WO2020147848A1 - Tricyclic substituted oxaspiro derivative, preparation method therefor, and pharmaceutical use thereof - Google Patents

Tricyclic substituted oxaspiro derivative, preparation method therefor, and pharmaceutical use thereof Download PDF

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WO2020147848A1
WO2020147848A1 PCT/CN2020/072851 CN2020072851W WO2020147848A1 WO 2020147848 A1 WO2020147848 A1 WO 2020147848A1 CN 2020072851 W CN2020072851 W CN 2020072851W WO 2020147848 A1 WO2020147848 A1 WO 2020147848A1
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alkyl
substituted
unsubstituted
compound
group
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PCT/CN2020/072851
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French (fr)
Chinese (zh)
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胡斌
刘力锋
石晓永
杨文�
关慧平
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN202080003464.1A priority Critical patent/CN112334465A/en
Publication of WO2020147848A1 publication Critical patent/WO2020147848A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a class of tricyclic substituted oxaspiro derivatives, their preparation methods and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, especially as MOR receptor agonists and in the preparation of treatment and prevention of pain, etc. Use in medicine for related diseases.
  • Opioid receptors are an important type of G protein-coupled receptor (GPCR), which is the target of the binding of endogenous opioid peptides and opioid drugs.
  • GPCR G protein-coupled receptor
  • Endogenous opioid peptides are naturally produced in mammals.
  • Opioid active substances the currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins and neoorphins.
  • opioid receptors in the central nervous system namely ⁇ (MOR), ⁇ (DOR), ⁇ (KOR) receptors and so on.
  • MOR ⁇
  • DOR ⁇
  • KOR KOR
  • GPCR mediates and regulates physiological functions mainly through two pathways: the G protein pathway and the ⁇ -arrestin pathway.
  • the traditional GPCR agonist binds to the receptor, it activates the G protein signal pathway, including calcium ion and other second messenger systems, adenyl cyclase (AC), and mitogen-activated protein kinase (mitogen-activated protein).
  • AC adenyl cyclase
  • mitogen-activated protein kinase mitogen-activated protein kinase
  • MAPK mitogen-activated protein kinases
  • ⁇ -arrestin preferential ligands mainly activate the ⁇ -arrestin pathway.
  • the ⁇ -arrestin-mediated GPCR reaction mainly includes three aspects: 1) As a negative regulator, it interacts with G protein-coupled receptor kinase (GRK) to desensitize GPCRs and stop G protein signal transduction. 2) As a scaffold protein (scaffold protein), it recruits endocytosis protein and induces GPCR endocytosis; 3) As a linker protein, it forms a complex with GPCR downstream signal molecules to activate signal transduction molecules in a G protein-independent manner, Such as MAPK, Src protein tyrosine kinase and Akt. The difference of ligand-stimulated G protein signal and/or ⁇ -arrestin signal ultimately determines the ligand-specific cellular biological effects of GPCR.
  • GRK G protein-coupled receptor kinase
  • MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.
  • opioid analgesics such as endogenous enkephalin and morphine.
  • endogenous enkephalin and the opioid drug etorphine can stimulate G protein and trigger receptor endocytosis, but morphine does not trigger receptor endocytosis at all. This is because morphine stimulates MOR phosphorylation.
  • the ability is too weak and can only recruit a small amount of ⁇ -arrestin on the membrane (Zhang et al., Proc Natl Acad Sci USA, 1998, 95(12): 7157-7162).
  • Such ligands exert their physiological functions entirely through the G protein signaling pathway instead of the ⁇ -arrestin pathway.
  • MOR agonists include WO2017106547, WO2017063509, WO2012129495, WO2017106306, and so on.
  • drugs can be designed based on the negative ⁇ -arrestin preference ligand of MOR to reduce the side effects mediated by ⁇ -arrestin and enhance the therapeutic effect.
  • the purpose of the present invention is to provide a compound with a novel structure that can be used as a MOR receptor agonist.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
  • R a is a substituted or unsubstituted C 6-10 aryl group, or a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl group;
  • R b is hydrogen or substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl);
  • W 1 is a bond, or C(R c R d );
  • W 2 is C(R e R f ), NR g or O;
  • R c, R d, R e , R f are each independently hydrogen, hydroxy, halo, cyano, a substituted or unsubstituted C 1-10 alkyl group (preferably a substituted or unsubstituted C 1-6 alkyl, More preferably substituted or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-6 alkoxy) (Substituted C 1-3 alkoxy) or NR 11 R 12 ;
  • R g is hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl), -COC 1 -10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -SO 2 C 1-10 alkyl (preferably -SO 2 C 1 -6 alkyl, more preferably -SO 2 C 1-3 alkyl);
  • Z 1 is N or CR 1 ;
  • Z 2 is NR 2 , O or C (R 3 R 4 );
  • Z 3 is C(R 5 R 6 ), NR 7 or O;
  • Z 4 is C(R 8 R 9 ), NR 10 or O;
  • W 2 , Z 1 , Z 2 , Z 3 , Z 4 do not contain heteroatoms at the same time, and W 2 , Z 1 do not contain heteroatoms at the same time, Z 1 , Z 2 do not contain heteroatoms at the same time, Z 2 , Z 3 , Z 4 Do not contain two or more heteroatoms at the same time;
  • R 1 is hydrogen or substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl);
  • R 2 , R 7 , and R 10 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1 -3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy) , Halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1 -6 alkoxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or- (CR 21 R 22 ) p -L 1 ; L
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 31 R 32 ) q -L 2 ; L 2 is C 3-8
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 51 R 52 ) r -L 3 ; L 3 is C 3-8
  • R 8 and R 9 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 81 R 82 ) m -L 4 ; L 4 is C
  • R 01 , R 02 , R 03 , and R 04 are each independently hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, More preferably substituted or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-6 alkoxy) Substituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
  • R 21 and R 22 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
  • R 31 and R 32 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
  • R 51 and R 52 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
  • R 81 and R 82 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
  • R 23 , R 24 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
  • R 33 , R 34 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
  • R 53 , R 54 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
  • R 83 , R 84 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
  • R 0 is substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl), NR 11 R 12 , Or substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl);
  • R 11 and R 12 are each independently hydrogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogen Substituted C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring; or R 11 , R 12 and the connected nitrogen atom form A substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring;
  • R 13 is each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl) or Halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
  • u 0, 1 or 2;
  • p, q, r, and m are each independently 0, 1, 2 or 3;
  • t is 0 or 1;
  • n 1, 2 or 3;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
  • the group A substituents are selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halo (C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), 5 or 6-membered monocyclic heteroaryl, C 1-10 alkyl (Preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl,
  • a C 6-10 aryl group is a phenyl group; a 5 or 6 membered monocyclic heteroaryl is pyridine.
  • the group A substituent is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-3 alkyl, halogen (preferably F or Cl ), nitro, phenyl, 5- or 6-membered monocyclic heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 -phenyl, -CO-phenyl, 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring or 4 to 6-membered saturated or unsaturated monocyclic ring, wherein R a0 , R b0
  • the group A substituent is selected from: cyano, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl Group, difluoroethyl, trifluoroethyl, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 Alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydr
  • Ra is a substituted or unsubstituted pyridine; the "substitution” means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R a is a substituted or unsubstituted phenyl group; the "substituted” means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A .
  • R c and R d are each independently hydrogen, hydroxyl, halogen, cyano, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R c and R d are hydrogen.
  • R e and R f are each independently hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R e and R f are hydrogen.
  • R b is hydrogen
  • R 01 , R 02 , R 03 and R 04 are each independently hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1 -3 Alkoxy or halo C 1-3 alkyl; the "substituted” means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R 01 , R 02 , R 03 and R 04 are hydrogen.
  • the second aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
  • W 1 , W 2 , Z 1 , Z 2 , Z 3 , Z 4 , t, and n are as defined in claim 1.
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is C(R 8 R 9 );
  • t is 0 or 1;
  • n is 1.
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • t is 0;
  • n is 1, 2, or 3.
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is NR 7 or O;
  • Z 4 is C(R 8 R 9 );
  • t is 0 or 1;
  • n is 1.
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is NR 10 or O;
  • t is 1;
  • n is 1, 2 or 3 .
  • Z 1 is CR 1 ;
  • Z 2 is NR 2 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is C(R 8 R 9 );
  • t is 0 or 1;
  • n is 1 .
  • Z 1 is CR 1 ;
  • Z 2 is NR 2 ;
  • Z 3 is C(R 5 R 6 );
  • t is 0;
  • n is 1, 2, or 3.
  • Z 1 is CR 1 ;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is C(R 8 R 9 ), NR 10 or O;
  • t is 0 or 1;
  • n is 1, 2 or 3.
  • W 1 is a bond, or C(R c R d ); W 2 is C(R e R f ).
  • W 1 is a bond, or C(R c R d );
  • W 2 is C(R e R f );
  • Z 1 , Z 2 , Z 3 , Z 4 , t, n are selected One from the following group:
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • t is 0;
  • n is 1, 2 or 3;
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is NR 7 or O;
  • Z 4 is C(R 8 R 9 );
  • t is 0 or 1;
  • n is 1;
  • Z 1 is N;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is NR 10 or O;
  • t is 1;
  • n is 1, 2 or 3;
  • Z 1 is CR 1 ;
  • Z 2 is NR 2 ;
  • Z 3 is C(R 5 R 6 );
  • t is 0;
  • n is 1, 2 or 3;
  • Z 1 is CR 1 ;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is C(R 8 R 9 ), NR 10 or O;
  • t is 0 or 1;
  • n is 1, 2 or 3.
  • W 1 is a bond, or C(R c R d ); W 2 is NR g or O.
  • W 1 is a bond, or C(R c R d );
  • W 2 is NR g or O;
  • Z 1 , Z 2 , Z 3 , Z 4 , t, n are selected from the following group One of:
  • Z 1 is CR 1 ;
  • Z 2 is NR 2 ;
  • Z 3 is C(R 5 R 6 );
  • t is 0;
  • n is 1, 2 or 3;
  • Z 1 is CR 1 ;
  • Z 2 is CR 3 R 4 ;
  • Z 3 is C(R 5 R 6 );
  • Z 4 is C(R 8 R 9 ), NR 10 or O;
  • t is 0 or 1;
  • n is 1, 2 or 3.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in the substituent group A is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2- Dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4 -Dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic ring in the substituent group A is selected from: cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl Ring, cyclohexadienyl ring.
  • the 5- or 6-membered monocyclic heteroaryl group in the group A substituent is selected from: thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, three Azole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1 , 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or Pyrazine.
  • the 5- or 6-membered monocyclic heteroaryl group described in Ra is selected from: thiophene, N-alkyl pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine .
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 2 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 3 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 4 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in R 11 and R 12 is selected from: aziridine, ethylene oxide, azetidine, and oxetane , Tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydronitrogen Cyclobutadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3- Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6 -Te
  • the 3- to 6-membered saturated monocyclic heterocyclic ring formed by R 3 and R 4 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 3- to 6-membered saturated monocyclic ring formed by R 3 , R 4 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
  • the 3- to 6-membered saturated monocyclic heterocycle formed by R 5 , R 6 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 3- to 6-membered saturated monocyclic ring formed by R 5 , R 6 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
  • the 3- to 6-membered saturated monocyclic heterocycle formed by R 8 and R 9 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
  • the 3- to 6-membered saturated monocyclic ring formed by R 8 , R 9 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
  • the 4- to 6-membered saturated or unsaturated monocyclic heterocycle formed by R 11 , R 12 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole, piperidine, piperazine, Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 1,2-dihydroazetidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro -1H-pyrrole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 23 and R 24 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 23 , R 24 and the connected carbon atom is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 33 , R 34 and the connected carbon atom is selected from: aziryl ring, ethylene oxide, azetidine, oxetane Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 33 , R 34 and the connected carbon atom is selected from the group consisting of: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R53 , R54 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R53 , R54 and the connected carbon atoms is selected from the group consisting of: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 83 and R 84 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran,
  • the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 83 and R 84 and the connected carbon atom is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
  • the 3 to 6 membered or 4 to 6 membered saturated monocyclic heterocyclic ring is selected from the following structures:
  • the hydrogen atoms on the above-mentioned 3- to 6-membered or 4- to 6-membered saturated monocyclic heterocyclic ring are optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
  • the 5- to 6-membered monocyclic heteroaryl group described in R a or Group A substituent is selected from the following structures:
  • the above-mentioned 5- to 6-membered monocyclic heteroaryl group is optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
  • R 1 is hydrogen or a substituted or unsubstituted C 1-3 alkyl group; the "substituted” means that 1, 2, or 3 hydrogen atoms in the group are each independently selected from A Group of substituents are substituted.
  • R 2 , R 7 , and R 10 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 21 R 22 ) p -L 1 ;
  • L 1 is C 3-6 cycloalkyl , C 1-3 alkoxy, -COC 1-3 alkyl, -COC 3-6 cycloalkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1- 3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-3 alkyl, -( CR 23
  • R 2 , R 7 , and R 10 are each independently hydrogen, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 3- 6 cycloalkyl or -(CR 21 R 22 ) p -L 1 ;
  • L 1 is C 3-6 cycloalkyl, C 1-3 alkoxy, -COC 1-3 alkyl, -COC 3-6 ring Alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated mono heterocyclic ring , -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-3 alkyl, -(CR 23 R 24 )C 1-3 alkyl, -(CR 23 R 24 )CN, -( CR 23 R 24 )OH or
  • R 11 and R 12 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring ; Or R 11 , R 12 and the connected nitrogen atom form a substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic ring; wherein the "substituted” refers to 1, 2 or 3 hydrogen atoms in the group It is substituted by substituents each independently selected from Group A.
  • R 21 and R 22 are the same or different, and are each independently hydrogen, hydroxyl, halogen, C 1-3 alkyl, substituted or unsubstituted C 1-10 alkoxy (preferably substituted Or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more It is preferably a halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 Alkyl) or -NR 13 SO 2 R 0 ; wherein the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R 23 , R 24 and the connected carbon atoms form a substituted or unsubstituted 3 to 6 membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6 membered saturated or unsaturated monocyclic ring Ring; wherein the "substitution” means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 31 R 32 ) q -L 2 ;
  • L 2 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 33 R 34 )C 1-3 alkyl, -(CR 33 R 34 )CN, -(CR 33 R 34 )OH or -(CR 33 R 34 ) C 1-3 alkoxy;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
  • cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 2 is unsubstituted or is substituted by 1, 2 or 3 substituents each independently selected from Group A Replaced by
  • the 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 51 R 52 ) r -L 3 ;
  • L 3 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 53 R 54 )C 1-3 alkyl, -(CR 53 R 54 )CN, -(CR 53 R 54 )OH or -(CR 53 R 54 ) C 1-3 alkoxy;
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
  • cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 3 is unsubstituted or is substituted by 1, 2 or 3 substituents each independently selected from Group A Replaced by
  • the 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
  • R 8 and R 9 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 81 R 82 ) m -L 4 ;
  • L 4 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 83 R 84 )C 1-3 alkyl, -(CR 83 R 84 )CN, -(CR 83 R 84 )OH or -(CR 83 R
  • substitution means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
  • cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 4 is unsubstituted or is independently selected from the group A by 1, 2 or 3 substituents Replaced by
  • the 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
  • the compound is selected from Table A or Table B.
  • the compound of Table A is selected from the following group:
  • the compound of Table B is selected from the following group:
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and pharmacy Acceptable carrier.
  • the fourth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention.
  • the fifth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention. It is used for preparing medicine for agonizing or antagonizing MOR receptor.
  • the sixth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention.
  • the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
  • the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  • the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • the seventh aspect of the present invention provides a method for preventing and/or treating related diseases mediated by MOR receptor agonists, which comprises administering a therapeutically effective amount of the compound according to the first or second aspect of the present invention, or A pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition as described in the third aspect of the present invention.
  • the eighth aspect of the present invention provides a method for preventing and/or treating pain and pain-related diseases, which comprises administering to a patient a therapeutically effective amount of the compound according to the first or second aspect of the present invention, or pharmaceutically acceptable Accepted salts, stereoisomers or solvates, or pharmaceutical compositions as described in the third aspect of the invention.
  • the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
  • the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  • the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
  • the inventors unexpectedly discovered that such tricyclic substituted oxaspiro derivatives not only have excellent analgesic effects, but also have good bias.
  • the compounds of the present invention have excellent Pharmacokinetic properties. Therefore, the series of compounds are expected to be developed as drugs for the treatment and prevention of pain and pain-related diseases. On this basis, the inventor completed the present invention.
  • alkyl refers to linear and branched saturated aliphatic hydrocarbon groups
  • C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably It is a C 1-3 alkyl group with similar definitions; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl
  • cycloalkyl and “cycloalkyl ring” are used interchangeably, and both refer to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl” refers to containing 3 to 8
  • the cyclic hydrocarbon group of carbon atoms is preferably a C 3-6 cycloalkyl group, and the definition is similar.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
  • spiro ring refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
  • spiro heterocyclic ring refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer 0 to 2) of heteroatoms, the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • the spiro heterocyclic ring is classified into a dispiro heterocyclic ring or a polyspiro heterocyclic ring, preferably a dispiro heterocyclic ring. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring.
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atoms are called bridgehead carbons.
  • the two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is a double ring or a triple ring bridged ring.
  • bridged heterocycle refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer of 0 to 2 ), the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:
  • 8 to 10 membered bicyclic ring refers to a bridged ring containing two rings containing 8 to 10 ring atoms.
  • the bicyclic ring may be a saturated full carbon bicyclic ring or a partially unsaturated full carbon bicyclic ring, and an 8 to 10 membered bicyclic ring Examples include (but are not limited to):
  • 8 to 10 membered bicyclic heterocyclic ring refers to a two-ring bridged heterocyclic ring containing 8 to 10 ring atoms, in which 1, 2, 3, 4, or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms.
  • 8- to 10-membered bi-heterocycles include, but are not limited to, tetrahydroquinoline ring, tetrahydroisoquinoline ring, decahydroquinoline ring and the like.
  • C 1-10 alkoxy refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above.
  • C 1-6 alkoxy is preferable, and C 1-3 alkoxy is more preferable.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • C 6-10 aryl and C 6-10 aryl ring are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated ⁇ -electron system (that is, sharing adjacent A ring) group with a pair of carbon atoms refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
  • a bond means that two groups connected by it are connected by a covalent bond.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo refers to the replacement of one or more (such as 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
  • halo C 1-10 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl examples include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halogenated C 1-10 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base etc.
  • amino refers to NH 2
  • cyano refers to CN
  • nitro refers to NO 2
  • benzyl refers to -CH 2 -phenyl
  • carboxy Refers to -C(O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • ""Hydroxy refers to -OH
  • thiol refers to SH
  • the structure of "cyclopropylene” is:
  • heteroatom refers to nitrogen, oxygen, or sulfur.
  • heteroaryl ring and “heteroaryl” are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ;
  • the ring array shares 6, 10 or 14 ⁇ electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms.
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • 3- to 6-membered saturated or unsaturated monocyclic ring refers to a saturated or unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms.
  • 3 to 6-membered saturated or unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexyl ring Dienyl ring and so on.
  • 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring means that 1, 2, or 3 carbon atoms in a 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t It is substituted by heteroatoms of integers 0 to 2), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Examples of 4- to 6-membered saturated or unsaturated monocyclic heterocycles include (but are not limited to) azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine , Piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine Diene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro- 1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyr
  • 5- to 6-membered monocyclic heteroaryl ring and “5- to 6-membered monocyclic heteroaryl” are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms
  • Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole
  • 8 to 10 membered bicyclic heteroaryl ring and “8 to 10 membered bicyclic heteroaryl ring” are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphth
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • substituted by a substituent means that when more than one hydrogen on the group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are of independent types.
  • L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), and the two R 01 or R 02 can be the same or different.
  • Independent type for example L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN) (CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl-substituted amino, amino, halogenated C 1-8 alkyl-substituted amino, acetyl Group, hydroxyl, hydroxymethyl, hydroxyethyl, carboxy
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in the solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) fall within the scope of the present invention.
  • the compound represented by formula (I) or formula (II) of the present invention may contain two or more chiral centers and exist in different optically active forms.
  • the stereoisomers of the compounds represented by formula (I) or formula (II) of the present invention may be enantiomers or diastereomers.
  • the compound represented by formula (I) or formula (II) may exist in the form of resolved optically pure specific stereoisomers, for example in the form of enantiomers or diastereomers, or Exist as a mixture of two stereoisomers, for example, as a mixture of enantiomers, such as a mixture of racemates, or a mixture of diastereomers, or enantiomers and diastereomers
  • the structure exists as a mixture.
  • the enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. Diastereoisomers can be resolved by methods known in the field, such as crystallization and preparative chromatography.
  • the enantiomers or diastereomers of the compounds represented by formula (I) or formula (II) of the present invention, and mixtures of these stereoisomers are all within the protection scope of the present invention.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the compound of the present invention or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or a prodrug of the present invention can be administered in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods.
  • the aforementioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • composition of the present invention is formulated, quantified and administered in a manner conforming to medical practice standards.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • therapeutically effective amount refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
  • the therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • pharmaceutically acceptable carrier refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the compound represented by formula (II) of the present invention can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples.
  • the raw material compound may be in the form of a salt
  • the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (II) of the present invention.
  • the compound represented by the formula (I-2) can be prepared according to the following method: the compound 1a and the corresponding compound represented by the formula (I-1) are subjected to a reductive amination reaction to prepare the compound represented by the formula (I-2) .
  • the compound represented by formula (II-2) can be prepared according to the following method: compound 1b and the corresponding compound represented by formula (II-1) undergo reductive amination reaction to prepare the compound represented by formula (II-2) .
  • the reductive amination reaction is known and can be.
  • an organic solvent such as DCM, DCE or THF, etc.
  • a catalyst such as tetraisopropyl titanate
  • a reducing agent such as sodium borohydride
  • the compound having an amino group, a carboxyl group, or a hydroxyl group used in the present invention can be prepared using a compound that has been protected by a protective group commonly used for this group as required. After passing through the reaction process of the above-mentioned reaction scheme, a known desorption can be carried out. Protection response.
  • a series of tricyclic substituted oxaspiro derivatives with novel structures are provided, which have high inhibitory activity on cAMP (EC 50 is 0.1 nM to 100 nM, more preferably 0.1 to 50 nM), and higher Emax Value (Emax is greater than 50%, more preferably Emax is greater than 100%), has excellent analgesic effects, and the compound of the present invention has a lower Emax value for ⁇ -arrestin (Emax is less than 50%, more preferably Emax is less than 20 %), the bias is good. Therefore, it can be developed as a medicine for the treatment and prevention of pain and pain-related diseases.
  • DMB 2,4-dimethoxybenzyl
  • THF tetrahydrofuran
  • EA ethyl acetate
  • PE petroleum ether
  • Ac 2 O acetic anhydride
  • NBS N-bromosuccinimide
  • DCM dichloromethane
  • DCE 1,2-dichloromethane
  • AIBN azobisisobutyronitrile
  • Pd(dppf)Cl 2 is [1,1'-bis(diphenylphosphorus)ferrocene] Palladium chloride
  • TFA trifluoroacetic acid
  • TBSCl tert-butyldimethylchlorosilane
  • NCS N-chlorosuccinimide
  • DHP dihydrotetrahydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB Is p-methoxybenzyl
  • LiHMDS lithium bis(trimethylsilyl)amide
  • Pd 2 (dba) 3 is
  • room temperature refers to about 20-25°C.
  • Step 1 Dissolve compound 1c-1 (4.0g, 24.4mmol), compound 1c.1 (4.1g, 24.4mmol) and Pd(dppf)Cl 2 (0.89g, 1.2mmol) in 50mL 1,4-diox The hexacyclic ring and 10ml of water were stirred at 80°C for 12h. 100 mL of water was added to the reaction solution, and extracted with EA (100 mL ⁇ 3).
  • Step 2 Compound 1c-2 (3.2 g, 18.9 mmol) and nickel chloride (3.57 g, 38.0 mmol) were added to 30 mL of methanol, sodium borohydride (1.44 g, 38.0 mmol) was added, and the reaction was stirred at room temperature for 6 hours. 100 mL of water was added to the reaction solution, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 5/1) to obtain compound 1c (1.28 g, brown liquid), Yield: 36.2%. MS m/z (ESI): 176.1 [M+H] + .
  • Step 1 Dissolve 2-methyl-3-butyn-2-ol 1d-1 (8.4g, 100mmol), triethylamine (15g, 150mmol) and 4-dimethylaminopyridine (0.6g, 5.0mmol) To 80ml DCM, add acetic anhydride (12.2g, 120mmol), and stir at room temperature for 12h. 100 mL of saturated ammonium chloride was added to the reaction solution, and it was extracted with DCM (100 mL ⁇ 3).
  • Step 2 3-acetoxyisopentyne compound 1d-2 (7.5g, 59.5mmol) and aniline (6.65g, 71.4mmol) were dissolved in 50mL THF, and cuprous chloride (0.59g, 59.5mmol) was added, Heat to reflux for 4h. 100mL of water was added to the reaction solution, extracted with EA (100mL ⁇ 3), washed with saturated brine (100mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the eluent system was determined by silica gel column chromatography ( PE/EA: 50/1) The resulting residue was purified to obtain compound 1d-3 (4.0 g, yellow liquid), yield: 25.0%. MS m/z (ESI): 160.1 [M+H] + .
  • Step 3 Compound 1d-3 (2.5g, 15.7mmol) was dissolved in 25ml ethanol and 25ml EA mixed solvent, palladium/carbon (250mg) was added, and the reaction was stirred at room temperature for 12h. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 1d (2.2 g, yellow liquid), yield: 88.0%. MS m/z (ESI): 162.1 [M+H] + .
  • Step 1 Dissolve compound 1-1 (2.38g, 0.02mol) in 40mL DMF, add potassium carbonate (5.52g, 0.04mol) and ethyl bromopropionate (5.43g, 0.03mol), and stir at 80°C for 18h.
  • Step 3 Dissolve compound 1-3 (69 mg, 0.4 mmol) and compound 1a (104 mg, 0.4 mmol) in 8 mL of DCE, add 5 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 18 h. Cool to room temperature, add sodium borohydride (46mg, 1.2mmol) to the reaction solution, stir for 3h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-1 (5 mg, yield: 3.0%). MS m/z (ESI): 418.3 [M+H] + .
  • Step 1 Dissolve compound 2-1 (2.66g, 20.0mmol) in 40mL DMF, add potassium carbonate (5.52g, 40.0mmol) and methyl bromopropionate (5.43g, 40.0mmol), stir and react at 80°C for 18h . 120mL of water was added to the reaction solution, extracted with EA (60mL ⁇ 3), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with silica gel column chromatography.
  • Step 3 Dissolve compound 2-3 (37 mg, 0.2 mmol) and compound 1a (52 mg, 0.2 mmol) in 5 mL of DCE, add 0.5 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 7 hours. Cool to room temperature, add sodium borohydride (23mg, 0.6mmol) to the reaction solution, stir for 18h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-2 (3.82 mg, yield: 4.4%). MS m/z(ESI): 432.3[M+H] + .
  • Step 2 Mix compound 3-2 (1 g, 4.57 mmol) with about 20 mL of polyphosphoric acid, and stir and react at 130°C for 3 hours.
  • Step 3 Dissolve compound 3-3 (37 mg, 0.2 mmol) and compound 1a (52 mg, 0.2 mmol) in 5 mL of DCE, add 0.5 mL of tetraisopropyl titanate, and stir to react overnight at 45°C. Cool to room temperature, add sodium borohydride (23mg, 0.6mmol) to the reaction solution, stir for 16h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-3 (8.42 mg, yield: 9.7%). MS m/z (ESI): 432.3 [M+H] + .
  • Step 3 Dissolve compound 4-3 (4 g, 21.4 mmol) in 80 mL of acetone and 25 mL of water, slowly add potassium permanganate (6.7 g, 42.8 mmol) at 0°C, and stir at room temperature for 2 days. Then add potassium permanganate (3.4g, 21.7mmol), and continue the reaction for 18h. 10g sodium thiosulfate was added, stirred for 10min, filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with EA (100ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 4-4 (1.5 g, yield: 32%). MS m/z (ESI): 218 [M+H] + .
  • Step 5 Dissolve compound 4-5 (0.16 g, 0.35 mmol) in 10 mL TFA and stir overnight. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 15 ml of ethanol, palladium/carbon (48 mg) was added, and the reaction was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to obtain brown solid compound 4-6. The crude product was directly used in the next step. MS m/z (ESI): 446 [M+H] + .
  • Step 6 Dissolve lithium tetrahydroaluminum (26 mg, 0.675 mmol) in 10 mL of dry THF, add compound 4-6 (0.1 g) in THF (1 mL), and stir overnight. Add 5mL water at 0°C, stir for 0.5h, filter, and concentrate the filtrate under reduced pressure. Preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%- The obtained residue was purified with 60% acetonitrile change) to obtain yellow solid compound H-4 (12.53 mg, yield: 13%).
  • Step 2 Dissolve compound 6-2 (4g, 25.2mmol) in 80ml of toluene, add ethyl bromoacetate (8.4g, 50.4mmol), stir and react at 45°C overnight. After concentration under reduced pressure, brown solid compound 6-3 was obtained, and the crude product was directly used in the next step. MS m/z (ESI): 246 [M+H] + .
  • Step 5 Dissolve compound 6-5 (65 mg, 0.3 mmol), compound 1a (78 mg, 0.3 mmol) and tetraisopropyl titanate (0.5 mL) in 6 mL of DCE, and react at 45° C. for 6 hours. Sodium borohydride (23mg, 0.61mmol) was added, and the reaction was continued overnight at 45°C. After cooling to room temperature, 2 mL of water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain yellow solid compound H-6 (12 mg, yield 8.99%). MS m/z (ESI): 446 [M+H] + .
  • Example 8 1-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-8) preparation
  • Step 1 At room temperature, dissolve compound 10-1 (1.46g, 10.0mmol) and diethyl succinate (2.61g, 15.0mmol) in 5ml tert-butanol, add the resulting solution to sodium (264mg) in 15ml In a suspension of tert-butanol.
  • the reaction solution was heated to reflux for 6h, and after cooling to room temperature, the reaction was quenched with 2M hydrochloric acid, and extracted with EA (50ml*3).
  • the organic phases were combined and washed with 1M sodium hydroxide solution.
  • the separated aqueous phase was washed with EA (30ml*2), acidified with 2M hydrochloric acid to pH ⁇ 2, and then extracted with EA (50ml*2).
  • Step 2 Dissolve compound 10-2 (1.80 g, 5.11 mmol) in a mixed solvent of 30 ml of acetic acid, 15 ml of concentrated hydrochloric acid and 20 ml of water, and heat to reflux for 24 hours.
  • the solvent was distilled off under reduced pressure, the residue was diluted with 50ml EA, washed with 2M sodium hydroxide solution, the aqueous phase was separated, washed with 30ml EA, the aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, and extracted with EA (50ml*2).
  • Step 3 Dissolve compound 10-3 (210mg) in 10ml ethanol, add 20mg Pd/C, replace with hydrogen three times at room temperature, react for 16h at room temperature and pressure, filter to remove the catalyst, and concentrate the filtrate under reduced pressure to obtain Compound 10-4 (101 mg, colorless and transparent liquid), the yield was 47.6%.
  • Step 4 Add three drops of DMSO to the compound of compound 10-4 (111mg, 0.54mmol) and polyphosphoric acid (2g), heat to 100°C and react for 1h, cool to 60°C and quench the reaction with crushed ice. Extract with EA (30ml*2). The organic phases were combined, washed with water (30ml), saturated sodium bicarbonate solution (30ml), saturated brine (30ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 10-5 (81mg, yellow oil). The yield was 80.2%. MS m/z (ESI): 187.1 [M+H] + .
  • Step 5 Compound 10-5 (38mg, 020mmol) and compound 1a (44mg, 0.17mmol) were dissolved in 5ml of dichloroethane, heated to 80°C and reacted for 16h, then sodium borohydride (13mg, 0.34mmol) was added, and then React at 80°C for 48h. After cooling to room temperature, it was filtered, the filter cake was washed with methanol, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-10 (5 mg, yellow solid) with a yield of 5.2%. MS m/z (ESI): 431.3 [M+H] + .
  • Step 1 Dissolve compound 11-1 (6.6 g, 44.6 mmol) in 60 ml of methanol, add sodium borohydride (2.03 g, 53.5 mmol) in batches at 0°C, return the reaction temperature to room temperature, and react for 2 hours. After removing the reaction solvent, 1M hydrochloric acid solution was added to quench the reaction, and EA extraction (50 mL x 3). The organic phases were combined, washed with water (80 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-2 (6.5 g, yellow oily liquid) with a yield of 97.2%.
  • Step 2 Dissolve compound 11-2 (5.0g, 33mmol) and trimethylsilyl cyanide (6.53g, 66mmol) in 60ml of acetonitrile, add boron trifluoride ether (9.37g, 66mmol) at 0°C, and the reaction temperature rises To room temperature, react for 2h. Saturated sodium bicarbonate solution (50ml) was added to the reaction solution, and DCM extraction (50ml*3). The organic phases were combined, washed with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Compound 11-3 (4.3 g, 27.0 mmol) and sodium hydroxide (10.8 g, 270 mmol) were dissolved in a mixed solvent of methanol (10 ml) and water (50 ml). Heat to 100°C for 24h. Adjust the pH value of the reaction solution to 1-2 with 6M hydrochloric acid solution, and extract with EA (50ml*3). The organic phases were combined, washed with water (80ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-4 (4.3g, yellow oily liquid) with a yield of 89.4%. MS m/z (ESI): 179.1 [M+H] + .
  • Step 4 Compound 11-4 (4.3g, 24.2mmol) was dissolved in THF (50ml), and borane THF solution (48ml, 48.4mmol) was added dropwise. After reacting overnight, it was quenched by adding methanol and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 80/20) to obtain compound 11-5 (3.67 g, colorless oily liquid) with a yield of 87.9%. MS m/z (ESI): 165.1 [M+H] + .
  • Step 5 Dissolve compound 11-5 (1.64g, 10.0mmol) in DCM (50ml), add Dess-Martin reagent (6.36g, 15.0mmol) in batches. React at room temperature for 3h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 90/10) to obtain compound 11-6 (1.44 g, colorless oily liquid) with a yield of 88.9%. MS m/z (ESI): 163.1 [M+H] + .
  • Step 6 Dissolve ethyl 2-(diethoxyphosphoryl)acetate (2.77 g, 12.3 mmol) in THF (30 ml), and add sodium hydrogen (0.5 g, 12.34 mmol) in portions at 0°C. After reacting at 0°C for 30 min, a THF solution (5 ml) of compound 11-6 (1.0 g, 6.17 mmol) was added. The reaction temperature was slowly raised to room temperature and then reacted for 2 hours. The reaction was quenched with 2M hydrochloric acid solution, and extracted with EA (50ml*3).
  • Step 7 Add compound 11-7 (100mg, 0.49mmol) and palladium/carbon (10mg) to ethanol (5ml), and react for 7h under hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 11-8 (88 mg, yellowish oily liquid) with a yield of 87.1%. MS m/z (ESI): 205.1 [MH] - .
  • Step 8 Heat compound 11-8 (68 mg, 0.33 mmol) and polyphosphoric acid (2 g) to 120° C. and react for 1 h. EA (20ml) was added to the reaction solution, washed with water (20ml) saturated brine (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 80/20) to obtain compound 11-9 (30 mg, yellow solid) with a yield of 38.0%. MS m/z (ESI): 189.1 [M+H] + .
  • Step 9 Dissolve compound 11-9 (28 mg, 0.11 mmol) and compound 1a (20 mg, 0.11 mmol) in DCE, and add 2 drops of tetraisopropyl titanate. After reacting at 80°C for 3h, sodium borohydride (8mg, 0.21mmol) was added, and the reaction was continued at 80°C for 16h. After cooling to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-11 (5 mg, yellow solid) with a yield of 6.8%. MS m/z(ESI): 433.3[M+H] + .
  • Step 1 Compound 6-1 (2.1g, 14.5mmol) and benzyl bromide (3.7g, 21.7mmol) were dissolved in 85ml of toluene and reacted at 90°C for 16h. After filtration, the filter cake was washed with PE and dried in vacuum to obtain compound 12-2 (3.8 g, brown solid). The crude product is directly used in the next reaction. MS m/z(ESI): 236.1.
  • Step 2 Dissolve compound 12-2 (3.8g) in 20ml water, and add 4M sodium hydroxide solution (10ml) with stirring. The reaction solution was extracted with EA (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-3 (2.8 g, brown oily liquid). The crude product was directly used in the next reaction. MS m/z(ESI): 236.1[M+H] + .
  • Step 3 Under stirring, slowly add ethyl bromoacetate (5 ml) to the oily compound 12-3 (2.8 g), and heat to 60° C. to react for 16 hours. After removing the remaining ethyl bromoacetate, compound 12-4 (3.5 g, brown oily liquid) was obtained, and the crude product was directly used in the next reaction. MS m/z(ESI): 322.2
  • Step 4 Compound 12-4 (3.5g) was dissolved in ethanol (50ml), and sodium borohydride (0.83g, 21.7mmol) was added in portions. After reacting overnight, the solvent was distilled off under reduced pressure. Water was added and extracted with DCM (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative liquid chromatography to obtain compound 12-5 (1.1 g, yellow oily liquid) with a yield of 31.4%. MS m/z(ESI): 324.2[M+H] + .
  • Step 5 Heat compound 12-5 (1 g, 3.1 mmol) and polyphosphoric acid (3 g) to 140° C. and react for 2 hours. The temperature was lowered to 60°C, and ice water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (20ml*4). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 70/30) to obtain compound 12-6 (500 mg, yellow oily liquid) with a yield of 53%. MS m/z(ESI): 278.2[M+H] + .
  • Step 6 Compound 12-6 (460 mg, 1.66 mmol) and palladium/carbon (50 mg) were added to ethanol (10 ml), and reacted for 16 h under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 12-7 (0.2 g, yellow oily liquid). The crude product was directly used in the next reaction. MS m/z(ESI): 188.1[M+H] + .
  • Step 7 Compound 12-7 (180mg), ethyl bromoacetate (161mg, 0.96mmol) and sodium carbonate (204mg, 1.92mmol) were added to acetonitrile (10ml) to react at room temperature for 3h. The solvent was distilled off under reduced pressure. The residue was diluted with DCM (30ml), washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 70/30) to obtain compound 12-8 (100 mg, yellow oily liquid) with a yield of 34.2%. MS m/z(ESI): 274.2[M+H] + .
  • Step 8 Dissolve compound 12-8 (30 mg, 0.11 mmol), compound 1a (29 mg, 0.11 mmol) and tetraisopropyl titanate (0.8 ml) in DCE. After reacting at 45°C for 16h, sodium borohydride (9mg, 0.22mmol) was added, and the reaction was continued at 45°C for 1h. After cooling to room temperature, add water, filter, and concentrate the filtrate under reduced pressure.
  • Step 1 Compound 6-1 (3.0g, 20.7mmol) and iodoisobutane (7.6g, 41.4mmol) were dissolved in 5ml of toluene and reacted at 90°C for 16h. After filtration, the filter cake was washed with toluene and dried in vacuum to obtain compound 14-2 (6.8 g, brown oily liquid). The crude product is directly used in the next reaction. MS m/z(ESI): 202.2.
  • Step 2 Dissolve compound 14-2 (2.5g) in 20ml water, and add 4M sodium hydroxide solution (10ml) with stirring. The reaction solution was extracted with EA (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-3 (1.8 g, brown oily liquid). The crude product was directly used in the next reaction. MS m/z (ESI): 202.2 [M+H] + .
  • Step 3 Under stirring, ethyl bromoacetate (6 ml) was added to compound 14-3 (1.8 g), and the mixture was heated to 60° C. to react for 16 h. After removing the remaining ethyl bromoacetate, compound 14-4 (2.5 g, brown oily liquid) was obtained, and the crude product was directly used in the next reaction. MS m/z(ESI): 288.2.
  • Step 4 Compound 14-4 (2.5g) was dissolved in ethanol (30ml), and sodium borohydride (0.66g, 17.4mmol) was added in portions. After reacting overnight, the solvent was distilled off under reduced pressure. Water was added and extracted with DCM (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative liquid chromatography to obtain compound 14-5 (0.25 g, yellow oily liquid) with a yield of 10%. MS m/z (ESI): 290.2 [M+H] + .
  • Step 5 Heat compound 14-5 (250mg, 0.87mmol) and polyphosphoric acid (2g) to 140°C and react for 2h. The temperature was lowered to 60°C, and ice water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (20ml*4). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0 ⁇ 70/30) to obtain compound 14-6 (180 mg, yellow oily liquid) with a yield of 85%. MS m/z (ESI): 244.2 [M+H] + .
  • Step 6 Add compound 14-6 (40mg, 0.16mmol), hydroxylamine hydrochloride (45mg, 0.64mmol) and sodium acetate (79mg, 0.96mmol) into a mixed solvent of ethanol (5ml) and water (1mL) at 140°C Next, microwave reaction for 45 minutes. After cooling to room temperature, most of the solvent was distilled off under reduced pressure. The residue was diluted with DCM (30ml), washed with saturated sodium bicarbonate solution (10ml) and saturated brine (10ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Compression and concentration gave compound 14-7 (35 mg, yellow oily liquid) with a yield of 85.4%. MS m/z (ESI): 259.2 [M+H] + .
  • Step 7 Add compound 14-7 (35mg, 0.14mmol) and palladium/carbon (10mg) to ethanol (10ml, containing 2 drops of 2M hydrochloric acid solution), and react for 5h under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 14-8 (25 mg, yellow oily liquid) with a yield of 73.5%. MS m/z (ESI): 245.2 [M+H] + .
  • Step 8 Dissolve compound 14-8 (20 mg, 0.11 mmol), compound 1b (20 mg, 0.11 mmol) and tetraisopropyl titanate (1 ml) in DCE. After reacting at 45°C for 3h, sodium borohydride (6mg, 0.15mmol) was added, and the reaction was continued at 45°C for 0.5h. After cooling to room temperature, water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-14 (10 mg, white solid). The yield was 26.7%. MS m/z(ESI): 488.4[M+H] + .
  • Step 2 Dissolve compound 15-2 (3.6 g, 20.3 mmol) in 40 mL THF, cool to 0° C. under nitrogen protection, add n-butyl lithium (20 mL, 50.0 mmol) dropwise, and stir at 0° C. for 1 h. The reaction solution was poured into 70 mL saturated ammonium chloride solution for quenching, and extracted with EA (50 mL ⁇ 3).
  • Step 3 Dissolve compound 15-3 (1.8 g, 11.3 mmol) in 20 mL of acetic acid, cool to 0° C. under nitrogen protection, add sodium cyanoborohydride (2.8 g, 44.5 mmol), and stir for reaction at room temperature for 2 hours. The solvent was distilled off under reduced pressure, pH was adjusted to 10 with 4M sodium hydroxide solution, and extracted with EA (50 mL ⁇ 3).
  • Step 4 Dissolve compound 15-4 (1.0g, 6.20mmol) in 8mL DMF, add anhydrous potassium carbonate (1.70g, 12.3mmol) and methyl 3-bromopropionate (2.0g, 11.98mmol), 100 The reaction was stirred overnight at °C. 30 mL of saturated brine was added to the reaction solution, and EA (50 mL) was extracted.
  • Step 5 Compound 15-5 (0.9g, 3.64mmol) was added to 22g polyphosphoric acid, and the reaction was stirred at 150°C for 7h.
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (PE/EA: 1/0-10/1) to obtain compound 15-6 (214 mg, yellow solid), yield: 22%.
  • Step 6 Compound 15-6 (42 mg, 0.195 mmol), hydroxylamine hydrochloride (54 mg, 0.777 mmol) and sodium acetate (96 mg, 1.17 mmol) were dissolved in a mixed solvent of 10 mL ethanol and 1 mL water, and reacted in a microwave at 120° C. for 45 min. The reaction solution was poured into 30 mL saturated sodium bicarbonate solution and extracted with DCM (30 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-7 (44 mg, yellow solid), yield: 99.0%. MS m/z (ESI): 231.1 [M+H] + .
  • Step 7 Dissolve compound 15-7 (44mg, 0.191mmol) in 8mL ethanol, add palladium/carbon (50mg) and 0.5M hydrochloric acid solution. Under a hydrogen atmosphere, the reaction was stirred at room temperature for 5 hours. After filtration, the filtrate was concentrated under reduced pressure, the residue was neutralized with saturated sodium bicarbonate solution, and concentrated under reduced pressure to remove water. DCM (50 mL) was added, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-8 (40 mg, orange oil), yield: 98%. MS m/z(ESI): 200.1[M-16] - .
