WO2021129584A1 - Pd-l1拮抗剂化合物 - Google Patents

Pd-l1拮抗剂化合物 Download PDF

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WO2021129584A1
WO2021129584A1 PCT/CN2020/138157 CN2020138157W WO2021129584A1 WO 2021129584 A1 WO2021129584 A1 WO 2021129584A1 CN 2020138157 W CN2020138157 W CN 2020138157W WO 2021129584 A1 WO2021129584 A1 WO 2021129584A1
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compound
alkyl
alkylene
esi
cycloalkyl
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PCT/CN2020/138157
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English (en)
French (fr)
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俞智勇
李磐
徐贝帝
周瑜
庞伟
温俏东
时永强
孙钊
吕萌
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杭州阿诺生物医药科技有限公司
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Priority to BR112022012737A priority Critical patent/BR112022012737A2/pt
Priority to KR1020227025665A priority patent/KR20220121254A/ko
Priority to MX2022008016A priority patent/MX2022008016A/es
Priority to AU2020413555A priority patent/AU2020413555A1/en
Priority to CN202080079596.2A priority patent/CN115066423B/zh
Priority to EP20907871.6A priority patent/EP4083032A4/en
Application filed by 杭州阿诺生物医药科技有限公司 filed Critical 杭州阿诺生物医药科技有限公司
Priority to JP2022522850A priority patent/JP2022552693A/ja
Priority to US17/780,979 priority patent/US20230054028A1/en
Priority to CA3160606A priority patent/CA3160606A1/en
Priority to IL294209A priority patent/IL294209A/en
Publication of WO2021129584A1 publication Critical patent/WO2021129584A1/zh
Priority to ZA2022/06266A priority patent/ZA202206266B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a PD-L1 antagonist compound and a method of using it to treat/prevent immune related disorders.
  • Tumor immunotherapy was named the most important scientific breakthrough of the year by the "Science” magazine in 2013 due to its excellent efficacy and innovation. Tumor immunotherapy is expected to become an innovation in the field of tumor treatment following surgery, chemotherapy, radiotherapy, and targeted therapy. Tumor immunotherapy is the application of immunological principles and methods to improve the immunogenicity of tumor cells and the sensitivity to effector cell killing, stimulate and enhance the body's anti-tumor immune response, and use immune cells and effector molecules to infuse the host body to cooperate with the body The immune system kills tumors and inhibits tumor growth. Tumor immunotherapy has attracted much attention recently and is the focus of the field of tumor treatment. In recent years, the good news of tumor immunotherapy has continued. At present, it has shown strong anti-tumor activity in the treatment of some tumor types such as melanoma and non-small cell lung cancer, and tumor immunotherapy drugs have been approved by the US FDA ( Food and Drug Administration, FDA) approved clinical applications.
  • FDA Food and Drug Administration
  • PD-1 (programmed death 1) is a member of the CD28 superfamily. Immunomodulation targeting PD-1 is of great significance in anti-tumor, anti-infection, anti-autoimmune diseases and organ transplant survival. Its ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.
  • PD-L1 (programmed cell death-Ligand 1) is the first type transmembrane protein with a size of 40kDa. Under normal circumstances, the immune system will respond to foreign antigens that accumulate in the lymph nodes or spleen, and promote the proliferation of antigen-specific T cells. The combination of PD-1 and PD-L1 can transmit inhibitory signals and reduce the proliferation of T cells.
  • T cells One way for tumor cells to evade destruction by T cells is by producing PD-L1 on its surface.
  • T cells recognizes PD-L1, it can transmit inhibitory signals, and T cells cannot detect tumor cells and send out attack signals to tumor cells.
  • PD-1 is a new type of immunotherapy that relieves tumor cells to evade the immune system.
  • the mechanism of PD-1 immunotherapy is to design specific protein antibodies against PD-1 or PD-L1, prevent the recognition process of PD-1 and PD-L1, and partially restore the function of T cells, so that T cells can kill tumor cells .
  • PD-1 is expressed in activated T cells, B cells and myeloid cells, and it has two ligands, namely PD-L1 and PD-L2.
  • PD-L1/L2 is expressed in antigen presenting cells, and PD-L1 is also expressed in a variety of tissues.
  • the combination of PD-1 and PD-L1 mediates the co-inhibitory signal of T cell activation, regulates T cell activation and proliferation, and plays a negative regulatory role similar to CTLA-4.
  • the Chinese scientist Lie Ping's laboratory first discovered that PD-L1 is highly expressed in tumor tissues and regulates the function of tumor infiltrating CD8 T cells. Therefore, immune regulation targeting PD-1/PD-L1 is of great significance to anti-tumor.
  • mAbs therapeutic monoclonal antibodies
  • finding convenient oral small molecule compounds for cancer patients to target and suppress immune checkpoints is also a frontier field of tumor immunotherapy.
  • Small molecule compounds can pass through the cell membrane and act on intracellular targets, so they have a wide range of applications.
  • small molecules often have good bioavailability and compliance after chemical modification, which can effectively avoid the decomposition and inactivation of enzymes in the digestive intestine.
  • the research on small molecules is also quite mature in many aspects such as production technology, dosage form design and drug delivery methods.
  • mAbs monoclonal antibodies
  • small molecule drugs which are more suitable for oral administration, can reduce serious immune-related adverse events.
  • small molecule drug inhibitors have many other advantages, such as more economical and stable manufacturing costs, and better permeability to organs and tumors. Taking into account the many advantages of the pharmacokinetic properties of small molecules, it will show flexibility in dosage in monotherapy or other combination schemes.
  • the small molecule compounds of the present invention can provide a compelling treatment option for patients and doctors.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, isotope derivative, hydrate, isomer, solvate, or metabolite thereof:
  • L 1 is selected from the group: -CR A R B -and -C(O)-;
  • L 2 and L 3 are selected from groups: -(CR C R D ) p , -(CR C R D ) p -NR a -(CR C R D ) q -, -(CR C R D ) p -O -(CR C R D ) q -and -C(O)-;
  • W 1 and W 2 each independently represent CR L or N;
  • R 1 each independently represents hydrogen, halogen, nitro, cyano or -NR a R b or C 1 -C 6 alkyl, C 3 -C 6 ring substituted with 0, 1, 2 or 3 substituents Alkyl, -O (C 1 -C 6 alkyl), -O (C 0 -C 6 alkylene) (C 5 -C 10 aryl), -O (C 0 -C 6 alkylene) ( 5-10 membered heteroaryl), -O (C 0 -C 6 alkylene) (C 3 -C 6 cycloalkyl) or -O (C 0 -C 6 alkylene) (3-6 membered hetero Cycloalkyl); wherein the substituents are selected from: -OR a , cyano, oxo, halogen, C 1 -C 6 alkyl, -(C 1 -C 6 alkylene) OR a , cyano C 1 -C 6 alkyl, C
  • R 2, R 3, R 4 , R 5 each independently represent hydrogen, halogen, nitro, cyano, -NR a R b, -SO 2 R a, -S (O) R a, -P (O) R a R b , C 1 -C 6 alkyl, -O (C 1 -C 6 alkyl), -O (C 3 -C 6 cycloalkyl), halo (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl;
  • Cy represents a benzene ring or a six-membered heteroaryl group substituted with 0, 1, 2, or 3 R 6 , wherein the six-membered heteroaryl group may optionally contain 1 or 2 nitrogen atoms; wherein the R 6 represents hydrogen, halogen, nitro, cyano, -NR a R b, -SO 2 R a, -S (O) R a , or -P (O) R a R b is 2 or 3, or C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -O (C 1 -C 6 alkyl), -O (C 0 -C 6 alkylene) (C 5- C 10 aryl), -O (C 0 -C 6 alkylene) (5-10 membered heteroaryl), -O (C 0 -C 6 alkylene) (C 3 -C 6 cycloalkyl) Or -O(C 0 -C 6 alkylene) (
  • R L represents: hydrogen, C 1 -C 6 alkyl, -O (C 1 -C 6 alkyl), -O (C 3 -C 6 cycloalkyl), halogen, nitro, cyano,- NR a R b , halogenated (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl;
  • T and A each independently represent: -(C 1 -C 6 alkyl), -(C 0 -C 6 alkylene) -(C 3 -C 12 cycloalkyl), -(C 0 -C 6 alkylene) -(3-12 membered heterocycle), -(C 0 -C 6 alkylene) -(C 6 -C 10 aryl) or- (C 0 -C 6 alkylene)-(5-10 membered heteroaryl), wherein the substituent is selected from: cyano, oxo, halogen, C 1 -C 6 alkyl, -(C 0- C 6 alkylene) OR a , cyano C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, -(C 0 -C 6 alkylene ) C (O) R a, - (C 0 -C 6 alkylene) C
  • R A and R B each independently represent: hydrogen, C 1 -C 6 alkyl, -(C 0 -C 3 alkylene) (C 3 -C 12 cycloalkyl), -(C 0 -C alkylene) (3-12 membered heterocyclyl), halo (C 1 -C 6 alkyl), or halo, or R a and R B together with the carbon atom to which they are attached are connected to form a 3-6 membered ring;
  • R C and R D each independently represent: hydrogen, C 1 -C 6 alkyl, -(C 0 -C 3 alkylene) (C 3 -C 12 cycloalkyl), -(C 0 -C 3 alkylene) Alkyl) (3-12 membered heterocycle), halo (C 1 -C 6 alkyl) or halogen, or R C and R D together with the carbon atoms to which they are connected together form a 3-6 membered ring;
  • R a and R b each independently represent: hydrogen, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl), -(C 0 -C 6 alkylene) OH, -(C 0- C 3 alkylene) (C 3 -C 12 cycloalkyl), -(C 0 -C 3 alkylene) (3-12 membered heterocycle), -(C 0 -C 3 alkylene) (C membered ring 6 -C 10 aryl), - (C 0 -C 3 alkylene) (5-10 membered heteroaryl ring), or halo (C 1 -C 6 alkyl), or R a and R b together with its The atoms connected together form a 3-6 membered ring;
  • n and o each independently represent 0, 1 or 2;
  • p and q each independently represent 0, 1, 2, or 3.
  • the compound of formula (I) has the following structure of formula (II):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , T, A, W 1 , W 2 , m, o are as defined in formula (I);
  • r 0, 1, 2 or 3.
  • the compound of formula (I) has the following structure of formula (III):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , T, A, W 1 , W 2 , m, o are as defined in formula (I);
  • W 3 represents CR M or N
  • R M represents: hydrogen, C 1 -C 6 alkyl, -O (C 1 -C 6 alkyl), -O (C 3 -C 6 cycloalkyl), halogen, nitro, cyano,- NR a R b , halogenated (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl;
  • r is represented as 0, 1, or 2.
  • the compound of formula (I) has the following structure of formula (IV):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L 2 , L 3 , T, A, W 1 , W 2 , m, o are as defined in formula (I);
  • W 4 represents CR N or N
  • R N represents: hydrogen, C 1 -C 6 alkyl, -O (C 1 -C 6 alkyl), -O (C 3 -C 6 cycloalkyl), halogen, nitro, cyano,- NR a R b , halogenated (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl;
  • r is represented as 0, 1, or 2.
  • L 1 is preferably selected from -CR A R B -, wherein R A and R B are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl and halo (C 1 -C 6 alkyl), preferably hydrogen.
  • L 2 and L 3 are each preferably independently selected from -CR C R D -and -CR C R D -NR a -(CR C R D ) q -, wherein q is selected from 0 , 1 or 2, wherein R C and R D are each independently selected from hydrogen, halogen, C 1 -C 6 alkyl and halo (C 1 -C 6 alkyl), preferably hydrogen; R a is each independently selected From hydrogen, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl) and -(C 0 -C 3 alkylene) C 3 -C 12 cycloalkyl.
  • W 1 and W 2 each preferably independently represent CH or N.
  • W 3 preferably represents CH or N.
  • W 4 preferably represents CH or N.
  • T and A each preferably independently represent substituted with 0, 1, 2 or 3 substituents: -(C 1 -C 6 alkyl), -(C 0 -C 6 Alkyl)-(C 3 -C 12 cycloalkyl) or -(C 0 -C 6 alkylene)-(3-12 membered heterocycle), wherein the substituent is selected from: cyano, oxo, Halogen, C 1 -C 6 alkyl, -(C 0 -C 6 alkylene) OR a , C 1 -C 6 cyanoalkyl, halo (C 1 -C 6 alkyl), C 3 -C 8 cycloalkyl, - (C 0 -C 6 alkylene) C (O) R a, - (C 0 -C 6 alkylene) C (O) OR a, - (C 0 -C 6 alkenylene Group) C(O)OR a ,
  • T and A each preferably independently represent a C 1 -C 6 alkyl group, a C 3 -C 12 cycloalkyl group or a 3-12 membered heterocyclic group substituted by 0, 1 or 2 substituents.
  • Ring wherein the substituent is selected from: cyano, oxo, -OR a , -(C 0 -C 6 alkylene)C(O)OR a , -(C 0 -C 6 alkenylene)C (O)OR a , -NR a C(O)R b , -NR a SO 2 R b and -C(O)NR a SO 2 R b , where R a and R b each independently represent hydrogen, C 1- C 6 alkyl or halo (C 1 -C 6 alkyl).
  • T and A each preferably independently represent the following groups optionally substituted with 0, 1 or 2 substituents: Wherein the substituent is selected from: C 1 -C 6 alkyl, -OR a , -(C 0 -C 6 alkylene) C (O) OR a and -(C 0 -C 6 alkenylene) C (O) OR a , where Ra represents hydrogen or a C 1 -C 6 alkyl group, preferably hydrogen, where ⁇ represents 1, 2 or 3.
  • T and A each preferably independently represent the following groups:
  • T and A each preferably independently represent the following groups optionally substituted with 0, 1 or 2 substituents: Wherein said substituents are selected from: C 1 -C 6 alkyl, -OR a, and halo, wherein, R e, R a each independently represent hydrogen or C 1 -C 6 alkyl; wherein ⁇ represents 1, 2 , 3, or 4.
  • T and A each preferably independently represent Wherein, R e represents hydrogen or C 1 -C 6 alkyl; where ⁇ represents 1, 2, 3 or 4.
  • T and A each preferably independently represent:
  • R 1 preferably represents -O (C 1 -C 6 alkyl), -O (C 0 -C 6 alkylene) substituted by 0, 1, 2 or 3 substituents (C 5 -C 10 aryl), -O (C 0 -C 6 alkylene) (5-10 membered heteroaryl), -O (C 0 -C 6 alkylene) (C 3 -C 6 Cycloalkyl) or -O(C 0 -C 6 alkylene) (3-6 membered heterocycloalkyl); wherein the substituent is selected from: cyano, oxo, halogen, cyano C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • R 2 preferably represents hydrogen, halogen, nitro, cyano, -SO 2 R a, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl; wherein Ra represents hydrogen, C 1 -C 6 alkyl or halo (C 1 -C 6 alkyl).
  • R 3 and R 4 each preferably independently represent hydrogen, halogen, nitro or cyano.
  • R 5 preferably represents hydrogen, halogen, nitro, cyano, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl) or C 3 -C 6 cycloalkyl .
  • R 6 preferably represents hydrogen, halogen, nitro, cyano, -SO 2 R a, C 1 -C 6 alkyl, halo (C 1 -C 6 alkyl), or C 3 -C 6 cycloalkyl or substituted with 0, 1, 2 or 3 substituents -O (C 1 -C 6 alkyl), -O (C 0 -C 6 alkylene) (C 5 -C 10 aryl), -O (C 0 -C 6 alkylene) (5-10 membered heteroaryl), -O (C 0 -C 6 alkylene) (C 3 -C 6 cycloalkyl) or -O(C 0 -C 6 alkylene) (3-6 membered heterocycloalkyl); wherein the substituent is selected from: cyano, oxo, halogen, cyano C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • RL preferably represents hydrogen or halogen.
  • R M and R N each preferably independently represent hydrogen.
  • the present invention provides a compound having the following structure:
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention, and optionally further comprising another therapeutic agent and/or immune checkpoint inhibitor.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the present invention also provides a compound of the present invention or a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for the prevention or treatment of diseases or disorders that can be treated by inhibiting the binding of PD-L1 and PD-1 Applications.
  • the disease is selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.
  • the present invention also provides the use of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for preventing or treating diseases or disorders that are responsive to inhibiting the binding of PD-L1 and PD-1.
  • the disease or condition is selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.
  • the present invention also provides a prevention or treatment of diseases or disorders that can be treated by inhibiting the binding of PD-L1 and PD-1 (preferably tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases)
  • the method comprising administering the compound of the present invention or the pharmaceutical composition of the present invention to a mammal in need thereof.
  • the present invention also provides a method for preventing or treating diseases or disorders that are responsive to inhibiting the binding of PD-L1 and PD-1, which comprises administering the compound of the present invention or the pharmaceutical combination of the present invention to a mammal in need thereof Things.
  • the term "disease or disorder that is responsive to inhibiting the binding of PD-L1 and PD-1” means any disease or disorder that can change the course of the disease by inhibiting the binding of PD-L1 and PD-1, or can cause disease, The mitigation, suppression, elimination, and improvement effects of diseases, disorders, etc., or such diseases or diseases can be prevented.
  • the disease or disorder responsive to inhibiting the binding of PD-L1 and PD-1 is selected from tumors, cancers, viral infections, inflammation-related diseases and autoimmune diseases.
  • the present invention also provides a method for inhibiting the binding of PD-L1 and PD-1, which comprises exposing the compound of the present invention or the pharmaceutical composition of the present invention to the PD-L1 and/or PD-1.
  • the pharmaceutical composition and the use and method of using the compound of the present invention or the pharmaceutical composition, the compound of the present invention especially includes the form of a pharmaceutically acceptable salt thereof.
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , Pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis,
  • cancer or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , Colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as Glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neurona
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another therapeutic agent or immune checkpoint inhibitor for the treatment of cancer or tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.
  • therapeutic agents for the treatment of cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmos Stine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, sulfhydryl Purine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectidine, dactinomycin, doxorubicin, Epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, t
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another therapeutic agent for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced Therapeutic effect.
  • therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases may include, but are not limited to, steroidal drugs (e.g., prednisone, prednisone, methylprednisolone Pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (e.g., Etanercept, Infliximab, Adali Monoclonal antibodies, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebas , Ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.
  • steroidal drugs e.g
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2,000 mg/kg body weight/day in the case of mammals including humans (body weight of about 70 kg). It is preferably 1 to 1,000 mg/kg body weight/day, and administered in a single or 4 divided doses per day, or following/not following a predetermined time.
  • the dosage of the active ingredient can be adjusted according to a number of relevant factors (such as the condition of the subject to be treated, the type and severity of the disease, the frequency of administration, and the doctor's opinion). In some cases, an amount less than the above dosage may be appropriate. If it does not cause harmful side effects, an amount larger than the above dose can be used and the amount can be administered in divided doses per day.
  • the present invention also provides a method for inhibiting PD-L1, which comprises exposing the compound of the present invention, its pharmaceutically acceptable salt or the pharmaceutical combination of the present invention to the PD-L1.
  • the pharmaceutically acceptable salt or pharmaceutically acceptable salt of the present invention can be formed using inorganic or organic acid.
  • the "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to such a salt: Within the scope of reasonable medical judgment, it is applicable to tissues in contact with humans and lower animals without inappropriate toxicity, irritation, allergic reactions, etc., which can be called a reasonable benefit/risk ratio.
  • the salt can be prepared in situ during the final isolation and purification of the compound of the present invention, or prepared separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may include metal salts, such as alkali metal salts (such as sodium or potassium salts) and alkaline earth metal salts (such as calcium or magnesium salts).
  • metal salts such as alkali metal salts (such as sodium or potassium salts) and alkaline earth metal salts (such as calcium or magnesium salts).
  • pharmaceutically acceptable non-toxic acid addition salts are amino acids with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, Citric acid, succinic acid, or malonic acid), or by using other methods in the prior art such as ion exchange.
  • salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, gluconate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, Persulfate, 3-phen
  • Representative alkali metal or alkaline earth metal salts include sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt and the like.
  • Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts and ammonium cations formed with counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower Alkyl sulfonate and aryl sulfonate.
  • the pharmaceutically acceptable salt of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in an organic solvent miscible with water (such as acetone, methanol, ethanol, and acetonitrile), and adding an excessive amount of organic acid or An aqueous mineral acid solution is used to precipitate the salt from the resulting mixture, the solvent and remaining free acid are removed therefrom, and then the precipitated salt is separated.
  • an organic solvent miscible with water such as acetone, methanol, ethanol, and acetonitrile
  • the precursor or metabolite of the present invention may be a precursor or metabolite known in the art, as long as the precursor or metabolite is transformed into a compound by metabolism in the body.
  • prodrugs refer to those prodrugs of the compounds of the present invention. Within the scope of reasonable medical judgment, they are suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., It can be called a reasonable benefit/risk ratio and is effective for its intended use.
  • prodrug refers to a compound that is rapidly transformed in the body to produce the parent compound of the above formula, for example, by metabolism in the body, or N-demethylation of the compound of the present invention.
  • the "solvate” in the present invention means the physical association of the compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to be separated.
  • the solvent molecules in the solvate can be arranged in regular and/or disordered arrangements.
  • Solvates can contain stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrate, ethanolate, methanolate, and isopropanolate. Solvation methods are well known in the art.
  • conformational isomerism refers to a stereoisomerism in which the rotation or distortion of carbon and carbon single bonds in organic molecules with a certain configuration causes different arrangements of atoms or groups of atoms in space.
  • Commonly used are alkanes and rings. The structure of alkane compounds, such as the chair conformation and the boat conformation that appear in the cyclohexane structure.
  • Stepoisomers refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and Single diastereomer.
  • the compounds of the present invention may have asymmetric centers, and each asymmetric center will produce two optical isomers.
  • the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure ones.
  • the compounds of the present invention may exist in the form of tautomers, which have different hydrogen attachment points through one or more double bond displacements. For example, the ketone and its enol form are keto-enol tautomers.
  • the “isotopic derivative” of the present invention refers to a molecule whose compound is labeled with an isotope in this patent.
  • the isotopes commonly used as isotope labels are: hydrogen isotopes: 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I And 125 I; nitrogen isotope: 13 N and 15 N; oxygen isotope: 15 O, 17 O and 18 O and sulfur isotope 35 S.
  • These isotope-labeled compounds can be used to study the distribution of medicinal molecules in tissues.
  • deuterium 2 H and carbon 13 C because they are easy to label and convenient to detect, they are more widely used.
  • the substitution of certain heavy isotopes, such as deuterium ( 2 H) can enhance the stability of metabolism, prolong the half-life and thus achieve the goal of reducing the dose and provide therapeutic advantages.
  • Isotopically-labeled compounds generally start from a labeled starting material, and use known synthesis techniques to complete their synthesis like non-isotopically-labeled compounds.
  • the compound or pharmaceutical composition of the present invention can be formulated into a dosage form for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes, intratumoral injection) according to any one of conventional methods, such as tablets, granules , Powder, capsule, syrup, emulsion, microemulsion, solution or suspension.
  • the pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as the following: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • a carrier such as the following: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • carriers used in the injection composition of the present invention are water, saline solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, Fatty acids, fatty acid
  • the present invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into a mixture of isomers or separate isomer forms.
  • the compounds of the present invention can be isolated in optically active or racemic form.
  • the compounds of the present invention may exist in a variety of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thus rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.
  • the definitions of the substituents of the present invention are independent and not related to each other.
  • R a (or R b ) in the substituents they are independent of the definitions of different substituents.
  • selecting one defined when one substituent does not mean that the R a (or R b) at the other substituents have the same definition.
  • More specifically, for example (only a non-exhaustive list) for NR a R b when the definition of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R in b, R a (or R b) is necessarily hydrogen.
  • substituent is selected from, for example, the following substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (the two amino substituents are selected (From alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkyl Thio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulf
  • alkyl or "alkylene” as used herein is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl base.
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms.
  • C2-C6 alkenyl contains two to six carbon atoms.
  • Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms.
  • C2-C6 alkynyl contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C1-C6 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), and tert-butoxy.
  • alkylthio or “thioalkoxy” means an alkyl group, as defined above, with the specified number of carbon atoms connected via a sulfur bridge; for example, methyl-S- and ethyl-S-.
  • aryl refers to a monocyclic ring having a total of 5 to 12 ring members , A bicyclic or tricyclic ring system, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like.
  • the fused aryl group may be connected to another group at a suitable position on the cycloalkyl ring or aromatic ring.
  • Example The dotted line drawn from the ring system indicates that the bond can be connected to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • Monocyclic cyclic alkyl refers to unbranched or branched cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, 1-methyl ring Propyl and 2-methylcyclopropyl.
  • the bicyclic cyclic alkyl group includes a bridged ring, a spiro ring, or a fused ring cycloalkyl group.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl.
  • Monocyclic cyclic alkenyl refers to unbranched or branched cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl, 1- Methylcyclopropenyl and 2-methylcyclopropenyl.
  • the bicyclic cyclic alkenyl group includes a bridged ring, a spiro ring or a condensed ring cyclic alkenyl group.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoromethyl Propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a designated number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group as defined above with the specified number of carbon atoms connected via an oxygen bridge.
  • C1-C6 haloalkoxy is meant to include C1, C2, C3, C4, C5, C6 haloalkoxy.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” means a haloalkyl group as defined above that has the specified number of carbon atoms connected by a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • Cx1-Cx2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent groups can be x1 to x2.
  • C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C1-C8 means that the group contains 1, 2, 3, 4, 5 , 6, 7 or 8 carbon atoms
  • C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C3-C8 means that the group contains 3, 4, 5 , 6, 7, or 8 carbon atoms
  • C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms
  • C0-C6 means that the group contains 0, 1, 2, 3, 4 , 5 or 6 carbon atoms
  • C1-C6 means that the group contains 1, 2, 3, 4, 5 or 6 carbon atoms
  • C2-C6 means that the group contains 2, 3, 4, 5 or 6 Carbon atoms
  • C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms
  • x1-x2-membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means the ring atoms of the group The number can be from x1 to x2.
  • the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 3-6 membered ring means that the cyclic group can be 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ; 3-8 membered ring means that the cyclic group can be a 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9
  • the membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, or 9; 4-7
  • the membered ring means that the cyclic group can be a 4, 5, 6 or 7 membered ring, and the number of ring atoms can be 4, 5, 6, or 7;
  • the ring atom may be a carbon atom or a heteroatom, such as a heteroatom selected from N, O, and S.
  • the heterocyclic ring may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S Of heteroatoms.
  • one or more halogens may each independently be selected from fluorine, chlorine, bromine and iodine.
  • heteroaryl means a stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered
  • Aromatic polycyclic heterocycles which are fully unsaturated, partially unsaturated, and contain carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and include Any of the following polycyclic groups in which any heterocyclic ring as defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized.
  • the nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined).
  • the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocyclic ring can optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocyclic ring is not more than one.
  • heterocycle When the term “heterocycle” is used, it is intended to include heteroaryl groups.
  • aryl hetero groups include, but are not limited to, acridinyl, azetidinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxanyl Azolyl, benzoxazoline, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furanyl, furazanyl, imi
  • heteroaryl may also include the biaryl structure formed by the above-defined “aryl” and monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “- "Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-”, “-pyrimidinylbiphenyl-”; wherein the present invention also includes condensed rings containing, for example, the aforementioned heterocyclic ring and Spiro compounds.
  • heterocycloalkyl or “heterocycle” as used herein refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiro heterocycles or bridged heterocycloalkyls.
  • Monocyclic heterocycloalkyl refers to a saturated or unsaturated but not aromatic cyclic alkyl system containing at least one heteroatom selected from O, N, S, and P.
  • the bicyclic heterocycloalkyl system refers to the fusion of a heterocycloalkyl group with a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
  • the "heterocycloalkyl” or “heterocycle” contains at least one or two heteroatoms selected from O, N, and S.
  • bridged cycloalkyl refers to polycyclic compounds that share two or more carbon atoms. It can be divided into two-ring bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged cyclic hydrocarbon composed of more than three rings.
  • spirocycloalkyl refers to a polycyclic hydrocarbon that shares one carbon atom (called a spiro atom) between single rings.
  • bridged heterocyclic group refers to a polycyclic compound sharing two or more carbon atoms, and the ring contains at least one atom selected from O, N, and S. It can be divided into two-ring bridged heterocyclic ring and polycyclic bridged heterocyclic ring.
  • heterospirocyclyl refers to a polycyclic hydrocarbon sharing one carbon atom (called a spiro atom) between single rings, and the ring contains at least one heteroatom selected from O, N, and S.
  • substitution means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atoms such as amines
  • these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (such as mCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention . Therefore, the shown and claimed nitrogen atoms are considered to encompass both the shown nitrogen and its N-oxides to obtain the derivatives of the present invention.
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • the group may be optionally substituted with up to three R groups, and R is independently selected from the definition of R at each occurrence.
  • combinations of substituents and/or variables are only allowed if the above-mentioned combinations produce stable compounds.
  • patient refers to an organism that is treated by the method of the present invention.
  • organisms preferably include, but are not limited to, mammals (e.g., murine, ape/monkey, horse, cow, pig, dog, cat, etc.) and most preferably refer to humans.
  • the term "effective amount” as used herein means the amount of a drug or agent (ie, a compound of the present invention) that will elicit a biological or medical response of a tissue, system, animal, or human sought by, for example, a researcher or clinician.
  • therapeutically effective amount means an amount that results in an improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or reduction in disease, compared to a corresponding subject who has not received the above-mentioned amount. Or the rate of progression of the disease.
  • the effective amount can be administered in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an effective amount for enhancing normal physiological functions.
  • treatment includes its broad meaning and encompasses therapeutic treatment and/or prophylactic treatment of a subject. Specifically, the “treatment” includes any treatment that leads to the alleviation, suppression, elimination, and improvement and/or prevention of a disease, disease, disorder, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, preventing or improving its symptom.
  • the therapeutic treatment includes alleviating, inhibiting, or improving the symptoms or conditions of the disease; inhibiting the occurrence of complications; improving the underlying metabolic syndrome; inhibiting the occurrence of the disease or symptom, such as controlling the development of the disease or condition; reducing the disease or symptom; Reduced disease or symptoms; reducing complications caused by diseases or symptoms, or treating signs caused by diseases or symptoms.
  • the preventive treatment includes pretreatment to prevent, block or delay, slow the occurrence or development of a disease or condition, or reduce the severity of the disease or condition.
  • therapeutic agent also includes agents or agents that have therapeutic treatment and/or preventive treatment on a subject.
  • pharmaceutically acceptable or “pharmaceutically acceptable” is used herein to refer to those compounds, substances, compositions and/or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment Use without excessive toxicity, irritation, allergic reactions and/or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • cancer refers to an abnormal growth of cells that cannot be controlled and which can metastasize (spread) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (such as bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as thyroid), prostate , Skin (melanoma) or hematoma (such as non-leukemic leukemia).
  • co-administration refers to administering several selected therapeutic drugs to a patient in the same or different modes of administration at the same or different times.
  • an “enhance” or “enhance”, as used herein, means that the expected result can be increased or prolonged in terms of potency or duration. Therefore, in terms of enhancing the therapeutic effect of a drug, the term “enhanced” refers to the ability of the drug to increase or extend the potency or duration of the drug in the system. "Synergy value” as used herein refers to the ability of another therapeutic drug to be maximized in an ideal system.
  • immune disease refers to a disease or symptom that produces an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually cell dysfunction, or destruction and dysfunction, or destruction of organs or tissues that may produce immune symptoms.
  • subject include mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cows, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, etc.
  • the selected mammal is a human.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or condition, especially its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the administration.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, and otic administration , Nasal administration and local administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the mode of administration of the compound of the present invention may be a local mode of administration.
  • the long-acting formulation is administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered through a targeted drug delivery system.
  • a targeted drug delivery system for example, liposomes encapsulated by organ-specific antibodies. In this specific embodiment, the liposomes are selectively targeted to specific organs and absorbed.
  • the phrase "pharmaceutically acceptable carrier” means a pharmaceutical substance, composition or vehicle, such as liquid or solid fillers, diluents, excipients, manufacturing aids (e.g. lubricants, talc, magnesium stearate) , Calcium stearate or zinc stearate or stearic acid) or solvent encapsulated substances, which involve carrying or transporting the subject compound from one organ or part of the body to another organ or part of the body.
  • manufacturing aids e.g. lubricants, talc, magnesium stearate
  • Calcium stearate or zinc stearate or stearic acid e.g. stearate or zinc stearate or stearic acid
  • composition means a composition comprising a compound of the invention and optionally other pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for the delivery of a biologically active agent to an animal (particularly a mammal), including (ie) adjuvants, excipients or vehicles, such as diluents, preservatives Agents, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavors, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on Depending on the mode of administration and the nature of the dosage form.
  • the pharmaceutical composition of the present invention may contain a therapeutically effective amount of one or more compounds of the present invention formulated together with optionally one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally Of one or more other therapeutic agents.
  • the compound of the present invention can be administered by any suitable means for any of the above-mentioned purposes, for example, oral administration, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried Dispersions), syrups and emulsions; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (for example, in a sterile injectable aqueous or non-aqueous solution or suspension Liquid form); nasal, including administration to the nasal membranes, such as by inhalation spray; topical, such as in the form of creams or ointments;
  • the pharmaceutically acceptable carrier is formulated according to many factors within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; the subject to whom the composition containing the active agent is to be administered; the expected route of administration of the composition; and the targeted therapeutic indication.
  • Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.
  • the above-mentioned carrier may include many different ingredients and additives in addition to the active agent, and the above-mentioned other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizing active agents, binders, and the like.
  • suitable pharmaceutical carriers and the factors involved in the selection of carriers please refer to many easily available sources, such as Allen LVJr.et al. Remington: The Science and Practice of Pharmacy (2Volumes), 22nd Edition (2012) , Pharmaceutical Press.
  • the dosage regimen of the compound of the present invention varies depending on known factors, such as the pharmacodynamic properties of the specific agent and its administration mode and route; the species, age, sex, health status, medical condition and weight of the recipient. ; The nature and degree of symptoms; the types of simultaneous treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect.
  • the daily oral dose of each active ingredient should be about 0.001 mg/day to about 10-5000 mg/day, preferably about 0.01 mg/day to about 1000 mg/day, and most preferably The ground is about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be about 0.01 mg/kg/min to about 10 mg/kg/min.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compound is usually in a suitable pharmaceutical diluent, excipient or carrier (herein) appropriately selected according to the intended administration form (e.g., oral tablets, capsules, elixirs and syrups) and consistent with conventional pharmaceutical practice.
  • a suitable pharmaceutical diluent, excipient or carrier e.g., oral tablets, capsules, elixirs and syrups
  • Administered in the form of a mixture of drugs collectively referred to as drug carriers).
  • a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will usually be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60-mesh screen and packed into No. 1 gelatin capsules.
  • a typical injectable preparation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a bottle, aseptically lyophilizing and sealing. For use, the contents of the bottle are mixed with 2 mL of physiological saline to produce an injectable preparation.
  • the scope of the present invention includes (alone or in combination with a pharmaceutically acceptable carrier) pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • the compound of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).
  • the compound of the present invention (which can be used in a suitable hydrated form) and/or the pharmaceutical composition of the present invention is formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed, so as to obtain the amount of the active ingredient that is effective for realizing the desired therapeutic response, composition, and administration mode of a specific patient without being toxic to the patient.
  • the selected dosage level will depend on many factors, including the activity of the particular compound of the invention or its ester, salt or amide used; route of administration; time of administration; excretion rate of the particular compound used; rate and extent of absorption The duration of treatment; other drugs, compounds and/or substances used in combination with the specific compound used; the age, sex, weight, condition, general health and previous medical history of the patient being treated and other factors well known in the medical field.
  • a doctor or veterinarian with ordinary skill in the art can easily determine and prescribe an effective amount of the required pharmaceutical composition.
  • the physician or veterinarian can start a competition of the compound of the present invention used in the pharmaceutical composition at a level lower than the required level, and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of the compound of the invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such effective doses usually depend on the above-mentioned factors.
  • oral, intravenous, intracerebroventricular, and subcutaneous doses of the compound of the present invention for patients range from about 0.01 to about 50 mg/kg body weight/day.
  • the effective daily dose of the active compound can be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the medication is administered once a day.
  • the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical preparation (composition).
  • kits/product packaging is also described here.
  • kits can be composed of a conveyor, a medicine pack or a container box.
  • the container box can be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes, and the like.
  • Each container contains all A single component in the method described. Suitable containers include bottles, vials, syringes and test tubes.
  • the container is made of acceptable materials such as glass or plastic.
  • the container may contain one or more of the compounds described herein.
  • the compounds may exist in the form of pharmaceutical components, or they may exist as a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an intravenous infusion bag or a bottle, and the stopper may be pierced by a hypodermic syringe needle).
