-5.90(m,1H),5.63-5.59(m,1H),4.86(s,2H),4.69(s,2H),4.44(d,J＝7.6Hz,2H),4.16(t,J＝4.8Hz,2H),3.96(td,J＝3.6,14.8Hz,2H),3.62(s,2H),2.18(s,2H),1.93(s,2H),1.31-1.22(m,4H)。
实施例72：化合物3-5-1的合成
Figure PCTCN2018079866-appb-000131
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物11.5得到化合物3-5-1(cis)。
m/z:[M+H] +552.9； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.41(s,J＝8.4Hz,1H),7.35(s,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),6.02(dt,J＝7.6,10.4Hz,1H),5.47(dt,J＝7.2,11.2Hz,1H),4.69(s,2H),4.27(d,J＝7.2Hz,2H),4.10(t,J＝4.8Hz,2H),3.45(s,2H),2.37(s,3H),2.35(s,2H),2.06(br.s,2H),1.85(br.s,2H),1.24(s,6H)。
实施例73：化合物3-5-2的合成
Figure PCTCN2018079866-appb-000132
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为7-氨基-4,4-二甲基-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯得到化合物3-5(cis)。
将化合物3-5(150mg，0.235mmol)的三氟乙酸(1mL)和二氯甲烷(5mL)的混合物溶液在室温下搅拌1小时。然后将反应液减压浓缩，残留物用prep-HPLC纯化得化合物3-5-2(cis)(44.6mg，产率：25％)为白色固体。
m/z:[M+H] +539.4； 1H NMR(400MHz,DMSO-d 6):δ8.86(s,1H),7.68(d,J＝2.4Hz,1H),7.58(d,J＝8.0Hz,1H),7.57(d,J＝8.8Hz,1H),7.49(d,J＝8.0Hz,1H),7.43(d,J＝8.8Hz,1H),5.96-5.89(m,1H),5.62-5.52(m,1H),4.81(s,2H),4.41(d,J＝7.6Hz,2H),4.30(s,2H),4.16-4.12(m,2H),3.32(s,2H),2.21-2.17(m,2H),1.91(br.s,2H),1.43(s,6H)。
实施例74：化合物3-5-3的合成
Figure PCTCN2018079866-appb-000133
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物22.5得到化合物3-5-3(cis)。
m/z:[M+H] +553.4； 1H NMR(400MHz,DMSO-d 6):δ10.18(s,1H),9.81-9.79(m,1H),8.84(s,1H),7.78(s,1H),7.61(d,J＝8.0Hz,1H),7.54(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.14(d,J＝8.4Hz,1H),5.72-5.69(m,1H),5.56-5.52(m,1H),4.97(s,2H),4.24(d,J＝7.2Hz,2H),4.01(t,J＝4.4Hz,2H),3.56-3.31(m,2H),3.08-2.91(m,2H),2.85(d,J＝4.4Hz,3H),2.09-2.01(m,2H),1.89(br.s,2H),1.52(s,3H),1.47(s,3H)。
实施例75：化合物3-6-1的合成
Figure PCTCN2018079866-appb-000134
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为5-氨基-2-甲基异吲哚-1-酮得到化合物3-6-1(cis)。
m/z:[M+H] +524.8； 1H NMR(400MHz,DMSO-d 6):δ8.93(s,1H),8.10(s,1H),7.74-7.71(m,2H),7.59(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,1H),5.80-5.91(m,1H),5.49-5.60(m,1H),4.83(s,2H),4.43(s,2H),4.27(d,J＝7.2Hz,2H),3.98-4.01(m,2H),3.06(s,3H),2.08(br.s,2H),1.81(br.s,2H)。
实施例76：化合物3-7-1的合成
Figure PCTCN2018079866-appb-000135
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物13.2得到化合物3-7-1(cis)。
m/z:[M+H] +565.9； 1H NMR(400MHz,CDCl 3):δ8.86(s,1H),7.96(br.s,1H),7.56(s,1H),7.39(d,J＝8.4Hz,1H),7.32(d,J＝8.4Hz,1H),7.23-7.27(m,1H),7.19(d,J＝3.2Hz,1H),6.45(d,J＝3.2Hz,1H),6.16-6.14(m,1H),5.55(dt,J＝10.8,7.6Hz,1H),4.76(s,2H),4.35(d,J＝7.6Hz,2H),4.26(t,J＝7.2Hz,2H),4.14-4.21(m,2H),2.74(t,J＝7.2Hz,2H),2.34(s,6H),2.15(br.s,2H),1.93(br.s,2H)。
实施例77：化合物3-7-2的合成
Figure PCTCN2018079866-appb-000136
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.5得到化合物3-7-2(cis)。
m/z:[M+H] +592.1； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.84(s,1H),7.48(d,J＝8.0Hz,1H),7.43(br.s,1H),7.40(s,1H),7.32(d,J＝8.4Hz,1H),7.29-7.19(m,1H),6.38(d,J＝2.8Hz,1H),6.07-6.05(m,1H),5.47(dt,J＝7.6,10.8Hz,1H),4.68(s,2H),4.44-4.39(m,1H),4.26(d,J＝7.6Hz,2H),4.09(t,J＝4.8Hz,2H),3.06-3.02(m,1H),2.81(d,J＝11.6Hz,1H),2.27(s,3H),2.13(t,J＝10.4Hz,1H),2.06-1.97(m,4H),1.86-1.69(m,5H)。
实施例78：化合物3-7-3的合成
Figure PCTCN2018079866-appb-000137
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物15.1得到化合物6-1。
把三氟乙酸(2mL)滴加到化合物6.1(51mg，0.075mmol)的二氯甲烷(10mL)中，反应体系在室温下搅拌2小时，浓缩。残留物用prep-HPLC纯化得到化合物3-7-3(23.5mg，产率：39％)为白色固体。
m/z:[M+H] +577.8； 1H NMR(400MHz,DMSO-d 6):δ10.11(br.s,1H),8.83(s,1H),8.67(br.s,1H),8.43(br.s,1H),7.97(s,1H),7.64(d,J＝8.0Hz,1H),7.54(s,1H),7.50(d,J＝8.8Hz,1H),7.41-7.37(m,2H),6.45(d,J＝3.2Hz,1H),5.84-5.83(m,1H),5.51(dt,J＝7.2,10.8Hz,1H),4.84(s,1H),4.69-4.66(m,1H),4.23(d,J＝7.2Hz,2H),4.00-3.98(m,2H),3.49-3.40(m,2H),3.23-3.15(m,2H),2.14-2.09(m,6H),1.80(s,2H)。
实施例79：化合物3-7-4的合成
Figure PCTCN2018079866-appb-000138
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物16.2得到化合物3-7-4(cis)。