  • Step 8 Dissolve compound 15-8 (40 mg, 0.185 mmol) and compound 1b (48 mg, 0.185 mmol) in 10 mL of DCE, add 0.4 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 7 hours. After cooling to room temperature, sodium borohydride (35 mg, 0.93 mmol) was added to the reaction solution, and the reaction was stirred overnight at 45°C. 3 mL of water was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative chromatography to obtain compound H- 15 (20 mg, yellow solid), yield: 23%. MS m/z (ESI): 460.1 [M+H] + .
  • Step 1 Dissolve 2-aminobenzyl alcohol 16-1 (11.0g, 89.3mmol) and DIEA (11.3g, 133.8mmol) in 150mL DCM, add trifluoroacetic anhydride (20.6g, 98.1mmol) dropwise at 0°C ), the reaction was stirred overnight at room temperature. 80 mL of saturated saline was added to the reaction solution, and the solution was separated. The organic phases were combined, washed with 0.5M hydrochloric acid solution (80 mL) and water (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-2 (18 g, yellow oil), yield: 92% . MS m/z (ESI): 237.1 [M+18] + .
  • Step 3 Dissolve compound 16-3 (8 g, 28 mmol) and triphenylphosphine (8.2 g, 31 mmol) in 100 mL of toluene, stir and react at 60° C. overnight. After the reaction solution was cooled to room temperature, compound 16-4 (14.5 g, white solid) was obtained by filtration, and the yield was 94.0%. MS m/z(ESI): 464.1 [M-79] - .
  • Step 4 Dissolve compound 16-4 (14.5 g, 26.6 mmol) in 20 mL DMF, and react in microwave at 200° C. for 30 min. The solvent was distilled off under reduced pressure, and EA (150 mL) was added. The organic phase was washed with saturated brine (80mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 1/0 ⁇ 10/1) The obtained residue was compound 16-5 (4 g, white solid), yield: 81%. MS m/z (ESI): 184 [MH] - .
  • Step 5 Compound 16-5 (1.6 g, 8.64 mmol) was dissolved in 25 mL TFA, sodium cyanoborohydride (1.7 g, 26.5 mmol) was added at 0°C, and the reaction was stirred for 1 h. 30 mL of water was added to the reaction solution, most of the solvent was distilled off under reduced pressure, and the residue was extracted with EA (50 mL).
  • Step 6 Dissolve compound 16-6 (0.8g, 4.27mmol) in 10mL DMF, add anhydrous potassium carbonate (1.80g, 13.0mmol) and methyl 3-bromopropionate (3.6g, 21.6mmol), 100 The reaction was stirred at °C for 2 days. 50 mL of saturated brine was added to the reaction solution, and EA (80 mL) was extracted. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (PE/EA: 1/0-10/1) to obtain compound 16- 7 (0.2g, colorless oily liquid), yield: 17%. MS m/z (ESI): 274.1 [M+H] + .
  • Step 7 Dissolve compound 16-7 (0.2 mg, 0.73 mmol) in 10 mL of THF and 1 mL of water, add lithium hydroxide monohydrate (92 mg, 2.19 mmol) in water (1 mL), and stir and react at room temperature overnight. Adjust the pH of the reaction solution to 4 with 1M hydrochloric acid solution, and extract with a DCM/methanol system (10:1) (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-8 (182 mg, pale yellow oil), yield: 96%. MS m/z (ESI): 260.1 [M+H] + .
  • Step 8 Dissolve compound 16-8 (182 mg, 0.702 mmol) in 10 mL DCM, add oxalyl chloride (134 mg, 1.05 mmol) and 2 drops of DMF at 0°C, and reverse for 17 hours.
  • the reaction solution was concentrated under reduced pressure to obtain the acid chloride intermediate.
  • the DCM solution (1 mL) of the acid chloride intermediate was added to the DCM solution (15 mL) of aluminum chloride (280 mg, 2.09 mmol) at -20°C, the temperature was slowly raised to room temperature, and the reaction was carried out overnight. Add 20 mL of ice water to neutralize 20 mL of saturated sodium bicarbonate, and extract with DCM (50 mL ⁇ 3).
  • Step 9 Dissolve compound 16-9 (30 mg, 0.127 mmol) and compound 1a (33 mg, 0.124 mmol) in 5 mL of DCE, add 0.7 mL of tetraisopropyl titanate, and stir for reaction at 45°C for 1 day. After cooling to room temperature, sodium borohydride (24 mg, 0.63 mmol) was added to the reaction solution, and the reaction was stirred at 45°C for 4 hours. 5 mL of water was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative chromatography to obtain compound H- 16 (11.89 mg, white solid), yield: 19%. MS m/z (ESI): 486.3 [M+H] + .
  • Example 17 1-sec-butyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (mixture of diastereomers H-17-1 and mixture of diastereomers H- 17-2) Preparation
  • Step 1 Using compound 6-1 and 2-iodobutane as raw materials, the preparation method refers to step 1 in Example 6 to obtain compound 17-2. MS m/z (ESI): 202.1 [M+H] + .
  • Step 2 The preparation method refers to step 2 in Example 6 to obtain compound 17-3. MS m/z (ESI): 288.2 [M+H] + .
  • Step 3 Preparation method Refer to step 3 in Example 6 to obtain ethyl 3-(2-sec-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propionate 17-4. MS m/z (ESI): 290.2 [M+H] + .
  • Step 4 Combine 3-(2-sec-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl) ethyl propionate 17-4 (680mg, 2.35mmol) and polyphosphoric acid (15g ) After mixing, heat to 140°C for 1 hour. The temperature was lowered to 60°C, and 30 mL of water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (50 mL x 3) and EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 5 Dissolve compound 17-5 (320 mg, 1.315 mmol), compound 1a (377 mg, 1.45 mmol) and tetraisopropyl titanate (4 mL) in 20 mL of DCE, and react at 50° C. for 36 hours. Sodium borohydride (200mg, 5.29mmol) was added, and the reaction was continued at 30°C for 2h. After cooling to room temperature, add 2 mL of water, filter, and concentrate the filtrate under reduced pressure.
  • Step 6 Dissolve compound 17-6 (320 mg, 1.315 mmol), compound 1a (377 mg, 1.45 mmol) and tetraisopropyl titanate (4 mL) in 20 mL of DCE, and react at 50° C. for 2 days. Sodium borohydride (200mg, 5.29mmol) was added, and the reaction was continued at 30°C for 1 hour. After cooling to room temperature, add 2 mL of water, filter, and concentrate the filtrate under reduced pressure.
  • Example 18 1-(Methylsulfonyl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-18)
  • Step 1 Dissolve compound 12-7 (132 mg, 0.70 mmol) in 20 mL of DCM, add triethylamine (140 mg, 1.38 mmol) and methanesulfonyl chloride (120 mg, 1.05 mmol) in sequence, and react at room temperature for 1 h. It was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography with a chromatography system (DCM/methanol: 20/1) to obtain compound 18-2 (72 mg, yellow solid) with a yield of 39%. MS m/z (ESI): 266.1 [M+H] + .
  • Step 2 Compound 18-2 (72 mg, 0.271 mmol), compound 1a (90 mg, 0.346 mmol) and tetraisopropyl titanate (1 mL) were dissolved in 8 mL of DCE. After reacting at 45°C for 18h, sodium borohydride (50mg, 1.32mmol) was added, and the reaction was continued at 45°C for 1h. After cooling to room temperature, 1 mL of water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-18 (37.28 mg, white solid), yield: 27%. MS m/z (ESI): 510.3 [M+H] + .
  • Step 1 Under an ice bath, dissolve compound 19-1 (10 g, 0.085 mol) in 100 mL of THF, add 60% sodium hydride (4.5 g, 0.11 mol), and stir for reaction in an ice bath for 30 min. Benzenesulfonyl chloride 19.1 (11 mL, 0.086 mol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 16 h. Add 100 mL of water to the reaction solution, extract with EA (50 mL ⁇ 2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 2 Dissolve compound 19-2 (3 g, 11.66 mmol) in 100 mL of THF, slowly add 2M lithium diisopropylamide (8.7 mL, 17.4 mmol) dropwise at -78°C, and stir for reaction at room temperature for 1 h. Iodoethane (1.1 mL, 13.75 mmol) was added dropwise at -78°C, and the reaction was stirred at room temperature for 16 h. Add 80 mL of water to the reaction solution, extract with EA (80 mL ⁇ 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • 2M lithium diisopropylamide 8.7 mL, 17.4 mmol
  • Iodoethane 1.1 mL, 13.75 mmol
  • EA 80 mL ⁇ 3
  • Step 3 Compound 19-3 (1.12 g, 3.92 mmol) was added to 10 mL of ethanol, 4N sodium hydroxide (5 mL, 20 mmol) was added, and the reaction was stirred at reflux for 40 h.
  • the reaction solution was concentrated under reduced pressure, 50mL of water was added, 5M hydrochloric acid was added to the reaction solution pH of 5-6, extracted with EA (50mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the compound 19-4 (560 mg, orange-red oil), yield: 98.2%.
  • Step 4 Compound 19-4 (560 mg, 3.86 mmol) was dissolved in 10 mL of acetic acid, sodium cyanoborohydride (900 mg, 14.32 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, 20mL 4N hydrochloric acid was added, stirred at room temperature for 1h, then 45mL 4N sodium hydroxide solution was added, extracted with EA (50mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 19-5 (560 mg, yellow oil) was obtained, yield: 98.6%. MS m/z (ESI): 148.1 [M+H] + .
  • Step 5 Compound 19-5 (560 mg, 3.80 mmol), methyl bromopropionate (1.3 g, 7.78 mmol) and potassium carbonate (1.1 g, 7.96 mmol) were added to 10 mL DMF. The reaction solution was sealed in a sealed tube, and the reaction was stirred at 110°C for 32 hours. Add 50mL saturated sodium chloride solution to the reaction solution, extract with EA (50mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 7 Add compound 19-7 (60 mg, 0.30 mmol), hydroxylamine hydrochloride (83 mg, 1.19 mmol) and sodium acetate (146 mg, 1.78 mmol) into 10 mL ethanol and 1 mL water.
  • the reaction solution was sealed in a microwave tube, and the reaction was stirred at 120° C. for 45 min in the microwave.
  • the reaction solution was concentrated under reduced pressure, 15 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM (15 mL ⁇ 3).
  • the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-8 (64 mg, yellow solid). ), yield: 99.4%.
  • Step 8 Dissolve compound 19-8 (64 mg, 0.30 mmol) in 8 mL of ethanol, add 1 mL of 0.5 N hydrochloric acid, and then add palladium/carbon (60 mg, 10%), replace with hydrogen three times, and stir and react for 5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 19-9 (60 mg, orange oil), yield: 99.9%. MS m/z(ESI): 186.1[M-16] - .
  • Step 9 Add compound 19-9 (60 mg, 0.29 mmol), compound 1b (75 mg, 0.29 mmol) and tetraisopropyl titanate (0.5 mL, 1.69 mmol) into 10 mL of DCE, and stir for reaction at 50° C. for 24 h.
  • Sodium borohydride 56mg, 1.48mmol was added, and the reaction was stirred at 50°C for 18h.
  • the reaction was quenched by adding 3 mL of water, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative chromatography to obtain compound H-19 (18 mg, brown oil), yield: 13.6%.
  • the preparation method refers to compound H-9.
  • the target compound H-20 (10.72 mg, brown solid) was obtained, and the yield was 23.3%.
  • Step 1 Dissolve 1,2,3,4-tetrahydroisoquinoline (20g, 150mmol) in DCM (50ml), add NBS (32g, 180mmol), stir and react at room temperature for 1h. Potassium hydroxide (12.6g, 225mmol) and water (50ml) were added to the reaction solution and stirred at room temperature for 2h. The solution was added with DCM (150 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 24-1 (23 g, yellow liquid). MS m/z (ESI): 132.1 [M+H] + .
  • Step 2 Compound 24-1 (10g), add malonic acid (15.8g, 151.5mmol), stir at 120°C for 3h. The reaction solution was added with isopropanol (40ml), stirred at 80°C for 30min, and filtered. The solid was dried to obtain a yellow solid compound 24-2 (11.6 g, yield 79%), MS m/z (ESI): 192.1 [M+H] + .
  • Step 3 Dissolve compound 24-2 (0.7g, 3.66mmol) in 10ml of methanol, add paraformaldehyde (0.7g) and sodium cyanoborohydride (0.748g, 11mmol), stir and react overnight at 40°C. The reaction solution was distilled under reduced pressure to obtain crude compound 24-3 (0.8 g, yellow solid). MS m/z (ESI): 206.1 [M+H] + .
  • Step 4 Dissolve compound 24-3 (800mg) in 5ml PPA, stir and react at 150°C for 2h.
  • the reaction solution was added with ice water (20 mL), saturated sodium carbonate solution was added to adjust the pH value to 8, and the mixture was extracted with DCM/methanol (10/1).
  • the organic phase was concentrated under reduced pressure and purified by column chromatography (PE containing 35% EA as the mobile phase) to obtain compound 24-4 (0.4 g, yield 55%) as a yellow liquid.
  • Step 5 Compound 24-4 (70 mg, 0.37 mmol), compound 1a (97 mg, 0.37 mmol) and tetraisopropyl titanate (1 mL) were stirred and reacted at 45°C for 16 hours. Sodium borohydride (30mg, 0.86mmol) was added and stirred at room temperature for 1h.
  • Example 25 N-methyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-25)
  • Step 1 The compound 12-8 (142 mg, 0.52 mmol) was dissolved in THF (10 mL) and water (2 mL), lithium hydroxide monohydrate (65 mg, 1.55 mmol) was added, and the reaction was stirred at room temperature for 2 h. The pH value of the reaction solution was adjusted to about 3 with 1M hydrochloric acid solution, and concentrated under reduced pressure to obtain compound 25-1 (127 mg). The crude product was used in the next step without purification. MS m/z (ESI): 246.1 [M+H] + .
  • Step 2 Add compound 25-1 (50mg), methylamine hydrochloride (137mg, 2.03mmol) and HATU (155mg, 0.41mmol) to DMF (10mL), then add DIEA (316mg, 2.44mmol), and react at room temperature overnight. Add EA (100 mL). The organic phase was washed with saturated brine (50mL x 1) and water (50mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The chromatographic system (DCM/methanol: 10/1 ) Purification to obtain compound 25-2 (31 mg, yield 59%) as a reddish brown oil. MS m/z (ESI): 259.1 [M+H] + .
  • Step 3 Dissolve compound 25-2 (31 mg, 0.12 mmol), compound 1a (40 mg, 0.15 mmol) and tetraisopropyl titanate (0.5 mL) in DCE (5 mL). After reacting at 50°C for 18 hours, sodium borohydride (30 mg, 0.79 mmol) was added, and the reaction was continued at 50°C for 2 hours. After cooling to room temperature, 1mL of water was added, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 26 N,N-Dimethyl-2-(7--((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-26)
  • Step 1 Using compound 25-1 and dimethylamine tetrahydrofuran solution as raw materials, the preparation method refers to step 1 in Example 25 to obtain compound 26-1. MS m/z (ESI): 273.1 [M+H] + .
  • Step 2 Using compound 26-1 and compound 1a as raw materials, the preparation method refers to step 2 in Example 25 to obtain compound H-26.
  • Example 27 N-isopropyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl (Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-27)
  • Step 1 Using compound 25-1 and isopropylamine hydrochloride as raw materials, the preparation method refers to step 1 in Example 25 to obtain compound 27-1. MS m/z (ESI): 287.2 [M+H] + .
  • Step 2 Using compound 27-1 and compound 1a as raw materials, the preparation method refers to step 2 in Example 25 to obtain compound H-27.
  • MS m/z(ESI):531.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD) ⁇ 8.51-8.48(m,1H),7.76-7.70(m,1H),7.45(dd, J 11.9, 8.1 Hz, 1H), 7.24-7.19 (m, 1H), 7.15-6.90 (m, 3H), 4.04-3.97 (m, 1H), 3.88-3.64 (m, 3H), 3.53-3.32 ( m, 2H), 3.10-2.96 (m, 3H), 2.86-2.65 (m, 2H), 2.46-2.36 (m, 3H), 2.14-1.83 (m, 5H), 1.75-1.24 (m, 10H), 1.15-1.08(m,7H), 0.78-0.61(m,1H).
  • Example 28 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-1-one (mixture of diastereomers H-28-1 and diastereomers Preparation of isomer mixture H-28-2)
  • Step 1 To a single port containing 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one hydrochloride (28-1) (80mg, 0.36mmol) Add DCM (3mL), DIEA (92.5mg, 0.72mmol) to the bottle, cool to 0°C, slowly add propionyl chloride (33.2mg, 0.36mmol) dropwise with stirring, continue stirring for 12 hours, LCMS shows that the reaction is complete, add water ( 5mL), extracted with DCM (20ml x 2), combined the organic phases, washed with saturated brine, dried, and concentrated to obtain a brown liquid.
  • Step 2 Dissolve 1-propionyl-1,2,3,8,9,9a-hexahydro-7H-benzoquinolin-7-one (28-2) (50mg, 0.2mmol) in DCE (5mL ), compound 1a (53.5 mg, 0.2 mmol) and tetraisopropyl titanate (0.5 mL) were reacted with stirring at 45°C for 16 hours.
  • Sodium borohydride 39mg, 1mmol
  • 20 mL of water was added to the reaction solution, filtered, and the filtrate was extracted with DCM (20 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude H-28.
  • Example 29 2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)-1-(pyrrolidin-1-yl)ethane-1-one (diastere Preparation of conformer mixture H-29-1 and diastereoisomer mixture H-29-2)
  • Step 1 Dissolve compound 25-1 (200mg, 0.82mmol) in 5mL DMF, add HATU (372mg, 0.98mmol) and pyrrolidine (289mg, 4.08mmol), DIPEA (315mg, 2.45mmol), stir at room temperature for reaction 12h. 10 mL of water was added to the reaction solution, and it was extracted with DCM (50 mL ⁇ 2). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM containing 10% methanol as the mobile phase) to obtain brown liquid compound 29-1 (200 mg, yield 82.3%).
  • DCM containing 10% methanol as the mobile phase
  • Step 2 Dissolve compound 29-1 (60 mg, 0.2 mmol) in DCE (5 mL), add compound 1a (52 mg, 0.2 mmol) and tetraisopropyl titanate (0.5 mL), stir and react at 45° C. for 16 hours. Add sodium borohydride (38mg, 1mmol) and stir at 30°C for 2h. Water (10 mL) was added to the reaction solution, filtered, and the filtrate was extracted with DCM (30 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude H-29.
  • Step 3 Purify and separate the crude H-29 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , The diastereomer mixture H-29-1 (37.03 mg, yield 34.1%, white solid) was obtained respectively.
  • Example 30 2-Cyclopropyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo(de)quinolin-1-yl)ethane-1-one (diastereomer mixture H- 30-1 and the preparation of diastereoisomer mixture H-30-2)
  • Step 1 Add 2-cyclopropylacetic acid (400 mg, 4.0 mmol) and thionyl chloride (3 mL, 41.3 mmol) to DCM (10 mL), and heat to reflux for 2 hours. After concentration under reduced pressure, the residue was dissolved in 10 mL of DCM, compound 28-1 (100 mg, 0.45 mmol) was added, and then DIEA (0.5 mL, 3.0 mmol) was added, and the reaction was carried out at room temperature overnight. It was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (DCM/7N ammonia methanol solution: 100/3) to obtain yellow solid compound 30-1 (50 mg, yield 42%). MS m/z (ESI): 270.1 [M+H] + .
  • Step 2 Dissolve compound 30-1 (50 mg, 0.19 mmol), compound 1a (58 mg, 0.22 mmol) and tetraisopropyl titanate (1 mL) in 10 mL DCE. After reacting at 50°C for 18 hours, sodium borohydride (50mg, 1.32mmol) was added, and the reaction was continued at 50°C for 1 hour. After cooling to room temperature, 1 mL of water was added, filtered, and the filtrate was concentrated under reduced pressure to obtain crude H-30.
  • sodium borohydride 50mg, 1.32mmol
  • Step 3 Purify and separate the crude H-30 by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30%-60% acetonitrile change )
  • the diastereoisomer mixture H-30-1 (white solid, 9.02 mg, yield 9.5%) was obtained respectively.
  • Step 1 Dissolve compound 12-7 (187 mg, 1 mmol) and TEA (110 mg, 1.1 mmol) in DCM (15 mL), add cyclopropaneyl chloride (104 mg, 1 mmol) dropwise under ice bath, and stir at room temperature for 2 h.
  • Step 2 Compound 31-1 (50 mg, 0.2 mmol) and compound 1a (51 mg, 0.2 mmol) were dissolved in DCE (10 mL), tetraisopropyl titanate (0.5 mL) was added, and the reaction was stirred at 45° C. for 18 h. After cooling to room temperature, sodium borohydride (30 mg, 0.8 mmol) was added to the reaction solution, stirred for 3 h, water (5 mL) was added to the reaction solution, stirred for 5 min, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound H-31.
  • Step 3 Purify and separate the crude H-31 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , Respectively obtain diastereoisomer mixture H-31-1 (13.44 mg, white solid, yield 13.5%).
  • Example 32 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-1-one (mixture of diastereomers H-32- 1 and the preparation of diastereoisomer mixture H-32-2)
  • Step 1 Using compound 12-7 and isopropanoyl chloride as raw materials, the preparation method refers to step 1 in Example 31 to obtain compound 32-1. MS m/z (ESI): 258.1 [M+H] + .
  • Step 2 Using compound 32-1 and compound 1a as raw materials, the preparation method refers to step 2 of Example 31, and concentrated under reduced pressure to obtain crude compound H-32.
  • Step 3 Purify and separate the crude H-32 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , The diastereomer mixture H-32-1 (65.8 mg, white solid, yield 43.8%) was obtained respectively.
  • Example 34 1-sec-butyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1 ,2,6,7,8,8a-Hexahydrobenzo[cd]indole-6-amine (mixture of diastereomers H-34-1, mixture of diastereomers H-34-2 And diastereoisomer mixture H-34-3) preparation
  • Step 2 Dissolve compound 34-1 (4.08 g, 18 mmol) in 70 mL TFA, add 10% wet Pd/C (2.5 g), replace with hydrogen three times, and then raise the temperature to 50° C. and stir for 18 h. Cool to room temperature, filter, and concentrate to obtain yellow solid compound 34-2 (2.95 g, yield: 71%). MS m/z (ESI): 230.3 [M+H] + .
  • Step 5 Compound 34-4 (150 mg, 0.31 mmol) was dissolved in absolute ethanol (15 mL), 10% wet Pd/C (70 mg) was added, replaced with hydrogen three times, then stirred at room temperature for 2 hours, filtered, and concentrated to obtain a yellow solid Compound 34-5 (130 mg, yield 86%). MS m/z (ESI): 488.3 [M+H] + .
  • Step 6 Dissolve compound 34-5 (130mg, 0.267mmol) in THF (15mL), add lithium aluminum hydride (30mg, 0.8mmol) under ice bath, heat to 50°C, stir for 1h, and use saturated ammonium chloride The aqueous solution was quenched, filtered, and concentrated to obtain the crude compound H-34.
  • Step 7 Purify and separate the crude H-34 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), The diastereomer mixture H-34-1MS m/z(ESI): 474.4[M+H] + was obtained respectively .
  • Example 35 N,N-Dimethyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionamide (H-35)
  • Step 1 Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline-7-hydrochloride (447mg, 2mmol), ethyl 2-bromopropionate to a single-mouth bottle (724 mg, 4 mmol), potassium carbonate (552 mg, 4 mmol), DMF (5 mL). Stir at 50 degrees for 12 hours. Cool to room temperature, add 20 mL of water, wash and extract with dichloromethane (50 mL x 2).
  • Step 2 Add water (5 mL) to lithium hydroxide monohydrate (84 mg, 2 mol) to dissolve, and pre-cool to (5 degrees). Add 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl) ethyl propionate (273mg , 1mol), methanol (5mL), tetrahydrofuran (10mL), add pre-cooled lithium hydroxide aqueous solution, stir for 2 hours, adjust the pH to about 3 with concentrated hydrochloric acid, extract with dichloromethane (80ml x 2), combine all The organic phase is washed with saturated brine, dried and concentrated to obtain the product 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propane Acid (220 mg, yield: 100%, white solid). MS m/z (ESI): 260.1 [M+H] + .
  • Step 3 Dissolve 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionic acid (100mg, 0.39mmol) In 5mL N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (293mg, 0.77 mmol) and dimethylamine tetrahydrofuran solution (1.93 mL, 3.86 mmol, 2M THF), N,N-diisopropylethylamine (149 mg, 1.16 mmol), and the reaction was stirred at room temperature for 12 hours.
  • 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionic acid 100mg, 0.39mmol
  • Step 4 Add N,N-dimethyl-2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propane Amide (29mg, 0.1mmol) was dissolved in 5 (mL) 1,2-dichloroethane, compound 1a (26mg, 0.1mmol) and tetraisopropyl titanate (0.5mL) were added, and the reaction was stirred at 45°C for 72 hours . Sodium borohydride (19mg, 0.5mmol) was added, stirred at 45°C and continued to react for 12 hours.
  • Example 36 N-(oxetan-3-yl)-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]deca (Alk-9-yl)ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-36)
  • Step 1 Dissolve 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetic acid (40mg, 0.16mmol) in In 3mL N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (123mg, 0.32mmol ) And oxetane-3-amine hydrochloride (36mg, 0.32mmol), N,N-diisopropylethylamine (63mg, 0.49mmol), and the reaction was stirred at room temperature for 12 hours.
  • Step 2 Add N-(oxetan-3-yl)-2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline- 1-yl)acetamide (20mg, 0.067mmol) was dissolved in 5 (mL) 1,2-dichloroethane, compound 1a (17mg, 0.067mmol) and tetraisopropyl titanate (0.5mL) were added, 45 The reaction was stirred at °C for 16 hours. Sodium borohydride (13 mg, 0.33 mmol) was added.
  • Example 37 1-(oxetan-3-yl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- (Yl)ethyl)-1,2,3,7,8,8a-hexahydrocyclopenta[[ij]isoquinolin-7-amine (H-37)
  • Step 1 Dissolve 1,2,3,4-tetrahydroisoquinoline (20g, 150mmol) in dichloromethane (50ml) solution, add N-bromosuccinimide (32g, 180mmol), room temperature The reaction was stirred for 1 hour. Sodium hydroxide (12.6g, 225mmol) and water (50ml) were added to the reaction solution, and the reaction was stirred at room temperature for 2 hours. The organic phase was concentrated under reduced pressure to obtain the target product 3,4-dihydroisoquinoline (23g) as a crude product. MS m/z (ESI): 133.1 [M+H] + .
  • Step 2 3,4-Dihydroisoquinoline (10g, 75.7mmol) was added to malonic acid (15.8g, 151.5mmol), and the reaction was stirred at 120°C for 3 hours.
  • the reaction solution was added with isopropanol (50ml) solution, stirred at 80°C for 30 minutes, and filtered.
  • the filter cake was washed with isopropanol to obtain the target product 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (11.6g) with a yield of 79%.
  • Step 3 Dissolve 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (1 g, 5.2 mmol) in PPA (10 g). The reaction was stirred at 150°C for 2 hours. Pour the reaction solution into ice water, add potassium carbonate to adjust the pH to 8, extract with dichloromethane/methanol (10/1), and concentrate the organic phase under reduced pressure to obtain the target compound 2,3,8,8a-tetrahydrocyclopenta[ij ] Isoquinoline-7(1H)-one (900mg), crude product. MS m/z (ESI): 174.1 [M+H] + .
  • Step 4 Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (200mg, 1.07mmol) in methanol (10ml) solution and add 3-oxa Cyclobutanone (154 mg, 2.14 mmol) and sodium cyanoborohydride (219 mg, 3.21 mmol) were stirred at room temperature overnight.
  • Step 5 Dissolve compound 1a (68mg, 0.26mmol) in 1,2-dichloroethane (5ml) solution, add 1-(oxetan-3-yl)-2,3,8,8a- Tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (60mg, 0.26mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (30 mg, 0.78 mmol), and stir at room temperature for 1 hour.
  • Example 38 1-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1 ,2,3,7,8,8a-hexahydrocyclopentyl[ij]isoquinoline-7-amine (H-38) preparation
  • Step 1 Dissolve 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (700mg, 3.66mmol) in acetone (10ml) solution, add acetic acid (0.5ml) and cyanogen Sodium borohydride (748mg, 11mmol) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a white solid, the solid was added with hydrochloric acid (3N) solution to adjust the pH to 5, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the target product 2-(2-isopropyl-1,2,3,4 -Tetrahydroisoquinolin-1-yl)acetic acid (300mg), crude product. MS m/z (ESI): 234.1 [M+H] + .
  • Step 2 Dissolve 2-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (300mg, 1.37mmol) in PPA (4ml) solution at 150°C The reaction was stirred for 2 hours. Pour the reaction solution into ice water, add potassium carbonate to adjust the pH to 8, extract with dichloromethane/methanol (10/1), and concentrate the organic phase under reduced pressure to obtain the target compound 1-isopropyl-2,3,8,8a- Tetrahydrocyclopentyl[ij]isoquinoline-7(1H)-one (500mg), crude product. MS m/z (ESI): 216.1 [M+H] + .
  • Step 3 Dissolve compound 1a (84mg, 0.32mmol) in 1,2-dichloroethane (5ml) solution, add 1-isopropyl-2,3,8,8a-tetrahydrocyclopentyl[ij ] Isoquinoline-7(1H)-one (70mg, 0.32mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (37 mg, 0.96 mmol), and stir at room temperature for 1 hour.
  • Example 39 2-Methyl-3-(7-(((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)butan-2-ol (mixture of diastereomers H-39 -1 and the preparation of diastereoisomer mixture H-39-2)
  • Step 1 Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline-7-hydrochloride (447mg, 2mmol), ethyl 2-bromopropionate to a single-mouth bottle (724 mg, 4 mmol), potassium carbonate (552 mg, 4 mmol), DMF (5 mL). Stir at 50 degrees for 12 hours. Cool to room temperature, add 20 mL of water, wash and extract with dichloromethane (50 mL x 2).
  • Step 2 Dissolve compound 35-1-a (50mg, 0.17mmol) in 5 (mL) 1,2-dichloroethane, add compound 1a (45.3mg, 0.17mmol) and tetraisopropyl titanate ( 0.5mL), the reaction was stirred at 45°C for 24 hours. Sodium borohydride (33 mg, 0.87 mmol) was added. Stirring was continued at 45°C for 2 hours.
  • Step 3 Dissolve compound 35-1-b (150mg, 0.52mmol) in 5 (mL) 1,2-dichloroethane, add compound 1a (136mg, 0.52mmol) and tetraisopropyl titanate (0.5 mL), the reaction was stirred at 45°C for 24 hours. Sodium borohydride (99 mg, 2.61 mmol) was added. Stirring was continued at 45°C for 2 hours.
  • Step 4 Under the protection of nitrogen, add tetrahydrofuran (20 mL), compound 39-a (10 mg, 0.019 mmol) to a three-necked flask (50 mL) at 0°C. Slowly add methylmagnesium iodide (0.2mL, 0.19mmol, 1mol/L) dropwise, after the dropwise addition is complete, continue stirring for 6 hours. Pour into ice water (20mL), extract with dichloromethane (50ml x 2), combine the organic phases, wash with saturated brine, dry, and concentrate to obtain a brown liquid.
  • tetrahydrofuran 20 mL
  • compound 39-a 10 mg, 0.019 mmol
  • methylmagnesium iodide 0.2mL, 0.19mmol, 1mol/L
  • Step 5 Add tetrahydrofuran (10 mL), compound 39-b (30 mg, 0.056 mmol) to a three-necked flask (50 mL) under the protection of nitrogen at 0°C. Slowly add methylmagnesium iodide (1.5mL, 0.56mmol, 1mol/L) dropwise, after the dropwise addition is complete, continue stirring for 6 hours. Pour into ice water (20mL), extract with dichloromethane (50ml x 2), combine the organic phases, wash with saturated brine, dry, and concentrate to obtain a brown liquid.
  • methylmagnesium iodide 1.5mL, 0.56mmol, 1mol/L
  • Example 40 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-3,7,8,8a-tetrahydrocyclopentyl[ij]isoquinoline-1(2H)-yl)propan-2-ol (H-40)
  • Step 1 Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (300mg, 1.73mmol) in 2,2-dimethylethylene oxide ( 4ml) solution, add cesium carbonate (569mg, 1.73mmol), stir at 80°C overnight.
  • Step 2 Dissolve compound 1a (147mg, 0.57mmol) in 1,2-dichloroethane (10ml) solution, add 1-(2-hydroxy-2-methylpropyl)-2,3,8, 8a-Tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (140mg, 0.57mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (65 mg, 1.71 mmol), and stir at room temperature for 1 hour.
  • Example 41 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-3 ,7,8,8a-Tetrahydrocyclopentan[ij]isoquinoline-1(2H)-yl)propan-1-one (H-41)
  • Step 1 Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (100mg, 0.58mmol) in dichloromethane (10ml) solution at 0°C Add triethylamine (118 mg, 1.16 mmol) and propionyl chloride (64 mg, 0.7 mmol), and stir at 0°C for 2 hours.
  • Step 2 Dissolve compound 1a (136mg, 0.52mmol) in 1,2-dichloroethane (10ml) solution, add 1-propionyl-2,3,8,8a-tetrahydrocyclopentane [ij] Isoquinolin-7(1H)-one (120mg, 0.52mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (60 mg, 1.56 mmol), and stir at room temperature for 1 hour.
  • Step 1 Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (140mg, 0.81mmol) in dichloromethane (10ml) solution at 0°C Add triethylamine (123mg, 1.2mmol) and cyclopropane acid chloride (101mg, 0.97mmol), and stir at 0°C for 2 hours.
  • Step 2 Dissolve compound 1a (129mg, 0.5mmol) in 1,2-dichloroethane (10ml) solution, add 1-(cyclopropanecarbonyl)-2,3,8,8a-tetrahydrocyclopentane [ij] Isoquinoline-7(1H)-one (120mg, 0.5mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (57 mg, 1.5 mmol), and stir at room temperature for 1 hour.
  • Step 1 To 2,3,9,9a-tetrahydro-1H-benzo[de]quinoline-7(8H)-one (187mg, 1mmol) in THF (20ml) was added 3-pentanone (344mg , 4mmol) and 1M zinc chloride ether solution (2ml). After stirring at room temperature for 0.5 hours, sodium cyanoborohydride (372mg, 6mmol) was added. Warm up to 55 degrees and stir overnight. Cool to room temperature, dilute with ethyl acetate, wash with water, saturated sodium chloride aqueous solution, dry, and concentrate.
  • Step 2 Combine 1-(pentyl-3-yl)-2,3,9,9a-tetrahydro-1H-benzo[de]quinoline-7(8H)-one (51mg, 0.20mmol) and compound 1a (52mg, 0.20mmol) was dissolved in 15mL 1,2-dichloroethane, 1mL tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (30mg, 0.8mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 2ml of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure.
  • sodium borohydride (30mg, 0.8mmol)
  • Example 44 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-2-ol (mixture of diastereomers H-44- 1 and the preparation of diastereoisomer mixture H-44-2)
  • Step 1 Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol), cesium carbonate (326mg, 1.0m) to 50ml sealed tube mol) and 10mL 2,2-dimethylethylene oxide, the mixture was stirred overnight in a 100°C oil bath, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated sodium chloride aqueous solution, dried, and concentrated.
  • Step 2 Add 1-(2-hydroxy-2-methylpropyl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (100mg, 0.386mmol) and compound 1a (100mg, 0.386mmol) were dissolved in 20mL of 1,2-dichloroethane, 1mL of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours.
  • Step 3 Purify the crude H-44 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain Diastereoisomer mixture H-44-1 (53 mg, white solid); MS m/z (ESI): 504.4 [M+H] + .
  • Example 45 1-(oxetan-3-yl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- (Base) ethyl)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-7-amine (diastereomeric mixture H-45-1 and non-pair Preparation of mixture of enantiomers H-45-2)
  • Step 1 Add 3-oxo heterocycle to 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol) in THF (20ml) solution Butanone (216mg, 3mmol) and 1M zinc chloride ether solution (2ml) were stirred at room temperature for 0.5 hours, and sodium cyanoborohydride (310mg, 5mmol) was added. Warm up to 55 degrees and stir overnight. Cool to room temperature, dilute with ethyl acetate, wash with water, saturated sodium chloride aqueous solution, dry, and concentrate.
  • Step 2 Add 1-(oxetan-3-yl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (50mg, 0.2mmol ) And compound 1a (52mg, 0.20mmol) were dissolved in 15mL 1,2-dichloroethane, 1mL tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (30mg, 0.8mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 3 mL of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure to obtain crude H- 45.
  • sodium borohydride (30mg, 0.8mmol)
  • Step 3 Purify the crude H-45 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain respectively Diastereoisomer mixture H-45-1 (3 mg, white solid); MS m/z (ESI): 488.4 [M+H] + .
  • Step 1 Dissolve methyl 2-(cyanomethyl)benzoate (1.75g, 10m mol) and tert-butyl bromoacetate (2.9g, 15m mol) in 30mL of dry N,N-dimethylformamide Sodium hydride (0.8g, 20mmol) was added under ice bath and stirred at room temperature for 18 hours. Dilute with ethyl acetate (100ml), wash with water (50mL ⁇ 2), wash with saturated brine (30mL ⁇ 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (petroleum ether).
  • Step 2 Methyl 2-(3-(tert-butoxy)-1-cyano-3-oxopropyl)benzoate (1.44g, 5mmol) was dissolved in 70mL ethanol, and 10% wet Pd/C( 0.6g), replaced with hydrogen three times, and stirred at room temperature for 18 hours. Filtered and concentrated to obtain tert-butyl 2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1.18 g, yellow solid), yield: 91%. MS m/z (ESI): 262.3 [M+H] + .
  • Step 3 Dissolve tert-butyl 2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1.18g, 4.55m mol) in 25mL dry N,N -In dimethylformamide, sodium hydride (0.36g, 9.1mmol) was added under ice bath, after stirring for 15 minutes, ethyl iodide (0.85g, 5.46mmol) was added, and stirring was carried out at room temperature for 18 hours. Dilute with ethyl acetate (100ml), wash with water (40mL ⁇ 2), wash with saturated brine (30mL ⁇ 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Step 4 To the round bottom containing 2-(2-ethyl-1-oxo1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid tert-butyl ester (1g, 3.46m mol) Add PPA (about 30ml) to the flask, gradually increase the temperature to 140 degrees, stir for 1 hour, cool to room temperature, dilute with ethyl acetate (100ml), wash with water (50mL ⁇ 2), and wash with saturated brine (30mL ⁇ 1).
  • PPA about 30ml
  • Step 5 Dissolve 2-ethyl-2,3,3a,4-tetrahydrocyclopenta[de]isoquinoline-1,5-dione (100mg, 0.46mmol) and compound 1a (121mg, 0.46mmol) To 20ml of 1,2-dichloroethane, 1.5ml of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours.
  • Step 6 Add 2-ethyl-5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]deccan-9-yl)ethyl)amino) -3,3a,4,5-Tetrahydrocyclopenta[de]isoquinoline-1(2H)-one (90mg, 0.196mmol) was dissolved in 20ml dry tetrahydrofuran, under ice bath, added lithium aluminum hydride (15mg, 0.39mmol), heated to 50°C, stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution under ice cooling, filtered, concentrated, and used preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mMNH 4 HCO 3 H 2 O (wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) was purified to obtain compound H-46 (3 mg), MS m/z (ESI): 446.3
  • Step 1 Dissolve 2,3,3a,4-tetrahydrocyclopenta[de]isoquinoline-1,5-dione (100mg, 0.53mmol) and compound 1a (139mg, 0.53mmol) in 25ml of 1, Add 1.5 mL of tetraisopropyl titanate to 2-dichloroethane, and stir and react at 45°C for 18 hours.
  • Step 2 Add 5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-3,3a, 4,5-Tetrahydrocyclopenta[de]isoquinoline-1(2H)-one (130mg, 0.3mmol) was dissolved in 25ml of acetonitrile, potassium carbonate (83mg, 0.6mol) and benzyl bromide (77mg, 0.45 mol), stirring at 70°C for 18 hours.
  • Step 5 N-benzyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-( 2,2,2-Trifluoroethyl)-1,2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (70mg, 0.119mmol) dissolved in 15mL of absolute ethanol Add 10% wet Pd/C (30mg), replace with hydrogen three times, then stir at room temperature for 3 hours, filter, concentrate, and use preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) purification to obtain compound H-47 (26 mg, white solid), yield: 44%.
  • Example 48 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)ethan-1-one( H-48) Preparation
  • Step 1 Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol) and 2-(1-(trifluoromethyl) ring Add HATU (380mg, 1mmol) and triethylamine (110mg, 1.1mmol) to a solution of propyl)acetic acid (168mg, 1mmol) in dichloromethane (20ml). After stirring for 18 hours at room temperature, the reaction solution was washed with water, dried and concentrated. .
  • Step 2 Add 1-(2-(1-(trifluoromethyl)cyclopropyl)acetyl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline -7-one (67 mg, 0.2 mmol) and compound 1a (52 mg, 0.20 mmol) were dissolved in 15 mL of 1,2-dichloroethane, 1 mL of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours.
  • the cell line used in the following test example is CHO-K1 OPRM1 ⁇ -Arrestin Cell Line, source: DiscoverX, number: 93-0213C2, batch number: 13K0402.
  • the cells are digested and subcultured with cell digestion solution.
  • 1 ⁇ Stimulation buffer Take 1ml of 5 ⁇ Stimulation buffer and add it to 4ml of distilled water, and mix well.
  • 50uM NK477 1ml Take 1ul 50mM NKH477 storage solution and add it to 999ul 1 ⁇ Stimulation buffer solution, shake and mix well.
  • cAMP-Cryptate (donor, lyophilized) reaction solution Take 1ml of 5 ⁇ cAMP-Cryptate stock solution and add it to 4ml of 1 ⁇ Lysis&Detection Buffer, and mix gently.
  • Anti-cAMP-d2 (receptor, lyophilized) reaction solution Take 1ml of 5 ⁇ Anti-cAMP-d2 storage solution and add it to 4ml of 1 ⁇ Lysis&Detection Buffer, and mix gently.
  • the cells are digested and subcultured with cell digestion solution.
  • the compound Before the compound is diluted, the compound is dissolved in DMSO to a storage concentration of 10mM.
  • the best fit curve is log(agonist) vs.response.
  • Table 2 The results are shown in Table 2:
  • the representative compound of the present invention has a higher inhibitory activity against cAMP and a higher Emax value.
  • the compound of the present invention has a lower Emax value for ⁇ -arrestin, and has a good bias.

Abstract

Provided are a tricyclic substituted oxaspiro derivative, a preparation method therefor, and a pharmaceutical use thereof. In particular, compounds of formula (I) and formula (II) or pharmaceutically acceptable salts, stereoisomers, or solvates thereof, preparation methods therefor, and uses thereof are disclosed.

Description

三环取代的氧杂螺环衍生物、其制法与医药上的用途Tricyclic substituted oxaspiro derivative, its preparation method and medical use 技术领域Technical field
本发明涉及一类三环取代的氧杂螺环衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂，特别是作为MOR受体激动剂和在制备治疗和预防疼痛等相关疾病的药物中的用途。The present invention relates to a class of tricyclic substituted oxaspiro derivatives, their preparation methods and pharmaceutical compositions containing the derivatives, and their use as therapeutic agents, especially as MOR receptor agonists and in the preparation of treatment and prevention of pain, etc. Use in medicine for related diseases.
背景技术Background technique
阿片受体是一类重要的G蛋白偶联受体(G protein coupled receptor,GPCR)，是内源性阿片肽及阿片类药物结合的靶点，内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类。中枢神经系统中存在其相应的阿片受体，即μ(MOR)、δ(DOR)、κ(KOR)受体等。研究发现，内源性阿片肽镇痛作用的强弱，主要取决于阿片受体表达的多少，阿片受体是阿片类药物以及内源性阿片肽镇痛作用的靶点。Opioid receptors are an important type of G protein-coupled receptor (GPCR), which is the target of the binding of endogenous opioid peptides and opioid drugs. Endogenous opioid peptides are naturally produced in mammals. Opioid active substances, the currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins and neoorphins. There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), κ (KOR) receptors and so on. Studies have found that the analgesic effects of endogenous opioid peptides are mainly determined by the expression of opioid receptors, which are the targets of opioid drugs and endogenous opioid peptides.