  • kits may contain a compound, and instructions, labels, or operating instructions for the method of use described herein.
  • a typical kit may include one or more containers.
  • each container contains one or more materials (such as reagents, or concentrated mother liquor, and/ Or equipment).
  • materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, and instructions for the built-in packaging. The entire set of instructions must be included.
  • the label can be displayed on the container or closely related to the container.
  • the appearance of a label on a container means that the label letters, numbers, or other features are pasted, molded, or engraved on the container; the label can also appear in a container box or shipping box containing a variety of containers, such as product inserts.
  • a label can be used to indicate a specific therapeutic use of the contents.
  • the label may also indicate instructions for use of the content, such as described in the above method.
  • the unit of weight-volume percentage in the present invention is well known to those skilled in the art, for example, refers to the weight of the solute in a 100 ml solution. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
  • the LC-MS experiment is measured under the following conditions:
  • Preparative HPLC usually uses alkaline methods (gradient of acetonitrile and water, water containing 10mM ammonium bicarbonate); use Thermo U3000AFC-3000; column: Globalsil C-18 12nm, 250 x 20mm, 10 ⁇ m, or equivalent; flow rate: 20mL/ min, to separate.
  • the compound INT-1f (1.50g, 4.33mmol) was dissolved in dichloromethane (30mL), N,N-diisopropylethylamine (1.68g, 13.0mmol) was added, and A Sulfonic anhydride (1.51 g, 8.65 mmol). Then add a mixture of N,N-diisopropylethylamine (1.68g, 13.0mmol) and dioxane hydrochloride (4M, 1.62mL) in dichloromethane (10mL). The reaction solution was stirred at 25°C for 16 hours. The reaction was quenched with water (30 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 2).
  • INT-4 can be obtained as a white solid.
  • 1 H NMR(500MHz,Chloroform-d) ⁇ 7.76(d,J 7.2Hz,1H), 7.28-7.22(m,7H), 4.53(s,2H), 4.05-3.67(m,1H), 3.42 –3.20(m,2H),2.40(s,3H),2.01–1.90(m,3H),1.82–1.71(m,1H),1.36(s,9H);
  • INT-17b can be obtained as a colorless oil.
  • INT-17 can be obtained as a light yellow oil.
  • compound INT-18a can be obtained.
  • 1 H NMR(500MHz, DMSO-d6) ⁇ 10.34(s,1H), 7.91-7.87(m,1H), 7.52-7.48(m,1H), 7.44-7.38(m,1H), 7.13-7.10( m,1H),7.04-7.00(m,1H),3.96(s,3H).
  • 3-bromo-4-chloroaniline (2.06g, 9.98mmol) was dissolved in sulfuric acid (25% w/w aqueous solution, 40mL), and stirred for half an hour; then the reaction solution was cooled to -5°C , Slowly drop in a water (10mL) solution pre-dissolved with sodium nitrite (826mg, 12.0mmol).
  • the aqueous phase was further extracted with ethyl acetate (50 mL x 2), and the combined organic phases were sequentially washed with saturated sodium thiosulfate solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • N-chlorosuccinimide (639mg, 4.78mmol) was added to a solution of 2,6-dibromoaniline (1.00g, 3.99mmol) in acetonitrile (20mL) in batches; The resulting reaction liquid was stirred at the same temperature for 16 hours. Water was added to the reaction solution, and a solid precipitated out; the obtained solid was further washed with water, and dried to obtain a white solid 20a (1.10 g, yield: 96.7%).
  • 1 H NMR 500MHz, DMSO-d6) ⁇ 7.53 (s, 2H), 5.48 (s, 2H).
  • the reaction solution was concentrated and diluted with saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (10 mL x 2); the combined organic phases were concentrated.
  • compound 48a was obtained by referring to the synthesis procedure of boron esterification of compound INT-7a.
  • compound INT-8c and compound INT-11 refer to the synthesis of compound INT-8 and compound 33 to obtain compound 66.
  • Dess-Martin oxidant (157 mg, 0.37 mmol) was added to a solution of compound 72b (130 mg, 0.37 mmol) in dichloromethane (6 mL); the reaction solution was stirred at 25° C. for one hour. Saturated sodium bicarbonate solution (20 mL) and dichloromethane (20 mL) were added to the reaction solution, and the obtained organic phase was further washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate.
  • N-chlorosuccinimide (467 mg, 3.50 mmol) was added to concentrated sulfuric acid (3 mL) in which compound INT-13b (300 mg, 1.66 mmol) was dissolved; the reaction solution was stirred at 25° C. for 2 hours. Ice water (25 mL) and ethyl acetate (25 mL) were added to the reaction solution; the organic phase was further washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to obtain a yellow solid 77a (360mg, yield: 86.8%).
  • 1 H NMR 500MHz, DMSO-d6) ⁇ 8.09 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.51 (s, 3H).
  • compound INT-8c and tranexamic acid methyl ester hydrochloride refer to the synthesis of compound INT-8 and compound 44 to obtain compound 102.
  • Embodiment 104
  • Embodiment 110 is a diagrammatic representation of Embodiment 110:
  • compound INT-6 and tranexamic acid methyl ester hydrochloride refer to the synthesis of compound INT-8 and compound 44 to obtain compound 112.
  • Embodiment 120 is a diagrammatic representation of Embodiment 120.
  • compound 135 is obtained by referring to the synthesis of compound 101.
  • trans-4-aminocyclohexanoic acid methyl ester hydrochloride was replaced with 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride to obtain compound 140.
  • Embodiment 144
  • trans-4-aminocyclohexanoic acid methyl ester hydrochloride was replaced with 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride to obtain compound 145.
  • the aqueous sulfuric acid solution (25% w/w) with compound 155a (1.0g, 4.5mmol) dissolved in it was stirred for half an hour; then cooled to -5°C and slowly added dropwise dissolved sodium nitrite (369mg, 5.4mmol). mmol) in water (5 mL).
  • the resulting reaction liquid was reacted at room temperature for 1 hour.
  • This detection method is used to evaluate the biological activity of the compound of the present invention at the cellular level.
  • This detection method uses the luciferase reporter gene method to detect the biological activity of the compound on cell-level PD-1/PD-L1 signal inhibition.
  • PD-1/NFAT-Reporter-Jurkat cells stably express human PD-1 and express the luciferase reporter gene regulated by NFAT elements;
  • TCR activator/PD-L1-CHO cells stably express human PD-L1 and TCR activation elements.
  • PD-1/NFAT-Reporter-Jurkat cells (Cat. No. 60535) and TCR activator/PD-L1-CHO cells (Cat. No. 60536) were purchased from BPS Bioscience; PD-L1 antibody (Atezolizumab, Catalog No. A2004) was purchased from Selleck; Fluorescence The prime enzyme detection reagent (ONE-Glo TM Luciferase Assay System, article number E6120) was purchased from Promega; the multifunctional microplate detector (model SpectraMax i3x) was purchased from Molecular Devices.
  • TCR activator/PD-L1-CHO cells Collect TCR activator/PD-L1-CHO cells and inoculate 35,000 cells/well into 96-well culture plates with a medium volume of 100 microliters and incubate overnight at 37°C. The next day, the culture medium was discarded, and the compound was added and incubated for 30 minutes. At the same time, a solvent control (dimethyl sulfoxide, DMSO, final concentration of 0.1%) and PD-L1 antibody (Atezolizumab, final concentration of about 10 nM) positive controls were set. Then add PD-1/NFAT-reporter-Jurkat cells. After continuing to incubate for 6 hours, detect the luciferase activity according to the luciferase detection reagent instructions.
  • the biological activity of the compound of the present invention was evaluated at the cellular level, and the activity results are shown in the following table.
  • the compound of the present invention can effectively inhibit PD-1/PD-L1 and has good PD-1/PD-L1 inhibitory activity.

Abstract

提供了一种式（I）化合物及其药物组合物，以及使用式（I）化合物预防和/或治疗免疫相关病症的方法。

Description

PD-L1拮抗剂化合物
本申请要求于2019年12月26日提交到中国专利局的发明名称为“PD-L1拮抗剂化合物”的中国专利申请201911368320.1的优先权，其内容通过引用以整体并入本文。
技术领域
本发明涉及一种PD-L1拮抗剂化合物，以及使用其治疗/预防免疫相关病症的方法。
背景技术
肿瘤免疫治疗由于其卓越的疗效和创新性，在2013年被《科学》杂志评为年度最重要的科学突破。肿瘤免疫治疗有望成为继手术、化疗、放疗、靶向治疗后肿瘤治疗领域的一场革新。肿瘤免疫治疗是应用免疫学原理和方法，提高肿瘤细胞的免疫原性和对效应细胞杀伤的敏感性，激发和增强机体抗肿瘤免疫应答，并应用免疫细胞和效应分子输注宿主体内，协同机体免疫***杀伤肿瘤、抑制肿瘤生长。肿瘤免疫治疗近来备受关注，是肿瘤治疗领域的焦点。近几年，肿瘤免疫治疗的好消息不断，目前已在一些肿瘤类型如黑色素瘤，非小细胞肺癌等的治疗中展示出了强大的抗肿瘤活性，并已有肿瘤免疫治疗药物获得美国FDA(Food and Drug Administration,FDA)批准临床应用。
PD-1(程序性死亡受体1，programmed death 1)为CD28超家族成员。以PD-1为靶点的免疫调节在抗肿瘤、抗感染、抗自身免疫性疾病及器官移植存活等方面均有重要的意义。其配体PD-L1也可作为靶点，相应的抗体也可以起到相同的作用。PD-L1(程序性死亡受体-配体1，programmed cell death-Ligand 1)是大小为40kDa的第一型跨膜蛋白。正常情形下免疫***会对聚集在***或脾脏的外来抗原产生反应，促进具有抗原特异性的T细胞增殖。而PD-1与PD-L1结合，可以传导抑制性的信号，减低T细胞的增殖。
肿瘤细胞逃避T细胞摧毁的一种途径是通过在它表面产生PD-L1。当免疫细胞T细胞表面的PD-1识别PD-L1后，可以传导抑制性信号，T细胞就不能发现 肿瘤细胞和向肿瘤细胞发出攻击信号。PD-1是通过解除肿瘤细胞逃避免疫***的新型免疫疗法。PD-1免疫疗法的作用机制是针对PD-1或PD-L1设计特定的蛋白质抗体，阻止PD-1和PD-L1的识别过程，部分恢复T细胞功能，从而使T细胞可以杀死肿瘤细胞。
PD-1表达于活化的T细胞，B细胞及髓系细胞，其有两个配体，即PD-L1和PD-L2。PD-L1/L2在抗原递呈细胞都表达，PD-L1在多种组织也有表达。PD-1与PD-L1的结合介导T细胞活化的共抑制信号，调节T细胞活化和增殖，起到类似于CTLA-4的负调节作用。华裔科学家陈列平实验室首先发现PD-L1在肿瘤组织高表达，而且调节肿瘤浸润CD8T细胞的功能。因此，以PD-1/PD-L1为靶点的免疫调节对抗肿瘤有重要的意义。
多个靶向PD-1/PD-L1相互作用的治疗性单克隆抗体(mAbs)已被美国FDA批准上市。除了开发相关单克隆抗体之外，寻找方便癌症患者的口服小分子化合物用来靶向抑制免疫检查点也是肿瘤免疫疗法的前沿领域。小分子化合物能够穿过细胞膜作用于细胞内靶点，所以应用范围广泛。其次，小分子经化学修饰后往往具有良好的生物利用度和依从性，有效避免消化肠道中酶类的分解失活。最后，在生产工艺、剂型设计和给药方式等多种层面，小分子的研究也颇为成熟。
大多数单克隆抗体(mAbs)的使用途径是高剂量的静脉注射。小分子药物，其更适合口服给药，可以减少严重的免疫相关不良事件。与单克隆抗体相比，小分子药物抑制剂有很多其他好处，例如，制造成本更经济、稳定，且器官和肿瘤的渗透性更好。考虑到小分子药物动力学性质的众多优点，它将会在单一疗法或其它组合方案里体现出剂量上的灵活性。本发明的小分子化合物的可为患者和医生提供一个引人注目的治疗选择。
发明内容
本发明提供了一种式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、水合物、异构体、溶剂化物、或其代谢产物：
Figure PCTCN2020138157-appb-000001
其中，L 1选自基团：-CR AR B-和-C(O)-；
L 2、L 3选自基团：-(CR CR D) p、-(CR CR D) p-NR a-(CR CR D) q-、-(CR CR D) p-O-(CR CR D) q-和-C(O)-；
W 1、W 2各自独立地表示CR L或者N；
R 1各自独立地表示氢、卤素、硝基、氰基或-NR aR b或者被0、1、2或3个取代基所取代的C 1-C 6烷基、C 3-C 6环烷基、-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述的取代基选自：-OR a、氰基、氧代、卤素、C 1-C 6烷基、-(C 1-C 6亚烷基)OR a、氰基C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、-C(O)R a、-(C 1-C 6亚烷基)C(O)R a、-C(O)OR a、-(C 1-C 6烷基)C(O)OR a、-NR aR b、-(C 1-C 6亚烷基)NR aR b、-C(O)NR aR b、-SO 2R a、-C(O)NR aSO 2R b和-NR aC(O)R b；
R 2、R 3、R 4、R 5各自独立地表示氢、卤素、硝基、氰基、-NR aR b、-SO 2R a、-S(O)R a、-P(O)R aR b、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤代(C 1-C 6烷基)或者C 3-C 6环烷基；
Cy表示被0、1、2或3个R 6所取代的苯环或六元杂芳基，其中所述六元杂芳基可以任选地含有1或2个氮原子；其中所述R 6表示氢、卤素、硝基、氰基、-NR aR b、-SO 2R a、-S(O)R a或-P(O)R aR b或者被0、1、2或3个取代基所取代的C 1-C 6烷基、C 3-C 6环烷基、-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：-OR a、氰基、氧代、卤素、C 1-C 6烷基、-(C 1-C 6亚烷基)OR a、氰基C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、-C(O)R a、-(C 1-C 6亚烷基)C(O)R a、-C(O)OR a、-(C 1-C 6亚烷基)C(O)OR a、-NR aR b、-(C 1-C 6亚烷基)NR aR b、-C(O)NR aR b、-SO 2R a、-C(O)NR aSO 2R b或者-NR aC(O)R b；
其中，R L表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
T、A各自独立地表示：被0、1、2或3个取代基所取代的-(C 1-C 6烷基)、-(C 0-C 6亚烷基)-(C 3-C 12环烷基)、-(C 0-C 6亚烷基)-(3-12元杂环)、-(C 0-C 6亚烷基)-(C 6-C 10芳基)或-(C 0-C 6亚烷基)-(5-10元杂芳基)，其中所述取代基选自：氰基、氧代、卤素、C 1-C 6烷基、-(C 0-C 6亚烷基)OR a、氰基C 1-C 6烷基、卤代(C 1-C 6烷基)、C 3-C 8环烷基、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-(C 0-C 6亚烷基)NR aR b、-C(O)NR aR b、-NR aSO 2R b、-C(O)NR aSO 2R b和-NR aC(O)R b；
其中，R A、R B各自独立地表示：氢、C 1-C 6烷基、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、卤代(C 1-C 6烷基)或卤素，或者R A与R B连同其共同相连的碳原子一起形成3-6元环；
R C、R D各自独立地表示：氢、C 1-C 6烷基、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、卤代(C 1-C 6烷基)或卤素，或者R C与R D连同其共同相连的碳原子一起形成3-6元环；
R a、R b各自独立地表示：氢、C 1-C 6烷基、卤代(C 1-C 6烷基)、-(C 0-C 6亚烷基)OH、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、-(C 0-C 3亚烷基)(C 6-C 10元芳环)、-(C 0-C 3亚烷基)(5-10元杂芳环)或卤代(C 1-C 6烷基)，或者R a与R b连同其共同相连的原子一起形成3-6元环；
其中，m、o均各自独立地表示0、1或2；
其中，p、q均各自独立地表示0、1、2或3。
优选地，所述式(I)化合物具有以下式(II)结构：
Figure PCTCN2020138157-appb-000002
其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如式(I)所定义；
其中，r表示0、1、2或3。
优选地，所述式(I)化合物具有以下式(III)结构：
Figure PCTCN2020138157-appb-000003
其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如式(I)所定义；
其中，W 3表示CR M或者N；
其中，R M表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
其中，r表示为0、1或2。
优选地，所述式(I)化合物具有以下式(IV)结构：
Figure PCTCN2020138157-appb-000004
其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如式(I)所定义；
其中，W 4表示CR N或者N；
其中，R N表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
其中，r表示为0、1或2。
在本发明的化合物中，L 1优选地选自-CR AR B-，其中R A、R B各自独立地选自氢、卤素、C 1-C 6烷基和卤代(C 1-C 6烷基)，优选为氢。
在本发明的化合物中，L 2和L 3各自优选地独立地选自-CR CR D-和-CR CR D-NR a-(CR CR D) q-，其中，q选自0、1或2，其中R C、R D各自独立地选自氢、卤素、C 1-C 6烷基和卤代(C 1-C 6烷基)，优选为氢；R a各自独立地选自氢、C 1-C 6烷 基、卤代(C 1-C 6烷基)和-(C 0-C 3亚烷基)C 3-C 12环烷基。
在本发明的化合物中，W 1、W 2各自优选地独立地表示CH或者N。
在本发明的化合物中，W 3优选地表示CH或者N。
在本发明的化合物中，W 4优选地表示CH或者N。
在本发明的化合物中，T、A各自优选地独立地表示被0、1、2或3个取代基所取代的：-(C 1-C 6烷基)、-(C 0-C 6亚烷基)-(C 3-C 12环烷基)或-(C 0-C 6亚烷基)-(3-12元杂环)，其中所述取代基选自：氰基、氧代、卤素、C 1-C 6烷基、-(C 0-C 6亚烷基)OR a、C 1-C 6氰基烷基、卤代(C 1-C 6烷基)、C 3-C 8环烷基、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-(C 0-C 6亚烷基)NR aR b、-C(O)NR aR b、-NR aSO 2R b、-C(O)NR aSO 2R b和-NR aC(O)R b，其中，R a和R b各自独立地表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
在本发明的化合物中，T、A各自优选地独立地表示被0、1或2个取代基所取代的C 1-C 6烷基、C 3-C 12环烷基或3-12元杂环，其中所述取代基选自：氰基、氧代、-OR a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-NR aC(O)R b、-NR aSO 2R b和-C(O)NR aSO 2R b，其中，R a和R b各自独立地表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
在本发明的化合物中，T、A各自优选地独立地表示任选地被选自0、1或2个取代基所取代的以下基团：
Figure PCTCN2020138157-appb-000005
其中所述取代基选自：C 1-C 6烷基、-OR a、-(C 0-C 6亚烷基)C(O)OR a和-(C 0-C 6亚烯基)C(O)OR a，其中，R a表示氢或者C 1-C 6烷基，优选为氢，其中，α表示1、2或3。
在本发明的化合物中，T、A各自优选地独立地表示以下基团：
Figure PCTCN2020138157-appb-000006
在本发明的化合物中，T、A各自优选地独立地表示任选地被选自0、1或2个取代基所取代的以下基团：
Figure PCTCN2020138157-appb-000007
其中，所述取代基选自：C 1-C 6烷基、-OR a和卤素，其中，R e、R a各自独立地表示氢或者C 1-C 6烷基；其中α表示1、2、3或4。
在本发明的化合物中，T、A各自优选地独立地表示
Figure PCTCN2020138157-appb-000008
其中，R e表示氢或者C 1-C 6烷基；其中α表示1、2、3或4。
在本发明的化合物中，T、A各自优选地独立地表示：
Figure PCTCN2020138157-appb-000009
在本发明的化合物中，R 1优选地表示被0、1、2或3个取代基所取代的-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：氰基、氧代、卤素、氰基C 1-C 6烷基和C 1-C 6卤代烷基。
在本发明的化合物中，R 2优选地表示氢、卤素、硝基、氰基、-SO 2R a、C 1-C 6烷基、卤代(C 1-C 6烷基)或者C 3-C 6环烷基；其中，R a表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
在本发明的化合物中，R 3、R 4各自优选地独立地表示氢、卤素、硝基或氰基。
在本发明的化合物中，R 5优选地表示氢、卤素、硝基、氰基、C 1-C 6烷基、卤代(C 1-C 6烷基)或者C 3-C 6环烷基。
在本发明的化合物中，R 6优选地表示氢、卤素、硝基、氰基、-SO 2R a、C 1-C 6烷基、卤代(C 1-C 6烷基)或C 3-C 6环烷基或者被0、1、2或3个取代基所取代的-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：氰基、氧代、卤素、氰基C 1-C 6烷基和C 1-C 6卤代烷基。
在本发明的化合物中，R L优选地表示氢或者卤素。
在本发明的化合物中，R M、R N各自优选地独立地表示氢。
具体实施方式
具体地，本发明提供了具有如下结构的化合物：
Figure PCTCN2020138157-appb-000010
Figure PCTCN2020138157-appb-000011
Figure PCTCN2020138157-appb-000012
Figure PCTCN2020138157-appb-000013
Figure PCTCN2020138157-appb-000014
Figure PCTCN2020138157-appb-000015
Figure PCTCN2020138157-appb-000016
Figure PCTCN2020138157-appb-000017
Figure PCTCN2020138157-appb-000018
Figure PCTCN2020138157-appb-000019
Figure PCTCN2020138157-appb-000020
Figure PCTCN2020138157-appb-000021
Figure PCTCN2020138157-appb-000022
Figure PCTCN2020138157-appb-000023
Figure PCTCN2020138157-appb-000024
Figure PCTCN2020138157-appb-000025
Figure PCTCN2020138157-appb-000026
除此之外，本发明还提供了一种药物组合物，其包含本发明所述的化合物，并且任选地进一步包含另外的治疗剂和/或免疫检查点抑制剂。本发明的药物组合物可以包含可药用载体。
除此之外，本发明还提供了本发明的化合物或者含有本发明化合物的药物组合物在制备用于预防或治疗可通过抑制PD-L1与PD-1结合来治疗的疾病或病症的药物中的应用。优选地，所述疾病选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明还提供了本发明化合物或者含有本发明化合物的药物组合物在制备用于预防或治疗对抑制PD-L1与PD-1之结合有响应的疾病或病症的药物中的应用。优选地，所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
除此之外，本发明还提供了一种预防或治疗可通过抑制PD-L1与PD-1结合来治疗的疾病或病症(优选肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病)的方法，其包括向有此需要的哺乳动物施用本发明的化合物或者本发明的药物组合物。
本发明还提供了一种预防或治疗对抑制PD-L1与PD-1之结合有响应的疾病或病症的方法，其包括向有此需要的哺乳动物施用本发明的化合物或者本发明的药物组合物。术语“对抑制PD-L1与PD-1之结合有响应的疾病或病症”意指这样的任何疾病或病症：通过抑制PD-L1与PD-1之结合可改变疾病进程，或可导致疾病、病症、障碍等的缓和、抑制、消除和改善效果或者可预防这样的疾病或 病症。优选地，所述对抑制PD-L1与PD-1之结合有响应的疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
本发明还提供了一种抑制PD-L1和PD-1结合的方法，其包括使本发明化合物或者本发明的药物组合物暴露于所述的PD-L1和/或PD-1。
在上述涉及本发明的化合物、药物组合物以及利用本发明化合物或药物组合物的用途和方法的实施方案中，所述的本发明化合物尤其包括其药学上可接受的盐的形式。
炎症性疾病、自身免疫性疾病和免疫介导性疾病的代表性实例可包括但不限于，关节炎、类风湿性关节炎、脊柱关节炎、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节炎性病症、狼疮、***性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、过敏性皮肤炎、疼痛、肺病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎症性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗塞、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克罗恩病、溃疡性结肠炎、肠易激综合征、哮喘、干燥综合征、自身免疫甲状腺疾病、荨麻疹(风疹)、多发性硬化、硬皮症、器官移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔兹海默病、糖尿病相关疾病、炎症、***性疾病、过敏性鼻炎、过敏性支气管炎、过敏性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、毛细胞白血病、何杰金氏病、非何杰金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤。
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、***癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、***状甲状腺癌、肾癌、肾实质癌、卵巢癌、***、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、***癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴 瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、***瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的治疗剂或免疫检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。
用于治疗癌症或肿瘤的治疗剂的代表性实例可包括但不限于细胞信号转导抑制剂、苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、***、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib、阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、PI3K抑制剂、CSF1R抑制剂、A2A和/或A2B受体拮抗剂、IDO抑制剂、抗PD-1抗体、LAG3抗体、 TIM-3抗体及抗CTLA-4抗体或其任意组合。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化***、甲基氢化***、可的松、羟基可的松、倍他米松、***等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用频率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外，本发明还提供了一种抑制PD-L1的方法，其包含使本发明的所述的化合物、其药学上可接受的盐或者本发明所述的药物组合暴露于所述的PD-L1。
术语定义
特别注意的是，在本文中，当提及具有特定结构式的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物，以及作为其替代性存在形式的可药用盐、溶剂合物、水合物等形式。本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式， 它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。
相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐或药学上可接受的盐可使用无机酸或有机酸而形成，所述的“可药用盐”或“药学上可接受的盐”是指这样的盐：在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱可以与合适的酸反应。此外，当本发明的化合物带有酸性部分时，其合适的可药用盐可包括金属盐，例如碱金属盐(如钠盐或钾盐)和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。其他可药用盐包括己二酸盐、海藻酸钠、抗坏血酸盐、天门冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。其他可药用盐包括(适当时)无毒铵盐、季铵盐和用反离子形成的铵阳离子，例如，卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)中，向其中添加过量 的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明所述的前体或代谢物可以为本领域公知的前体或代谢物，只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药，在合理的医学判断范围内，其适用于接触人和更低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物，例如通过在体内代谢，或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或更多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或更多个溶剂分子纳入结晶固体的晶格中时，溶剂合物将能够被分离。溶剂合物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)。构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或更多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或更多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消 旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是：氢同位素： 2H和 3H；碳同位素： 11C, 13C和 14C；氯同位素： 35Cl和 37Cl；氟同位素： 18F；碘同位素： 123I和 125I；氮同位素： 13N和 15N；氧同位素： 15O, 17O和 18O和硫同位素 35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘 2H和碳 13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢( 2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
可根据常规方法中的任何一种将本发明化合物或药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
用于口服施用的本发明药物组合物可通过将活性成分与例如以下的载体混合来制备：纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、右旋糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂和稀释剂。在本发明的注射组合物中采用的载体的实例是水、盐溶液、葡萄糖溶液、葡萄糖样溶液(glucose-like solution)、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂和乳化剂。
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。
如果无另外说明，用于本发明申请(包括说明书和权利要求书)中的术语定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环***等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如对于取代基中R a(或者R b)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于R a(或者R b)在一种取代基中选择一种定义时，并不意味着该R a(或者R b)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NR aR b中，当R a(或者R b)的定义选自氢时，其并不意味着在-C(O)-NR aR b中，R a(或者R b)必然为氢。
除非另有定义，否则当取代基被标注为“任选取代的”时，所述取代基选自例如以下取代基，诸如烷基、环烷基、芳基、杂环基、卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基团(其中两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、磺酰氨基例如-SO 2NH 2、取代的磺酰氨基、硝基、氰基、羧基、氨基甲酰基例如-CONH 2、取代的氨基甲 酰基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有两个选自烷基、芳基或芳基烷基的取代基的情况、烷氧基羰基、芳基、取代的芳基、胍基、杂环基，例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等和取代的杂环基。
本文使用的术语“烷基”或“亚烷基”意欲包括具有指定碳原子数的支链和直链饱和脂族烃基团。例如，“C1-C6烷基”表示具有1个至6个碳原子的烷基。烷基的实例包括但不限于甲基(Me)、乙基(Et)、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基。
术语“烯基”表示含一个或更多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。
术语“炔基”表示含一个或更多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的有机官能团(C＝O)。
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至12个环成员的单环、二环或三环的环***，其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。在本发明的某些实施方案中，“芳基”是指芳族环***，其包括但不限于苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。术语“芳烷基”或“芳基烷基”是指连接至芳基环的烷基残基。非限制性实例包括苄基、苯乙基等。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。例从环***中画出的虚线表明键可连接至任意合适的环原子。
术语“环烷基”是指单环或二环的环状烷基。单环的环状烷基指非支化或者支 化的的环状烷基，包括但不限于环丙基、环丁基、环戊基、环己基、降莰烷基、1-甲基环丙基和2-甲基环丙基。二环的环状烷基包括桥环、螺环或融合环的环烷基。
术语“环烯基”是指单环或二环的环状烯基。单环的环状烯基指非支化或者支化的环状烯基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基和降莰烯基、1-甲基环丙烯基和2-甲基环丙烯基。二环的环状烯基包括桥环、螺环或稠合环的环状烯基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如，“C1-C6卤代烷氧基”意欲包括C1、C2、C3、C4、C5、C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
本公开内容中，当提到一些取代基团时使用Cx1-Cx2的表述，这表示所述取代基团中的碳原子数可以是x1至x2个。例如，C0-C8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C1-C8表示所述基团含有1、2、3、4、5、6、7或8个碳原子，C2-C8表示所述基团含有2、3、4、5、6、7或8个碳原子，C3-C8表示所述基团含有3、4、5、6、7或8个碳原子，C4-C8表示所述基团含有4、5、6、7或8个碳原子，C0-C6表示所述基团含有0、1、2、3、4、5或6个碳原子，C1-C6表示所述基团含有1、2、3、4、5或6个碳原子，C2-C6表示所述基团含有2、3、4、5或6个碳原子，C3-C6表示所述基团含有3、4、5或6个碳原子。
本公开内容中，当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述，这表示该基团的环原子数可以是x1至x2个。例如， 所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环，其环原子数可以是3、4、5、6、7、8、9、10、11或12个；3-6元环表示该环状基团可以是3、4、5或6元环，其环原子数可以是3、4、5或6个；3-8元环表示该环状基团可以是3、4、5、6、7或8元环，其环原子数可以是3、4、5、6、7或8个；3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环，其环原子数可以是3、4、5、6、7、8或9个；4-7元环表示该环状基团可以是4、5、6或7元环，其环原子数可以是4、5、6或7个；5-8元环表示该环状基团可以是5、6、7或8元环，其环原子数可以是5、6、7或8个；5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环，其环原子数可以是5、6、7、8、9、10、11或12个；6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环，其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子，例如选自N、O和S的杂原子。当所述环是杂环时，所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子，例如选自N、O和S的杂原子。
本发明内容中，一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
术语“杂芳基”意指稳定的3元、4元、5元、6元、或7元芳香单环或芳香二环或7元、8元、9元、10元、11元、12元芳香多环杂环，其为完全不饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子；且包括任何以下多环基团，其中上文所定义的任意杂环与苯环稠合。氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。当使用术语“杂环”时，其意欲包括杂芳基。芳杂基的实施例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪 基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”；其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
本文使用的术语“杂环烷基”或“杂环”指的是一个单环杂环烷基体系，或为一个二环杂环烷基体系，同时还包括螺杂环或桥杂环烷基。单环的杂环烷基指的是至少含一个选自O、N、S、P的杂原子的饱和或不饱和但不为芳香性的环状烷基体系。二环杂环烷基体系指的是一个杂环烷基与一个苯基、或一个环烷基、或一个环烯基、或一个杂环烷基、或一个杂芳基稠合。优选地，所述“杂环烷基”或“杂环”中包含至少一个或两个选自O、N、S的杂原子。
本文使用的术语“桥环烷基”指的是共用两个或两个以上碳原子的多环化合物。可分为二环桥环烃及多环桥环烃。前者由两个脂环共用两个以上碳原子所构成；后者是由三个以上的环组成的桥环烃。
本文使用的术语“螺环烷基”指的是单环之间共用一个碳原子(称螺原子)的多环烃。
本文使用的术语“桥环杂基”指的是共用两个或两个以上碳原子的多环化合物，该环中至少含一个选自O、N、S原子。可分为二环桥环杂环及多环桥杂环。
本文使用的术语“杂螺环基”指的是单环之间共用一个碳原子(称螺原子)的多环烃，该环中至少含一个选自O、N、S的杂原子。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、***、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或更多个给药、施用或剂量给予且不意欲被特 定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括其广义上的含义，涵盖对对象的治疗性处理和/或预防性处理。具体而言，所述“治疗”包括导致病症、疾病、障碍等的缓和、抑制、消除和改善和/或预防的任何处理，例如减轻、减少、调节、改善、消除、预防、防止或改善其症状。所述治疗性处理包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善潜在代谢综合征；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或治疗由疾病或症状引起的征兆。所述预防性处理包括事先处理以防止、阻断或延迟、减缓疾病或病症的发生或发展或者减弱疾病或病症的严重程度。
同样，“治疗剂”也包括对对象具有治疗性处理和/或预防性处理的药剂或试剂。
术语“药用”或“药学上可接受的”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
特定药学及医学术语
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、***、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在***中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的***中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“对象”、“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、***给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、***内注射、及鼻内注射。
本发明化合物给药方式可以是局部的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药***来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本文使用的短语“可药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与任选的其它可药用载体的组合物。“可药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。
本发明的药用组合物可包含治疗有效量的与任选的一种或多种可药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，以及任选的一种或多种其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式；或经瘤内注射。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配可药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约 1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
用于口服给药的典型胶囊剂含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使该混合物穿过60目网筛，并包装成1号明胶胶囊。
典型的可注射制剂可如下制备：以无菌方式将至少一种本发明化合物(250mg)置于瓶中、以无菌方式冻干并密封。为进行使用，将瓶内容物与2mL生理盐水混合，以产生可注射制剂。
本发明范围包括(单独或与可药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的***速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容 器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
具体实施例
当未提及制备途径时，相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。 1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示，即δ值。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦合常数以J值列出，以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
LC-MS实验在以下条件下测量：
仪器：Thermo U3000,ALLtech ELSD,MSQ，UV检测器结合ELSD和MSD(流出比为4:1)。柱：Waters X-Bridge C-18,3.5μm，4.6x50mm；柱温：30℃。梯度【时间(min)/溶剂B在A中(％)】：0.00/5.0，0.70/95，1.40/95，1.41/5，1.50/5。(溶剂A＝0.01％三氟乙酸在水中；溶剂B＝0.01％三氟乙酸在乙腈中)。UV检测：214/254/280/300nm；DAD检测：200-400nm；流速：4mL/min；MS：ESI，100-1500m/z
制备型HPLC通常使用碱性方法(乙腈和水的梯度，水中含有10mM碳酸氢铵)；用Thermo U3000AFC-3000；柱：Globalsil C-18 12nm,250 x 20mm,10μm,或相当；流速：20mL/min，进行分离。
中间体的合成
化合物INT-1的制备：
Figure PCTCN2020138157-appb-000027
将2-氯-5-羟基苯甲酸(29.0g，168mmol)溶于四氢呋喃(100mL)中，在氮气氛围和冰浴下滴加硼烷(1.0M的四氢呋喃溶液，336mL)。滴加完毕，反应液升至室温搅拌16小时。TLC检测原料消耗完全，冰浴下向反应液中滴加甲醇淬灭反应，直至不再有气泡冒出。浓缩溶剂得到淡黄色固体INT-1a(26.6g，收率：99.8％)。
将化合物INT-1a(26.6g，168mmol)和咪唑(11.5g，169mmol)溶于二氯甲烷(300mL)中，在0℃条件下分批加入预先溶于二氯甲烷(100mL)溶液中的叔丁基二甲基氯硅烷(25.5g,169mmol)。混合物升温至30℃搅拌16小时，用水(100mL)淬灭反应，水相用二氯甲烷萃取(100mL x 2)。合并有机相用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到淡黄色液体INT-1b(33.4g,收率:73％)。
将化合物INT-1b(8.0g,29.3mmol)溶于乙腈(100mL)，相继加入三乙胺(14.8g,147mmol)，氯化镁(5.58g,58.6mmol)和多聚甲醛(8.80g,293mmol)。混合物在氮气氛围下加热至90℃，剧烈搅拌20小时。向反应液中加入水(100mL)稀释，用饱和柠檬酸水溶液调节pH＝3-4，然后用乙酸乙酯萃取(200mL x 2)。合并有机相用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到白色固体INT-1c(5.0g,收率:56.7％)。 1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.23(s,1H),7.58(s,1H),7.25(s,1H),4.72(s,2H),0.96(s,9H),0.14(s,6H).
将5-氯甲基-3-氰基吡啶盐酸盐(3.20g,17.0mmol)溶于N,N-二甲基甲酰胺(20mL)中，在冰浴下加入N,N-二异丙基乙胺(5.48g,42.4mmol)和碳酸钾(5.86g,42.4mmol)。搅拌10分钟后，在上述反应液中加入INT-1c(4.25g,14.1mmol)和碘化钾(234mg,1.41mmol)。反应液在冰浴下搅拌30分钟，然后升至50℃搅拌16小时。将反应液在冰浴下冷却，加入100mL水后有固体析出，过滤固体，用水洗涤，干燥，然后固体粗品用硅胶柱层析分离得到白色固体INT-1d(5.00g,收率:84.9％)。MS(ESI):m/z 417.2(M+H) +.