m/z:[M+H] +636.1； 1H NMR(400MHz,CDCl 3):δ8.87(s,1H),7.97(s,1H),7.57(d,J＝7.6Hz,1H),7.41(d,J＝8.0Hz,1H),7.34(d,J＝8.8Hz,1H),7.25(d,J＝2.0Hz,1H),7.22(d,J＝3.2Hz,1H),6.50(d,J＝3.2Hz,1H),6.25-6.15(m,1H),5.58-5.51(m,1H),4.77 (s,2H),4.44-4.39(m,3H),4.36(d,J＝7.2Hz,2H),4.18(t,J＝4.8Hz,2H),3.77(s,3H),3.05-2.99(m,2H),2.16-2.12(m,4H),2.01-1.94(m,4H)。
实施例80：化合物3-7-5的合成
Figure PCTCN2018079866-appb-000139
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.4得到化合物3-7-5(cis)。
m/z:[M+H] +592.0； 1H NMR(400MHz,DMSO-d 6):δ11.21(s,1H),10.21(s,1H),8.85(s,1H),7.97(s,1H),7.69-7.35(m,5H),6.44(d,J＝4.0Hz,1H),5.75-.5.67(m,1H),5.51(dt,J＝7.2,10.8Hz,1H),4.85(s,2H),4.69-4.63(m,1H),4.23(d,J＝7.6Hz,2H),3.99(t,J＝4.8Hz,2H),3.64-3.54(m,2H),3.27-3.21(m,2H),2.79(d,J＝4.8Hz,3H),2.52-47(m,2H),2.15-2.08(m,4H),1.80(br.s,2H)。
实施例81：化合物3-7-6的合成
Figure PCTCN2018079866-appb-000140
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.6得到化合物3-7-6(cis)。
m/z:[M+H] +577.9； 1H NMR(400MHz,CDCl 3):δ8.84(s,1H),7.93(br.s,1H),7.56(d,J＝8.4Hz,2H),7.44-7.36(m,3H),7.22(dd,J＝2.0Hz,9.2Hz,1H),6.45(d,J＝3.2Hz,1H),6.14(dd,J＝7.6,18.0Hz,1H),5.54(dt,J＝7.6,10.8Hz,1H),5.04-4.96(m,1H),4.74(s,2H),4.33(d,J＝7.6Hz,2H),4.21-4.12(m,2H),3.02-2.83(m,3H),2.58-2.46(m,2H),2.43(s,3H),2.18-2.05(m,3H),1.95-1.87(m,2H)。
实施例82：化合物3-7-7的合成
Figure PCTCN2018079866-appb-000141
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.7得到化合物3-7-7(cis)。
m/z:[M+H] +620.1； 1H NMR(400MHz,CD 3OD):δ8.68(s,1H),7.85(s,1H),7.43(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.33(d,J＝9.2Hz,1H),7.26(dd,J＝2.4,9.2Hz,1H),7.21(d,J＝3.2Hz,1H),6.37(d,J＝3.2Hz,1H),5.87-5.83(m,1H),5.47-5.44(m,1H),4.67(s,2H),4.63-4.62(m,1H),4.26(d,J＝7.2Hz,2H),4.00(t,J＝4.4Hz,2H),3.56-3.53 (m,3H),3.30-3.22(m,2H),2.29-2.04(m,4H),2.04(br.s,2H),1.77(br.s,2H),1.34(d,J＝6.8Hz,6H)。
实施例83：化合物3-7-8的合成
Figure PCTCN2018079866-appb-000142
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物18.6得到化合物3-7-8(cis)。
m/z:[M+H] +564.0； 1H NMR(400MHz,DMSO-d 6):δ10.51(br.s,1H),10.14(br.s,1H),8.84(s,1H),8.01(br.s,1H),7.65(d,J＝8.4Hz,1H),7.53(d,J＝8.4Hz,1H),7.49-7.38(m,3H),6.42(s,1H),5.94-5.77(m,1H),5.57-5.47(m,1H),4.85(s,2H),4.65-4.37(m,2H),4.23(d,J＝7.6Hz,4H),4.04-3.89(m,4H),3.02(s,3H),2.14-2.02(m,2H),1.86-1.73(m,2H)。
实施例84：化合物3-7-9的合成
Figure PCTCN2018079866-appb-000143
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物16.6得到化合物3-7-9(cis)。
m/z:[M+H] +683.9； 1H NMR(400MHz,DMSO-d 6):δ10.08(dd,J＝7.6,9.6Hz,1H),8.82(s,1H),7.94(s,1H),7.66(d,J＝8.4Hz,1H),7.53(d,J＝8.0Hz,1H),7.47(d,J＝3.2Hz,1H),7.45(s,1H),7.37(d,J＝8.8Hz,1H),6.39(d,J＝3.2Hz,1H),5.87-5.81(m,1H),5.52(dt,J＝6.8,11.2Hz,1H),4.82(s,2H),4.36-4.29(m,1H),4.22(d,J＝7.2Hz,2H),4.00-3.97(m,2H),3.34-3.24(m,2H),3.07(s,3H),3.02(s,2H),2.79(t,J＝6.8Hz,2H),2.33-2.22(m,2H),2.08-2.02(m,2H),1.92-1.84(m,4H),1.75-1.81(m,2H)。
实施例85：化合物3-7-10的合成
Figure PCTCN2018079866-appb-000144
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物16.4得到化合物3-7-10(cis)。
m/z:[M+H] +622.0； 1H NMR(400MHz,CDCl 3):δ8.81(s,1H),7.95(d,J＝1.6Hz,1H), 7.55(d,J＝7.6Hz,1H),7.39(d,J＝8.4Hz,1H),7.32(d,J＝8.8Hz,1H),7.26-7.21(m,2H),6.47(d,J＝2.8Hz,1H),6.14-6.10(m,1H),5.53(dt,J＝7.2,11.2Hz,1H),4.75(s,2H),4.33(d,J＝7.6Hz,2H),4.27-4.21(m,1H),4.16(t,J＝4.8Hz,2H),3.68(t,J＝5.6Hz,2H),3.13(d,J＝12.0Hz,2H),2.64(t,J＝5.6Hz,2H),2.40-2.31(m,2H),2.06-2.01(m,6H),1.92(br.s 2H)。
实施例86：化合物3-7-11的合成
Figure PCTCN2018079866-appb-000145
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物19.6得到化合物3-7(cis)。
将化合物3-7(130mg，0.19mmol)的二氯甲烷(10mL)和三氟乙酸(2mL)混合物在室温下搅拌2小时，将反应体系直接浓缩，残留物用prep-HPLC纯化得到化合物3-7-11(cis)(46.7mg，产率：43％)为黄色固体。
m/z:[M+H] +563.9； 1H NMR(400MHz,CD 3OD):δ8.69(s,1H),7.88(d,J＝2.0Hz,1H),7.45(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.33(d,J＝8.8Hz,1H),7.29(dd,J＝2.0,8.8Hz,1H),7.21(d,J＝2.8Hz,1H),6.43(d,J＝2.8Hz,1H),5.86(dd,J＝3.2,7.2Hz,1H),5.50-5.46(m,1H),4.70(s,2H),4.37(s,2H),4.29(d,J＝7.6Hz,2H),4.05-4.03(m,2H),2.07(br.s,2H),1.80(br.s,2H),1.06-0.94(m,4H).