目前的研究认为，GPCR介导及调控生理功能，主要经由两条途径：G蛋白途径和β-arrestin途径。传统的GPCR激动剂与受体结合后，激活G蛋白信号途径，包括钙离子等第二信使系统、腺苷酸环化酶(adenyl cyclase，AC)、丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)等，而β-arrestin偏爱性配体则主要激活β-arrestin途径。而β-arrestin介导的GPCR反应主要包括3个方面：1)作为负性调控因子，与G蛋白偶联受体激酶(GRK)作用，使GPCRs发生受体脱敏反应，中止G蛋白信号转导；2)作为支架蛋白(scaffold protein)，募集胞吞蛋白，诱导GPCR内吞；3)作为接头蛋白，与GPCR下游信号分子形成复合物，以G蛋白非依赖的方式激活信号转导分子，如MAPK、Src蛋白酪氨酸激酶和Akt等。配体刺激G蛋白信号和/或β-arrestin信号的差异，最终决定了GPCR的配体特异性细胞生物学效应。Current research believes that GPCR mediates and regulates physiological functions mainly through two pathways: the G protein pathway and the β-arrestin pathway. After the traditional GPCR agonist binds to the receptor, it activates the G protein signal pathway, including calcium ion and other second messenger systems, adenyl cyclase (AC), and mitogen-activated protein kinase (mitogen-activated protein). kinases, MAPK), etc., while β-arrestin preferential ligands mainly activate the β-arrestin pathway. The β-arrestin-mediated GPCR reaction mainly includes three aspects: 1) As a negative regulator, it interacts with G protein-coupled receptor kinase (GRK) to desensitize GPCRs and stop G protein signal transduction. 2) As a scaffold protein (scaffold protein), it recruits endocytosis protein and induces GPCR endocytosis; 3) As a linker protein, it forms a complex with GPCR downstream signal molecules to activate signal transduction molecules in a G protein-independent manner, Such as MAPK, Src protein tyrosine kinase and Akt. The difference of ligand-stimulated G protein signal and/or β-arrestin signal ultimately determines the ligand-specific cellular biological effects of GPCR.
MOR是内源性脑啡肽和吗啡等阿片类镇痛药物的作用靶点。早期研究显示，内源性脑啡肽和阿类药物埃托啡可以激动G蛋白并引发受体内吞，但是吗啡却完全不会引发受体的内吞，这是因为吗啡激动MOR磷酸化的能力太弱，仅能募集微量的β-arrestin于膜上(Zhang等，Proc Natl Acad Sci USA,1998,95(12):7157-7162)。此类配体完全通过G蛋白信号通路而不是β-arrestin途径来发挥其生理功能。研究发现给β-arrestin2基因敲除小鼠注射吗啡后，由G蛋白信号介导的镇痛效果更强且维持时间更长(Bohn等，Science，1999年)。可以预见，如果此类配体的负性β-arrestin偏爱性更强，甚至可以逃脱β-arrestin介导的受体脱敏，则可导致G蛋白信号传递时间延长，产生更强大的镇痛作用。MOR is the target of opioid analgesics such as endogenous enkephalin and morphine. Early studies have shown that endogenous enkephalin and the opioid drug etorphine can stimulate G protein and trigger receptor endocytosis, but morphine does not trigger receptor endocytosis at all. This is because morphine stimulates MOR phosphorylation. The ability is too weak and can only recruit a small amount of β-arrestin on the membrane (Zhang et al., Proc Natl Acad Sci USA, 1998, 95(12): 7157-7162). Such ligands exert their physiological functions entirely through the G protein signaling pathway instead of the β-arrestin pathway. Studies have found that after injection of morphine into β-arrestin2 gene knockout mice, the analgesic effect mediated by G protein signal is stronger and lasts longer (Bohn et al., Science, 1999). It is foreseeable that if the negative β-arrestin preference of such ligands is stronger and can even escape β-arrestin-mediated receptor desensitization, it may lead to a longer time for G protein signal transmission and a stronger analgesic effect. .
目前公开的MOR激动剂专利申请包括WO2017106547、WO2017063509、WO2012129495、WO2017106306等。Currently published patent applications for MOR agonists include WO2017106547, WO2017063509, WO2012129495, WO2017106306, and so on.
阿片类药物长期使用会产生耐受以及呼吸抑制、便秘等副作用，而这些副作用被证明与β-arrestin的功能密切相关。为了减小阿片类药物的副作用，可基于MOR的负性β-arrestin偏 爱性配体设计药物，使β-arrestin介导的副作用降低，增强治疗效果。Long-term use of opioids can produce side effects such as tolerance, respiratory depression and constipation, and these side effects have been shown to be closely related to the function of β-arrestin. In order to reduce the side effects of opioids, drugs can be designed based on the negative β-arrestin preference ligand of MOR to reduce the side effects mediated by β-arrestin and enhance the therapeutic effect.
发明内容Summary of the invention
本发明的目的是提供一种结构新颖的可作为MOR受体激动剂的化合物。The purpose of the present invention is to provide a compound with a novel structure that can be used as a MOR receptor agonist.
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体或溶剂化物：The first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
Figure PCTCN2020072851-appb-000001
Figure PCTCN2020072851-appb-000001
式中，In the formula,
R a为取代或未取代的C 6-10芳基、或取代或未取代的5或6元单环杂芳基； R a is a substituted or unsubstituted C 6-10 aryl group, or a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl group;
R b为氢或取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)； R b is hydrogen or substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl);
W 1为一个键，或C(R cR d)； W 1 is a bond, or C(R c R d );
W 2为C(R eR f)、NR g或O； W 2 is C(R e R f ), NR g or O;
R c、R d、R e、R f各自独立地为氢、羟基、卤素、氰基、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)或NR 11R 12； R c, R d, R e , R f are each independently hydrogen, hydroxy, halo, cyano, a substituted or unsubstituted C 1-10 alkyl group (preferably a substituted or unsubstituted C 1-6 alkyl, More preferably substituted or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-6 alkoxy) (Substituted C 1-3 alkoxy) or NR 11 R 12 ;
R g为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、-COC 1-10烷基(优选为-COC 1-6烷基，更优选为-COC 1-3烷基)、-CONR 11R 12、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)； R g is hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl), -COC 1 -10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -SO 2 C 1-10 alkyl (preferably -SO 2 C 1 -6 alkyl, more preferably -SO 2 C 1-3 alkyl);
Z 1为N或CR 1； Z 1 is N or CR 1 ;
Z 2为NR 2、O或C(R 3R 4)； Z 2 is NR 2 , O or C (R 3 R 4 );
Z 3为C(R 5R 6)、NR 7或O； Z 3 is C(R 5 R 6 ), NR 7 or O;
Z 4为C(R 8R 9)、NR 10或O； Z 4 is C(R 8 R 9 ), NR 10 or O;
W 2、Z 1、Z 2、Z 3、Z 4不同时含杂原子，且W 2、Z 1不同时含杂原子，Z 1、Z 2不同时含杂原子，Z 2、Z 3、Z 4不同时含两个或以上的杂原子； W 2 , Z 1 , Z 2 , Z 3 , Z 4 do not contain heteroatoms at the same time, and W 2 , Z 1 do not contain heteroatoms at the same time, Z 1 , Z 2 do not contain heteroatoms at the same time, Z 2 , Z 3 , Z 4 Do not contain two or more heteroatoms at the same time;
R 1为氢或取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)； R 1 is hydrogen or substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl);
R 2、R 7、R 10各自独立地为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-10烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、取代或未取代的C 3-8环烷基(优选为取代或未取代的C 3-6环烷基)或-(CR 21R 22) p-L 1；L 1为C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-COC 1-10烷基(优选为-COC 1-6烷基，更优选为-COC 1-3烷基)、-COC 3-8环烷基(优选为-COC 3-6环烷基)、-CONR 11R 12、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-CO-(CR 21R 22) u-(CR 23R 24)C 1-10烷基(优选为-CO-(CR 21R 22) u-(CR 23R 24)C 1-6烷基，更优选为-CO-(CR 21R 22) u-(CR 23R 24)C 1-3烷基)、-(CR 23R 24)C 1-10烷基(优选为-(CR 23R 24)C 1-6烷基，更优选为-(CR 23R 24)C 1-3烷基)、-(CR 23R 24)CN、-(CR 23R 24)OH或-(CR 23R 24)C 1-10烷氧基(优选为-(CR 23R 24)C 1-6烷氧基，更优选为-(CR 23R 24)C 1-3烷氧基)； R 2 , R 7 , and R 10 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1 -3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy) , Halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1 -6 alkoxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or- (CR 21 R 22 ) p -L 1 ; L 1 is C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy) , More preferably C 1-3 alkoxy), -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -COC 3-8 cycloalkane Group (preferably -COC 3-6 cycloalkyl), -CONR 11 R 12 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably- C(O)OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-10 alkyl (preferably -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-6 alkyl, more preferably -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-3 alkyl), -(CR 23 R 24 )C 1-10 alkyl (preferably -(CR 23 R 24 )C 1-6 alkyl, more preferably -(CR 23 R 24 )C 1-3 alkyl), -(CR 23 R 24 )CN, -(CR 23 R 24 )OH or -(CR 23 R 24 )C 1-10 alkoxy (preferably -(CR 23 R 24 )C 1-6 alkoxy, more preferably -(CR 23 R 24 )C 1-3 alkoxy);
R 3、R 4各自独立地为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-10烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、取代或未取代的C 3-8环烷基(优选为取代或未取代的C 3-6环烷基)或-(CR 31R 32) q-L 2；L 2为C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-COC 1-10烷基(优选为-COC 1-6烷基，更优选为-COC 1-3烷基)、-CONR 11R 12、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 33R 34)C 1-10烷基(优选为-(CR 33R 34)C 1-6烷基，更优选为-(CR 33R 34)C 1-3烷基)、-(CR 33R 34)CN、-(CR 33R 34)OH或-(CR 33R 34)C 1-10烷氧基(优选为-(CR 33R 34)C 1-6烷氧基，更优选为-(CR 33R 34)C 1-3烷氧基)；或者R 3、R 4与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)； R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 31 R 32 ) q -L 2 ; L 2 is C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably Is C 1-3 alkoxy), -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C(O )OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 33 R 34 ) C 1-10 alkyl (preferably -(CR 33 R 34 )C 1-6 alkyl, more preferably -(CR 33 R 34 )C 1-3 alkyl), -(CR 33 R 34 )CN , -(CR 33 R 34 )OH or -(CR 33 R 34 )C 1-10 alkoxy (preferably -(CR 33 R 34 )C 1-6 alkoxy, more preferably -(CR 33 R 34 ) C 1-3 alkoxy); or R 3 , R 4 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring; the 3 to 6-membered saturated monocyclic ring The ring or 3 to 6-membered saturated monocyclic ring is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
R 5、R 6各自独立地为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-10烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、取代或未取代的C 3-8环烷基(优选为取代或未取代的C 3-6环烷基)或-(CR 51R 52) r-L 3；L 3为C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-COC 1-10烷基(优选为-COC 1-6烷基，更优选为-COC 1-3烷基)、-CONR 11R 12、-C(O)OC 1-10烷基(优 选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 53R 54)C 1-10烷基(优选为-(CR 53R 54)C 1-6烷基，更优选为-(CR 53R 54)C 1-3烷基)、-(CR 53R 54)CN、-(CR 53R 54)OH或-(CR 53R 54)C 1-10烷氧基(优选为-(CR 53R 54)C 1-6烷氧基，更优选为-(CR 53R 54)C 1-3烷氧基)；或者R 5、R 6与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基、C 1-10烷基、卤代C 1-10烷基； R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 51 R 52 ) r -L 3 ; L 3 is C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably Is C 1-3 alkoxy), -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C(O )OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 53 R 54 )C 1-10 alkyl (preferably -(CR 53 R 54 )C 1-6 alkyl, more preferably -(CR 53 R 54 )C 1-3 alkyl), -(CR 53 R 54 )CN , -(CR 53 R 54 )OH or -(CR 53 R 54 )C 1-10 alkoxy (preferably -(CR 53 R 54 )C 1-6 alkoxy, more preferably -(CR 53 R 54 ) C 1-3 alkoxy); or R 5 , R 6 and the connected carbon atoms together form a 3- to 6-membered saturated monocyclic ring or a 3- to 6-membered saturated monocyclic ring; the 3- to 6-membered saturated monocyclic The ring or 3 to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy, C 1-10 alkyl, halogenated C 1- 10 alkyl;
R 8、R 9各自独立地为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-10烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、取代或未取代的C 3-8环烷基(优选为取代或未取代的C 3-6环烷基)或-(CR 81R 82) m-L 4；L 4为C 3-8环烷基(优选为C 3-6环烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-COC 1-10烷基(优选为-COC 1-6烷基，更优选为-COC 1-3烷基)、-CONR 11R 12、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 83R 84)C 1-10烷基(优选为-(CR 83R 84)C 1-6烷基，更优选为-(CR 83R 84)C 1-3烷基)、-(CR 83R 84)CN、-(CR 83R 84)OH或-(CR 83R 84)C 1-10烷氧基(优选为-(CR 83R 84)C 1-6烷氧基，更优选为-(CR 83R 84)C 1-3烷氧基)；或者R 8、R 9与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)； R 8 and R 9 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkane Group), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-10 alkoxy (preferably halogenated C 1-6 alkane Oxy, more preferably halogenated C 1-3 alkoxy), substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl) or -(CR 81 R 82 ) m -L 4 ; L 4 is C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably Is C 1-3 alkoxy), -COC 1-10 alkyl (preferably -COC 1-6 alkyl, more preferably -COC 1-3 alkyl), -CONR 11 R 12 , -C(O )OC 1-10 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 83 R 84 )C 1-10 alkyl (preferably -(CR 83 R 84 )C 1-6 alkyl, more preferably -(CR 83 R 84 )C 1-3 alkyl), -(CR 83 R 84 )CN , -(CR 83 R 84 )OH or -(CR 83 R 84 )C 1-10 alkoxy (preferably -(CR 83 R 84 )C 1-6 alkoxy, more preferably -(CR 83 R 84 ) C 1-3 alkoxy group); or R 8 , R 9 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring; the 3 to 6-membered saturated monocyclic ring The ring or 3 to 6-membered saturated monocyclic ring is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
R 01、R 02、R 03、R 04各自独立地为氢、羟基、氰基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)； R 01 , R 02 , R 03 , and R 04 are each independently hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, More preferably substituted or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-6 alkoxy) Substituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
R 21、R 22相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、-NR 11R 12、-NR 13COC 1-10烷基(优选为-NR 13COC 1-6烷基，更优选为-NR 13COC 1-3烷基)或-NR 13SO 2R 0； R 21 and R 22 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
R 31、R 32相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、-NR 11R 12、-NR 13COC 1-10烷基(优选为 -NR 13COC 1-6烷基，更优选为-NR 13COC 1-3烷基)或-NR 13SO 2R 0； R 31 and R 32 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
R 51、R 52相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、-NR 11R 12、-NR 13COC 1-10烷基(优选为-NR 13COC 1-6烷基，更优选为-NR 13COC 1-3烷基)或-NR 13SO 2R 0； R 51 and R 52 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
R 81、R 82相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、-NR 11R 12、-NR 13COC 1-10烷基(优选为-NR 13COC 1-6烷基，更优选为-NR 13COC 1-3烷基)或-NR 13SO 2R 0； R 81 and R 82 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted Or unsubstituted C 1-3 alkyl), substituted or unsubstituted C 1-10 alkoxy (preferably substituted or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1 -3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 alkyl) or -NR 13 SO 2 R 0 ;
R 23、R 24与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 23 , R 24 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
R 33、R 34与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 33 , R 34 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
R 53、R 54与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 53 , R 54 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
R 83、R 84与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 83 , R 84 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
R 0为取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)、NR 11R 12、或取代或未取代的C 3-8环烷基(优选为取代或未取代的C 3-6环烷基)； R 0 is substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl), NR 11 R 12 , Or substituted or unsubstituted C 3-8 cycloalkyl (preferably substituted or unsubstituted C 3-6 cycloalkyl);
R 11、R 12各自独立地为氢、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、取代或未取代的3至6元饱和或不饱和单杂环；或者R 11、R 12与相连的氮原子形成取代或未取代的4至6元饱和或不饱和单杂环； R 11 and R 12 are each independently hydrogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-10 alkyl (preferably halogen Substituted C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring; or R 11 , R 12 and the connected nitrogen atom form A substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring;
R 13各自独立地为氢、取代或未取代的C 1-10烷基(优选为取代或未取代的C 1-6烷基，更优选为取代或未取代的C 1-3烷基)或卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)； R 13 is each independently hydrogen, substituted or unsubstituted C 1-10 alkyl (preferably substituted or unsubstituted C 1-6 alkyl, more preferably substituted or unsubstituted C 1-3 alkyl) or Halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl);
u为0、1或2；u is 0, 1 or 2;
p、q、r、m各自独立地为0、1、2或3；p, q, r, and m are each independently 0, 1, 2 or 3;
t为0或1；t is 0 or 1;
n为1、2或3；n is 1, 2 or 3;
所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
所述L 1、L 2、L 3、L 4中的C 3-8环烷基、C 1-10烷氧基、-COC 1-10烷基、-C(O)OC 1-10烷基、-SO 2C 1-10烷基和4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代； C 3-8 cycloalkyl, C 1-10 alkoxy, -COC 1-10 alkyl, -C(O)OC 1-10 alkyl in L 1 , L 2 , L 3 , L 4 , -SO 2 C 1-10 alkyl and 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from Group A;
所述A组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤素(优选为F或Cl)、硝基、C 6-10芳基(优选苯基)、5或6元单环杂芳基、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。 The group A substituents are selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halo (C 1-3 alkyl), halogen (preferably F or Cl), nitro, C 6-10 aryl (preferably phenyl), 5 or 6-membered monocyclic heteroaryl, C 1-10 alkyl (Preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl), -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -CHO, -OC(O ) C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 aryl, such as -SO 2 -benzene Group), -COC 6-10 aryl (preferably -COC 6 aryl, such as -CO-phenyl), 4 to 6-membered saturated or unsaturated monocyclic ring or 4 to 6-membered saturated or unsaturated monocyclic ring, Wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在另一优选例中，
Figure PCTCN2020072851-appb-000002
为
Figure PCTCN2020072851-appb-000003
In another preferred example,
Figure PCTCN2020072851-appb-000002
for
Figure PCTCN2020072851-appb-000003
在另一优选例中，R a中所述C 6-10芳基为苯基；所述5或6元单环杂芳基为吡啶。 In another preferred embodiment, in the R a C 6-10 aryl group is a phenyl group; a 5 or 6 membered monocyclic heteroaryl is pyridine.
在另一优选例中，
Figure PCTCN2020072851-appb-000004
为
Figure PCTCN2020072851-appb-000005
In another preferred example,
Figure PCTCN2020072851-appb-000004
for
Figure PCTCN2020072851-appb-000005
在另一优选例中，所述A组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-3烷基、卤素(优选为F或Cl)、硝基、苯基、5或6元单环杂芳基、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、C 3-6环烷氧基、C 2-4烯基、C 2-4炔基、-CONR a0R b0、-C(O)OC 1-3烷基、-CHO、-OC(O)C 1-3烷基、-SO 2C 1-3烷基、-SO 2-苯基、-CO-苯基、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。 In another preferred example, the group A substituent is selected from: cyano, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogenated C 1-3 alkyl, halogen (preferably F or Cl ), nitro, phenyl, 5- or 6-membered monocyclic heteroaryl, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -CHO, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 -phenyl, -CO-phenyl, 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring or 4 to 6-membered saturated or unsaturated monocyclic ring, wherein R a0 , R b0 are each Independently hydrogen or C 1-3 alkyl.
在另一优选例中，A组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、氟、氯、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙基、环丁基、环戊基、环己基、-CONR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、-SO 2C 1-3烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃，其中R a0、R b0各自独立地为氢或C 1-3烷基。 In another preferred embodiment, the group A substituent is selected from: cyano, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl Group, difluoroethyl, trifluoroethyl, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, -CONR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, -SO 2 C 1-3 Alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide Or tetrahydropyran, wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
在另一优选例中，R a为取代或未取代的吡啶；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred example, Ra is a substituted or unsubstituted pyridine; the "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R a为取代或未取代的苯基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred example, R a is a substituted or unsubstituted phenyl group; the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A .
在另一优选例中，R c、R d各自独立地为氢、羟基、卤素、氰基、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或NR 11R 12；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R c and R d are each independently hydrogen, hydroxyl, halogen, cyano, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ; The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R c、R d为氢。 In another preferred example, R c and R d are hydrogen.
在另一优选例中，R e、R f各自独立地为氢、羟基、卤素、氰基、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或NR 11R 12；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R e and R f are each independently hydrogen, hydroxy, halogen, cyano, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ; The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R e、R f为氢。 In another preferred example, R e and R f are hydrogen.
在另一优选例中，R b为氢。 In another preferred embodiment, R b is hydrogen.
在另一优选例中，R 01、R 02、R 03、R 04各自独立地为氢、羟基、氰基、卤素、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或卤代C 1-3烷基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R 01 , R 02 , R 03 and R 04 are each independently hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1 -3 Alkoxy or halo C 1-3 alkyl; the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R 01、R 02、R 03、R 04为氢。 In another preferred example, R 01 , R 02 , R 03 and R 04 are hydrogen.
在另一优选例中，
Figure PCTCN2020072851-appb-000006
为
Figure PCTCN2020072851-appb-000007
In another preferred example,
Figure PCTCN2020072851-appb-000006
for
Figure PCTCN2020072851-appb-000007
本发明第二方面提供了一种式(Ⅱ)所示的化合物，或其药学上可接受的盐、立体异构体或溶剂化物：：The second aspect of the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
Figure PCTCN2020072851-appb-000008
Figure PCTCN2020072851-appb-000008
式中，W 1、W 2、Z 1、Z 2、Z 3、Z 4、t、n如权利要求1所定义。 In the formula, W 1 , W 2 , Z 1 , Z 2 , Z 3 , Z 4 , t, and n are as defined in claim 1.
在另一优选例中，Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)；t为0或1；n为1。 In another preferred example, Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1.
在另一优选例中，Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；t为0；n为1、2或3。 In another preferred example, Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2, or 3.
在另一优选例中，Z 1为N；Z 2为CR 3R 4；Z 3为NR 7或O；Z 4为C(R 8R 9)；t为0或1；n为1。 In another preferred example, Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is NR 7 or O; Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1.
在另一优选例中，Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为NR 10或O；t为1；n为1、 2或3。 In another preferred example, Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is NR 10 or O; t is 1; n is 1, 2 or 3 .
在另一优选例中，Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)；t为0或1；n为1。 In another preferred example, Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1 .
在另一优选例中，Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3。 In another preferred example, Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2, or 3.
在另一优选例中，Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n为1、2或3。 In another preferred example, Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
在另一优选例中，W 1为一个键，或C(R cR d)；W 2为C(R eR f)。 In another preferred example, W 1 is a bond, or C(R c R d ); W 2 is C(R e R f ).
在另一优选例中，W 1为一个键，或C(R cR d)；W 2为C(R eR f)；Z 1、Z 2、Z 3、Z 4、t、n为选自下组的一种： In another preferred example, W 1 is a bond, or C(R c R d ); W 2 is C(R e R f ); Z 1 , Z 2 , Z 3 , Z 4 , t, n are selected One from the following group:
(ⅰ)Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；t为0；n为1、2或3； (I) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
(ⅱ)Z 1为N；Z 2为CR 3R 4；Z 3为NR 7或O；Z 4为C(R 8R 9)；t为0或1；n为1； (Ii) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is NR 7 or O; Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1;
(ⅲ)Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为NR 10或O；t为1；n为1、2或3； (Iii) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is NR 10 or O; t is 1; n is 1, 2 or 3;
(ⅳ)Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3； (Iv) Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
(ⅴ)Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n为1、2或3。 (Ⅴ) Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
在另一优选例中，W 1为一个键，或C(R cR d)；W 2为NR g或O。 In another preferred example, W 1 is a bond, or C(R c R d ); W 2 is NR g or O.
在另一优选例中，W 1为一个键，或C(R cR d)；W 2为NR g或O；Z 1、Z 2、Z 3、Z 4、t、n为选自下组的一种： In another preferred example, W 1 is a bond, or C(R c R d ); W 2 is NR g or O; Z 1 , Z 2 , Z 3 , Z 4 , t, n are selected from the following group One of:
(ⅰ)Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3； (I) Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
(ⅱ)Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n为1、2或3。 (Ii) Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
在另一优选例中，A组取代基中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。In another preferred embodiment, the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in the substituent group A is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole , Piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2- Dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4 -Dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
在另一优选例中，A组取代基中所述的4至6元饱和或不饱和单环选自：环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。In another preferred example, the 4- to 6-membered saturated or unsaturated monocyclic ring in the substituent group A is selected from: cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl Ring, cyclohexadienyl ring.
在另一优选例中，A组取代基中所述的5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。In another preferred example, the 5- or 6-membered monocyclic heteroaryl group in the group A substituent is selected from: thiophene, N-alkanepyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, three Azole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1 , 2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or Pyrazine.
在另一优选例中，R a中所述的5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-恶二唑、噻二唑、吡啶、 哒嗪、嘧啶或吡嗪。 In another preferred embodiment, the 5- or 6-membered monocyclic heteroaryl group described in Ra is selected from: thiophene, N-alkyl pyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2 ,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine or pyrazine .
在另一优选例中，L 1中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。 In another preferred embodiment, the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 1 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
在另一优选例中，L 2中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。 In another preferred embodiment, the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 2 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
在另一优选例中，L 3中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。 In another preferred example, the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 3 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
在另一优选例中，L 4中所述的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃或1,2,3,6-四氢吡啶。 In another preferred embodiment, the 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 4 is selected from: azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine Pyridine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine, 1,2-dihydro Oxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-di Hydrogen-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran or 1,2,3,6-tetrahydropyridine.
在另一优选例中，R 11、R 12中所述的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。 In another preferred example, the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in R 11 and R 12 is selected from: aziridine, ethylene oxide, azetidine, and oxetane , Tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydronitrogen Cyclobutadiene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3- Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6 -Tetrahydropyridine.
在另一优选例中，R 3、R 4与相连的碳原子共同形成的3至6元饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。 In another preferred embodiment, the 3- to 6-membered saturated monocyclic heterocyclic ring formed by R 3 and R 4 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
在另一优选例中，R 3、R 4与相连的碳原子共同形成的3至6元饱和单环选自：环丙基环、环丁基环、环戊基环、环己基环。 In another preferred example, the 3- to 6-membered saturated monocyclic ring formed by R 3 , R 4 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
在另一优选例中，R 5、R 6与相连的碳原子共同形成的3至6元饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。 In another preferred embodiment, the 3- to 6-membered saturated monocyclic heterocycle formed by R 5 , R 6 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
在另一优选例中，R 5、R 6与相连的碳原子共同形成的3至6元饱和单环选自：环丙基环、 环丁基环、环戊基环、环己基环。 In another preferred example, the 3- to 6-membered saturated monocyclic ring formed by R 5 , R 6 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
在另一优选例中，R 8、R 9与相连的碳原子共同形成的3至6元饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃。 In another preferred embodiment, the 3- to 6-membered saturated monocyclic heterocycle formed by R 8 and R 9 and the connected carbon atoms is selected from: aziridine, ethylene oxide, azetidine, and oxetane Alkane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran.
在另一优选例中，R 8、R 9与相连的碳原子共同形成的3至6元饱和单环选自：环丙基环、环丁基环、环戊基环、环己基环。 In another preferred example, the 3- to 6-membered saturated monocyclic ring formed by R 8 , R 9 and the connected carbon atoms is selected from the group consisting of cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclohexyl ring.
在另一优选例中，R 11、R 12与相连的氮原子形成的4至6元饱和或不饱和单杂环选自：氮杂环丁烷、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、1,2-二氢氮杂环丁二烯、2,5-二氢-1H-吡咯、2,3-二氢-1H-吡咯、1,2,3,4-四氢吡啶、1,2,3,6-四氢吡啶。 In another preferred embodiment, the 4- to 6-membered saturated or unsaturated monocyclic heterocycle formed by R 11 , R 12 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole, piperidine, piperazine, Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 1,2-dihydroazetidine, 2,5-dihydro-1H-pyrrole, 2,3-dihydro -1H-pyrrole, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine.
在另一优选例中，R 23、R 24与相连的碳原子形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。 In another preferred example, the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 23 and R 24 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2, 3,6-Tetrahydropyridine.
在另一优选例中，R 23、R 24与相连的碳原子形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。 In another preferred example, the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 23 , R 24 and the connected carbon atom is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
在另一优选例中，R 33、R 34与相连的碳原子形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。 In another preferred example, the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 33 , R 34 and the connected carbon atom is selected from: aziryl ring, ethylene oxide, azetidine, oxetane Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2, 3,6-Tetrahydropyridine.
在另一优选例中，R 33、R 34与相连的碳原子形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。 In another preferred embodiment, the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 33 , R 34 and the connected carbon atom is selected from the group consisting of: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
在另一优选例中，R 53、R 54与相连的碳原子形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。 In another preferred embodiment, the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R53 , R54 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2, 3,6-Tetrahydropyridine.
在另一优选例中，R 53、R 54与相连的碳原子形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。 In another preferred example, the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R53 , R54 and the connected carbon atoms is selected from the group consisting of: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
在另一优选例中，R 83、R 84与相连的碳原子形成的3至6元饱和或不饱和单杂环选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶。 In another preferred embodiment, the 3- to 6-membered saturated or unsaturated monocyclic heterocyclic ring formed by R 83 and R 84 and the connected carbon atom is selected from: aziridine, ethylene oxide, azetidine, oxa Cyclobutane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2- Dihydroazetidine, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2 ,3-Dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2, 3,6-Tetrahydropyridine.
在另一优选例中，R 83、R 84与相连的碳原子形成的3至6元饱和或不饱和单环选自：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环。 In another preferred embodiment, the 3- to 6-membered saturated or unsaturated monocyclic ring formed by R 83 and R 84 and the connected carbon atom is selected from: cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, and cyclopentenyl ring , Cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring.
在另一优选例中，所述3至6元或4至6元饱和单杂环选自以下结构：In another preferred embodiment, the 3 to 6 membered or 4 to 6 membered saturated monocyclic heterocyclic ring is selected from the following structures:
Figure PCTCN2020072851-appb-000009
Figure PCTCN2020072851-appb-000010
上述3至6元或4至6元饱和单杂环上的氢原子任选地被1、2或3个各自独立地选自A组的取代基所取代。
Figure PCTCN2020072851-appb-000009
Figure PCTCN2020072851-appb-000010
The hydrogen atoms on the above-mentioned 3- to 6-membered or 4- to 6-membered saturated monocyclic heterocyclic ring are optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
在另一优选例中，R a或A组取代基中所述的5至6元单环杂芳基选自以下结构： In another preferred example, the 5- to 6-membered monocyclic heteroaryl group described in R a or Group A substituent is selected from the following structures:
Figure PCTCN2020072851-appb-000011
Figure PCTCN2020072851-appb-000012
上述5至6元单环杂芳基任选地被1、2或3个各自独立地选自A组的取代基所取代。
Figure PCTCN2020072851-appb-000011
Figure PCTCN2020072851-appb-000012
The above-mentioned 5- to 6-membered monocyclic heteroaryl group is optionally substituted with 1, 2 or 3 substituents each independently selected from Group A.
在另一优选例中，R 1为氢或取代或未取代的C 1-3烷基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred example, R 1 is hydrogen or a substituted or unsubstituted C 1-3 alkyl group; the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are each independently selected from A Group of substituents are substituted.
在另一优选例中，R 2、R 7、R 10各自独立地为氢、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、取代或未取代的C 3-6环烷基或-(CR 21R 22) p-L 1；L 1为C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-COC 3-6环烷基、-CONR 11R 12、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-CO-(CR 21R 22) u-(CR 23R 24)C 1-3烷基、-(CR 23R 24)C 1-3烷基、-(CR 23R 24)CN、-(CR 23R 24)OH或-(CR 23R 24)C 1-3烷氧基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；L 1中所述的C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-C(O)OC 1-3烷基、-SO 2C 1-3烷基和4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代。 In another preferred example, R 2 , R 7 , and R 10 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 21 R 22 ) p -L 1 ; L 1 is C 3-6 cycloalkyl , C 1-3 alkoxy, -COC 1-3 alkyl, -COC 3-6 cycloalkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1- 3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-3 alkyl, -( CR 23 R 24 )C 1-3 alkyl, -(CR 23 R 24 )CN, -(CR 23 R 24 )OH or -(CR 23 R 24 )C 1-3 alkoxy; the "substituted" refers to the group 1, 2 or 3 hydrogen atoms are each independently selected from the substituents of group a; L in said C 1 3-6 cycloalkyl, C 1-3 alkoxy, -COC 1-3 alkyl, -C (O) OC 1-3 alkyl, -SO 2 C 1-3 alkyl and 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring are unsubstituted or substituted by 1, 2 Or three substituents independently selected from Group A.
在另一优选例中，R 2、R 7、R 10各自独立地为氢、C 1-6烷基、羟基取代的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基或-(CR 21R 22) p-L 1；L 1为C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-COC 3-6环烷基、-CONR 11R 12、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-CO-(CR 21R 22) u-(CR 23R 24)C 1-3烷基、-(CR 23R 24)C 1-3烷基、-(CR 23R 24)CN、-(CR 23R 24)OH或-(CR 23R 24)C 1-3烷氧基；其中L 1中所述的C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-C(O)OC 1-3烷基、-SO 2C 1-3烷基和4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地 选自A组的取代基所取代。 In another preferred embodiment, R 2 , R 7 , and R 10 are each independently hydrogen, C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, halogenated C 1-6 alkyl, C 3- 6 cycloalkyl or -(CR 21 R 22 ) p -L 1 ; L 1 is C 3-6 cycloalkyl, C 1-3 alkoxy, -COC 1-3 alkyl, -COC 3-6 ring Alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated mono heterocyclic ring , -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-3 alkyl, -(CR 23 R 24 )C 1-3 alkyl, -(CR 23 R 24 )CN, -( CR 23 R 24 )OH or -(CR 23 R 24 )C 1-3 alkoxy; wherein the C 3-6 cycloalkyl, C 1-3 alkoxy, -COC 1-3 described in L 1 Alkyl, -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, and 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring are unsubstituted or independently by 1, 2 or 3 Is substituted with a substituent selected from Group A.
在另一优选例中，R 11、R 12各自独立地为氢、C 1-3烷基、卤代C 1-3烷基、取代或未取代的3至6元饱和或不饱和单杂环；或者R 11、R 12与相连的氮原子形成取代或未取代的4至6元饱和或不饱和单杂环；其中所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R 11 and R 12 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring ; Or R 11 , R 12 and the connected nitrogen atom form a substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic ring; wherein the "substituted" refers to 1, 2 or 3 hydrogen atoms in the group It is substituted by substituents each independently selected from Group A.
在另一优选例中，R 21、R 22相同或不同，且各自独立地为氢、羟基、卤素、C 1-3烷基、取代或未取代的C 1-10烷氧基(优选为取代或未取代的C 1-6烷氧基，更优选为取代或未取代的C 1-3烷氧基)、卤代C 1-10烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、-NR 11R 12、-NR 13COC 1-10烷基(优选为-NR 13COC 1-6烷基，更优选为-NR 13COC 1-3烷基)或-NR 13SO 2R 0；其中所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R 21 and R 22 are the same or different, and are each independently hydrogen, hydroxyl, halogen, C 1-3 alkyl, substituted or unsubstituted C 1-10 alkoxy (preferably substituted Or unsubstituted C 1-6 alkoxy, more preferably substituted or unsubstituted C 1-3 alkoxy), halogenated C 1-10 alkyl (preferably halogenated C 1-6 alkyl, more It is preferably a halogenated C 1-3 alkyl), -NR 11 R 12 , -NR 13 COC 1-10 alkyl (preferably -NR 13 COC 1-6 alkyl, more preferably -NR 13 COC 1-3 Alkyl) or -NR 13 SO 2 R 0 ; wherein the "substituted" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R 23、R 24与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环；其中所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 In another preferred embodiment, R 23 , R 24 and the connected carbon atoms form a substituted or unsubstituted 3 to 6 membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6 membered saturated or unsaturated monocyclic ring Ring; wherein the "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A.
在另一优选例中，R 3、R 4各自独立地为氢、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、取代或未取代的C 3-6环烷基或-(CR 31R 32) q-L 2；L 2为C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-CONR 11R 12、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 33R 34)C 1-3烷基、-(CR 33R 34)CN、-(CR 33R 34)OH或-(CR 33R 34)C 1-3烷氧基；或者R 3、R 4与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环； In another preferred example, R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 31 R 32 ) q -L 2 ; L 2 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 33 R 34 )C 1-3 alkyl, -(CR 33 R 34 )CN, -(CR 33 R 34 )OH or -(CR 33 R 34 ) C 1-3 alkoxy; or R 3 , R 4 and the connected carbon atoms together form a 3- to 6-membered saturated monocyclic ring or a 3- to 6-membered saturated monocyclic ring;
所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
L 2中所述的环烷基、烷氧基、烷基或4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代； The cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 2 is unsubstituted or is substituted by 1, 2 or 3 substituents each independently selected from Group A Replaced by
所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-3烷氧基、C 1-3烷基、卤代C 1-3烷基。 The 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
在另一优选例中，R 5、R 6各自独立地为氢、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、取代或未取代的C 3-6环烷基或-(CR 51R 52) r-L 3；L 3为C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-CONR 11R 12、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 53R 54)C 1-3烷基、-(CR 53R 54)CN、-(CR 53R 54)OH或-(CR 53R 54)C 1-3烷氧基；或者R 5、R 6与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环； In another preferred embodiment, R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 51 R 52 ) r -L 3 ; L 3 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 53 R 54 )C 1-3 alkyl, -(CR 53 R 54 )CN, -(CR 53 R 54 )OH or -(CR 53 R 54 ) C 1-3 alkoxy; or R 5 , R 6 and the connected carbon atoms together form a 3- to 6-membered saturated monocyclic ring or a 3- to 6-membered saturated monocyclic ring;
所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
L 3中所述的环烷基、烷氧基、烷基或4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代； The cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 3 is unsubstituted or is substituted by 1, 2 or 3 substituents each independently selected from Group A Replaced by
所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-3烷氧基、C 1-3烷基、卤代C 1-3烷基。 The 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
在另一优选例中，R 8、R 9各自独立地为氢、取代或未取代的C 1-10烷基、取代或未取代的C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、取代或未取代的C 3-6环烷基或-(CR 81R 82) m-L 4；L 4为C 3-6环烷基、C 1-3烷氧基、-COC 1-3烷基、-CONR 11R 12、-C(O)OC 1-3烷基、-SO 2C 1-3烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 83R 84)C 1-3烷基、-(CR 83R 84)CN、-(CR 83R 84)OH或-(CR 83R 84)C 1-3烷氧基；或者R 8、R 9与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环； In another preferred embodiment, R 8 and R 9 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl or -(CR 81 R 82 ) m -L 4 ; L 4 is C 3-6 cycloalkyl, C 1 -3 alkoxy, -COC 1-3 alkyl, -CONR 11 R 12 , -C(O)OC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -(CR 83 R 84 )C 1-3 alkyl, -(CR 83 R 84 )CN, -(CR 83 R 84 )OH or -(CR 83 R 84 ) C 1-3 alkoxy; or R 8 , R 9 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring;
所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
L 4中所述的环烷基、烷氧基、烷基或4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代； The cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring described in L 4 is unsubstituted or is independently selected from the group A by 1, 2 or 3 substituents Replaced by
所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-3烷氧基、C 1-3烷基、卤代C 1-3烷基。 The 3- to 6-membered saturated monocyclic ring or the 3- to 6-membered saturated monocyclic ring is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen, C 1-3 alkoxy, C 1- 3 alkyl, halogenated C 1-3 alkyl.
在另一优选例中，所述化合物选自表A或表B。In another preferred embodiment, the compound is selected from Table A or Table B.
在另一优选例中，表A化合物选自下组：In another preferred embodiment, the compound of Table A is selected from the following group:
Figure PCTCN2020072851-appb-000013
Figure PCTCN2020072851-appb-000013
Figure PCTCN2020072851-appb-000014
Figure PCTCN2020072851-appb-000014
Figure PCTCN2020072851-appb-000015
Figure PCTCN2020072851-appb-000015
在另一优选例中，表B化合物选自下组：In another preferred embodiment, the compound of Table B is selected from the following group:
Figure PCTCN2020072851-appb-000016
Figure PCTCN2020072851-appb-000016
Figure PCTCN2020072851-appb-000017
Figure PCTCN2020072851-appb-000017
本发明第三方面提供了一种药物组合物，所述药物组合物包括本发明第一或第二所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物；以及药学可接受的载体。The third aspect of the present invention provides a pharmaceutical composition comprising the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and pharmacy Acceptable carrier.
本发明第四方面提供了本发明第一或第二方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如本发明第三方面所述药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。The fourth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention. Use in preparing medicines for preventing and/or treating related diseases mediated by MOR receptor agonists.
本发明第五方面提供了本发明第一或第二方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如本发明第三方面所述药物组合物在制备用于激动或拮抗MOR受体的药物中用途。The fifth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention. It is used for preparing medicine for agonizing or antagonizing MOR receptor.
本发明第六方面提供了本发明第一或第二方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如本发明第三方面所述药物组合物在制备预防和/或治疗疼痛和疼痛相关疾病的药物中的用途。The sixth aspect of the present invention provides the compound according to the first or second aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to the third aspect of the present invention. Use in preparing medicines for preventing and/or treating pain and pain-related diseases.
在另一优选例中，所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。In another preferred embodiment, the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
在另一优选例中，所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。In another preferred example, the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
在另一优选例中，所述癌症选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。In another preferred embodiment, the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
本发明第七方面提供了一种预防和/或治疗MOR受体激动剂介导的相关疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如本发明第三方面所述药物组合物。The seventh aspect of the present invention provides a method for preventing and/or treating related diseases mediated by MOR receptor agonists, which comprises administering a therapeutically effective amount of the compound according to the first or second aspect of the present invention, or A pharmaceutically acceptable salt, stereoisomer or solvate thereof, or a pharmaceutical composition as described in the third aspect of the present invention.
本发明第八方面体提供了一种预防和/或治疗疼痛和疼痛相关疾病的方法，包括给予所需患者治疗有效量的本发明第一或第二方面所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如本发明第三方面所述药物组合物。The eighth aspect of the present invention provides a method for preventing and/or treating pain and pain-related diseases, which comprises administering to a patient a therapeutically effective amount of the compound according to the first or second aspect of the present invention, or pharmaceutically acceptable Accepted salts, stereoisomers or solvates, or pharmaceutical compositions as described in the third aspect of the invention.
在另一优选例中，所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。In another preferred embodiment, the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
在另一优选例中，所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。In another preferred example, the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
在另一优选例中，所述癌症选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。In another preferred embodiment, the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia and leukemia.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的 各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.
具体实施方式detailed description
本发明人经过广泛而深入的研究，意外地发现了这类三环取代的氧杂螺环衍生物，不仅具有优异的镇痛效果，还具有较好的偏向性，此外本发明的化合物具有优异的药代动力学特性。因此该系列化合物有望开发成为用于治疗和预防疼痛和疼痛相关疾病的药物。在此基础上，发明人完成了本发明。After extensive and in-depth research, the inventors unexpectedly discovered that such tricyclic substituted oxaspiro derivatives not only have excellent analgesic effects, but also have good bias. In addition, the compounds of the present invention have excellent Pharmacokinetic properties. Therefore, the series of compounds are expected to be developed as drugs for the treatment and prevention of pain and pain-related diseases. On this basis, the inventor completed the present invention.
术语定义Definition of Terms
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C 1-10烷基为包含1至10个碳原子的烷基，优选为C 1-6烷基，更优选为C 1-3烷基，定义类似；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等更优选。 As used herein, "alkyl" refers to linear and branched saturated aliphatic hydrocarbon groups, C 1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C 1-6 alkyl, more preferably It is a C 1-3 alkyl group with similar definitions; non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , N-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-Dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2 ,4-Dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3 -Dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl , 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl 2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl , And its various branched isomers are more preferred.
如本文所用，“环烷基”和“环烷基环”可互换使用，均指饱和或部分不饱和单环环状烃基，“C 3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C 3-6环烷基，定义类似。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环戊基、环己烯基。 As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably, and both refer to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group, and "C 3-8 cycloalkyl" refers to containing 3 to 8 The cyclic hydrocarbon group of carbon atoms is preferably a C 3-6 cycloalkyl group, and the definition is similar. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl , Cyclooctyl, etc., preferably cyclopropyl, cyclopentyl, and cyclohexenyl.