将化合物INT-1d(5.0g,12.0mmol)溶于甲苯(10mL)中，加入乙二醇(14.9g,240mmol)和对甲苯磺酸(228mg,1.20mmol)，然后滴加原甲酸三甲酯(2.55g,24.0mmol)。混合物在氮气氛围下加热至80℃搅拌16小时。反应液在冰浴下冷却，用饱和碳酸氢钠水溶液(50mL)淬灭，水相用乙酸乙酯萃取(100mL x 2)。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到白色固体INT-1e(5.50g,收率:99.5％)。MS(ESI):m/z 461.2(M+H) +.
将化合物INT-1e(2.20g,4.77mmol)溶于四氢呋喃(10mL)中，加入四丁基氟化铵的四氢呋喃溶液(1M,7.16mL)，反应液在30℃条件下搅拌半小时。用水(30mL)稀释，水相用乙酸乙酯萃取(50mL x 2)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用乙酸乙酯和石油醚混合液(v/v＝3/100,20mL)打浆，过滤得到淡黄色固体INT-1f(1.58g,收率:95.5％)。MS(ESI):m/z 347.2(M+H) +.
将化合物INT-1f(1.50g,4.33mmol)溶于二氯甲烷(30mL)中，加入N,N- 二异丙基乙胺(1.68g,13.0mmol)，在0℃和氮气氛围下加入甲磺酸酐(1.51g,8.65mmol)。然后加入N,N-二异丙基乙胺(1.68g,13.0mmol)和盐酸二氧六环(4M,1.62mL)的二氯甲烷(10mL)混合液。反应液在25℃条件下搅拌16小时。用水(30mL)淬灭反应，水相用二氯甲烷萃取(50mL x 2)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到淡黄色固体INT-1g(1.40g,收率:88.6％)。MS(ESI):m/z 365.2(M+H) +.
将化合物INT-1g(1.36g,3.72mmol)，4-溴-1H-吲唑(734mg,3.72mmol)和碳酸钾(1.03g,7.45mmol)溶于N,N-二甲基甲酰胺(10mL)中。混合物在50℃下搅拌16小时。反应液在冰浴下冷却，加入100mL水有固体析出，过滤，用水洗涤，干燥；所得固体粗品再用硅胶柱层析分离得到淡黄色固体INT-1h(1.08g,收率:55.2％)。 1H NMR(500MHz,DMSO-d6)δ8.96(d,J＝2.0Hz,1H),8.82(s,1H),8.27(s,1H),8.05(s,1H),7.70(d,J＝8.5Hz,1H),7.45(s,1H),7.40(d,J＝7.5Hz,1H),7.32(t,J＝7.5Hz,1H),6.91(s,1H),6.04(s,1H),5.71(s,2H),5.16(s,2H),4.04–4.01(m,2H),3.97–3.89(m,2H)；MS(ESI):m/z 525.0(M+H) +.
将化合物INT-1h(1.00g,1.90mmol)溶于四氢呋喃(20mL)中，加入盐酸(4.0M的水溶液,5.0mL)。反应液在30℃条件下搅拌1小时。然后用饱和碳酸氢钠水溶液中和，水相用乙酸乙酯萃取(50mL x 2)。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到淡黄色固体INT-1i(900mg,收率:98.2％)。MS(ESI):m/z 481.0(M+H) +.
将化合物INT-1i(840mg,1.74mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入O-叔丁基-L-丝氨酸叔丁酯(418mg,1.92mmol)和乙酸(209mg,3.48mmol)，反应液在30℃下搅拌1小时。然后向反应液中加入三乙酰氧基硼氢化钠(1.48g,6.96mmol)，反应在30℃下搅拌1小时。然后加入水(50mL)淬灭，水相用乙酸乙酯萃取(50mL x 2)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到淡黄色固体INT-1j(720mg,收率:60.5％)。MS(ESI):m/z 682.1(M+H) +.
将中间体INT-1j(1.00g,1.46mmol)，联硼酸频哪醇酯(558mg,2.20mmol)，醋酸钾(431mg,4.39mmol)和Pd(dppf)Cl 2(107mg,0.15mmol)混合于二氧六环(15mL)中。反应液在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室 温，用乙酸乙酯(100mL)稀释，硅藻土过滤，再用100mL乙酸乙酯洗涤，所得滤液浓缩。残留物用硅胶柱层析分离(二氯甲烷/甲醇,v/v＝20/1)得到淡黄色固体INT-1(600mg,收率:56.1％)。MS(ESI):m/z 730.7(M+H) +.
化合物INT-2的制备：
Figure PCTCN2020138157-appb-000028
将(S)-5-羟甲基-2-吡咯烷酮(10.0g,86.9mmol)溶于无水四氢呋喃(200mL)中，加入邻苯二甲酰亚胺(12.8g,86.9mmol)和三苯基膦(34.2g,130mmol)。在冰浴条件和氮气氛围下向反应液中缓慢滴加偶氮二甲酸二异丙酯(26.4g,130mmol)。反应液升至室温搅拌过夜，过滤所产生的沉淀，干燥得到白色固体INT-2a(11.4g,收率:53.7％)。MS(ESI):m/z 245.1(M+H) +.
将化合物INT-2a(1.0g,4.09mmol)溶于乙醇(20mL)中，加入80％水合肼(512mg,8.19mmol)。反应液加热至85℃搅拌2小时，待反应冷却至室温，过滤除去所产生的沉淀。滤液浓缩后加入二氯甲烷(50mL)，过滤所得滤液进一步真空浓缩后得到黄色油状液体INT-2(430mg,收率:92.0％)。 1H NMR(500MHz,DMSO-d 6)δ7.65(s,1H),3.43–3.37(m,1H),2.47–2.42(m,2H),2.12–2.04(m,2H),2.03–1.96(m,1H),1.66–1.60(m,1H),1.58(s,2H).
化合物INT-3的制备：
Figure PCTCN2020138157-appb-000029
将4-甲酰基苯硼酸频哪醇酯(4.50g,19.4mmol)和1,3-二溴-2-氯苯(10.5g,38.8mmol)溶于二氧六环和水(60mL,v/v＝5/1)的混合溶剂中，加入碳酸钾 (8.04g,58.2mmol)和Pd(dppf)Cl 2(1.42g,1.94mmol)。反应液在氮气氛围下加热至80℃搅拌3小时。用水(100mL)淬灭反应，水相用乙酸乙酯萃取(200mL x 2)。合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯,v/v＝4/1)得到白色固体INT-3a(3.7g,收率:64.6％)。
将化合物INT-3a(1.00g,3.38mmol)溶于N,N-二甲基甲酰胺(10mL)中，依次加入化合物INT-2(541mg,4.74mmol)和醋酸(203mg,3.38mmol)。所得反应液在室温下搅拌1小时，然后加入三乙酰氧基硼氢化钠(2.87g,13.5mmol)。所得反应液进一步在室温下搅拌过夜，用饱和碳酸氢钠水溶液(50mL)淬灭反应，水相用乙酸乙酯萃取(50mL x 3)。合并有机相，依次用水(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色固体INT-3b(1.41g,收率:99.5％)。MS(ESI):m/z 393.3(M+H) +.
将化合物INT-3b(1.41g,3.58mmol)溶于二氯甲烷(15mL)中，依次加入三乙胺(725mg,7.16mmol)和二碳酸二叔丁酯(860mg,3.94mmol)。反应液在室温下搅拌2小时，接着用200mL二氯甲烷稀释；所得有机相依次用水(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(二氯甲烷/甲醇,v/v＝20/1)得到白色固体INT-3(1.55g,收率:87.6％)。 1H NMR(500MHz,DMSO-d 6)δ7.78(dd,J＝7.8Hz,1H),7.69(s,1H),7.44–7.25(m,6H),4.53–4.39(m,2H),3.80–3.70(m,1H),3.26–3.10(m,2H),2.17–1.99(m,3H),1.76–1.66(m,1H),1.38(s,9H)；MS(ESI):m/z 493.3(M+H) +.
化合物INT-4的制备：
Figure PCTCN2020138157-appb-000030
从1,3-二溴-2-甲苯起，参照化合物INT-3的合成方法，可以得到白色固体INT-4。 1H NMR(500MHz,Chloroform-d)δ7.76(d,J＝7.2Hz,1H),7.28–7.22(m,7H),4.53(s,2H),4.05–3.67(m,1H),3.42–3.20(m,2H),2.40(s,3H),2.01–1.90(m,3H),1.82–1.71(m,1H),1.36(s,9H)；MS(ESI):m/z 473.4(M+H) +.
化合物INT-5的制备：
Figure PCTCN2020138157-appb-000031
将化合物INT-3a(1.50g,5.08mmol)溶于N,N-二甲基甲酰胺(20mL)中，依次加入(R)-3-羟基吡咯烷盐酸盐(1.88g,15.2mmol)和无水醋酸钠(1.25g,15.2mmol)。反应液在室温下搅拌过夜。然后加入三乙酰氧基硼氢化钠(4.31g,20.3mmol)，反应液在室温下进一步继续搅拌2小时；用饱和碳酸氢钠水溶液(100mL)淬灭反应，水相用乙酸乙酯萃取(100mL x 2)。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(二氯甲烷/甲醇,v/v＝20/1)得到淡黄色固体INT-5(1.60g,收率:80.6％)。 1H NMR(500MHz,Methanol-d 4)δ7.71–7.67(m,1H),7.46–7.41(m,2H),7.38–7.33(m,2H),7.32(d,J＝7.8Hz,1H),7.25(t,J＝7.8Hz,1H),4.41–4.31(m,1H),3.81–3.66(m,2H),2.88–2.83(m,1H),2.83–2.76(m,1H),2.64–2.58(m,1H),2.56–2.51(m,1H),2.22–2.12(m,1H),1.79–1.70(m,1H)；MS(ESI):m/z 366.1(M+H) +.
化合物INT-6的制备：
Figure PCTCN2020138157-appb-000032
从4-溴-2-甲氧基苯甲醛起，参照化合物INT-1的最后一步Suzuki硼酯化反应得到化合物INT-6a。
从化合物INT-6a起，参照化合物INT-3的合成方法，可以得到化合物INT-6。 1H NMR(500MHz,DMSO-d 6)δ7.78(d,J＝8.0Hz,1H),7.70(s,1H),7.42–7.38(m,1H),7.33(t,J＝7.5Hz,1H),7.11–7.03(m,1H),7.02–7.00(m,1H),6.98–6.93(m,1H),4.47-4.34(m,2H),3.81(s,3H),3.77–3.71(m,1H),3.26–3.17(m,2H),2.18–2.10(m,1H),2.09–2.00(m,2H),1.74–1.64(m,1H),1.47–1.26(m,9H).MS(ESI):m/z 523.2(M+H) +.
化合物INT-7的制备：
Figure PCTCN2020138157-appb-000033
将中间体INT-1i(1.00g,2.08mmol)，联硼酸频那醇酯(635mg,2.50mmol)，醋酸钾(612mg,6.24mmol)和Pd(dppf)Cl 2(152mg,0.21mmol)混合于二氧六环(20mL)溶液中，反应液在氮气氛围下加热至90℃搅拌过夜。待反应液冷却至室温，用乙酸乙酯(100mL)稀释，硅藻土过滤，滤饼再用乙酸乙酯(100mL)进一步洗涤；所得滤液减压浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯,v/v＝1/1)得到淡黄色固体INT-7a(940mg,收率:85.5％)。MS(ESI):m/z 529.2(M+H) +.
将化合物INT-7a(96.4mg,0.18mmol)和化合物INT-3(75.0mg,0.15mmol)溶于二氧六环和水(11mL,v/v＝10/1)的混合溶剂中，加入碳酸钾(63.0mg,0.46mmol)和Pd(dppf)Cl 2(11.1mg,0.015mmol)，混合物在氮气氛围下加热至80℃搅拌3小时。然后用水(50mL)淬灭反应，水相用乙酸乙酯萃取(50mL x 2)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离(二氯甲烷/甲醇,v/v＝95/5)得到淡黄色固体INT-7(120mg,收率:96.9％)。MS(ESI):m/z 815.2(M+H) +.
化合物INT-8的制备：
Figure PCTCN2020138157-appb-000034
从化合物INT-1c和碘甲烷起，参照INT-1i的合成得到化合物INT-8b。MS(ESI):m/z 379.1(M+H) +.
从化合物INT-8b起，参照化合物INT-7的合成得到化合物INT-8c和化合物INT-8。它们的谱图信息如下：
INT-8c: 1H NMR(500MHz,Chloroform-d)δ10.31(s,1H),8.50(s,1H),7.83(s,1H),7.69(d,J＝7.0Hz,1H),7.47(d,J＝8.5Hz,1H),7.44-7.37(m,1H),6.42(s,1H),5.73(s,2H),3.60(s,3H),1.42(s,12H)；MS(ESI):m/z 427.3(M+H) +.
INT-8:MS(ESI):m/z 713.5(M+H) +.
化合物INT-9的制备：
Figure PCTCN2020138157-appb-000035
从化合物INT-8c和化合物INT-6起，参照化合物INT-8的合成得到化合物INT-9。MS(ESI):m/z 743.6(M+H) +.
化合物INT-10的制备：
Figure PCTCN2020138157-appb-000036
从3-溴-2-氯苯酚起，参照化合物INT-7a的合成方法得到化合物INT-10a。MS(ESI):m/z 253.3(M-H) -.
从化合物INT-10a和6-氯-2-甲氧基-3-吡啶甲醛起，参照化合物INT-3a的合成方法得到化合物INT-10b。MS(ESI):m/z 262.0(M-H) -.
将化合物INT-10b(500mg,1.90mmol)溶于无水二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(490mg,3.80mmol)，冰浴冷却至0℃，随后慢慢滴加三氟甲磺酸酐(804mg,2.85mmol)。反应液逐渐升至室温，继续搅拌2小时。用50mL饱和氯化铵水溶液淬灭反应，水相用乙酸乙酯萃取(30mL x 2)。合并有 机相，用50mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到桔黄色油状物INT-10(482mg,收率:64.2％)。MS(ESI):m/z396.2(M+H) +.
化合物INT-11的制备：
Figure PCTCN2020138157-appb-000037
在25℃条件下，将溶有(R)-1-Boc-3-羧基吡咯烷(1.00g,4.65mmol)，碘甲烷(1.00g,7.05mmol)和碳酸钾(2.00g,14.5mmol)的N’N-二甲基甲酰胺(3mL)反应液搅拌3小时。随后加入水(50mL)稀释，并用乙酸乙酯萃取(50mL x 2)；合并有机相，用50mL饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到黄色油状物INT-11a(1.00g,收率:93.9％)。
在溶有化合物INT-11a(1.00g,4.36mmol)的二氯甲烷(2mL)溶液中加入盐酸(4M的1,4-二氧六环溶液，5mL)；反应液在25℃条件下搅拌3小时。所得反应液浓缩后得到黄色固体INT-11(700mg,收率:96.9％)。 1H NMR(500MHz,DMSO-d6)δ9.70(brs,2H),3.66(s,3H),3.42–3.35(m,1H),3.30–3.22(m,2H),3.19–3.13(m,2H),2.22–2.14(m,1H),2.06–1.99(m,1H).
化合物INT-12的制备：
Figure PCTCN2020138157-appb-000038
从化合物INT-8c和化合物INT-5起，参照化合物INT-8的合成得到化合物INT-12。MS(ESI):m/z 586.4(M+H) +.
化合物INT-13的制备：
Figure PCTCN2020138157-appb-000039
在冰浴条件下，将二氯亚砜(11.7g,98.6mmol)加到溶有2-羟基-4-甲基苯甲酸(5.0g,32.9mmol)的甲醇(20mL)溶液；反应液在65℃条件下搅拌16小时。反应液浓缩，残余物中加入乙酸乙酯(100mL)和水(100mL)；有机相用饱和碳酸氢钠溶液(100mL)，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物INT-13a(5.25g,收率:96.1％)。
在溶有化合物INT-13a(5.25g,31.6mmol)的N,N-二甲基甲酰胺(30mL)中加入碘甲烷(5.83g,41.1mmol)和碳酸钾(8.73g,63.2mmol)；反应液在25℃条件下搅拌6小时。反应液浓缩，残余物中加入乙酸乙酯(100mL)和水(100mL)；有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色油状物INT-13b(5.6g,收率:98.4％)。
在溶有化合物INT-13b(1.0g,5.55mmol)的甲醇(15mL)溶液中加入三氟甲磺酸银(1.57g,6.10mmol)和碘(1.55g,6.10mmol)；反应液在25℃条件下搅拌2小时。随后过滤，滤液用乙酸乙酯(50mL)稀释，并用亚硫酸钠水溶液(5％w/w,50mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到橘色固体INT-13(1.6g,收率:94.2％)。 1H NMR(500MHz,Chloroform-d)δ8.20(s,1H),6.86(s,1H),3.88(s,3H),3.87(s,3H),2.45(s,3H)；MS(ESI):m/z 306.9(M+H) +.
化合物INT-14的制备：
Figure PCTCN2020138157-appb-000040
将二氯亚砜(185mg,1.55mol)加入至溶有反式-(N-Boc-4-氨基环己基)乙酸(100mg,0.39mmol)的甲醇(3mL)溶液；反应液在70℃条件下搅拌3小时。反应液浓缩后得到白色固体INT-14(70mg,收率:86.7％)。 1H NMR(500MHz,DMSO-d6)δ8.15–7.92(m,3H),3.56(s,3H),2.87(s,1H),2.21–2.15(m,2H),1.95–1.87(m,2H),1.74–1.66(m,2H),1.63–1.53(m,1H),1.35–1.25(m,2H),1.06–0.95(m,2H).
化合物INT-15的制备：
Figure PCTCN2020138157-appb-000041
在冰浴条件下，在溶有4-溴-2,6-二氟苯甲醛(1.10g,4.98mmol)的甲醇(10mL)溶液中逐滴加入甲醇钠(5.4M的甲醇溶液，1.11mL)；反应液在相同条件下搅拌3小时。反应液用盐酸(1M的水溶液，12mL)淬灭并搅拌10分钟；所得溶液进一步用水(100mL)稀释，并用乙酸乙酯(100mL x 2)萃取。合并有机相用饱和食盐水(150mL)洗涤，无水硫酸钠干燥，浓缩。残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝10/1)纯化得到白色固体INT-15a(660mg,收率:56.9％)和白色固体INT-15b(204mg,收率:16.7％)。
化合物INT-15a: 1H NMR(500MHz,Chloroform-d)δ10.36(s,1H),6.97–6.93(m,2H),3.94(s,3H).
化合物INT-15b: 1H NMR(500MHz,Chloroform-d)δ10.42(s,1H),6.76(s,2H),3.90(s,6H).
从化合物INT-15a起，参照化合物INT-6的合成方法，可以得到化合物INT-15。 1H NMR(500MHz,DMSO-d6)δ7.83(d,J＝8.0Hz,1H),7.71(s,1H),7.45(d,J＝7.8Hz,1H),7.37(t,J＝7.8Hz,1H),6.90–6.86(m,2H),4.54–4.50(m,2H),3.84(s,3H),3.77–3.73(m,1H),3.17(d,J＝5.3Hz,2H),2.12–2.02(m,3H),1.71–1.65(m,1H),1.40–1.32(m,9H)；MS(ESI):m/z 541.5(M+H) +.
化合物INT-16的制备：
Figure PCTCN2020138157-appb-000042
从化合物INT-8c和化合物INT-15起，参照化合物INT-8的合成得到化合物INT-16。MS(ESI):m/z 761.7(M+H) +.
化合物INT-17的制备：
Figure PCTCN2020138157-appb-000043
在110℃条件下，将溶有S-2-氨基己二酸(5g,31mmol)的醋酸和水(25mL,v/v＝1/4)的溶液搅拌16小时。反应液浓缩后所得残余物用乙醇溶解；其中没有反应完的起始原料不会被乙醇所溶解。乙醇滤液浓缩后得到白色固体INT-17a(3g,收率:67.6％)。MS(ESI):m/z 142.1(M-H) –
从化合物INT-17a起，参照化合物INT-13a的合成方法，可以得到无色油状物INT-17b。
在0℃条件下，将硼氢化钠(433mg,11.5mmol)加入溶有化合物INT-17b(450mg,2.9mmol)的乙醇(10mL)溶液中；所得混合液在室温下搅拌16小时。少量醋酸加入去淬灭反应，所得反应液浓缩后所得残余物用二氯甲烷溶解。有机相用少量饱和食盐水洗涤，无水硫酸钠干燥，浓缩后得到无色油状物INT-17c(369mg,收率:99.8％)。MS(ESI):m/z 130.2(M+H) +.
从化合物INT-17c起，参考化合物INT-2的合成方法，可以得到淡黄色油状物INT-17。 1H NMR(500MHz,DMSO-d6)δ7.34(s,1H),3.22–3.06(m,1H),2.59–2.42(m,2H),2.18–1.98(m,2H),1.75(brs,2H),1.64–1.50(m,2H),1.37–1.18(m,2H)。
化合物INT-18的制备：
Figure PCTCN2020138157-appb-000044
从化合物INT-15a起，参照化合物INT-1的最后一步Suzuki硼酯化反应和化合物INT-3a的合成方法，可以得到化合物INT-18a。 1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),7.91–7.87(m,1H),7.52–7.48(m,1H),7.44–7.38(m,1H),7.13–7.10(m,1H),7.04–7.00(m,1H),3.96(s,3H).
从化合物INT-18a起，参照化合物INT-1的最后一步Suzuki硼酯化反应得到化合物INT-18。 1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),7.68–7.64(m,1H),7.55–7.51(m,1H),7.44(t,J＝7.5Hz,1H),7.05(s,1H),6.97–6.89(m,1H),3.93(s,3H),1.31(s,12H)；MS(ESI):m/z 391.7(M+H) +.
实施例化合物的合成
实施例1：
Figure PCTCN2020138157-appb-000045
从化合物INT-1和化合物INT-5起，参照化合物INT-7的合成，得到化合物1a。MS(ESI):m/z 889.9(M+H) +.
将化合物1a(20mg,0.022mmol)溶于二氯甲烷(2mL)中，并加入三氟乙酸(2mL)，反应液在25℃条件下搅拌6小时。反应液浓缩后，残余物用经制备高效液相色谱柱层析纯化得到白色固体1(6.5mg，收率:37.4％)。 1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.84(s,1H),8.33(s,1H),7.87(s,1H),7.72–7.67(m,1H),7.55–7.45(m,7H),7.40(d,J＝8.0Hz,2H),7.18–7.15(m,1H),6.83(s,1H),5.74–5.69(m,2H),5.11–5.05(m,2H),4.24–4.18(m,1H),3.93(d,J＝14.5Hz,1H),3.85(d,J＝14.5Hz,1H),3.65(d,J＝13.0Hz,1H),3.61–3.55(m,2H),3.12–3.07(m,1H),2.72–2.68(m,1H),2.65–2.58(m,2H),2.38–2.32(m,2H),2.05–1.97(m,1H),1.59–1.52(m,1H)；MS(ESI):m/z 777.8(M+H) +.
实施例2：
Figure PCTCN2020138157-appb-000046
从化合物INT-1和化合物INT-4起，参照化合物1的合成，得到化合物2。 1H NMR(500MHz,DMSO-d6)δ8.95(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.34(t,J＝2.0Hz,1H),7.84(s,1H),7.71–7.64(m,2H),7.55(s,1H),7.46–7.37(m,6H),7.34–7.31(m,1H),7.28(d,J＝7.5,1H),7.09(d,J＝7.0Hz,1H),6.86(s,1H),5.71(s,2H),5.14–5.08(m,2H),3.96–3.84(m,2H),3.79–3.74(m,2H),3.64–3.57(m,3H),3.13–3.09(m,1H),2.55(d,J＝6.0Hz,2H),2.15–2.05(m,3H),1.99(s,3H),1.73–1.67(m,1H)；MS(ESI):m/z 784.3(M+H) +.
实施例3：
Figure PCTCN2020138157-appb-000047
从化合物INT-1和化合物INT-3a起，参照化合物INT-7的合成，得到化合物3a。MS(ESI):m/z 818.4(M+H) +.
从化合物3a和***啉起，参照化合物INT-3b合成过程中的还原胺化步骤，得到化合物3b。MS(ESI):m/z 889.9(M+H) +.
从化合物3b起，参照化合物1合成中的最后一步脱Boc保护步骤，得到化合物3。 1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.84(s,1H),8.33(s,1H),7.86(s,1H),7.72-7.67(m,1H),7.56-7.45(m,7H),7.41(d,J＝7.5Hz,2H),7.17(d, J＝7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.13–5.05(m,2H),3.92(d,J＝14.0Hz,1H),3.85(d,J＝14.0Hz,1H),3.63-3.56(m,6H),3.52(s,2H),3.13-3.06(m,1H),2.40(s,4H)；MS(ESI):m/z 777.6(M+H) +.
实施例4：
Figure PCTCN2020138157-appb-000048
从化合物3a和N-甲基乙醇胺起，参照化合物3的合成，得到化合物4。 1H NMR(500MHz,DMSO-d6)δ8.95(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.33(d,J＝2.5Hz,1H),7.87(s,1H),7.71(d,J＝8.5Hz,1H),7.56(s,1H),7.55–7.46(m,6H),7.41(d,J＝8.0Hz,2H),7.17(d,J＝7.0Hz,1H),6.84(s,1H),5.72(s,2H),5.14–5.06(m,2H),3.96(d,J＝14.0Hz,1H),3.88(d,J＝14.0Hz,1H),3.69–3.63(m,1H),3.61–3.58(m,1H),3.57(s,2H),3.54(t,J＝6.5Hz,2H),3.18–3.14(m,1H),2.55–2.53(m,2H),2.20(s,3H)；MS(ESI):m/z 765.7(M+H) +.
实施例5：
Figure PCTCN2020138157-appb-000049
从化合物3a和乙醇胺起，参照化合物3的合成，得到化合物5。 1H NMR(500MHz,DMSO-d6)δ8.94(s,1H),8.83(s,1H),8.32(s,1H),7.86(s,1H),7.70(d,J＝8.5Hz,1H),7.56–7.50(m,3H),7.49–7.43(m,6H),7.17(d,J＝7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.13–5.05(m,2H),3.90(d,J＝14.0Hz,1H),3.86–3.80(m,3H),3.60–3.54(m,2H),3.51(t,J＝6.0Hz,2H),3.10–3.05(m,1H),2.65(t,J＝6.0Hz,2H)；MS(ESI):m/z 751.4(M+H) +.
实施例6：
Figure PCTCN2020138157-appb-000050
从化合物INT-3a和N-甲基乙醇胺起，参照化合物INT-3b合成中的还原胺化步骤，得到化合物6a。MS(ESI):m/z 354.2(M+H) +.
在冰浴条件下，在溶有化合物6a(207mg,0.58mmol)的四氢呋喃(5mL)溶液中依次加入N,N-二异丙基乙胺(226mg,1.75mmol)和甲基磺酸酐(203mg,1.17mmol)。反应液在冰浴条件下搅拌半小时后升温至25℃，并在相同温度下继续搅拌2小时。反应液中加入水(20mL)稀释，水相用二氯甲烷(20mL x 2)萃取，合并有机相用无水硫酸钠干燥，过滤，浓缩得到化合物6b。在冰浴条件和氮气氛围下，在溶有(R)-(-)-3-羟基四氢呋喃(103mg,1.17mmol)的四氢呋喃(5mL)中加入钠氢(60％w/w在煤油中，46.8mg)；反应液在冰浴条件下搅拌半小时，然后加入上述得到的化合物6b。所得反应液升温至50℃搅拌过夜；冷却至室温后，反应液用水(20mL)淬灭，水相用乙酸乙酯(20mL x 2)萃取；合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用制备薄层层析分离(二氯甲烷/甲醇,v/v＝15/1)得到黄色油状物6c(110mg,收率:44.4％)。MS(ESI):m/z 424.3(M+H) +.
从化合物INT-1和化合物6c起，参照化合物1的合成，得到化合物6。 1H NMR(500MHz,DMSO-d6)δ8.94(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.34–8.32(m,1H),7.86(s,1H),7.70(d,J＝8.5Hz,1H),7.55–7.45(m,7H),7.40(d,J＝8.0Hz,2H),7.20–7.15(m,1H),6.81(s,1H),5.72(s,2H),5.12–5.05(m,2H),4.12–4.08(m,1H),3.89–3.77(m,2H),3.73–3.68(m,1H),3.67–3.62(m,3H),3.57(s,2H),3.55–3.48(m,4H),3.02–2.94(m,1H),2.55(t,J＝6.0Hz,2H),2.20(s,3H), 1.94–1.83(m,2H)；MS(ESI):m/z 835.7(M+H) +.
实施例7：
Figure PCTCN2020138157-appb-000051
在冰浴条件下，在溶有化合物INT-3(200mg,0.40mmol)的四氢呋喃(2mL)中加入钠氢(60％w/w在煤油中，32.4mg)，反应液在冰浴条件下继续搅拌半小时。随后在室温条件下，将反应液中加入碘甲烷(86mg,0.61mmol)；所得反应液在室温条件下搅拌过夜。反应液用水(20mL)淬灭，水相用乙酸乙酯(20mL x 2)萃取；合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物硅胶柱层析分离(二氯甲烷/甲醇,v/v＝10/1)得到黄色油状物7a(200mg,收率:97％)。MS(ESI):m/z 507.4(M+H) +.
从化合物INT-1和化合物7a起，参照化合物1的合成，得到化合物7。 1H NMR(500MHz,DMSO-d6)δ8.99–8.90(m,1H),8.90–8.79(m,1H),8.32(s,1H),7.86(s,1H),7.70(d,J＝8.5Hz,1H),7.57–7.43(m,9H),7.17(d,J＝7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.15–5.05(m,2H),3.97–3.91(m,1H),3.89–3.83(m,1H),3.78(s,2H),3.68–3.52(m,3H),3.18–3.10(m,1H),2.73–2.63(m,5H),2.33–2.22(m,1H),2.18–2.08(m,1H),2.06–1.98(m,1H),1.87–1.77(m,1H)；MS(ESI):m/z818.6(M+H) +.
实施例8：
Figure PCTCN2020138157-appb-000052
从化合物INT-1和化合物INT-6起，参照化合物1的合成，得到化合物8。 1H NMR(500MHz,DMSO-d6)δ8.95(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.34(d,J＝2.0Hz,1H),7.88(s,1H),7.74–7.68(m,2H),7.57–7.49(m,4H),7.48–7.45(m,1H),7.42(d,J＝8.0Hz,1H),7.19–7.15(m,1H),7.11–7.04(m,2H),6.85(s,1H),5.72(s,2H),5.15–5.06(m,2H),3.95(d,J＝14.5Hz,1H),3.87(d,J＝14.5Hz,1H),3.83(s,3H),3.76–3.73(m,2H),3.66–3.62(m,2H),3.61–3.55(m,1H),3.15–3.11(m,1H),2.58–2.54(m,2H),2.14–2.06(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 834.7(M+H) +.
实施例9：
Figure PCTCN2020138157-appb-000053
从化合物INT-1和1,3-二溴-2-氯苯起，参照化合物INT-7合成中的最后一步Suzuki反应，得到化合物9a。MS(ESI):m/z 792.6(M+H) +.
从化合物9a起，参照化合物INT-7a的合成，得到化合物9b。MS(ESI):m/z840.6(M+H) +.
从化合物9b和2-溴-5-醛基吡啶起，参照化合物INT-7合成中的最后一步 Suzuki反应，得到化合物9c。MS(ESI):m/z 819.4(M+H) +.
从化合物9c和化合物INT-2起，参照化合物INT-3b合成中的还原胺化步骤，得到化合物9d。MS(ESI):m/z 917.8(M+H) +.
从化合物9d起，参照化合物1合成中的最后一步脱Boc步骤，得到化合物9。 1H NMR(500MHz,DMSO-d6)δ8.96(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.65(d,J＝2.0Hz,1H),8.33(s,1H),7.92–7.83(m,2H),7.75–7.66(m,3H),7.65–7.55(m,3H),7.52–7.44(m,1H),7.21–7.14(m,1H),6.86(s,1H),5.73(s,2H),5.15–5.05(m,2H),3.99–3.73(m,4H),3.69–3.55(m,3H),3.21–3.15(m,1H),2.58–2.52(m,2H),2.18–2.03(m,3H),1.75–1.64(m,1H)；MS(ESI):m/z805.8(M+H) +.
实施例10：
Figure PCTCN2020138157-appb-000054
从化合物9b和5-溴-2-吡啶甲醛起，参照化合物9的合成，得到化合物10。 1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),8.84(s,1H),8.64(s,1H),8.33(s,1H),7.96(d,J＝8.0Hz,1H),7.90(s,1H),7.74–7.69(m,2H),7.62–7.44(m,6H),7.18(d,J＝7.0Hz,1H),6.83(s,1H),5.72(s,2H),5.14–5.05(m,2H),3.93–3.73(m,4H),3.68–3.50(m,3H),3.03–2.94(m,1H),2.58(d,J＝6.2Hz,2H),2.16–2.05(m,3H),1.75–1.66(m,1H)；MS(ESI):m/z 805.3(M+H) +.
实施例11：
Figure PCTCN2020138157-appb-000055
从化合物9b和4-溴-3-甲氧基苯甲醛起，参照化合物9的合成，得到化合物11。 1H NMR(500MHz,DMSO-d6)δ8.88(d,J＝2.0Hz,1H),8.77(d,J＝2.0Hz,1H),8.27–8.25(m,1H),7.73(s,1H),7.66–7.59(m,2H),7.47(s,1H),7.45–7.37(m,3H),7.32–7.28(m,1H),7.15–7.08(m,2H),7.05(s,1H),6.93(d,J＝7.7Hz,1H),6.78(s,1H),5.64(s,2H),5.06–5.00(m,2H),3.87–3.82(m,1H),3.80–3.75(m,1H),3.74–3.67(m,6H),3.58–3.56(m,1H),3.51–3.50(m,1H),3.04–2.99(m,1H),2.51–2.47(m,2H),2.08–1.99(m,3H),1.68–1.59(m,1H)；MS(ESI):m/z 834.7(M+H) +.
实施例12：
Figure PCTCN2020138157-appb-000056
从4-甲酰基苯硼酸频哪醇酯和1,3-二溴-2-氟苯起，参照化合物INT-3a的合成，得到化合物12a。 1H NMR(500MHz,Chloroform-d)δ10.08(s,1H),7.97(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),7.61(t,J＝7.0Hz,1H),7.40(t,J＝7.0Hz,1H),7.14(t,J＝7.5Hz,1H).
从化合物12a，化合物INT-2和化合物INT-1起，参照化合物INT-3和化合物1的合成得到化合物12。 1H NMR(500MHz,DMSO-d6)δ8.93(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.34–8.32(m,1H),8.02(d,J＝2.5Hz,1H),7.72(d,J＝8.5Hz,1H),7.68(s,1H),7.64–7.57(m,4H),7.53(s,1H),7.51–7.42(m,4H),7.30–7.26(m,1H),6.85(s,1H),5.72(s,2H),5.15–5.07(m,2H),3.90(d,J＝14.5Hz,1H),3.85–3.72(m,3H),3.65–3.60(m,1H),3.56(d,J＝5.5Hz,2H),3.07– 2.99(m,1H),2.54–2.52(m,2H),2.14–2.05(m,3H),1.73–1.64(m,1H)；MS(ESI):m/z 788.3(M+H) +.
实施例13：
Figure PCTCN2020138157-appb-000057
从4-甲酰基苯硼酸频哪醇酯和2,6-二溴-苯腈起，参照化合物INT-3a的合成，得到化合物13a。 1H NMR(500MHz,Chloroform-d)δ10.11(s,1H),8.02(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,2H),7.54(t,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H).
从化合物13a，化合物INT-2和化合物INT-1起，参照化合物INT-3和化合物1的合成得到化合物13。 1H NMR(500MHz,DMSO-d6)δ8.94(d,J＝2.0Hz,1H),8.81(d,J＝2.0Hz,1H),8.31–8.29(m,1H),8.07(d,J＝2.5Hz,1H),7.93-7.87(m,1H),7.80–7.72(m,2H),7.70–7.63(m,4H),7.56–7.45(m,4H),7.37–7.33(m,1H),6.70(s,1H),5.78–5.73(m,2H),5.06–4.99(m,2H),3.90(d,J＝15.0Hz,1H),3.84–3.75(m,3H),3.71(d,J＝15.0Hz,1H),3.66–3.61(m,1H),3.58–3.54(m,1H),3.09–3.02(m,1H),2.56–2.53(m,2H),2.14–2.05(m,3H),1.73–1.65(m,1H)；MS(ESI):m/z 795.7(M+H) +.