实施例87：化合物3-7-12的合成
Figure PCTCN2018079866-appb-000146
然后用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物19.8得到化合物3-8(cis)。用化合物3-7-11的合成方法，用化合物3-8反应得到化合物3-7-12(cis)。
m/z:[M+H] +578.4； 1H NMR(400MHz,DMSO-d 6):δ10.12(s,1H),8.85-8.84(m,3H),8.01(s,1H),7.64(d,J＝8.4Hz,1H),7.53(d,J＝9.2Hz,2H),7.42(d,J＝8.8Hz,1H),7.41(s,1H),6.50(d,J＝3.2Hz,1H),5.84-5.82(m,1H),5.55-5.49(m,1H),4.85(s,2H),4.55(s,2H),4.23(d,J＝7.2Hz,2H),3.99(t,J＝4.0Hz,2H),2.51(s,3H),2.09(s,2H),1.80(s,2H),1.11-0.85(m,4H)。
实施例88：化合物3-7-13的合成
Figure PCTCN2018079866-appb-000147
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物20.2得到化合物3-7-13(cis)：
m/z:[M+H] +592.4； 1H NMR(400MHz,DMSO-d 6):δ10.81(s,1H),10.12(s,1H),9.40(s,1H),8.84(s,1H),7.86(s,1H),7.70(d,J＝7.6Hz,1H),7.52(d,J＝6.8Hz,1H),7.49(d,J＝4.8Hz,1H),7.25(d,J＝9.2Hz,1H),7.08(d,J＝2.0Hz,1H),5.88-5.80(m,1H),5.55-5.49(m,1H),4.84(s,2H),4.23(d,J＝7.2Hz,2H),4.00-3.98(m,2H),3.52(d,J＝10.8Hz,2H),3.17-3.09(m,2H),3.02-2.97(m,1H),2.83(d,J＝4.8Hz,3H),2.15-2.05(m,4H),1.93-1.81(m,4H)。
实施例89：化合物3-7-14的合成
Figure PCTCN2018079866-appb-000148
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.9得到化合物3-7-14(cis)：
m/z:[M+H] +621.4； 1H NMR(400MHz,CDCl 3):δ8.80(s,1H),7.99(s,1H),7.85(s,1H),7.45-7.32(m,4H),6.05-6.02(m,1H),5.51-5.44(m,1H),4.69(s,2H),4.34(d,J＝7.2Hz,1H),4.28(d,J＝7.6Hz,2H),4.10(t,J＝4.4Hz,2H),3.00(s,2H),2.77(s,1H),2.35--2.28(m,4H),2.06-2.00(m,4H),1.85(s,2H),1.04(d,J＝5.2Hz,6H)。
实施例90：化合物3-7-15的合成
Figure PCTCN2018079866-appb-000149
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物14.8得到化合物3-7-15(cis)：
m/z:[M+H] +621.3； 1H NMR(400MHz,CDCl 3):δ8.86(s,1H),8.33(d,J＝2.4Hz,1H),8.23(d,J＝2.0Hz,1H),7.44(d,J＝8.4Hz,1H),7.39(d,J＝3.2Hz,1H),7.35(d,J＝8.4Hz,1H),6.43(d,J＝3.2Hz,1H),6.13-6.06(m,1H),5.57-5.50(m,1H),4.84-4.74(m,1H),4.74(s,2H),4.33(d,J＝7.2Hz,2H),4.18-4.12(m,2H),3.09(d,J＝10.8Hz,2H),2.93-2.84(m,1H),2.53-2.49(m,2H),2.17-2.08(m,6H),1.94-1.87(m,2H),1.13(d,J＝6.4Hz,6H)。
实施例91：化合物3-7-16的合成
Figure PCTCN2018079866-appb-000150
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物24.3得到化合物3-7-16(cis)：
m/z:[M+H] +607.4； 1H NMR(400MHz,CDCl 3):δ8.89(s,1H),7.54(s,1H),7.48(d,J＝8.0Hz,1H),7.46(s,1H),7.37(d,J＝8.0Hz,1H),6.98(d,J＝3.2Hz,1H),6.56(s,1H),6.45(d,J＝4.4Hz,1H),6.08-6.05(m,1H),5.58-5.55(m,1H),4.77(s,2H),4.36(d,J＝8.8Hz,2H),4.19(dd,J＝4.4,4.8Hz,2H),3.70(s,3H),3.25(s,4H),2.67(s,4H),2.41(s,3H),2.14(m,2H),1.94(m,2H)。
实施例92：化合物3-7-17的合成
Figure PCTCN2018079866-appb-000151
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物26.6得到化合物3-7-17(cis)：
m/z:[M+H] +594.2； 1H NMR(400MHz,DMSO-d 6):δ10.12-10.13(br.s,1H),9.86(s,1H),8.87(s,1H),7.97(s,1H),7.76(s,1H),7.65-7.70(t,J＝8.8Hz,1H),7.47-7.49(d,J＝8.4Hz,1H),7.10-7.12(m,1H),6.94(s,1H),5.77-5.80(br.s,1H),5.51-5.55(m,1H),4.86-4.88(m,2H),4.39-4.41(t,J＝7.2Hz,2H),3.99-4.01(m,2H),3.81-3.84(m,2H),3.35(s,2H),3.27-3.32(m,2H),2.98-3.04(m,2H),2.87-2.89(m,3H),2.07(s,2H),1.80(s,2H)。
实施例93：化合物3-7-18的合成
Figure PCTCN2018079866-appb-000152
利用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物27.6得到化合物3-7-18(cis)：
m/z:[M+H] +609.2； 1H NMR(400MHz,CDCl 3):δ8.90(s,1H),7.74-7.80(m,2H),7.54-7.56(m,1H),7.45-7.47(m,1H),6.68(s,1H),6.05-6.08(m,1H),5.55-5.58(m,1H),4.81(s,2H),4.37-4.39(m,2H),4.17-4.19(m,2H),3.58-3.59(m,3H),3.10-3.30(br.s,1H),2.87(s,3H),2.62(s,3H),2.14(s,2H),1.94(s,2H),1.39-1.43(m,2H)。
实施例94：化合物3-8-1的合成
Figure PCTCN2018079866-appb-000153
用化合物3-3-1的合成方法，将步骤2中的化合物9.2替换为化合物21.1得到化合物3-8-1(cis)。
m/z:[M+H] +604.4； 1H NMR(400MHz,CD 3OD):δ8.86(s,1H),8.29(s,1H),7.69(s,1H),7.57(d,J＝8.8Hz,1H),7.52(d,J＝8.8Hz,1H),7.47(dd,J＝1.6,10.0Hz,1H),7.43(s,1H),7.21(dd,J＝2.4,8.8Hz,1H),7.12(d,J＝2.4Hz,1H),5.89-5.86(m,1H),5.51-5.47(m,1H),4.71(s,2H),4.30(d,J＝7.2Hz,2H),4.05(t,J＝4.4Hz,2H),3.87(d,J＝12.4Hz,2H),3.57(d,J＝11.2Hz,2H),3.28-3.23(m,2H),3.04-2.91(m,2H),2.89(s,3H),2.06(br.s,2H),1.81(br.s,2H)。
实施例95：化合物4-1-1的合成
Figure PCTCN2018079866-appb-000154
步骤1:将2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(324mg，1.46mmol)，化合物4.2(400mg，粗品)，醋酸铜(358mg，2.92mmol)和吡啶(3mL)加入到氯仿(30mL)中。反应体系在60℃下搅拌16小时。然后将反应液直接减压浓缩后用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物5-1(150mg，产率：23％)为无色液体。
步骤2：将Hoveyda-Grubbs试剂(30mg)加入到化合物5-1(150mg，0.343mmol)的二氯甲烷(30mL)溶液中，将反应体系在40℃下搅拌16小时。冷却，减压浓缩除去二氯甲烷，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得化合物5-2(50mg，产率：33％)为白色固体。
步骤3：将间氯过氧苯甲酸(25mg，0.122mmol)加入到化合物5-2(50mg，0.122mmol)的二氯甲烷(10mL)溶液中，反应体系在室温下搅拌1小时，减压浓缩除去二氯甲烷得到化合物5-3(78mg，粗品)为白色固体。
m/z:[M+H] +426.0
步骤4：将化合物5-3(78mg，粗品)、N,N-二异丙基乙胺(0.5mL)和化合物10.8(25mg，0.134mmol)的甲苯(10mL)溶液在70℃下搅拌过夜，减压浓缩除去溶剂，残留物用prep-HPLC纯化得化合物4-1-1(10mg，两步产率：15％)为白色固体。