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为4元/5元、5元/5元或5元/6元双螺环。例如：As used herein, "spiro ring" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have fully conjugated π electrons. system. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
Figure PCTCN2020072851-appb-000018
Figure PCTCN2020072851-appb-000018
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例如： As used herein, "spiro heterocyclic ring" refers to a polycyclic hydrocarbon sharing one atom (called a spiro atom) between single rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer 0 to 2) of heteroatoms, the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. According to the number of rings, the spiro heterocyclic ring is classified into a dispiro heterocyclic ring or a polyspiro heterocyclic ring, preferably a dispiro heterocyclic ring. More preferably, it is a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro heterocyclic ring. E.g:
Figure PCTCN2020072851-appb-000019
Figure PCTCN2020072851-appb-000019
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：As used herein, "bridged ring" refers to a polycyclic group that shares two or more carbon atoms. The shared carbon atoms are called bridgehead carbons. The two bridgehead carbons can be a carbon chain or a bond. , Called the bridge. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is a double ring or a triple ring bridged ring. E.g:
Figure PCTCN2020072851-appb-000020
Figure PCTCN2020072851-appb-000020
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O) n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如： As used herein, "bridged heterocycle" refers to a polycyclic group that shares two or more atoms, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer of 0 to 2 ), the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably a bicyclic or tricyclic bridged heterocyclic ring. E.g:
Figure PCTCN2020072851-appb-000021
Figure PCTCN2020072851-appb-000021
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，8至10元双环的实例包括(但不限于)：As used herein, "8 to 10 membered bicyclic ring" refers to a bridged ring containing two rings containing 8 to 10 ring atoms. The bicyclic ring may be a saturated full carbon bicyclic ring or a partially unsaturated full carbon bicyclic ring, and an 8 to 10 membered bicyclic ring Examples include (but are not limited to):
Figure PCTCN2020072851-appb-000022
Figure PCTCN2020072851-appb-000022
如本文所用，“8至10元双杂环”是指含8至10个环原子的含两个环的桥杂环，其中1、2、3、4或5个环碳原子被选自氮、氧或硫的杂原子所取代。8至10元双杂环的实例包括(但不限 于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。As used herein, "8 to 10 membered bicyclic heterocyclic ring" refers to a two-ring bridged heterocyclic ring containing 8 to 10 ring atoms, in which 1, 2, 3, 4, or 5 ring carbon atoms are selected from nitrogen , Oxygen or sulfur heteroatoms. Examples of 8- to 10-membered bi-heterocycles include, but are not limited to, tetrahydroquinoline ring, tetrahydroisoquinoline ring, decahydroquinoline ring and the like.
如本文所用，“C 1-10烷氧基”指-O-(C 1-10烷基)，其中烷基的定义如上所述。优选C 1-6烷氧基，更优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。 As used herein, "C 1-10 alkoxy" refers to -O-(C 1-10 alkyl), where the definition of alkyl is as described above. C 1-6 alkoxy is preferable, and C 1-3 alkoxy is more preferable. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy and the like.
如本文所用，“C 3-8环烷氧基”指-O-(C 3-8环烷基)，其中环烷基的定义如上所述。优选C 3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。 As used herein, "C 3-8 cycloalkoxy" refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is defined as described above. Preferred is C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
如本文所用，“C 6-10芳基”和“C 6-10芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。 As used herein, "C 6-10 aryl" and "C 6-10 aryl ring" are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic rings with a conjugated π-electron system (that is, sharing adjacent A ring) group with a pair of carbon atoms refers to an aryl group containing 6 to 10 carbon atoms; phenyl and naphthyl are preferred, and phenyl is more preferred.
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。As used herein, "a bond" means that two groups connected by it are connected by a covalent bond.
如本文所用，“卤素”指氟、氯、溴或碘。As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。As used herein, "halo" refers to the replacement of one or more (such as 1, 2, 3, 4, or 5) hydrogens in a group with halogen.
例如，“卤代C 1-10烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。 For example, "halo C 1-10 alkyl" means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group. Examples of halogenated C 1-8 alkyl include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
又例如，“卤代C 1-10烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。 As another example, "halogenated C 1-10 alkoxy" means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。 For another example, "halo C 3-8 cycloalkyl" refers to a cycloalkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
如本文所用，“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代C 1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。 As used herein, "deuterated C 1-8 alkyl" refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base etc.
如本文所用，“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苄基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2020072851-appb-000023
As used herein, “amino” refers to NH 2 , “cyano” refers to CN, “nitro” refers to NO 2 , “benzyl” refers to -CH 2 -phenyl, “oxo” refers to =0, “carboxy” Refers to -C(O)OH, "acetyl" refers to -C(O)CH 3 , "hydroxymethyl" refers to -CH 2 OH, "hydroxyethyl" refers to -CH 2 CH 2 OH or -CHOHCH 3 , ""Hydroxy" refers to -OH, "thiol" refers to SH, and the structure of "cyclopropylene" is:
Figure PCTCN2020072851-appb-000023
如本文所用，“杂原子”是指氮、氧或硫。As used herein, "heteroatom" refers to nitrogen, oxygen, or sulfur.
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。As used herein, "heteroaryl ring" and "heteroaryl" are used interchangeably and refer to having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl ; The ring array shares 6, 10 or 14 π electrons; and in addition to carbon atoms, there are groups with 1 to 5 heteroatoms. "Heteroatom" refers to nitrogen, oxygen, or sulfur.
如本文所用，“3至6元饱和或不饱和单环”是指含3至6个环原子的饱和或不饱和的全碳单环。3至6元饱和或不饱和单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、 环戊烯基环、环己基环、环己烯基环、环己二烯基环等。As used herein, "3- to 6-membered saturated or unsaturated monocyclic ring" refers to a saturated or unsaturated all-carbon monocyclic ring containing 3 to 6 ring atoms. Examples of 3 to 6-membered saturated or unsaturated monocyclic rings include (but are not limited to): cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexyl ring Dienyl ring and so on.
如本文所用，“4至6元饱和或不饱和单杂环”是指4至6元单环中的1、2或3个碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。4至6元饱和或不饱和单杂环的实例包括(但不限于)氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶等。 As used herein, "4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring" means that 1, 2, or 3 carbon atoms in a 4- to 6-membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t It is substituted by heteroatoms of integers 0 to 2), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Examples of 4- to 6-membered saturated or unsaturated monocyclic heterocycles include (but are not limited to) azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine , Piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazetidine Diene, 1,2-dihydrooxetadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro- 1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydro Pyridine and others.
如本文所用，“5至6元单环杂芳基环”和“5至6元单环杂芳基”可互换使用，均是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。As used herein, "5- to 6-membered monocyclic heteroaryl ring" and "5- to 6-membered monocyclic heteroaryl" are used interchangeably, and both refer to a mono-heteroaryl ring containing 5 to 6 ring atoms, Examples include (but are not limited to): thiophene ring, N-alkane pyrrole ring, furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine Ring, pyrimidine ring, pyrazine ring, etc.
如本文所用，“8至10元双环杂芳基环”和“8至10元双环杂芳基”可互换使用，均是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。As used herein, "8 to 10 membered bicyclic heteroaryl ring" and "8 to 10 membered bicyclic heteroaryl ring" are used interchangeably, and both refer to a bicyclic heteroaryl ring containing 8 to 10 ring atoms, for example including (But not limited to): benzofuran, benzothiophene, indole, isoindole, quinoline, isoquinoline, indazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, cinnoline, Phthalazine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8 -Naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine.
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。As used herein, "substituted" refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently substituted with each other Ground is substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。Unless otherwise defined, the "substituents independently selected from ..." in the present invention means that when more than one hydrogen on the group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are of independent types.
除非另有定义，本发明所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如L为(CR 01R 02) s，当s为2时，即L为(CR 01R 02)-(CR 01R 02)，其中的两个R 01或R 02可以相同或不同，为各自独立的种类，例如L可以为C(CH 3)(CN)-C(CH 2CH 3)(OH)，C(CH 3)(CN)-C(CH 3)(OH)或C(CN)(CH 2CH 3)-C(OH)(CH 2CH 3)。 Unless otherwise defined, the "...same or different, and each independently is..." in the present invention means that when there are more than one identical substituent groups in the general formula, the groups may be the same or different, each Independent species. For example, L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), and the two R 01 or R 02 can be the same or different. Independent type, for example L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN) (CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
如本文所用，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C 1-10烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-10烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷基取代的胺基、胺基、卤代C 1-8烷基取代的胺基、 乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷氧基(优选为C 3-6环烷氧基)、C 2-10烯基(优选为C 2-6烯基，更优选为C 2-4烯基)、C 2-10炔基(优选为C 2-6炔基，更优选为C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。。 As used herein, any group herein may be substituted or unsubstituted. When the above groups are substituted, the substituents are preferably 1 to 5 or less groups independently selected from CN, halogen, C 1-10 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 Alkyl), C 1-10 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1- 6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl-substituted amino, amino, halogenated C 1-8 alkyl-substituted amino, acetyl Group, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 aryl (preferably phenyl), C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy), C 2-10 alkenyl (preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl), C 2-10 alkynyl (preferably C 2-6 alkynyl, more preferably C 2-4 Alkynyl), -CONR a0 R b0 , -C(O)OC 1-10 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl ), -CHO, -OC(O)C 1-10 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (preferably -SO 2 C 6 Aryl, such as -SO 2 -phenyl), -COC 6-10 aryl (preferably -COC 6 aryl, such as -CO-phenyl), 4 to 6-membered saturated or unsaturated monocyclic heterocycles, 4 to 6-membered saturated or unsaturated monocyclic ring, 5- to 6-membered monocyclic heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring, wherein R a0 , R b0 Each is independently hydrogen or C 1-3 alkyl. .
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。The various substituent groups described herein above can themselves be substituted by the groups described herein.
本文所述的4至6元(5至6元)饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：When the 4- to 6-membered (5 to 6-membered) saturated monocyclic heterocyclic ring described herein is substituted, the positions of the substituents can be in their possible chemical positions. Representative substitution situations of exemplary monocyclic heterocyclic rings are shown below :
Figure PCTCN2020072851-appb-000024
Figure PCTCN2020072851-appb-000025
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2020072851-appb-000026
表示与其他原子的连接。
Figure PCTCN2020072851-appb-000024
Figure PCTCN2020072851-appb-000025
Wherein "Sub" means various substituents described herein;
Figure PCTCN2020072851-appb-000026
Represents the connection with other atoms.
除非另有定义，当本发明所述的4至6元饱和单杂环为取代基时，其自身也可以为取代或被1、2或3个选自下组的取代基所取代：卤素、羟基、C 1-3烷基、O＝、NR a0R b0、羟甲基、羟乙基、羧基、-C(O)OC 1-3烷基、乙酰基、卤代C 1-3烷基、C 1-3烷氧基、C 3-6环烷基、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、噻吩环、N-烷基吡咯环、呋喃环、 噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环；其中R a0、R b0各自独立地为氢或C 1-3烷基。 Unless otherwise defined, when the 4- to 6-membered saturated monocyclic heterocyclic ring in the present invention is a substituent, it may itself be substituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, Hydroxyl, C 1-3 alkyl, O=, NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-3 alkyl, acetyl, halogenated C 1-3 alkyl , C 1-3 alkoxy, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, two Oxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, thiophene ring, N-alkylpyrrole ring, furan ring, thiazole ring , Imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine Ring; wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
所述“药学上可接受的盐”包括药学可接受的酸加成盐和药学可接受的碱加成盐。The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
“药学可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like.
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。The "solvate" mentioned in the present invention refers to a complex formed by the compound of the present invention and a solvent. They either react in the solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate". Solvates of compounds of formula (I) fall within the scope of the present invention.
本发明式(I)或式(Ⅱ)所示的化合物可以含有两个或两个以上的手性中心，并以不同的光学活性形式存在。本发明式(I)或式(Ⅱ)所示的化合物的立体异构体可以是对映异构体，也可以是非对映异构体。式(I)或式(Ⅱ)所示的化合物可以是以拆分过的光学纯的特定立体异构体形式存在，例如以对映异构体或非对映异构体形式存在，也可以以两种立体异构体的混合物形式存在，例如以对映异构体的混合物，如外消旋体混合物，或非对映异构体的混合物，或对映异构体和非对映异构体的混合物形式存在。其中对映异构体可以通过本专业已知的方法，例如结晶以及手性色谱等方法拆分得到。非对映异构体可由本专业已知方法，比如结晶以及制备色谱等方法拆分得到。本发明式(I)或式(Ⅱ)所示的化合物的对映异构体或非对映异构体，以及这些立体异构体的混合物均在本发明保护范围之内。The compound represented by formula (I) or formula (II) of the present invention may contain two or more chiral centers and exist in different optically active forms. The stereoisomers of the compounds represented by formula (I) or formula (II) of the present invention may be enantiomers or diastereomers. The compound represented by formula (I) or formula (II) may exist in the form of resolved optically pure specific stereoisomers, for example in the form of enantiomers or diastereomers, or Exist as a mixture of two stereoisomers, for example, as a mixture of enantiomers, such as a mixture of racemates, or a mixture of diastereomers, or enantiomers and diastereomers The structure exists as a mixture. The enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. Diastereoisomers can be resolved by methods known in the field, such as crystallization and preparative chromatography. The enantiomers or diastereomers of the compounds represented by formula (I) or formula (II) of the present invention, and mixtures of these stereoisomers are all within the protection scope of the present invention.
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。The present invention includes prodrugs of the aforementioned compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound. For specific preparation methods of prodrugs, please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
通常，本发明化合物或其药学可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。Generally, the compound of the present invention or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or a prodrug of the present invention can be administered in a suitable dosage form with one or more pharmaceutical carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through general pharmaceutical methods. The aforementioned carrier needs to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like. Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or a suspension with the aforementioned carriers.
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。The composition of the present invention is formulated, quantified and administered in a manner conforming to medical practice standards. The "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋 白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention that will cause an individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc. the amount.
本发明的药物组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。The therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof contained in the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of excipient, which is compatible with the patient and most It is preferably a mammal, more preferably a human, which is suitable for delivering the active agent to the target target without terminating the activity of the agent.
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。As used herein, "patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。As used herein, "treating" refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
制备方法Preparation
下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。The experimental methods without specific conditions in the following examples are usually in accordance with the conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with the conditions described in the manufacturer The suggested conditions.
除非另行定义，本文所用的术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同等的方法及材料皆可应用于本发明中。Unless otherwise defined, the terms used herein 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 present invention.
用于本发明的化合物的制备方法：The preparation method of the compound used in the present invention:
本发明式(Ⅱ)表示的化合物可通过已知的方法制备，例如，通过下述方法、与之等同的方法或实施例中所述的方法。在下面的制备方法中，原料化合物可以是盐的形式，该盐可以是本发明式(Ⅱ)表示的化合物所示例的任何药学上可接受的盐。The compound represented by formula (II) of the present invention can be prepared by a known method, for example, by the following method, a method equivalent thereto, or the method described in the examples. In the following preparation method, the raw material compound may be in the form of a salt, and the salt may be any pharmaceutically acceptable salt exemplified by the compound represented by formula (II) of the present invention.
反应方案(I)Reaction scheme (I)
Figure PCTCN2020072851-appb-000027
Figure PCTCN2020072851-appb-000027
(在上述方案的各式中，所有符号如说明书中所述。)(In each formula of the above scheme, all symbols are as described in the specification.)
具体地，式(I-2)表示的化合物可按照以下方法制得：将化合物1a和相应的式(I-1)表示的化合物发生还原胺化反应制得式(I-2)表示的化合物。Specifically, the compound represented by the formula (I-2) can be prepared according to the following method: the compound 1a and the corresponding compound represented by the formula (I-1) are subjected to a reductive amination reaction to prepare the compound represented by the formula (I-2) .
反应方案(Ⅱ)Reaction scheme (Ⅱ)
Figure PCTCN2020072851-appb-000028
Figure PCTCN2020072851-appb-000028
(在上述方案的各式中，所有符号如说明书中所述。)(In each formula of the above scheme, all symbols are as described in the specification.)
具体地，式(Ⅱ-2)表示的化合物可按照以下方法制得：将化合物1b和相应的式(Ⅱ-1)表示的化合物发生还原胺化反应制得式(Ⅱ-2)表示的化合物。Specifically, the compound represented by formula (II-2) can be prepared according to the following method: compound 1b and the corresponding compound represented by formula (II-1) undergo reductive amination reaction to prepare the compound represented by formula (II-2) .
所述还原胺化反应是已知的且可为。例如，在有机溶剂(如DCM、DCE或THF等)中，在催化剂(如钛酸四异丙酯)催化下，使用还原剂(如硼氢化钠)，羰基跟胺发生还原胺化反应。The reductive amination reaction is known and can be. For example, in an organic solvent (such as DCM, DCE or THF, etc.), under the catalysis of a catalyst (such as tetraisopropyl titanate), using a reducing agent (such as sodium borohydride), the carbonyl group undergoes a reductive amination reaction with the amine.
用于本发明的具有氨基、羧基或羟基的化合物可使用根据需要已通过常用于该基团的保护基进行保护的化合物来制备，在通过上述反应方案的反应过程后，可进行已知的脱保护反应。The compound having an amino group, a carboxyl group, or a hydroxyl group used in the present invention can be prepared using a compound that has been protected by a protective group commonly used for this group as required. After passing through the reaction process of the above-mentioned reaction scheme, a known desorption can be carried out. Protection response.
上述化合物之外的式(Ⅱ)表示的化合物可通过组合描述于本说明书中实施例或组合已知方法来制备。Compounds represented by formula (II) other than the above compounds can be prepared by combining the examples described in this specification or combining known methods.
与现有技术相比，本发明的主要优点在于：Compared with the prior art, the main advantages of the present invention are:
提供了一系列结构新颖的三环取代的氧杂螺环衍生物，其对cAMP具有较高的抑制活性(EC 50为0.1nM至100nM，更佳地为0.1至50nM)，以及较高的Emax值(Emax大于50％，更佳地Emax大于100％)，具有优异的镇痛效果，此外本发明的化合物对β-arrestin具有较低的Emax值(Emax小于50％，更佳地Emax小于20％)，偏向性好。因此可开发成为用于治疗和预防疼痛和疼痛相关疾病的药物。 A series of tricyclic substituted oxaspiro derivatives with novel structures are provided, which have high inhibitory activity on cAMP (EC 50 is 0.1 nM to 100 nM, more preferably 0.1 to 50 nM), and higher Emax Value (Emax is greater than 50%, more preferably Emax is greater than 100%), has excellent analgesic effects, and the compound of the present invention has a lower Emax value for β-arrestin (Emax is less than 50%, more preferably Emax is less than 20 %), the bias is good. Therefore, it can be developed as a medicine for the treatment and prevention of pain and pain-related diseases.
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，否则百分比和份数按重量计算。除非另行定义，本文所用的术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同等的方法及材料皆可应用于本发明中。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, the terms used herein 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 present invention.
如本文所用，DMB为2,4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac 2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，DCE为1,2-二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl 2为[1,1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为二氢四氢吡喃，LiAlH 4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd 2(dba) 3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,DMAP为4-二甲氨基吡啶，THP为四氢四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA或DIPEA为N,N-二异丙基乙胺，BINAP为(2R,3S)-2,2'-双二苯膦基-1,1'-联萘，PPA为多聚磷酸。 As used herein, DMB is 2,4-dimethoxybenzyl, THF is tetrahydrofuran, EA is ethyl acetate, PE is petroleum ether, Ac 2 O is acetic anhydride, NBS is N-bromosuccinimide, DCM is dichloromethane, DCE is 1,2-dichloromethane, AIBN is azobisisobutyronitrile, Pd(dppf)Cl 2 is [1,1'-bis(diphenylphosphorus)ferrocene] Palladium chloride, TFA is trifluoroacetic acid, TBSCl is tert-butyldimethylchlorosilane, NCS is N-chlorosuccinimide, DHP is dihydrotetrahydropyran, LiAlH 4 is lithium aluminum hydride, PMB Is p-methoxybenzyl, LiHMDS is lithium bis(trimethylsilyl)amide, Pd 2 (dba) 3 is tris(dibenzylideneacetone) dipalladium, and RuPhos is 2-dicyclohexylphosphorus-2',6'-Diisopropoxy-1,1'-biphenyl, DMAP is 4-dimethylaminopyridine, THP is tetrahydrotetrahydropyran, n-BuLi is n-butyllithium, TMsOTf is trifluoromethyl Trimethylsilyl sulfonate, TEBAC is triethylbenzylammonium chloride, HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea Fluorophosphate, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, DIEA or DIPEA is N,N-diisopropylethylamine, BINAP is (2R,3S)-2,2'-bis-two Phenylphosphino-1,1'-binaphthyl, PPA is polyphosphoric acid.
如本文所用，室温是指约为20-25℃。As used herein, room temperature refers to about 20-25°C.
中间体1c的制备Preparation of Intermediate 1c
Figure PCTCN2020072851-appb-000029
Figure PCTCN2020072851-appb-000029
步骤1：将化合物1c-1(4.0g，24.4mmol)、化合物1c.1(4.1g，24.4mmol)和Pd(dppf)Cl 2(0.89g，1.2mmol)溶解于50mL 1,4-二氧六环和10ml水中，80℃搅拌反应12h。向反应液中加入100mL水，用EA萃取(100mL×3)。合并有机相，用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：10/1)纯化所得残余物，得到化合物1c-2(3.4g，棕色液体)，产率：82.5％。MS m/z(ESI):170.1[M+H] +。 Step 1: Dissolve compound 1c-1 (4.0g, 24.4mmol), compound 1c.1 (4.1g, 24.4mmol) and Pd(dppf)Cl 2 (0.89g, 1.2mmol) in 50mL 1,4-diox The hexacyclic ring and 10ml of water were stirred at 80°C for 12h. 100 mL of water was added to the reaction solution, and extracted with EA (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 10/1). Compound 1c-2 (3.4 g, brown liquid) was obtained with a yield of 82.5%. MS m/z (ESI): 170.1 [M+H] + .
步骤2：化合物1c-2(3.2g，18.9mmol)和氯化镍(3.57g，38.0mmol)加入到30mL甲醇中，加入硼氢化钠(1.44g，38.0mmol)，室温下搅拌反应6h。向反应液中加入100mL水，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：5/1)纯化所得残余物，得到化合物1c(1.28g，棕色液体)，产率：36.2％。MS m/z(ESI):176.1[M+H] +。 Step 2: Compound 1c-2 (3.2 g, 18.9 mmol) and nickel chloride (3.57 g, 38.0 mmol) were added to 30 mL of methanol, sodium borohydride (1.44 g, 38.0 mmol) was added, and the reaction was stirred at room temperature for 6 hours. 100 mL of water was added to the reaction solution, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 5/1) to obtain compound 1c (1.28 g, brown liquid), Yield: 36.2%. MS m/z (ESI): 176.1 [M+H] + .
中间体1d的制备Preparation of intermediate 1d
Figure PCTCN2020072851-appb-000030
Figure PCTCN2020072851-appb-000030
步骤1：将2-甲基-3-丁炔-2-醇1d-1(8.4g，100mmol)、三乙胺(15g，150mmol)和4-二甲氨基吡啶(0.6g，5.0mmol)溶解到80ml DCM中，加入乙酸酐(12.2g，120mmol)，室温下搅拌反应12h。向反应液中加入100mL饱和氯化铵，用DCM萃取(100mL×3)。合并有机相，用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得到3-乙酰氧基异戊炔，化合物1d-2(7.5g，棕色液体)，产率：47.1％。Step 1: Dissolve 2-methyl-3-butyn-2-ol 1d-1 (8.4g, 100mmol), triethylamine (15g, 150mmol) and 4-dimethylaminopyridine (0.6g, 5.0mmol) To 80ml DCM, add acetic anhydride (12.2g, 120mmol), and stir at room temperature for 12h. 100 mL of saturated ammonium chloride was added to the reaction solution, and it was extracted with DCM (100 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-acetoxyisopentyne, compound 1d-2 (7.5 g, brown liquid), yield: 47.1%.
步骤2：3-乙酰氧基异戊炔化合物1d-2(7.5g，59.5mmol)和苯胺(6.65g，71.4mmol)溶解到50mL THF中，加入氯化亚铜(0.59g，59.5mmol)，加热回流反应4h。向反应液中加入100mL水，用EA萃取(100mL×3)，用饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：50/1)纯化所得残余物，得到化合物1d-3(4.0g，黄色液体)，产率：25.0％。MS m/z(ESI):160.1[M+H] +。 Step 2: 3-acetoxyisopentyne compound 1d-2 (7.5g, 59.5mmol) and aniline (6.65g, 71.4mmol) were dissolved in 50mL THF, and cuprous chloride (0.59g, 59.5mmol) was added, Heat to reflux for 4h. 100mL of water was added to the reaction solution, extracted with EA (100mL×3), washed with saturated brine (100mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the eluent system was determined by silica gel column chromatography ( PE/EA: 50/1) The resulting residue was purified to obtain compound 1d-3 (4.0 g, yellow liquid), yield: 25.0%. MS m/z (ESI): 160.1 [M+H] + .
步骤3：化合物1d-3(2.5g，15.7mmol)溶解于25ml乙醇和25mlEA混合溶剂中，加入钯/碳(250mg),室温搅拌反应12h。过滤，滤液减压浓缩，得到化合物1d(2.2g，黄色液体)，产率：88.0％。MS m/z(ESI):162.1[M+H] +。 Step 3: Compound 1d-3 (2.5g, 15.7mmol) was dissolved in 25ml ethanol and 25ml EA mixed solvent, palladium/carbon (250mg) was added, and the reaction was stirred at room temperature for 12h. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 1d (2.2 g, yellow liquid), yield: 88.0%. MS m/z (ESI): 162.1 [M+H] + .
实施例1 N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-6-胺(H-1)的制备Example 1 N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,5,6- Preparation of tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-6-amine (H-1)
Figure PCTCN2020072851-appb-000031
Figure PCTCN2020072851-appb-000031
步骤1：将化合物1-1(2.38g，0.02mol)溶解于40mL DMF中，加入碳酸钾(5.52g，0.04mol)和溴丙酸乙酯(5.43g，0.03mol)，80℃搅拌18h。向反应液中加入120mL水，用EA萃取(60mL×3)，合并有机相，用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝3/1)纯化所得残余物，得到黄色油状液体化合物1-2(1.78g，产率：40.6％)。MS m/z(ESI):220.2[M+H] +。 Step 1: Dissolve compound 1-1 (2.38g, 0.02mol) in 40mL DMF, add potassium carbonate (5.52g, 0.04mol) and ethyl bromopropionate (5.43g, 0.03mol), and stir at 80°C for 18h. 120mL of water was added to the reaction solution, extracted with EA (60mL×3), the organic phases were combined, washed with saturated brine (50mL×1), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography The obtained residue was purified with an eluent (PE/EA=3/1) to obtain compound 1-2 (1.78 g, yield: 40.6%) as a yellow oily liquid. MS m/z (ESI): 220.2 [M+H] + .
步骤2：将化合物1-2(1.78g，8.1mmol)与约40mL多聚磷酸混合，130℃搅拌反应2h。冷却至室温，向反应液中加入70mL冰水，在冰浴下，用30％氨水调节PH值＝9-10，用EA萃取(70mL×3)，合并有机相，用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝5/1)纯化所得残余物，得到褐色固体化合物1-3(0.5g，产率：35.7％)。MS m/z(ESI):174.3[M+H] +。 Step 2: Mix compound 1-2 (1.78 g, 8.1 mmol) with about 40 mL of polyphosphoric acid, and stir and react at 130°C for 2 hours. Cool to room temperature, add 70mL ice water to the reaction solution, adjust the PH value = 9-10 with 30% ammonia water in an ice bath, extract with EA (70mL×3), combine the organic phases, and wash with saturated brine (50mL ×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent (PE/EA=5/1) to obtain brown solid compound 1-3 (0.5g , Yield: 35.7%). MS m/z (ESI): 174.3 [M+H] + .
步骤3：将化合物1-3(69mg，0.4mmol)和化合物1a(104mg，0.4mmol)溶解于8mL DCE中，加入5mL钛酸四异丙酯，45℃搅拌反应18h。冷却至室温，向反应液加入硼氢化钠(46mg，1.2mmol)，搅拌3h，向反应液中加入5mL水，搅拌0.5h，过滤，滤液减压浓缩，制备色谱纯化所得残余物，得到褐色固体化合物H-1(5mg，产率：3.0％)。MS m/z(ESI):418.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.54–8.46(m,1H),8.28(s,2H),7.72-7.65(m,1H),7.46-7.40(m,1H),7.19-7.13(m,1H),6.83(d,J＝7.1Hz,1H),6.71(dd,J＝10.5,7.8Hz,1H),6.43-6.38(m,1H),3.61-3.48(m,3H),3.37–3.32(m,1H),3.24-3.20(m,1H),3.10–3.03(m,1H),2.88–2.72(m,3H),2.44-2.30(m,3H),2.03–1.69(m,5H),1.68-1.25(m,8H),0.97-0.90(m,1H),0.63-0.54(m,1H). Step 3: Dissolve compound 1-3 (69 mg, 0.4 mmol) and compound 1a (104 mg, 0.4 mmol) in 8 mL of DCE, add 5 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 18 h. Cool to room temperature, add sodium borohydride (46mg, 1.2mmol) to the reaction solution, stir for 3h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-1 (5 mg, yield: 3.0%). MS m/z (ESI): 418.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.54-8.46 (m, 1H), 8.28 (s, 2H), 7.72-7.65 (m, 1H), 7.46-7.40 (m, 1H), 7.19-7.13 ( m, 1H), 6.83 (d, J = 7.1 Hz, 1H), 6.71 (dd, J = 10.5, 7.8 Hz, 1H), 6.43-6.38 (m, 1H), 3.61-3.48 (m, 3H), 3.37 --3.32(m,1H), 3.24-3.20(m,1H), 3.10-3.03(m,1H), 2.88-2.72(m,3H), 2.44-2.30(m,3H), 2.03-1.69(m, 5H), 1.68-1.25 (m, 8H), 0.97-0.90 (m, 1H), 0.63-0.54 (m, 1H).
实施例2:2-甲基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-6-胺(H-2)的制备Example 2: 2-Methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1, Preparation of 2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-6-amine (H-2)
Figure PCTCN2020072851-appb-000032
Figure PCTCN2020072851-appb-000032
步骤1：将化合物2-1(2.66g，20.0mmol)溶解于40mL DMF中，加入碳酸钾(5.52g，40.0mmol)和溴丙酸甲酯(5.43g，40.0mmol)，80℃搅拌反应18h。向反应液中加入120mL水，用EA萃取(60mL×3)，合并有机相，用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝5/1～3/1)纯化所得残余物，得到黄色油状液体化合物2-2(3g，产率：68.3％)。MS m/z(ESI):220.2[M+H] +。 Step 1: Dissolve compound 2-1 (2.66g, 20.0mmol) in 40mL DMF, add potassium carbonate (5.52g, 40.0mmol) and methyl bromopropionate (5.43g, 40.0mmol), stir and react at 80°C for 18h . 120mL of water was added to the reaction solution, extracted with EA (60mL×3), the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and washed with silica gel column chromatography. The obtained residue was purified by removing the agent (PE/EA=5/1～3/1) to obtain compound 2-2 (3g, yield: 68.3%) as a yellow oily liquid. MS m/z (ESI): 220.2 [M+H] + .
步骤2：将化合物2-2(3g，13.7mmol)与约30mL多聚磷酸混合，130℃搅拌反应3h。冷 却至室温，向反应液中加入70mL冰水，在冰浴下，用30％氨水调节PH值＝9-10，用EA萃取(70mL×3)。合并有机相，用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝5/1)纯化所得残余物，得到红色油状液体化合物2-3(0.89g，产率：34.7％)。MS m/z(ESI):188.1[M+H] +。 Step 2: Mix compound 2-2 (3 g, 13.7 mmol) with about 30 mL of polyphosphoric acid, and stir and react at 130° C. for 3 hours. After cooling to room temperature, 70 mL of ice water was added to the reaction solution. Under an ice bath, the pH value was adjusted to 9-10 with 30% ammonia water, and extracted with EA (70 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent (PE/EA=5/1) to obtain Red oily liquid compound 2-3 (0.89 g, yield: 34.7%). MS m/z (ESI): 188.1 [M+H] + .
步骤3：将化合物2-3(37mg，0.2mmol)和化合物1a(52mg，0.2mmol)溶解于5mL DCE中，加入0.5mL钛酸四异丙酯，45℃搅拌反应7h。冷却至室温，向反应液加入硼氢化钠(23mg，0.6mmol)，搅拌18h，向反应液中加入5mL水，搅拌0.5h，过滤，滤液减压浓缩，制备色谱纯化所得残余物，得到褐色固体化合物H-2(3.82mg，产率：4.4％)。MS m/z(ESI):432.3[M+H] +. 1H NMR(400MHz,DMSO-d6)δ8.53–8.45(m,1H),7.68(m,1H),7.42(m,1H),7.15(m,1H),6.76(m,2H),6.44–6.33(m,1H),3.60-3.55(m,1H),3.51–3.43(m,1H),3.30-3.26(m,3H),3.09(m,1H),3.00–2.85(m,1H),2.63–2.48(m,1H),2.43–2.25(m,4H),2.06-1.98(m,1H),1.92-1.70(m,3H),1.67–1.25(m,9H),1.17(m,3H),0.98–0.88(m,1H),0.62-1.58(m,1H). Step 3: Dissolve compound 2-3 (37 mg, 0.2 mmol) and compound 1a (52 mg, 0.2 mmol) in 5 mL of DCE, add 0.5 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 7 hours. Cool to room temperature, add sodium borohydride (23mg, 0.6mmol) to the reaction solution, stir for 18h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-2 (3.82 mg, yield: 4.4%). MS m/z(ESI): 432.3[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.53-8.45(m,1H),7.68(m,1H),7.42(m,1H) ,7.15(m,1H),6.76(m,2H),6.44-6.33(m,1H), 3.60-3.55(m,1H),3.51-3.43(m,1H),3.30-3.26(m,3H) ,3.09(m,1H),3.00–2.85(m,1H),2.63–2.48(m,1H),2.43–2.25(m,4H),2.06-1.98(m,1H),1.92-1.70(m, 3H), 1.67--1.25(m,9H), 1.17(m,3H), 0.98--0.88(m,1H), 0.62-1.58(m,1H).
实施例3:N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,6,7-四氢-1H,5H-吡啶并[3，2,1-ij]喹啉-1-胺(H-3)的制备Example 3: N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3,6,7 -Preparation of tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-amine (H-3)
Figure PCTCN2020072851-appb-000033
Figure PCTCN2020072851-appb-000033
步骤1：将化合物3-1(1.33g，10.0mmol)溶解于20mL醋酸中，加入丙烯酸甲酯(1.29g，15.0mmol)，100℃搅拌过夜。待反应液冷却至室温后，减压浓缩出去溶剂，残余物用EA(100ml)稀释，用饱和碳酸氢钠(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝2/3)纯化所得残余物，得到黄色油状液体化合物3-2。MS m/z(ESI):220.1[M+H] +. Step 1: Dissolve compound 3-1 (1.33 g, 10.0 mmol) in 20 mL of acetic acid, add methyl acrylate (1.29 g, 15.0 mmol), and stir overnight at 100°C. After the reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure. The residue was diluted with EA (100ml), washed with saturated sodium bicarbonate (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography with an eluent (PE/EA=2/3) to obtain compound 3-2 as a yellow oily liquid. MS m/z(ESI): 220.1[M+H] + .
步骤2：将化合物3-2(1g，4.57mmol)与约20mL多聚磷酸混合，130℃搅拌反应3h。反应液冷却至40℃，加入70mL水，在冰浴下，用30％氨水调节PH值＝9-10，用EA萃取(70mL×3)，合并有机相，用饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝10/1)纯化所得残余物，得红色油状液体化合物3-3(0.35g，产率：40.7％)。MS m/z(ESI):188.1[M+H] +。 Step 2: Mix compound 3-2 (1 g, 4.57 mmol) with about 20 mL of polyphosphoric acid, and stir and react at 130°C for 3 hours. The reaction solution was cooled to 40°C, 70 mL of water was added, and the pH value was adjusted to 9-10 with 30% ammonia in an ice bath, extracted with EA (70 mL×3), and the organic phases were combined and washed with saturated brine (50 mL). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue obtained by silica gel column chromatography with eluent (PE/EA=10/1) to obtain compound 3-3 (0.35g, yield) as a red oily liquid : 40.7%). MS m/z (ESI): 188.1 [M+H] + .
步骤3：将化合物3-3(37mg，0.2mmol)和化合物1a(52mg，0.2mmol)溶解于5mL DCE中，加入0.5mL钛酸四异丙酯，45℃搅拌反应过夜。冷却至室温，向反应液加入硼氢化钠(23mg，0.6mmol)，搅拌16h，向反应液中加入5mL水，搅拌0.5h，过滤，滤液减压浓缩，制备色谱纯化所得残余物，得褐色固体化合物H-3(8.42mg，产率：9.7％)。MS m/z(ESI):432.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.69-7.66(m,1H),7.50–7.31(m,1H),7.24–7.11(m,1H),6.77–6.54(m,2H),6.29-2.25(m,1H),3.61–3.47(m,2H),3.13–2.95(m,3H),2.94–2.78(m,1H),2.68–2.48(m,2H),2.44–2.20(m,3H),2.02–1.83(m,1H),1.87–1.68(m,3H), 1.66–1.03(m,12H),0.94-0.90(m,1H),0.59-0.56(m,1H). Step 3: Dissolve compound 3-3 (37 mg, 0.2 mmol) and compound 1a (52 mg, 0.2 mmol) in 5 mL of DCE, add 0.5 mL of tetraisopropyl titanate, and stir to react overnight at 45°C. Cool to room temperature, add sodium borohydride (23mg, 0.6mmol) to the reaction solution, stir for 16h, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography to obtain a brown solid Compound H-3 (8.42 mg, yield: 9.7%). MS m/z (ESI): 432.3 [M+H] + . 1 H NMR(400MHz, DMSO-d6) δ8.50(s,1H), 7.69-7.66(m,1H), 7.50-7.31(m,1H), 7.24-7.11(m,1H), 6.77-6.54( m, 2H), 6.29-2.25 (m, 1H), 3.61-3.47 (m, 2H), 3.13-2.95 (m, 3H), 2.94-2.78 (m, 1H), 2.68-2.48 (m, 2H), 2.44–2.20(m,3H), 2.02–1.83(m,1H), 1.87–1.68(m,3H), 1.66–1.03(m,12H), 0.94-0.90(m,1H), 0.59-0.56(m ,1H).
实施例4:1-甲基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)1,2,6,7,8,8a-六氢苯并[cd]吲哚-6-胺(H-4，非对映异构体混合物1)的制备Example 4: 1-Methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)1,2 Preparation of ,6,7,8,8a-hexahydrobenzo[cd]indole-6-amine (H-4, diastereoisomer mixture 1)
实施例5:1-甲基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)1,2,6,7,8,8a-六氢苯并[cd]吲哚-6-胺(H-5，非对映异构体混合物2)的制备Example 5: 1-Methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)1,2 Preparation of ,6,7,8,8a-hexahydrobenzo[cd]indole-6-amine (H-5, diastereoisomer mixture 2)
Figure PCTCN2020072851-appb-000034
Figure PCTCN2020072851-appb-000034
步骤1：将化合物4-1(5g，30.0mmol)溶解于80mL DMF中，加入碳酸铯(14.7g，45.0mmol)和碘甲烷(8.4g，60.0mmol)，室温搅拌反应过夜。过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝4/1～2/1)纯化所得残余物，得黄色固体化合物4-2(5.2g，产率：95.6％)。MS m/z(ESI):184[M+H] +。 Step 1: Dissolve compound 4-1 (5g, 30.0mmol) in 80mL DMF, add cesium carbonate (14.7g, 45.0mmol) and methyl iodide (8.4g, 60.0mmol), stir and react at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent (PE/EA=4/1～2/1) to obtain yellow solid compound 4-2 (5.2g, yield: 95.6%) ). MS m/z (ESI): 184 [M+H] + .
步骤2：将化合物4-2(4g，21.9mmol)溶解于30mLTFA，加入钯/碳(1.2g)，在氢气气氛下50℃搅拌反应过夜。反应液冷却至室温，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝5/1～2/1)纯化所得残余物，得黄色固体化合物4-3。MS m/z(ESI):188.1[M+H] +。 Step 2: Compound 4-2 (4 g, 21.9 mmol) was dissolved in 30 mL TFA, palladium/carbon (1.2 g) was added, and the reaction was stirred overnight at 50° C. under a hydrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent (PE/EA=5/1～2/1) to obtain yellow solid compound 4-3. MS m/z (ESI): 188.1 [M+H] + .
步骤3：将化合物4-3(4g，21.4mmol)溶解于80mL丙酮和25ml水中，0℃下缓慢加入高锰酸钾(6.7g，42.8mmol)，室温搅拌反应2天。再补加高锰酸钾(3.4g，21.7mmol)，继续反应18h。加入10g硫代硫酸钠，搅拌10min，过滤，滤液减压浓缩，残余物用EA(100ml x 3)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色固体化合物4-4(1.5g，产率：32％)。MS m/z(ESI):218[M+H] +。 Step 3: Dissolve compound 4-3 (4 g, 21.4 mmol) in 80 mL of acetone and 25 mL of water, slowly add potassium permanganate (6.7 g, 42.8 mmol) at 0°C, and stir at room temperature for 2 days. Then add potassium permanganate (3.4g, 21.7mmol), and continue the reaction for 18h. 10g sodium thiosulfate was added, stirred for 10min, filtered, the filtrate was concentrated under reduced pressure, and the residue was extracted with EA (100ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain yellow solid compound 4-4 (1.5 g, yield: 32%). MS m/z (ESI): 218 [M+H] + .
步骤4：将化合物4-4(109mg，0.5mmol)和化合物1a(130mg，0.5mmol)溶解于5mL DCE中，加入0.5mL钛酸四异丙酯，45℃搅拌反应过夜。冷却至室温，向反应液加入硼氢化钠(57mg，1.5mmol)，室温搅拌2h，向反应液中加入5mL水，搅拌0.5h，过滤，滤液减压浓缩，制备薄层色谱纯化(PE/EA＝1/4，加5％三乙胺)所得残余物，得褐色固体化合物4-5(160mg，产率：69.6％)。MS m/z(ESI):462[M+H] +。 Step 4: Dissolve compound 4-4 (109 mg, 0.5 mmol) and compound 1a (130 mg, 0.5 mmol) in 5 mL of DCE, add 0.5 mL of tetraisopropyl titanate, and stir to react overnight at 45°C. Cool to room temperature, add sodium borohydride (57mg, 1.5mmol) to the reaction solution, stir for 2h at room temperature, add 5mL water to the reaction solution, stir for 0.5h, filter, concentrate the filtrate under reduced pressure, and purify by preparative thin layer chromatography (PE/EA = 1/4, adding 5% triethylamine) to the residue to obtain brown solid compound 4-5 (160 mg, yield: 69.6%). MS m/z (ESI): 462 [M+H] + .
步骤5：将化合物4-5(0.16g，0.35mmol)溶解于10mLTFA，搅拌过夜。过滤，滤液减压浓缩。残余物溶解于15ml乙醇，加入钯/碳(48mg)，在氢气气氛下室温搅拌反应过夜。过滤，滤液减压浓缩，得棕色固体化合物4-6，粗产品直接用于下一步。MS m/z(ESI):446[M+H] +。 Step 5: Dissolve compound 4-5 (0.16 g, 0.35 mmol) in 10 mL TFA and stir overnight. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 15 ml of ethanol, palladium/carbon (48 mg) was added, and the reaction was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to obtain brown solid compound 4-6. The crude product was directly used in the next step. MS m/z (ESI): 446 [M+H] + .
步骤6：将四氢铝锂(26mg，0.675mmol)溶解于10mL干燥THF，加入化合物4-6(0.1g)的THF溶液(1ml)，搅拌过夜。0℃下加入5mL水，搅拌0.5h，过滤，滤液减压浓缩，制备色谱(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯 度：30％-60％乙腈变化)纯化所得残余物，分别得黄色固体化合物H-4(12.53mg，产率：13％)。MS m/z(ESI):432.3[M+H] +.1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝4.9,1.8Hz,1H),7.74-7.62(m,1H),7.43(dd,J＝8.1,1.1Hz,1H),7.18-7.15(m,1H),7.07-6.89(m,3H),3.90(d,J＝12.6Hz,1H),3.63–3.49(m,2H),3.48–3.33(m,3H),3.01(q,J＝4.5Hz,1H),2.39(d,J＝1.9Hz,4H),2.36–2.25(m,2H),2.03-1.69(m,5H),1.64–1.11(m,10H),1.00–0.89(m,1H),0.58(dq,J＝13.3,8.9Hz,1H). Step 6: Dissolve lithium tetrahydroaluminum (26 mg, 0.675 mmol) in 10 mL of dry THF, add compound 4-6 (0.1 g) in THF (1 mL), and stir overnight. Add 5mL water at 0℃, stir for 0.5h, filter, and concentrate the filtrate under reduced pressure. Preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%- The obtained residue was purified with 60% acetonitrile change) to obtain yellow solid compound H-4 (12.53 mg, yield: 13%). MS m/z(ESI): 432.3[M+H] + .1H NMR(400MHz,DMSO-d6)δ8.50(dd,J=4.9,1.8Hz,1H),7.74-7.62(m,1H), 7.43(dd,J=8.1,1.1Hz,1H),7.18-7.15(m,1H),7.07-6.89(m,3H),3.90(d,J=12.6Hz,1H),3.63-3.49(m, 2H), 3.48–3.33(m,3H), 3.01(q,J=4.5Hz,1H), 2.39(d,J=1.9Hz,4H), 2.36–2.25(m,2H), 2.03-1.69(m ,5H),1.64–1.11(m,10H),1.00–0.89(m,1H),0.58(dq,J=13.3,8.9Hz,1H).