实施例14：
Figure PCTCN2020138157-appb-000058
从4-甲酰基苯硼酸频哪醇酯和1-溴-3-碘苯起，参照化合物INT-3a的合成，得到化合物14a。
从化合物14a，化合物INT-2和化合物INT-1起，参照化合物INT-3和化合物1的合成得到化合物14。 1H NMR(500MHz,DMSO-d6)δ8.91(d,J＝2.0Hz,1H),8.83(d,J＝2.0Hz,1H),8.32–8.30(m,1H),8.21–8.18(m,1H),7.96–7.94(m,1H),7.76–7.71(m,4H),7.69–7.62(m,3H),7.55(s,1H),7.51–7.44(m,3H),7.38(d,J＝7.0Hz,1H),6.83(s,1H),5.76–5.70(m,2H),5.16–5.08(m,2H),3.94(d,J＝14.0Hz,1H),3.87(d,J＝14.0Hz,1H),3.79(d,J＝14.0Hz,1H),3.75(d,J＝14.0Hz,1H),3.66–3.61(m,2H),3.61–3.55(m,1H),3.15–3.12(m,1H),2.54–2.52(m,2H),2.13–2.04(m,3H),1.72–1.64(m,1H)；MS(ESI):m/z 770.7(M+H) +.
实施例15：
Figure PCTCN2020138157-appb-000059
在室温条件下，将3-溴-4-氯苯胺(2.06g,9.98mmol)溶于硫酸(25％w/w的水溶液,40mL)，并且搅拌半小时；随后将反应液冷却至-5℃，将预先溶有亚硝酸钠(826mg,12.0mmol)的水(10mL)溶液慢慢滴入。滴加完成后，反应液在-5℃的条件下进一步搅拌一小时；随后将预先溶有碘化钾(3.31g,20.0mmol)的乙酸乙酯和水的混合溶液(50mL,v/v＝3/2)，在滴加过程中保证反应内温在-5℃以下。水相进一步用乙酸乙酯(50mL x 2)萃取，合并有机相依次用饱和硫代硫酸钠溶液(100mL x 2)和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物硅胶柱层析分离得到淡黄色固体15a(2.05g,收率:64.7％)。 1H NMR(500MHz,CDCl 3)δ7.95(d,J＝2.0Hz,1H),7.57–7.53(m,1H),7.17(d,J＝8.5Hz,1H).
将4-甲酰基苯硼酸频哪醇酯(439mg,1.89mmol)和化合物15a(500mg, 1.58mmol)溶于二氧六环和水(10mL,v/v＝4/1)的混合溶剂中，加入碳酸氢钠(397mg,4.73mmol)和Pd(dppf)Cl 2(58mg,0.079mmol)。反应液在氮气氛围下加热至80℃搅拌3小时。用水(50mL)淬灭反应，水相用乙酸乙酯萃取(50mL x2)。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯,v/v＝10/1)得到黄色油状物15b(271mg,收率:58.2％)。
从化合物15b，化合物INT-2和化合物INT-1起，参照化合物INT-3和化合物1的合成得到化合物15。 1H NMR(500MHz,DMSO-d6)δ8.93(s,1H),8.84(s,1H),8.34(s,1H),7.85(s,1H),7.81–7.76(m,2H),7.74–7.65(m,5H),7.55–7.40(m,4H),7.25–7.19(m,1H),6.81(s,1H),5.72(s,2H),5.13–5.04(m,2H),3.90–3.83(m,1H),3.78–3.69(m,3H),3.63–3.53(m,3H),3.06–2.97(m,1H),2.57–2.55(m,2H),2.13–2.03(m,3H),1.70–1.63(m,1H)；MS(ESI):m/z 804.7(M+H) +.
实施例16：
Figure PCTCN2020138157-appb-000060
在室温条件下，在溶有3-溴-4-甲基苯胺(584mg,3.14mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入N-氯代丁二酰亚胺(419mg,3.14mmol)；反应液升温至80℃，并且在该温度下搅拌1小时。用水(50mL)淬灭反应，水相用乙酸乙酯萃取(50mL x 2)。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯,v/v＝10/1)得到白色固体16a(292mg,收率:42.2％)。 1H NMR(500MHz,DMSO-d 6)δ6.97(d,J＝8.2Hz,1H),6.70(d,J＝8.2Hz,1H),5.41(s,2H),2.22(s,3H).
从4-甲酰基苯硼酸频哪醇酯和化合物16a起，参照化合物INT-3a的合成，得到化合物16b。
在室温条件下，在溶有化合物16b(100mg,0.41mmol)的乙腈(1mL)溶液中加入亚硝酸叔丁酯(50mg,0.49mmol)和溴化亚铜(91mg,0.63mmol)；反应液升温至60℃，并且在该温度下搅拌一小时。用水(20mL)淬灭反应，水相用乙酸乙酯萃取(20mL x 2)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(石油醚/乙酸乙酯,v/v＝10/1)得到白色固体16c(28mg,收率:22.2％)。 1H NMR(500MHz,Chloroform-d)δ10.09(s,1H),8.02–7.95(m,2H),7.56(d,J＝8.2Hz,1H),7.35(d,J＝8.0Hz,2H),7.08(d,J＝8.2Hz,1H),2.01(s,3H).
从化合物16c，化合物INT-2和化合物INT-1起，参照化合物INT-3和化合物1的合成得到化合物16。 1H NMR(500MHz,DMSO-d6)δ8.98–8.88(m,1H),8.85–8.77(m,1H),8.32–8.23(m,1H),7.81(s,1H),7.67–7.63(m,2H),7.53(s,1H),7.47–7.42(m,3H),7.42–7.39(m,2H),7.27–7.21(m,2H),7.14–7.09(m,1H),6.82(s,1H),5.69(s,2H),5.11–5.04(m,2H),3.95–3.82(m,2H),3.82–3.75(m,2H),3.66–3.61(m,2H),3.59–3.55(m,1H),3.17–3.13(m,1H),2.62–2.56(m,2H),2.14–2.10(m,1H),2.08(s,3H),2.08–2.04(m,1H),2.02–1.92(m,1H),1.74–1.64(m,1H)；MS(ESI):m/z 818.5(M+H) +.
实施例17：
Figure PCTCN2020138157-appb-000061
从3-溴-4-氯苯胺起，参照化合物16的合成，得到化合物17。 1H NMR(500MHz,DMSO-d6)δ8.95–8.88(m,1H),8.85–8.76(m,1H),8.34–8.27(m,1H),7.90–7.84(m,1H),7.72–7.64(m,3H),7.54(d,J＝8.3Hz,1H),7.49–7.40(m,4H),7.29(d,J＝7.7Hz,2H),7.14(d,J＝7.0Hz,1H),6.73(s,1H),5.68(s,2H),5.09–4.99(m,2H),3.80–3.71(m,2H),3.66(s,2H),3.63–3.57(m,1H),3.42–3.34(m, 2H),3.21–3.16(m,1H),2.56–2.52(m,2H),2.13–2.04(m,3H),1.70–1.64(m,1H)；MS(ESI):m/z 838.2(M+H) +.
实施例18：
Figure PCTCN2020138157-appb-000062
从4-溴苯乙醇起，参照化合物INT-7a的合成得到化合物18a。MS(ESI):m/z249.1(M+H) +.
从化合物18a和1,3-二溴-2-甲苯起，参照化合物INT-3a的合成，得到化合物18b。MS(ESI):m/z 311.0(M+H) +.
从化合物18b起，参照化合物6b的合成得到化合物18c。MS(ESI):m/z 389.0(M+H) +.
在50℃条件下，将混有化合物18c(290mg,0.74mmol),(R)-3-羟基吡咯烷盐酸盐(138mg,1.12mmol)和碳酸铯(727mg,2.23mmol)的乙腈(10mL)溶液搅拌16小时。用水(30mL)淬灭反应，水相用乙酸乙酯萃取(30mL x 2)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离(二氯甲烷/甲醇,v/v＝10/1)得到黄色油状物18d(140mg,收率:49.0％)。MS(ESI):m/z 380.2(M+H) +.
从化合物18d和化合物INT-1起，参照化合物1的合成得到化合物18。 1H NMR(500MHz,DMSO-d6)δ8.93(d,J＝2.0Hz,1H),8.83(d,J＝2.0Hz,1H),8.33–8.31(m,1H),7.86(s,1H),7.69(d,J＝8.5Hz,1H),7.53–7.51(m,2H),7.48–7.45(m,2H),7.44–7.41(m,2H),7.34–7.32(m,3H),7.16(d,J＝7.0Hz,1H),6.79(s,1H),5.71(s,2H),5.08(d,J＝3.0Hz,2H),4.20–4.18(m,1H),3.86–3.81(m,2H),3.53–3.51(m,2H),2.97(t,J＝6.0Hz,1H),2.80–2.76(m,4H),2.68–2.63(m,4H),2.00–1.96(m,1H),1.57–1.53(m,1H)；MS(ESI):m/z 791.5(M+H) +.
实施例19：
Figure PCTCN2020138157-appb-000063
从4-溴苯丙醇起，参照化合物18的合成，得到化合物19。 1H NMR(500MHz,DMSO-d6)δ8.94(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.54(s,1H),8.35–8.33(m,1H),7.86(s,1H),7.69(d,J＝8.5Hz,1H),7.55–7.51(m,2H),7.49–7.42(m,5H),7.30(d,J＝8.0Hz,2H),7.16(d,J＝7.0Hz,1H),6.75(s,1H),5.70(s,2H),5.13–4.98(m,2H),4.22–4.15(m,2H),3.71–3.64(m,2H),3.24–3.17(m,3H),2.71–2.63(m,3H),2.56–2.53(m,1H),2.42–2.38(m,3H),2.30–2.27(m,1H),2.01–1.93(m,1H),1.79–1.73(m,2H),1.56–1.50(m,1H)；MS(ESI):m/z 805.7(M+H) +.
实施例20：
Figure PCTCN2020138157-appb-000064
在25℃条件下，将N-氯代丁二酰亚胺(639mg,4.78mmol)分批加入至溶有2,6-二溴苯胺(1.00g,3.99mmol)的乙腈(20mL)溶液中；所得反应液在相同温度下搅拌16小时。反应液中加水，有固体析出；所得到的固体进一步用水洗涤，干燥后得到白色固体20a(1.10g,收率:96.7％)。 1H NMR(500MHz,DMSO-d6)δ7.53(s,2H),5.48(s,2H).
从化合物20a起，参照化合物16c的合成，其中将溴化亚铜换成氯化亚铜，得到化合物20b。 1H NMR(500MHz,DMSO-d6)δ8.00(s,2H).
从化合物20b起，参照化合物12的合成，得到化合物20。 1H NMR(500MHz,DMSO-d6)δ8.95–8.88(m,1H),8.83–8.76(m,1H),8.32–8.23(m,1H),7.90(s,1H),7.70(d,J＝8.5Hz,1H),7.68–7.64(m,1H),7.61–7.58(m,1H),7.56–7.41(m,7H),7.21–7.14(m,1H),6.79–6.66(m,1H),5.70(s,2H),5.13–5.01(m,2H),3.83–3.70(m,4H),3.61(t,J＝6.5Hz,1H),3.51–3.47(m,1H),3.44–3.41(m,1H),2.86(s,1H),2.53–2.52(m,2H),2.16–2.00(m,3H),1.73–1.63(m,1H)；MS(ESI):m/z 838.3(M+H) +.
实施例21：
Figure PCTCN2020138157-appb-000065
在25℃条件下，将N-溴代丁二酰亚胺(6.28g,35.3mmol)分批加入至溶有5-氯-2-甲基苯胺(2.00g,14.1mmol)的乙腈(30mL)溶液中；所得反应液在相同温度下搅拌16小时。用水(100mL)淬灭反应，水相用乙酸乙酯萃取(100mL x 3)。合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到深红色固体21a(4.00g,收率:94.6％)。 1H NMR(500MHz,Chloroform-d)δ7.27(s,1H),4.25(s,2H),2.18(s,3H).
在25℃条件和氮气氛围下，将亚硝酸叔丁酯(3.91g,33.4mmol)缓慢滴加至溶有化合物21a(4.00g,13.4mmol)的乙醇(30mL)溶液；反应液在50度条件下搅拌2小时。反应液冷却后浓缩，所得残余物用硅胶柱层析分离得到白色固体21b(2.1g,收率:55.3％)。 1H NMR(500MHz,Chloroform-d)δ7.41(s,2H),2.29(s,3H).
从化合物21b起，参照化合物12的合成，得到化合物21。 1H NMR(500MHz,DMSO-d6)δ8.93(d,J＝2.0Hz,1H),8.82(d,J＝2.0Hz,1H),8.31–8.29(m,1H),7.84(s,1H),7.72–7.63(m,2H),7.53(s,1H),7.48–7.39(m,5H),7.33–7.25(m,2H),7.13(d,J＝7.0Hz,1H),6.82(s,1H),5.70(s,2H),5.14–5.04(m,2H),3.93(d, J＝14.5Hz,1H),3.85(d,J＝14.5Hz,1H),3.80–3.73(m,2H),3.67–3.54(m,3H),3.14(t,J＝5.5Hz,1H),2.54–2.53(m,2H),2.38(s,3H),2.12–2.04(m,3H),1.72–1.64(m,1H)；MS(ESI):m/z 818.8(M+H) +.
实施例22：
Figure PCTCN2020138157-appb-000066
从化合物INT-7和甘氨酸叔丁酯起，参照化合物INT-1j合成中的还原胺化以及化合物1合成中的脱Boc保护基步骤得到化合物22。 1H NMR(500MHz,DMSO-d6)δ8.95(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.34–8.32(m,1H),7.87(s,1H),7.71(d,J＝8.5Hz,1H),7.67(s,1H),7.56–7.46(m,9H),7.17(d,J＝7.0Hz,1H),6.86(s,1H),5.73(s,2H),5.11(s,2H),3.93(s,2H),3.90–3.82(m,2H),3.71–3.67(m,1H),3.18(s,2H),2.73–2.61(m,2H),2.17–2.09(m,3H),1.75–1.69(m,1H)；MS(ESI):m/z 774.7(M+H) +.
实施例23：
Figure PCTCN2020138157-appb-000067
从化合物INT-7和丝氨酸异丙酯起，参照化合物22的合成得到化合物23。 1H NMR(500MHz,DMSO-d6)δ8.97(d,J＝1.9Hz,1H),8.83(d,J＝1.9Hz,1H),8.30(d,J＝1.9Hz,1H),7.87(s,1H),7.74–7.68(m,2H),7.55–7.43(m,9H),7.17(d,J＝7.0Hz,1H),6.85(s,1H),5.71(s,2H),5.09(s,2H),4.86–4.80(m,1H),3.81 –3.72(m,3H),3.66–3.60(m,2H),3.54(d,J＝5.0Hz,2H),3.19(t,J＝5.0Hz,1H),2.56–2.54(m,2H),2.14–2.07(m,3H),1.74–1.65(m,1H),1.11(d,J＝6.0Hz,3H),1.08(d,J＝6.5Hz,3H)；MS(ESI):m/z 846.7(M+H) +.
实施例24：
Figure PCTCN2020138157-appb-000068
从化合物INT-7和乙醇胺起，参照化合物22的合成得到化合物24。 1H NMR(500MHz,DMSO-d6)δ8.96(d,J＝2.0Hz,1H),8.83(d,J＝2.0Hz,1H),8.29(s,1H),7.87(s,1H),7.71(d,J＝9.5Hz,2H),7.54(t,J＝7.5Hz,1H),7.52–7.43(m,8H),7.17(d,J＝7.0Hz,1H),6.84(s,1H),5.72(s,2H),5.09(s,2H),3.79(d,J＝13.5Hz,1H),3.77–3.73(m,3H),3.66–3.61(m,1H),3.47(t,J＝5.5Hz,2H),2.59(t,J＝5.5Hz,2H),2.57–2.54(m,2H),2.15–2.06(m,3H),1.72–1.66(m,1H)；MS(ESI):m/z 760.6(M+H) +.
实施例25：
Figure PCTCN2020138157-appb-000069
从化合物INT-7和脯氨酸叔丁酯起，参照化合物22的合成得到化合物25。 1H NMR(500MHz,DMSO-d6)δ8.95(d,J＝2.0Hz,1H),8.82(d,J＝2.0Hz,1H),8.35–8.33(m,1H),7.88(s,1H),7.72–7.68(m,2H),7.55–7.44(m,9H),7.17(d,J＝7.0Hz,1H),6.82(s,1H),5.72(s,2H),5.14–5.06(m,2H),3.98(d,J＝14.0Hz,1H),3.82(d,J＝14.0Hz,1H),3.77(d,J＝7.5Hz,2H),3.65–3.62(m,1H),3.05– 3.02(m,1H),2.56–2.54(m,2H),2.15–2.03(m,5H),1.90–1.84(m,1H),1.81–1.65(m,4H)；MS(ESI):m/z 814.8(M+H) +.
实施例26：
Figure PCTCN2020138157-appb-000070
从化合物INT-1j起，参照化合物INT-1j合成中的还原胺化以及化合物INT-1合成中硼酯化步骤得到化合物26b。MS(ESI):m/z 744.6(M+H) +.
从化合物26b和化合物INT-3起，参照化合物1的合成得到化合物26。 1H NMR(500MHz,DMSO-d6)δ8.94(d,J＝2.0Hz,1H),8.80(d,J＝2.0Hz,1H),8.27(s,1H),7.87(s,1H),7.72–7.68(m,2H),7.57–7.43(m,9H),7.17(d,J＝7.0Hz,1H),6.80(s,1H),5.71(s,2H),5.09(s,2H),3.82–3.69(m,6H),3.66–3.58(m,2H),2.55(d,J＝6.0Hz,2H),2.28(s,3H),2.14–2.07(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 818.8(M+H) +.
实施例27：
Figure PCTCN2020138157-appb-000071
从化合物INT-7起，参照化合物1合成过程中的脱Boc保护基步骤得到化合物27a。MS(ESI):m/z 715.5(M+H) +.
在25℃条件下，在溶有化合物27a(45mg,0.054mmol)的N’N-二甲基甲酰胺(2mL)中加入(R)-3-羟基吡咯烷盐酸盐(21mg,0.14mmol)和N,N-二异丙基乙胺(70mg,0.54mmol)；所得反应液在相同温度下搅拌一小时。随后加入三醋酸硼氢化钠(58mg,0.27mmol)，反应液进一步在25℃条件下搅拌16小时。反应液中加入水(20mL)；并用乙酸乙酯(15mL x 2)萃取。有机相浓缩，残余物用经制备高效液相色谱柱层析纯化得到白色固体27(10mg，收率:22.6％)。 1H NMR(500MHz,DMSO-d6)δ8.93(d,J＝2.0Hz,1H),8.79(d,J＝2.0Hz,1H),8.26–8.24(m,1H),7.85(s,1H),7.71–7.65(m,2H),7.52–7.40(m,9H),7.15(d,J＝6.9Hz,1H),6.80(s,1H),5.69(s,2H),5.07(s,2H),3.77(d,J＝12.5Hz,1H),3.74(d,J＝12.5Hz,1H),3.62–3.56(m,3H),2.92–2.86(m,1H),2.69–2.61(m,2H),2.54–2.52(m,4H),2.11–2.05(m,3H),1.95–1.90(m,2H),1.70–1.64(m,1H)；MS(ESI):m/z 814.8(M+H) +.
实施例28：
Figure PCTCN2020138157-appb-000072
从化合物INT-7a，化合物INT-6和丝氨酸异丙酯起，参照化合物INT-7和化合物23的合成得到化合物28。 1H NMR(500MHz,DMSO-d6)δ8.96(d,J＝2.0Hz,1H),8.82(d,J＝2.0Hz,1H),8.30–8.28(m,1H),7.88(s,1H),7.71(d,J＝8.6Hz,1H),7.68(s,1H),7.56–7.47(m,4H),7.46(s,1H),7.42(d,J＝7.7Hz,1H),7.17(d,J＝7.1Hz,1H),7.09(d,J＝1.6Hz,1H),7.08–7.04(m,1H),6.84(s,1H),5.71(s,2H),5.09(s,2H),4.87–4.81(m,1H),4.78(t,J＝5.8Hz,1H),3.83(s,3H),3.77(d,J＝14.7Hz,1H),3.75–3.73(m,1H),3.66–3.60(m,2H),3.54(t,J＝5.6Hz,2H),3.30–3.28(m,1H),3.19(t,J＝5.3Hz,1H),2.56(d,J＝6.0Hz,2H),2.16–2.05(m, 3H),1.75–1.64(m,1H),1.11(d,J＝6.2Hz,3H),1.09(d,J＝6.2Hz,3H)；MS(ESI):m/z 876.2(M+H) +.
实施例29：
Figure PCTCN2020138157-appb-000073
从化合物INT-10，化合物INT-2，化合物INT-7a和乙醇胺起，参照化合物INT-3，化合物INT-7和化合物23的合成得到化合物29。 1H NMR(500MHz,DMSO-d6)δ8.97(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),8.33–8.31(m,1H),7.85(s,1H),7.83(d,J＝7.5Hz,1H),7.73(d,J＝9.0Hz,1H),7.72(s,1H),7.69–7.65(m,1H),7.60–7.54(m,2H),7.52–7.47(m,2H),7.32(d,J＝7.5Hz,1H),7.18(d,J＝7.0Hz,1H),6.87(s,1H),5.72(s,2H),5.11(s,2H),3.92(s,3H),3.80(s,2H),3.72(d,J＝4.0Hz,2H),3.66–3.62(m,1H),3.48(t,J＝5.5Hz,2H),2.64(t,J＝5.5Hz,2H),2.56(d,J＝6.0Hz,2H),2.14–2.07(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 791.6(M+H) +.
实施例30：
Figure PCTCN2020138157-appb-000074
从化合物INT-8和O-叔丁基-L-丝氨酸叔丁酯起，参照化合物22的合成得到化合物30。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.78(d,J＝8.5Hz,1H),7.69(s,1H),7.56–7.44(m,9H),7.17(d,J＝7.0Hz,1H),6.72(s,1H),5.75(s,2H),3.89(d,J＝14.5Hz,1H),3.83–3.75(m,3H),3.68–3.63(m,2H),3.61(s,3H),3.60 –3.57(m,1H),3.14(t,J＝5.5Hz,1H),2.57(d,J＝6.5Hz,2H),2.16–2.07(m,3H),1.74–1.67(m,1H)；MS(ESI):m/z 702.5(M+H) +.
实施例31：
Figure PCTCN2020138157-appb-000075
从化合物INT-8和(R)-(-)-4-氨基-3-羟基丁酸起，参照化合物27的合成得到化合物31。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.55–7.50(m,2H),7.49–7.43(m,7H),7.17(d,J＝7.0Hz,1H),6.69(s,1H),5.74(s,2H),3.94–3.90(m,1H),3.80–3.77(m,2H),3.69–3.68(m,2H),3.65–3.63(m,1H),3.60(s,3H),2.57–2.53(m,4H),2.45–2.39(m,1H),2.28–2.22(m,1H),2.13–2.05(m,3H),1.75–1.65(m,1H)；MS(ESI):m/z 716.7(M+H) +.
实施例32：
Figure PCTCN2020138157-appb-000076
从化合物INT-8和甘氨酸叔丁酯起，参照化合物22的合成得到化合物32。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J＝9.0Hz,1H),7.67(s,1H),7.55–7.50(m,2H),7.49–7.42(m,7H),7.17(d,J＝7.0Hz,1H),6.70(s,1H),5.74(s,2H),3.80–3.72(m,4H),3.65–3.62(m,1H),3.60(s,3H),3.07(s,2H),2.55–2.53(m,2H),2.14–2.07(m,3H),1.72–1.66(m,1H)；MS(ESI):m/z 672.6(M+H) +.
实施例33：
Figure PCTCN2020138157-appb-000077
从化合物INT-8和化合物INT-11起，参照化合物INT-5的合成得到化合物33a。MS(ESI):m/z 826.7(M+H) +.
在25℃条件下，在溶有化合物33a(90mg,0.11mmol)的甲醇和水(9mL,v/v＝8/1)的混合溶液中加入氢氧化锂(10mg,0.42mmol)；反应液在相同温度下搅拌一小时。反应液浓缩后加饱和氯化铵稀释，水相用乙酸乙酯(10mL x 2)萃取；合并有机相浓缩。残余物溶于二氯甲烷和三氟乙酸的混合溶液(4mL,v/v＝3/1)，在25℃条件下进一步反应2小时。反应液浓缩后，残余物用经制备高效液相色谱柱层析纯化得到白色固体33(10.3mg，收率:23.5％)。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.69(s,1H),7.55–7.50(m,2H),7.49–7.43(m,6H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.83–3.74(m,2H),3.67–3.62(m,1H),3.58(s,3H),3.56–3.48(m,2H),2.95–2.88(m,1H),2.68–2.64(m,2H),2.59–2.54(m,2H),2.54–2.51(m,1H),2.15–2.06(m,3H),1.98–1.90(m,2H),1.74–1.66(m,1H)；MS(ESI):m/z 712.7(M+H) +.
实施例34：
Figure PCTCN2020138157-appb-000078
从(R)-1-Boc-3-羧基吡咯烷起，参照化合物INT-11的合成得到化合物34a。
从化合物34a和化合物INT-8起，参照化合物33的合成得到化合物34。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.43(m,8H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),6.67(s,1H),5.73(s,2H),3.81–3.73(m,2H),3.66–3.61(m,1H),3.58(s,3H),3.56–3.47(m,2H),2.92–2.86(m,1H),2.69–2.62(m,2H),2.56–2.53(m,2H),2.49–2.46(m,1H),2.14–2.07(m,3H),1.96–1.90(m,2H),1.74–1.66(m,1H)；MS(ESI):m/z 712.7(M+H) +.
实施例35：
Figure PCTCN2020138157-appb-000079
从N-Boc-(R)-3-甲酸哌啶，参照化合物INT-11的合成得到化合物35a。
从化合物35a和化合物INT-8起，参照化合物33的合成得到化合物35。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.42(m,8H),7.39(s,1H),7.17(d,J＝7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.80–3.73(m,2H),3.65–3.61(m,1H),3.58(s,3H),3.41(s,2H),2.78–2.72(m,1H),2.59–2.53(m,3H),2.44–2.40(m,1H),2.24–2.18(m,1H),2.13–2.04(m,4H),1.79–1.73(m,1H),1.72–1.67(m,1H),1.64–1.59(m,1H),1.50–1.42(m,1H),1.40–1.33(m,1H)；MS(ESI):m/z 726.7(M+H) +.
实施例36：
Figure PCTCN2020138157-appb-000080
从N-Boc-(S)-3-甲酸哌啶，参照化合物INT-11的合成得到化合物36a。
从化合物36a和化合物INT-8起，参照化合物33的合成得到化合物36。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.50(m,2H),7.49–7.43(m,6H),7.39(s,1H),7.17(d,J＝7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.83–3.74(m,2H),3.66–3.63(m,1H),3.58(s,3H),3.42(s,2H),2.77–2.73(m,1H),2.56(m,3H),2.45–2.39(m,1H),2.23–2.16(m,1H),2.15–2.04(m,4H),1.79–1.73(m,1H),1.72–1.66(m,1H),1.64–1.59(m,1H),1.50–1.42(m,1H),1.41–1.33(m,1H)；MS(ESI):m/z 726.7(M+H) +.
实施例37：
Figure PCTCN2020138157-appb-000081
从4-哌啶甲酸甲酯和化合物INT-8起，参照化合物33的合成得到化合物37。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.78–7.76(m,1H),7.67(s,1H),7.53–7.46(m,7H),7.35(s,1H),7.32(s,1H),7.17(d,J＝7.0Hz,1H),6.69(s,1H),5.73(s,2H),3.81–3.73(m,2H),3.65–3.62(m,1H),3.58(s,3H),3.52–3.50(m,2H),2.80–2.77(m,1H),2.74–2.70(m,1H),2.20–2.15(m,1H),2.13–2.08(m,3H),2.02–1.98(m,4H),1.78–1.74(m,2H),1.72–1.67(m,1H),1.56–1.52(m,2H)；MS(ESI):m/z 726.7(M+H) +.
实施例38：
Figure PCTCN2020138157-appb-000082
从3-甲酸甲酯氮杂环丁烷盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物38。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J＝8.5Hz, 1H),7.68(s,1H),7.55–7.44(m,8H),7.27(s,1H),7.17(d,J＝7.0Hz,1H),6.67(s,1H),5.72(s,2H),3.84–3.77(m,2H),3.68–3.63(m,1H),3.58(s,3H),3.47(s,2H),3.42–3.38(m,2H),3.23–3.17(m,3H),2.58(d,J＝6.0Hz,2H),2.16–2.06(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 698.7(M+H) +.
实施例39：
Figure PCTCN2020138157-appb-000083
从止血环酸甲酯盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物39。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.69(s,1H),7.55–7.50(m,2H),7.48–7.41(m,7H),7.17(d,J＝7.0Hz,1H),6.70(s,1H),5.74(s,2H),3.83–3.75(m,2H),3.68(s,2H),3.67–3.62(m,1H),3.60(s,3H),2.57(d,J＝6.0Hz,2H),2.40(d,J＝6.5Hz,2H),2.15–2.06(m,4H),1.88(d,J＝11.0Hz,2H),1.80(d,J＝11.0Hz,2H),1.74–1.67(m,1H),1.43–1.37(m,1H),1.32–1.22(m,2H),0.94–0.84(m,2H)；MS(ESI):m/z 754.8(M+H) +.
实施例40：
Figure PCTCN2020138157-appb-000084
从反式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物40。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.79(d,J＝8.5Hz,1H),7.67(s,1H),7.56–7.51(m,3H),7.50–7.45(m,6H),7.18(d,J＝7.0Hz,1H),6.78(s,1H),5.76(s,2H),3.95(s,2H),3.88–3.80(m,2H),3.69–3.65(m,1H),3.64(s,3H),2.81(s,1H),2.62(d,J＝6.5Hz,2H),2.18–2.09(m,4H),2.04(d,J＝11.0Hz,2H),1.94(d,J＝11.0Hz,2H),1.75–1.67(m,1H),1.37–1.22(m,4H)；MS(ESI):m/z 740.7(M+H) +.
实施例41：
Figure PCTCN2020138157-appb-000085
从顺式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物41。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.78(d,J＝8.5Hz,1H),7.67(s,1H),7.56–7.51(m,3H),7.50–7.45(m,6H),7.18(d,J＝7.0Hz,1H),6.76(s,1H),5.76(s,2H),3.92–3.78(m,4H),3.69–3.66(m,1H),3.63(s,3H),2.87–2.83(m,1H),2.61(d,J＝6.0Hz,2H),2.46–2.44(m,1H),2.15–2.07(m,3H),2.00–1.92(m,2H),1.81–1.67(m,3H),1.53–1.44(m,4H)；MS(ESI):m/z 740.7(M+H) +.
实施例42：
Figure PCTCN2020138157-appb-000086
从反式-4-羟基-L-脯氨酸甲酯盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物42。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.55–7.50(m,2H),7.49–7.43(m,7H),7.17(d,J＝7.0Hz,1H),6.69(d,J＝7.0Hz,1H),5.74(s,2H),4.21–4.15(m,1H),3.87–3.82(m,1H),3.80–3.76(m,2H),3.67–3.62(m,2H),3.61–3.57(m,3H),3.50–3.45(m,1H),3.21–3.19(m,1H),2.58–2.53(m,3H),2.13–2.07(m,3H),2.02–1.90(m,1H),1.81–1.75(m,1H),1.73–1.67(m,1H)；MS(ESI):m/z 728.7(M+H) +.
实施例43：
Figure PCTCN2020138157-appb-000087
从L-脯氨酸甲酯盐酸盐和化合物INT-8起，参照化合物33的合成得到化合物43。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.78(d,J＝8.5Hz,1H),7.69(s,1H),7.55–7.43(m,10H),7.17(d,J＝7.0Hz,1H),6.70(s,1H),5.75(s,2H),3.93(d,J＝14.0Hz,1H),3.84–3.77(m,3H),3.67–3.62(m,1H),3.60(s,3H),3.37–3.33(m,1H),3.10–3.04(m,1H),2.59–2.52(m,3H),2.14–2.05(m,4H),1.90–1.83(m,1H),1.80–1.74(m,1H),1.73–1.66(m,2H)；MS(ESI):m/z 712.7(M+H) +.
实施例44：
Figure PCTCN2020138157-appb-000088
从化合物INT-8和4-氨甲基苯甲酸甲酯盐酸盐起，参照化合物INT-5的合成得到化合物44a。MS(ESI):m/z 862.7(M+H) +.
从化合物44a起，参照化合物INT-1j合成中的还原胺化步骤得到化合物44b。MS(ESI):m/z 876.8(M+H) +.
从化合物44b起，参照化合物33合成中的最后两步得到化合物44。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.88(d,J＝8.0Hz,2H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.54–7.50(m,2H),7.49–7.44(m,7H),7.40(d,J＝7.5Hz,2H),7.17(d,J＝7.0Hz,1H),6.68(s,1H),5.74(s,2H),3.81–3.73(m,2H),3.66–3.62(m,1H),3.59–3.53(m,2H),3.57(s,3H),3.45(s,2H),2.56–2.53(m,2H),2.14–2.07(m,6H),1.72–1.66(m,1H)；MS(ESI):m/z 762.7(M+H) +.
实施例45：
Figure PCTCN2020138157-appb-000089
从化合物INT-8和对氨基苯乙酸甲酯起，参照化合物44的合成得到化合物45。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.54–7.50(m,2H),7.49–7.43(m,6H),7.17(d,J＝7.0Hz,1H),7.02(d,J＝8.0Hz,2H),6.92(s,1H),6.75(s,1H),6.55(d,J＝8.0Hz,2H),5.72(s,2H),4.41(s,2H),3.81–3.73(m,2H),3.66–3.61(m,4H),3.35(s,2H),2.98(s,3H),2.58–2.53(m,2H),2.14–2.06(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 762.7(M+H) +.
实施例46：
Figure PCTCN2020138157-appb-000090
从化合物INT-8和对氨基苯甲酸甲酯起，参照化合物44的合成得到化合物46。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.79(d,J＝8.6Hz,1H),7.74–7.70(m,2H),7.64–7.60(m,5H),7.59–7.50(m,3H),7.50–7.46(m,1H),7.17(d,J＝7.1Hz,1H),6.87(s,1H),6.85–6.81(m,1H),6.68–6.63(m,2H),5.72(s,2H),4.53(s,2H),4.25(s,2H),3.91–3.85(m,1H),3.68(s,3H),3.09(s,3H),2.57–2.53(m,2H),2.23–2.14(m,3H),1.83–1.77(m,1H)；MS(ESI):m/z 748.7(M+H) +.
实施例47：
Figure PCTCN2020138157-appb-000091
从化合物INT-8和止血环酸甲酯盐酸盐起，参照化合物44的合成得到化合物47。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.67(s,1H),7.53–7.40(m,8H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.78–3.71(m,2H),3.64–3.60(m,1H),3.55(s,3H),3.35–3.31(m,2H),2.53–2.51(m,2H),2.13–2.07(m,4H),2.07(s,3H),2.01–1.96(m,1H),1.85–1.76(m,4H),1.71–1.65(m,1H),1.46–1.39(m,1H),1.28–1.17(m,3H),0.82–0.73(m,2H)；MS(ESI):m/z 768.4(M+H) +.
实施例48：
Figure PCTCN2020138157-appb-000092
从4-溴-2-甲基苯甲醛起，参照化合物INT-7a的硼酯化合成步骤得到化合物48a。 1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),7.79(d,J＝7.5Hz,1H),7.66(d,J＝7.5Hz,1H),7.60(s,1H),2.61(s,3H),1.29(s,12H).
从化合物48a和1,3-二溴-2-氯苯起，参照化合物INT-3a的合成得到化合物48b。 1H NMR(500MHz,DMSO-d6)δ10.27(s,1H),7.89(d,J＝7.9Hz,1H),7.85–7.81(m,1H),7.48–7.34(m,4H),2.66(s,3H).
从化合物48b，化合物INT-2，化合物INT-8c和化合物INT-11起，参照化合物INT-3，化合物INT-8和化合物33的合成得到化合物48。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J＝8.6Hz,1H),7.67(s,1H),7.53–7.38(m,5H), 7.35(s,1H),7.30–7.23(m,2H),7.14(d,J＝7.0Hz,1H),6.66(s,1H),5.71(s,2H),3.74–3.67(m,2H),3.65–3.61(m,1H),3.56(s,3H),3.52–3.48(m,2H),2.92–2.85(m,1H),2.64–2.61(m,2H),2.59–2.56(m,2H),2.34(s,3H),2.11–2.05(m,3H),1.94–1.89(m,2H),1.71–1.66(m,1H)；MS(ESI):m/z 726.2(M+H) +.