m/z:[M+H] +549.8； 1H NMR(400MHz,CD 3OD):δ8.83(s,1H),7.60(s,1H),7.43-7.33 (m,2H),7.23(d,J＝8.4Hz,1H),6.67(d,J＝8.8Hz,1H),5.99-5.94(m,1H),5.78-5.71(m,1H),4.74(s,2H),4.33-4.28(m,1H),4.00-3.96(m,1H),3.67(s,3H),2.60(s,2H),2.47(s,3H),2.23-1.62(m,6H),1.03-0.90(m,4H)。
实施例96：化合物5-1-1的合成
Figure PCTCN2018079866-appb-000155
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物5.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺得到化合物5-1-1(cis)。
m/z:[M+H] +582.0； 1H NMR(400MHz,CDCl 3):δ8.78(s,1H),7.65(br.s,1H),7.51(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.12(s,1H),7.02(d,J＝8.0Hz,1H),6.82(d,J＝8.0Hz,1H),6.00-5.97(m,1H),5.49-5.46(m,1H),4.29(d,J＝4.0Hz,2H),4.08(t,J＝4.0Hz,2H),3.68(s,3H),3.03(s,4H),2.91(t,J＝8.0Hz,2H),2.70(dd,J＝4.0,8.0Hz,2H),2.59(s,4H),2.31(s,3H),2.02(s,2H),1.82(s,2H)。
实施例97：化合物6-1-1的合成
Figure PCTCN2018079866-appb-000156
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物6.1，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物13.2得到化合物6-1-1(cis)。
m/z:[M+H] +538.8； 1H NMR(400MHz,CD 3OD):δ8.80(s,1H),8.04(t,J＝8.0Hz,1H),7.96-7.88(m,1H),7.75(d,J＝7.6Hz,1H),7.63(d,J＝8.0Hz,1H),7.31-7.24(m,3H),6.36(s,1H),5.57-5.35(m,2H),4.32-4.29(m,2H),3.92-3.87(m,1H),3.66(s,1H),2.75(t,J＝6.8Hz,2H),2.33(s,6H),2.23-1.61(m,6H),1.44(s,3H)。
实施例98：化合物7-1-1的合成
Figure PCTCN2018079866-appb-000157
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物7.2，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物7-1-1(cis)。
m/z:[M+H] +578.9； 1H NMR(400MHz,DMSO-d 6):δ10.09(s,1H),8.84(s,1H),7.67(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,2H),7.35(dd,J＝1.6,8.4Hz,1H),6.65(d,J＝8.4 Hz,1H),5.87-5.82(m,1H),5.50(dt,J＝7.2,11.2Hz,1H),4.27(d,J＝7.2Hz,2H),3.99(t,J＝4.0Hz,2H),3.49(s,2H),2.42(s,2H),2.31(s,3H),2.08(s,2H),1.77(s,2H),1.48(s,6H),0.91-0.80(m,4H)。
实施例99：化合物7-2-1的合成
Figure PCTCN2018079866-appb-000158
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物7.2，将步骤4中的4-(N-甲基哌嗪)苯胺替换为3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺得到化合物7-2-1(cis)。
m/z:[M+H] +612.0； 1H NMR(400MHz,DMSO-d 6):δ10.05(s,1H),8.83(s,1H),7.64(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.40(s,1H),7.19(d,J＝8.4Hz,1H),6.82(d,J＝8.8Hz,1H),5.80-5.75(m,1H),5.54-5.49(m,1H),4.26(d,J＝7.2Hz,2H),3.99(s,2H),3.61(s,3H),2.91(s,4H),2.44(s,4H),2.21(s,3H),2.06(s,2H),1.77(s,2H),1.51(s,6H)。
实施例100：化合物8-1-1的合成
Figure PCTCN2018079866-appb-000159
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.2，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物8-1-1(cis)。
m/z:[M+H] +553.4； 1H NMR(400MHz,CDCl 3):δ8.84(s,1H),7.52-7.46(m,3H),7.32-7.29(m,2H),5.90-5.81(m,1H),5.78-5.66(m,1H),4.78-4.65(m,1H),4.58(d,J＝7.6Hz,2H),4.40-4.19(m,4H),3.95-3.90(m,1H),3.44-3.38(m,1H),3.03(s,6H),2.54(s,2H),1.25(d,J＝4.0Hz,6H)。
实施例101：化合物8-1-2的合成
Figure PCTCN2018079866-appb-000160
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.2，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物8-1-2(cis)。
m/z:[M+H] +550.8； 1H NMR(400MHz,DMSO-d 6):δ10.28(d,J＝3.6Hz,1H),10.23(d,J＝3.6Hz,1H),8.89(s,1H),7.68(d,J＝5.2Hz,1H),7.55(s,1H),7.50-7.46(m,1H),6.81(d,J＝8.8Hz,1H),5.81-5.76(m,1H),5.55-5.50(m,1H),4.43(d,J＝6.8Hz,2H),4.39- 4.35(m,2H),4.12-4.03(m,1H),3.59-3.44(m,3H),3.28(d,J＝8.4Hz,1H),2.93-2.85(m,4H),2.51-2.43(m,2H),2.36(d,J＝8.0Hz,1H),2.08-1.98(m,1H),1.31-1.14(m,4H)。
实施例102：化合物8-2-1的合成
Figure PCTCN2018079866-appb-000161
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物8-2-1(cis)。
m/z:[M+H] +537.4； 1H NMR(400MHz,DMSO-d 6):δ10.23-10.19(m,2H),8.84(s,1H),7.69(s,1H),7.55(dd,J＝2.4,8.8Hz,1H),7.26(d,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.84(d,J＝8.8Hz,1H),5.86-5.83(m,1H),5.50-5.47(m,1H),4.51(d,J＝15.6Hz,1H),4.43(d,J＝7.2Hz,1H),4.25-4.21(m,4H),3.54-3.49(m,4H),3.24(d,J＝12.8Hz,2H),2.94(d,J＝4.0Hz,3H),2.08(br.s,2H),1.71(br.s,2H),1.35-0.95(m,4H)。
实施例103：化合物8-2-2的合成
Figure PCTCN2018079866-appb-000162
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.3，将步骤4中的4-(N-甲基哌嗪)苯胺替换为3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺得到化合物8-2-2(cis)。
m/z:[M+H] +570.4； 1H NMR(400MHz,CDCl 3):δ8.75(s,1H),7.36(d,J＝4.0Hz,1H),7.27(s,1H),6.94(d,J＝8.0Hz,1H),6.88(dd,J＝2.4,8.4Hz,1H),6.80(d,J＝8.4Hz,1H),6.70(d,J＝8.0Hz,1H),5.88(dd,J＝7.2,11.2Hz,1H),5.44(dt,J＝7.2,11.2Hz,1H),4.30(d,J＝7.6Hz,2H),4.17(t,J＝4.8Hz,2H),3.68-3.60(m,5H),3.46(t,J＝4.8Hz,2H),3.00(br.s,4H),2.57(br.s,4H),2.31(s,3H),2.06(br.s,2H),1.66(s,2H)。
实施例104：化合物8-3-1的合成
Figure PCTCN2018079866-appb-000163