和黄色化合物固体H-5(12.43mg，产率：13％)。MS m/z(ESI):432.3[M+H] +.1H NMR(400MHz,DMSO-d6)δ8.52-8.44(m,1H),7.69-7.66(m,1H),7.44-7.41(m,1H),7.17-7.10(m,1H),7.04(h,J＝7.5Hz,2H),6.96(d,J＝6.5Hz,1H),3.88(d,J＝12.6Hz,1H),3.62-3.45(m,3H),3.39(dd,J＝12.8,2.7Hz,1H),3.11(d,J＝7.6Hz,1H),2.44-2.38(m,1H),2.37(s,3H),2.30-2.26(m,2H),2.07–1.70(m,5H),1.69–1.19(m,10H),1.18–1.04(m,1H),0.94-0.90(m,1H),0.66–0.50(m,1H). And yellow compound solid H-5 (12.43 mg, yield: 13%). MS m/z(ESI): 432.3[M+H] + .1H NMR(400MHz,DMSO-d6)δ8.52-8.44(m,1H), 7.69-7.66(m,1H),7.44-7.41(m ,1H),7.17-7.10(m,1H),7.04(h,J=7.5Hz,2H),6.96(d,J=6.5Hz,1H),3.88(d,J=12.6Hz,1H),3.62 -3.45(m,3H), 3.39(dd,J=12.8,2.7Hz,1H), 3.11(d,J=7.6Hz,1H), 2.44-2.38(m,1H), 2.37(s,3H), 2.30-2.26(m,2H),2.07-1.70(m,5H),1.69-1.19(m,10H),1.18-1.04(m,1H),0.94-0.90(m,1H),0.66-0.50(m ,1H).
实施例6:1-甲基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-6)的制备Example 6: 1-Methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2, Preparation of 3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-6)
Figure PCTCN2020072851-appb-000035
Figure PCTCN2020072851-appb-000035
步骤1：将化合物6-1(5g，34.5mmol)溶解于80mL丙酮，加入碘甲烷(9.8g，69.0mmol)，室温反应过夜。过滤，滤饼溶解于30mL水，搅拌下加入4M氢氧化钠溶液至pH＝9-10，EA萃取(50mL x 3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得棕色油状物化合物6-2(4g,产率：72.7％)。MS m/z(ESI):160[M+H] +. Step 1: Dissolve compound 6-1 (5 g, 34.5 mmol) in 80 mL of acetone, add methyl iodide (9.8 g, 69.0 mmol), and react at room temperature overnight. After filtering, the filter cake was dissolved in 30 mL of water, 4M sodium hydroxide solution was added with stirring to pH=9-10, and EA extraction (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-2 (4 g, yield: 72.7%) as a brown oil. MS m/z(ESI): 160[M+H] + .
步骤2：将化合物6-2(4g,25.2mmol)溶解于80ml甲苯，加入溴乙酸乙酯(8.4g,50.4mmol)，45℃搅拌反应过夜。减压浓缩后得棕色固体化合物6-3，粗产品直接用于下一步。MS m/z(ESI):246[M+H] +。 Step 2: Dissolve compound 6-2 (4g, 25.2mmol) in 80ml of toluene, add ethyl bromoacetate (8.4g, 50.4mmol), stir and react at 45°C overnight. After concentration under reduced pressure, brown solid compound 6-3 was obtained, and the crude product was directly used in the next step. MS m/z (ESI): 246 [M+H] + .
步骤3：化合物6-3(8g)溶解于60mL乙醇，加入硼氢化钠(2.47g,65.0mmol)，室温反应5h。向反应液中加入50ml水，EA(80mL x 3)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂(PE/EA＝3/2，加1％三乙胺)纯化所得残余物，得红色油状液体化合物6-4(5g,产率62.5％)。MS m/z(ESI):248[M+H] +。 Step 3: Compound 6-3 (8g) was dissolved in 60mL ethanol, sodium borohydride (2.47g, 65.0mmol) was added and reacted at room temperature for 5h. 50 ml of water was added to the reaction solution, and EA (80 mL x 3) was extracted. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent (PE/EA=3/2, 1% triethylamine) to obtain compound 6-4 (5 g, yield 62.5%) as a red oily liquid. MS m/z (ESI): 248 [M+H] + .
步骤4：将化合物6-4(700mg,2.83mmol)和多聚磷酸(10g)混合后加热至130℃反应1h。降温至60℃，向反应液加入30mL水。用25％氨水溶液调整pH值至9左右，经EA(30mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂(PE/EA＝3/1)纯化所得残余物，得红色油状液体化合物6-5(400mg,产率70.2％)。MS m/z(ESI):202[M+H] +。 Step 4: Mix compound 6-4 (700 mg, 2.83 mmol) and polyphosphoric acid (10 g) and heat to 130° C. for reaction for 1 h. The temperature was lowered to 60°C, and 30 mL of water was added to the reaction solution. Adjust the pH value to about 9 with 25% ammonia solution, and extract with EA (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with eluent (PE/EA=3/1) to obtain compound 6-5 (400 mg, yield 70.2%) as a red oily liquid. MS m/z (ESI): 202 [M+H] + .
步骤5：将化合物6-5(65mg,0.3mmol)、化合物1a(78mg,0.3mmol)和钛酸四异丙酯 (0.5mL)溶解于6mL DCE，45℃反应6h。加入硼氢化钠(23mg,0.61mmol)，45℃下继续反应过夜。冷却到室温后，加2mL水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得黄色固体化合物H-6(12mg,产率8.99％)。MS m/z(ESI):446[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.50-8.47(m,1H),8.18(s,2H),7.69-7.66(m,1H),7.48-7.35(m,1H),7.19-7.15(m,1H),7.18-7.06(m,1H),7.08–6.96(m,1H),6.92(d,J＝7.2Hz,1H),3.86-3.81(m,1H),3.57-3.52(m,2H),3.06–2.90(m,1H),2.94-2.82(m,1H),2.65-2.61(m,1H),2.46–2.21(m,7H),2.16-2.12(m,1H),2.02-1.71(m,4H),1.71–1.25(m,8H),1.18-1.12(m,1H),0.97-0.89(m,1H),0.60-0.56(m,1H). Step 5: Dissolve compound 6-5 (65 mg, 0.3 mmol), compound 1a (78 mg, 0.3 mmol) and tetraisopropyl titanate (0.5 mL) in 6 mL of DCE, and react at 45° C. for 6 hours. Sodium borohydride (23mg, 0.61mmol) was added, and the reaction was continued overnight at 45°C. After cooling to room temperature, 2 mL of water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain yellow solid compound H-6 (12 mg, yield 8.99%). MS m/z (ESI): 446 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.50-8.47 (m, 1H), 8.18 (s, 2H), 7.69-7.66 (m, 1H), 7.48-7.35 (m, 1H), 7.19-7.15 ( m,1H),7.18-7.06(m,1H),7.08-6.96(m,1H),6.92(d,J=7.2Hz,1H),3.86-3.81(m,1H),3.57-3.52(m, 2H),3.06--2.90(m,1H),2.94-2.82(m,1H),2.65-2.61(m,1H),2.46-2.21(m,7H),2.16-2.12(m,1H),2.02- 1.71(m,4H), 1.71-1.25(m,8H), 1.18-1.12(m,1H), 0.97-0.89(m,1H), 0.60-0.56(m,1H).
实施例7:1-乙基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-7)的制备Example 7: 1-Ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2, Preparation of 3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-7)
Figure PCTCN2020072851-appb-000036
Figure PCTCN2020072851-appb-000036
以化合物6-1和碘乙烷为原料，制备方法参考化合物H-6。得到目标产物化合物H-7(6.2mg,黄色固体)。产率4.5％。MS m/z(ESI):460[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.50-8.48(m,1H),8.20(s,2H),7.70-7.66(m,1H),7.43-7.40(m,1H),7.22–7.08(m,1H),7.10–6.98(m,1H),6.97-6.93(m,1H),4.01–3.95(m,1H),3.62–3.50(m,2H),3.39-3.35(m,1H),3.08-3.02(m,1H),2.85-2.82(m,2H),2.68(d,J＝15.9Hz,1H),2.47–2.24(m,4H),2.18-2.15(m,1H),2.07–1.09(m,13H),1.05–0.88(m,3H),0.60-0.56(m,1H). Using compound 6-1 and iodoethane as raw materials, the preparation method refers to compound H-6. The target compound H-7 (6.2 mg, yellow solid) was obtained. The yield was 4.5%. MS m/z (ESI): 460 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.50-8.48 (m, 1H), 8.20 (s, 2H), 7.70-7.66 (m, 1H), 7.43-7.40 (m, 1H), 7.22-7.08 ( m,1H),7.10-6.98(m,1H),6.97-6.93(m,1H),4.01-3.95(m,1H),3.62-3.50(m,2H), 3.39-3.35(m,1H), 3.08-3.02(m,1H),2.85-2.82(m,2H), 2.68(d,J=15.9Hz,1H), 2.47–2.24(m,4H), 2.18-2.15(m,1H), 2.07– 1.09(m,13H),1.05-0.88(m,3H),0.60-0.56(m,1H).
实施例8:1-异丙基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-8)的制备Example 8: 1-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-8) preparation
Figure PCTCN2020072851-appb-000037
Figure PCTCN2020072851-appb-000037
以化合物6-1和碘代异丙烷为原料，制备方法参考化合物H-6。得化合物H-8(2mg,棕色固体)。产率2.1％。MS m/z(ESI):474[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.49-8.45(m,1H),7.66-7.62(m,1H),7.37-7.33(m,1H),7.18–7.10(m,1H),7.03–6.88(m,2H),6.83(d,J＝6.8Hz,1H),3.57–3.47(m,3H),3.26-3.21(m,2H),3.00–2.91(m,1H),2.67-2.62(m,2H),2.36(d,J＝13.5Hz,1H),2.28(d,J＝13.6Hz,3H),2.18–2.09(m,1H),1.99–1.17(m,13H),1.16-1.13(s,1H),1.05-1.01(m,4H),0.97–0.88(m,1H),0.83-0.80(m,3H),0.57-0.53(m,1H). Using compound 6-1 and iodoisopropane as raw materials, the preparation method refers to compound H-6. Compound H-8 (2mg, brown solid) was obtained. The yield was 2.1%. MS m/z (ESI): 474 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.49-8.45(m,1H), 7.66-7.62(m,1H), 7.37-7.33(m,1H), 7.18-7.10(m,1H), 7.03- 6.88(m,2H),6.83(d,J=6.8Hz,1H),3.57–3.47(m,3H),3.26-3.21(m,2H),3.00–2.91(m,1H),2.67-2.62( m, 2H), 2.36 (d, J = 13.5 Hz, 1H), 2.28 (d, J = 13.6 Hz, 3H), 2.18-2.09 (m, 1H), 1.99-1.17 (m, 13H), 1.16-1.13 (s, 1H), 1.05-1.01 (m, 4H), 0.97-0.88 (m, 1H), 0.83-0.80 (m, 3H), 0.57-0.53 (m, 1H).
实施例9:5-甲基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,6,7-四氢-1H，5H-吡啶并[3,2,1-ij]喹啉-1-胺(H-9)的制备Example 9: 5-Methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2, Preparation of 3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-amine (H-9)
Figure PCTCN2020072851-appb-000038
Figure PCTCN2020072851-appb-000038
以化合物9-1和3-溴丙酸甲酯为原料，制备方法参考化合物H-1。得化合物H-9(1.81mg，黄色油状物)，产率：2％。MS m/z(ESI):446.3[M+H] +. 1H NMR(400MHz,CD3OD)δ8.52-8.48(m,1H),7.76-7.70(m,1H),7.46(d,J＝7.9Hz,1H),7.21(dd,J＝12.3,7.3Hz,1H),6.74(d,J＝7.3Hz,1H),6.60(dd,J＝31.4,7.2Hz,1H),6.31-6.28(m,1H),3.76-3.72(m,2H),3.51-3.46(m,1H),3.40–3.30(m,1H),3.27–3.20(m,1H),3.10–3.00(m,1H),2.93–2.65(m,2H),2.63–2.36(m,4H),2.12–1.93(m,2H),1.88(d,J＝13.7Hz,1H),1.82–1.33(m,11H),1.12-1.08(m,4H),0.76–0.64(m,1H). Using compound 9-1 and methyl 3-bromopropionate as raw materials, the preparation method refers to compound H-1. Compound H-9 (1.81 mg, yellow oil) was obtained, yield: 2%. MS m/z(ESI): 446.3[M+H] + . 1 H NMR(400MHz,CD3OD)δ8.52-8.48(m,1H),7.76-7.70(m,1H),7.46(d,J= 7.9Hz, 1H), 7.21 (dd, J = 12.3, 7.3 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 6.60 (dd, J = 31.4, 7.2 Hz, 1H), 6.31-6.28 ( m, 1H), 3.76-3.72 (m, 2H), 3.51-3.46 (m, 1H), 3.40-3.30 (m, 1H), 3.27-3.20 (m, 1H), 3.10-3.00 (m, 1H), 2.93–2.65(m,2H), 2.63–2.36(m,4H), 2.12–1.93(m,2H), 1.88(d,J=13.7Hz,1H), 1.82–1.33(m,11H),1.12- 1.08 (m, 4H), 0.76-0.64 (m, 1H).
实施例10 N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,3a,4,5,6-六氢-1H-菲-1-胺(H-10)的制备Example 10 N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3,3a,4, Preparation of 5,6-hexahydro-1H-phenanthrene-1-amine (H-10)
Figure PCTCN2020072851-appb-000039
Figure PCTCN2020072851-appb-000039
步骤1：室温下，把化合物10-1(1.46g,10.0mmol)和丁二酸二乙酯(2.61g,15.0mmol)溶解于5ml叔丁醇，将所得溶液加入到钠(264mg)于15ml叔丁醇的悬浮液中。反应液加热回流反应6h，冷却到室温后，用2M盐酸淬灭反应，EA萃取(50ml*3)。合并有机相后用1M氢氧化钠溶液洗涤，分离出水相用EA洗涤(30ml*2)，用2M的盐酸酸化至pH～2，再用EA萃取(50ml*2)。合并有机相，用饱和食盐水洗涤(50ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～50/50)纯化所得残余物，得到化合物10-2(0.9g,棕色液体)，产率32.8％。MS m/z(ESI):275.1[M+H] +. 1H NMR(400MHz,DMSO-d6)δ7.26(d,J＝7.6Hz,1H),7.22–7.16(m,1H),7.13(d,J＝3.6Hz,2H),5.92(t,J＝4.5Hz,1H),4.04(q,J＝7.1Hz,2H),3.97(dd,J＝10.0,4.4Hz,1H),2.80(dd,J＝16.9,10.1Hz,1H),2.61(t,J＝8.0Hz,2H),2.54–2.40(m,1H),2.16(dd,J＝12.5,7.6Hz,2H),1.08(t,J＝7.1Hz,3H). Step 1: At room temperature, dissolve compound 10-1 (1.46g, 10.0mmol) and diethyl succinate (2.61g, 15.0mmol) in 5ml tert-butanol, add the resulting solution to sodium (264mg) in 15ml In a suspension of tert-butanol. The reaction solution was heated to reflux for 6h, and after cooling to room temperature, the reaction was quenched with 2M hydrochloric acid, and extracted with EA (50ml*3). The organic phases were combined and washed with 1M sodium hydroxide solution. The separated aqueous phase was washed with EA (30ml*2), acidified with 2M hydrochloric acid to pH~2, and then extracted with EA (50ml*2). The organic phases were combined, washed with saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～50/50) From the obtained residue, compound 10-2 (0.9 g, brown liquid) was obtained with a yield of 32.8%. MS m/z(ESI): 275.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.22-7.16(m,1H),7.13 (d, J = 3.6 Hz, 2H), 5.92 (t, J = 4.5 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.97 (dd, J = 10.0, 4.4 Hz, 1H), 2.80 (dd,J=16.9,10.1Hz,1H), 2.61(t,J=8.0Hz,2H), 2.54-2.40(m,1H), 2.16(dd,J=12.5,7.6Hz,2H), 1.08( t,J=7.1Hz,3H).
步骤2：将化合物10-2(1.80g,5.11mmol)溶解于30ml乙酸、15ml浓盐酸和20ml水的混合溶剂中，加热回流24h。减压蒸馏除去溶剂，残余物用50mlEA稀释，用2M氢氧化钠溶液洗涤，分离出水相，用30mlEA洗涤，水相用浓盐酸调节pH至2～3，用EA萃取(50ml*2)。合并有机相，饱和食盐水洗涤(30ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～70/30)纯化所得残余物，得到化合物10-3(230mg,白色固体)，产率17.4％。MS m/z(ESI):203.1[M+H] +. 1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.25–6.97(m,4H),5.84(t,J＝4.4Hz,1H),2.62(t,J＝7.9Hz,4H),2.37(t,J＝7.6Hz,2H),2.14(dd,J＝12.4,7.8Hz,2H). Step 2: Dissolve compound 10-2 (1.80 g, 5.11 mmol) in a mixed solvent of 30 ml of acetic acid, 15 ml of concentrated hydrochloric acid and 20 ml of water, and heat to reflux for 24 hours. The solvent was distilled off under reduced pressure, the residue was diluted with 50ml EA, washed with 2M sodium hydroxide solution, the aqueous phase was separated, washed with 30ml EA, the aqueous phase was adjusted to pH 2 to 3 with concentrated hydrochloric acid, and extracted with EA (50ml*2). The organic phases were combined, washed with saturated brine (30ml), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～70/30) From the residue, compound 10-3 (230 mg, white solid) was obtained with a yield of 17.4%. MS m/z(ESI): 203.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.25-6.97(m,4H),5.84(t,J= 4.4Hz, 1H), 2.62 (t, J = 7.9 Hz, 4H), 2.37 (t, J = 7.6 Hz, 2H), 2.14 (dd, J = 12.4, 7.8 Hz, 2H).
步骤3：将化合物10-3(210mg)溶解于10ml乙醇中，加入20毫克Pd/C，室温下用氢 气置换三次后，在常温常压下反应16h，过滤除去催化剂，滤液减压浓缩，得到化合物10-4(101mg,无色透明液体)，产率47.6％。MS m/z(ESI):203.1[M-H] -。 Step 3: Dissolve compound 10-3 (210mg) in 10ml ethanol, add 20mg Pd/C, replace with hydrogen three times at room temperature, react for 16h at room temperature and pressure, filter to remove the catalyst, and concentrate the filtrate under reduced pressure to obtain Compound 10-4 (101 mg, colorless and transparent liquid), the yield was 47.6%. MS m/z (ESI): 203.1 [MH] - .
步骤4：向化合物10-4(111mg,0.54mmol)和多聚磷酸(2g)的化合物中加入三滴DMSO，加热到100℃反应1h，冷却到60℃后用碎冰淬灭反应，反应液用EA萃取(30ml*2)。合并有机相，依次用水(30ml)，饱和碳酸氢钠溶液(30ml)，饱和食盐水洗涤(30ml)，无水硫酸钠干燥，减压浓缩，得到化合物10-5(81mg,黄色油状物)，产率80.2％。MS m/z(ESI):187.1[M+H] +。 Step 4: Add three drops of DMSO to the compound of compound 10-4 (111mg, 0.54mmol) and polyphosphoric acid (2g), heat to 100°C and react for 1h, cool to 60°C and quench the reaction with crushed ice. Extract with EA (30ml*2). The organic phases were combined, washed with water (30ml), saturated sodium bicarbonate solution (30ml), saturated brine (30ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 10-5 (81mg, yellow oil). The yield was 80.2%. MS m/z (ESI): 187.1 [M+H] + .
步骤5：化合物10-5(38mg,020mmol)和化合物1a(44mg,0.17mmol)溶解于5ml二氯乙烷中，加热到80℃反应16h后加入硼氢化钠(13mg,0.34mmol)，继续在80℃下反应48h。冷却到室温后，过滤，滤饼用甲醇洗涤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-10(5mg,黄色固体)，产率5.2％。MS m/z(ESI):431.3[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.31(s,1H),7.76–7.58(m,1H),7.41(dd,J＝16.3,9.5Hz,1H),7.36–6.67(m,4H),3.53(d,J＝20.3Hz,4H),2.66(d,J＝6.4Hz,2H),2.46–2.14(m,5H),2.09–0.84(m,18H),0.58(dd,J＝8.8,4.4Hz,1H). Step 5: Compound 10-5 (38mg, 020mmol) and compound 1a (44mg, 0.17mmol) were dissolved in 5ml of dichloroethane, heated to 80℃ and reacted for 16h, then sodium borohydride (13mg, 0.34mmol) was added, and then React at 80°C for 48h. After cooling to room temperature, it was filtered, the filter cake was washed with methanol, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-10 (5 mg, yellow solid) with a yield of 5.2%. MS m/z (ESI): 431.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.31(s,1H),7.76-7.58(m,1H),7.41(dd,J=16.3,9.5Hz,1H),7.36 –6.67(m,4H),3.53(d,J=20.3Hz,4H), 2.66(d,J=6.4Hz,2H), 2.46–2.14(m,5H), 2.09–0.84(m,18H), 0.58(dd,J=8.8,4.4Hz,1H).
实施例11 N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,3a,4,5,6-六氢萘并[1,8-bc]吡喃-6-胺(H-11)的制备Example 11 N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2,3,3a,4, Preparation of 5,6-Hexahydronaphtho[1,8-bc]pyran-6-amine (H-11)
Figure PCTCN2020072851-appb-000040
Figure PCTCN2020072851-appb-000040
步骤1：将化合物11-1(6.6g，44.6mmol)溶解于60ml甲醇，0℃下分批加入硼氢化钠(2.03g，53.5mmol)，反应温度回升到室温，反应2h。除去反应溶剂后，加入1M盐酸溶液淬灭反应，EA萃取(50mL x 3)。合并有机相，用水(80ml)和饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物11-2(6.5g,黄色油状液体)，产率97.2％。 1H NMR(400MHz,dmso)δ7.30–7.23(m,1H),7.13–7.06(m,1H),6.82(t,J＝7.4Hz,1H),6.70(d,J＝8.2Hz,1H),5.29(d,J＝4.0Hz,1H),4.57(d,J＝3.3Hz,1H),4.17–4.09(m,2H),2.01–1.93(m,1H),1.89–1.78(m,1H). Step 1: Dissolve compound 11-1 (6.6 g, 44.6 mmol) in 60 ml of methanol, add sodium borohydride (2.03 g, 53.5 mmol) in batches at 0°C, return the reaction temperature to room temperature, and react for 2 hours. After removing the reaction solvent, 1M hydrochloric acid solution was added to quench the reaction, and EA extraction (50 mL x 3). The organic phases were combined, washed with water (80 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-2 (6.5 g, yellow oily liquid) with a yield of 97.2%. 1 H NMR(400MHz,dmso)δ7.30–7.23(m,1H), 7.13–7.06(m,1H), 6.82(t,J=7.4Hz,1H), 6.70(d,J=8.2Hz,1H ), 5.29(d,J=4.0Hz,1H),4.57(d,J=3.3Hz,1H),4.17–4.09(m,2H),2.01–1.93(m,1H),1.89–1.78(m, 1H).
步骤2：将化合物11-2(5.0g,33mmol)和三甲基氰硅烷(6.53g,66mmol)溶解于60ml乙腈，0℃下加入三氟化硼乙醚(9.37g,66mmol)，反应温度回升到室温，反应2h。向反应液中加入饱和碳酸氢钠溶液(50ml)，DCM萃取(50ml*3)。合并有机相，用水(50ml)和饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～80/20)纯化所得残余物，得化合物11-3(3.67g,黄色油状液体)，产率 69.9％。 1H NMR(400MHz,dmso)δ7.29–7.24(m,1H),7.19(ddd,J＝7.6,4.8,1.5Hz,1H),6.92(td,J＝7.5,1.2Hz,1H),6.80(dd,J＝8.3,1.0Hz,1H),4.41(t,J＝6.1Hz,1H),4.22–4.12(m,2H),2.32–2.12(m,2H). Step 2: Dissolve compound 11-2 (5.0g, 33mmol) and trimethylsilyl cyanide (6.53g, 66mmol) in 60ml of acetonitrile, add boron trifluoride ether (9.37g, 66mmol) at 0°C, and the reaction temperature rises To room temperature, react for 2h. Saturated sodium bicarbonate solution (50ml) was added to the reaction solution, and DCM extraction (50ml*3). The organic phases were combined, washed with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～80/20) to obtain compound 11-3 (3.67 g, yellow oily liquid) with a yield of 69.9%. 1 H NMR(400MHz,dmso)δ7.29–7.24(m,1H), 7.19(ddd,J=7.6,4.8,1.5Hz,1H), 6.92(td,J=7.5,1.2Hz,1H), 6.80 (dd,J=8.3,1.0Hz,1H), 4.41(t,J=6.1Hz,1H), 4.22-4.12(m,2H), 2.32-2.12(m,2H).
步骤3：将化合物11-3(4.3g,27.0mmol)和氢氧化钠(10.8g,270mmol)溶解于甲醇(10ml)和水(50ml)的混合溶剂中。加热至100℃反应24h。用6M盐酸溶液将反应液pH值调至1-2，EA(50ml*3)萃取。合并有机相，用水(80ml)和饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物11-4(4.3g,黄色油状液体)，产率89.4％。MS m/z(ESI):179.1[M+H] +。 Step 3: Compound 11-3 (4.3 g, 27.0 mmol) and sodium hydroxide (10.8 g, 270 mmol) were dissolved in a mixed solvent of methanol (10 ml) and water (50 ml). Heat to 100°C for 24h. Adjust the pH value of the reaction solution to 1-2 with 6M hydrochloric acid solution, and extract with EA (50ml*3). The organic phases were combined, washed with water (80ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-4 (4.3g, yellow oily liquid) with a yield of 89.4%. MS m/z (ESI): 179.1 [M+H] + .
步骤4：化合物11-4(4.3g,24.2mmol)溶解于THF(50ml)，逐滴加入硼烷THF溶液(48ml,48.4mmol)。反应过夜后加入甲醇淬灭、减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～80/20)纯化所得残余物，得化合物11-5(3.67g,无色油状液体)，产率87.9％。MS m/z(ESI):165.1[M+H] +。 Step 4: Compound 11-4 (4.3g, 24.2mmol) was dissolved in THF (50ml), and borane THF solution (48ml, 48.4mmol) was added dropwise. After reacting overnight, it was quenched by adding methanol and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～80/20) to obtain compound 11-5 (3.67 g, colorless oily liquid) with a yield of 87.9%. MS m/z (ESI): 165.1 [M+H] + .
步骤5：将化合物11-5(1.64g,10.0mmol)溶解于DCM(50ml)，分批加入戴斯-马丁试剂(6.36g,15.0mmol)。在室温下反应3h。过滤除去不溶物，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～90/10)纯化所得残余物，得化合物11-6(1.44g,无色油状液体)，产率88.9％。MS m/z(ESI):163.1[M+H] +。 1H NMR(400MHz,dmso)δ9.68–9.66(m,1H),7.26–7.20(m,1H),7.14(dddd,J＝8.1,7.3,1.7,0.6Hz,1H),6.90(td,J＝7.4,1.2Hz,1H),6.82–6.75(m,1H),4.17(dddd,J＝11.1,4.7,3.7,1.1Hz,1H),3.85–3.76(m,1H),3.76–3.71(m,1H),2.29(dddd,J＝14.1,4.6,3.9,2.6Hz,1H),2.03–1.91(m,1H). Step 5: Dissolve compound 11-5 (1.64g, 10.0mmol) in DCM (50ml), add Dess-Martin reagent (6.36g, 15.0mmol) in batches. React at room temperature for 3h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～90/10) to obtain compound 11-6 (1.44 g, colorless oily liquid) with a yield of 88.9%. MS m/z (ESI): 163.1 [M+H] + . 1 H NMR(400MHz,dmso)δ9.68–9.66(m,1H), 7.26–7.20(m,1H), 7.14(dddd, J=8.1,7.3,1.7,0.6Hz,1H), 6.90(td, J = 7.4, 1.2 Hz, 1H), 6.82–6.75 (m, 1H), 4.17 (dddd, J = 11.1, 4.7, 3.7, 1.1 Hz, 1H), 3.85–3.76 (m, 1H), 3.76–3.71 ( m, 1H), 2.29 (dddd, J = 14.1, 4.6, 3.9, 2.6 Hz, 1H), 2.03-1.91 (m, 1H).
步骤6：将2-(二乙氧基磷酰基)乙酸乙酯(2.77g,12.3mmol)溶解于THF(30ml)，0℃下分批加入钠氢(0.5g,12.34mmol)。0℃下反应30min后加入化合物11-6(1.0g,6.17mmol)的THF溶液(5ml)。反应温度缓缓升至室温后再反应2h。用2M盐酸溶液淬灭反应，EA萃取(50ml*3)。合并有机相，用饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～80/20)纯化所得残余物，得化合物11-7(0.53g,黄色油状液体)，产率42.0％。MS m/z(ESI):205.1[M+H] +。 1H NMR(400MHz,dmso)δ12.30(s,1H),7.56(dd,J＝8.0,1.4Hz,1H),7.10(dt,J＝8.4,3.1Hz,1H),6.85(dt,J＝12.1,2.5Hz,1H),6.76(dt,J＝9.5,4.7Hz,1H),6.15(t,J＝7.2Hz,1H),4.12–4.03(m,2H),3.17(t,J＝10.5Hz,2H),2.55(dd,J＝13.9,8.5Hz,2H). Step 6: Dissolve ethyl 2-(diethoxyphosphoryl)acetate (2.77 g, 12.3 mmol) in THF (30 ml), and add sodium hydrogen (0.5 g, 12.34 mmol) in portions at 0°C. After reacting at 0°C for 30 min, a THF solution (5 ml) of compound 11-6 (1.0 g, 6.17 mmol) was added. The reaction temperature was slowly raised to room temperature and then reacted for 2 hours. The reaction was quenched with 2M hydrochloric acid solution, and extracted with EA (50ml*3). The organic phases were combined, washed with saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～80/20) The obtained residue was compound 11-7 (0.53 g, yellow oily liquid) with a yield of 42.0%. MS m/z (ESI): 205.1 [M+H] + . 1 H NMR (400MHz, dmso) δ 12.30 (s, 1H), 7.56 (dd, J = 8.0, 1.4 Hz, 1H), 7.10 (dt, J = 8.4, 3.1 Hz, 1H), 6.85 (dt, J = 12.1, 2.5 Hz, 1H), 6.76 (dt, J = 9.5, 4.7 Hz, 1H), 6.15 (t, J = 7.2 Hz, 1H), 4.12-4.03 (m, 2H), 3.17 (t, J = 10.5Hz, 2H), 2.55 (dd, J=13.9, 8.5Hz, 2H).
步骤7：将化合物11-7(100mg,0.49mmol)和钯/碳(10mg)加入到乙醇(5ml)中，氢气环境下反应7h。反应液经硅藻土过滤，滤液减压浓缩，得化合物11-8(88mg,泛黄色油状液体)，产率87.1％。MS m/z(ESI):205.1[M-H] -。 Step 7: Add compound 11-7 (100mg, 0.49mmol) and palladium/carbon (10mg) to ethanol (5ml), and react for 7h under hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 11-8 (88 mg, yellowish oily liquid) with a yield of 87.1%. MS m/z (ESI): 205.1 [MH] - .
步骤8：将化合物11-8(68mg,0.33mmol)和多聚磷酸(2g)加热到120℃反应1h。向反应液加入EA(20ml)，用水(20ml)饱和食盐水洗涤(20ml)和饱和食盐水(20ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～80/20)纯化所得残余物，得化合物11-9(30mg,黄色固体)，产率38.0％。MS m/z(ESI):189.1 [M+H] +。 Step 8: Heat compound 11-8 (68 mg, 0.33 mmol) and polyphosphoric acid (2 g) to 120° C. and react for 1 h. EA (20ml) was added to the reaction solution, washed with water (20ml) saturated brine (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～80/20) to obtain compound 11-9 (30 mg, yellow solid) with a yield of 38.0%. MS m/z (ESI): 189.1 [M+H] + .
步骤9：将化合物11-9(28mg,0.11mmol)和化合物1a(20mg,0.11mmol)溶解于DCE，加入2滴钛酸四异丙酯。80℃下反应3h后，加入硼氢化钠(8mg,0.21mmol)，继续在80℃下反应16h。冷却到室温后，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得化合物H-11(5mg,黄色固体)，产率6.8％。MS m/z(ESI):433.3[M+H] +. 1H NMR(400MHz,cdcl 3)δ8.49(dd,J＝15.3,4.1Hz,1H),8.36(s,1H),7.62(dt,J＝13.8,7.1Hz,1H),7.33–7.25(m,1H),7.11(dd,J＝14.6,7.3Hz,1H),6.97(ddd,J＝46.8,27.3,7.9Hz,2H),6.73–6.59(m,1H),4.33(d,J＝6.6Hz,1H),4.19–3.92(m,2H),3.71(d,J＝6.4Hz,2H),2.68–2.31(m,3H),2.24(ddd,J＝55.7,31.1,13.6Hz,5H),2.01–1.82(m,3H),1.83–1.55(m,5H),1.54–1.28(m,4H),1.20(d,J＝12.6Hz,1H),1.08(s,1H),0.64(dd,J＝22.4,8.9Hz,1H). Step 9: Dissolve compound 11-9 (28 mg, 0.11 mmol) and compound 1a (20 mg, 0.11 mmol) in DCE, and add 2 drops of tetraisopropyl titanate. After reacting at 80°C for 3h, sodium borohydride (8mg, 0.21mmol) was added, and the reaction was continued at 80°C for 16h. After cooling to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-11 (5 mg, yellow solid) with a yield of 6.8%. MS m/z(ESI): 433.3[M+H] + . 1 H NMR(400MHz, cdcl 3 )δ8.49(dd, J = 15.3, 4.1Hz, 1H), 8.36(s, 1H), 7.62( dt,J=13.8,7.1Hz,1H),7.33-7.25(m,1H),7.11(dd,J=14.6,7.3Hz,1H), 6.97(ddd,J=46.8,27.3,7.9Hz,2H) ,6.73-6.59(m,1H),4.33(d,J=6.6Hz,1H),4.19-3.92(m,2H),3.71(d,J=6.4Hz,2H),2.68-2.31(m,3H ), 2.24(ddd,J=55.7,31.1,13.6Hz,5H),2.01–1.82(m,3H),1.83–1.55(m,5H),1.54–1.28(m,4H),1.20(d,J = 12.6Hz, 1H), 1.08 (s, 1H), 0.64 (dd, J = 22.4, 8.9 Hz, 1H).
实施例12 2-(7-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酸异丙酯(H-12，非对映异构体混合物1)的制备Example 12 2-(7-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)amino)-2,3, Preparation of 7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)isopropyl acetate (H-12, diastereoisomer mixture 1)
实施例13 2-(7-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酸异丙酯(H-13，非对映异构体混合物2)的制备Example 13 2-(7-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)amino)-2,3, Preparation of 7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)isopropyl acetate (H-13, diastereoisomer mixture 2)
Figure PCTCN2020072851-appb-000041
Figure PCTCN2020072851-appb-000041
步骤1：将化合物6-1(2.1g，14.5mmol)和苄溴(3.7g，21.7mmol)溶解于85ml甲苯，90℃下反应16h。过滤，滤饼经PE洗涤，真空干燥，得化合物12-2(3.8g,棕色固体)。粗产品直接用于下一步反应。MS m/z(ESI):236.1.Step 1: Compound 6-1 (2.1g, 14.5mmol) and benzyl bromide (3.7g, 21.7mmol) were dissolved in 85ml of toluene and reacted at 90°C for 16h. After filtration, the filter cake was washed with PE and dried in vacuum to obtain compound 12-2 (3.8 g, brown solid). The crude product is directly used in the next reaction. MS m/z(ESI): 236.1.
步骤2：将化合物12-2(3.8g)溶解于20ml水，搅拌下加入4M氢氧化钠溶液(10ml)。反应液用EA萃取(50ml*3)。合并有机相，用饱和食盐水(100ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得化合物12-3(2.8g,棕色油状液体)，粗产品直接用于下一步反应。MS m/z(ESI):236.1[M+H] +. Step 2: Dissolve compound 12-2 (3.8g) in 20ml water, and add 4M sodium hydroxide solution (10ml) with stirring. The reaction solution was extracted with EA (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-3 (2.8 g, brown oily liquid). The crude product was directly used in the next reaction. MS m/z(ESI): 236.1[M+H] + .
步骤3：在搅拌下，将溴乙酸乙酯(5ml)缓慢的加到油状的化合物12-3(2.8g)中，加热至60℃反应16h。除去残余的溴乙酸乙酯后得化合物12-4(3.5g,棕色油状液体)，粗产品直接用于下一步反应。MS m/z(ESI):322.2.Step 3: Under stirring, slowly add ethyl bromoacetate (5 ml) to the oily compound 12-3 (2.8 g), and heat to 60° C. to react for 16 hours. After removing the remaining ethyl bromoacetate, compound 12-4 (3.5 g, brown oily liquid) was obtained, and the crude product was directly used in the next reaction. MS m/z(ESI): 322.2
步骤4：化合物12-4(3.5g)溶解于乙醇(50ml)，分批加入硼氢化钠(0.83g,21.7mmol)。反应过夜后减压蒸馏出溶剂。加水并用DCM(50ml*3)萃取。合并有机相，用饱和食盐水(100ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用制备液相色谱纯化所得残余物，得化合物12-5(1.1g,黄色油状液体)，产率31.4％。MS m/z(ESI):324.2[M+H] +. Step 4: Compound 12-4 (3.5g) was dissolved in ethanol (50ml), and sodium borohydride (0.83g, 21.7mmol) was added in portions. After reacting overnight, the solvent was distilled off under reduced pressure. Water was added and extracted with DCM (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative liquid chromatography to obtain compound 12-5 (1.1 g, yellow oily liquid) with a yield of 31.4%. MS m/z(ESI): 324.2[M+H] + .
步骤5：将化合物12-5(1g,3.1mmol)和多聚磷酸(3g)加热到140℃反应2h。降温至 60℃，向反应液加入冰水。用25％氨水溶液调整pH值至9左右，经DCM(20ml*4)萃取。合并有机相，用饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～70/30)纯化所得残余物，得化合物12-6(500mg,黄色油状液体)，产率53％。MS m/z(ESI):278.2[M+H] +. Step 5: Heat compound 12-5 (1 g, 3.1 mmol) and polyphosphoric acid (3 g) to 140° C. and react for 2 hours. The temperature was lowered to 60°C, and ice water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (20ml*4). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～70/30) to obtain compound 12-6 (500 mg, yellow oily liquid) with a yield of 53%. MS m/z(ESI): 278.2[M+H] + .
步骤6：将化合物12-6(460mg,1.66mmol)和钯/碳(50mg)加入到乙醇(10ml)中，氢气环境下反应16h。反应液经硅藻土过滤，滤液减压浓缩，得化合物12-7(0.2g,黄色油状液体)，粗产品直接用于下一步反应。MS m/z(ESI):188.1[M+H] +. Step 6: Compound 12-6 (460 mg, 1.66 mmol) and palladium/carbon (50 mg) were added to ethanol (10 ml), and reacted for 16 h under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 12-7 (0.2 g, yellow oily liquid). The crude product was directly used in the next reaction. MS m/z(ESI): 188.1[M+H] + .
步骤7：将化合物12-7(180mg)、溴乙酸乙酯(161mg,0.96mmol)和碳酸钠(204mg,1.92mmol)加入到乙腈(10ml)中室温反应3h。减压蒸馏除去溶剂。残留物经DCM(30ml)稀释，用水(20ml)和饱和食盐水(20ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～70/30)纯化所得残余物，得化合物12-8(100mg,黄色油状液体)，产率34.2％。MS m/z(ESI):274.2[M+H] +. Step 7: Compound 12-7 (180mg), ethyl bromoacetate (161mg, 0.96mmol) and sodium carbonate (204mg, 1.92mmol) were added to acetonitrile (10ml) to react at room temperature for 3h. The solvent was distilled off under reduced pressure. The residue was diluted with DCM (30ml), washed with water (20ml) and saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～70/30) to obtain compound 12-8 (100 mg, yellow oily liquid) with a yield of 34.2%. MS m/z(ESI): 274.2[M+H] + .
步骤8：将化合物12-8(30mg,0.11mmol)、化合物1a(29mg,0.11mmol)和钛酸四异丙酯(0.8ml)溶解于DCE。45℃下反应16h后，加入硼氢化钠(9mg,0.22mmol)，继续在45℃下反应1h。冷却到室温后，加水，过滤，滤液减压浓缩，用制备液相色谱(制备柱：21.2X250mmC18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化所得残余物，分别得到目标产物H-12(2.02mg,淡粉色固体)，MS m/z(ESI):532.4[M+H] +. 1H NMR(400MHz,dmso)δ8.47(t,J＝2.0Hz,1H),8.25(s,1H),7.66(dd,J＝13.8,6.4Hz,1H),7.38(t,J＝8.9Hz,1H),7.19–7.11(m,1H),7.10–6.93(m,2H),6.88(d,J＝6.9Hz,1H),4.90(dt,J＝12.4,6.2Hz,1H),3.69–3.47(m,6H),3.39(dd,J＝29.5,16.6Hz,2H),2.96(dd,J＝11.6,5.3Hz,1H),2.91–2.73(m,2H),2.63(d,J＝12.3Hz,1H),2.32(dd,J＝28.1,12.6Hz,3H),2.12–1.99(m,1H),1.99–1.77(m,3H),1.77–1.68(m,1H),1.60(t,J＝13.1Hz,2H),1.55–1.23(m,6H),1.16(d,J＝6.2Hz,6H),0.98–0.84(m,1H),0.58(dt,J＝12.8,8.8Hz,1H). Step 8: Dissolve compound 12-8 (30 mg, 0.11 mmol), compound 1a (29 mg, 0.11 mmol) and tetraisopropyl titanate (0.8 ml) in DCE. After reacting at 45°C for 16h, sodium borohydride (9mg, 0.22mmol) was added, and the reaction was continued at 45°C for 1h. After cooling to room temperature, add water, filter, and concentrate the filtrate under reduced pressure. Use preparative liquid chromatography (preparative column: 21.2X250mmC18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%-60% Acetonitrile change) the residue obtained was purified to obtain the target product H-12 (2.02mg, pale pink solid), MS m/z (ESI): 532.4[M+H] + . 1 H NMR (400MHz, dmso) δ8. 47(t,J=2.0Hz,1H),8.25(s,1H),7.66(dd,J=13.8,6.4Hz,1H),7.38(t,J=8.9Hz,1H),7.19–7.11(m ,1H),7.10–6.93(m,2H),6.88(d,J=6.9Hz,1H), 4.90(dt,J=12.4,6.2Hz,1H), 3.69–3.47(m,6H), 3.39( dd, J = 29.5, 16.6 Hz, 2H), 2.96 (dd, J = 11.6, 5.3 Hz, 1H), 2.91–2.73 (m, 2H), 2.63 (d, J = 12.3 Hz, 1H), 2.32 (dd ,J=28.1,12.6Hz,3H), 2.12–1.99(m,1H),1.99–1.77(m,3H),1.77–1.68(m,1H),1.60(t,J=13.1Hz,2H), 1.55–1.23(m,6H), 1.16(d,J=6.2Hz,6H), 0.98–0.84(m,1H), 0.58(dt,J=12.8,8.8Hz,1H).
和H-13：MS m/z(ESI):532.4[M+H] +.1H NMR(400MHz,dmso)δ8.50(d,J＝3.5Hz,1H),8.29(s,2H),7.72–7.65(m,1H),7.43(d,J＝7.6Hz,1H),7.19–7.13(m,1H),7.03–6.89(m,2H),6.88–6.83(m,1H),4.94–4.86(m,1H),3.68–3.51(m,8H),2.99–2.92(m,1H),2.81(d,J＝6.3Hz,2H),2.62(d,J＝13.8Hz,1H),2.44–2.24(m,3H),2.07–1.72(m,5H),1.69–1.23(m,8H),1.16(d,J＝6.2Hz,6H),0.98–0.88(m,1H),0.63–0.54(m,1H). And H-13: MS m / z (ESI): 532.4 [M + H] + .1H NMR (400MHz, dmso) δ8.50 (d, J = 3.5Hz, 1H), 8.29 (s, 2H), 7.72 –7.65(m,1H),7.43(d,J=7.6Hz,1H), 7.19–7.13(m,1H), 7.03–6.89(m,2H), 6.88–6.83(m,1H), 4.94–4.86 (m,1H), 3.68–3.51(m,8H), 2.99–2.92(m,1H), 2.81(d,J=6.3Hz,2H), 2.62(d,J=13.8Hz,1H), 2.44– 2.24(m,3H),2.07–1.72(m,5H),1.69–1.23(m,8H),1.16(d,J=6.2Hz,6H),0.98–0.88(m,1H),0.63–0.54( m,1H).