实施例49：
Figure PCTCN2020138157-appb-000093
从4-溴-2-氯苯甲醛起，参照化合物48的合成得到化合物49。 1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.77(d,J＝8.5Hz,1H),7.69(s,1H),7.65(d,J＝7.9Hz,1H),7.59(d,J＝1.8Hz,1H),7.57–7.45(m,5H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),6.68(s,1H),5.73(s,2H),3.90–3.80(m,2H),3.70–3.61(m,1H),3.58(s,3H),3.56–3.49(m,2H),2.96–2.86(m,1H),2.69–2.63(m,2H),2.61–2.56(m,2H),2.53–2.50(m,2H),2.17–2.06(m,3H),1.97–1.90(m,2H),1.75–1.66(m,1H)；MS(ESI):m/z 746.6(M+H) +.
实施例50：
Figure PCTCN2020138157-appb-000094
从4-溴-3-氯苯甲醛起，参照化合物48的合成得到化合物50。 1H NMR(500MHz,DMSO-d6)δ7.80(s,1H),7.76(d,J＝8.5Hz,1H),7.66(s,1H),7.57–7.47(m,4H),7.39–7.38(m,3H),7.34(s,1H),7.16(d,J＝7.0Hz,1H),6.66(s,1H),5.71(s,2H),3.80–3.72(m,2H),3.63–3.60(m,1H),3.56(s,3H),3.53–3.47(m,2H),2.90–2.83(m,1H),2.65–2.59(m,2H),2.55–2.51(m,2H),2.47–2.45(m,2H),2.14– 2.03(m,3H),1.95–1.87(m,2H),1.72–1.63(m,1H)；MS(ESI):m/z 746.5(M+H) +.
实施例51：
Figure PCTCN2020138157-appb-000095
从4-溴-2-(三氟甲氧基)苯甲醛起，参照化合物48的合成得到化合物51。 1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.82–7.73(m,2H),7.69(s,1H),7.61–7.50(m,5H),7.51–7.48(m,1H),7.38(s,1H),7.19(d,J＝7.0Hz,1H),6.69(s,1H),5.75(s,2H),3.88-3.80(m,2H),3.65(t,J＝6.5Hz,1H),3.59(s,3H),3.57–3.49(m,2H),2.85-2.75(m,1H),2.70–2.60(m,2H),2.60–2.55(m,2H),2.56–2.53(m,1H),2.50–2.43(m,1H),2.18–2.08(m,3H),1.98–1.85(m,2H),1.77–1.67(m,1H)；MS(ESI):m/z 796.7(M+H) +.
实施例52：
Figure PCTCN2020138157-appb-000096
从化合物INT-9和化合物INT-11起，参照化合物33的合成得到化合物52。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.77(d,J＝8.6Hz,1H),7.68(s,1H),7.57–7.47(m,4H),7.42(d,J＝7.7Hz,1H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.7Hz,1H),7.08–7.04(m,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.75–3.72(m,2H),3.66–3.62(m,1H),3.59(s,3H),3.55–3.50(m,2H),2.95–2.87(m,1H),2.70–2.62(m,2H),2.60–2.54(m,2H),2.53–2.51(m,2H),2.17– 2.04(m,3H),1.97–1.90(m,2H),1.75–1.65(m,1H)；MS(ESI):m/z 742.2(M+H) +.
实施例53：
Figure PCTCN2020138157-appb-000097
从化合物INT-9和O-叔丁基-L-丝氨酸叔丁酯起，参照化合物22的合成得到化合物53。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.78(d,J＝8.4Hz,1H),7.67(s,1H),7.55–7.48(m,5H),7.42(d,J＝7.7Hz,1H),7.17(d,J＝7.0Hz,1H),7.10(s,1H),7.07(d,J＝8.1Hz,1H),6.73(s,1H),5.74(s,2H),3.88(d,J＝14.6Hz,1H),3.84(s,3H),3.81–3.74(m,3H),3.68–3.63(m,2H),3.61(s,3H),3.60–3.57(m,1H),3.14(t,J＝5.4Hz,1H),2.62–2.57(m,2H),2.18–2.04(m,3H),1.76–1.66(m,1H)；MS(ESI):m/z 732.6(M+H) +.
实施例54：
Figure PCTCN2020138157-appb-000098
从化合物INT-9和止血环酸甲酯盐酸盐起，参照化合物33的合成得到化合物54。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.6Hz,1H),7.67(s,1H),7.57–7.45(m,5H),7.45–7.39(m,2H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.6Hz,1H),7.06(d,J＝7.2Hz,1H),6.70(s,1H),5.73(s,2H),3.83(s,3H),3.75–3.73(m,2H),3.66–3.62(m,3H),3.60(s,3H),2.59–2.54(m,2H),2.37–2.33(m,2H),2.18–2.05(m,4H),1.90–1.84(m,2H),1.82–1.76(m,2H),1.72–1.68(m, 1H),1.42–1.32(m,1H),1.32–1.20(m,3H),0.95–0.82(m,2H)；MS(ESI):m/z784.7(M+H) +.
实施例55：
Figure PCTCN2020138157-appb-000099
从化合物INT-9和止血环酸甲酯盐酸盐起，参照化合物44的合成得到化合物55。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.77(d,J＝8.6Hz,1H),7.67(s,1H),7.56–7.46(m,4H),7.42(d,J＝7.7Hz,1H),7.38(s,1H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.6Hz,1H),7.08–7.04(m,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.79–3.71(m,2H),3.66–3.62(m,1H),3.58(s,3H),3.36(s,2H),2.58–2.56(m,2H),2.15–2.06(m,9H),1.89–1.80(m,4H),1.74–1.66(m,1H),1.51–1.42(m,1H),1.33–1.23(m,2H),0.88–0.76(m,2H)；MS(ESI):m/z 798.7(M+H) +.
实施例56：
Figure PCTCN2020138157-appb-000100
从反式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-9起，参照化合物33的合成得到化合物56。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.74(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.43(m,4H),7.42(s,1H),7.40(d,J＝8.0Hz,1H),7.15(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.05-7.01(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75-3.68(m,2H),3.65-3.59(m,3H),3.58(s,3H),2.56–2.52(m,2H), 2.32–2.24(m,1H),2.14–2.03(m,4H),1.92–1.80(m,4H),1.72–1.63(m,1H),130–1.18(m,2H),1.05–0.95(m,2H)；MS(ESI):m/z 770.7(M+H) +.
实施例57：
Figure PCTCN2020138157-appb-000101
从反式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-9起，参照化合物44的合成得到化合物57。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.55–7.43(m,4H),7.39(d,J＝8.0Hz,1H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.07–7.01(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75–3.67(m,2H),3.64–3.59(m,1H),3.57(s,3H),3.44(s,2H),2.56–2.52(m,2H),2.39–2.31(m,1H),2.14–2.10(m,7H),1.95–1.86(m,2H),1.81–1.74(m,2H),1.71–1.65(m,1H),1.31–1.23(m,4H)；MS(ESI):m/z 784.8(M+H) +.
实施例58：
Figure PCTCN2020138157-appb-000102
从化合物INT-9和化合物INT-2起，参照化合物22的合成得到化合物58。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.63(s,1H),7.53–7.44(m,4H),7.41(s,1H),7.40(d,J＝8.0Hz,1H),7.15(d,J＝7.0Hz,1H),7.06(s,1H),7.04(d,J＝8.0Hz,1H),6.68(s,1H),5.71(s,2H),3.81(s, 3H),3.76–3.68(m,2H),3.66–3.59(m,4H),3.58(s,3H),2.56–2.52(m,2H),2.47–2.42(m,2H),2.14–2.03(m,6H),1.70–1.60(m,2H)；MS(ESI):m/z 741.8(M+H) +.
实施例59：
Figure PCTCN2020138157-appb-000103
从顺式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-9起，参照化合物33的合成得到化合物59。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.74(d,J＝8.5Hz,1H),7.67(s,1H),7.53–7.45(m,4H),7.43(s,1H),7.39(d,J＝7.5Hz,1H),7.15(d,J＝7.0Hz,1H),7.08–7.06(m,1H),7.05–7.02(m,1H),6.67(s,1H),5.70(s,2H),3.81(s,3H),3.75–3.67(m,2H),3.62–3.60(m,3H),3.58(s,3H),2.55–2.52(m,3H),2.31–2.25(m,1H),2.13–2.04(m,3H),1.87–1.79(m,2H),1.72–1.63(m,1H),1.57–1.48(m,2H),1.46–1.37(m,4H)；MS(ESI):m/z 770.7(M+H) +.
实施例60：
Figure PCTCN2020138157-appb-000104
从顺式-4-氨基环己甲酸甲酯盐酸盐和化合物INT-9起，参照化合物44的合成得到化合物60。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.53–7.44(m,4H),7.40(d,J＝7.5Hz,1H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),7.09–7.06(m,1H),7.05–7.01(m,1H),6.67(s,1H),5.71(s,2H), 3.81(s,3H),3.75–3.67(m,2H),3.64–3.60(m,1H),3.56(s,2H),3.42–3.35(m,3H),2.57–2.52(m,2H),2.45–2.40(m,1H),2.38–2.31(m,1H),2.14–2.07(m,3H),2.06(s,3H),2.01–1.93(m,2H),1.72–1.63(m,1H),1.60–1.52(m,2H),1.50–1.37(m,4H)；MS(ESI):m/z 784.7(M+H) +.
实施例61：
Figure PCTCN2020138157-appb-000105
从化合物INT-11和化合物INT-12起，参照化合物33的合成得到化合物61。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J＝8.5Hz,1H),7.53–7.48(m,2H),7.48–7.43(m,4H),7.41–7.36(m,2H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.65(s,1H),5.71(s,2H),4.21–4.16(m,1H),3.70–3.45(m,4H),3.56(s,3H),2.92–2.85(m,1H),2.72–2.66(m,1H),2.64–2.57(m,3H),2.45–2.40(m,3H),2.36–2.32(m,1H),2.02–1.96(m,1H),1.95–1.88(m,2H),1.58–1.52(m,1H)；MS(ESI):m/z 685.8(M+H) +.
实施例62：
Figure PCTCN2020138157-appb-000106
从化合物INT-12和化合物35a起，参照化合物33的合成得到化合物62。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.77(d,J＝8.5Hz,1H),7.55–7.50(m,2H),7.49–7.45(m,4H),7.42–7.37(m,3H),7.17(d,J＝7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.24–4.19(m,1H),3.66–3.58(m,2H),3.57(s,3H),3.41(s,2H),2.80–2.72(m,1H),2.73–2.67(m,1H),2.64–2.55(m,2H),2.46–2.43(m,1H),2.42–2.38(m,1H),2.37–2.34(m,1H),2.22–2.12(m,1H),2.08–1.98(m,2H),1.80– 1.71(m,1H),1.65–1.53(m,2H),1.50–1.42(m,1H),1.40–1.31(m,1H)；MS(ESI):m/z 699.7(M+H) +.
实施例63：
Figure PCTCN2020138157-appb-000107
从化合物INT-12和止血环酸甲酯盐酸盐起，参照化合物33的合成得到化合物63。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.76(d,J＝8.5Hz,1H),7.55–7.50(m,2H),7.49–7.45(m,4H),7.42–7.38(m,3H),7.17(d,J＝7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.24–4.18(m,1H),3.64(d,J＝13.0Hz,1H),3.60–3.56(m,6H),2.73–2.67(m,1H),2.64–2.60(m,1H),2.46–2.42(m,1H),2.37–2.34(m,1H),2.31(d,J＝6.5Hz,2H),2.12–2.06(m,1H),2.04–1.98(m,1H),1.89–1.84(m,2H),1.82–1.77(m,2H),1.59–1.52(m,1H),1.39–1.32(m,1H),1.31–1.21(m,2H),0.93–0.83(m,2H)；MS(ESI):m/z 727.5(M+H) +.
实施例64：
Figure PCTCN2020138157-appb-000108
从(S)-3-羟基吡咯烷盐酸盐和化合物INT-3a起，参照化合物INT-5和化合物INT-8的合成得到化合物64a。MS(ESI):m/z 586.4(M+H) +.
从化合物64a和化合物INT-11起，参照化合物33的合成得到化合物64。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.75(d,J＝8.5Hz,1H),7.52–7.47(m, 2H),7.47–7.42(m,4H),7.39(s,1H),7.37(d,J＝8.0Hz,1H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.65(s,1H),5.71(s,2H),4.22–4.15(m,1H),3.64–3.57(m,2H),3.56(s,3H),3.52–3.45(m,2H),2.90–2.82(m,1H),2.70–2.56(m,4H),2.45–2.38(m,3H),2.35–2.30(m,1H),2.02–1.95(m,1H),1.94–1.86(m,2H),1.62–1.50(m,1H)；MS(ESI):m/z 685.5(M+H) +.
实施例65：
Figure PCTCN2020138157-appb-000109
从3-羟基氮杂环丁烷盐酸盐起，参照化合物64的合成得到化合物65。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.76(d,J＝8.6Hz,1H),7.54–7.50(m,2H),7.49–7.44(m,4H),7.38–7.33(m,3H),7.17(d,J＝7.0Hz,1H),6.67(s,1H),5.73(s,2H),5.34–5.26(m,1H),4.23–4.19(m,1H),3.61(s,2H),3.58(s,3H),3.56–3.46(m,6H),2.94–2.88(m,1H),2.82–2.78(m,2H),2.67–2.64(m,2H),1.97–1.91(m,2H)；MS(ESI):m/z 671.6(M+H) +.
实施例66：
Figure PCTCN2020138157-appb-000110
从N-乙酰基乙二胺和化合物INT-3a起，参照化合物INT-3的合成得到化合物66a。MS(ESI):m/z 481.2(M+H) +.
从化合物66a，化合物INT-8c和化合物INT-11起，参照化合物INT-8和化合物33的合成得到化合物66。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.82–7.77(m,1H),7.75(d,J＝8.5Hz,1H),7.53–7.48(m,2H),7.47–7.40(m,6H), 7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.73(s,2H),3.56(s,3H),3.52–3.47(m,2H),3.16–3.12(m,2H),2.93–2.84(m,1H),2.67–2.61(m,2H),2.57(t,J＝6.5Hz,2H),2.45–2.42(m,2H),1.96–1.87(m,2H),1.77(s,3H)；MS(ESI):m/z 700.2(M+H) +.
实施例67：
Figure PCTCN2020138157-appb-000111
从(R)-5-羟甲基-2-吡咯烷酮和化合物INT-3a起，参照化合物INT-2和化合物INT-3的合成得到化合物67a。MS(ESI):m/z 493.2(M+H) +.
从化合物67a，化合物INT-8c和化合物INT-11起，参照化合物INT-8和化合物33的合成得到化合物67。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.74(d,J＝8.5Hz,1H),7.65(s,1H),7.53–7.48(m,2H),7.47–7.39(m,6H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.65(s,1H),5.71(s,2H),3.77–3.71(m,2H),3.64–3.59(m,1H),3.56(s,3H),3.52–3.48(m,2H),2.91–2.83(m,1H),2.66–2.60(m,2H),2.55–2.51(m,2H),2.47–2.45(m,2H),2.15–2.04(m,3H),1.95–1.88(m,2H),1.72–1.64(m,1H)；MS(ESI):m/z 712.6(M+H) +.
实施例68：
Figure PCTCN2020138157-appb-000112
在冰浴条件下，在溶有N-叔丁氧羰基-1,2-乙二胺(99mg,0.62mmol)的二氯 甲烷(3mL)中依次加入甲磺酸酐(135mg,0.77mmol)和三乙胺(102mg,1.01mmol)；反应液在相同条件下搅拌一小时。反应液中加入饱和碳酸氢钠溶液(20mL)，并用乙酸乙酯(20mL x 2)萃取。合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥；滤液浓缩后得到白色固体68a(160mg,收率:86.6％)。
在溶有化合物68a(160mg,0.67mmol)的二氯甲烷(2mL)溶液中加入盐酸(4M的1,4-二氧六环溶液,1.7mL)；反应液在20℃条件下搅拌16小时。反应液浓缩得到黄色油状物68b(90mg,收率:76.8％)。 1H NMR(500MHz,DMSO-d6)δ8.14(s,3H),7.36(t,J＝6.0Hz,1H),3.27–3.16(m,2H),2.94(s,3H),2.92–2.84(m,2H).
从化合物68b起，参照化合物64的合成得到化合物68。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.53–7.48(m,2H),7.47–7.43(m,4H),7.43–7.40(m,2H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.94(s,1H),6.65(s,1H),5.71(s,2H),3.74(s,2H),3.56(s,3H),3.54–3.52(m,2H),3.05(t,J＝6.5Hz,2H),2.92–2.89(m,1H),2.88(s,3H),2.67–2.60(m,4H),2.47–2.45(m,2H),1.95–1.87(m,2H)；MS(ESI):m/z 736.9(M+H) +.
实施例69：
Figure PCTCN2020138157-appb-000113
从化合物INT-11，化合物INT-3a和化合物INT-8c起，参照化合物INT-5和化合物INT-8的合成得到化合物69a。MS(ESI):m/z 628.5(M+H) +.
从化合物69a和(R)-3-羟基吡咯烷盐酸盐起，参照化合物33的合成得到化合物69。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.76(d,J＝8.5Hz,1H),7.55–7.50(m,2H),7.50–7.45(m,4H),7.40(d,J＝8.0Hz,2H),7.37(s,1H),7.17(d,J＝ 7.0Hz,1H),6.67(s,1H),5.73(s,2H),4.20–4.15(m,1H),3.66–3.59(m,2H),3.58(s,3H),3.53(d,J＝14.5Hz,1H),3.48(d,J＝14.5Hz,1H),2.96–2.91(m,1H),2.74(t,J＝8.5Hz,1H),2.66–2.62(m,2H),2.61–2.58(m,1H),2.42–2.32(m,4H),2.01–1.94(m,3H),1.56–1.49(m,1H)；MS(ESI):m/z 685.3(M+H) +.
实施例70：
Figure PCTCN2020138157-appb-000114
从化合物INT-11，4-溴-2-甲氧基苯甲醛和化合物INT-8c起，参照化合物INT-5和化合物INT-8的合成得到化合物70a。MS(ESI):m/z 658.4(M+H) +.
从化合物70a和化合物INT-2起，参照化合物33的合成得到化合物70。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.63(s,1H),7.53–7.44(m,4H),7.41(s,1H),7.37(d,J＝8.0Hz,1H),7.15(d,J＝7.0Hz,1H),7.09–7.07(m,1H),7.06–7.02(m,1H),6.67(s,1H),5.71(s,2H),3.80(s,3H),3.62–3.59(m,4H),3.58–3.56(m,4H),2.95–2.89(m,1H),2.77–2.71(m,1H),2.70–2.65(m,1H),2.58–2.52(m,2H),2.47–2.43(m,2H),2.11–2.02(m,3H),1.98–1.92(m,2H),1.67–1.60(m,1H)；MS(ESI):m/z 742.7(M+H) +.
实施例71：
Figure PCTCN2020138157-appb-000115
从化合物70a和(R)-3-羟基吡咯烷盐酸盐起，参照化合物33的合成得到化合 物71。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.52–7.44(m,4H),7.36(d,J＝7.5Hz,1H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),7.09–7.07(m,1H),7.06–7.02(m,1H),6.66(s,1H),5.71(s,2H),4.18–4.11(m,1H),3.80(s,3H),3.61–3.59(m,2H),3.56(s,3H),3.53–3.46(m,2H),2.95–2.87(m,1H),2.78–2.71(m,1H),2.69–2.64(m,1H),2.64–2.53(m,4H),2.41–2.35(m,1H),2.34–2.29(m,1H),1.99–1.92(m,3H),1.55–1.48(m,1H)；MS(ESI):m/z715.8(M+H) +.
实施例72：
Figure PCTCN2020138157-appb-000116
在溶有4-(溴甲基)-3-氯苯甲酸甲酯(200mg,0.76mmol)和4-溴吲唑(150mg,0.76mmol)的乙腈(6mL)溶液中加入碳酸钾(231mg,1.67mmol)；反应液在65℃条件下搅拌10小时。反应液冷却至室温后，滤液浓缩后所得残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/30)得到白色固体72a(150mg,收率:52.1％)。MS(ESI):m/z 379.2(M+H) +.
在-65℃条件下，在溶有化合物72a(150mg,0.40mmol)的二氯甲烷(10mL)溶液中缓慢滴加二异丁基氢化铝(1.5M的甲苯溶液，0.79mL)；所得反应液在相同温度下搅拌半小时。反应液随后用甲醇(2mL)淬灭，并升至室温；加入酒石酸钾钠(10％w/w水溶液,10mL)后剧烈搅拌2小时。所得混合液中再加入二氯甲烷(20mL)；有机相进一步用饱和食盐水(30mL)洗涤，无水硫酸钠干燥。滤液浓缩后得到无色油状物72b(130mg,收率:93.6％)。MS(ESI):m/z 351.1(M+H) +.
在溶有化合物72b(130mg,0.37mmol)的二氯甲烷(6mL)溶液中加入戴斯-马丁氧化剂(157mg,0.37mmol)；反应液在25℃条件下搅拌一小时。反应液中加入饱和碳酸氢钠溶液(20mL)和二氯甲烷(20mL)，所得有机相进一步用饱和食盐水(30mL)洗涤，无水硫酸钠干燥。滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/30)得到无色油状物72c(120mg,收率:92.8％)。MS(ESI):m/z 349.1(M+H) +.
从化合物72c，O-叔丁基-L-丝氨酸叔丁酯和化合物INT-3起，参照化合物INT-1和化合物1的合成得到化合物72。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.75(d,J＝8.5Hz,1H),7.69(s,1H),7.56(d,J＝1.5Hz,1H),7.52–7.44(m,8H),7.29–7.25(m,1H),7.18(d,J＝7.0Hz,1H),6.92(d,J＝8.0Hz,1H),5.77(s,2H),3.90(d,J＝14.0Hz,1H),3.81–3.76(m,3H),3.65–3.63(m,1H),3.62–3.56(m,2H),3.09(t,J＝5.5Hz,1H),2.57–2.54(m,2H),2.13–2.07(m,3H),1.74–1.67(m,1H)；MS(ESI):m/z 672.5(M+H) +.
实施例73：
Figure PCTCN2020138157-appb-000117
在溶有2-甲氧基-4-甲基苯甲酸甲酯(250mg,1.39mmol)和N-溴代丁二酰亚胺(296mg,1.66mmol)的四氯化碳(8mL)溶液中加入偶氮二异丁腈(9.4mg,0.17mmol)；反应液在80℃条件下搅拌16小时。反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/25)得到白色固体73a(204mg,收率:34.0％)。
从化合物73a，4-溴吲唑，O-叔丁基-L-丝氨酸叔丁酯和化合物INT-3起，参照化合物INT-1和化合物1的合成得到化合物73。 1H NMR(500MHz,DMSO-d6)δ8.18–8.16(m,2H),7.87(s,1H),7.77(d,J＝8.6Hz,1H),7.66(s,1H),7.52–7.49(m,1H),7.48–7.25(m,5H),7.13(d,J＝7.0Hz,1H),7.04(s,1H),6.77(d,J＝7.6 Hz,1H),5.68(s,2H),3.96-3.92(m,1H),3.78(d,J＝7.1Hz,2H),3.75(s,3H),3.69–3.61(m,2H),3.60–3.51(m,2H),3.14-3.08(m,1H),2.56(d,J＝6.4Hz,2H),2.12–2.06(m,3H),1.73–1.65(m,1H)；MS(ESI):m/z 668.7(M+H) +.
实施例74：
Figure PCTCN2020138157-appb-000118
在溶有6-羟甲基烟酸甲酯(470mg,2.81mmol)的二氯甲烷(10mL)溶液中加入二氯亚砜(1.67g,14.1mmol)；反应液在25℃条件下搅拌3小时。反应液浓缩，残余物用硅胶柱层析(乙酸乙酯/石油醚＝0/100–40/100)得到白色固体74a(420mg,收率:80.5％)。MS(ESI):m/z 186.0(M+H) +.
从化合物74a起，参照化合物73的合成得到化合物74。 1H NMR(500MHz,DMSO-d6)δ8.49(d,J＝2.0Hz,1H),8.18(s,1H),7.87(s,1H),7.77–7.69(m,2H),7.67(s,1H),7.51(d,J＝7.5Hz,1H),7.48–7.44(m,6H),7.15(d,J＝7.0Hz,1H),7.05(d,J＝8.0Hz,1H),5.77(s,2H),3.91(d,J＝13.5Hz,1H),3.82–3.73(m,3H),3.66–3.60(m,1H),3.60–3.53(m,2H),3.09(t,J＝5.5Hz,1H),2.55(d,J＝6.0Hz,2H),2.16–2.03(m,3H),1.78–1.61(m,1H)；MS(ESI):m/z 639.5(M+H) +.
实施例75：
Figure PCTCN2020138157-appb-000119
在溶有化合物INT-13(550mg,1.80mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入氰化亚铜(322mg,3.59mmol)；反应液在120℃和氮气氛围下搅拌16小时。反应液过滤，滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/30)得到白色固体75a(210mg,收率:57.0％)。
从化合物75a起，参照化合物73的合成得到化合物75。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.84-7.82(m,2H),7.67(s,1H),7.54–7.50(m,2H),7.50–7.42(m,6H),7.18(d,J＝6.9Hz,1H),6.92(s,1H),5.82(s,2H),3.85(d,J＝14.9Hz,1H),3.80–3.73(m,3H),3.71(s,3H),3.64-3.60(m,2H),3.60–3.54(m,1H),3.15-3.11(m,1H),2.55–2.54(m,2H),2.13–2.06(m,3H),1.71–1.67(m,1H)；MS(ESI):m/z 693.2(M+H) +.
实施例76：
Figure PCTCN2020138157-appb-000120
在冰浴条件下，在溶有化合物INT-13b(100mg,0.55mmol)的浓硫酸(2mL)中滴加预先溶有硝酸钾(56.1mg,0.55mmol)的浓硫酸(0.5mL)溶液；反应液在相同条件下继续搅拌半小时。反应液中加入大量冰水，析出固体经用冰水洗后，干燥得到白色固体76a(115mg,收率:92.0％)。 1H NMR(500MHz,DMSO-d6)δ8.39(s,1H),7.29(s,1H),3.95(s,3H),3.82(s,3H),2.64(s,3H).
从化合物76a起，参照化合物73的合成得到化合物76。 1H NMR(500MHz,DMSO-d6)δ8.29(s,1H),7.96(s,1H),7.79(d,J＝8.5Hz,1H),7.67(s,1H),7.53(d,J＝7.5Hz,1H),7.51-7.49(m,3H),7.47–7.43(m,4H),7.19(d,J＝7.0Hz,1H),6.13(s,1H),6.11(s,1H),3.87(d,J＝15.4Hz,1H),3.81–3.72(m,3H),3.67–3.57(m,3H),3.51(s,3H),3.15–3.12(m,1H),2.56–2.52(m,2H),2.14–2.08(m,3H),1.72–1.66(m,1H)；MS(ESI):m/z 713.8(M+H) +.
实施例77：
Figure PCTCN2020138157-appb-000121
在溶有化合物INT-13b(300mg,1.66mmol)的浓硫酸(3mL)中加入N-氯代丁二酰亚胺(467mg,3.50mmol)；反应液在25℃条件下搅拌2小时。反应液中加入冰水(25mL)和乙酸乙酯(25mL)；有机相进一步用饱和碳酸氢钠溶液(30mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。滤液浓缩得到黄色固体77a(360mg,收率:86.8％)。 1H NMR(500MHz,DMSO-d6)δ7.74(s,1H),3.84(s,3H),3.80(s,3H),2.45(s,3H)；MS(ESI):m/z 249.7(M+H) +.
从化合物77a起，参照化合物73的合成得到化合物77。 1H NMR(500MHz,DMSO-d6)δ7.86(d,J＝8.5Hz,1H),7.80(s,1H),7.67(s,1H),7.65(s,1H),7.56–7.50(m,2H),7.48–7.43(m,6H),7.17(d,J＝7.0Hz,1H),5.81(s,2H),3.95(d,J＝14.5Hz,1H),3.82-3.79(m,3H),3.77(s,3H),3.66–3.59(m,3H),3.20(t,J＝5.1Hz,1H),2.57–2.58(m,2H),2.13–2.07(m,3H),1.74-1.66(m,1H)；MS(ESI):m/z736.7(M+H) +.
实施例78：
Figure PCTCN2020138157-appb-000122
在冰浴条件下，在溶有3-氯-4-甲基苯甲酸甲酯(500mg,2.71mmol)的浓硫酸(2mL)中加入N-碘代丁二酰亚胺(731mg,3.25mmol)；反应液在25℃条件下搅拌2小时。反应液中加入冰水(50mL)和乙酸乙酯(50mL)；有机相进一步用饱和碳酸氢钠溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯＝100/0–100/15)分离得到白色固体78a(820mg,收率:97.5％)。
在氮气氛围和100℃条件下，将混有化合物78a(1.00g,3.22mmol),碘化亚铜(61.3mg,0.32mmol)，1,10-菲罗啉(116mg,0.64mmol)和碳酸铯(2.10g,6.44mmol)的甲醇(5mL)溶液搅拌24小时。反应液过滤后，滤液浓缩；残余 物用甲醇(5mL)溶解，然后加入二氯亚砜(1.4mL)；所得到反应液在60℃条件下搅拌2小时。反应液中加入乙酸乙酯(50mL)和水(50mL)；有机相进一步用饱和碳酸氢钠溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥。残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/5)分离得到白色固体78b(480mg,收率:69.4％)。 1H NMR(500MHz,Chloroform-d)δ7.67(d,J＝1.6Hz,1H),7.39(d,J＝1.6Hz,1H),3.91(s,3H),3.88(s,3H),2.31(s,3H).
从化合物78b起，参照化合物73的合成得到化合物78。 1H NMR(500MHz,DMSO-d6)δ8.22(s,1H),7.77(d,J＝8.5Hz,1H),7.74(s,1H),7.66(s,1H),7.52–7.48(m,2H),7.46–7.43(m,5H),7.14–7.11(m,3H),5.67(s,2H),3.94(d,J＝14.2Hz,1H),3.81–3.78(m,2H),3.77(s,3H),3.65–3.61(m,4H),3.15–3.09(m,1H),2.57–2.55(d,J＝6.0Hz,2H),2.13–2.07(m,3H),1.73–1.66(m,1H)；MS(ESI):m/z 702.7(M+H) +.
实施例79：
Figure PCTCN2020138157-appb-000123
从化合物78a起，参照化合物75a的合成方法得到化合物79a。
从化合物79a起，参照化合物73的合成得到化合物79。 1H NMR(500MHz,DMSO-d6)δ8.20(s,1H),7.93(d,J＝1.6Hz,1H),7.90–7.85(m,2H),7.83(s,1H),7.67(s,1H),7.58–7.54(m,1H),7.51(d,J＝7.4Hz,1H),7.48–7.42(m,5H),7.18(d,J＝7.1Hz,1H),5.82(s,2H),3.95(d,J＝14.8Hz,1H),3.81–3.74(m,3H),3.65-3.62(m,1H),3.61–3.56(m,2H),3.12(t,J＝5.3Hz,1H),2.56(d,J＝6.1Hz,2H),2.13–2.07(m,3H),1.72–1.66(m,1H)；MS(ESI):m/z 697.5(M+H) +.
实施例80：
Figure PCTCN2020138157-appb-000124
在溶有2-羟基-6-甲基烟酸(1.00g,6.53mmol)的氯仿(35mL)溶液中加入碘甲烷(3.24g,22.9mmol)和碳酸银(1.81g,6.55mmol)；反应液在65℃条件下搅拌16小时。反应液过滤，滤液浓缩得到无色油状物80a(390mg,收率:33.0％)。 1H NMR(500MHz,Chloroform-d)δ8.06(d,J＝7.7Hz,1H),6.77(d,J＝7.7Hz,1H),4.03(s,3H),3.87(s,3H),2.48(s,3H)；MS(ESI):m/z 182.0(M+H) +.
在溶有化合物80a(363mg,2.00mmol)的乙腈(10mL)溶液中加入N-氯代丁二酰亚胺(321mg,2.40mmol)；反应液在70℃条件下搅拌10小时。反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/20)分离得到无色油状物80b(420mg,收率:97.2％)。 1H NMR(500MHz,DMSO-d6)δ8.09(s,1H),3.91(s,3H),3.80(s,3H),2.51(s,3H).
从化合物80b起，参照化合物73的合成得到化合物80。 1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.84(s,1H),7.79(d,J＝8.4Hz,1H),7.67(s,1H),7.53–7.51(m,1H),7.48–7.44(m,7H),7.14(d,J＝7.0Hz,1H),5.82(s,2H),3.79–3.76(m,2H),3.66–3.55(m,5H),3.38(s,3H),3.13–3.08(m,1H),2.58–2.54(m,2H),2.13–2.08(m,3H),1.73–1.67(m,1H)；MS(ESI):m/z 703.2(M+H) +.
实施例81：
Figure PCTCN2020138157-appb-000125
从3-甲氧基-4-甲基苯甲酸起，参照化合物80b的合成得到化合物81a。 1H NMR(500MHz,DMSO-d6)δ13.25(s,1H),7.32(s,1H),7.30(s,1H),3.82(s,3H),2.17(s,3H).
在溶有化合物81a(300mg,1.50mmol)的二氯甲烷(8mL)溶液中加入草酰氯(345mg,2.72mmol)和1滴N,N-二甲基甲酰胺；反应液在25℃条件下搅拌3小时，随后反应液浓缩。所得残余物用二氯甲烷(3mL)再次溶解后加入到溶有4-溴吲唑(265mg,1.35mmol)，4-二甲氨基吡啶(18.3mg,0.15mmol)和三乙胺(302mg,2.99mmol)的二氯甲烷(8mL)溶液；反应液在25℃条件下搅拌16小时。反应液浓缩，残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝100/0–100/20)分离得到白色固体81b(410mg,收率:72.2％)。
从化合物81b起，参照化合物73a的合成得到化合物81c。
在溶有化合物81c(120mg,0.26mmol)和O-叔丁基-L-丝氨酸叔丁酯(171mg,0.78mmol)的N’N-二甲基甲酰胺(2mL)中加入碳酸钾(72mg,0.52mmol)；反应液在25℃条件下搅拌一小时。反应液中加入乙酸乙酯(20mL)和水(20mL)；有机相进一步用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。残余物用硅胶薄层层析板(石油醚/乙酸乙酯,v/v＝4/1)分离得到白色固体81d(70mg,收率:45.0％)。MS(ESI):m/z 594.4(M+H) +.
从化合物81d起，参照INT-1合成过程中的硼酯化步骤得到化合物81e。MS(ESI):m/z 642.8(M+H) +.
在90℃条件和氮气氛围下，将混有化合物81e(35mg,0.038mmol)，化合物INT-3(18.9mg,0.038mmol)，Pd(dppf)Cl 2(2.8mg,0.0038mmol)和氟化钾(6.7mg,0.11mmol)的1.4-二氧六环(4mL)溶液搅拌16小时。反应液浓缩，残余物用硅胶薄层层析板(二氯甲烷/甲醇,v/v＝20/1)分离得到无色油状物81f(20mg,收率:36.7％)。MS(ESI):m/z 928.2(M+H) +.
从化合物81f起，参照化合物1合成的最后一步脱Boc保护基步骤得到化合物81。 1H NMR(500MHz,DMSO-d6)δ8.49(d,J＝8.0Hz,1H),8.27(s,1H),7.82(t,J＝8.0Hz,1H),7.65(s,1H),7.57(s,1H),7.55–7.53(m,1H),7.52–7.49(m,3H),7.47–7.40(m,5H),3.79(s,3H),3.76–3.74(m,2H),3.62–3.59(m,3H),3.50–3.48(m,2H),3.12–3.11(m,1H),2.53–2.52(m,2H),2.10–2.06(m,3H),1.69–1.65(m,1H)；MS(ESI):m/z 716.0(M+H) +.
实施例82：
Figure PCTCN2020138157-appb-000126
从化合物80b起，依次参照化合物73a的溴代步骤，化合物72a的取代步骤和化合物INT-11d合成过程中的酯水解和酸胺缩合步骤得到化合物82a。MS(ESI):m/z 595.4(M+H) +.
从化合物82a和化合物INT-3起，参照化合物81合成过程中的最后两步得到化合物82。 1H NMR(500MHz,DMSO-d6)δ8.51(d,J＝7.0Hz,1H),8.23(s,1H),7.88(s,1H),7.76(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.45(m,7H),7.15(d,J＝7.0Hz,1H),5.93(s,2H),4.28–4.26(m,1H),3.85–3.75(m,3H),3.67–3.60(m, 2H),3.39(s,3H),2.59(d,J＝6.2Hz,2H),2.14–2.07(m,3H),1.72-1.69(m,1H)；MS(ESI):m/z 717.2(M+H) +.