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物23.4，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物10.8得到化合物8-3-1(cis)。
m/z:[M+H] +552.8； 1H NMR(400MHz,CDCl 3):δ8.74(s,1H),7.85(t,J＝4.0Hz,1H),7.38(s,1H),7.33(d,J＝2.0Hz,1H),7.26(d,J＝8.4Hz,1H),7.20(d,J＝8.0Hz,1H),6.61(d,J＝8.4Hz,1H),6.46-6.39(m,1H),5.92-5.86(m,1H),4.80(s,4H),4.26(t,J＝4.4Hz,2 H),3.90(s,2H),3.67(s,2H),2.51(s,2H),2.42(s,3H),0.98-0.85(m,4H)。
实施例105：化合物9-1-1的合成
Figure PCTCN2018079866-appb-000164
利用化合物1-1-1的合成方法，将步骤1中的化合物1.1替换为化合物2.6，将步骤4中的4-(N-甲基哌嗪)苯胺替换为化合物11.5得到化合物9-1-1(cis)。
m/z:[M+H] +511.0； 1H NMR(400MHz,CDCl 3):δ8.75(s,1H),7.54(dd,J＝7.6,8.4Hz,1H),7.42(s,1H),7.33(s,1H),7.16-7.23(m,1H),6.99(d,J＝7.6Hz,1H),6.28(d,J＝8.4Hz,1H),6.11(dt,J＝7.6,10.8Hz,1H),5.44(dt,J＝7.6,10.8Hz,1H),4.31(d,J＝7.6Hz,2H),3.62(br.s,2H),3.47(s,2H),2.91(s,3H),2.37(s,3H),2.34(d,J＝2.4Hz,2H),2.07(br.s,2H),1.63-1.57(m,2H),1.24(s,6H)。
实施例106：2-((7-溴庚-2-炔-1-基)氧基)四氢-2H-吡喃的合成
Figure PCTCN2018079866-appb-000165
在-78℃的干冰丙酮浴冷却下将正丁基锂(12.6mL)滴加到哌喃(4g，28.5mmol)的无水四氢呋喃(40mL)溶液中，体系内温不超过-70℃，在此温度搅拌45分钟，然后将1,4-二溴丁烷(18.5g，85.6mmol)和六甲基磷酰三胺(8mL)的无水四氢呋喃(40mL)溶液滴加到上述反应液中，继续在此温度搅拌1小时，然后反应体系逐渐升至室温并搅拌过夜。冰浴条件下用饱和氯化铵水溶液淬灭反应，加水稀释后用乙酸乙酯萃取(30mL×3)，合并有机相并依次用水、饱和食盐水洗涤，分离有机相并浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)得到2-((7-溴庚-2-炔-1-基)氧基)四氢-2H-吡喃(7g，产率：87％)为油状液体。
利用2-((7-溴庚-2-炔-1-基)氧基)四氢-2H-吡喃的合成方法，将1,4-二溴丁烷替换为1,3-二溴丙烷得到2-((6-溴己-2-炔-1-基)氧基)四氢-2H-吡喃。
利用2-((7-溴庚-2-炔-1-基)氧基)四氢-2H-吡喃的合成方法，将1,4-二溴丁烷替换为1,5-二溴戊烷得到2-((8-溴辛-2-炔-1-基)氧基)四氢-2H-吡喃。
实施例107：化合物10-1-1的合成
Figure PCTCN2018079866-appb-000166
Figure PCTCN2018079866-appb-000167
步骤1：将化合物3-1(430mg，1.16mmol)加入到2-((6-溴己-2-炔-1-基)氧基)四氢-2H-吡喃(303mg，1.16mmol)和碳酸钾(481mg，3.48mmol)的N,N-二甲基甲酰胺(15mL)溶液中，将反应体系在室温下搅拌3小时，然后加水淬灭，水相用乙酸乙酯萃取(15mL×3)，合并有机相并依次用水、饱和食盐水洗涤，有机相浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝2/1)得到化合物6-2(333mg，产率：52％)为油状液体。
步骤2：将Pd(dppf)Cl 2的二氯甲烷络合物(10.4mg，0.013mmol)加入到化合物6-2(140mg，0.25mmol)和甲酸氨(32mg，0.51mmol)的1,4-二氧六环(5mL)溶液中，将反应体系用氮气置换三次，然后在氮气保护下升温至100℃并搅拌2小时。将反应液冷至室温，过滤、滤液浓缩,残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物6-3(40mg，产率：31％)为棕色固体。
步骤3：将对甲苯磺酸(3mg，0.016mmol)加入到化合物6-3(40mg，0.078mmol)的甲醇(5mL)溶液中，将反应体系升温至50℃并搅拌2小时。然后将反应液冷至室温，过滤、滤液浓缩，残留物用prep-TLC(二氯甲烷/甲醇＝10/1)纯化得到化合物6-4(15mg，产率：45％)为棕色固体。
m/z:[M+H] +427.2
步骤4：冰浴条件下，将甲基磺酰氯(31.1mg，0.27mmol)加入到化合物6-4(77mg，0.18mmol)和三乙胺(36.5mg，0.36mmol)的二氯甲烷(10mL)溶液中，反应体系在室温下搅拌1小时，加水淬灭反应，水相用二氯甲烷萃取(5mL×3)，合并有机相并依次用水、饱和食盐水洗涤，有机相浓缩得到化合物6-5(91mg，粗品)，不需纯化直接用于下一步反应。
步骤5：将碳酸钾(74.5mg，0.54mmol)加入到化合物6-5(91mg，0.18mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应体系室温搅拌过夜，加水淬灭反应，水相用乙酸乙酯萃取(15mL×3)，合并有机相并依次用水、饱和食盐水洗涤，有机相浓缩，残留物用硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化得到化合物6-6(20mg，产率：27％)为棕色固体。
m/z:[M+H] +409.2
步骤6：将间氯过氧苯甲酸(10mg，0.05mmol)加入到化合物6-6(20mg，0.05mmol) 的二氯甲烷(10mL)溶液中，反应体系室温搅拌2小时，然后直接浓缩得到化合物6-7(21.2mg，粗品)，不需纯化直接用于下一步反应。
m/z:[M+H] +425.1
步骤7：将化合物6-7(21.2mg，0.05mmol)加入到3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺(11.1mg，0.05mmol)和N,N-二异丙基乙胺(12.9mg，0.1mmol)的甲苯溶液(10mL)中，将反应体系升温至75℃并搅拌过夜，然后将反应体系直接浓缩，残留物用prep-HPLC纯化得到化合物10-1-1(9.3mg，产率：27％)为黄色固体。
m/z:[M+H] +582.2； 1H NMR(400MHz,DMSO-d 6):δ10.35(s,1H),9.52(s,1H),8.88(s,1H),7.67(d,J＝8.4Hz,1H),7.43(s,1H),7.39(d,J＝8.4Hz,1H),7.27(dd,J＝2.0,8.8Hz,1H),6.91(d,J＝8.8Hz,1H),4.81(s,2H),3.72(s,3H),3.51-3.43(m,4H),3.24-3.08(m,6H),2.91-2.82(m,5H),2.11(br.s,2H),1.88-1.83(m,2H)。
实施例108：化合物10-1-2的合成
Figure PCTCN2018079866-appb-000168
利用化合物10-1-1的合成方法，将步骤8中的3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺替换为4-(4-甲基哌嗪-1-基)苯胺得到化合物10-1-2。
m/z:[M+H] +552.2； 1H NMR(400MHz,CDCl 3):δ13.09-13.12(br.s,1H),8.37-8.52(d,J＝6.0Hz,1H),7.32-7.54(m,3H),7.25-7.28(m,1H),6.96-7.07(m,2H),4.67(s,2H),3.57-3.68(m,6H),3.05-3.08(br.s,2H),2.88(s,3H),2.02(s,2H),2.15(s,2H),1.41-1.43(m,2H),0.93-0.95(m,2H)。
实施例109：化合物10-1-3的合成
Figure PCTCN2018079866-appb-000169
利用化合物10-1-1的合成方法，将步骤2中的2-((6-溴己-2-炔-1-基)氧基)四氢-2H-吡喃替换为2-((7-溴庚-2-炔-1-基)氧基)四氢-2H-吡喃得到化合物10-1-3。
m/z:[M+H] +596.3； 1H NMR(400MHz,CDCl 3):δ12.89-12.91(br.s,1H),8.87(s,1H),7.39-7.48(m,3H),7.13-7.22(m,1H),6.92-6.94(d,J＝8.4Hz,1H),4.74(s,2H),4.55(s,2H),4.25-4.29(m,2H),3.83(s,3H),3.44-3.58(m,6H),3.14-3.19(br.s,2H),3.14(s,3H),2.36-2.39(t,J＝6.4Hz,2H),1.89-1.96(br.s,2H),1.62-1.66(m,2H)。
实施例110：化合物10-1-4的合成
Figure PCTCN2018079866-appb-000170
利用化合物10-1-1的合成方法，将步骤2中的2-((6-溴己-2-炔-1-基)氧基)四氢-2H-吡喃替换为2-((8-溴辛-2-炔-1-基)氧基)四氢-2H-吡喃得到化合物10-1-4。
m/z:[M+H] +610.4； 1H NMR(400MHz,CDCl 3):δ8.85(s,1H),7.54-7.56(br.s,1H),7.39-7.41(d,J＝8.0Hz,1H),7.28-7.29(m,1H),7.02-7.10(m,2H),6.86-6.88(d,J＝8.4Hz,1H),4.76(s,2H),4.47(s,2H),4.21-4.25(t,J＝6.8Hz,2H),3.73(s,3H),3.20(s,4H),2.53(s,3H),2.20(s,2H),1.93-1.98(m,2H),1.51-1.59(m,4H)。