实施例14 1-异丁基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-14)的制备Example 14 1-Isobutyl-N-(2--((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2, Preparation of 3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-14)
Figure PCTCN2020072851-appb-000042
Figure PCTCN2020072851-appb-000042
步骤1：将化合物6-1(3.0g，20.7mmol)和碘代异丁烷(7.6g，41.4mmol)溶解于5ml甲苯，90℃下反应16h。过滤，滤饼经甲苯洗涤，真空干燥，得化合物14-2(6.8g,棕色油状液体)。粗产品直接用于下一步反应。MS m/z(ESI):202.2。Step 1: Compound 6-1 (3.0g, 20.7mmol) and iodoisobutane (7.6g, 41.4mmol) were dissolved in 5ml of toluene and reacted at 90°C for 16h. After filtration, the filter cake was washed with toluene and dried in vacuum to obtain compound 14-2 (6.8 g, brown oily liquid). The crude product is directly used in the next reaction. MS m/z(ESI): 202.2.
步骤2：将化合物14-2(2.5g)溶解于20ml水，搅拌下加入4M氢氧化钠溶液(10ml)。反应液用EA萃取(50ml*3)。合并有机相，用饱和食盐水(100ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得化合物14-3(1.8g,棕色油状液体)，粗产品直接用于下一步反应。MS m/z(ESI):202.2[M+H] +。 Step 2: Dissolve compound 14-2 (2.5g) in 20ml water, and add 4M sodium hydroxide solution (10ml) with stirring. The reaction solution was extracted with EA (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 14-3 (1.8 g, brown oily liquid). The crude product was directly used in the next reaction. MS m/z (ESI): 202.2 [M+H] + .
步骤3：在搅拌下，将溴乙酸乙酯(6ml)加到化合物14-3(1.8g)中，加热至60℃反应16h。除去残余的溴乙酸乙酯后得化合物14-4(2.5g,棕色油状液体)，粗产品直接用于下一步反应。MS m/z(ESI):288.2。Step 3: Under stirring, ethyl bromoacetate (6 ml) was added to compound 14-3 (1.8 g), and the mixture was heated to 60° C. to react for 16 h. After removing the remaining ethyl bromoacetate, compound 14-4 (2.5 g, brown oily liquid) was obtained, and the crude product was directly used in the next reaction. MS m/z(ESI): 288.2.
步骤4：化合物14-4(2.5g)溶解于乙醇(30ml)，分批加入硼氢化钠(0.66g,17.4mmol)。反应过夜后减压蒸馏出溶剂。加水并用DCM(50ml*3)萃取。合并有机相，用饱和食盐水(100ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用制备液相色谱纯化所得残余物，得化合物14-5(0.25g,黄色油状液体)，产率10％。MS m/z(ESI):290.2[M+H] +。 Step 4: Compound 14-4 (2.5g) was dissolved in ethanol (30ml), and sodium borohydride (0.66g, 17.4mmol) was added in portions. After reacting overnight, the solvent was distilled off under reduced pressure. Water was added and extracted with DCM (50ml*3). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative liquid chromatography to obtain compound 14-5 (0.25 g, yellow oily liquid) with a yield of 10%. MS m/z (ESI): 290.2 [M+H] + .
步骤5：将化合物14-5(250mg,0.87mmol)和多聚磷酸(2g)加热到140℃反应2h。降温至60℃，向反应液加入冰水。用25％氨水溶液调整pH值至9左右，经DCM(20ml*4)萃取。合并有机相，用饱和食盐水(50ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA：100/0～70/30)纯化所得残余物，得化合物14-6(180mg,黄色油状液体)，产率85％。MS m/z(ESI):244.2[M+H] +。 Step 5: Heat compound 14-5 (250mg, 0.87mmol) and polyphosphoric acid (2g) to 140°C and react for 2h. The temperature was lowered to 60°C, and ice water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (20ml*4). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 100/0～70/30) to obtain compound 14-6 (180 mg, yellow oily liquid) with a yield of 85%. MS m/z (ESI): 244.2 [M+H] + .
步骤6：将化合物14-6(40mg,0.16mmol)，盐酸羟胺(45mg,0.64mmol)和乙酸钠(79mg,0.96mmol)加入到乙醇(5ml)和水(1mL)的混合溶剂中，140℃下，微波反应45min。降温至室温后，减压蒸馏除去大部分溶剂，残留物经DCM(30ml)稀释，用饱和碳酸氢钠溶液(10ml)和饱和食盐水(10ml)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得化合物14-7(35mg,黄色油状液体)，产率85.4％。MS m/z(ESI):259.2[M+H] +。 Step 6: Add compound 14-6 (40mg, 0.16mmol), hydroxylamine hydrochloride (45mg, 0.64mmol) and sodium acetate (79mg, 0.96mmol) into a mixed solvent of ethanol (5ml) and water (1mL) at 140°C Next, microwave reaction for 45 minutes. After cooling to room temperature, most of the solvent was distilled off under reduced pressure. The residue was diluted with DCM (30ml), washed with saturated sodium bicarbonate solution (10ml) and saturated brine (10ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced Compression and concentration gave compound 14-7 (35 mg, yellow oily liquid) with a yield of 85.4%. MS m/z (ESI): 259.2 [M+H] + .
步骤7：将化合物14-7(35mg,0.14mmol)和钯/碳(10mg)加入到乙醇(10ml，含有2滴2M盐酸溶液)中，氢气环境下反应5h。反应液经硅藻土过滤，滤液减压浓缩，得化合物14-8(25mg,黄色油状液体)，产率73.5％。MS m/z(ESI):245.2[M+H] +。 Step 7: Add compound 14-7 (35mg, 0.14mmol) and palladium/carbon (10mg) to ethanol (10ml, containing 2 drops of 2M hydrochloric acid solution), and react for 5h under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 14-8 (25 mg, yellow oily liquid) with a yield of 73.5%. MS m/z (ESI): 245.2 [M+H] + .
步骤8：将化合物14-8(20mg,0.11mmol)、化合物1b(20mg,0.11mmol)和钛酸四异 丙酯(1ml)溶解于DCE。45℃下反应3h后，加入硼氢化钠(6mg,0.15mmol)，继续在45℃下反应0.5h。冷却到室温后，加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得化合物H-14(10mg,白色固体)。产率26.7％。MS m/z(ESI):488.4[M+H] +. 1H NMR(400MHz,cdcl 3)δ8.57–8.45(m,1H),8.23(s,1H),7.70–7.59(m,1H),7.34(dd,J＝21.1,8.0Hz,1H),7.22–6.98(m,4H),4.04(s,2H),3.76–3.69(m,2H),3.58–3.46(m,1H),3.34–3.20(m,1H),3.07(d,J＝15.9Hz,1H),3.02–2.73(m,4H),2.67(s,1H),2.54(d,J＝13.1Hz,1H),2.48–2.22(m,5H),2.11(dd,J＝50.3,35.5Hz,3H),1.99–1.82(m,2H),1.79–1.55(m,3H),1.41(d,J＝42.8Hz,4H),1.16–0.90(m,6H),0.66(dd,J＝13.9,7.0Hz,1H). Step 8: Dissolve compound 14-8 (20 mg, 0.11 mmol), compound 1b (20 mg, 0.11 mmol) and tetraisopropyl titanate (1 ml) in DCE. After reacting at 45°C for 3h, sodium borohydride (6mg, 0.15mmol) was added, and the reaction was continued at 45°C for 0.5h. After cooling to room temperature, water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-14 (10 mg, white solid). The yield was 26.7%. MS m/z(ESI): 488.4[M+H] + . 1 H NMR(400MHz,cdcl 3 )δ8.57–8.45(m,1H),8.23(s,1H),7.70–7.59(m,1H ), 7.34(dd,J=21.1,8.0Hz,1H),7.22-6.98(m,4H),4.04(s,2H),3.76-3.69(m,2H),3.58-3.46(m,1H), 3.34–3.20(m,1H),3.07(d,J=15.9Hz,1H),3.02–2.73(m,4H),2.67(s,1H),2.54(d,J=13.1Hz,1H),2.48 –2.22(m,5H),2.11(dd,J=50.3,35.5Hz,3H),1.99–1.82(m,2H),1.79–1.55(m,3H),1.41(d,J=42.8Hz,4H ), 1.16–0.90(m,6H),0.66(dd,J=13.9,7.0Hz,1H).
实施例15：2-异丙基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-6-胺(H-15)的制备Example 15: 2-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1 ,2,5,6-Tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-6-amine (H-15)
Figure PCTCN2020072851-appb-000043
Figure PCTCN2020072851-appb-000043
步骤1：将2-甲基苯胺15-1(5.0g，46.7mmol)溶解于200mL DCM中，0℃下加入DIEA(9.0g，69.6mmol)，然后逐滴加入异丁酰氯(5.5g，51.6mmol)，室温搅拌反应2h。向反应液中加入50mL水，分液，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～3/1)纯化所得残余物，得化合物15-2(8.0g，白色固体)，产率：97％。MS m/z(ESI):178.1[M+H] +。 Step 1: Dissolve 2-methylaniline 15-1 (5.0g, 46.7mmol) in 200mL DCM, add DIEA (9.0g, 69.6mmol) at 0°C, and then add isobutyryl chloride (5.5g, 51.6 mmol), the reaction was stirred at room temperature for 2h. Add 50 mL of water to the reaction solution, separate the layers, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and use silica gel column chromatography to eluent (PE/EA=1/0～3/1) The obtained residue was purified to obtain compound 15-2 (8.0 g, white solid), yield: 97%. MS m/z (ESI): 178.1 [M+H] + .
步骤2：将化合物15-2(3.6g，20.3mmol)溶解于40mLTHF中，氮气保护下冷却至0℃，逐滴加入正丁基锂(20mL,50.0mmol)，0℃下搅拌反应1h。将反应液倒入70mL饱和氯化铵溶液中淬灭，EA萃取(50mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～4/1)纯化所得残余物，得化合物15-3(1.7g，黄色固体)，产率：53.0％。MS m/z(ESI):160.1[M+H] +。 Step 2: Dissolve compound 15-2 (3.6 g, 20.3 mmol) in 40 mL THF, cool to 0° C. under nitrogen protection, add n-butyl lithium (20 mL, 50.0 mmol) dropwise, and stir at 0° C. for 1 h. The reaction solution was poured into 70 mL saturated ammonium chloride solution for quenching, and extracted with EA (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent (PE/EA=1/0～4/1) to obtain compound 15-3( 1.7g, yellow solid), yield: 53.0%. MS m/z (ESI): 160.1 [M+H] + .
步骤3：将化合物15-3(1.8g，11.3mmol)溶解于20mL醋酸中，氮气保护下冷却至0℃，加入氰基硼氢化钠(2.8g,44.5mmol)，室温搅拌反应2h。减压蒸馏除去溶剂，用4M氢氧化钠溶液调节pH＝10，EA萃取(50mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA：1/0～5/1)纯化所得残余物，得化合物15-4(1.45g，无色油状物)，产率：80.0％。MS m/z(ESI):162.2[M+H] +。 Step 3: Dissolve compound 15-3 (1.8 g, 11.3 mmol) in 20 mL of acetic acid, cool to 0° C. under nitrogen protection, add sodium cyanoborohydride (2.8 g, 44.5 mmol), and stir for reaction at room temperature for 2 hours. The solvent was distilled off under reduced pressure, pH was adjusted to 10 with 4M sodium hydroxide solution, and extracted with EA (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with eluent (PE/EA: 1/0～5/1) to obtain compound 15-4 ( 1.45g, colorless oil), yield: 80.0%. MS m/z (ESI): 162.2 [M+H] + .
步骤4：将化合物15-4(1.0g，6.20mmol)溶解于8mL DMF中，加入无水碳酸钾(1.70g，12.3mmol)和3-溴丙酸甲酯(2.0g，11.98mmol)，100℃搅拌反应过夜。向反应液中加入30mL饱和食盐水，EA(50mL)萃取。合并有机相，用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～5/1)纯化所得残余物，得化 合物15-5(1.1g，无色油状液体)，产率：73％。MS m/z(ESI):248.1[M+H] +。 Step 4: Dissolve compound 15-4 (1.0g, 6.20mmol) in 8mL DMF, add anhydrous potassium carbonate (1.70g, 12.3mmol) and methyl 3-bromopropionate (2.0g, 11.98mmol), 100 The reaction was stirred overnight at °C. 30 mL of saturated brine was added to the reaction solution, and EA (50 mL) was extracted. The organic phases were combined, washed with saturated brine (80 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 1/0～5/1) The obtained residue was compound 15-5 (1.1 g, colorless oily liquid), yield: 73%. MS m/z (ESI): 248.1 [M+H] + .
步骤5：化合物15-5(0.9g，3.64mmol)加入到22g多聚磷酸中，150℃搅拌反应7h。将反应液倒入30mL冰水中，加入氨水调节至PH＝9,用EA(50mL×3)和DCM(50mL×3)分别萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～10/1)纯化所得残余物，得化合物15-6(214mg，黄色固体)，产率：22％。MS m/z(ESI):216.1[M+H] +。 Step 5: Compound 15-5 (0.9g, 3.64mmol) was added to 22g polyphosphoric acid, and the reaction was stirred at 150°C for 7h. The reaction solution was poured into 30 mL ice water, ammonia water was added to adjust to pH=9, and the mixture was extracted with EA (50 mL×3) and DCM (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (PE/EA: 1/0-10/1) to obtain compound 15-6 (214 mg, yellow solid), yield: 22%. MS m/z (ESI): 216.1 [M+H] + .
步骤6：化合物15-6(42mg，0.195mmol)、盐酸羟胺(54mg，0.777mmol)和乙酸钠(96mg，1.17mmol)溶解于10mL乙醇和1mL水的混合溶剂中，120℃微波反应45min。将反应液中倒入30mL饱和碳酸氢钠溶液中，DCM萃取(30mL×3)。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物15-7(44mg，黄色固体)，产率：99.0％。MS m/z(ESI):231.1[M+H] +。 Step 6: Compound 15-6 (42 mg, 0.195 mmol), hydroxylamine hydrochloride (54 mg, 0.777 mmol) and sodium acetate (96 mg, 1.17 mmol) were dissolved in a mixed solvent of 10 mL ethanol and 1 mL water, and reacted in a microwave at 120° C. for 45 min. The reaction solution was poured into 30 mL saturated sodium bicarbonate solution and extracted with DCM (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-7 (44 mg, yellow solid), yield: 99.0%. MS m/z (ESI): 231.1 [M+H] + .
步骤7：将化合物15-7(44mg，0.191mmol)溶解于8mL乙醇，加入钯/碳(50mg)和0.5M盐酸溶液。在氢气气氛下，室温搅拌反应5h。过滤，滤液减压浓缩，残余物用饱和碳酸氢钠溶液中和至中性，减压浓缩除去水。加入DCM(50mL)，过滤，滤液减压浓缩，得化合物15-8(40mg，橙色油状物)，产率：98％。MS m/z(ESI):200.1[M-16] -。 Step 7: Dissolve compound 15-7 (44mg, 0.191mmol) in 8mL ethanol, add palladium/carbon (50mg) and 0.5M hydrochloric acid solution. Under a hydrogen atmosphere, the reaction was stirred at room temperature for 5 hours. After filtration, the filtrate was concentrated under reduced pressure, the residue was neutralized with saturated sodium bicarbonate solution, and concentrated under reduced pressure to remove water. DCM (50 mL) was added, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-8 (40 mg, orange oil), yield: 98%. MS m/z(ESI): 200.1[M-16] - .
步骤8：将化合物15-8(40mg，0.185mmol)和化合物1b(48mg，0.185mmol)溶解于10mLDCE中，加入0.4mL钛酸四异丙酯，45℃搅拌反应7h。冷却至室温，向反应液加入硼氢化钠(35mg，0.93mmol)，45℃搅拌反应过夜，向反应液中加入3mL水，过滤，滤液减压浓缩，制备色谱纯化所得残余物，得化合物H-15(20mg，黄色固体)，产率：23％。MS m/z(ESI):460.1[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.54–8.43(m,1H),7.75-7.70(m,1H),7.46(t,J＝7.8Hz,1H),7.26–7.13(m,1H),6.87–6.63(m,2H),6.51–6.35(m,1H),3.81–3.61(m,3H),3.25-3.15(m,2H),2.79–2.59(m,2H),2.56–2.32(m,3H),2.12–1.96(m,3H),1.93–1.82(m,2H),1.81–1.24(m,10H),1.10-1.01(m,1H),0.94(d,J＝6.9Hz,3H),0.86(dd,J＝6.8,2.1Hz,3H),0.78–0.61(m,1H). Step 8: Dissolve compound 15-8 (40 mg, 0.185 mmol) and compound 1b (48 mg, 0.185 mmol) in 10 mL of DCE, add 0.4 mL of tetraisopropyl titanate, and stir for reaction at 45° C. for 7 hours. After cooling to room temperature, sodium borohydride (35 mg, 0.93 mmol) was added to the reaction solution, and the reaction was stirred overnight at 45°C. 3 mL of water was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative chromatography to obtain compound H- 15 (20 mg, yellow solid), yield: 23%. MS m/z (ESI): 460.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.54–8.43(m,1H), 7.75-7.70(m,1H), 7.46(t,J=7.8Hz,1H), 7.26–7.13(m,1H) ,6.87–6.63(m,2H),6.51–6.35(m,1H), 3.81–3.61(m,3H), 3.25-3.15(m,2H), 2.79–2.59(m,2H), 2.56–2.32( m,3H),2.12–1.96(m,3H),1.93–1.82(m,2H),1.81–1.24(m,10H),1.10-1.01(m,1H),0.94(d,J=6.9Hz, 3H), 0.86(dd,J=6.8,2.1Hz,3H),0.78-0.61(m,1H)
实施例16：N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2-三氟甲基-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-6-胺(H-16)的制备Example 16: N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-trifluoromethyl- Preparation of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-6-amine (H-16)
Figure PCTCN2020072851-appb-000044
Figure PCTCN2020072851-appb-000044
步骤1：将2-氨基苄醇16-1(11.0g，89.3mmol)和DIEA(11.3g，133.8mmol)溶解于150mL DCM中，0℃下逐滴加入三氟乙酸酐(20.6g，98.1mmol)，室温搅拌反应过夜。向反应液中加入80mL饱和食盐水，分液。合并有机相，用0.5M盐酸溶液(80mL)和水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物16-2(18g，黄色油状物)，产率：92％。MS  m/z(ESI):237.1[M+18] +。 Step 1: Dissolve 2-aminobenzyl alcohol 16-1 (11.0g, 89.3mmol) and DIEA (11.3g, 133.8mmol) in 150mL DCM, add trifluoroacetic anhydride (20.6g, 98.1mmol) dropwise at 0°C ), the reaction was stirred overnight at room temperature. 80 mL of saturated saline was added to the reaction solution, and the solution was separated. The organic phases were combined, washed with 0.5M hydrochloric acid solution (80 mL) and water (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-2 (18 g, yellow oil), yield: 92% . MS m/z (ESI): 237.1 [M+18] + .
步骤2：将化合物16-2(18g，82mmol)溶解于150mLDCM中，加入三溴化磷(22g,81mmol)，50℃搅拌反应2h。向反应液加入70mL水，用DCM(100mL×2)和EA(50mL×2)分别萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂(PE/EA＝1/0～10/1)纯化所得残余物，得化合物16-3(8g，白色固体)，产率：35.0％。MS m/z(ESI):202.1[M-79] -。 Step 2: Dissolve compound 16-2 (18 g, 82 mmol) in 150 mL DCM, add phosphorus tribromide (22 g, 81 mmol), and stir for reaction at 50° C. for 2 h. 70 mL of water was added to the reaction solution, and extracted with DCM (100 mL×2) and EA (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent (PE/EA=1/0-10/1) to obtain compound 16-3 ( 8g, white solid), yield: 35.0%. MS m/z(ESI): 202.1[M-79] - .
步骤3：将化合物16-3(8g，28mmol)与三苯基膦(8.2g，31mmol)溶解于100mL甲苯中，60℃搅拌反应过夜。待反应液冷却至室温，过滤得化合物16-4(14.5g，白色固体)，产率：94.0％。MS m/z(ESI):464.1[M-79] -。 Step 3: Dissolve compound 16-3 (8 g, 28 mmol) and triphenylphosphine (8.2 g, 31 mmol) in 100 mL of toluene, stir and react at 60° C. overnight. After the reaction solution was cooled to room temperature, compound 16-4 (14.5 g, white solid) was obtained by filtration, and the yield was 94.0%. MS m/z(ESI): 464.1 [M-79] - .
步骤4：将化合物16-4(14.5g，26.6mmol)溶解于20mL DMF中，200℃微波反应30min。减压蒸馏除去溶剂，加入EA(150mL)。有机相用饱和食盐水洗涤(80mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～10/1)纯化所得残余物，得化合物16-5(4g，白色固体)，产率：81％。MS m/z(ESI):184[M-H] -。 Step 4: Dissolve compound 16-4 (14.5 g, 26.6 mmol) in 20 mL DMF, and react in microwave at 200° C. for 30 min. The solvent was distilled off under reduced pressure, and EA (150 mL) was added. The organic phase was washed with saturated brine (80mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with an eluent system (PE/EA: 1/0～10/1) The obtained residue was compound 16-5 (4 g, white solid), yield: 81%. MS m/z (ESI): 184 [MH] - .
步骤5：化合物16-5(1.6g，8.64mmol)溶解于25mLTFA,0℃下加入氰基硼氢化钠(1.7g，26.5mmol)，搅拌反应1h。向反应液中加入30mL水，减压蒸馏除去大部分溶剂，残留物用EA(50mL)萃取。合并有机相，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，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～10/1)纯化所得残余物，得化合物16-6(1.5g，无色油状物)，产率：94％。MS m/z(ESI):188.1[M+H] +。 Step 5: Compound 16-5 (1.6 g, 8.64 mmol) was dissolved in 25 mL TFA, sodium cyanoborohydride (1.7 g, 26.5 mmol) was added at 0°C, and the reaction was stirred for 1 h. 30 mL of water was added to the reaction solution, most of the solvent was distilled off under reduced pressure, and the residue was extracted with EA (50 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography was used to determine the eluent system (PE/EA: 1/0-10/1) The residue obtained was purified to obtain compound 16-6 (1.5 g, colorless oil), yield: 94%. MS m/z (ESI): 188.1 [M+H] + .
步骤6：将化合物16-6(0.8g，4.27mmol)溶解于10mL DMF中，加入无水碳酸钾(1.80g，13.0mmol)和3-溴丙酸甲酯(3.6g，21.6mmol)，100℃搅拌反应2天。向反应液中加入50mL饱和食盐水，EA(80mL)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～10/1)纯化所得残余物，得化合物16-7(0.2g，无色油状液体)，产率：17％。MS m/z(ESI):274.1[M+H] +。 Step 6: Dissolve compound 16-6 (0.8g, 4.27mmol) in 10mL DMF, add anhydrous potassium carbonate (1.80g, 13.0mmol) and methyl 3-bromopropionate (3.6g, 21.6mmol), 100 The reaction was stirred at °C for 2 days. 50 mL of saturated brine was added to the reaction solution, and EA (80 mL) was extracted. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system (PE/EA: 1/0-10/1) to obtain compound 16- 7 (0.2g, colorless oily liquid), yield: 17%. MS m/z (ESI): 274.1 [M+H] + .
步骤7：将化合物16-7(0.2mg，0.73mmol)溶解于10mLTHF和1mL水中，加入一水合氢氧化锂(92mg，2.19mmol)水溶液(1mL)，室温搅拌反应过夜。用1M盐酸溶液调整反应液pH值至4，DCM/甲醇体系(10:1)(30mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物16-8(182mg，范黄色油状物)，产率：96％。MS m/z(ESI):260.1[M+H] +。 Step 7: Dissolve compound 16-7 (0.2 mg, 0.73 mmol) in 10 mL of THF and 1 mL of water, add lithium hydroxide monohydrate (92 mg, 2.19 mmol) in water (1 mL), and stir and react at room temperature overnight. Adjust the pH of the reaction solution to 4 with 1M hydrochloric acid solution, and extract with a DCM/methanol system (10:1) (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 16-8 (182 mg, pale yellow oil), yield: 96%. MS m/z (ESI): 260.1 [M+H] + .
步骤8：将化合物16-8(182mg，0.702mmol)溶解于10mL DCM中，0℃下加入草酰氯(134mg，1.05mmol)和2滴DMF，反17h。反应液减压浓缩得到酰氯中间体。-20℃下将酰氯中间体的DCM溶液(1mL)加入到氯化铝(280mg，2.09mmol)的DCM溶液(15mL)中，温度慢慢升至室温后反应过夜。加入20mL冰水中和20mL饱和碳酸氢钠，DCM(50mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA：1/0～10/1)纯化所得残余物，得化合物16-9(64mg，泛黄色固体)，产率：40％。MS m/z(ESI):242.1[M+H] +。 Step 8: Dissolve compound 16-8 (182 mg, 0.702 mmol) in 10 mL DCM, add oxalyl chloride (134 mg, 1.05 mmol) and 2 drops of DMF at 0°C, and reverse for 17 hours. The reaction solution was concentrated under reduced pressure to obtain the acid chloride intermediate. The DCM solution (1 mL) of the acid chloride intermediate was added to the DCM solution (15 mL) of aluminum chloride (280 mg, 2.09 mmol) at -20°C, the temperature was slowly raised to room temperature, and the reaction was carried out overnight. Add 20 mL of ice water to neutralize 20 mL of saturated sodium bicarbonate, and extract with DCM (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography with an eluent system (PE/EA: 1/0-10/1) to obtain compound 16-9 (64 mg, yellowish solid), yield: 40%. MS m/z (ESI): 242.1 [M+H] + .
步骤9：将化合物16-9(30mg，0.127mmol)和化合物1a(33mg，0.124mmol)溶解于5 mLDCE中，加入0.7mL钛酸四异丙酯，45℃搅拌反应1天。冷却至室温，向反应液加入硼氢化钠(24mg，0.63mmol)，45℃搅拌反应4h，向反应液中加入5mL水，过滤，滤液减压浓缩，制备色谱纯化所得残余物，得化合物H-16(11.89mg，白色固体)，产率：19％。MS m/z(ESI):486.3[M+H] +。1H NMR(400MHz,CD3OD)δ8.54–8.44(m,1H),7.76–7.67(m,1H),7.45(t,J＝8.0Hz,1H),7.24–7.16(m,1H),6.90–6.73(m,2H),6.61–6.49(m,1H),4.03–3.98(m,1H),3.76–3.64(m,3H),3.38–3.31(m,1H),3.22(dd,J＝16.3,9.8Hz,1H),3.07–2.90(m,2H),2.55–2.36(m,3H),2.11–1.94(m,2H),1.92–1.80(m,3H),1.77–1.33(m,8H),1.10–1.04(m,1H),0.78–0.63(m,1H). Step 9: Dissolve compound 16-9 (30 mg, 0.127 mmol) and compound 1a (33 mg, 0.124 mmol) in 5 mL of DCE, add 0.7 mL of tetraisopropyl titanate, and stir for reaction at 45°C for 1 day. After cooling to room temperature, sodium borohydride (24 mg, 0.63 mmol) was added to the reaction solution, and the reaction was stirred at 45°C for 4 hours. 5 mL of water was added to the reaction solution, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative chromatography to obtain compound H- 16 (11.89 mg, white solid), yield: 19%. MS m/z (ESI): 486.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.54–8.44(m,1H), 7.76–7.67(m,1H), 7.45(t,J=8.0Hz,1H), 7.24–7.16(m,1H), 6.90– 6.73(m,2H), 6.61–6.49(m,1H), 4.03–3.98(m,1H), 3.76–3.64(m,3H), 3.38–3.31(m,1H), 3.22(dd,J=16.3 ,9.8Hz,1H),3.07–2.90(m,2H),2.55–2.36(m,3H),2.11–1.94(m,2H),1.92–1.80(m,3H),1.77–1.33(m,8H) ), 1.10--1.04(m,1H), 0.78--0.63(m,1H).
实施例17：1-仲丁基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(非对映异构体混合物H-17-1和非对映异构体混合物H-17-2)的制备Example 17: 1-sec-butyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (mixture of diastereomers H-17-1 and mixture of diastereomers H- 17-2) Preparation
Figure PCTCN2020072851-appb-000045
Figure PCTCN2020072851-appb-000045
步骤1：以化合物6-1与2-碘丁烷为原料，制备方法参考实施例6中的步骤1得化合物17-2。MS m/z(ESI):202.1[M+H] +。 Step 1: Using compound 6-1 and 2-iodobutane as raw materials, the preparation method refers to step 1 in Example 6 to obtain compound 17-2. MS m/z (ESI): 202.1 [M+H] + .
步骤2：制备方法参考实施例6中的步骤2得化合物17-3。MS m/z(ESI):288.2[M+H] +。 Step 2: The preparation method refers to step 2 in Example 6 to obtain compound 17-3. MS m/z (ESI): 288.2 [M+H] + .
步骤3：制备方法参考实施例6中的步骤3得3-(2-仲丁基-1,2,3,4-四氢异喹啉-1-基)丙酸乙酯17-4。MS m/z(ESI):290.2[M+H] +。 Step 3: Preparation method Refer to step 3 in Example 6 to obtain ethyl 3-(2-sec-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl)propionate 17-4. MS m/z (ESI): 290.2 [M+H] + .
步骤4：将3-(2-仲丁基-1,2,3,4-四氢异喹啉-1-基)丙酸乙酯17-4(680mg,2.35mmol)和多聚磷酸(15g)混合后加热至140℃反应1h。降温至60℃，向反应液加入30mL水。用25％氨水溶液调整pH值至9左右，经DCM(50mL x 3)和EA(50mL x 3)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用硅胶柱色谱法以洗脱剂体系(PE/EA＝6/1～1/1)纯化，分别得到非对映异构体混合物17-5和非对映异构体混合物17-6(146mg,棕色油状液体)，总产率为25％。MS m/z(ESI):244.2[M+H] +。 Step 4: Combine 3-(2-sec-butyl-1,2,3,4-tetrahydroisoquinolin-1-yl) ethyl propionate 17-4 (680mg, 2.35mmol) and polyphosphoric acid (15g ) After mixing, heat to 140°C for 1 hour. The temperature was lowered to 60°C, and 30 mL of water was added to the reaction solution. Adjust the pH to about 9 with 25% aqueous ammonia solution, and extract with DCM (50 mL x 3) and EA (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography with eluent system (PE/EA=6/1～1/1) to obtain diastereomer mixture 17-5 and diastereoisomer mixture 17-6 (146mg , Brown oily liquid), the total yield is 25%. MS m/z (ESI): 244.2 [M+H] + .
步骤5：将化合物17-5(320mg,1.315mmol)、化合物1a(377mg,1.45mmol)和钛酸四异丙酯(4mL)溶解于20mL DCE，50℃反应36h。加入硼氢化钠(200mg,5.29mmol)，30℃下继续反应2h。冷却到室温后，加2mL水，过滤，滤液减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)纯化所得残余物，得到H-17-1(121.07mg,棕色固体)。产率19％。MS m/z(ESI):488.4[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.51–8.42(m,1H),7.76–7.65(m,1H),7.43(dd,J＝14.9,8.2Hz,1H),7.22-7.17(m,1H),7.09–6.89(m,3H),3.82–3.56(m,4H),3.21–3.02(m,2H),2.97-2.88(m,1H),2.78(d,J＝16.1Hz,1H),2.51–2.31(m,4H),2.24-2.19(m,1H),2.08–1.83(m,4H),1.80–1.20(m,12H),1.14(d,J＝6.6Hz,3H),1.11-1.4(m,1H),0.90(t,J＝7.4Hz,3H),0.76–0.62(m,1H). Step 5: Dissolve compound 17-5 (320 mg, 1.315 mmol), compound 1a (377 mg, 1.45 mmol) and tetraisopropyl titanate (4 mL) in 20 mL of DCE, and react at 50° C. for 36 hours. Sodium borohydride (200mg, 5.29mmol) was added, and the reaction was continued at 30°C for 2h. After cooling to room temperature, add 2 mL of water, filter, and concentrate the filtrate under reduced pressure. Use preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30 %-60% acetonitrile change) the resulting residue was purified to obtain H-17-1 (121.07 mg, brown solid). The yield was 19%. MS m/z(ESI): 488.4[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.51–8.42(m,1H),7.76–7.65(m,1H),7.43(dd, J = 14.9, 8.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.09-6.89 (m, 3H), 3.82-3.56 (m, 4H), 3.21-3.02 (m, 2H), 2.97-2.88 ( m,1H), 2.78(d,J=16.1Hz,1H), 2.51–2.31(m,4H),2.24-2.19(m,1H),2.08–1.83(m,4H),1.80–1.20(m, 12H), 1.14(d,J=6.6Hz,3H),1.11-1.4(m,1H),0.90(t,J=7.4Hz,3H),0.76-0.62(m,1H).
步骤6：将化合物17-6(320mg,1.315mmol)、化合物1a(377mg,1.45mmol)和钛酸四异丙酯(4mL)溶解于20mL DCE，50℃反应2天。加入硼氢化钠(200mg,5.29mmol)，30℃下继续反应1小时。冷却到室温后，加2mL水，过滤，滤液减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)纯化所得残余物，得到H-17-2，(7.92mg,棕色固体)。产率1.2％。MS m/z(ESI):488.4[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.55–8.46(m,1H),7.76-7.73(m,1H),7.49(d,J＝8.1Hz,1H),7.25–7.16(m,1H),7.09–6.82(m,3H),3.80–3.44(m,4H),3.22–3.04(m,2H),2.96-2.77(m,2H),2.66–2.33(m,4H),2.22–1.23(m,17H),1.17(d,J＝6.6Hz,3H),1.12-1.05(m,1H),0.91(t,J＝7.4Hz,3H),0.75-0.65(m,1H). Step 6: Dissolve compound 17-6 (320 mg, 1.315 mmol), compound 1a (377 mg, 1.45 mmol) and tetraisopropyl titanate (4 mL) in 20 mL of DCE, and react at 50° C. for 2 days. Sodium borohydride (200mg, 5.29mmol) was added, and the reaction was continued at 30°C for 1 hour. After cooling to room temperature, add 2 mL of water, filter, and concentrate the filtrate under reduced pressure. Use preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30 %-60% acetonitrile change) The resulting residue was purified to obtain H-17-2 (7.92 mg, brown solid). The yield was 1.2%. MS m/z(ESI): 488.4[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.55–8.46(m,1H),7.76-7.73(m,1H),7.49(d, J=8.1Hz,1H), 7.25–7.16(m,1H), 7.09–6.82(m,3H), 3.80–3.44(m,4H), 3.22–3.04(m,2H), 2.96-2.77(m, 2H), 2.66–2.33(m,4H), 2.22–1.23(m,17H), 1.17(d,J=6.6Hz,3H),1.12-1.05(m,1H),0.91(t,J=7.4Hz ,3H),0.75-0.65(m,1H).
实施例18：1-(甲基磺酰基)-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-18)的制备Example 18: 1-(Methylsulfonyl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-18)
Figure PCTCN2020072851-appb-000046
Figure PCTCN2020072851-appb-000046
步骤1：将化合物12-7(132mg,0.70mmol)溶解于20mLDCM中，依次加入三乙胺(140mg,1.38mmol)和甲烷磺酰氯(120mg,1.05mmol)，室温反应1h。减压浓缩，用制备薄层色谱以层析体系(DCM/甲醇：20/1)纯化所得残余物，得到化合物18-2(72mg,黄色固体)，产率39％。MS m/z(ESI):266.1[M+H] +。 Step 1: Dissolve compound 12-7 (132 mg, 0.70 mmol) in 20 mL of DCM, add triethylamine (140 mg, 1.38 mmol) and methanesulfonyl chloride (120 mg, 1.05 mmol) in sequence, and react at room temperature for 1 h. It was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography with a chromatography system (DCM/methanol: 20/1) to obtain compound 18-2 (72 mg, yellow solid) with a yield of 39%. MS m/z (ESI): 266.1 [M+H] + .
步骤2：将化合物18-2(72mg,0.271mmol)、化合物1a(90mg,0.346mmol)和钛酸四异丙酯(1mL)溶解于8mL DCE。45℃下反应18h后，加入硼氢化钠(50mg,1.32mmol)，45℃下继续反应1h。冷却到室温后，加入1mL水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得化合物H-18(37.28mg,白色固体)，产率：27％。MS m/z(ESI):510.3[M+H] +。1H NMR(400MHz,CD3OD)δ8.56–8.46(m,1H),7.81–7.67(m,1H),7.54–7.40(m,1H),7.28–6.89(m,4H),4.92-4.86(m,1H),4.56–4.33(m,1H),3.98-3.93(m,1H),3.79–3.67(m,2H),3.17 –2.87(m,5H),2.86–2.58(m,2H),2.57–1.22(m,17H),1.08(s,1H),0.78–0.62(m,1H). Step 2: Compound 18-2 (72 mg, 0.271 mmol), compound 1a (90 mg, 0.346 mmol) and tetraisopropyl titanate (1 mL) were dissolved in 8 mL of DCE. After reacting at 45°C for 18h, sodium borohydride (50mg, 1.32mmol) was added, and the reaction was continued at 45°C for 1h. After cooling to room temperature, 1 mL of water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-18 (37.28 mg, white solid), yield: 27%. MS m/z (ESI): 510.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ 8.56-8.46 (m, 1H), 7.81-7.67 (m, 1H), 7.54-7.40 (m, 1H), 7.28-6.89 (m, 4H), 4.92-4.86 (m ,1H),4.56–4.33(m,1H),3.98-3.93(m,1H),3.79–3.67(m,2H),3.17–2.87(m,5H),2.86-2.58(m,2H),2.57 --1.22(m,17H),1.08(s,1H),0.78--0.62(m,1H).
实施例19:2-乙基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,5,6-四氢-4H-吡咯并[3,2,1-ij]喹啉-6-胺(H-19)的制备Example 19: 2-Ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1, Preparation of 2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-6-amine (H-19)
Figure PCTCN2020072851-appb-000047
Figure PCTCN2020072851-appb-000047
步骤1：冰浴下，将化合物19-1(10g，0.085mol)溶解于100mLTHF中，加入60％氢化钠(4.5g，0.11mol)，冰浴搅拌反应30min。向反应液中滴加入苯磺酰氯19.1(11mL，0.086mol)，室温搅拌反应16h。向反应液中加入100mL水，用EA萃取(50mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系PE/EA＝10:1纯化所得残余物，得化合物19-2(22g，浅黄色固体)，产率：99.0％。MS m/z(ESI):258.1[M+H] +。 Step 1: Under an ice bath, dissolve compound 19-1 (10 g, 0.085 mol) in 100 mL of THF, add 60% sodium hydride (4.5 g, 0.11 mol), and stir for reaction in an ice bath for 30 min. Benzenesulfonyl chloride 19.1 (11 mL, 0.086 mol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 16 h. Add 100 mL of water to the reaction solution, extract with EA (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Use silica gel column chromatography to eluent system PE/EA=10: 1 Purify the obtained residue to obtain compound 19-2 (22 g, pale yellow solid), yield: 99.0%. MS m/z (ESI): 258.1 [M+H] + .
步骤2：将化合物19-2(3g，11.66mmol)溶解于100mLTHF中，-78℃下缓慢滴加入2M二异丙基氨基锂(8.7mL，17.4mmol)，室温搅拌反应1h。-78℃下滴加入碘代乙烷(1.1mL，13.75mmol)，室温搅拌反应16h。向反应液中加入80mL水，用EA萃取(80mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系PE/EA＝5:1纯化所得残余物，得到化合物19-3(1.12g，黄色固体)，产率：33.6％。MS m/z(ESI):286.1[M+H] +。 Step 2: Dissolve compound 19-2 (3 g, 11.66 mmol) in 100 mL of THF, slowly add 2M lithium diisopropylamide (8.7 mL, 17.4 mmol) dropwise at -78°C, and stir for reaction at room temperature for 1 h. Iodoethane (1.1 mL, 13.75 mmol) was added dropwise at -78°C, and the reaction was stirred at room temperature for 16 h. Add 80 mL of water to the reaction solution, extract with EA (80 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Use silica gel column chromatography to eluent system PE/EA=5: 1 Purify the obtained residue to obtain compound 19-3 (1.12 g, yellow solid), yield: 33.6%. MS m/z (ESI): 286.1 [M+H] + .
步骤3：将化合物19-3(1.12g，3.92mmol)加入于10mL乙醇中，加入4N氢氧化钠(5mL，20mmol)，回流搅拌反应40h。反应液减压浓缩，加入50mL水，加5M盐酸至反应液pH为5～6，用EA萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物19-4(560mg，桔红色油状物)，产率：98.2％。MS m/z(ESI):146.1[M+H] +。 Step 3: Compound 19-3 (1.12 g, 3.92 mmol) was added to 10 mL of ethanol, 4N sodium hydroxide (5 mL, 20 mmol) was added, and the reaction was stirred at reflux for 40 h. The reaction solution was concentrated under reduced pressure, 50mL of water was added, 5M hydrochloric acid was added to the reaction solution pH of 5-6, extracted with EA (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the compound 19-4 (560 mg, orange-red oil), yield: 98.2%. MS m/z (ESI): 146.1 [M+H] + .
步骤4：将化合物19-4(560mg，3.86mmol)溶解于10mL乙酸中，加入氰基硼氢化钠(900mg，14.32mmol)，室温搅拌反应3h。反应液减压浓缩，加入20mL 4N盐酸，室温搅拌1h，然后加入45mL 4N氢氧化钠溶液，用EA萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物19-5(560mg，黄色油状物)，产率：98.6％。MS m/z(ESI):148.1[M+H] +。 Step 4: Compound 19-4 (560 mg, 3.86 mmol) was dissolved in 10 mL of acetic acid, sodium cyanoborohydride (900 mg, 14.32 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, 20mL 4N hydrochloric acid was added, stirred at room temperature for 1h, then 45mL 4N sodium hydroxide solution was added, extracted with EA (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 19-5 (560 mg, yellow oil) was obtained, yield: 98.6%. MS m/z (ESI): 148.1 [M+H] + .
步骤5：将化合物19-5(560mg，3.80mmol)，溴丙酸甲酯(1.3g，7.78mmol)和碳酸钾(1.1g，7.96mmol)加入10mL DMF中。将反应液封入封管中，110℃搅拌反应32h。向反应液中加入50mL饱和氯化钠溶液，用EA萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系PE/EA＝10:1纯化所得残余物，得化合物19-6(650mg，黄色油状物)，产率：73.3％。MS m/z(ESI):234.1[M+H] +。 Step 5: Compound 19-5 (560 mg, 3.80 mmol), methyl bromopropionate (1.3 g, 7.78 mmol) and potassium carbonate (1.1 g, 7.96 mmol) were added to 10 mL DMF. The reaction solution was sealed in a sealed tube, and the reaction was stirred at 110°C for 32 hours. Add 50mL saturated sodium chloride solution to the reaction solution, extract with EA (50mL×3), combine the organic phases, wash with saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained was purified by silica gel column chromatography with the eluent system PE/EA=10:1 to obtain compound 19-6 (650 mg, yellow oil), yield: 73.3%. MS m/z (ESI): 234.1 [M+H] + .
步骤6：将化合物19-6(650mg，2.79mmol)加入多聚磷酸(17g，50.31mmol)中，150℃搅拌反应7h。反应液先用冰淬灭，然后向反应液中加入氨水溶液调节pH大于9，用EA萃取 (50mL×3)和DCM萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系PE/EA＝10:1纯化所得残余物，得化合物19-7(241mg，黄色固体)，产率：43.0％。MS m/z(ESI):202.1[M+H] +。 Step 6: Compound 19-6 (650 mg, 2.79 mmol) was added to polyphosphoric acid (17 g, 50.31 mmol), and the reaction was stirred at 150°C for 7 hours. The reaction solution was first quenched with ice, and then an aqueous ammonia solution was added to the reaction solution to adjust the pH to greater than 9, and extracted with EA (50mL×3) and DCM (50mL×3). The organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with an eluent system PE/EA=10:1 to obtain compound 19-7 (241 mg, yellow solid), yield: 43.0%. MS m/z (ESI): 202.1 [M+H] + .