实施例83：
Figure PCTCN2020138157-appb-000127
在80℃条件下，溶有4-溴吲唑(500mg,2.54mmol)和1-氟-4-甲基-1,4-二氮杂双环[2.2.2]辛烷四氟硼酸盐(4.49g,12.7mmol)的乙腈(20mL)溶液搅拌15小时。反应液加入乙酸乙酯(100mL)，随后用水(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥。残余物用硅胶柱层析分离得到白色固体83a(231mg,收率:42.3％)。MS(ESI):m/z 215.1(M+H) +.
从化合物83a，O-叔丁基-L-丝氨酸叔丁酯和化合物INT-3起，参照化合物INT-8和化合物1的合成得到化合物83。 1H NMR(500MHz,DMSO-d6)δ7.84–7.79(m,1H),7.66(s,1H),7.62–7.58(m,1H),7.52–7.43(m,8H),7.17(d,J＝7.0Hz,1H),6.84(s,1H),5.62(s,2H),3.91–3.79(m,4H),3.67(s,3H),3.65–3.56(m,3H),3.17–3.15(m,1H),2.60–2.55(m,2H),2.14–2.09(m,3H),1.73–1.67(m,1H)；MS(ESI):m/z 720.6(M+H) +.
实施例84：
Figure PCTCN2020138157-appb-000128
在25℃条件下，溶有4-溴吲唑(200mg,1.02mmol)，N-氯代丁二酰亚胺(149mg,1.12mmol)的N’N-二甲基甲酰胺(3mL)的溶液搅拌15小时。反应液加入乙酸乙酯(50mL)，随后用水(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥。残余物用硅胶柱层析分离得到白色固体84a(122mg,收率:51.9％)。MS(ESI):m/z 231.3(M+H) +.
从化合物84a起，参照化合物83的合成得到化合物84。 1H NMR(500MHz,DMSO-d6)δ7.85(d,J＝8.5Hz,1H),7.65(s,1H),7.59–7.55(m,1H),7.50–7.47(m,2H),7.45–7.39(m,6H),7.11(d,J＝7.0Hz,1H),6.84(d,J＝1.5Hz,1H),5.75–5.68(m,1H),5.70(s,1H),3.89–3.86(m,1H),3.79–3.75(m,3H),3.65(s,3H),3.62–3.59(m,3H),3.14–3.12(m,1H),2.54(d,J＝6.0Hz,2H),2.11–2.06(m,3H),1.70–1.65(m,1H)；MS(ESI):m/z 736.5(M+H) +.
实施例85：
Figure PCTCN2020138157-appb-000129
从化合物INT-8和5-氨乙基四氮唑起，参照化合物22的合成得到化合物85。 1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.74(d,J＝8.5Hz,1H),7.55–7.38(m,9H),7.14(d,J＝7.0Hz,1H),6.71(s,1H),5.72(s,2H),3.95–3.91(m,2H),3.79–3.71(m,4H),3.65–3.62(m,1H),3.57(s,3H),2.55(d,J＝6.0Hz,2H),2.15–2.04(m,3H),1.72–1.61(m,1H)；MS(ESI):m/z 696.1(M+H) +.
实施例86：
Figure PCTCN2020138157-appb-000130
从化合物INT-1c，溴乙酸叔丁酯，4-溴吲唑起，参照化合物INT-1i的合成得到化合物86a。MS(ESI):m/z 479.4(M+H) +.
从化合物86a，化合物INT-3和乙醇胺起，参照化合物INT-7和化合物22 的合成得到化合物86。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.53–7.41(m,9H),7.15(d,J＝6.9Hz,1H),6.94(s,1H),5.70(s,2H),4.26(s,2H),4.01(s,2H),3.81–3.72(m,2H),3.67–3.58(m,3H),2.86(t,J＝5.4Hz,2H),2.57–2.50(m,2H),2.13–2.04(m,3H),1.72–1.64(m,1H)；MS(ESI):m/z 702.4(M+H) +.
实施例87：
Figure PCTCN2020138157-appb-000131
从(R)-3-羟基吡咯烷盐酸盐，4-溴-2-甲氧基苯甲醛和化合物INT-8c起，参照化合物INT-5和化合物INT-8的合成得到化合物87a。MS(ESI):m/z 616.4(M+H) +.
从化合物87a和化合物INT-11起，参照化合物33的合成得到化合物87。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.55–7.47(m,4H),7.39(d,J＝7.5Hz,1H),7.36(s,1H),7.17(d,J＝7.0Hz,1H),7.08(s,1H),7.06(d,J＝7.5Hz,1H),6.68(s,1H),5.73(s,2H),4.23–4.17(m,1H),3.82(s,3H),3.64–3.56(m,5H),3.55–3.47(m,2H),2.88–2.82(m,1H),2.75–2.69(m,1H),2.67–2.61(m,3H),2.47–2.43(m,2H),2.41–2.36(m,2H),2.05–1.97(m,1H),1.95–1.89(m,2H),1.58–1.52(m,1H)；MS(ESI):m/z 715.7(M+H) +.
实施例88：
Figure PCTCN2020138157-appb-000132
从乙醇胺，4-溴-2-甲氧基苯甲醛和化合物INT-8c起，参照化合物INT-3和化合物INT-8的合成得到化合物88a。MS(ESI):m/z 690.4(M+H) +.
从化合物88a和化合物INT-11起，参照化合物33的合成得到化合物88。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.77(d,J＝8.5Hz,1H),7.55–7.47(m,4H),7.41(d,J＝7.5Hz,1H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),7.11(s,1H),7.09–7.04(m,1H),6.69(s,1H),5.73(s,2H),3.84(s,3H),3.79(d,J＝3.5Hz,2H),3.58(s,3H),3.56–3.47(m,4H),2.94–2.85(m,1H),2.70–2.62(m,4H),2.50–2.48(m,2H),1.96–1.90(m,2H)；MS(ESI):m/z 689.6(M+H) +.
实施例89：
Figure PCTCN2020138157-appb-000133
从化合物76a起，参照化合物73的合成得到化合物89a。MS(ESI):m/z 925.5(M+H) +.
在溶有化合物89a(150mg,0.16mmol)的醋酸(3mL)溶液加入锌粉(32 mg,0.49mmol)；反应液在70℃条件下搅拌半小时。反应液浓缩，残余物用制备薄层层析(二氯甲烷/甲醇,v/v＝20/1)得到黄色油状物89b(30mg,收率:20.7％)。MS(ESI):m/z 895.9(M+H) +.
从化合物89b起，参照化合物1合成过程中最后一步脱Boc保护基步骤得到化合物89。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.84(d,J＝8.6Hz,1H),7.67(s,1H),7.54–7.42(m,8H),7.14(d,J＝6.9Hz,1H),6.80(s,1H),6.68(s,1H),5.55(s,2H),5.00–4.95(m,1H),3.84–3.73(m,4H),3.63(s,3H),3.60–3.51(m,3H),3.04–3.02(m,1H),2.56–2.52(m,2H),2.13–2.06(m,3H),1.73-1.66(m,1H)；MS(ESI):m/z 683.1(M+H) +.
实施例90：
Figure PCTCN2020138157-appb-000134
从1,3-二溴-2-甲苯，4-溴-2-甲氧基苯甲醛，化合物INT-2和化合物INT-8c起，参照化合物INT-3和化合物INT-8的合成得到化合物90a。MS(ESI):m/z 723.5(M+H) +.
从化合物90a和化合物INT-11起，参照化合物33的合成得到化合物90。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.73(d,J＝8.5Hz,1H),7.66(s,1H),7.49(t,J＝8.5Hz,1H),7.43–7.36(m,3H),7.34–7.30(m,2H),7.10(d,J＝7.0Hz,1H),7.03(s,1H),7.00(d,J＝7.0Hz,1H),6.67(s,1H),5.73(s,2H),3.84(s,3H),3.82–3.77(m,2H),3.70–3.65(m,1H),3.58(s,3H),3.53(d,J＝9.0Hz,2H),2.95–2.88(m,1H),2.68–2.62(m,4H),2.53–2.52(m,2H),2.16–2.08(m,3H),2.00(s,3H),1.97–1.91(m,2H),1.75–1.68(m,1H)；MS(ESI):m/z 722.3(M+H) +.
实施例91：
Figure PCTCN2020138157-appb-000135
从化合物INT-10，化合物INT-2，化合物INT-8c和止血环酸甲酯盐酸盐起，参照化合物INT-3，化合物INT-8和化合物44的合成得到化合物91。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.86(d,J＝7.4Hz,1H),7.79(d,J＝8.5Hz,1H),7.68–7.64(m,2H),7.59–7.49(m,3H),7.43–7.32(m,2H),7.18(d,J＝7.0Hz,1H),6.71(s,1H),5.74(s,2H),3.94(s,3H),3.91–3.77(m,2H),3.73–3.67(m,1H),3.59(s,3H),3.41–3.35(m,2H),2.72–2.65(m,1H),2.53–2.52(m,1H),2.19–2.01(m,9H),1.91–1.79(m,4H),1.77–1.68(m,1H),1.53–1.40(m,1H),1.34–1.21(m,2H),0.88–0.78(m,2H)；MS(ESI):m/z 799.7(M+H) +.
实施例92：
Figure PCTCN2020138157-appb-000136
从化合物76a，4-溴吲唑，化合物INT-6起，参照化合物73a，化合物82a和化合物INT-8的合成得到化合物92a。MS(ESI):m/z 754.5(M+H) +.
从化合物92a和反式-4-氨基环己甲酸甲酯盐酸盐起，参照化合物44的合成得到化合物92。 1H NMR(500MHz,DMSO-d6)δ8.18(s,1H),7.96(s,1H),7.78(d,J＝8.5Hz,1H),7.65(s,1H),7.54–7.48(m,4H),7.41(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.5Hz,1H),7.08–7.04(m,1H),6.11–6.08(m,3H),3.82(s,3H),3.78–3.72(m,2H),3.66–3.62(m,1H),3.51–3.49(m,2H),3.48(s, 3H),2.57(d,J＝6.0Hz,2H),2.46–2.36(m,2H),2.13(s,3H),2.11–2.07(m,3H),1.94–1.89(m,2H),1.82–1.77(m,2H),1.72–1.65(m,1H),1.32–1.26(m,4H)；MS(ESI):m/z 795.7(M+H) +.
实施例93：
Figure PCTCN2020138157-appb-000137
从反式-4-氨基环丁甲酸甲酯盐酸盐和化合物INT-9起，参照化合物44的合成得到化合物93。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.44(m,4H),7.40(d,J＝7.5Hz,1H),7.33(s,1H),7.15(d,J＝7.5Hz,1H),7.08–7.06(m,1H),7.05–7.01(m,1H),6.68(s,1H),5.71(s,2H),3.81(s,3H),3.75–3.67(m,2H),3.64–3.60(m,1H),3.57(s,3H),3.30–3.24(m,2H),3.04–2.98(m,1H),2.84–2.79(m,1H),2.55–2.50(m,2H),2.20–2.12(m,2H),2.12–2.03(m,5H),1.91(s,3H),1.70–1.64(m,1H)；MS(ESI):m/z 756.6(M+H) +.
实施例94：
Figure PCTCN2020138157-appb-000138
从(4-哌啶)乙酸甲酯和化合物INT-9起，参照化合物44的合成得到化合物94。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.44(m,4H),7.40(d,J＝7.5Hz,1H),7.33(s,1H),7.15(d,J＝7.0Hz,1H),7.09–7.06(m,1H),7.05–7.01(m,1H),6.68(s,1H),5.71(s,2H),3.81(s,3H),3.74–3.68(m,2H),3.64–3.59(m,1H),3.56(s,3H),2.76–2.69(m,2H),2.56–2.51(m, 2H),2.14–2.03(m,5H),1.96–1.87(m,2H),1.77–1.64(m,2H),1.63–1.54(m,2H),1.22–1.14(m,2H)；MS(ESI):m/z 770.6(M+H) +.
实施例95：
Figure PCTCN2020138157-appb-000139
从化合物INT-9和化合物INT-14起，参照化合物44的合成得到化合物95。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.53–7.44(m,4H),7.39(d,J＝7.5Hz,1H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),7.08–7.05(m,1H),7.05–7.01(m,1H),6.67(s,1H),5.70(s,2H),3.81(s,3H),3.72–3.69(m,2H),3.64–3.58(m,1H),3.56(s,3H),3.44–3.35(m,2H),2.54–2.51(m,2H),2.35–2.29(m,1H),2.12–2.10(m,1H),2.09(s,3H),2.07–2.05(m,1H),2.04(d,J＝7.0Hz,2H),1.76–1.71(m,4H),1.69–1.63(m,1H),1.59–1.51(m,1H),1.29–1.20(m,2H),0.99–0.86(m,2H)；MS(ESI):m/z 798.7(M+H) +.
实施例96：
Figure PCTCN2020138157-appb-000140
参照化合物92的合成，将反式-4-氨基环己甲酸甲酯盐酸盐替换成止血环酸甲酯盐酸盐得到化合物96。 1H NMR(500MHz,DMSO-d6)δ8.21(s,1H),7.98(s,1H),7.80(d,J＝8.5Hz,1H),7.66(s,1H),7.56–7.48(m,4H),7.44–7.43(m,1H),7.19(d,J＝6.9Hz,1H),7.13–7.11(m,1H),7.09–7.07(m,1H),6.13–6.11(m,3H),3.85(s,3H),3.80-3.79(m,2H),3.71–3.64(m,1H),3.49(s,3H),3.41(s,2H),2.64–2.62(m,2H),2.59-2.51(m,2H),2.14(s,3H),2.13–2.07(m,4H),1.89–1.81(m,4H),1.73–1.68(m,1H),1.50–1.45(m,1H),1.33–1.24(m,2H),0.88–0.80 (m,2H)；MS(ESI):m/z 809.8(M+H).
实施例97：
Figure PCTCN2020138157-appb-000141
从化合物4-溴-2-羟基苯甲醛起，参照化合物INT-7a的硼酯化和化合物INT-3a的合成得到化合物97a。
从化合物97a起，参照化合物INT-8a的烷基化反应步骤得到化合物97b。 1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),7.86–7.82(m,1H),7.74(d,J＝8.0Hz,1H),7.47–7.43(m,1H),7.37(t,J＝8.0Hz,1H),7.24(d,J＝1.4Hz,1H),7.10–7.06(m,1H),4.23(q,J＝7.0Hz,2H),1.38(t,J＝7.0Hz,3H).
从化合物97b，化合物INT-2，化合物INT-8c和止血环酸甲酯盐酸盐起，参照化合物48的合成得到化合物97。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.65(s,1H),7.55–7.44(m,4H),7.39(d,J＝7.7Hz,1H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),7.05(d,J＝1.7Hz,1H),7.04–7.00(m,1H),6.67(s,1H),5.71(s,2H),4.08(q,J＝6.9Hz,2H),3.74–3.68(m,2H),3.64–3.59(m,1H),3.56(s,3H),3.34(s,2H),2.55–2.53(m,2H),2.13–2.03(m,9H),1.86–1.75(m,4H),1.72–1.66(m,1H),1.46–1.40(m,1H),1.33(t,J＝6.9Hz,3H),1.27–1.21(m,2H),0.84–0.75(m,2H)；MS(ESI):m/z 812.8(M+H).
实施例98：
Figure PCTCN2020138157-appb-000142
参照化合物97的合成，将碘乙烷替换成2-碘代丙烷，得到化合物98。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.76(d,J＝8.5Hz,1H),7.64(s,1H),7.55–7.43(m,4H),7.39(d,J＝7.7Hz,1H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),7.07(d,J＝1.6Hz,1H),7.01–6.97(m,1H),6.67(s,1H),5.71(s,2H),4.70–4.62(m,1H),3.74–3.66(m,2H),3.64–3.60(m,1H),3.56(s,3H),3.34(s,2H),2.54–2.52(m,2H),2.13–2.03(m,9H),1.89–1.78(m,4H),1.71–1.65(m,1H),1.48–1.39(m,1H),1.29–1.26(m,6H),1.26–1.20(m,2H),0.86–0.74(m,2H)；MS(ESI):m/z826.7(M+H).
实施例99：
Figure PCTCN2020138157-appb-000143
从(R)-N-Boc-3-四氢吡咯乙酸起，参照化合物INT-14的合成得到化合物99a。 1H NMR(500MHz,DMSO-d6)δ9.27–8.91(m,2H),3.59(s,3H),3.32–3.26(m,1H),3.23–3.15(m,1H),3.13–3.02(m,1H),2.80–2.71(m,1H),2.55–2.49(m,3H),2.10–2.02(m,1H),1.55–1.48(m,1H).
从化合物99a和化合物INT-9起，参照化合物44的合成得到化合物99。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.45(m,4H),7.40(d,J＝7.5Hz,1H),7.33(s,1H),7.15(d,J＝7.0Hz,1H),7.08–7.06(m,1H),7.05–7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75–3.68(m,2H),3.64–3.60(m,1H),3.56(s,3H),3.48(s,2H),2.68–2.62(m,1H),2.55–2.51(m,2H),2.47–2.42(m,2H),2.40–2.34(m,1H),2.28–2.23(m,2H),2.15–2.05(m,4H),1.97–1.89(m,1H),1.72–1.64(m,1H),1.37–1.29(m,1H)；MS(ESI):m/z 756.7(M+H).
实施例100：
Figure PCTCN2020138157-appb-000144
从化合物INT-9和止血环酸甲酯盐酸盐起，参照化合物INT-5的合成以及化合物1的合成中最后一步脱Boc保护基的步骤得到化合物100a。MS(ESI):m/z798.7(M+H).
在溶有化合物100a(40mg,0.050mmol)的N,N-二甲基甲酰胺(2mL)中加入甲醛(34％水溶液，0.10mL)，醋酸(6.0mg,0.10mmol)和三醋酸硼氢化钠(42mg,0.20mmol)；反应液在25℃条件下搅拌2小时。反应液中加入饱和碳酸氢钠溶液(20mL)，并用乙酸乙酯萃取(20mL x 2)。合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，浓缩得到棕色油状物100b(35mg,收率:84.5％)。MS(ESI):m/z 826.7(M+H).
从化合物100b起，参照化合物33合成过程中的酯水解步骤得到化合物100。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.55–7.45(m,5H),7.44(d,J＝7.5Hz,1H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),7.09–7.07(m,1H),7.06–7.03(m,1H),6.67(s,1H),5.71(s,2H),3.80(s,3H),3.74–3.68(m,1H),3.56(s,3H),3.53–3.49(m,2H),3.36(s,2H),2.44–2.39(m,1H),2.36–2.30(m,1H),2.17(s,3H),2.11–2.05(m,9H),1.87–1.78(m,4H),1.70–1.64(m,1H),1.48–1.40(m,1H),1.32–1.21(m,2H),0.86–0.76(m,2H)；MS(ESI):m/z 812.7(M+H).
实施例101：
Figure PCTCN2020138157-appb-000145
从化合物INT-16和止血环酸甲酯盐酸盐起，参照化合物44的合成得到化合物101。 1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.78(d,J＝8.5Hz,1H),7.65(s,1H),7.57–7.49(m,4H),7.38(s,1H),7.17(d,J＝7.0Hz,1H),7.00–6.96(m,2H),6.69(s,1H),5.73(s,2H),3.87(s,3H),3.79–3.71(m,2H),3.61–3.59(m,1H),3.58(s,3H),3.36(s,2H),2.53–2.51(m,2H),2.13–2.03(m,6H),2.09(s,3H),1.88–1.78(m,4H),1.70–1.62(m,1H),1.49–1.41(m,1H),1.32–1.22(m,2H),0.87–0.76(m,2H)；MS(ESI):m/z 816.3(M+H).
实施例102：
Figure PCTCN2020138157-appb-000146
从化合物INT-15b起，参照化合物INT-3的合成得到化合物102a。MS(ESI):m/z 553.6(M+H).
从化合物102a，化合物INT-8c和止血环酸甲酯盐酸盐起，参照化合物INT-8和化合物44的合成得到化合物102。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.78(d,J＝8.5Hz,1H),7.63(s,1H),7.56–7.48(m,4H),7.38(s,1H),7.17(d,J＝7.0Hz,1H),6.77(s,2H),6.70(s,1H),5.73(s,2H),3.82(s,6H),3.76–3.70(m,2H),3.60–3.56(m,4H),3.36(s,2H),2.53–2.52(m,2H),2.13–2.04(m,9H),1.89–1.79(m,4H),1.70–1.61(m,1H),1.50–1.42(m,1H),1.32–1.23(m,2H),0.87–0.77(m,2H)；MS(ESI):m/z 828.5(M+H).
实施例103：
Figure PCTCN2020138157-appb-000147
在25℃条件下，将溶有L-脯氨酸(132mg,1.14mmol)，氢氧化钠(46mg,1.14mmol)的二甲亚砜(5mL)溶液搅拌1小时；随后加入化合物INT-13(350mg,1.14mmol)，甲烷亚磺酸钠(1.17g,11.4mmol)和碘化亚铜(218mg,1.14mmol)；所得反应液用氮气置换3次，并在氮气氛围和120℃条件下搅拌2小时。反应液用水(50mL)稀释，并用乙酸乙酯萃取(50mL x 2)；合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。残余物用硅胶柱层析(石油醚/乙酸乙酯,v/v＝1/1)分离得到白色固体103a(232mg,收率:94.5％)。 1H NMR(500MHz,Chloroform-d)δ8.48(s,1H),6.89(s,1H),3.98(s,3H),3.89(s,3H),3.07(s,3H),2.74(s,3H)；MS(ESI):m/z 259.1(M+H).
从化合物103a起，参照化合物92的合成得到化合物103。 1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.96(s,1H),7.78(d,J＝8.5Hz,1H),7.66(s,1H),7.56–7.47(m,4H),7.40(d,J＝7.6Hz,1H),7.18(d,J＝7.0Hz,1H),7.07(d,J＝1.6Hz,1H),7.06–7.02(m,1H),6.31(s,1H),6.14(s,2H),3.82(s,3H),3.76–3.67(m,2H),3.64–3.59(m,1H),3.48(s,2H),3.47(s,3H),3.21(s,3H),2.56–2.52(m,2H),2.39–2.33(m,1H),2.11(s,3H),2.11–2.07(m,3H),2.07–2.04(m,1H),1.94–1.87(m,2H),1.82–1.76(m,2H),1.71–1.64(m,1H),1.32–1.23(m,4H)；MS(ESI):m/z828.2(M+H).
实施例104：
Figure PCTCN2020138157-appb-000148
从化合物INT-9和顺式-3-氨基环丁烷羧酸甲酯盐酸盐起，参照化合物44的合成得到化合物104。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.0Hz,1H),7.66(s,1H),7.52–7.47(m,4H),7.40(d,J＝7.5Hz,1H),7.32(s,1H),7.15(d,J＝7.0Hz,1H),7.07(s,1H),7.04(d,J＝7.5Hz,1H),6.68(s,1H),5.72(s,2H),3.81(s,3H),3.75–3.68(m,2H),3.64–3.60(m,1H),3.57(s,3H),3.26(s,2H),2.82–2.75(m,1H),2.67–2.60(m,1H),2.57–2.52(m,2H),2.23–2.17(m,2H),2.14–2.04(m,3H),1.94–1.87(m,2H),1.92(s,3H),1.71–1.64(m,1H)；MS(ESI):m/z755.9(M+H).
实施例105：
Figure PCTCN2020138157-appb-000149
从化合物INT-9和4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐起，参照化合物44的合成得到化合物105。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.43(m,4H),7.40(d,J＝7.5Hz,1H),7.38(s,1H),7.15(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.05–7.02(m,1H),6.66(s,1H),5.70(s,2H),3.81(s,3H),3.74–3.68(m,2H),3.64–3.59(m,1H),3.57(s,3H),3.41(s,2H),2.56–2.52(m,2H),2.14–2.04(m,3H),1.99(s,3H),1.75–1.66(m,7H),1.60–1.49(m,6H)；MS(ESI):m/z 810.2(M+H).
实施例106：
Figure PCTCN2020138157-appb-000150
从化合物INT-9和6-氨基螺[3.3]庚烷-2-羧酸甲酯盐酸盐起，参照化合物44 的合成得到化合物106。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.54–7.44(m,4H),7.40(d,J＝7.5Hz,1H),7.30(s,1H),7.15(d,J＝7.0Hz,1H),7.08–7.06(m,1H),7.05–7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75–3.67(m,2H),3.64–3.59(m,1H),3.56(s,3H),3.21(s,2H),2.93–2.86(m,1H),2.74–2.68(m,1H),2.55–2.52(m,2H),2.20–1.98(m,9H),1.88(s,3H),1.80–1.74(m,1H),1.72–1.65(m,2H)；MS(ESI):m/z 796.2(M+H).
实施例107：
Figure PCTCN2020138157-appb-000151
从化合物75a起，参照化合物92的合成得到化合物107。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.82(d,J＝8.5Hz,1H),7.70(s,1H),7.65(s,1H),7.53–7.46(m,4H),7.40(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.06–7.02(m,1H),6.90(s,1H),5.80(s,2H),3.81(s,3H),3.71(d,J＝3.0Hz,2H),3.69(s,3H),3.63–3.60(m,1H),3.47(s,2H),2.54–2.52(m,2H),2.39–2.36(m,1H),2.12–2.06(m,4H),2.10(s,3H),1.93–1.88(m,2H),1.81–1.76(m,2H),1.70–1.66(m,1H),1.30–1.25(m,4H)；MS(ESI):m/z 775.3(M+H).
实施例108：
Figure PCTCN2020138157-appb-000152
参照化合物107的合成，将反式-4-氨基环己甲酸甲酯盐酸盐替换成化合物 INT-14，得到化合物108。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.83(d,J＝8.5Hz,1H),7.71(s,1H),7.63(s,1H),7.54–7.46(m,4H),7.42(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),7.11(s,1H),7.07(d,J＝7.5Hz,1H),6.92(s,1H),5.80(s,2H),3.87–3.78(m,2H),3.83(s,3H),3.71–3.66(m,1H),3.70(s,3H),3.51–3.45(m,2H),2.54–2.52(m,2H),2.14–2.04(m,8H),1.78–1.68(m,5H),1.59–1.53(m,1H),1.31–1.21(m,2H),0.98–0.90(m,2H)；MS(ESI):m/z 789.1(M+H).
实施例109：
Figure PCTCN2020138157-appb-000153
从顺式-(N-BOC-4-氨基环己基)乙酸起，参照化合物INT-14的合成得到化合物109a。 1H NMR(500MHz,DMSO-d6)δ7.95(brs,3H),3.57(s,3H),3.18–3.08(m,1H),2.27(d,J＝7.5Hz,2H),1.95–1.86(m,1H),1.69–1.56(m,4H),1.54–1.38(m,4H).
从化合物109a和化合物INT-9起，参照化合物44的合成得到化合物109。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.76(d,J＝8.5Hz,1H),7.65(s,1H),7.54–7.46(m,4H),7.40(d,J＝7.5Hz,1H),7.37(s,1H),7.15(d,J＝7.0Hz,1H),7.08–7.06(m,1H),7.05–7.02(m,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.71(d,J＝3.0Hz,2H),3.64–3.59(m,1H),3.57(s,3H),3.43(s,2H),2.56–2.52(m,2H),2.36–2.31(m,1H),2.21–2.16(m,2H),2.13–2.04(m,3H),2.07(s,3H),1.98–1.91(m,1H),1.72–1.66(m,1H),1.61–1.53(m,2H),1.51–1.39(m,6H)；MS(ESI):m/z 798.3(M+H).
实施例110：
Figure PCTCN2020138157-appb-000154
在冰浴条件下，在溶有化合物INT-8b(500mg,1.32mmol)的二氯甲烷(10mL)溶液中滴加三溴化硼(1M的二氯甲烷溶液，3.95mL)；反应液在相同条件下搅拌1小时。反应液中加入冰水(30mL)淬灭，所得混合液进一步搅拌半小时；水相后二氯甲烷萃取(50mL x 2)。合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩。残余物用硅胶柱层析得到白色固体110a(370mg,收率:76.8％)。MS(ESI):m/z 365.2(M+H).
从化合物110a起，参照化合物INT-8a的烷基化反应步骤得到化合物110b。 1H NMR(500MHz,DMSO-d6)δ10.21(s,1H),8.13(s,1H),7.79(d,J＝8.3Hz,1H),7.48–7.24(m,2H),6.80(s,1H),5.78(s,2H),4.55–4.32(m,1H),1.19(d,J＝6.0Hz,6H).
从化合物110b，化合物INT-6和止血环酸甲酯盐酸盐起，参照化合物INT-8和化合物44的合成得到化合物110。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.74(d,J＝8.5Hz,1H),7.64(s,1H),7.54–7.45(m,4H),7.43(d,J＝8.0Hz,1H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),7.12(s,1H),7.08(d,J＝7.5Hz,1H),6.41(s,1H),5.72(s,2H),4.20–4.12(m,1H),3.86–3.82(m,2H),3.84(s,3H),3.71–3.66(m,1H),3.33(s,2H),2.73–2.63(m,2H),2.14–2.06(m,9H),1.87–1.77(m,4H),1.72–1.68(m,1H),1.48–1.39(m,1H),1.30–1.22(m,2H),1.05(d,J＝6.0Hz,6H),0.86–0.76(m,2H)；MS(ESI):m/z 826.3(M+H).
实施例111：
Figure PCTCN2020138157-appb-000155
从2-氟-5-羟基苯甲酸起，参照化合物INT-1c和化合物INT-8b的合成得到化合物111a。MS(ESI):m/z 363.1(M+H).
从化合物111a，化合物INT-2和止血环酸甲酯盐酸盐起，参照化合物INT-8和化合物44的合成得到化合物111。 1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.79(d,J＝8.5Hz,1H),7.67(s,1H),7.53–7.49(m,2H),7.48–7.42(m,6H),7.18–7.12(m,2H),6.88(d,J＝6.0Hz,1H),5.69(s,2H),3.80–3.72(m,2H),3.66–3.60(m,1H),3.65(s,3H),3.36(s,2H),2.56–2.53(m,2H),2.14–2.07(m,6H),2.09(s,3H),1.89–1.78(m,4H),1.73–1.66(m,1H),1.50–1.40(m,1H),1.31–1.22(m,2H),0.85–0.76(m,2H)；MS(ESI):m/z 752.3(M+H).
实施例112：
Figure PCTCN2020138157-appb-000156
从5-羟基-2-甲基苯甲酸起，参照化合物INT-1c和化合物INT-8b的合成得到化合物112a。MS(ESI):m/z 359.2(M+H).
从化合物112a，化合物INT-6和止血环酸甲酯盐酸盐起，参照化合物INT-8和化合物44的合成得到化合物112。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.75(d,J＝8.5Hz,1H),7.66(s,1H),7.55–7.46(m,4H),7.44(d,J＝7.5Hz,1H),7.15(d,J＝7.0Hz,1H),7.12(s,2H),7.09(d,J＝7.5Hz,1H),6.60(s,1H),5.66(s,2H),3.88–3.82(m,2H),3.85(s,3H),3.72–3.67(m,1H),3.57(s,3H),3.43–3.40(m,2H),2.67(d,J＝6.0Hz,2H),2.25(s,3H),2.18–2.04(m,9H),1.89–1.80(m,4H),1.76–1.68(m,1H),1.55–1.45(m,1H),1.32–1.23(m,2H),0.86–0.75(m, 2H)；MS(ESI):m/z 778.4(M+H).
实施例113：
Figure PCTCN2020138157-appb-000157
从化合物INT-16和反式-4-氨基环丁甲酸甲酯盐酸盐起，参照化合物101的合成得到化合物113。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.76(d,J＝8.5Hz,1H),7.62(s,1H),7.56–7.45(m,4H),7.34(s,1H),7.15(d,J＝7.0Hz,1H),7.02–6.93(m,2H),6.68(s,1H),5.72(s,2H),3.86(s,3H),3.83–3.72(m,2H),3.62–3.58(m.1H),3.57(s,3H),3.27–3.25(m,2H),3.06–2.97(m,1H),2.87–2.78(m,1H),2.56–2.52(m,2H),2.22–2.15(m,2H),2.14–1.99(m,5H),1.92(s,3H),1.69–1.60(m,1H)；MS(ESI):m/z 774.2(M+H).
实施例114：
Figure PCTCN2020138157-appb-000158
从化合物INT-16和反式-4-氨基环己甲酸甲酯盐酸盐起，参照化合物101的合成得到化合物114。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.47(m,4H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),6.98–6.93(m,2H),6.67(s,1H),5.71(s,2H),3.86(s,3H),3.77–3.70(m,2H),3.60–3.56(m,1H),3.57(s,3H),3.45(brs,2H),2.52–2.50(m,2H),2.40–2.35(m,1H),2.12–2.03(m,7H),1.94–1.87(m,2H),1.81–1.75(m,2H),1.69–1.60(m,1H),1.32–1.23(m,4H)；MS(ESI):m/z 802.2(M+H).
实施例115：
Figure PCTCN2020138157-appb-000159
从化合物INT-16和化合物109a起，参照化合物101的合成得到化合物115。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.45(m,4H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),6.99–6.93(m,2H),6.67(s,1H),5.71(s,2H),3.86(s,3H),3.78–3.69(m,2H),3.60–3.58(m,1H),3.57(s,3H),3.45(s,2H),2.53–2.50(m,2H),2.36–2.31(m,1H),2.09(s,3H),2.07–2.02(m,5H),1.78–1.70(m,4H),1.68–1.60(m,1H),1.59–1.50(m,1H),1.31–1.18(m,2H),0.98–0.86(m,2H)；MS(ESI):m/z 816.2(M+H).
实施例116：
Figure PCTCN2020138157-appb-000160
从化合物INT-16和4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐起，参照化合物101的合成得到化合物116。 1H NMR(500MHz,DMSO-d6)δ7.97–7.88(m,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.47(m,4H),7.38(s,1H),7.15(d,J＝7.0Hz,1H),6.98–6.94(m,2H),6.66(s,1H),5.70(s,2H),3.85(s,3H),3.77–3.69(m,2H),3.65–3.59(m,1H),3.57(s,3H),3.41(s,2H),2.60–2.54(m,2H),2.14–2.03(m,3H),1.99(s,3H),1.76–1.69(m,6H),1.67–1.61(m,1H),1.58–1.52(m,6H)；MS(ESI):m/z 828.1(M+H).
实施例117：
Figure PCTCN2020138157-appb-000161
从4-溴-6-氯吲唑起，参照化合物INT-8和化合物30的合成得到化合物117。 1H NMR(500MHz,DMSO-d6)δ8.03(s,1H),7.93(s,1H),7.66(s,1H),7.55–7.44(m,8H),7.24(s,1H),6.78(s,1H),5.74(brs,2H),3.91–3.85(m,1H),3.79–3.76(m,2H),3.69–3.57(m,7H),3.15–3.08(m,1H),2.57–2.55(m,2H),2.15–2.07(m,3H),1.74–1.66(m,1H)；MS(ESI):m/z 736.0(M+H).
实施例118：
Figure PCTCN2020138157-appb-000162
从化合物118a起，参照化合物INT-14的合成得到化合物118b。
从化合物118b和化合物INT-9起，参照化合物44的合成得到化合物118。 1H NMR(500MHz,DMSO-d6)δ7.90(s,1H),7.75(d,J＝8.5Hz,1H),7.65(s,1H),7.53–7.45(m,4H),7.40(d,J＝7.5Hz,1H),7.36(s,1H),7.15(d,J＝7.5Hz,1H),7.08–7.06(m,1H),7.04(d,J＝8.5Hz,1H),6.67(s,1H),5.71(s,2H),3.81(s,3H),3.75–3.67(m,2H),3.65–3.59(m,1H),3.56(s,3H),3.34(s,2H),2.56–2.52(m,2H),2.14–2.03(m,10H),1.80–1.73(m,2H),1.72–1.65(m,3H),1.58–1.53(m,1H),1.44–1.36(m,1H),0.97–0.86(m,2H),0.83–0.75(m,2H)；MS(ESI):m/z812.2(M+H).