实施例111：化合物7-2的合成
Figure PCTCN2018079866-appb-000171
步骤1：在-78℃的干冰丙酮浴冷却下将正丁基锂(22mL)滴加到哌喃(7g，50mmol)和N,N-二甲基丙烯基脲(640mg，5.0mmol)的无水四氢呋喃(100mL)溶液中，使内温不超过-70℃，反应体系在此温度下搅拌30分钟，然后将环氧丙烷(8.8g，200mmol)滴加到上述反应液中，继续在此温度下搅拌1小时，然后将反应体系缓慢升至室温搅拌过夜。反应体系在冰浴条件下用饱和氯化铵水溶液淬灭，加水并用乙酸乙酯(30mL×3)萃取，合并有机相并依次用水、饱和食盐水洗涤，有机相用无水硫酸钠干燥、过滤、浓缩，残留物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)得到5-((四氢-2H-吡喃-2-基)氧基)戊-3-炔-1-醇(5.0g，产率：54％)为无色油状物。
步骤2：在冰浴条件下将偶氮二甲酸二异丙酯(883mg，4.37mmol)加入到三苯基膦(1.15g,4.37mmol)的无水四氢呋喃(10mL)中，反应体系在0℃下搅拌5分钟，将5-((四氢-2H-吡喃-2-基)氧基)戊-3-炔-1-醇(804mg，4.37mmol)和化合物3.2(1.0g，4.37mmol)加入到上述反应中，室温搅拌过夜，将反应液直接浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化得到化合物7-1(1.7g，产率：100％)为油状液体。
步骤3：将化合物7-1(1.7g，4.37mmol)、2-烯丙基-6-(甲硫基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮(971.3mg，4.37mmol)、碘化亚铜(835mg，4.37mmol)、N,N-二甲基乙二胺(385mg，4.37mmol)和碳酸钾(1.21g，8.74mmol)溶入到1,4-二氧六环(40mL)和N,N-二甲基甲酰胺(4mL)的混合溶液中，反应体系在100℃下搅拌过夜。将反应液冷至室温，过滤、滤液浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物7-2(270mg，产率：12％)为油状液体。
m/z:[M+H] +537.1
实施例112：化合物10-1-5的合成
Figure PCTCN2018079866-appb-000172
利用化合物10-1-1的合成方法(步骤3～8)，将步骤3中的化合物6-2替换为化合物7-2得到化合物10-1-5。
m/z:[M+H] +568.2； 1H NMR(400MHz,CDCl 3):δ8.85(s,1H),7.38-7.48(m,3H),7.18-7.20(br.s,1H),6.92-6.94(d,J＝8.8Hz,1H),5.02-5.10(br.s,1H),4.77-4.78(d,J＝5.6Hz,2H),4.39-4.49(m,2H),3.80-3.89(m,4H),3.44-3.55(m,5H),3.15(br.s,2H),2.86(s,3H),2.53-2.57(m,2H),1.61-1.69(m,2H)。
生物测试实施例
实施例1：Wee1的酶活性检测
本发明中，运用ATP-Glo Max发光检测激酶试剂盒(Promega)进行Wee1酶催化试验。通过定量检测激酶反应后溶液中保留的ATP数量来评价激酶活性。试验中发光信号与ATP数量呈正比，与激酶活性呈反比。试验中化合物浓度范围为0.5nM～30μM。将化合物用10％DMSO溶解，取5μL的溶液加入到50μL的反应中，最终反应中DMSO的浓度为1％。30℃下反应50分钟。50μL反应混合液中包含40mM三羟甲基氨基甲烷，pH7.4，10mM MgCl 2，0.1mg/ml BSA，2mM DTT，0.1mg/ml Poly(Lys,Tyr)底物，10μM ATP及Wee1。酶促反应后，加入50μL ATP-Glo Max发光检测激酶试验溶液(Promega)，并在室温下孵化15分钟。使用酶标仪测量发光信号。在部分试验中，加入已知的Wee1抑制剂作为阳性对照。运用Graphpad软件分析发光数据。将Wee1缺失情况下的发光强度和Wee1存在情况下的发光强度差定义为100％活性(Lut–Luc)。利用化合物存在情况下的发光强度信号(Lu)，％活性按照以下方法计算：
％活性＝{(Lut–Lu)/(Lut–Luc)}×100％，其中Lu＝化合物的发光强度：
运用非线性回归分析绘制％活性值与对应系列化合物浓度量效曲线，方程式为Y＝B+(T-B)/1+10((LogEC 50-X)×Hill Slope)，Y＝活性百分比，B＝最小活性百分比，T＝最大活性百分比，X＝化合物和Hill坡度的对数＝坡度因子或Hill系数。IC 50值由引起半数最大活性百分比浓度决定。
Figure PCTCN2018079866-appb-000173
Figure PCTCN2018079866-appb-000174
实施例2：以p-CDK1Y15ELISA测试为基础的Wee1细胞活性检测
在此项发明中，运用细胞试验来评价化合物的生物活性。这一试验运用人类结肠腺癌细胞系WiDr开展。运用p-CDK1Y15ELISA试验法评估特定Wee1抑制剂的活性。详细试验方法描述如下：
将WiDr细胞放在含有10％FBS的Dulbecco’s Modified Eagle’s介质中培养，培养环境37℃及5％CO 2。化合物浓度范围0.5nM～30μM。将化合物稀释后加入至24孔板中，与细胞一起孵化24个小时。将DMSO作为阴性对照。在部分试验中加入已知的Wee1抑制剂作为阳性对照。根据生产厂商的指示，在p-CDK1Y15试验中，细胞被溶解并经过比色ELISA试剂盒测试判断p-CDK1Y15的数量。运用分光光度计测量光密度。运用 Graphpad软件分析OD数据，得到IC 50值和化合物的拟合曲线。
化合物编号 IC 50(nM)
3-1-1 336
3-2-2 139
3-2-3 326
3-3-2 114
3-3-7 250
3-3-13 68.8
3-7-3 80.6
3-7-5 38.8
3-7-7 51.4
3-7-13 114
3-7-16 31.4
AZD-1775 254
实施例3：细胞增殖试验
本发明中，运用细胞试验法来评价化合物的生物活性。MG63(ATCC CRL-1427)，人类骨肉瘤细胞系，将细胞种于Dulbecco’s Modified Eagle’s介质96孔板中培养，补给10％胎牛血清及1％(V/V)左旋谷酰胺，培养环境为37℃及5％CO 2。化合物浓度范围为4.5nM～30μM。将Wee1抑制剂储备液溶入DMSO并加入至指示浓度的介质中，孵化72小时。阴性对照细胞仅用vehicle进行处理。在部分试验中，加入已知的Wee1抑制剂作为阳性对照。在产品说明书的指示下运用细胞计数试剂盒-8(CCK-8，Sigma-Aldrich)来评价细胞活性。运用Graphpad软件对数据进行分析，并得到IC 50值及化合物拟合曲线。
化合物编号 IC 50(nM)
1-1-1 2405
1-2-1 593
2-2-1 439
3-1-1 1149
3-2-2 261
3-3-1 295
3-3-2 567
3-3-7 571
3-3-13 82.0
3-5-1 232
3-5-2 327
3-7-3 222
3-7-5 60.4
3-7-6 554
3-7-7 44.3
3-7-8 654
3-7-9 193
3-7-10 56.4
3-7-13 150
3-7-15 211
3-7-16 99.1
3-7-17 270
3-8-1 160
8-1-2 323
10-1-1 490
AZD1775 785
注：生物实施例1、2和3中的阳性对照为AZD1775，化学名称：2-烯丙基-1-(6-(2-羟基丙-2-基)吡啶-2-基)-6-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-吡唑[3,4-d]嘧啶-3(2H)-酮(2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one)。

Claims (20)

  1. 一种如式I所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
    Figure PCTCN2018079866-appb-100001
    其中，α键为单键、双键或三键；
    L为CRR’、O、或NR’；L 1为CRR 1、O或C(O)；W为N或CR 7；
    R和R 1分别为氢、卤素、-OR a、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基的取代基取代在任意位置；或者R和R 1与它们共同连接的C原子一起形成3-8元环烷基；
    R’为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-C(O)NR aS(O) 2R b、-S(O) 1-2R b、-S(O) 2NR aR b、-S(O) 2N(R a)C(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NR c)R a、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基；当所述烷基、环烷基、杂环烷基、环烷基烷基或杂环烷基烷基被取代时，可被1～3个选自：-OH、-NH 2、-NO 2、-SH、卤素、C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基的取代基取代在任意位置；
    R 2为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