步骤7：将化合物19-7(60mg，0.30mmol)，盐酸羟胺(83mg，1.19mmol)和醋酸钠(146mg，1.78mmol)加入10mL乙醇和1mL水中。将反应液封入微波管中，在微波中120℃搅拌反应45min。反应液减压浓缩，加入15mL饱和碳酸氢钠溶液，用DCM萃取(15mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得化合物19-8(64mg，黄色固体)，产率：99.4％。MS m/z(ESI):217.1[M+H] +。 Step 7: Add compound 19-7 (60 mg, 0.30 mmol), hydroxylamine hydrochloride (83 mg, 1.19 mmol) and sodium acetate (146 mg, 1.78 mmol) into 10 mL ethanol and 1 mL water. The reaction solution was sealed in a microwave tube, and the reaction was stirred at 120° C. for 45 min in the microwave. The reaction solution was concentrated under reduced pressure, 15 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 19-8 (64 mg, yellow solid). ), yield: 99.4%. MS m/z (ESI): 217.1 [M+H] + .
步骤8：将化合物19-8(64mg，0.30mmol)溶解于8mL乙醇中，加入1mL 0.5N盐酸，然后加入钯/碳(60mg，10％)，氢气置换三次，搅拌反应5h。过滤，滤液减压浓缩，得化合物19-9(60mg，桔色油状物)，产率：99.9％。MS m/z(ESI):186.1[M-16] -。 Step 8: Dissolve compound 19-8 (64 mg, 0.30 mmol) in 8 mL of ethanol, add 1 mL of 0.5 N hydrochloric acid, and then add palladium/carbon (60 mg, 10%), replace with hydrogen three times, and stir and react for 5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 19-9 (60 mg, orange oil), yield: 99.9%. MS m/z(ESI): 186.1[M-16] - .
步骤9：将化合物19-9(60mg，0.29mmol)，化合物1b(75mg，0.29mmol)和钛酸四异丙酯(0.5mL，1.69mmol)加入10mLDCE中，50℃搅拌反应24h。加入硼氢化钠(56mg，1.48mmol)，50℃搅拌反应18h。加入3mL水淬灭反应，过滤，滤液减压浓缩，用制备色谱法纯化，得化合物H-19(18mg，棕色油状物)，产率：13.6％。MS m/z(ESI):446.3[M+H] +. 1H NMR(400MHz,CD 3OD):δ8.52-8.43(m,1H),7.79-7.64(m,1H),7.53-7.40(m,1H),7.22-7.18(m,1H),6.90-6.66(m,2H),6.55-6.38(m,1H),3.82-3.65(m,3H),3.20(m,2H),2.96-2.91(m,1H),2.70-2.32(m,5H),2.13-1.31(m,15H),1.11-1.04(m,1H),0.92(t,3H),0.75-0.60(m,1H). Step 9: Add compound 19-9 (60 mg, 0.29 mmol), compound 1b (75 mg, 0.29 mmol) and tetraisopropyl titanate (0.5 mL, 1.69 mmol) into 10 mL of DCE, and stir for reaction at 50° C. for 24 h. Sodium borohydride (56mg, 1.48mmol) was added, and the reaction was stirred at 50°C for 18h. The reaction was quenched by adding 3 mL of water, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative chromatography to obtain compound H-19 (18 mg, brown oil), yield: 13.6%. MS m/z(ESI): 446.3[M+H] + . 1 H NMR(400MHz, CD 3 OD): δ8.52-8.43(m,1H), 7.79-7.64(m,1H), 7.53-7.40 (m,1H),7.22-7.18(m,1H),6.90-6.66(m,2H),6.55-6.38(m,1H),3.82-3.65(m,3H), 3.20(m,2H), 2.96 -2.91(m,1H),2.70-2.32(m,5H),2.13-1.31(m,15H),1.11-1.04(m,1H),0.92(t,3H),0.75-0.60(m,1H) .
实施例20：5-乙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,6,7-四氢-1H，5H-吡啶并[3,2,1-ij]喹啉-1-胺(H-20)的制备Example 20: 5-Ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2, Preparation of 3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-amine (H-20)
Figure PCTCN2020072851-appb-000048
Figure PCTCN2020072851-appb-000048
以化合物2-乙基-1,2,3,4-四氢喹啉和3-溴丙酸甲酯为原料，制备方法参考化合物H-9。得到目标产物化合物H-20(10.72mg，棕色固体)，产率：23.3％。MS m/z(ESI):200.1[M-260] +。 1H NMR(400MHz,CD 3OD)δ8.55–8.46(m,1H),7.78-7.71(m,1H),7.51-7.43(m,1H),7.27–7.15(m,1H),6.73(d,J＝7.1Hz,1H),6.65–6.50(m,1H),6.35-6.28(m,1H),3.79–3.65(m,2H),3.51-3.43(m,1H),3.26–2.87(m,3H),2.74–2.60(m,1H),2.60–2.33(m,4H),2.12-1.81(m,4H),1.84–1.24(m,13H),1.15-1.05(m,1H),0.95-0.83(m,3H),0.72-0.65(m,1H). Using the compound 2-ethyl-1,2,3,4-tetrahydroquinoline and methyl 3-bromopropionate as raw materials, the preparation method refers to compound H-9. The target compound H-20 (10.72 mg, brown solid) was obtained, and the yield was 23.3%. MS m/z (ESI): 200.1 [M-260] + . 1 H NMR (400MHz, CD 3 OD) δ 8.55-8.46 (m, 1H), 7.78-7.71 (m, 1H), 7.51-7.43 (m, 1H), 7.27-7.15 (m, 1H), 6.73 ( d,J=7.1Hz,1H), 6.65–6.50(m,1H), 6.35-6.28(m,1H), 3.79–3.65(m,2H), 3.51-3.43(m,1H), 3.26–2.87( m,3H), 2.74–2.60(m,1H), 2.60–2.33(m,4H), 2.12–1.81(m,4H), 1.84–1.24(m,13H), 1.15-1.05(m,1H), 0.95-0.83 (m, 3H), 0.72-0.65 (m, 1H).
实施例21：5-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,6,7-四氢-1H，5H-吡啶并[3,2,1-ij]喹啉-1-胺(H-21)的制备Example 21: 5-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2 Preparation of ,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-amine (H-21)
Figure PCTCN2020072851-appb-000049
Figure PCTCN2020072851-appb-000049
以化合物1c和3-溴丙酸甲酯为原料，制备方法参考化合物H-1。得化合物H-21(10.17mg，棕色固体)，产率：10.0％。MS m/z(ESI):214.1[M+H-260] +。 1H NMR(400MHz,CD 3OD)δ8.57-8.42(m,1H),7.80-7.68(m,1H),7.51-7.38(m,1H),7.25–7.14(m,1H),6.74(d,J＝7.6Hz,1H),6.64–6.49(m,1H),6.32(dt,J＝13.4,6.7Hz,1H),3.77–3.62(m,2H),3.52-3.43(m,1H),3.41-3.32(m,1H),3.21-3.12(m,1H),3.10–2.99(m,1H),2.86-2.78(m,1H),2.73–2.61(m,1H),2.59–2.30(m,4H),2.05–1.83(m,5H),1.73–1.29(m,10H),1.12-1.03(m,1H),0.96(dd,J＝6.8,2.6Hz,3H),0.90–0.81(m,3H),0.77–0.66(m,1H). Using compound 1c and methyl 3-bromopropionate as raw materials, the preparation method refers to compound H-1. Compound H-21 (10.17 mg, brown solid) was obtained, yield: 10.0%. MS m/z (ESI): 214.1 [M+H-260] + . 1 H NMR (400MHz, CD 3 OD) δ 8.57-8.42 (m, 1H), 7.80-7.68 (m, 1H), 7.51-7.38 (m, 1H), 7.25-7.14 (m, 1H), 6.74 ( d,J=7.6Hz,1H),6.64–6.49(m,1H),6.32(dt,J=13.4,6.7Hz,1H),3.77–3.62(m,2H),3.52-3.43(m,1H) ,3.41-3.32(m,1H),3.21-3.12(m,1H),3.10-2.99(m,1H), 2.86-2.78(m,1H), 2.73-2.61(m,1H), 2.59-2.30( m,4H),2.05–1.83(m,5H),1.73–1.29(m,10H),1.12-1.03(m,1H),0.96(dd,J=6.8,2.6Hz,3H),0.90–0.81( m,3H),0.77--0.66(m,1H).
实施例22：5,5-二甲基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,6,7-四氢-1H，5H-吡啶并[3,2,1-ij]喹啉-1-胺(H-22)的制备Example 22: 5,5-Dimethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl) Preparation of -2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-1-amine (H-22)
Figure PCTCN2020072851-appb-000050
Figure PCTCN2020072851-appb-000050
以化合物1d和3-溴丙酸甲酯为原料，制备方法参考化合物H-1。得化合物H-22(28.77mg，黄色固体)，产率：45.2％。MS m/z(ESI):200.1[M-260] +。1H NMR(400MHz,CD 3OD)δ8.54–8.46(m,1H),7.78–7.71(m,1H),7.48(d,J＝8.1Hz,1H),7.22(m,1H),6.78(d,J＝7.2Hz,1H),6.65(dd,J＝20.6,6.6Hz,1H),6.37(m,1H),3.78–3.66(m,2H),3.61(s,1H),3.24-3.15(m,1H),3.11-3.04(m,1H),2.73–2.58(m,3H),2.54–2.38(m,2H),2.15-2.11(m,1H),2.05-1.98(m,1H),1.86-1.74(m,2H),1.73-1.62(m,6H),1.61–1.39(m,5H),1.21-1.17(m,6H),1.11–1.03(m,1H),0.73-0.62(m,1H). Using compound 1d and methyl 3-bromopropionate as raw materials, the preparation method refers to compound H-1. Compound H-22 (28.77 mg, yellow solid) was obtained. Yield: 45.2%. MS m/z (ESI): 200.1 [M-260] + . 1H NMR (400MHz, CD 3 OD) δ 8.54–8.46 (m, 1H), 7.78–7.71 (m, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.22 (m, 1H), 6.78 ( d,J=7.2Hz,1H),6.65(dd,J=20.6,6.6Hz,1H),6.37(m,1H),3.78–3.66(m,2H),3.61(s,1H),3.24-3.15 (m,1H),3.11-3.04(m,1H),2.73-2.58(m,3H),2.54-2.38(m,2H),2.15-2.11(m,1H),2.05-1.98(m,1H) ,1.86-1.74(m,2H),1.73-1.62(m,6H),1.61-1.39(m,5H),1.21-1.17(m,6H),1.11-1.03(m,1H),0.73-0.62( m,1H).
实施例24：1-甲基-N-(2–((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,7,8,8a-六氢环戊基[ij]异喹啉-7-胺(H-24)的制备Example 24: 1-methyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1, Preparation of 2,3,7,8,8a-hexahydrocyclopentyl[ij]isoquinoline-7-amine (H-24)
Figure PCTCN2020072851-appb-000051
Figure PCTCN2020072851-appb-000051
步骤1：将1,2,3,4-四氢异喹啉(20g，150mmol)溶于DCM(50ml)，加NBS(32g，180mmol)，在室温下搅拌反应1h。向反应液中加入氢氧化钾(12.6g，225mmol)和水(50ml)，室温搅拌2h。溶液加入DCM(150mL)，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物24-1(23g，黄色液体)。MS m/z(ESI):132.1[M+H] +。 Step 1: Dissolve 1,2,3,4-tetrahydroisoquinoline (20g, 150mmol) in DCM (50ml), add NBS (32g, 180mmol), stir and react at room temperature for 1h. Potassium hydroxide (12.6g, 225mmol) and water (50ml) were added to the reaction solution and stirred at room temperature for 2h. The solution was added with DCM (150 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 24-1 (23 g, yellow liquid). MS m/z (ESI): 132.1 [M+H] + .
步骤2：化合物24-1(10g)，加入丙二酸(15.8g，151.5mmol)，120℃下搅拌3h。反应液加入异丙醇(40ml)，在80℃下搅拌30min，过滤。固体干燥得到黄色固体化合物24-2(11.6g，产率79％)，MS m/z(ESI):192.1[M+H] +。 Step 2: Compound 24-1 (10g), add malonic acid (15.8g, 151.5mmol), stir at 120°C for 3h. The reaction solution was added with isopropanol (40ml), stirred at 80°C for 30min, and filtered. The solid was dried to obtain a yellow solid compound 24-2 (11.6 g, yield 79%), MS m/z (ESI): 192.1 [M+H] + .
步骤3：将化合物24-2(0.7g，3.66mmol)溶解于10ml甲醇中，加入多聚甲醛(0.7g)和氰基硼氢化钠(0.748g，11mmol)，40℃搅拌反应过夜。反应液减压蒸馏得到粗品化合物24-3(0.8g，黄色固体)。MS m/z(ESI):206.1[M+H] +。 Step 3: Dissolve compound 24-2 (0.7g, 3.66mmol) in 10ml of methanol, add paraformaldehyde (0.7g) and sodium cyanoborohydride (0.748g, 11mmol), stir and react overnight at 40°C. The reaction solution was distilled under reduced pressure to obtain crude compound 24-3 (0.8 g, yellow solid). MS m/z (ESI): 206.1 [M+H] + .
步骤4：将化合物24-3(800mg)溶解于5ml PPA中，150℃搅拌反应2h。反应液加入冰水(20mL)，加入饱和碳酸钠溶液调节pH值至8，DCM/甲醇(10/1)萃取。有机相减压浓缩，柱层析纯化(PE含35％EA为流动相)，得到黄色液体化合物24-4(0.4g，产率55％)。MS m/z(ESI):188.1[M+H] +。 Step 4: Dissolve compound 24-3 (800mg) in 5ml PPA, stir and react at 150°C for 2h. The reaction solution was added with ice water (20 mL), saturated sodium carbonate solution was added to adjust the pH value to 8, and the mixture was extracted with DCM/methanol (10/1). The organic phase was concentrated under reduced pressure and purified by column chromatography (PE containing 35% EA as the mobile phase) to obtain compound 24-4 (0.4 g, yield 55%) as a yellow liquid. MS m/z (ESI): 188.1 [M+H] + .
步骤5：化合物24-4(70mg，0.37mmol)，化合物1a(97mg，0.37mmol)和钛酸四异丙酯(1mL),45℃搅拌反应16h。加入硼氢化钠(30mg，0.86mmol)，室温搅拌1h。向反应液中加入20mL水，过滤，滤液用DCM(20mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH4HCO3H2O，梯度：30％-60％乙腈变化)，得到白色固体化合物H-24(40.55mg，产率8.8％)。MS m/z(ESI):432.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ8.55-8.53(m,1H),7.64-7.58(m,1H),7.32-7.28(t,J＝8Hz,1H),7.12-7.06(m,2H),6.98-6.96(m,1H),6.93-6.91(m,1H),4.15-4.10(m,1H),3.76-3.74(m,2H),3.04-2.98(m,3H),2.81-2.80(m,1H),2.66-2.55(m,2H),2.45-2.42(m,2H),2.34(s,3H),2.27-2.20(m,1H),2.08-1.90(m,2H),1.85-1.68(m,3H),1.64-1.46(m,6H),1.39-1.20(m,3H)。 Step 5: Compound 24-4 (70 mg, 0.37 mmol), compound 1a (97 mg, 0.37 mmol) and tetraisopropyl titanate (1 mL) were stirred and reacted at 45°C for 16 hours. Sodium borohydride (30mg, 0.86mmol) was added and stirred at room temperature for 1h. 20mL of water was added to the reaction solution, filtered, the filtrate was extracted with DCM (20mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH4HCO3H2O , Gradient: 30%-60% change in acetonitrile) to obtain white solid compound H-24 (40.55 mg, yield 8.8%). MS m/z(ESI): 432.2[M+H] + ; 1 H NMR(400MHz,CDCl 3 )δ8.55-8.53(m,1H),7.64-7.58(m,1H),7.32-7.28(t ,J=8Hz,1H),7.12-7.06(m,2H),6.98-6.96(m,1H),6.93-6.91(m,1H),4.15-4.10(m,1H),3.76-3.74(m, 2H),3.04-2.98(m,3H),2.81-2.80(m,1H),2.66-2.55(m,2H),2.45-2.42(m,2H),2.34(s,3H),2.27-2.20( m, 1H), 2.08-1.90 (m, 2H), 1.85-1.68 (m, 3H), 1.64-1.46 (m, 6H), 1.39-1.20 (m, 3H).
实施例25：N-甲基-2-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(H-25)的制备Example 25: N-methyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-25)
Figure PCTCN2020072851-appb-000052
Figure PCTCN2020072851-appb-000052
步骤1：将合物12-8(142mg，0.52mmol)溶解于THF(10mL)和水(2mL)中，加入一水合氢氧化锂(65mg，1.55mmol)，室温搅拌反应2h。用1M盐酸溶液调反应液pH值至3左右，减压浓缩，得到化合物25-1(127mg)，粗产品不纯化直接用于下一步。MS m/z(ESI):246.1[M+H] +。 Step 1: The compound 12-8 (142 mg, 0.52 mmol) was dissolved in THF (10 mL) and water (2 mL), lithium hydroxide monohydrate (65 mg, 1.55 mmol) was added, and the reaction was stirred at room temperature for 2 h. The pH value of the reaction solution was adjusted to about 3 with 1M hydrochloric acid solution, and concentrated under reduced pressure to obtain compound 25-1 (127 mg). The crude product was used in the next step without purification. MS m/z (ESI): 246.1 [M+H] + .
步骤2：将化合物25-1(50mg)，甲胺盐酸盐(137mg,2.03mmol)和HATU(155mg，0.41mmol)加入DMF(10mL)中，然后加入DIEA(316mg，2.44mmol)，室温反应过夜。加 入EA(100mL)。有机相用饱和食盐水(50mL x 1)和水(50mL x 2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备薄层色谱以层析体系(DCM/甲醇：10/1)纯化，得到红棕色油状物化合物25-2(31mg，产率59％)。MS m/z(ESI):259.1[M+H] +。 Step 2: Add compound 25-1 (50mg), methylamine hydrochloride (137mg, 2.03mmol) and HATU (155mg, 0.41mmol) to DMF (10mL), then add DIEA (316mg, 2.44mmol), and react at room temperature overnight. Add EA (100 mL). The organic phase was washed with saturated brine (50mL x 1) and water (50mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The chromatographic system (DCM/methanol: 10/1 ) Purification to obtain compound 25-2 (31 mg, yield 59%) as a reddish brown oil. MS m/z (ESI): 259.1 [M+H] + .
步骤3：将化合物25-2(31mg,0.12mmol)、化合物1a(40mg,0.15mmol)和钛酸四异丙酯(0.5mL)溶解于DCE(5mL)。50℃下反应18小时后，加入硼氢化钠(30mg,0.79mmol)，50℃下继续反应2小时。冷却到室温后，加入1mL水，过滤，滤液减压浓缩，用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)纯化，得到白色固体化合物H-25(15.24mg,产率25％)。MS m/z(ESI):503.2[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.47(t,J＝5.0Hz,1H),7.74-7.68(m,1H),7.43(dd,J＝11.1,8.1Hz,1H),7.22-7.18(m,1H),7.12–6.88(m,3H),3.84–3.64(m,3H),3.48–3.31(m,2H),3.15–2.91(m,3H),2.79–2.66(m,4H),2.44-2.34(m,3H),2.11–1.82(m,5H),1.78–1.18(m,11H),1.09-1.03(m,1H),0.76–0.62(m,1H)。 Step 3: Dissolve compound 25-2 (31 mg, 0.12 mmol), compound 1a (40 mg, 0.15 mmol) and tetraisopropyl titanate (0.5 mL) in DCE (5 mL). After reacting at 50°C for 18 hours, sodium borohydride (30 mg, 0.79 mmol) was added, and the reaction was continued at 50°C for 2 hours. After cooling to room temperature, 1mL of water was added, filtered, and the filtrate was concentrated under reduced pressure. Preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30 %-60% acetonitrile change) to obtain a white solid compound H-25 (15.24mg, yield 25%). MS m/z(ESI):503.2[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.47(t,J=5.0Hz,1H),7.74-7.68(m,1H),7.43 (dd,J=11.1,8.1Hz,1H),7.22-7.18(m,1H),7.12–6.88(m,3H),3.84–3.64(m,3H),3.48–3.31(m,2H),3.15 --2.91(m,3H),2.79-2.66(m,4H),2.44-2.34(m,3H),2.11-1.82(m,5H),1.78-1.18(m,11H),1.09-1.03(m, 1H), 0.76–0.62 (m, 1H).
实施例26:N,N-二甲基-2-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(H-26)的制备Example 26: N,N-Dimethyl-2-(7--((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-26)
Figure PCTCN2020072851-appb-000053
Figure PCTCN2020072851-appb-000053
步骤1：以化合物25-1与二甲胺四氢呋喃溶液为原料，制备方法参考实施例25中的步骤1得化合物26-1。MS m/z(ESI):273.1[M+H] +。 Step 1: Using compound 25-1 and dimethylamine tetrahydrofuran solution as raw materials, the preparation method refers to step 1 in Example 25 to obtain compound 26-1. MS m/z (ESI): 273.1 [M+H] + .
步骤2：以化合物26-1和化合物1a为原料，制备方法参考实施例25中的步骤2得化合物H-26。MS m/z(ESI):517.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.51–8.44(m,1H),7.75-7.68(m,1H),7.43(dd,J＝11.4,8.1Hz,1H),7.22-7.18(m,1H),7.09-6.92(m,3H),3.86–3.64(m,4H),3.49(t,J＝10.9Hz,1H),3.20–2.96(m,6H),2.92(s,3H),2.74-2.65(m,2H),2.49–2.31(m,3H),2.27–2.15(m,1H),2.09–1.80(m,4H),1.76–1.22(m,10H),1.09-1.03(m,1H),0.74–0.62(m,1H)。 Step 2: Using compound 26-1 and compound 1a as raw materials, the preparation method refers to step 2 in Example 25 to obtain compound H-26. MS m/z(ESI): 517.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.51–8.44(m,1H),7.75-7.68(m,1H),7.43(dd, J = 11.4, 8.1 Hz, 1H), 7.22-7.18 (m, 1H), 7.09-6.92 (m, 3H), 3.86-3.64 (m, 4H), 3.49 (t, J = 10.9 Hz, 1H), 3.20 --2.96(m,6H), 2.92(s,3H), 2.74-2.65(m,2H), 2.49-2.31(m,3H), 2.27-2.15(m,1H), 2.09-1.80(m,4H) ,1.76–1.22(m,10H), 1.09-1.03(m,1H), 0.74–0.62(m,1H).
实施例27:N-异丙基-2-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(H-27)的制备Example 27: N-isopropyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl (Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-27)
Figure PCTCN2020072851-appb-000054
Figure PCTCN2020072851-appb-000054
步骤1：以化合物25-1与异丙胺盐酸盐为原料，制备方法参考实施例25中的步骤1得化合物27-1。MS m/z(ESI):287.2[M+H] +。 Step 1: Using compound 25-1 and isopropylamine hydrochloride as raw materials, the preparation method refers to step 1 in Example 25 to obtain compound 27-1. MS m/z (ESI): 287.2 [M+H] + .
步骤2：以化合物27-1和化合物1a为原料，制备方法参考实施例25中的步骤2得化合物H-27。MS m/z(ESI):531.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.51-8.48(m,1H),7.76-7.70(m,1H),7.45(dd,J＝11.9,8.1Hz,1H),7.24-7.19(m,1H),7.15–6.90(m,3H),4.04-3.97(m,1H),3.88–3.64(m,3H),3.53–3.32(m,2H),3.10-2.96(m,3H),2.86–2.65(m,2H),2.46-2.36(m,3H),2.14–1.83(m,5H),1.75–1.24(m,10H),1.15-1.08(m,7H),0.78–0.61(m,1H)。 Step 2: Using compound 27-1 and compound 1a as raw materials, the preparation method refers to step 2 in Example 25 to obtain compound H-27. MS m/z(ESI):531.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.51-8.48(m,1H),7.76-7.70(m,1H),7.45(dd, J = 11.9, 8.1 Hz, 1H), 7.24-7.19 (m, 1H), 7.15-6.90 (m, 3H), 4.04-3.97 (m, 1H), 3.88-3.64 (m, 3H), 3.53-3.32 ( m, 2H), 3.10-2.96 (m, 3H), 2.86-2.65 (m, 2H), 2.46-2.36 (m, 3H), 2.14-1.83 (m, 5H), 1.75-1.24 (m, 10H), 1.15-1.08(m,7H), 0.78-0.61(m,1H).
实施例28:1-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙烷-1-酮(非对映异构体混合物H-28-1和非对映异构体混合物H-28-2)的制备Example 28: 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-1-one (mixture of diastereomers H-28-1 and diastereomers Preparation of isomer mixture H-28-2)
Figure PCTCN2020072851-appb-000055
Figure PCTCN2020072851-appb-000055
步骤1：向装有1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮盐酸盐(28-1)(80mg,0.36mmol)的单口瓶中加入DCM(3mL)，DIEA(92.5mg,0.72mmol),降温到0℃,搅拌下缓慢滴加丙酰氯(33.2mg,0.36mmol),继续搅拌12小时，LCMS显示反应完全，加入水(5mL)，用DCM(20ml x 2)萃取，合并有机相，饱和食盐水洗，干燥，浓缩得棕色液体。柱层析纯化(DCM含10％甲醇为流动相)得1-丙酰基-1,2,3,8,9,9a-六氢-7H-苯并喹啉-7-酮(28-2)(80mg，产率91.76％，棕色液体)。MS m/z(ESI):244.1[M+H] +。 Step 1: To a single port containing 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one hydrochloride (28-1) (80mg, 0.36mmol) Add DCM (3mL), DIEA (92.5mg, 0.72mmol) to the bottle, cool to 0℃, slowly add propionyl chloride (33.2mg, 0.36mmol) dropwise with stirring, continue stirring for 12 hours, LCMS shows that the reaction is complete, add water ( 5mL), extracted with DCM (20ml x 2), combined the organic phases, washed with saturated brine, dried, and concentrated to obtain a brown liquid. Purified by column chromatography (DCM containing 10% methanol as mobile phase) to obtain 1-propionyl-1,2,3,8,9,9a-hexahydro-7H-benzoquinolin-7-one (28-2) (80mg, yield 91.76%, brown liquid). MS m/z (ESI): 244.1 [M+H] + .
步骤2：将1-丙酰基-1,2,3,8,9,9a-六氢-7H-苯并喹啉-7-酮(28-2)(50mg，0.2mmol)溶解于DCE(5mL)中，化合物1a(53.5mg，0.2mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应16小时。加入硼氢化钠(39mg，1mmol)后30℃搅拌2h。向反应液中加入20mL水，过滤，滤液用DCM(20mL×2)萃取，无水硫酸钠干燥，减压浓缩得粗品H-28。Step 2: Dissolve 1-propionyl-1,2,3,8,9,9a-hexahydro-7H-benzoquinolin-7-one (28-2) (50mg, 0.2mmol) in DCE (5mL ), compound 1a (53.5 mg, 0.2 mmol) and tetraisopropyl titanate (0.5 mL) were reacted with stirring at 45°C for 16 hours. Sodium borohydride (39mg, 1mmol) was added and stirred at 30°C for 2h. 20 mL of water was added to the reaction solution, filtered, and the filtrate was extracted with DCM (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude H-28.
步骤3：将粗品H-28用制备色谱法纯化分离(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，分别得到非对映异构体混合物H-28-1(6.31mg，产率6.03％，白色固体)：MS m/z(ESI):488.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.50-8.38(m,1H),7.67(t,J＝6.8Hz,1H),7.39(t,J＝7.4Hz,1H),7.21–7.12(m,1H),7.09–6.98(m,2H),6.95-6.76(m,1H),5.38-5.18(m,1H),4.80-4.72(m,1H),4.14–3.99(m,1H), 3.72-3.60(m,3H),3.09-2.98(m 1H),2.83-2.64(m,2H),2.45-2.20(m,5H),2.02–1.77(m,5H),1.73–1.31(m,9H),1.15(t,J＝7.4Hz,3H),1.09-1.01(m,1H),0.72-0.61(m,1H)。 Step 3: Purify and separate the crude H-28 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), The diastereoisomer mixture H-28-1 (6.31mg, yield 6.03%, white solid) was obtained respectively: MS m/z(ESI): 488.3[M+H] + ; 1 H NMR (400MHz, CD 3 OD)δ8.50-8.38(m,1H), 7.67(t,J=6.8Hz,1H), 7.39(t,J=7.4Hz,1H), 7.21–7.12(m,1H), 7.09–6.98 (m,2H),6.95-6.76(m,1H),5.38-5.18(m,1H),4.80-4.72(m,1H),4.14-3.99(m,1H), 3.72-3.60(m,3H) , 3.09-2.98 (m 1H), 2.83-2.64 (m, 2H), 2.45-2.20 (m, 5H), 2.02-1.77 (m, 5H), 1.73-1.31 (m, 9H), 1.15 (t, J =7.4Hz, 3H), 1.09-1.01 (m, 1H), 0.72-0.61 (m, 1H).
和非对映异构体混合物H-28-2(17.36mg，产率17.35％，白色固体)：MS m/z(ESI):488.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.51(dd,J＝13.3,3.8Hz,1H),7.80–7.70(m,1H),7.55–7.40(m,1H),7.26–7.17(m,1H),7.17–7.04(m,1H),7.05–6.85(m,2H),4.98-4.92(m,1H),4.79-4.59(m,1H),4.06(d,J＝14.7Hz,1H),3.78-3.70(m,2H),3.51-3.39(m,1H),3.15–3.03(m,1H),2.93–2.79(m,1H),2.77–2.60(m,2H),2.59-2.38(m,4H),2.21–2.03(m,3H),2.21-2.00(m,5H),1.64–1.31(m,6H),1.20–1.05(m,4H),0.73-0.62(m,1H)。 And diastereoisomer mixture H-28-2 (17.36mg, yield 17.35%, white solid): MS m/z(ESI): 488.3[M+H] + ; 1 H NMR (400MHz, CD 3 OD)δ8.51(dd,J=13.3,3.8Hz,1H), 7.80-7.70(m,1H), 7.55-7.40(m,1H), 7.26-7.17(m,1H), 7.17-7.04(m ,1H),7.05-6.85(m,2H),4.98-4.92(m,1H),4.79-4.59(m,1H),4.06(d,J=14.7Hz,1H),3.78-3.70(m,2H) ), 3.51-3.39 (m, 1H), 3.15-3.03 (m, 1H), 2.93-2.79 (m, 1H), 2.77-2.60 (m, 2H), 2.59-2.38 (m, 4H), 2.21-2.03 (m, 3H), 2.21-2.00 (m, 5H), 1.64-1.31 (m, 6H), 1.20-1.05 (m, 4H), 0.73-0.62 (m, 1H).
实施例29:2-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)-1-(吡咯烷-1-基)乙烷-1-酮(非对映异构体混合物H-29-1和非对映异构体混合物H-29-2)的制备Example 29: 2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)-1-(pyrrolidin-1-yl)ethane-1-one (diastere Preparation of conformer mixture H-29-1 and diastereoisomer mixture H-29-2)
Figure PCTCN2020072851-appb-000056
Figure PCTCN2020072851-appb-000056
步骤1：将化合物25-1(200mg，0.82mmol)溶解于5mL DMF中，加入HATU(372mg，0.98mmol)和吡咯烷(289mg，4.08mmol)，DIPEA(315mg，2.45mmol)，室温下搅拌反应12h。向反应液中加入10mL水，用DCM萃取(50mL×2)。合并有机相，用水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化(DCM含10％甲醇为流动相)，得到棕色液体化合物29-1(200mg，产率82.3％)。Step 1: Dissolve compound 25-1 (200mg, 0.82mmol) in 5mL DMF, add HATU (372mg, 0.98mmol) and pyrrolidine (289mg, 4.08mmol), DIPEA (315mg, 2.45mmol), stir at room temperature for reaction 12h. 10 mL of water was added to the reaction solution, and it was extracted with DCM (50 mL×2). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM containing 10% methanol as the mobile phase) to obtain brown liquid compound 29-1 (200 mg, yield 82.3%).
步骤2：将化合物29-1(60mg，0.2mmol)溶解于DCE(5mL)中，加入化合物1a(52mg，0.2mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应16小时。加入硼氢化钠(38mg，1mmol)后30℃搅拌2h。向反应液中加入水(10mL)，过滤，滤液用DCM(30mL×2)萃取，无水硫酸钠干燥，减压浓缩得粗品H-29。Step 2: Dissolve compound 29-1 (60 mg, 0.2 mmol) in DCE (5 mL), add compound 1a (52 mg, 0.2 mmol) and tetraisopropyl titanate (0.5 mL), stir and react at 45° C. for 16 hours. Add sodium borohydride (38mg, 1mmol) and stir at 30°C for 2h. Water (10 mL) was added to the reaction solution, filtered, and the filtrate was extracted with DCM (30 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude H-29.
步骤3：将粗品H-29用制备色谱法纯化分离(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：30％-60％乙腈变化)，分别得到非对映异构体混合物H-29-1(37.03mg，产率34.1％，白色固体)。MS m/z(ESI):543.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.58–8.49(m,1H),8.44–8.25(s,1H),7.77(dd,J＝16.1,8.0Hz,1H),7.49(dd,J＝12.3,8.2Hz,1H),7.19(m,4H),4.61–4.47(m,1H),3.81–3.63(m,4H),3.62–3.37(m,4H),3.26-3.08(m,1H),3.15-3.03(m,1H),2.96-2.73m,3H),2.51-2.43(m,2H),2.41-2.24(m,3H),2.23–2.10(m,1H),2.09–1.80(m,6H),1.80–1.24(m,10H),1.10-1.07(s,1H),0.73–0.61(m,1H). Step 3: Purify and separate the crude H-29 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , The diastereomer mixture H-29-1 (37.03 mg, yield 34.1%, white solid) was obtained respectively. MS m/z(ESI): 543.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.58–8.49(m,1H),8.44–8.25(s,1H),7.77(dd, J = 16.1, 8.0 Hz, 1H), 7.49 (dd, J = 12.3, 8.2 Hz, 1H), 7.19 (m, 4H), 4.61–4.47 (m, 1H), 3.81–3.63 (m, 4H), 3.62 --3.37(m,4H),3.26-3.08(m,1H),3.15-3.03(m,1H),2.96-2.73m,3H),2.51-2.43(m,2H),2.41-2.24(m,3H) ), 2.23 - 2.10 (m, 1H), 2.09 - 1.80 (m, 6H), 1.80 - 1.24 (m, 10H), 1.10-1.07 (s, 1H), 0.73 - 0.61 (m, 1H).
和非对映异构体混合物H-29-2(1.31mg，产率1.2％，白色固体)。MS m/z(ESI):543.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.59-8.48(m,1H),7.79-7.71(m,1H),7.50(d,J＝7.5Hz,1H),7.28-7.18(m,1H),7.04(dd,J＝16.5,8.6Hz,1H),6.97–6.81(m,2H),3.77–3.39(m,9H),3.22(d,J＝15.2Hz,1H),3.18-3.07(m,1H),3.08-1.97(m,1H),2.83-2.69(m,2H),2.64–2.34(m,4H),2.16–2.00(m,3H),1.98–1.82(m,5H),1.75-1.62(m,3H),1.64–1.35(m,7H),1.11-1.02(s,1H),0.5-0.61(m,1H). And diastereoisomer mixture H-29-2 (1.31 mg, yield 1.2%, white solid). MS m/z(ESI): 543.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.59-8.48(m,1H),7.79-7.71(m,1H),7.50(d, J = 7.5Hz, 1H), 7.28-7.18 (m, 1H), 7.04 (dd, J = 16.5, 8.6Hz, 1H), 6.97-6.81 (m, 2H), 3.77-3.39 (m, 9H), 3.22 (d,J=15.2Hz,1H),3.18-3.07(m,1H),3.08-1.97(m,1H),2.83-2.69(m,2H),2.64-2.34(m,4H),2.16-2.00 (m,3H),1.98-1.82(m,5H),1.75-1.62(m,3H),1.64--1.35(m,7H),1.11-1.02(s,1H),0.5-0.61(m,1H) .
实施例30:2-环丙基-1-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙烷-1-酮(非对映异构体混合物H-30-1和非对映异构体混合物H-30-2)的制备Example 30: 2-Cyclopropyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo(de)quinolin-1-yl)ethane-1-one (diastereomer mixture H- 30-1 and the preparation of diastereoisomer mixture H-30-2)
Figure PCTCN2020072851-appb-000057
Figure PCTCN2020072851-appb-000057
步骤1：将2-环丙基乙酸(400mg，4.0mmol)和氯化亚砜(3mL，41.3mmol)加入DCM(10mL)中，加热到回流反应2小时。减压浓缩，残余物溶解于10mL DCM中，加入化合物28-1(100mg，0.45mmol)，然后加入DIEA(0.5mL，3.0mmol)，室温反应过夜。减压浓缩，用制备薄层色谱以层析体系(DCM/7N氨甲醇溶液：100/3)纯化得黄色固体化合物30-1(50mg，产率42％)。MS m/z(ESI):270.1[M+H] +。 Step 1: Add 2-cyclopropylacetic acid (400 mg, 4.0 mmol) and thionyl chloride (3 mL, 41.3 mmol) to DCM (10 mL), and heat to reflux for 2 hours. After concentration under reduced pressure, the residue was dissolved in 10 mL of DCM, compound 28-1 (100 mg, 0.45 mmol) was added, and then DIEA (0.5 mL, 3.0 mmol) was added, and the reaction was carried out at room temperature overnight. It was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (DCM/7N ammonia methanol solution: 100/3) to obtain yellow solid compound 30-1 (50 mg, yield 42%). MS m/z (ESI): 270.1 [M+H] + .
步骤2：将化合物30-1(50mg,0.19mmol)、化合物1a(58mg,0.22mmol)和钛酸四异丙酯(1mL)溶解于10mL DCE。50℃下反应18小时后，加入硼氢化钠(50mg,1.32mmol)，50℃下继续反应1h。冷却到室温后，加入1mL水，过滤，滤液减压浓缩得粗品H-30。Step 2: Dissolve compound 30-1 (50 mg, 0.19 mmol), compound 1a (58 mg, 0.22 mmol) and tetraisopropyl titanate (1 mL) in 10 mL DCE. After reacting at 50°C for 18 hours, sodium borohydride (50mg, 1.32mmol) was added, and the reaction was continued at 50°C for 1 hour. After cooling to room temperature, 1 mL of water was added, filtered, and the filtrate was concentrated under reduced pressure to obtain crude H-30.
步骤3：将粗品H-30用制备液相色谱纯化分离(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：30％-60％乙腈变化)分别得到非对映异构体混合物H-30-1(白色固体，9.02mg,产率9.5％)。MS m/z(ESI):514.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.56–8.47(m,1H),7.80–7.70(m,1H),7.52(t,J＝8.3Hz,1H),7.24-7.18(m,1H),7.14-7.05(m,1H),7.02-6.88(m,2H),4.99–4.91(m,1H),4.76-4.55(m,1H),4.07(d,J＝12.5Hz,1H),3.78-3.71(m,2H),3.49-3.41(m,1H),3.10(t,J＝11.6Hz,1H),2.90-2.83(m,1H),2.78–2.29(m,6H),2.20–2.00(m,3H),1.97–1.27(m,10H),1.16-0.99(m,3H),0.78–0.64(m,1H),0.56-0.50(m,2H),0.22-0.18(m,2H). Step 3: Purify and separate the crude H-30 by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 30%-60% acetonitrile change ) The diastereoisomer mixture H-30-1 (white solid, 9.02 mg, yield 9.5%) was obtained respectively. MS m/z(ESI): 514.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.56–8.47(m,1H),7.80–7.70(m,1H),7.52(t, J = 8.3Hz, 1H), 7.24-7.18 (m, 1H), 7.14-7.05 (m, 1H), 7.02-6.88 (m, 2H), 4.99-4.91 (m, 1H), 4.76-4.55 (m, 1H),4.07(d,J=12.5Hz,1H),3.78-3.71(m,2H),3.49-3.41(m,1H),3.10(t,J=11.6Hz,1H),2.90-2.83(m ,1H), 2.78–2.29(m,6H), 2.20–2.00(m,3H), 1.97–1.27(m,10H), 1.16-0.99(m,3H), 0.78–0.64(m,1H), 0.56 -0.50(m,2H),0.22-0.18(m,2H).
和非对映异构体混合物H-30-2(白色固体，30.54mg,产率34％)。MS m/z(ESI):514.3[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.50–8.38(m,1H),7.69-7.65(m,1H),7.40(t,J＝8.2Hz, 1H),7.18-7.15(m,1H),7.08–6.76(m,3H),5.37-5.15(m,1.5H),4.75-4.72(m,0.5H),4.08(d,J＝12.8Hz,1H),3.80–3.55(m,3H),3.10-3.02(m,1H),2.88-2.57(m,3H),2.46-2.23(m,5H),2.04–1.33(m,13H),1.07-1.02(m,2H),0.70–0.65(m,1H),0.57-0.51(m,2H),0.24-0.20(m,2H)。 And diastereoisomer mixture H-30-2 (white solid, 30.54 mg, yield 34%). MS m/z(ESI): 514.3[M+H] + ; 1 H NMR(400MHz,CD 3 OD)δ8.50–8.38(m,1H),7.69-7.65(m,1H),7.40(t, J=8.2Hz, 1H), 7.18-7.15(m,1H), 7.08-6.76(m,3H), 5.37-5.15(m,1.5H), 4.75-4.72(m,0.5H), 4.08(d, J = 12.8Hz, 1H), 3.80-3.55 (m, 3H), 3.10-3.02 (m, 1H), 2.88-2.57 (m, 3H), 2.46-2.23 (m, 5H), 2.04-1.33 (m, 13H), 1.07-1.02 (m, 2H), 0.70-0.65 (m, 1H), 0.57-0.51 (m, 2H), 0.24-0.20 (m, 2H).
实施例31:环丙基(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)甲烷酮(非对映异构体混合物H-31-1和非对映异构体混合物H-31-2)的制备Example 31: Cyclopropyl(7--((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)- 2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)methane ketone (mixture of diastereomers H-31-1 and diastereomers Preparation of body mixture H-31-2)
Figure PCTCN2020072851-appb-000058
Figure PCTCN2020072851-appb-000058
步骤1：将化合物12-7(187mg，1mmol)和TEA(110mg，1.1m mol)溶解于DCM(15mL)中，冰浴下滴加环丙烷酰氯(104mg，1mmol)，室温搅拌2h。反应液水洗，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱纯化(PE/EA＝3/1)，得到白色固体化合物31-1(216mg，产率85％)。MS m/z(ESI):256.2[M+H] +。 Step 1: Dissolve compound 12-7 (187 mg, 1 mmol) and TEA (110 mg, 1.1 mmol) in DCM (15 mL), add cyclopropaneyl chloride (104 mg, 1 mmol) dropwise under ice bath, and stir at room temperature for 2 h. The reaction solution was washed with water, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified with a silica gel column (PE/EA=3/1) to obtain a white solid compound 31-1 (216 mg, yield 85%). MS m/z (ESI): 256.2 [M+H] + .
步骤2：将化合物31-1(50mg，0.2mmol)和化合物1a(51mg，0.2mmol)溶解于DCE(10mL)中，加入钛酸四异丙酯(0.5mL)，45℃搅拌反应18h。冷却至室温，向反应液加入硼氢化钠(30mg，0.8mmol)，搅拌3h，向反应液中加入水(5mL)，搅拌5min，过滤，滤液减压浓缩得粗品化合物H-31。Step 2: Compound 31-1 (50 mg, 0.2 mmol) and compound 1a (51 mg, 0.2 mmol) were dissolved in DCE (10 mL), tetraisopropyl titanate (0.5 mL) was added, and the reaction was stirred at 45° C. for 18 h. After cooling to room temperature, sodium borohydride (30 mg, 0.8 mmol) was added to the reaction solution, stirred for 3 h, water (5 mL) was added to the reaction solution, stirred for 5 min, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound H-31.
步骤3：将粗品H-31用制备色谱纯化，分离(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：30％-60％乙腈变化)，分别得到非对映异构体混合物H-31-1(13.44mg，白色固体，产率13.5％)。MS m/z(ESI):500.4[M+H] +；1H NMR(400MHz,DMSO-d6)δ8.49(m,1H),7.69(m,1H),7.49–7.41(m,1H),7.15(m,1H),7.08(s,1H),7.06–6.91(m,2H),4.84(s,1H),4.48(d,J＝72.1Hz,1H),3.66–3.35(m,2H),2.92–2.48(m,2H),2.41(s,1H),2.32(d,J＝13.2Hz,1H),2.15–1.84(m,4H),1.84–1.13(m,15H),0.94(m,2H),0.82–0.52(m,5H)。 Step 3: Purify and separate the crude H-31 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , Respectively obtain diastereoisomer mixture H-31-1 (13.44 mg, white solid, yield 13.5%). MS m/z(ESI): 500.4[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.49(m,1H),7.69(m,1H),7.49–7.41(m,1H), 7.15(m,1H), 7.08(s,1H), 7.06–6.91(m,2H), 4.84(s,1H), 4.48(d,J=72.1Hz,1H), 3.66–3.35(m,2H) ,2.92–2.48(m,2H),2.41(s,1H), 2.32(d,J=13.2Hz,1H), 2.15–1.84(m,4H),1.84–1.13(m,15H),0.94(m ,2H),0.82–0.52(m,5H).