实施例119：
Figure PCTCN2020138157-appb-000163
在氮气气氛下，将溶有3-氧代环丁基氨基甲酸叔丁酯(1.0g,5.4mmol)和乙氧甲酰基亚甲基三苯基膦(2.1g,5.9mmol)的甲苯(15mL)溶液在110℃条件下搅拌6小时。反应液中加入水(100mL)和乙酸乙酯(100mL)；水相进一步用乙酸乙酯萃取(100mL x 2)。合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，浓缩。残余物用硅胶柱层析得到白色固体119a(1.1g,收率:79.8％)。MS(ESI):m/z 256.3(M+H)。
在氢气气氛下，将混有化合物119a(1.1g,4.3mmol)，钯(10％w/w吸附在活性炭，150mg)的甲醇(15mL)溶液在25℃条件下搅拌过夜。反应液过滤，滤液浓缩得到白色固体119b(1.1g,收率:99.8％)。MS(ESI):m/z 258.3(M+H)。
在溶有化合物119b(1.1g,4.3mmol)的二氯甲烷(15mL)溶液中加入盐酸(4M在1,4-二氧六环中,5.4mL)；所得反应液在室温条件下搅拌2小时。反应液浓缩后得到无色油状物119c(0.83g,收率:99.5％)。
从化合物119c和化合物INT-9起，参照化合物44的合成得到化合物119(从核磁判断，该化合物应该为顺反异构体的混合物，比例为6:4)。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.77(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.47(m,4H),7.42(d,J＝7.0Hz,1H),7.34(d,J＝8.5Hz,1H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.5Hz,1H),7.06(dd,J＝7.5,1.5Hz,1H),6.69(s,1H),5.73(s,2H),3.83(s,3H),3.77–3.69(m,2H),3.66–3.61(m,1H),3.58(s,3H),3.25(s,2H),3.03–2.95(m,0.4H),2.74–2.69(m,0.6H),2.58–2.54(m,2H),2.43–2.35(m,1H),2.31–2.27(m,1.2H),2.23–2.06(m,5H),2.04–1.97(m,0.8H),1.91(s,3H),1.80–1.73(m,0.8H),1.72–1.64(m,1H),1.51–1.41(m,1.2H)；MS(ESI):m/z 770.0(M+H)。
实施例120：
Figure PCTCN2020138157-appb-000164
从反式-4-(Boc-氨基)环己基甲醛起，参照化合物119a和化合物119c的合成得到化合物120b。MS(ESI):m/z 198.6(M+H)。
从化合物120b和化合物INT-9起，参照化合物44的合成得到化合物120。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.78(d,J＝8.5Hz,1H),7.66(s,1H),7.56–7.47(m,4H),7.42(d,J＝7.7Hz,1H),7.39(s,1H),7.17(d,J＝7.0Hz,1H),7.10(s,1H),7.09–7.05(m,1H),6.77–6.71(m,1H),6.69(s,1H),5.73(s,2H),5.72–5.66(m,1H),3.84(s,3H),3.82–3.73(m,2H),3.68–3.63(m,1H),3.59(s,3H),3.53–3.42(m,2H),2.61–2.56(m,2H),2.44–2.36(m,1H),2.17–2.06(m,7H),1.86–1.75(m,4H),1.75–1.66(m,1H),1.40–1.27(m,2H),1.18–1.08(m,2H)；MS(ESI):m/z 810.2(M+H)。
实施例121：
Figure PCTCN2020138157-appb-000165
从化合物120a起，参照化合物119的合成得到化合物121。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.56–7.46(m,4H),7.41(d,J＝7.7Hz,1H),7.38(s,1H),7.17(d,J＝7.0Hz,1H),7.08(d,J＝1.7Hz,1H),7.08–7.04(m,1H),6.68(s,1H),5.72(s,2H),3.83(s,3H),3.77–3.69(m,2H),3.66–3.61(m,1H),3.58(s,3H),3.46(brs,2H),2.57–2.54(m,2H),2.38–2.30(m, 1H),2.18(t,J＝7.5Hz,2H),2.15–2.05(m,6H),1.81–1.65(m,5H),1.38(t,J＝7.5Hz,2H),1.29–1.17(m,2H),1.17–1.08(m,1H),0.92–0.82(m,2H)；MS(ESI):m/z 812.2(M+H)。
实施例122和123：
Figure PCTCN2020138157-appb-000166
从化合物INT-9，环丙胺和4-氧代环己甲酸甲酯起，参照化合物44的合成得到化合物122和化合物123。
化合物122： 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.76(d,J＝8.5Hz,1H),7.67(s,1H),7.55–7.45(m,4H),7.41(d,J＝7.5Hz,1H),7.31(s,1H),7.17(d,J＝7.0Hz,1H),7.09–7.07(m,1H),7.07–7.03(m,1H),6.66(s,1H),5.71(s,2H),3.83(s,3H),3.73–3.72(m,2H),3.68(s,2H),3.65–3.60(m,1H),3.59(s,3H),2.56–2.53(m,2H),2.46–2.42(m,1H),2.14–2.03(m,5H),1.93–1.87(m,2H),1.83–1.78(m,2H),1.72–1.67(m,1H),1.38–1.30(m,2H),1.26–1.20(m,2H),0.40–0.35(m,2H),0.26–0.17(m,2H)；MS(ESI):m/z 810.2(M+H)。
化合物123： 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.74(d,J＝8.5Hz,1H),7.65(s,1H),7.52–7.45(m,4H),7.40(d,J＝7.5Hz,1H),7.29(s,1H),7.15(d,J＝7.0Hz,1H),7.07–7.06(m,1H),7.05–7.02(m,1H),6.63(s,1H),5.70(s,2H),3.81(s,3H),3.72–3.70(m,2H),3.68–3.66(m,1H),3.64(s,2H),3.57(s,3H),2.55–2.52(m,2H),2.45–2.42(m,1H),2.13–2.03(m,5H),1.70–1.65(m,1H),1.60– 1.55(m,2H),1.47–1.40(m,2H),1.31–1.25(m,4H),0.37–0.32(m,2H),0.22–0.17(m,2H)；MS(ESI):m/z 810.2(M+H)。
实施例124：
Figure PCTCN2020138157-appb-000167
参照化合物110的合成，将异丙基碘换成碘乙烷，得到化合物124。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.68(s,1H),7.55–7.47(m,4H),7.42(d,J＝7.7Hz,1H),7.37(s,1H),7.17(d,J＝7.0Hz,1H),7.09(d,J＝1.6Hz,1H),7.08–7.05(m,1H),6.59(s,1H),5.73(s,2H),3.83(s,3H),3.78(q,J＝7.0Hz,2H),3.75–3.71(m,2H),3.65–3.61(m,1H),3.36(brs,2H),2.56–2.53(m,2H),2.14–2.03(m,6H),2.08(s,3H),1.89–1.80(m,4H),1.72–1.66(m,1H),1.50–1.42(m,1H),1.29–1.24(m,2H),1.18(t,J＝7.0Hz,3H),0.85–0.79(m,2H)；MS(ESI):m/z 812.2(M+H)。
实施例125：
Figure PCTCN2020138157-appb-000168
从化合物INT-9，反式-4-氨基环己甲酸甲酯盐酸盐和苯甲醛起，参照化合物44的合成得到化合物125。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.74(d,J＝8.5Hz,1H),7.65(s,1H),7.53–7.43(m,4H),7.44(s,1H),7.40(d,J＝7.5Hz,1H),7.30–7.23(m,4H),7.22–7.13(m,2H),7.08–7.06(m,1H),7.05–7.02(m,1H),6.62(s,1H),5.68(s,2H),3.81(s,3H),3.77–3.70(m,2H),3.66–3.61(m,1H),3.57(s,2H),3.54(s,3H),3.51(s,2H),2.59–2.54(m,2H),2.41–2.36(m,1H),2.14–2.04(m,4H),1.94–1.87(m,2H),1.84–1.79(m,2H),1.71–1.65(m,1H),1.41– 1.32(m,2H),1.20–1.11(m,2H)；MS(ESI):m/z 860.1(M+H)。
实施例126：
Figure PCTCN2020138157-appb-000169
从化合物INT-9，反式-4-氨基环己甲酸甲酯盐酸盐和环丙甲醛起，参照化合物44的合成得到化合物126。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.67(s,1H),7.56(s,1H),7.55–7.46(m,4H),7.41(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),7.10–7.08(m,1H),7.08–7.03(m,1H),6.67(s,1H),5.72(s,3H),3.83(s,3H),3.76–7.68(m,2H),3.66–3.62(m,1H),3.59(s,3H),3.55(s,2H),2.56–2.53(m,2H),2.32(d,J＝6.0Hz,2H),2.15–2.05(m,4H),1.93–1.88(m,2H),1.80–1.73(m,2H),1.72–1.66(m,1H),1.30–1.21(m,5H),0.75–0.69(m,1H),0.37–0.31(m,2H),0.03–0.00(m,2H)；MS(ESI):m/z 824.1(M+H)。
实施例127：
Figure PCTCN2020138157-appb-000170
参照化合物110的合成，将异丙基碘换成2-溴乙酰胺，得到化合物127。 1H NMR(500MHz,DMSO-d6)δ7.87(d,J＝1.0Hz,1H),7.73(d,J＝8.5Hz,1H),7.65(s,1H),7.54(s,1H),7.51–7.47(m,4H),7.40(d,J＝7.5Hz,1H),7.37(s,1H),7.34(s,1H),7.15(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.06–7.02(m,1H),6.79(s,1H),5.68(s,2H),4.28(s,2H),3.81(s,3H),3.72(d,J＝3.0Hz,2H),3.64–3.61(m,1H),3.43(s,2H),2.58–2.55(m,2H),2.15–2.09(m,6H),2.08(s,3H),1.83–1.76(m,4H),1.69–1.66(m,1H),1.46–1.43(m,1H),1.26–1.22(m,2H),0.83–0.78(m,2H)；MS(ESI):m/z 841.2(M+H)。
实施例128：
Figure PCTCN2020138157-appb-000171
参照化合物110的合成，将异丙基碘换成2-溴乙酸叔丁酯，得到化合物128。 1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.73(d,J＝8.5Hz,1H),7.67(s,1H),7.51–7.46(m,4H),7.42–7.37(m,2H),7.14(d,J＝7.0Hz,1H),7.07(d,J＝1.5Hz,1H),7.06–7.01(m,1H),6.79(s,1H),5.65(s,2H),4.09(brs,2H),3.81(s,3H),3.73–3.69(m,2H),3.63–3.60(m,1H),3.41(s,2H),2.54–2.52(m,2H),2.33–2.28(m,1H),2.20(s,3H),2.12–2.05(m,5H),1.86–1.80(m,4H),1.71–1.66(m,1H),1.59–1.50(m,1H),1.29–1.23(m,2H),0.87–0.80(m,2H)；MS(ESI):m/z 843.2(M+H)。
实施例129：
Figure PCTCN2020138157-appb-000172
从化合物INT-9和反式-4-氨基环己甲酸甲酯盐酸盐起，参照化合物44的合成(不包括最后一步脱Boc)得到化合物129a。MS(ESI):m/z 883.6(M+H)。
从化合物129a和甲磺酰胺起，参照化合物82a合成中酸胺缩合条件和化合物1的最后一步脱Boc条件得到化合物129。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.78(d,J＝8.5Hz,1H),7.67(s,1H),7.56–7.47(m,4H),7.44(d,J＝7.5Hz,1H),7.41(s,1H),7.17(d,J＝7.0Hz,1H),7.12(s,1H),7.08(d,J＝7.5Hz,1H),6.70 (s,1H),5.73(s,2H),3.85(s,3H),3.84-3.79(m,2H),3.71–3.65(m,1H),3.59(s,3H),3.53(s,2H),3.05(s,3H),2.65(d,J＝6.0Hz,2H),2.46–2.40(m,1H),2.15(s,3H),2.14–2.05(m,4H),1.88–1.78(m,4H),1.75–1.68(m,1H),1.35–1.22(m,4H)；MS(ESI):m/z 861.3(M+H)。
实施例130：
Figure PCTCN2020138157-appb-000173
从化合物INT-16和化合物118b起，参照化合物101的合成得到化合物130。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.75(d,J＝8.5Hz,2H),7.63(s,1H),7.54–7.48(m,4H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),6.99–6.93(m,2H),6.67(s,1H),5.71(s,2H),3.85(s,3H),3.76–3.70(m,2H),3.60–3.57(m,1H),3.56(s,3H),3.34(s,2H),2.53–2.50(m,2H),2.11–2.02(m,10H),1.79–1.74(m,2H),1.71–1.66(m,2H),1.65–1.60(m,1H),1.58–1.51(m,1H),1.44–1.36(m,1H),0.95–0.87(m,2H),0.83–0.74(m,2H)；MS(ESI):m/z 830.1(M+H)。
实施例131：
Figure PCTCN2020138157-appb-000174
从化合物INT-16和化合物121a起，参照化合物101的合成得到化合物131。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.47(m,4H),7.36(s,1H),7.15(d,J＝7.0Hz,1H),6.98–6.92(m,2H),6.66(s,1H),5.71(s,2H),3.85(s,3H),3.77–3.69(m,2H),3.62–3.59(m,1H),3.56(s, 3H),3.44(s,2H),2.55–2.52(m,2H),2.36–2.31(m,1H),2.19–2.14(m,2H),2.09(s,3H),2.07–2.02(m,3H),1.77–1.69(m,4H),1.66–1.60(m,1H),1.39–1.33(m,2H),1.24–1.17(m,2H),1.13–1.08(m,1H),0.89–0.82(m,2H)；MS(ESI):m/z830.1(M+H)。
实施例132：
Figure PCTCN2020138157-appb-000175
从化合物INT-16和化合物120b起，参照化合物101的合成得到化合物132。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.54–7.47(m,4H),7.37(s,1H),7.15(d,J＝7.0Hz,1H),6.99–6.94(m,2H),6.76–6.69(m,1H),6.67(s,1H),5.71(s,2H),5.69–5.64(m,1H),3.86(s,3H),3.77–3.71(m,2H),3.61–3.58(m,1H),3.57(s,3H),3.46(s,2H),2.52–2.50(m,2H),2.14–2.02(m,8H),1.84–1.74(m,4H),1.69–1.60(m,1H),1.34–1.24(m,2H),1.16–1.07(m,2H)；MS(ESI):m/z 828.1(M+H)。
实施例133：
Figure PCTCN2020138157-appb-000176
参考化合物91的合成，将止血环酸甲酯盐酸盐换成4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐，得到化合物133。 1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.82(d,J＝7.5Hz,1H),7.78(d,J＝8.6Hz,1H),7.68–7.64(m,2H),7.58–7.49(m,3H),7.40(s,1H),7.32(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),6.69(s,1H),5.72(s,2H),3.92(s,3H),3.76–3.68(m,2H),3.66–3.62(m,1H),3.59(s,3H),3.43(s, 2H),2.60–2.54(m,2H),2.16–2.07(m,3H),2.01(s,3H),1.77–1.65(m,7H),1.61–1.54(m,6H)；MS(ESI):m/z 811.1(M+H)。
实施例134：
Figure PCTCN2020138157-appb-000177
参照化合物110的合成，将异丙基碘换成(S)-5-溴甲基-2-吡咯烷酮，得到化合物134。 1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.78–7.73(m,2H),7.66(s,1H),7.52–7.46(m,4H),7.40(d,J＝7.5Hz,1H),7.37(s,1H),7.15(d,J＝7.0Hz,1H),7.07(s,1H),7.04(d,J＝7.5Hz,1H),6.72(s,1H),5.70(s,2H),3.81(s,3H),3.80–3.76(m,1H),3.75–3.72(m,1H),3.72–3.70(m,2H),3.66–3.60(m,2H),3.40–3.35(m,2H),2.57–2.52(m,2H),2.17(d,J＝11.0Hz,1H),2.12–2.08(m,6H),2.08(s,3H),2.06–2.04(m,1H),1.87–1.75(m,5H),1.70–1.64(m,1H),1.47–1.40(m,1H),1.30–1.20(m,3H),0.85–0.77(m,2H)；MS(ESI):m/z 881.2(M+H)。
实施例135：
Figure PCTCN2020138157-appb-000178
从化合物80b，4-溴吲唑和化合物INT-15起，参照化合物73a和化合物INT-16的合成得到化合物135a。MS(ESI):m/z 661.4(M+H)。
从化合物135a和4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐起，参照化合物 101的合成得到化合物135。 1H NMR(500MHz,DMSO-d6)δ7.85(s,1H),7.79(d,J＝8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.57–7.43(m,4H),7.12(d,J＝7.0Hz,1H),6.96(s,1H),6.94(d,J＝8.5Hz,1H),5.78(s,2H),3.85(s,3H),3.74–3.73(m,2H),3.58-3.56(m,3H),3.37(s,3H),2.51-2.50(m,2H),2.10-2.03(m,3H),1.99(s,3H),1.70-1.67(m,6H),1.64-1.62(m,1H),1.54-1.51(m,6H)；MS(ESI):m/z829.2(M+H)。
实施例136：
Figure PCTCN2020138157-appb-000179
从化合物INT-16和3-氨基双环[1.1.1]戊烷-1-羧酸甲酯盐酸盐起，参照化合物101的合成得到化合物136。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.75(d,J＝8.5Hz,1H),7.63(s,1H),7.56–7.46(m,4H),7.33(s,1H),7.15(d,J＝7.0Hz,1H),7.00–6.94(m,2H),6.67(s,1H),5.72(s,2H),3.86(s,3H),3.78–3.70(m,2H),3.57(s,3H),3.56–3.52(m,1H),3.40(s,2H),2.55–2.52(m,2H),2.10–2.03(m,6H),1.89(s,6H),1.68–1.60(m,1H)；MS(ESI):m/z 786.0(M+H)。
实施例137：
Figure PCTCN2020138157-appb-000180
从化合物INT-10，化合物INT-2，化合物80b和4-溴吲唑起，参照化合物INT-3， 化合物73a和化合物16的合成得到化合物137a。MS(ESI):m/z 644.3(M+H)。
从化合物137a和4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐起，参照化合物101的合成得到化合物137。 1H NMR(500MHz,DMSO-d6)δ7.83–7.80(m,3H),7.70–7.65(m,3H),7.55(t,J＝7.5Hz,1H),7.50–7.47(m,2H),7.31(d,J＝7.4Hz,1H),7.14(d,J＝7.0Hz,1H),5.80(s,2H),3.92(s,3H),3.73–3.71(m,2H),3.65–3.63(m,1H),3.39(s,3H),3.36(brs,2H),2.56(d,J＝6.0Hz,2H),2.14–2.07(m,3H),2.00(s,3H),1.72-1.68(m,7H),1.56-1.52(m,6H)；MS(ESI):m/z 812.1(M+H)。
实施例138：
Figure PCTCN2020138157-appb-000181
参照化合物107的合成，将化合物INT-6换成化合物INT-15，得到化合物138。 1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.84(d,J＝8.6Hz,1H),7.71(s,1H),7.65(s,1H),7.56–7.50(m,4H),7.18(d,J＝7.0Hz,1H),6.99–6.97(m,2H),6.92(s,1H),5.82(s,2H),3.87(s,3H),3.76–3.73(m,2H),3.71(s,3H),3.62-3.58(m,1H),3.49(s,2H),2.60-2.55(m,2H),2.45–2.35(m,1H),2.12(s,3H),2.10–2.04(m,3H),1.94-1.92(m,2H),1.81-1.79(m,2H),1.69–1.62(m,1H),1.34-1.23(m,5H)；MS(ESI):m/z 793.0(M+H)。
实施例139：
Figure PCTCN2020138157-appb-000182
参照化合物138的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成反式-4-氨基环丁甲酸甲酯盐酸盐，得到化合物139。 1H NMR(500MHz,DMSO-d6)δ7.94(s, 1H),7.82(d,J＝8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.55–7.48(m,4H),7.17(d,J＝7.1Hz,1H),6.99–6.95(m,2H),6.91(s,1H),5.80(s,2H),3.85(s,3H),3.73(d,J＝4.2Hz,2H),3.69(s,3H),3.58–3.56(m,1H),3.26(brs,2H),3.03-3.01(m,1H),2.80-2.76(m,1H),2.51-2.48(m,2H),2.20-2.15(m,2H),2.09–2.02(m,5H),1.92(s,3H),1.66–1.62(m,1H)；MS(ESI):m/z 765.1(M+H)。
实施例140：
Figure PCTCN2020138157-appb-000183
参照化合物138的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐，得到化合物140。 1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.84(d,J＝8.5Hz,1H),7.73(s,1H),7.65(s,1H),7.56–7.49(m,4H),7.18(d,J＝7.0Hz,1H),7.00–6.97(m,2H),6.91(s,1H),5.81(s,2H),3.87(s,3H),3.75(d,J＝4.5Hz,2H),3.70(s,3H),3.62–3.56(m,1H),3.45(s,2H),2.54-2.52(m,2H),2.09–2.05(m,3H),2.02(s,3H),1.75-1.72(m,6H),1.68-1.63(m,1H),1.59-1.56(m,6H)；MS(ESI):m/z 819.0(M+H)。
实施例141：
Figure PCTCN2020138157-appb-000184
参照化合物138的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成化合物INT-14，得到化合物141。 1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.82(d,J＝8.5Hz,1H),7.69(s,1H),7.63(s,1H),7.56–7.48(m,4H),7.17(d,J＝7.0Hz,1H),6.97–6.95(m,2H),6.90(s,1H),5.80(s,2H),3.85(s,3H),3.73(d,J＝4.1Hz,2H), 3.69(s,3H),3.58-3.55(m,1H),3.46(s,2H),2.52-2.49(m,2H),2.36–2.33(m,1H),2.10(s,3H),2.08–2.01(m,5H),1.77–1.70(m,4H),1.66–1.61(m,1H),1.58-1.52(m,1H),1.29–1.22(m,2H),0.96-0.89(m,2H)；MS(ESI):m/z 807.1(M+H)。
实施例142：
Figure PCTCN2020138157-appb-000185
参照化合物92的合成，将化合物INT-6换成化合物INT-15，得到化合物142。 1H NMR(500MHz,DMSO-d6)δ8.17(s,1H),7.99(s,1H),7.78(d,J＝8.5Hz,1H),7.64(s,1H),7.57–7.46(m,4H),7.17(d,J＝7.0Hz,1H),7.00–6.95(m,2H),6.10(s,1H),6.09(s,2H),3.86(s,3H),3.73(d,J＝4.5Hz,2H),3.59–3.55(m,1H),3.49(s,2H),3.48(s,3H),2.53–2.51(m,2H),2.43–2.37(m,1H),2.13(s,3H),2.11–2.01(m,4H),1.95–1.86(m,2H),1.84–1.75(m,2H),1.68–1.59(m,1H),1.33–1.23(m,4H)；MS(ESI):m/z 813.3(M+H)。
实施例143：
Figure PCTCN2020138157-appb-000186
参照化合物142的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成反式-4-氨基环丁甲酸甲酯盐酸盐，得到化合物143。 1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.99(s,1H),7.79(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.48(m,4H),7.17(d,J＝6.5Hz,1H),7.00–6.96(m,2H),6.12(s,1H),6.09(s,2H),3.86(s,3H),3.77–3.70(m,2H),3.59–3.55(m,1H),3.48(s,3H),3.32–3.30(m,2H),3.09–3.02(m,1H),2.87–2.78(m,1H),2.52–2.48(m,2H),2.21–2.16(m,2H),2.12–2.02(m, 5H),1.95(s,3H),1.67–1.60(m,1H)；MS(ESI):m/z 785.3(M+H)。
实施例144：
Figure PCTCN2020138157-appb-000187
参照化合物142的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成化合物INT-14，得到化合物144。 1H NMR(500MHz,DMSO-d6)δ8.17(s,1H),7.98(s,1H),7.78(d,J＝8.5Hz,1H),7.63(s,1H),7.57–7.47(m,4H),7.17(d,J＝6.5Hz,1H),7.00–6.95(m,2H),6.09(s,1H),6.09(s,2H),3.86(s,3H),3.77–3.70(m,2H),3.59–3.55(m,1H),3.49(s,2H),3.48(s,3H),2.54–2.50(m,2H),2.36–2.33(m,1H),2.13(s,3H),2.10–2.02(m,5H),1.78–1.70(m,4H),1.67–1.64(m,1H),1.57–1.52(m,1H),1.32–1.21(m,2H),0.98–0.88(m,2H)；MS(ESI):m/z 827.1(M+H)。
实施例145：
Figure PCTCN2020138157-appb-000188
参照化合物142的合成，将反式-4-氨基环己甲酸甲酯盐酸盐换成4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐，得到化合物145。 1H NMR(500MHz,DMSO-d6)δ8.18(s,1H),7.98(s,1H),7.78(d,J＝8.5Hz,1H),7.63(s,1H),7.56–7.47(m,4H),7.17(d,J＝7.0Hz,1H),7.00–6.95(m,2H),6.09(s,1H),6.08(s,2H),3.86(s,3H),3.77–3.70(m,2H),3.59–3.55(m,1H),3.48(s,3H),3.45(s,2H),2.54–2.50(m,2H),2.10–2.04(m,3H),2.03(s,3H),1.74–1.69(m,6H),1.68–1.62(m,1H),1.60–1.55(s,6H)；MS(ESI):m/z 839.1(M+H)。
实施例146：
Figure PCTCN2020138157-appb-000189
在混有化合物INT-13(50mg,0.16mmol)和氟磺酰基二氟乙酸甲酯(314mg,1.6mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入碘化亚铜(156mg,0.82mmol)；所得混合液在150度条件下搅拌4小时。反应液过滤后，滤液中加入乙酸乙酯和水的混合液(100mL,v/v＝1/1)。所得有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩。残余物用硅胶柱层析得到白色固体146a(40mg,收率:98.7％)。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.27(s,1H),3.90(s,3H),3.80(s,3H)；MS(ESI):m/z 249.0(M+H)。
从化合物146a起，参照化合物92的合成，其中将反式-4-氨基环己甲酸甲酯盐酸盐换成化合物INT-14，得到化合物146。 1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.70(s,1H),7.67–7.62(m,2H),7.54–7.46(m,4H),7.40(d,J＝7.7Hz,1H),7.17(d,J＝7.0Hz,1H),7.07(d,J＝1.6Hz,1H),7.04(dd,J＝7.5,1.6Hz,1H),6.32(s,1H),5.82(s,2H),3.82(s,3H),3.71(d,J＝3.0Hz,2H),3.65–3.59(m,1H),3.48(s,2H),3.46(s,3H),2.55–2.53(m,2H),2.37–2.33(m,1H),2.12–2.06(m,6H),2.02(d,J＝7.1Hz,2H),1.76–1.67(m,5H),1.58–1.51(m,1H),1.29–1.21(m,2H),0.97–0.87(m,2H)；MS(ESI):m/z 832.2(M+H)。
实施例147：
Figure PCTCN2020138157-appb-000190
参照化合物146的合成，将化合物INT-6换成化合物INT-15，得到化合物 147。 1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.70(s,1H),7.68–7.61(m,2H),7.57–7.47(m,4H),7.17(d,J＝7.0Hz,1H),7.01–6.94(m,2H),6.33(s,1H),5.82(s,2H),3.86(s,3H),3.78–3.70(m,2H),3.62–3.54(m,1H),3.48(s,2H),3.46(s,3H),2.55–2.50(m,2H),2.36–2.31(m,1H),2.10(s,3H),2.09–2.01(m,5H),1.77–1.69(m,4H),1.67–1.61(m,1H),1.59–1.52(m,1H),1.31–1.24(m,2H),0.97–0.88(m,2H)；MS(ESI):m/z 850.1(M+H)。
实施例148：
Figure PCTCN2020138157-appb-000191
参照化合物147的合成，将化合物INT-14换成反式-4-氨基环己甲酸甲酯盐酸盐，得到化合物148。 1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.70(s,1H),7.69–7.61(m,2H),7.57–7.46(m,4H),7.17(d,J＝7.0Hz,1H),7.00–6.95(m,2H),6.33(s,1H),5.82(s,2H),3.86(s,3H),3.78–3.68(m,2H),3.61–3.55(m,1H),3.48(s,2H),3.46(s,3H),2.56–2.50(m,2H),2.39–2.33(m,1H),2.10(s,3H),2.09–2.02(m,4H),1.94–1.87(m,2H),1.82–1.74(m,2H),1.68–1.60(m,1H),1.34–1.24(m,4H)；MS(ESI):m/z 836.1(M+H)。
实施例149：
Figure PCTCN2020138157-appb-000192
参照化合物147的合成，将化合物INT-14换成反式-4-氨基环己甲酸甲酯盐酸盐，得到化合物149。 1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.69–7.62(m,3H),7.57–7.47(m,4H),7.17(d,J＝6.9Hz,1H),7.04–6.92(m,2H),6.34(s, 1H),5.83(s,2H),3.86(s,3H),3.79–3.70(m,2H),3.61–3.54(m,1H),3.46(s,3H),3.29(s,2H),3.06–2.97(m,1H),2.83–2.75(m,1H),2.56–2.52(m,2H),2.19–2.14(m,2H),2.11–2.01(m,5H),1.91(s,3H),1.68–1.61(m,1H)；MS(ESI):m/z808.1(M+H)。
实施例150：
Figure PCTCN2020138157-appb-000193
参照化合物147的合成，将化合物INT-14换成4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐，得到化合物150。 1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.72(s,1H),7.67–7.61(m,2H),7.58–7.47(m,4H),7.17(d,J＝7.0Hz,1H),7.05–6.94(m,2H),6.32(s,1H),5.82(s,2H),3.86(s,3H),3.78–3.70(m,2H),3.61–3.55(m,1H),3.46(s,3H),3.44(s,2H),2.60–2.54(m,2H),2.10–2.02(m,3H),1.99(s,3H),1.74–1.68(m,6H),1.66–1.62(m,1H),1.59–1.53(m,6H)；MS(ESI):m/z 862.1(M+H)。
实施例151：
Figure PCTCN2020138157-appb-000194
参照化合物137的合成，将4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐换成反式-4-氨基环己甲酸甲酯盐酸盐，得到化合物151。 1H NMR(500MHz,DMSO-d6)δ7.83–7.78(m,3H),7.72–7.63(m,3H),7.54(t,J＝7.5Hz,1H),7.50–7.45(m,2H),7.30(d,J＝7.5Hz,1H),7.13(d,J＝7.0Hz,1H),5.80(s,2H),3.90(s,3H),3.70(d,J＝3.5Hz,2H),3.65–3.60(m,1H),3.39(s,2H),3.37(s,3H),2.55–2.53(m, 2H),2.37–2.33(m,1H),2.12–2.05(m,4H),2.08(s,3H),1.93–1.87(m,2H),1.78–1.73(m,2H),1.71–1.66(m,1H),1.29–1.23(m,4H)；MS(ESI):m/z 786.0(M+H)。
实施例152：
Figure PCTCN2020138157-appb-000195
参考化合物91的合成，将止血环酸甲酯盐酸盐换成反式-4-氨基环己甲酸甲酯盐酸盐，得到化合物152。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.83(d,J＝7.5Hz,1H),7.78(d,J＝8.5Hz,1H),7.70–7.65(m,2H),7.59–7.49(m,3H),7.38(s,1H),7.32(d,J＝7.4Hz,1H),7.18(d,J＝7.0Hz,1H),6.69(s,1H),5.73(s,2H),3.92(s,3H),3.76–3.70(m,2H),3.66–3.61(m,1H),3.59(s,3H),3.46(s,2H),2.56–2.55(m,2H),2.42–2.35(m,1H),2.16–2.06(m,4H),2.12(s,3H),1.96–1.88(m,2H),1.83–1.76(m,2H),1.74–1.66(m,1H),1.34–1.23(m,4H)；MS(ESI):m/z 784.8(M+H)。
实施例153：
Figure PCTCN2020138157-appb-000196
参考化合物57的合成，将化合物INT-2换成化合物INT-17，得到化合物153。 1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.77(d,J＝8.5Hz,1H),7.54–7.48(m,4H),7.41(d,J＝8.0Hz,1H),7.38(s,1H),7.19–7.14(m,2H),7.10(brs,1H),7.07–7.03(m,1H),6.68(s,1H),5.73(s,2H),3.83(s,3H),3.76–3.66(m,2H),3.58(s,3H),3.46(s,2H),3.41–3.36(m,1H),2.61–2.58(m,2H),2.16–2.05(m,3H), 2.13(s,3H),1.95–1.89(m,2H),1.83–1.74(m,4H),1.63–1.54(m,1H),1.36–1.23(m,6H)；MS(ESI):m/z 799.1(M+H)。
实施例154：
Figure PCTCN2020138157-appb-000197
在-78℃条件下，将二异丙基氨基锂(2.0M的四氢呋喃溶液，2.6mL)加入至溶有1-氯-2-溴-4-氟苯(1.0g,4.8mmol)的四氢呋喃(6mL)溶液中；所得反应液在相同温度下搅拌1小时。随后N,N-二甲基甲酰胺(1.7g,24mmol)加入至反应液中，所得混合液进一步在-78℃条件下搅拌1小时。反应液用氯化铵水溶液(40mL,5％w/w)淬灭，水相用乙酸乙酯萃取(30mL x 3)。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析(乙酸乙酯/石油醚＝10/1)分离得到白色固体154a(830mg,收率:73.2％)。MS(ESI):m/z 237.1(M+H)。
在90℃条件下，将混有化合物154a(830mg,3.5mmol)，水合肼(2.0mL,85％分析纯度)的乙二醇二甲醚(5mL)搅拌3小时。待反应冷却后，乙酸乙酯(50mL)和水(50mL)加入至反应液；有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析(乙酸乙酯/石油醚＝10/1)分离得到淡黄色固体154b(725mg,收率:89.6％)。MS(ESI):m/z 231.0(M+H)。
从化合物154b起，参照化合物INT-9和化合物30的合成得到化合物154。 1H NMR(500MHz,DMSO-d6)δ7.83(d,J＝9.0Hz,1H),7.71(s,1H),7.65(s,1H),7.57(d,J＝9.0Hz,1H),7.55–7.53(m,2H),7.48(s,1H),7.43–7.39(m,2H),7.07–7.02(m,2H),6.75(s,1H),5.73(s,2H),3.88–3.84(m,1H),3.82(s,3H),3.79–3.73(m,3H),3.65–3.64(m,1H),3.62(s,3H),3.60–3.55(m,2H),3.13–3.11(m,1H),2.59–2.54(m,2H),2.11–2.06(m,3H),1.71–1.65(m,1H)；MS(ESI):m/z765.9(M+H)。
实施例155：
Figure PCTCN2020138157-appb-000198
在溶有4-溴-2-氟苯胺(1.0g,5.3mmol)的乙腈(10mL)溶液中分批加入N-氯代丁二酰亚胺(843mg,6.3mmol)；反应液在回流条件下搅拌2小时。待反应液冷却后加入5％碳酸钾水溶液(50mL)；所得水相用二氯甲烷萃取(50mL x2)。合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析(石油醚作为洗脱剂)分离得到白色固体155a(1.0g,收率:84.6％)。 1H NMR(500MHz,Chloroform-d)δ7.21(t,J＝2.0Hz,1H),7.09(dd,J＝10.0,2.0Hz,1H),4.04(brs,2H)。