    R 2和R’为独立取代基，或者，R 2和R’相互连接形成A环；所述A环为取代或未取代的C 3-15环烷基或取代或未取代的3-15元杂环烷基；所述A环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、硫代基、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷 基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 3为氢、卤素、羟基、氰基、硝基、巯基、氨基、烷基、烷氧基、烷硫基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、芳基、环烷基、杂环烷基、杂芳基、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-S(O) 0-2R c或-S(O) 2N(R c) 2；
    R 4和R 5分别独立地为氢、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的烷氨基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、烷氧基、烷氨基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；
    R 4和R 5为独立取代基，或者，R 4和R 5与其所连接的环原子一起形成B环，所述B环为取代或未取代的单环环烷基、取代或未取代的单环杂环烷基、取代或未取代的螺环基、取代或未取代的螺杂环基、取代或未取代的苯基、或取代或未取代的5-12元杂芳基；所述B环被取代时，可选择性地被如下一个或多个基团取代在任意位置：氧代基、卤素、-CN、-NO 2、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 6和R 7分别独立地为氢、卤素、羟基、巯基、氰基、硝基、羧基、氨基、烷基、烷 氧基、烷硫基、烷氨基、卤代烷基、卤代烷氧基、C 2-6炔基、C 2-6烯基、羟基烷基、氨基烷基、芳基、环烷基、取代或未取代的杂环烷基、或杂芳基；所述杂环烷基被取代时，可选择性被1～3个卤素、C 1-3烷基、C 1-3烷氧基和卤代C 1-3烷基取代在任意位置；
    每个R a和每个R b分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
    每个R c独立地选自氢、C 1-6烷基、卤代C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、3-8元杂环烷基C 1-6烷基、C 3-8环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；
    每个R d和每个R e分别独立地选自氢、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2- 6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述C 1-6烷基、C 1- 6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、或5-6元杂芳基为未取代或者选择性地被1～3个选自卤素、羟基、氨基、羧基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基和卤代C 1-6烷氧基中的一种或多种取代基取代在任意位置；
    m’为1～3的整数；
    m和n分别独立地为0～5的整数。
  2. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：α键为双键；m’为1。
  3. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：α键为三键；m’为1。
  4. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述R’为氢、-C(O)OR a、-C(O)R a、-C(O)NR aR b、-S(O) 1-2R b、-C(O)NHS(O) 2R b、-S(O) 2NR aR b、-S(O) 2NHC(O)R b、-S(O)(＝NCN)R a、-S(O)(＝NH)R a、C 1-6烷基、或C 3-8环烷基；
    和/或，R 2为H；
    和/或，R 3为H、F、-OH、或C 1-6烷氧基；
    和/或，R 4为H、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷胺基、取代或未取代的C 3-8环烷基、取代或未取代的3-9元杂环烷基、取代或未取代的苯基、取代或未取代的5-6元杂芳基、取代或未取代的C 3-8环烷基C 1-6烷基、取代或未取代的3-8元杂环烷基C 1-6烷基、取代或未取代的苯基C 1-6烷基、取代或未取代的5-6元杂芳基C 1-6烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基；
    和/或，R 5为H、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷胺基、取代或未取代的C 3-8环烷基、取代或未取代的3-9元杂环烷基、取代或未取代的苯基、取代或未取 代的5-6元杂芳基、取代或未取代的C 3-8环烷基C 1-6烷基、取代或未取代的3-8元杂环烷基C 1-6烷基、取代或未取代的苯基C 1-6烷基、取代或未取代的5-6元杂芳基C 1-6烷基、取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基。
  5. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：R 4为
    Figure PCTCN2018079866-appb-100002
    或，R 5为
    Figure PCTCN2018079866-appb-100003
    Figure PCTCN2018079866-appb-100004
  6. 如权利要求1所述的化合物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述R 2和R’相互连接形成A环；所述A环为取代或未取代的5-8元杂环烷基；
    和/或，所述R 4和R 5与其所连接的环原子一起形成B环，所述B环优选为取代或未取代的C 4-8单环环烷基、取代或未取代的4-8元单环杂环烷基、取代或未取代的C 7-12螺环基、取代或未取代的7-12元螺杂环基、取代或未取代的苯基、或取代或未取代的5-10元杂芳基。
  7. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：如式I所示化合物为如式II或II’所示化合物：
    Figure PCTCN2018079866-appb-100005
    其中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、-O-、-C(O)-、或-S(O) 1-2-；
    Z为H/H、O或S；
    R 8和R 9分别独立地为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、- NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1- 2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 8a分别独立地为氢、卤素或烷基；
    或者，R 8和R 8a分别与它们共同连接的C原子一起形成3-8元环烷基或杂环烷基；所述杂环烷基包含有1～2个选自N、O、S(O) 1-2的杂原子或基团；
    R 3、R 4、R 5、R 6、W、L 1、m、n、R c、R d、R e的定义如权利要求1所述。
  8. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述的如式I所示化合物为式I-1、I-2、I-3或I-6所示：
    Figure PCTCN2018079866-appb-100006
    I-1中，M为连接键、-CR 12R 12a-、-NR 13-、或-O-；
    U为连接键、-CR 12R 12a-、-NR 13-、-C(O)-、或-S(O) 1-2-；
    V为连接键、-NR 13-、-O-、或-CR 12R 12a-；
    R 10、R 11和R 12分别独立地为氢、卤素、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 10a、R 11a和R 12a分别独立地为氢、羟基、烷氧基、卤素或烷基；
    或者，R 10和R 10a、R 11和R 11a、R 12和R 12a分别与它们共同连接的C原子一起形成C 3- 8环烷基或3-8元杂环烷基；所述杂环烷基包含有1～2个选自N、O、S(O) 1-2的杂原子或基团；
    或者，R 10和R 10a、R 11和R 11a、R 12和R 12a分别与它们共同连接的C原子一起形成羰基；
    R 13为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的 芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    Figure PCTCN2018079866-appb-100007
    I-2中，T为N或CR 14’；
    R 14和R 14’分别独立地为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    Figure PCTCN2018079866-appb-100008
    I-3或I-6中，D为CR 17、或N；
    E为-CR 17R 17a-或-NR 15-；
    s为0、1或2；
    t为0、1或2；
    R 15为氢、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基 烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 16为氢、卤素、氧代基、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR d、-C(O)R d、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 17为氢、卤素、-CN、-SR d、-OR d、-OC(O)R d、-OC(O)OR d、-OC(O)NR dR e、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-NR dC(O)R e、-N(R d)C(O)OR e、-N(R d)C(O)NR dR e、-NR dS(O) 2R e、-NR dC(＝NH)R e、-NR dC(＝NH)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、-NR dS(O) 2NR dR e、取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的环烷基烷基、取代或未取代的杂环烷基烷基、取代或未取代的芳基烷基、取代或未取代的杂芳基烷基、取代或未取代的烯基、取代或未取代的炔基；所述烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、杂环烷基烷基、芳基烷基、杂芳基烷基、烯基或炔基被取代时，可选择性地被如下一个或多个基团取代在任意位置：卤素、烷基、卤代烷基、卤代烷氧基、羟基烷基、氨基烷基、烯基、炔基、-CN、-NO 2、-SR c、-OR c、-OC(O)R c、-OC(O)OR c、-OC(O)N(R c) 2、-C(O)OR c、-C(O)R c、-C(O)N(R c) 2、-N(R c) 2、-NHC(O)R c、-NHC(O)OR c、-NHC(O)N(R c) 2、-NHS(O) 2R c、-NHC(＝NH)R c、-NHC(＝NH)N(R c) 2、-S(O) 1-2R c、-S(O) 2N(R c) 2和-NHS(O) 2N(R c) 2；
    R 17a为氢、卤素或烷基。
  9. 如权利要求8所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：I-1中，R 10、R 10a和它们共同连接的C原子一起形成三元环、U为-CH 2-、R 11和R 11a为H；
    或，R 11、R 11a和它们共同连接的C原子一起形成三元环、U为-CH 2-、R 10和R 10a为H；
    或，R 11和R 11a为H、U为
    Figure PCTCN2018079866-appb-100009
    R 10和R 10a为H；
    或，R 11和R 11a分别为-CH 3、U为-CH 2-、R 10和R 10a为H；
    和/或，R 3为H。
  10. 如权利要求8所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：I-2中，T为N或CH；R 14为取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 3-8环烷基C 1-6烷基、或取代或未取代的3-8元杂环烷基C 1-6烷基；所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基可选择性地被如下1～3基团取代在任意位置：卤素、C 1-4烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、-CN、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-S(O) 1- 2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；R d和R e分别独立地为H或C 1-4烷基；
    或，T为CR 14’；R 14’为取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的3-8元杂环烷基、取代或未取代的C 3-8环烷基C 1-6烷基、或取代或未取代的3-8元杂环烷基C 1-6烷基；所述C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基可选择性地被如下1～3基团取代在任意位置：卤素、C 1-4烷基、卤代C 1-3烷基、卤代C 1-3烷氧基、羟基C 1-3烷基、氨基C 1-3烷基、-CN、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e和-NR dS(O) 2NR dR e；R d和R e分别独立地为H或C 1-4烷基；R 14为氢；
    或，T为CH；R 14为氢或C 1-6烷基；R 6为-N(CH 3) 2、哌嗪基、哌啶基、吡咯烷基或氮杂环丁烷基；其中所述哌嗪基、哌啶基、吡咯烷基或氮杂环丁烷基可以选择性被1个选自F、Cl、-CH 3、-OCH 3、-OCF 3、-CF 3、或-CHF 2的取代基取代在任意位置。
  11. 如权利要求8所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：I-3或I-6中，D为N或CH；
    和/或，R 6为H、F、Cl、-CN、-CH 3、-CH 2OH、或-CH 2OCH 3；
    和/或，R 15为H、-OR d、-C(O)OR d、-C(O)R d、-C(O)NR dR e、-S(O) 1-2R e、-S(O) 2NR dR e、取代或未取代的C 1-4烷基；所述C 1-4烷基可选择性地被如下1～3基团取代在任意位置：卤素、卤代C 1-3烷基、-CN、-OR c和-N(R c) 2；R c、R d和R e分别独立地为H或C 1-4烷基；
    和/或，R 16为H、-CH 3、-CH 2OH、或-CH 2OCH 3。
  12. 如权利要求7～11任一项所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述的如式I所示化合物为式II-1、II-2、II-3或II-6：
    Figure PCTCN2018079866-appb-100010
    II-1中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
    Z为H/H、O或S；
    Figure PCTCN2018079866-appb-100011
    II-2中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
    Z为H/H、O或S；
    Figure PCTCN2018079866-appb-100012
    II-3或II-6中，X和Y分别为连接键、-CR 8R 8a-、-NR 9-、O、-C(O)-、或-S(O) 1-2-；
    Z为H/H、O或S。
  13. 如权利要求12所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：X为连接键或O；Y为-CH 2-、-CH(CH 3)-、或-C(CH 3) 2-。
  14. 如权利要求1所述的如式I所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于：所述的如式(I)所示的化合物为如下任一结构：
    Figure PCTCN2018079866-appb-100013
    Figure PCTCN2018079866-appb-100014
    Figure PCTCN2018079866-appb-100015
    Figure PCTCN2018079866-appb-100016
    Figure PCTCN2018079866-appb-100017
    Figure PCTCN2018079866-appb-100018
    Figure PCTCN2018079866-appb-100019
    Figure PCTCN2018079866-appb-100020
    其中，
    Figure PCTCN2018079866-appb-100021
    表示双键构型为顺式、反式，或者顺反异构的混合物。
  15. 一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如权利要求1～14任一项所述的如式I所述化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；所述的药学上可接受的辅料为药学上可接受的载体、稀释剂和/或赋形剂。
  16. 如权利要求1～14任一项所述的如式I所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求15所述药物组合物在制备Wee1抑制剂中的应用。
  17. 如权利要求1～14任一项所述的如式I所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求15所述药物组合物在制备癌症的化学疗法或放射性疗法的增敏剂中的应用。
  18. 如权利要求1～14任一项所述的如式I所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求15所述药物组合物在制备治疗和/或缓解由Wee1介导的相关疾病的药物中的应用。
  19. 如权利要求18所述的应用，其特征在于：所述药物进一步和一种或多种其它种类的治疗剂和/或治疗方法联合使用，用于治疗和/或缓解由Wee1介导的相关疾病。
  20. 如权利要求18或19任一项所述的应用，其特征在于：所述的由Wee1介导的相关疾病为癌症。
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