在室温条件下，将溶有化合物155a(1.0g,4.5mmol)的硫酸水溶液(25％w/w)搅拌半小时；随后冷却至-5℃后缓慢滴加溶有亚硝酸钠(369mg,5.4mmol)的水(5mL)溶液。反应液在-5℃条件下进一步搅拌1小时；并在相同温度下缓慢滴加溶有碘化钾(1.5g,8.9mmol)的乙酸乙酯和水的混合溶液(50mL,v/v＝3/2)。所得反应液在室温条件下反应1小时。反应液经分层后，水相进一步用乙酸乙酯萃取(30mL x 2)；合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析(石油醚作为洗脱剂)分离得到无色油状物155b(800mg,收率:53.6％)。 1H NMR(500MHz,Chloroform-d)δ7.45(t,J＝2.0Hz,1H),7.13(dd,J＝7.0,2.0Hz,1H)。
在氮气氛围和80℃条件下，将混有化合物155b(1.0g,3.0mmol)，乙烯基硼酸频哪醇酯(1.4g,9.0mmol)，Pd(dppf)Cl 2(109mg,0.15mmol)和碳酸氢钠(504mg,6.0mmol)的1,4-二氧六环和水的混合溶液(11mL,v/v＝10/1)搅拌16小时。反应液用硅藻土过滤，滤液浓缩，残留物用硅胶柱层析(石油醚作为洗脱剂)分离得到无色油状物155c(550mg,收率:58.7％)。
在室温条件下，将混有化合物155c(520mg,2.2mmol)的1,4-二氧六环和水 的混合溶液(6mL,v/v＝1/1)中加入二水合锇酸钾(8.1mg,0.02mmol)和高碘酸钠(1.4g,6.6mmol)；反应液在相同温度下搅拌2小时。反应液中加入水(30mL)，并用乙酸乙酯萃取(30mL x 2)。合并有机相用饱和食盐水(100mL)洗涤，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,v/v＝10/1)分离得到无色油状物155d(400mg,收率:76.3％)。 1H NMR(500MHz,Chloroform-d)δ10.40(brs,1H),7.48(d,J＝1.5Hz,1H),7.33–7.29(m,1H)。
从化合物155d起，参照化合物INT-16和化合物101的合成得到化合物155。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.48(m,4H),7.36(s,1H),7.19–7.17(m,1H),7.15(d,J＝7.0Hz,1H),7.11–7.09(m,1H),6.67(s,1H),5.71(s,2H),3.85(s,3H),3.85–3.83(m,2H),3.62–3.57(m,1H),3.56(s,3H),3.34(s,2H),2.54–2.51(m,2H),2.11–2.04(m,8H),1.86–1.77(m,4H),1.67–1.61(m,1H),1.48–1.39(m,1H),1.27–1.19(m,3H),0.85–0.75(m,2H)；MS(ESI):m/z 832.2(M+H)。
实施例156：
Figure PCTCN2020138157-appb-000199
将甲醇钠(1.8g,33.5mmol)加入至溶有4,6-二氯烟酸甲酯(4.6g,22.3mmol)的四氢呋喃(40mL)溶液；所得反应液在50℃条件下搅拌16小时。反应液中加入水(100mL)；并用乙酸乙酯萃取(100mL x 2)。合并有机相用饱和食盐水(150mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到白色固体156a(2.8g,收率:62.2％)。MS(ESI):m/z 202.1(M+H)。
从化合物156a起，参照化合物72c的合成得到化合物156b。MS(ESI):m/z172.1(M+H)。
从化合物156b起，参照化合物INT-10和化合物133的合成得到化合物156。 1H NMR(500MHz,DMSO-d6)δ8.24(d,J＝1.7Hz,1H),7.94(s,1H),7.78(d,J＝8.5Hz,1H),7.68(s,1H),7.61–7.48(m,5H),7.40(s,1H),7.18(d,J＝7.0Hz,1H), 6.68(s,1H),5.72(s,2H),3.88(s,3H),3.86(s,2H),3.65–3.60(m,1H),3.58(s,3H),3.43(s,2H),2.66–2.56(m,2H),2.15–2.05(m,3H),2.00(s,3H),1.77–1.67(m,7H),1.61–1.52(m,6H)；MS(ESI):m/z 811.1(M+H)。
实施例157：
Figure PCTCN2020138157-appb-000200
从化合物INT-15a起，参照化合物INT-1e的合成得到化合物157a。MS(ESI):m/z 276.8(M+H)。
从化合物157a起，参照155c的合成得到化合物157c。 1H NMR(500MHz,DMSO-d6)δ10.27(s,1H),7.31(d,J＝1.5Hz,1H),6.19(d,J＝1.5Hz,1H),4.11–4.07(m,2H),3.96–3.92(m,2H),3.90(s,3H)。
在0℃条件下，将硼氢化钠(29mg,0.77mmol)加入至溶有化合物157c(400mg,1.53mmol)的四氢呋喃(20mL)溶液；反应液随后在室温条件下搅拌半小时。反应液中加入饱和碳酸氢钠(20mL)溶液，并用乙酸乙酯萃取(20mL x 2)。合并有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到黄色固体157d(400mg,收率:99.2％)。MS(ESI):m/z 263.3(M+H)。
从化合物157d起，参照化合物INT-8c和化合物INT-1i的合成得到化合物157e。MS(ESI):m/z 445.5(M+H)。
从化合物157e起，参照化合物133的合成得到化合物157。 1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.81(d,J＝7.5Hz,1H),7.78(d,J＝8.5Hz,1H),7.68–7.63(m,2H),7.56–7.49(m,3H),7.30(d,J＝7.5Hz,1H),7.17(d,J＝7.0Hz,1H),6.58(s,1H),5.76(s,2H),3.90(s,3H),3.70(d,J＝3.5Hz,2H),3.64–3.61(m,1H),3.60(s,3H),3.45(s,2H),2.54(d,J＝6.0Hz,2H),2.14–2.05(m,3H),1.89(s,3H), 1.74–1.69(m,6H),1.69–1.64(m,1H),1.62–1.57(m,6H)；MS(ESI):m/z 829.3(M+H)。
实施例158：
Figure PCTCN2020138157-appb-000201
从1-氯-2-氟-4-溴苯起，参照化合物154的合成得到化合物158。 1H NMR(500MHz,DMSO-d6)δ8.05(s,1H),7.66(s,1H),7.56–7.49(m,4H),7.45–7.39(m,2H),7.16(d,J＝7.6Hz,1H),7.08(d,J＝1.6Hz,1H),7.05(dd,J＝7.6,1.6Hz,1H),6.04–6.00(m,3H),3.81(s,3H),3.73–3.69(m,2H),3.66–3.56(m,3H),3.45–3.41(m,2H),3.38(s,3H),3.25–3.22(m,1H),2.55–2.50(m,2H),2.11–2.05(m,3H),1.71–1.65(m,1H)；MS(ESI):m/z 766.0(M+H)。
实施例159：
Figure PCTCN2020138157-appb-000202
参照化合物116的合成，将还原胺化步骤中用的甲醛换成乙醛得到化合物159。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55(s,1H),7.54–7.47(m,4H),7.15(d,J＝7.0Hz,1H),7.00–6.95(m,2H),6.64(s,1H),5.70(s,2H),3.86(s,3H),3.77–3.71(m,2H),3.62–3.57(m,1H),3.60(s,3H),3.56(s,2H),2.57–2.50(m,4H),2.10–2.03(m,3H),1.72–1.66(m,6H),1.65–1.61(m,1H),1.56–1.51(m,6H),0.78(t,J＝7.0Hz,3H)；MS(ESI):m/z 842.1(M+H)。
实施例160：
Figure PCTCN2020138157-appb-000203
在60℃条件下，将溶有4-(((苄氧基)羰基)氨基)双环[2.2.2]辛烷-1-羧酸(150mg,0.49mmol)的二氯亚砜(2mL)溶液搅拌2小时。反应液浓缩后，残余物用乙腈(3mL)溶解，并加入三甲基硅烷化重氮甲烷(2M在正己烷中，0.24mL)；所得反应液在室温条件下搅拌2小时。随后在0℃条件下，在上述溶液中加入三乙胺(0.13mL)，三氟乙酸银(154mg,0.70mmol)和甲醇(1mL)；所得反应液在室温条件下搅拌16小时。反应液过滤，滤液浓缩；残留物用硅胶柱层析分离得到白色固体160a(50mg,收率:32.4％)。 1H NMR(500MHz,DMSO-d6)δ7.37–7.26(m,5H),6.87(s,1H),4.92(s,2H),3.53(s,3H),2.05(s,2H),1.75–1.66(m,6H),1.55–1.42(m,6H)；MS(ESI):m/z 332.4(M+H)。
在室温条件和氢气氛围下，将溶有化合物160a(100mg,0.30mmol)和氢氧化钯(10％w/w在活性炭，20mg)的甲醇(3mL)溶液搅拌1小时。反应液用硅藻土过滤，滤液浓缩后残余物用二氯甲烷(2mL)溶解，并且滴加盐酸(4M在乙酸乙酯，0.15mL)；所得反应液在室温搅拌半小时。反应液浓缩后得到固体残余物，用乙酸乙酯洗涤得到白色固体160b(60mg，收率:85.1％)。MS(ESI):m/z198.5(M+H)。
从化合物INT-16和化合物160b起，参照化合物101的合成得到化合物160。 1H NMR(500MHz,DMSO-d6)δ7.93(s,1H),7.76(d,J＝8.5Hz,1H),7.63(s,1H),7.55–7.47(m,4H),7.40(s,1H),7.16(d,J＝7.0Hz,1H),6.98–6.95(m,2H),6.67(s,1H),5.72(s,2H),3.87(s,3H),3.79–3.71(m,2H),3.65–3.59(m,1H),3.58(s,3H),3.41(s,2H),2.60–2.54(m,2H),2.14–2.03(m,3H),1.99(s,3H),1.96(s,2H),1.76–1.69(m,1H),1.60–1.46(m,12H)；MS(ESI):m/z 842.3(M+H)。
实施例161：
Figure PCTCN2020138157-appb-000204
参照化合物116的合成，将2-氯-1,3-二溴苯换成2-甲基-1,3-二溴苯，得到化合物161。 1H NMR(500MHz,DMSO-d6)δ7.92(d,J＝1.5Hz,1H),7.73(d,J＝8.5Hz,1H),7.65(s,1H),7.52–7.47(m,1H),7.40–7.36(m,2H),7.35–7.31(m,2H),7.09(d,J＝7.0Hz,1H),6.93–6.88(m,2H),6.65(s,1H),5.72(s,2H),3.87(s,3H),3.78–3.71(m,2H),3.64–3.60(m,1H),3.57(s,3H),3.42(s,2H),2.56–2.53(m,2H),2.13–2.06(m,3H),2.03(s,3H),2.00(s,3H),1.76–1.68(m,6H),1.69–1.63(m,1H),1.60–1.53(m,6H)；MS(ESI):m/z 808.1(M+H)。
实施例162：
Figure PCTCN2020138157-appb-000205
从化合物INT-16和反式-4-氨基环己醇起，参照化合物101的合成得到化合物162。 1H NMR(500MHz,DMSO-d6)δ7.93(d,J＝1.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.64(s,1H),7.54–7.48(m,4H),7.35(s,1H),7.15(d,J＝7.0Hz,1H),6.98–6.94(m,2H),6.67(s,1H),5.71(s,2H),4.43(d,J＝4.5Hz,1H),3.85(s,3H),3.77–3.70(m,2H),3.62–3.60(m,1H),3.56(s,3H),3.42(s,2H),3.35–3.32(m,1H),2.55–2.52(m,1H),2.36–2.33(m,1H),2.10–2.04(m,6H),1.84–1.78(m,2H),1.72–1.67(m,2H),1.65–1.59(m,1H),1.31–1.20(m,2H),1.14–1.06(m,2H)；MS(ESI):m/z 774.1(M+H)。
实施例163：
Figure PCTCN2020138157-appb-000206
参照化合物135的合成，将4-氨基双环[2.2.2]辛烷-1-羧酸甲酯盐酸盐换成反式-4-氨基环己甲酸甲酯盐酸盐，得到化合物163。 1H NMR(500MHz,DMSO-d6)δ7.88–7.83(m,1H),7.81–7.75(m,1H),7.71–7.61(m,2H),7.55–7.44(m,4H),7.15–7.09(m,1H),6.99–6.92(m,2H),5.83–5.76(m,2H),3.88–3.83(m,3H),3.76–3.70(m,2H),3.59–3.54(m,1H),3.40–3.38(m,2H),3.37–3.36(m,3H),2.51–2.50(m,2H),2.35–2.30(m,1H),2.10–2.03(m,6H),1.90–1.81(m,3H),1.76–1.69(m,2H),1.68–1.61(m,1H),1.24–1.16(m,4H)；MS(ESI):m/z 803.1(M+H)。
实施例164：
Figure PCTCN2020138157-appb-000207
参照化合物133的合成，将2-氯-1,3-二溴苯换成2-甲基-1,3-二溴苯，得到化合物164。 1H NMR(500MHz,DMSO-d6)δ7.81–7.77(m,2H),7.72(d,J＝8.5Hz,1H),7.67(s,1H),7.50–7.44(m,2H),7.40–7.35(m,2H),7.34–7.30(m,1H),7.18(d,J＝7.4Hz,1H),7.08(d,J＝7.0Hz,1H),6.65(s,1H),5.70(s,2H),3.88(s,3H),3.75–3.68(m,2H),3.66–3.59(m,1H),3.57(s,3H),3.41(s,2H),2.54(d,J＝6.0Hz,2H),2.15–2.05(m,3H),2.09(s,3H),1.99(s,3H),1.75–1.69(m,6H),1.69–1.65(m,1H),1.59–1.52(m,6H)；MS(ESI):m/z 791.0(M+H)。
实施例165：
Figure PCTCN2020138157-appb-000208
在-78℃条件和氮气氛围下，将二异丁基氢化铝(1M在甲苯中,30.6mL)缓慢滴加至溶有5-溴-3-氟-2-吡啶甲腈(4.1g,20.4mmol)的四氢呋喃(40mL)溶液中；反应液随后在相同温度下搅拌2小时。随后反应液中加入水(50mL)，并用硅藻土过滤；所得滤液用乙酸乙酯萃取(50mL x 2)。合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到白色固体165a(2.7g,收率:64.9％)。MS(ESI):m/z 204.0(M+H)。
从化合物165a起，参照化合物156a的合成得到化合物165b。MS(ESI):m/z216.3(M+H)。
从化合物165b和3-溴-2-甲基苯酚起，参照化合物INT-10和化合物133的合成得到化合物165。 1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),7.83(s,1H),7.74(d,J＝8.5Hz,1H),7.68(s,1H),7.52–7.48(m,1H),7.46–7.43(m,1H),7.42–7.38(m,2H),7.37–7.33(m,1H),7.19(s,1H),7.09(d,J＝6.9Hz,1H),6.66(s,1H),5.72(s,2H),3.92(s,3H),3.78–3.69(m,2H),3.67–3.60(m,1H),3.58(s,3H),3.43–3.38(m,2H),2.55(d,J＝6.0Hz,2H),2.15–2.06(m,3H),2.05(s,3H),2.01(s,3H),1.77–1.71(m,6H),1.71–1.65(m,1H),1.61–1.54(m,6H)；MS(ESI):m/z791.0(M+H)。
实施例166：
Figure PCTCN2020138157-appb-000209
参照化合物135的合成，将2-氯-1,3-二溴苯换成2-甲基-1,3-二溴苯，得到化 合物166。 1H NMR(500MHz,DMSO-d6)δ7.87(d,J＝1.0Hz,1H),7.79–7.75(m,1H),7.72(s,1H),7.67(s,1H),7.50–7.46(m,1H),7.41–7.37(m,1H),7.36–7.29(m,2H),7.09–7.05(m,1H),6.95–6.89(m,2H),5.82(s,2H),3.88(s,3H),3.80–3.72(m,2H),3.65–3.55(m,1H),3.38(s,3H),3.35–3.30(m,2H),2.54–2.50(m,2H),2.13–2.05(m,3H),2.02(s,6H),1.76–1.70(m,6H),1.69–1.64(m,1H),1.60–1.53(m,6H)；MS(ESI):m/z 809.1(M+H)。
实施例167：
Figure PCTCN2020138157-appb-000210
参照化合物133的合成，将化合物INT-2换成化合物67a，得到化合物167。 1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.78(d,J＝8.5Hz,1H),7.69(s,1H),7.57–7.49(m,4H),7.39(s,1H),7.16(d,J＝7.0Hz,1H),7.05–6.97(m,2H),6.69(s,1H),5.72(s,2H),3.87(s,3H),3.78–3.71(m,2H),3.59–3.53(m,1H),3.58(s,3H),3.42(s,2H),2.54–2.53(m,2H),2.11–2.04(m,3H),2.00(s,3H),1.75–1.70(m,6H),1.67–1.63(m,1H),1.60–1.54(m,6H)；MS(ESI):m/z 828.1(M+H)。
实施例168：
Figure PCTCN2020138157-appb-000211
参照化合物133的合成，将化合物INT-2换成化合物INT-18，得到化合物168。 1H NMR(500MHz,DMSO-d6)δ7.94(s,1H),7.78(d,J＝8.7Hz,1H),7.55–7.50(m,4H),7.39(s,1H),7.19–7.11(m,2H),7.01–6.97(m,2H),6.69(s,1H),5.72(s,2H),3.87(s,3H),3.75–3.70(m,2H),3.58(s,3H),3.42(s,2H),3.36–3.35 (m,1H),2.53–2.52(m,2H),2.12–2.07(m,2H),2.00(s,3H),1.76–1.70(m,8H),1.58–1.54(m,7H),1.34–1.27(m,1H)；MS(ESI):m/z 842.1(M+H)。
实施例169：
Figure PCTCN2020138157-appb-000212
参照化合物137的合成，将2-氯-1,3-二溴苯换成2-甲基-1,3-二溴苯，得到化合物169。 1H NMR(500MHz,DMSO-d6)δ7.81(d,J＝7.5Hz,1H),7.79–7.74(m,2H),7.73–7.69(m,2H),7.51–7.44(m,2H),7.42–7.37(m,1H),7.35–7.29(m,1H),7.20(d,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),5.81(s,2H),3.90(s,3H),3.75–3.67(m,2H),3.66–3.59(m,1H),3.37(s,3H),3.35(s,2H),2.58–2.54(m,2H),2.14–2.06(m,3H),2.10(s,3H),2.00(s,3H),1.75–1.66(m,7H),1.61–1.44(m,6H)；MS(ESI):m/z 792.2(M+H)。
实施例170：
Figure PCTCN2020138157-appb-000213
在0℃条件下，将溶有亚硝酸钠(10g,147mmol)的水(50mL)溶液缓慢滴入预先溶有2-氨基-5-溴-3-甲氧基吡嗪(2g,9.8mmol)和氢碘酸(57％w/w,50mL)的乙腈和水的混合溶液(250mL,v/v＝3/2)。反应液在搅拌条件下升至50℃，并且在该条件下反应16小时。反应液用20％氢氧化钠水溶液中和，并用乙酸乙酯萃取(100mL x 2)。合并有机相用饱和硫代硫酸钠溶液和饱和食盐水(各150mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到棕色固体170a(1.55g,收率:50.2％)。
在氮气氛围和-40℃条件下，将异丙基氯化镁-氯化锂(1.3M的四氢呋喃溶 液，1.83mL)缓慢滴至预先溶有化合物170a(500mg,1.6mmol)的四氢呋喃(10mL)溶液中。反应液在相同条件下进一步搅拌半小时，随后升至15℃后缓慢加入N,N-二甲基甲酰胺(1.2mL)；所得反应液在15℃条件下进一步搅拌2小时。反应液用柠檬酸中和，并用乙酸乙酯萃取(50mL x 2)。合并有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析分离得到淡黄色固体170b(300mg,收率:87.1％)。MS(ESI):m/z 217.0(M+H)。
从化合物165b和3-溴-2-甲基苯酚起，参照化合物INT-10和化合物133的合成得到化合物170。 1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),7.81(s,1H),7.74(d,J＝8.4Hz,1H),7.67(s,1H),7.53(d,J＝7.4Hz,1H),7.51–7.46(m,1H),7.44-7.37(m,3H),7.09(d,J＝7.0Hz,1H),6.66(s,1H),5.70(s,2H),3.95(s,3H),3.87(s,2H),3.63–3.60(m,1H),3.57(s,3H),3.41(s,2H),2.60–2.57(m,2H),2.11(s,3H),2.10–2.02(m,3H),1.99(s,3H),1.73–1.67(m,7H),1.58–1.53(m,6H)；MS(ESI):m/z 792.1(M+H)。
实施例171：
Figure PCTCN2020138157-appb-000214
从化合物INT-16，反式-4-氨基环己甲酸甲酯盐酸盐和叔丁基二甲基硅氧烷基乙醛起，参照化合物125的合成得到化合物171。 1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.80(d,J＝8.5Hz,1H),7.69(s,1H),7.60–7.50(m,5H),7.17(d,J＝7.1Hz,1H),7.09–6.99(m,2H),6.69(s,1H),5.73(s,2H),3.89(s,3H),3.85–3.80(m,2H),3.78–3.47(m,5H),3.60(s,3H),2.56–2.53(m,2H),2.16–2.04(m,5H),1.94–1.87(m,2H),1.81–1.65(m,4H),1.63–1.53(m,1H),1.31–1.20(m,4H)；MS(ESI):m/z 832.0(M+H)。
实施例172：
Figure PCTCN2020138157-appb-000215
参照化合物135的合成，将化合物INT-2换成化合物INT-18，得到化合物172。 1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.81(d,J＝8.5Hz,1H),7.71(s,1H),7.57–7.47(m,4H),7.17–7.12(m,2H),7.01–6.96(m,2H),5.81(s,2H),3.88(s,3H),3.76–3.69(m,2H),3.38(s,3H),3.36-3.29(m,3H),2.57–2.53(m,2H),2.15–2.05(m,2H),2.00(s,3H),1.79–1.68(m,8H),1.60–1.52(m,7H),1.35–1.28(m,1H)；MS(ESI):m/z 843.1(M+H)。
实施例173：
Figure PCTCN2020138157-appb-000216
在0℃条件下，将溶有硝酸钾(55mg,0.54mmol)的浓硫酸(1mL)滴加至预先溶有3-氯-4-甲基苯甲酸甲酯(100mg,0.54mmol)的浓硫酸(2mL)。反应液在相同条件下搅拌半小时；随后将反应液倒至冰水中，并用乙酸乙酯萃取(15mL x 2)。合并有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩。残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1,v/v)分离得到无色油状物173a (100mg,收率:80.4％)。 1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.93(s,1H),3.83(s,3H),2.44(s,3H).
从化合物173a和反式-4-氨基环己甲酸甲酯盐酸盐起，参照化合物72c的合成和化合物44的还原胺化得到化合物173c。MS(ESI):m/z 549.0(M+H)。
将锌粉(44mg,0.67mmol)加至溶有化合物173c(74mg,0.13mmol)的醋酸(4mL)溶液；所得反应液在60℃条件下加热搅拌2小时。反应液浓缩后加入乙酸乙酯(20mL)和饱和碳酸氢钠溶液(20mL)；有机相用无水硫酸钠干燥，浓缩后得到化合物173d。MS(ESI):m/z 519.0(M+H)。
从化合物173d，化合物INT-18和化合物INT-2起，依次参照化合物INT-7的Suzuki反应，化合物INT-3b的还原胺化反应以及化合物33的酯水解反应得到化合物173。 1H NMR(500MHz,DMSO-d6)δ7.92(s,1H),7.69(d,J＝8.6Hz,1H),7.64(s,1H),7.55–7.46(m,4H),7.15(d,J＝7.0Hz,1H),7.04(s,1H),6.98–6.96(m,2H),6.23(s,1H),5.60(s,2H),5.38(s,2H),3.86(s,3H),3.73(d,J＝4.3Hz,2H),3.58–3.56(m,1H),3.42(s,2H),2.53–2.50(m,2H),2.34–2.30(m,1H),2.23(brs,1H),2.10–1.95(m,3H),2.03(s,3H),1.92–1.86(m,2H),1.77-1.71(m,2H),1.66–1.61(m,1H),1.32–1.18(m,4H)；MS(ESI):m/z 787.8(M+H)。
测试实施例
细胞水平PD-1/PD-L1信号抑制的生物活性检测
本检测方法用于本发明所述化合物的细胞水平生物学活性评价。
实验原理
本检测方法采用荧光素酶报告基因法检测化合物对细胞水平PD-1/PD-L1信号抑制的生物活性。PD-1/NFAT-Reporter-Jurkat细胞稳定表达人PD-1，且表达由NFAT元件调控的荧光素酶报告基因；TCR activator/PD-L1-CHO细胞稳定表达人PD-L1和TCR激活元件。当两株细胞共培养时，PD-1/PD-L1的结合会抑制TCR信号通路，从而抑制下游NFAT控制的荧光素酶报告基因表达。当加入PD-1/PD-L1抗体或者抑制剂，这种抑制作用被反转，荧光素酶表达，从而可以检测PD-1/PD-L1抑制剂对荧光素酶活性影响。
实验材料与设备
PD-1/NFAT-Reporter-Jurkat细胞(货号60535)以及TCR activator/PD-L1-CHO细胞(货号60536)购自BPS Bioscience公司；PD-L1抗体(Atezolizumab，货号A2004)购自Selleck公司；荧光素酶检测试剂(ONE-Glo TM Luciferase Assay System，货号E6120)购自Promega公司；多功能微孔板检测仪(型号SpectraMax i3x)购自Molecular Devices公司。
实验主要过程
按常规细胞培养实验操作流程培养PD-1/NFAT-Reporter-Jurkat细胞和TCR activator/PD-L1-CHO细胞。
收集TCR activator/PD-L1-CHO细胞并按照35000个/每孔，接种到96孔培养板中，培养基体积为100微升，37℃孵育过夜。第二天，弃去培养基，加入化合物孵育30分钟，同时设置溶剂对照(二甲基亚砜，DMSO，终浓度0.1％)和PD-L1抗体(Atezolizumab，终浓度约10nM)阳性对照。再加入PD-1/NFAT-reporter-Jurkat细胞。继续培养6小时后，按荧光素酶检测试剂说明书检测荧光素酶活性。
以PD-L1抗体作为阳性对照，计算测试化合物的PD-1/PD-L1结合抑制率(％)＝(化合物处理孔化学发光值/溶剂对照孔化学发光值平均值–1)/(PD-L1抗体孔化学发光值平均值/溶剂对照孔化学发光值平均值–1)×100％。
根据上述检测方法，对本发明所述化合物进行细胞水平生物学活性评价，活性结果见下表。
Figure PCTCN2020138157-appb-000217
Figure PCTCN2020138157-appb-000218
Figure PCTCN2020138157-appb-000219
Figure PCTCN2020138157-appb-000220
1.参比化合物来自专利US20180057455的实例40260；内部合成得到
由上述结果可见，本发明的化合物可有效抑制PD-1/PD-L1，具有良好的PD-1/PD-L1抑制活性。

Claims (29)

  1. 式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物：
    Figure PCTCN2020138157-appb-100001
    其中，L 1选自基团：-CR AR B-和-C(O)-；
    L 2、L 3选自基团：-(CR CR D) p、-(CR CR D) p-NR a-(CR CR D) q-、-(CR CR D) p-O-(CR CR D) q-和-C(O)-；
    W 1、W 2各自独立地表示CR L或者N；
    R 1各自独立地表示氢、卤素、硝基、氰基或-NR aR b或者被0、1、2或3个取代基所取代的C 1-C 6烷基、C 3-C 6环烷基、-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：-OR a、氰基、氧代、卤素、C 1-C 6烷基、-(C 1-C 6亚烷基)OR a、氰基C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、-C(O)R a、-(C 1-C 6亚烷基)C(O)R a、-C(O)OR a、-(C 1-C 6烷基)C(O)OR a、-NR aR b、-(C 1-C 6亚烷基)NR aR b、-C(O)NR aR b、-SO 2R a、-C(O)NR aSO 2R b和-NR aC(O)R b；R 2、R 3、R 4、R 5各自独立地表示氢、卤素、硝基、氰基、-NR aR b、-SO 2R a、-S(O)R a、-P(O)R aR b、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤代(C 1-C 6烷基)或者C 3-C 6环烷基；
    Cy表示被0、1、2或3个R 6所取代的苯环或六元杂芳基，其中所述六元杂芳基可以任选地含有1或2个氮原子；其中所述R 6表示氢、卤素、硝基、氰基、-NR aR b、-SO 2R a、-S(O)R a或-P(O)R aR b或者被0、1、2或3个取代基所取代的C 1-C 6烷基、C 3-C 6环烷基、-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：-OR a、氰基、氧代、卤素、C 1-C 6烷基、-(C 1-C 6亚烷基)OR a、氰基C 1-C 6烷基、C 1-C 6卤代烷基、C 3-C 8环烷基、-C(O)R a、-(C 1-C 6 亚烷基)C(O)R a、-C(O)OR a、-(C 1-C 6亚烷基)C(O)OR a、-NR aR b、-(C 1-C 6亚烷基)NR aR b、-C(O)NR aR b、-SO 2R a、-C(O)NR aSO 2R b或者-NR aC(O)R b；
    其中，R L表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
    T、A各自独立地表示：被0、1、2或3个取代基所取代的-(C 1-C 6烷基)、-(C 0-C 6亚烷基)-(C 3-C 12环烷基)、-(C 0-C 6亚烷基)-(3-12元杂环)、-(C 0-C 6亚烷基)-(C 6-C 10芳基)或-(C 0-C 6亚烷基)-(5-10元杂芳基)，其中所述取代基选自：氰基、氧代、卤素、C 1-C 6烷基、-(C 0-C 6亚烷基)OR a、氰基C 1-C 6烷基、卤代(C 1-C 6烷基)、C 3-C 8环烷基、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-(C 0-C 6亚烷基)NR aR b、-C(O)NR aR b、-NR aSO 2R b、-C(O)NR aSO 2R b和-NR aC(O)R b；
    其中，R A、R B各自独立地表示：氢、C 1-C 6烷基、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、卤代(C 1-C 6烷基)或卤素，或者R A与R B连同其共同相连的碳原子一起形成3-6元环；
    R C、R D各自独立地表示：氢、C 1-C 6烷基、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、卤代(C 1-C 6烷基)或卤素，或者R C与R D连同其共同相连的碳原子一起形成3-6元环；
    R a、R b各自独立地表示：氢、C 1-C 6烷基、卤代(C 1-C 6烷基)、-(C 0-C 6亚烷基)OH、-(C 0-C 3亚烷基)(C 3-C 12环烷基)、-(C 0-C 3亚烷基)(3-12元杂环)、-(C 0-C 3亚烷基)(C 6-C 10元芳环)、-(C 0-C 3亚烷基)(5-10元杂芳环)或卤代(C 1-C 6烷基)，或者R a与R b连同其共同相连的原子一起形成3-6元环；
    其中，m、o均各自独立地表示0、1或2；
    其中，p、q均各自独立地表示0、1、2或3。
  2. 如权利要求1所述的式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中所述式(I)化合物具有以下式(II)结构：
    Figure PCTCN2020138157-appb-100002
    其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如权利要求1所定义；
    其中，r表示0、1、2或3。
  3. 如权利要求1所述的式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中所述式(I)化合物具有以下式(III)结构：
    Figure PCTCN2020138157-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如权利要求1所定义；
    其中，W 3表示CR M或者N；
    其中，R M表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
    其中，r表示为0、1或2。
  4. 如权利要求1所述的式(I)化合物或其药学上可接受的盐、前药、同位素衍生物、异构体、溶剂化物、或其代谢产物，其中所述式(I)化合物具有以下式(IV)结构：
    Figure PCTCN2020138157-appb-100004
    其中，R 1、R 2、R 3、R 4、R 5、R 6、L 1、L 2、L 3、T、A、W 1、W 2、m、o如权利要求1所定义；
    其中，W 4表示CR N或者N；
    其中，R N表示：氢、C 1-C 6烷基、-O(C 1-C 6烷基)、-O(C 3-C 6环烷基)、卤素、硝基、氰基、-NR aR b、卤代(C 1-C 6烷基)或C 3-C 6环烷基；
    其中，r表示为0、1或2。
  5. 如权利要求1至4任意一项所述的化合物，其中，L 1选自-CR AR B-，其中R A、R B各自独立地选自氢、卤素、C 1-C 6烷基和卤代(C 1-C 6烷基)，优选为氢。
  6. 如权利要求1至4任意一项所述的化合物，其中，L 2和L 3各自独立地选自-CR CR D-和-CR CR D-NR a-(CR CR D) q-，其中，q选自0、1或2，其中R C、R D各自独立地选自氢、卤素、C 1-C 6烷基和卤代(C 1-C 6烷基)，优选为氢；R a各自独立地选自氢、C 1-C 6烷基、卤代(C 1-C 6烷基)和-(C 0-C 3亚烷基)C 3-C 12环烷基。
  7. 如权利要求1至6任意一项所述的化合物，其中W 1、W 2各自独立地表示CH或者N。
  8. 如权利要求3、5或6任意一项所述的化合物，其中W 3表示CH或者N。
  9. 如权利要求4至6任意一项所述的化合物，其中W 4表示CH或者N。
  10. 如权利要求1至9任意一项所述的化合物，其中T、A各自独立地表示被0、1、2或3个取代基所取代的：-(C 1-C 6烷基)、-(C 0-C 6亚烷基)-(C 3-C 12环烷基)或-(C 0-C 6亚烷基)-(3-12元杂环)，其中所述取代基选自：氰基、氧代、卤素、C 1-C 6烷基、-(C 0-C 6亚烷基)OR a、氰基C 1-C 6烷基、卤代(C 1-C 6烷基)、C 3-C 8环烷基、-(C 0-C 6亚烷基)C(O)R a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-(C 0-C 6亚烷基)NR aR b、-C(O)NR aR b、-NR aSO 2R b、-C(O)NR aSO 2R b和-NR aC(O)R b，其中，R a和R b各自独立地表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
  11. 如权利要求10所述的化合物，其中T、A各自独立地表示被0、1或2个取代基所取代的C 1-C 6烷基、C 3-C 12环烷基或3-12元杂环，其中所述取代基选自：氰基、氧代、-OR a、-(C 0-C 6亚烷基)C(O)OR a、-(C 0-C 6亚烯基)C(O)OR a、-NR aSO 2R b、-C(O)NR aSO 2R b和-NR aC(O)R b，其中，R a和R b各自独立地表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
  12. 如权利要求11所述的化合物，其中T、A各自独立地表示任选地被选自0、1或2个取代基所取代的以下基团：
    Figure PCTCN2020138157-appb-100005
    其中所述取代基选自C 1-C 6烷基、-OR a、-(C 0-C 6亚烷基)C(O)OR a和-(C 0-C 6亚烯基)C(O)OR a，其中，R a表示氢或者C 1-C 6烷基，优选为氢，其中，α表示1、2或3。
  13. 如权利要求12所述的化合物，其中T、A各自独立地表示以下基团：
    Figure PCTCN2020138157-appb-100006
  14. 如权利要求11所述的化合物，其中T、A各自独立地表示任选地被选自0、1或2个取代基所取代的以下基团：
    Figure PCTCN2020138157-appb-100007
    其中所述取代基选自：C 1-C 6 烷基、-OR a和卤素，其中，R e、R a各自独立地表示氢或者C 1-C 6烷基；其中，α表示1、2、3或4。
  15. 如权利要求14上述的化合物，其中T、A各自独立地表示
    Figure PCTCN2020138157-appb-100008
    其中，R e表示氢或者C 1-C 6烷基；其中α表示1、2、3或4。
  16. 如权利要求11所述的化合物，其中T、A各自独立地表示：
    Figure PCTCN2020138157-appb-100009
  17. 如权利要求1至16任意一项所述的化合物，其中R 1表示被0、1、2或3个取代基所取代的-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)，其中所述取代基选自：氰基、氧代、卤素、氰基C 1-C 6烷基和C 1-C 6卤代烷基。
  18. 如权利要求1至16任意一项所述的化合物，其中R 2表示氢、卤素、硝基、氰基、-SO 2R a、C 1-C 6烷基、卤代(C 1-C 6烷基)或者C 3-C 6环烷基；其中，R a表示氢、C 1-C 6烷基或者卤代(C 1-C 6烷基)。
  19. 如权利要求1至16任意一项所述的化合物，其中R 3、R 4各自独立地表示氢、卤素、硝基或氰基。
  20. 如权利要求1至16任意一项所述的化合物，其中R 5表示氢、卤素、硝基、氰基、C 1-C 6烷基、卤代(C 1-C 6烷基)或者C 3-C 6环烷基。
  21. 如权利要求1至16任意一项所述的化合物，其中R 6表示氢、卤素、硝基、氰基、-SO 2R a、C 1-C 6烷基、卤代(C 1-C 6烷基)或C 3-C 6环烷基或者被0、1、2或3个取代基所取代的-O(C 1-C 6烷基)、-O(C 0-C 6亚烷基)(C 5-C 10芳基)、-O(C 0-C 6亚烷基)(5-10元杂芳基)、-O(C 0-C 6亚烷基)(C 3-C 6环烷基)或-O(C 0-C 6亚烷基)(3-6元杂环烷基)；其中所述取代基选自：氰基、氧代、卤素、氰基C 1-C 6烷基和C 1-C 6卤代烷基。
  22. 如权利要求1-21任意一项所述的化合物，其中R L表示氢或者卤素。
  23. 如权利要求3-21任意一项所述的化合物，其中R M、R N各自独立地表示氢。
  24. 具有如下结构的化合物：
    Figure PCTCN2020138157-appb-100010
    Figure PCTCN2020138157-appb-100011
    Figure PCTCN2020138157-appb-100012
    Figure PCTCN2020138157-appb-100013
    Figure PCTCN2020138157-appb-100014
    Figure PCTCN2020138157-appb-100015
    Figure PCTCN2020138157-appb-100016
    Figure PCTCN2020138157-appb-100017
    Figure PCTCN2020138157-appb-100018
    Figure PCTCN2020138157-appb-100019
    Figure PCTCN2020138157-appb-100020
    Figure PCTCN2020138157-appb-100021
    Figure PCTCN2020138157-appb-100022
    Figure PCTCN2020138157-appb-100023
    Figure PCTCN2020138157-appb-100024
  25. 药物组合物，其包含如权利要求1至24任意一项所述的化合物及任选地药学上可接受的载体。
  26. 如权利要求1至24任一项所述的化合物或者权利要求25所述的药物组合物在制备用于预防或治疗对抑制PD-L1与PD-1结合有响应的疾病或病症的药物中 的应用。
  27. 如权利要求26所述的应用，其中所述疾病或病症选自肿瘤、癌症、病毒感染、炎症相关疾病和自身免疫性疾病。
  28. 一种治疗对抑制PD-L1与PD-1结合有响应的疾病或病症的方法，其包括向有此需要的哺乳动物施用权利要求1至24任意一项所述的化合物或者权利要求25所述的药物组合物。
  29. 一种抑制PD-L1和PD-1结合的方法，其包括使权利要求1至24任意一项所述的化合物或者权利要求25所述的药物组合物暴露于所述的PD-L1和/或PD-1。
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