和非对映异构体混合物H-31-2(20.3mg，白色固体，产率20.3％)。MS m/z(ESI):500.4[M+H] +；1H NMR(400MHz,DMSO-d6)δ8.49–8.39(m,1H),7.61(m,1H),7.32(d,J＝8.0Hz,1H),7.11(m,1H),6.99(m,3H),6.78(m,1H),5.70–5.38(m,1H),4.47(d,J＝74.5Hz,1H),3.67–3.40(m,4H),3.12–2.42(m,8H),2.41–1.14(m,11H),0.81(m,7H),0.60–0.46(m,1H)。 And diastereoisomer mixture H-31-2 (20.3 mg, white solid, yield 20.3%). MS m/z(ESI): 500.4[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.49–8.39(m,1H),7.61(m,1H),7.32(d,J=8.0 Hz, 1H), 7.11 (m, 1H), 6.99 (m, 3H), 6.78 (m, 1H), 5.70-5.38 (m, 1H), 4.47 (d, J = 74.5 Hz, 1H), 3.67-3.40 (m,4H), 3.12–2.42(m,8H), 2.41–1.14(m,11H), 0.81(m,7H), 0.60–0.46(m,1H).
实施例32:2-甲基-1-(7–((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙烷-1-酮(非对映异构体混合物H-32-1和非对映异构体混合物H-32-2)的制备Example 32: 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-1-one (mixture of diastereomers H-32- 1 and the preparation of diastereoisomer mixture H-32-2)
Figure PCTCN2020072851-appb-000059
Figure PCTCN2020072851-appb-000059
步骤1：以化合物12-7和异丙酰氯为原料，制备方法参考实施例31步骤1，制得化合物32-1。MS m/z(ESI):258.1[M+H] +。 Step 1: Using compound 12-7 and isopropanoyl chloride as raw materials, the preparation method refers to step 1 in Example 31 to obtain compound 32-1. MS m/z (ESI): 258.1 [M+H] + .
步骤2：以化合物32-1和化合物1a为原料，制备方法参考实施例31步骤2，减压浓缩得粗品化合物H-32。Step 2: Using compound 32-1 and compound 1a as raw materials, the preparation method refers to step 2 of Example 31, and concentrated under reduced pressure to obtain crude compound H-32.
步骤3：将粗品H-32用制备色谱纯化，分离(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：30％-60％乙腈变化)，分别得到非对映异构体混合物H-32-1(65.8mg，白色固体，产率43.8％)。MS m/z(ESI):502.4[M+H] +；1H NMR(400MHz,DMSO-d6)δ8.49–8.40(m,1H),7.63-7.60(m,1H),7.33-7.31(m,1H),7.22–7.06(m,1H),6.98-6.96(m,2H),6.89–6.64(m,1H),5.45(s,1H),4.53-4.51(m,1H),4.03(d,J＝13.3Hz,1H),3.67–3.41(m,3H),3.04–2.47(m,5H),2.44–2.16(m,3H),2.14–1.12(m,15H),1.10–0.80(m,6H),0.55-0.52(m,1H)。 Step 3: Purify and separate the crude H-32 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) , The diastereomer mixture H-32-1 (65.8 mg, white solid, yield 43.8%) was obtained respectively. MS m/z(ESI): 502.4[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.49–8.40(m,1H),7.63-7.60(m,1H),7.33-7.31(m ,1H),7.22-7.06(m,1H),6.98-6.96(m,2H),6.89-6.64(m,1H),5.45(s,1H),4.53-4.51(m,1H),4.03(d ,J=13.3Hz,1H), 3.67–3.41(m,3H),3.04–2.47(m,5H), 2.44–2.16(m,3H), 2.14–1.12(m,15H), 1.10–0.80(m ,6H),0.55-0.52(m,1H).
和非对映异构体混合物H-32-2(20.53mg，白色固体，产率13.6％)。MS m/z(ESI):502.4[M+H] +；1H NMR(400MHz,DMSO-d6)δ8.54–8.46(m,1H),7.74–7.64(m,1H),7.45(m,1H),7.15(m,1H),7.08–6.90(m,2H),4.80(d,J＝10.4Hz,1H),4.58(s,1H),4.04(d,J＝13.3Hz,1H),3.70–3.32(m,2H),3.24(s,1H),3.07–2.83(m,2H),2.84–2.48(m,3H),2.47–2.24(m,4H),2.15–1.09(m,14H),1.09–0.81(m,6H),0.60-0.57(m,1H)。 And diastereoisomer mixture H-32-2 (20.53 mg, white solid, yield 13.6%). MS m/z(ESI):502.4[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ8.54–8.46(m,1H),7.74–7.64(m,1H),7.45(m,1H ),7.15(m,1H),7.08–6.90(m,2H),4.80(d,J=10.4Hz,1H),4.58(s,1H),4.04(d,J=13.3Hz,1H),3.70 --3.32(m,2H), 3.24(s,1H), 3.07–2.83(m,2H), 2.84–2.48(m,3H), 2.47–2.24(m,4H), 2.15–1.09(m,14H) ,1.09-0.81(m,6H),0.60-0.57(m,1H).
实施例34:1-仲丁基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,6,7,8,8a-六氢苯并[cd]吲哚-6-胺(非对映异构体混合物H-34-1、非对映异构体混合物H-34-2和非对映异构体混合物H-34-3)的制备Example 34: 1-sec-butyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1 ,2,6,7,8,8a-Hexahydrobenzo[cd]indole-6-amine (mixture of diastereomers H-34-1, mixture of diastereomers H-34-2 And diastereoisomer mixture H-34-3) preparation
Figure PCTCN2020072851-appb-000060
Figure PCTCN2020072851-appb-000060
步骤1：将化合物4-1(5.07g，0.03mol)溶解于70mL DMF中，加入碳酸钾(8.28g，0.06mol)和2-碘丁烷(8.24g，0.045mol)，80℃搅拌18h。冷却至室温，用EA(180ml)稀释，水洗(120mL×2)，饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法(PE/EA＝3/1)纯化，得到黄色固体化合物34-1(4.08g，产率60.5％)。MS m/z(ESI):226.2[M+H] +。 Step 1: Dissolve compound 4-1 (5.07g, 0.03mol) in 70mL DMF, add potassium carbonate (8.28g, 0.06mol) and 2-iodobutane (8.24g, 0.045mol), stir at 80°C for 18h. Cooled to room temperature, diluted with EA (180ml), washed with water (120mL×2), saturated brine (50mL×1), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The silica gel column chromatography (PE/EA = 3/1) Purification to obtain yellow solid compound 34-1 (4.08 g, yield 60.5%). MS m/z (ESI): 226.2 [M+H] + .
步骤2：将化合物34-1(4.08g，18mmol)溶解于70mL TFA中，加入10％湿Pd/C(2.5g)，氢气置换三次，然后升温至50℃搅拌18h。冷却至室温，过滤，浓缩，得到黄色固体化合物34-2(2.95g，产率：71％)。MS m/z(ESI):230.3[M+H] +。 Step 2: Dissolve compound 34-1 (4.08 g, 18 mmol) in 70 mL TFA, add 10% wet Pd/C (2.5 g), replace with hydrogen three times, and then raise the temperature to 50° C. and stir for 18 h. Cool to room temperature, filter, and concentrate to obtain yellow solid compound 34-2 (2.95 g, yield: 71%). MS m/z (ESI): 230.3 [M+H] + .
步骤3：将化合物34-2(2.95g，12.9mmol)溶解于20mL丙酮中，加入高锰酸钾(10.2g，64.4mmol)，室温搅拌反应18h，过滤，滤液减压浓缩，用硅胶柱色谱法(PE/EA＝1/1)纯化，得到黄色固体化合物34-3(668mg，产率20％)。MS m/z(ESI):260.3[M+H] +。 Step 3: Dissolve compound 34-2 (2.95g, 12.9mmol) in 20mL of acetone, add potassium permanganate (10.2g, 64.4mmol), stir and react at room temperature for 18h, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography Purification method (PE/EA=1/1) yielded yellow solid compound 34-3 (668 mg, yield 20%). MS m/z (ESI): 260.3 [M+H] + .
步骤4：将化合物34-3(200mg，0.77mmol)和化合物1a(201mg，0.77mmol)溶解于30mL DCE中，加入钛酸四异丙酯(2mL)，45℃搅拌反应18h。冷却至室温，向反应液加入硼氢化钠(88mg，2.31mmol)，搅拌3h，向反应液中加入5mL水，搅拌5min，过滤，滤液减压浓缩，用硅胶柱色谱法(DCM/甲醇＝30/1)纯化，得到黄色固体化合物34-4(150mg，产率40％)。MS m/z(ESI):486.2[M+H] +。 Step 4: Compound 34-3 (200 mg, 0.77 mmol) and compound 1a (201 mg, 0.77 mmol) were dissolved in 30 mL of DCE, tetraisopropyl titanate (2 mL) was added, and the reaction was stirred at 45° C. for 18 h. After cooling to room temperature, sodium borohydride (88mg, 2.31mmol) was added to the reaction solution, stirred for 3h, 5mL of water was added to the reaction solution, stirred for 5min, filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (DCM/methanol=30 /1) Purification to obtain yellow solid compound 34-4 (150 mg, yield 40%). MS m/z (ESI): 486.2 [M+H] + .
步骤5：化合物34-4(150mg，0.31mmol)溶解于无水乙醇(15mL)中，加入10％湿Pd/C(70mg)，氢气置换三次，然后室温搅拌2h，过滤，浓缩，得到黄色固体化合物34-5(130mg，产率86％)。MS m/z(ESI):488.3[M+H] +。 Step 5: Compound 34-4 (150 mg, 0.31 mmol) was dissolved in absolute ethanol (15 mL), 10% wet Pd/C (70 mg) was added, replaced with hydrogen three times, then stirred at room temperature for 2 hours, filtered, and concentrated to obtain a yellow solid Compound 34-5 (130 mg, yield 86%). MS m/z (ESI): 488.3 [M+H] + .
步骤6：将化合物34-5(130mg，0.267mmol)溶解于THF(15mL)中，冰浴下，加入氢化铝锂(30mg,0.8mmol)，升温至50℃，搅拌1h，用饱和氯化铵水溶液淬灭，过滤，浓缩得粗 品化合物H-34。Step 6: Dissolve compound 34-5 (130mg, 0.267mmol) in THF (15mL), add lithium aluminum hydride (30mg, 0.8mmol) under ice bath, heat to 50℃, stir for 1h, and use saturated ammonium chloride The aqueous solution was quenched, filtered, and concentrated to obtain the crude compound H-34.
步骤7：将粗品H-34用制备色谱纯化分离(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O，波长：254/214nm，梯度：30％-60％乙腈变化)，分别得到非对映异构体混合物H-34-1MS m/z(ESI):474.4[M+H] +。 Step 7: Purify and separate the crude H-34 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), The diastereomer mixture H-34-1MS m/z(ESI): 474.4[M+H] + was obtained respectively .
非对映异构体混合物H-34-2。MS m/z(ESI):474.4[M+H] +； 1H NMR(400MHz,DMSO-d 6)δ8.49(m,1H),7.73–7.62(m,1H),7.46–7.37(m,1H),7.07–6.88(m,3H),3.86(d,J＝12.8Hz,1H),3.75–3.65(m,1H),3.64–3.47(m,3H),3.45–3.34(m,1H),2.78–2.64(m,1H),2.44–2.21(m,3H),2.11–1.69(m,5H),1.67–1.16(m,13H),1.06(dd,J＝6.6,1.7Hz,3H),0.98–0.88(m,2H),0.83(m,3H),0.57(m,1H)。 Diastereoisomer mixture H-34-2. MS m/z(ESI): 474.4[M+H] + ; 1 H NMR(400MHz,DMSO-d 6 )δ8.49(m,1H),7.73-7.62(m,1H),7.46-7.37(m ,1H),7.07–6.88(m,3H), 3.86(d,J=12.8Hz,1H), 3.75–3.65(m,1H), 3.64–3.47(m,3H), 3.45–3.34(m,1H) ),2.78–2.64(m,1H),2.44–2.21(m,3H),2.11–1.69(m,5H),1.67–1.16(m,13H),1.06(dd,J=6.6,1.7Hz,3H ), 0.98–0.88 (m, 2H), 0.83 (m, 3H), 0.57 (m, 1H).
和非对映异构体混合物H-34-3。MS m/z(ESI):474.4[M+H] +； 1H NMR(400MHz,DMSO-d6)δ8.49(m,1H),7.69(m,1H),7.43(d,J＝8.1Hz,1H),7.16(m,1H),7.07–6.89(m,3H),3.75–3.63(m,2H),3.62–3.38(m,4H),2.78(m,1H),2.40(s,1H),2.29(d,J＝13.6Hz,2H),2.05–1.23(m,18H),1.23–1.05(m,2H),0.95(d,J＝6.4Hz,3H),0.83(m,3H),0.62–0.52(m,1H)。 And a mixture of diastereomers H-34-3. MS m/z(ESI): 474.4[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.49(m,1H),7.69(m,1H),7.43(d,J=8.1Hz ,1H),7.16(m,1H),7.07-6.89(m,3H),3.75-3.63(m,2H),3.62-3.38(m,4H),2.78(m,1H),2.40(s,1H) ), 2.29(d,J=13.6Hz,2H),2.05-1.23(m,18H),1.23-1.05(m,2H),0.95(d,J=6.4Hz,3H),0.83(m,3H) ,0.62–0.52(m,1H).
实施例35：N，N-二甲基-2-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酰胺(H-35)的制备Example 35: N,N-Dimethyl-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl )Ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionamide (H-35)
Figure PCTCN2020072851-appb-000061
Figure PCTCN2020072851-appb-000061
步骤1：单口瓶中加入1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-盐酸盐(447mg,2mmol)，2-溴丙酸乙酯(724mg，4mmol)，碳酸钾(552mg，4mmol)，DMF(5mL)。50度搅拌12小时。冷却到室温，加入20毫升水，用二氯甲烷洗涤萃取(50mL x2)。饱和食盐水洗(20mL x2),无水硫酸钠干燥，旋干，纯化得到化合物2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸乙酯：(270mg,产率：47％，棕色固体)。MS m/z(ESI):288.1[M+H] +。 Step 1: Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline-7-hydrochloride (447mg, 2mmol), ethyl 2-bromopropionate to a single-mouth bottle (724 mg, 4 mmol), potassium carbonate (552 mg, 4 mmol), DMF (5 mL). Stir at 50 degrees for 12 hours. Cool to room temperature, add 20 mL of water, wash and extract with dichloromethane (50 mL x 2). Wash with saturated brine (20mL x2), dry with anhydrous sodium sulfate, spin dry, and purify to obtain compound 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de] Quinolin-1-yl) ethyl propionate: (270 mg, yield: 47%, brown solid). MS m/z (ESI): 288.1 [M+H] + .
步骤2：将水(5mL)加入到一水合氢氧化锂(84mg，2mol)中溶解，预冷到(5度)。在100mL圆底烧瓶中加入2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸乙酯(273mg，1mol)，甲醇(5mL)，,四氢呋喃(10mL)，再加入预冷的氢氧化锂水溶液，搅拌2小时，浓盐酸调PH约到3，用二氯甲烷萃取(80ml x2)，合并所有的有机相，饱和食盐水洗，干燥，浓缩得到产物2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸(220mg,产率：100％，白色固体)。MS m/z(ESI):260.1[M+H] +。 Step 2: Add water (5 mL) to lithium hydroxide monohydrate (84 mg, 2 mol) to dissolve, and pre-cool to (5 degrees). Add 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl) ethyl propionate (273mg , 1mol), methanol (5mL), tetrahydrofuran (10mL), add pre-cooled lithium hydroxide aqueous solution, stir for 2 hours, adjust the pH to about 3 with concentrated hydrochloric acid, extract with dichloromethane (80ml x 2), combine all The organic phase is washed with saturated brine, dried and concentrated to obtain the product 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propane Acid (220 mg, yield: 100%, white solid). MS m/z (ESI): 260.1 [M+H] + .
步骤3：将2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸(100mg，0.39mmol) 溶解于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(293mg，0.77mmol)和二甲胺四氢呋喃溶液(1.93mL，3.86mmol,2M THF)，N,N-二异丙基乙胺(149mg，1.16mmol)，室温下搅拌反应12小时。向反应液中加入10mL水，用二氯甲烷萃取(50mL×2)。合并有机相，用水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化(二氯甲烷含10％甲醇为流动相)，得到N，N-二甲基-2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酰胺(60mg，产率：54.3％,棕色液体)。MS m/z(ESI):287.2[M+H] +。 Step 3: Dissolve 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionic acid (100mg, 0.39mmol) In 5mL N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (293mg, 0.77 mmol) and dimethylamine tetrahydrofuran solution (1.93 mL, 3.86 mmol, 2M THF), N,N-diisopropylethylamine (149 mg, 1.16 mmol), and the reaction was stirred at room temperature for 12 hours. 10 mL of water was added to the reaction solution and extracted with dichloromethane (50 mL×2). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane containing 10% methanol as the mobile phase) to obtain N,N-dimethyl-2 -(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propionamide (60mg, yield: 54.3%, brown liquid) . MS m/z (ESI): 287.2 [M+H] + .
步骤4：将N，N-二甲基-2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酰胺(29mg，0.1mmol)溶解于5(mL)1,2-二氯乙烷中，加入化合物1a(26mg，0.1mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应72小时。加入硼氢化钠(19mg，0.5mmol)，45℃搅拌继续反应12小时。向反应液中加入10mL水，过滤，滤液用二氯甲烷(30mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3 H2O，波长：254/214nm，梯度：30％-60％乙腈变化)，得到化合物H-35(3.23mg，产率:6％，白色固体)。MS m/z(ESI):531.4[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.58-8.50(m,1H),8.48(s,1H),7.76(dd,J＝15.5,7.7Hz,1H),7.48(dd,J＝12.3,8.1Hz,1H),7.25(dd,J＝12.0,6.9Hz,1H),7.18-7.05(m,3H),4.59-4.52(m,1H),4.50–4.39(m,1H),4.29(dd,J＝13.1,6.4Hz,1H),3.76-3.71(m,2H),3.55-3.48(m,1H),3.11(s,3H),2.92(s,3H),2.89–2.81(m,2H),2.75-2.69(m,1H),2.61–2.51(m,1H),2.49-2.42(m,3H),2.37–2.21(m,2H),2.19–2.09(m,1H),2.08-1.99(m,1H),1.91–1.84(m,1H),1.74-1.61(m,4H),1.54–1.28(m,5H),1.12(d,J＝6.6Hz,3H),1.08-1.02(m,1H),0.73–0.63(m,1H). Step 4: Add N,N-dimethyl-2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propane Amide (29mg, 0.1mmol) was dissolved in 5 (mL) 1,2-dichloroethane, compound 1a (26mg, 0.1mmol) and tetraisopropyl titanate (0.5mL) were added, and the reaction was stirred at 45°C for 72 hours . Sodium borohydride (19mg, 0.5mmol) was added, stirred at 45°C and continued to react for 12 hours. 10mL of water was added to the reaction solution, filtered, the filtrate was extracted with dichloromethane (30mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H2O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), to obtain compound H-35 (3.23 mg, yield: 6%, white solid). MS m/z (ESI): 531.4 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.58-8.50 (m, 1H), 8.48 (s, 1H), 7.76 (dd, J = 15.5, 7.7 Hz, 1H), 7.48 (dd, J = 12.3, 8.1Hz, 1H), 7.25 (dd, J = 12.0, 6.9 Hz, 1H), 7.18-7.05 (m, 3H), 4.59-4.52 (m, 1H), 4.50-4.39 (m, 1H), 4.29 (dd ,J=13.1,6.4Hz,1H),3.76-3.71(m,2H),3.55-3.48(m,1H),3.11(s,3H),2.92(s,3H),2.89–2.81(m,2H) ), 2.75-2.69(m,1H), 2.61-2.51(m,1H), 2.49-2.42(m,3H), 2.37-2.21(m,2H), 2.19-2.09(m,1H), 2.08-1.99 (m,1H),1.91–1.84(m,1H),1.74-1.61(m,4H),1.54–1.28(m,5H), 1.12(d,J=6.6Hz,3H),1.08-1.02(m ,1H),0.73-0.63(m,1H).
实施例36：N-(氧杂环丁-3-基)-2-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(H-36)的制备Example 36: N-(oxetan-3-yl)-2-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]deca (Alk-9-yl)ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (H-36)
Figure PCTCN2020072851-appb-000062
Figure PCTCN2020072851-appb-000062
步骤1：将2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酸(40mg，0.16mmol)溶解于3mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(123mg，0.32mmol)和氧杂环丁烷-3-胺盐酸盐(36mg，0.32mmol)，N,N-二异丙基乙胺(63mg，0.49mmol)，室温下搅拌反应12小时。向反应液中加入10mL水，用二氯甲烷萃取(50mL×2)。合并有机相，用水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化(二氯甲烷含10％甲醇为流动相)，得到产物N-(氧杂环丁-3-基)-2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(40mg，产率：82.3％,棕色液体)。MS m/z(ESI):301.1[M+H] +。 Step 1: Dissolve 2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetic acid (40mg, 0.16mmol) in In 3mL N,N-dimethylformamide, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (123mg, 0.32mmol ) And oxetane-3-amine hydrochloride (36mg, 0.32mmol), N,N-diisopropylethylamine (63mg, 0.49mmol), and the reaction was stirred at room temperature for 12 hours. 10 mL of water was added to the reaction solution and extracted with dichloromethane (50 mL×2). The organic phases were combined, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (dichloromethane containing 10% methanol as the mobile phase) to obtain the product N-(oxetan- 3-yl)-2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)acetamide (40mg, yield: 82.3%, brown liquid). MS m/z (ESI): 301.1 [M+H] + .
步骤2：将N-(氧杂环丁-3-基)-2-(7-氧代-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)乙酰胺(20mg，0.067mmol)溶解于5(mL)1,2-二氯乙烷中，加入化合物1a(17mg，0.067mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应16小时。加入硼氢化钠(13mg，0.33mmol)。向 反应液中加入10mL水，过滤，滤液用二氯甲烷(30mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3 H2O，波长：254/214nm，梯度：30％--60％乙腈变化)，得到化合物H-36(1.07mg，产率：2.9％，白色固体)。MS m/z(ESI):545.3[M+H] +。 1H NMR(400MHz,CD3OD)δ8.49(t,J＝5.3Hz,1H),7.76-7.66(m,1H),7.45(dd,J＝12.1,8.1Hz,1H),7.26-7.18(m,1H),7.12–6.93(m,3H),4.99–4.91(m,2H),4.58(dd,J＝13.6,6.6Hz,2H),3.78-3.56(m,3H),3.54–3.39(m,2H),3.18–2.99(m,3H),2.79-2.70(m,2H),2.48–2.31(m,3H),2.17–1.85(m,5H),1.76–1.28(m,11H),1.12-1.02(m,1H),0.77-0.72(m,1H). Step 2: Add N-(oxetan-3-yl)-2-(7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline- 1-yl)acetamide (20mg, 0.067mmol) was dissolved in 5 (mL) 1,2-dichloroethane, compound 1a (17mg, 0.067mmol) and tetraisopropyl titanate (0.5mL) were added, 45 The reaction was stirred at °C for 16 hours. Sodium borohydride (13 mg, 0.33 mmol) was added. 10mL of water was added to the reaction solution, filtered, the filtrate was extracted with dichloromethane (30mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H2O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), to obtain compound H-36 (1.07 mg, yield: 2.9%, white solid). MS m/z (ESI): 545.3 [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.49(t,J=5.3Hz,1H),7.76-7.66(m,1H),7.45(dd,J=12.1,8.1Hz,1H),7.26-7.18(m ,1H),7.12–6.93(m,3H),4.99–4.91(m,2H),4.58(dd,J=13.6,6.6Hz,2H),3.78-3.56(m,3H),3.54–3.39(m ,2H),3.18–2.99(m,3H),2.79-2.70(m,2H),2.48–2.31(m,3H),2.17–1.85(m,5H),1.76–1.28(m,11H),1.12 -1.02(m,1H),0.77-0.72(m,1H).
实施例37：1-(氧杂环丁-3-基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,7,8,8a-六氢环戊[[ij]异喹啉-7-胺(H-37)的制备Example 37: 1-(oxetan-3-yl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- (Yl)ethyl)-1,2,3,7,8,8a-hexahydrocyclopenta[[ij]isoquinolin-7-amine (H-37)
Figure PCTCN2020072851-appb-000063
Figure PCTCN2020072851-appb-000063
步骤1：将1,2,3,4-四氢异喹啉(20g,150mmol)溶于二氯甲烷(50ml)溶液中，加入N-溴代丁二酰亚胺(32g，180mmol)，室温搅拌反应1小时。反应液加入氢氧化钠(12.6g，225mmol)和水(50ml)，室温搅拌反应2小时。有机相减压浓缩得到目标产物3,4-二氢异喹啉(23g)，粗品。MS m/z(ESI):133.1[M+H] +。 Step 1: Dissolve 1,2,3,4-tetrahydroisoquinoline (20g, 150mmol) in dichloromethane (50ml) solution, add N-bromosuccinimide (32g, 180mmol), room temperature The reaction was stirred for 1 hour. Sodium hydroxide (12.6g, 225mmol) and water (50ml) were added to the reaction solution, and the reaction was stirred at room temperature for 2 hours. The organic phase was concentrated under reduced pressure to obtain the target product 3,4-dihydroisoquinoline (23g) as a crude product. MS m/z (ESI): 133.1 [M+H] + .
步骤2：将3,4-二氢异喹啉(10g，75.7mmol)加入丙二酸(15.8g，151.5mmol)，在120度搅拌反应3小时。反应液加入异丙醇(50ml)溶液，80度搅拌反应30分钟，过滤。滤饼用异丙醇洗涤，得到目标产物2-(1,2,3,4-四氢异喹啉-1-基)乙酸(11.6g)，产率79％。MS m/z(ESI):192.1[M+H] +。 Step 2: 3,4-Dihydroisoquinoline (10g, 75.7mmol) was added to malonic acid (15.8g, 151.5mmol), and the reaction was stirred at 120°C for 3 hours. The reaction solution was added with isopropanol (50ml) solution, stirred at 80°C for 30 minutes, and filtered. The filter cake was washed with isopropanol to obtain the target product 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (11.6g) with a yield of 79%. MS m/z (ESI): 192.1 [M+H] + .
步骤3：将2-(1,2,3,4-四氢异喹啉-1-基)乙酸(1g，5.2mmol)溶于PPA(10g)。150℃搅拌反应2小时。将反应液倒入冰水中，加入碳酸钾调节pH至8，二氯甲烷/甲醇(10/1)萃取，有机相减压浓缩得到目标化合物2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(900mg)，粗品。MS m/z(ESI):174.1[M+H] +。 Step 3: Dissolve 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (1 g, 5.2 mmol) in PPA (10 g). The reaction was stirred at 150°C for 2 hours. Pour the reaction solution into ice water, add potassium carbonate to adjust the pH to 8, extract with dichloromethane/methanol (10/1), and concentrate the organic phase under reduced pressure to obtain the target compound 2,3,8,8a-tetrahydrocyclopenta[ij ] Isoquinoline-7(1H)-one (900mg), crude product. MS m/z (ESI): 174.1 [M+H] + .
步骤4：将2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(200mg，1.07mmol)，溶于甲醇(10ml)溶液中，加入3-氧杂环丁酮(154mg，2.14mmol)和氰基硼氢化钠(219mg，3.21mmol)，室温搅拌过夜。有机相减压浓缩，用薄层层析以洗脱剂体系A(石油醚：乙酸乙酯＝1:1)纯化所得残余物，得到产物1-(氧杂环丁-3-基)-2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(70mg)，产率29％。MS m/z(ESI):230.1[M+H] +。 Step 4: Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (200mg, 1.07mmol) in methanol (10ml) solution and add 3-oxa Cyclobutanone (154 mg, 2.14 mmol) and sodium cyanoborohydride (219 mg, 3.21 mmol) were stirred at room temperature overnight. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with eluent system A (petroleum ether: ethyl acetate = 1:1) to obtain the product 1-(oxetan-3-yl)-2 ,3,8,8a-Tetrahydrocyclopenta[ij]isoquinolin-7(1H)-one (70mg), the yield was 29%. MS m/z (ESI): 230.1 [M+H] + .
步骤5：将化合物1a(68mg,0.26mmol)溶于1,2-二氯乙烷(5ml)溶液中，加入1-(氧杂环丁-3-基)-2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(60mg,0.26mmol)和钛酸四异丙酯(0.5ml)，加热到60℃反应过夜。冷却到室温，加入硼氢化钠(30mg，0.78mmol)，室温搅拌1小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-37(19.91mg)，产率16％。MS m/z(ESI):474.1[M+H] +。 1H NMR(400MHz,DMSO-d6):δ8.53-8.52(m,1H),7.68-7.61(m,1H),7.34-7.30(t,J＝8Hz,1H),7.16-6.96(m,4H),4.77-4.73(t,J＝8Hz,1H),4.68-4.65(m,2H),4.20-4.17(m,1H),3.78-3.72(m,3H),3.18-3.15(m,1H),2.94-2.81(m,3H),2.66-2.63(m,1H),2.36-2.29(m,4H),2.06-1.94(m,3H),1.73-1.24(m,11H),0.73-0.68(m,1H). Step 5: Dissolve compound 1a (68mg, 0.26mmol) in 1,2-dichloroethane (5ml) solution, add 1-(oxetan-3-yl)-2,3,8,8a- Tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (60mg, 0.26mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (30 mg, 0.78 mmol), and stir at room temperature for 1 hour. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain compound H-37 (19.91 mg) with a yield of 16%. MS m/z (ESI): 474.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.53-8.52 (m, 1H), 7.68-7.61 (m, 1H), 7.34-7.30 (t, J = 8Hz, 1H), 7.16-6.96 (m, 4H), 4.77-4.73 (t, J = 8Hz, 1H), 4.68-4.65 (m, 2H), 4.20-4.17 (m, 1H), 3.78-3.72 (m, 3H), 3.18-3.15 (m, 1H) ), 2.94-2.81 (m, 3H), 2.66-2.63 (m, 1H), 2.36-2.29 (m, 4H), 2.06-1.94 (m, 3H), 1.73-1.24 (m, 11H), 0.73-0.68 (m,1H).
实施例38：1-异丙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,7,8,8a-六氢环戊基[ij]异喹啉-7-胺(H-38)的制备Example 38: 1-isopropyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1 ,2,3,7,8,8a-hexahydrocyclopentyl[ij]isoquinoline-7-amine (H-38) preparation
Figure PCTCN2020072851-appb-000064
Figure PCTCN2020072851-appb-000064
步骤1：将2-(1,2,3,4-四氢异喹啉-1-基)乙酸(700mg，3.66mmol)，溶于丙酮(10ml)溶液中，加入醋酸(0.5ml)和氰基硼氢化钠(748mg，11mmol)，室温搅拌反应过夜。反应液减压浓缩得到白色固体，固体加入盐酸(3N)溶液调节pH至5，乙酸乙酯萃取，有机相减压浓缩得到目标产物2-(2-异丙基-1,2,3,4-四氢异喹啉-1-基)乙酸(300mg)，粗品。MS m/z(ESI):234.1[M+H] +。 Step 1: Dissolve 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (700mg, 3.66mmol) in acetone (10ml) solution, add acetic acid (0.5ml) and cyanogen Sodium borohydride (748mg, 11mmol) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain a white solid, the solid was added with hydrochloric acid (3N) solution to adjust the pH to 5, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain the target product 2-(2-isopropyl-1,2,3,4 -Tetrahydroisoquinolin-1-yl)acetic acid (300mg), crude product. MS m/z (ESI): 234.1 [M+H] + .
步骤2：将2-(2-异丙基-1,2,3,4-四氢异喹啉-1-基)乙酸(300mg，1.37mmol)，溶于PPA(4ml)溶液中，150度搅拌反应2小时。将反应液倒入冰水中，加入碳酸钾调节pH至8，二氯甲烷/甲醇(10/1)萃取，有机相减压浓缩得到目标化合物1-异丙基-2,3,8,8a-四氢环戊基[ij]异喹啉-7(1H)-酮(500mg)，粗品。MS m/z(ESI):216.1[M+H] +。 Step 2: Dissolve 2-(2-isopropyl-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (300mg, 1.37mmol) in PPA (4ml) solution at 150°C The reaction was stirred for 2 hours. Pour the reaction solution into ice water, add potassium carbonate to adjust the pH to 8, extract with dichloromethane/methanol (10/1), and concentrate the organic phase under reduced pressure to obtain the target compound 1-isopropyl-2,3,8,8a- Tetrahydrocyclopentyl[ij]isoquinoline-7(1H)-one (500mg), crude product. MS m/z (ESI): 216.1 [M+H] + .
步骤3：将化合物1a(84mg,0.32mmol)溶于1,2-二氯乙烷(5ml)溶液中，加入1-异丙基-2,3,8,8a-四氢环戊基[ij]异喹啉-7(1H)-酮(70mg,0.32mmol)和钛酸四异丙酯(0.5ml)，加热到60℃反应过夜。冷却到室温，加入硼氢化钠(37mg，0.96mmol)，室温搅拌1小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-38(1.63mg)，产率1％。MS m/z(ESI):460.1[M+H] +。 1H NMR(400MHz,DMSO-d6):δ8.57-8.54(m,1H),7.62-7.60(m,1H),7.32-7.28(t,J＝8Hz,1H),7.10-7.05(m,2H),6.97-6.93(m,2H),4.16-4.11(m,1H),3.76-3.75(d,J＝4Hz,2H),3.59-3.57(m,1H),3.17-3.10(m,1H),2.85-2.83(m,1H),2.40-2.25(m,4H),2.19-2.15(m,2H),1.94-1.91(m,2H),1.75-1.63(m,12H),1.20-1.17(m,3H),0.99-0.97(m,3H). Step 3: Dissolve compound 1a (84mg, 0.32mmol) in 1,2-dichloroethane (5ml) solution, add 1-isopropyl-2,3,8,8a-tetrahydrocyclopentyl[ij ] Isoquinoline-7(1H)-one (70mg, 0.32mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (37 mg, 0.96 mmol), and stir at room temperature for 1 hour. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain compound H-38 (1.63 mg) with a yield of 1%. MS m/z (ESI): 460.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.57-8.54 (m, 1H), 7.62-7.60 (m, 1H), 7.32-7.28 (t, J = 8Hz, 1H), 7.10-7.05 (m, 2H), 6.97-6.93 (m, 2H), 4.16-4.11 (m, 1H), 3.76-3.75 (d, J = 4Hz, 2H), 3.59-3.57 (m, 1H), 3.17-3.10 (m, 1H) ), 2.85-2.83 (m, 1H), 2.40-2.25 (m, 4H), 2.19-2.15 (m, 2H), 1.94-1.91 (m, 2H), 1.75-1.63 (m, 12H), 1.20-1.17 (m,3H),0.99-0.97(m,3H).
实施例39：2-甲基-3-(7-(((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基) 氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丁-2-醇(非对映异构体混合物H-39-1和非对映异构体混合物H-39-2)的制备Example 39: 2-Methyl-3-(7-(((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl Yl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)butan-2-ol (mixture of diastereomers H-39 -1 and the preparation of diastereoisomer mixture H-39-2)
Figure PCTCN2020072851-appb-000065
Figure PCTCN2020072851-appb-000065
步骤1：单口瓶中加入1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-盐酸盐(447mg,2mmol)，2-溴丙酸乙酯(724mg，4mmol)，碳酸钾(552mg，4mmol)，DMF(5mL)。50度搅拌12小时。冷却到室温，加入20毫升水，用二氯甲烷洗涤萃取(50mL x2)。饱和食盐水洗(20mL x2),无水硫酸钠干燥，旋干，制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到非对应异构体混合物35-1-a：(180mg,产率：33.3％，棕色固体)和35-1-b(90mg,产率：15.6％，棕色固体)。MS m/z(ESI):288.1[M+H] +。 Step 1: Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline-7-hydrochloride (447mg, 2mmol), ethyl 2-bromopropionate to a single-mouth bottle (724 mg, 4 mmol), potassium carbonate (552 mg, 4 mmol), DMF (5 mL). Stir at 50 degrees for 12 hours. Cool to room temperature, add 20 mL of water, wash and extract with dichloromethane (50 mL x 2). Wash with saturated brine (20mL x 2), dry with anhydrous sodium sulfate, spin dry, and purify by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30% -60% acetonitrile change), the diastereoisomer mixture 35-1-a: (180mg, yield: 33.3%, brown solid) and 35-1-b (90mg, yield: 15.6%, brown solid) . MS m/z (ESI): 288.1 [M+H] + .
步骤2：将化合物35-1-a(50mg，0.17mmol)溶解于5(mL)1,2-二氯乙烷中，加入化合物1a(45.3mg，0.17mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应24小时。加入硼氢化钠(33mg，0.87mmol)。45℃继续搅拌2小时。向反应液中加入20mL水，过滤，滤液用二氯甲烷(20mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到产物2-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸康-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸乙酯(39-a)(30mg,产率：32.4％，棕色液体)。MS m/z(ESI):532.3[M+H] +。 Step 2: Dissolve compound 35-1-a (50mg, 0.17mmol) in 5 (mL) 1,2-dichloroethane, add compound 1a (45.3mg, 0.17mmol) and tetraisopropyl titanate ( 0.5mL), the reaction was stirred at 45°C for 24 hours. Sodium borohydride (33 mg, 0.87 mmol) was added. Stirring was continued at 45°C for 2 hours. 20mL of water was added to the reaction solution, filtered, the filtrate was extracted with dichloromethane (20mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), the product 2-(7-((2-((R)-9-(pyridin-2-yl)) -6-oxaspiro[4.5]decacon-9-yl)ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl ) Ethyl propionate (39-a) (30 mg, yield: 32.4%, brown liquid). MS m/z (ESI): 532.3 [M+H] + .
步骤3：将化合物35-1-b(150mg，0.52mmol)溶解于5(mL)1,2-二氯乙烷中，加入化合物1a(136mg，0.52mmol)和钛酸四异丙酯(0.5mL),45℃搅拌反应24小时。加入硼氢化钠(99mg，2.61mmol)。45℃继续搅拌2小时。向反应液中加入20mL水，过滤，滤液用二氯甲烷(20mL×2)萃取，无水硫酸钠干燥，减压浓缩，浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到产物2-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸康-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙酸乙酯(39-b)(90mg,产率：32.5％，白色固体)。MS m/z(ESI):532.3[M+H] +。 Step 3: Dissolve compound 35-1-b (150mg, 0.52mmol) in 5 (mL) 1,2-dichloroethane, add compound 1a (136mg, 0.52mmol) and tetraisopropyl titanate (0.5 mL), the reaction was stirred at 45°C for 24 hours. Sodium borohydride (99 mg, 2.61 mmol) was added. Stirring was continued at 45°C for 2 hours. 20mL of water was added to the reaction solution, filtered, the filtrate was extracted with dichloromethane (20mL×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative chromatography (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), the product 2-(7-((2-((R)-9-(pyridin-2-yl)) -6-oxaspiro[4.5]decacon-9-yl)ethyl)amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl ) Ethyl propionate (39-b) (90 mg, yield: 32.5%, white solid). MS m/z (ESI): 532.3 [M+H] + .
步骤4：在氮气保护下，0度下向三口瓶(50mL)中加入四氢呋喃(20mL),化合物39-a(10mg，0.019mmol)。缓慢滴加甲基碘化镁(0.2mL，0.19mmol,1mol/L)，滴加完毕，继续搅拌6小时。倒入冰水(20mL)中，用二氯甲烷(50ml x2)萃取，合并有机相，饱和食盐水洗，干燥，浓缩得棕色液体。浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到化合物H-39-1(1.31mg,产率：13.4％，黄色液体)。MS m/z(ESI):518.3[M+H] +。 1H NMR(400MHz,CD 3OD) δ8.51-8.45(m,1H),7.79-7.72(m,1H),7.47–7.40(m,1H),7.20(dd,J＝7.2,5.2Hz,1H),7.07–7.01(m,1H),6.96-6.84(m,2H),3.86-3.75(m,1H),3.72-3.63(m,2H),3.63-3.52(m,1H),3.27-3.18(m,1H),3.01–2.90(m,2H),2.63-2.49(m,2H),2.40(dd,J＝25.2,12.1Hz,3H),2.27-2.21(m,1H),2.10-1.91(m,3H),1.89–1.84(m,1H),1.72–1.60(m,4H),1.53–1.38(m,5H),1.31-1.19(m,1H),1.19(t,J＝10.3Hz,6H),1.11–1.06(m,3H),1.05(s,1H),0.73-0.64(m,1H). Step 4: Under the protection of nitrogen, add tetrahydrofuran (20 mL), compound 39-a (10 mg, 0.019 mmol) to a three-necked flask (50 mL) at 0°C. Slowly add methylmagnesium iodide (0.2mL, 0.19mmol, 1mol/L) dropwise, after the dropwise addition is complete, continue stirring for 6 hours. Pour into ice water (20mL), extract with dichloromethane (50ml x 2), combine the organic phases, wash with saturated brine, dry, and concentrate to obtain a brown liquid. The concentrate was purified by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain compound H-39-1 (1.31 mg, yield: 13.4%, yellow liquid). MS m/z (ESI): 518.3 [M+H] + . 1 H NMR(400MHz,CD 3 OD) δ8.51-8.45(m,1H),7.79-7.72(m,1H),7.47-7.40(m,1H),7.20(dd,J=7.2,5.2Hz, 1H), 7.07--7.01 (m, 1H), 6.96-6.84 (m, 2H), 3.86-3.75 (m, 1H), 3.72-3.63 (m, 2H), 3.63-3.52 (m, 1H), 3.27- 3.18(m,1H),3.01–2.90(m,2H),2.63-2.49(m,2H), 2.40(dd,J=25.2,12.1Hz,3H), 2.27-2.21(m,1H), 2.10- 1.91(m,3H),1.89–1.84(m,1H),1.72–1.60(m,4H),1.53–1.38(m,5H),1.31-1.19(m,1H),1.19(t,J=10.3 Hz, 6H), 1.11--1.06 (m, 3H), 1.05 (s, 1H), 0.73-0.64 (m, 1H).
步骤5：在氮气保护下，0度下向三口瓶(50mL)中加入四氢呋喃(10mL),化合物39-b(30mg，0.056mmol)。缓慢滴加甲基碘化镁(1.5mL，0.56mmol,1mol/L)，滴加完毕，继续搅拌6小时。倒入冰水(20mL)中,用二氯甲烷(50ml x2)萃取，合并有机相，饱和食盐水洗，干燥，浓缩得棕色液体。浓缩物用制备色谱法纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到化合物H-39-2(1.31mg,产率：13.4％，白色固体)。MS m/z(ESI):518.3[M+H] +。 1H NMR(400MHz,CD3OD)δ8.46(dd,J＝11.0,4.0Hz,1H),7.68(t,J＝7.2Hz,1H),7.40(t,J＝7.6Hz,1H),7.18(dd,J＝11.7,6.7Hz,1H),7.03–6.90(m,2H),6.85–6.71(m,1H),4.24-4.10(m,1H),3.78-3.60(m,3H),2.97–2.74(m,4H),2.61-2.49(m,1H),2.48–2.28(m,3H),2.08–1.80(m,5H),1.77–1.55(m,5H),1.52–1.32(m,5H),1.30-1.14(m,6H),1.05(dd,J＝10.3,7.1Hz,3H),0.94-0.86(m,1H),0.75–0.60(m,1H)。 Step 5: Add tetrahydrofuran (10 mL), compound 39-b (30 mg, 0.056 mmol) to a three-necked flask (50 mL) under the protection of nitrogen at 0°C. Slowly add methylmagnesium iodide (1.5mL, 0.56mmol, 1mol/L) dropwise, after the dropwise addition is complete, continue stirring for 6 hours. Pour into ice water (20mL), extract with dichloromethane (50ml x 2), combine the organic phases, wash with saturated brine, dry, and concentrate to obtain a brown liquid. The concentrate was purified by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain compound H-39-2 (1.31 mg, yield: 13.4%, white solid). MS m/z (ESI): 518.3 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.46 (dd, J = 11.0, 4.0 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.18 ( dd,J=11.7,6.7Hz,1H), 7.03–6.90(m,2H), 6.85–6.71(m,1H), 4.24-4.10(m,1H), 3.78-3.60(m,3H), 2.97– 2.74 (m, 4H), 2.61-2.49 (m, 1H), 2.48-2.28 (m, 3H), 2.08-1.80 (m, 5H), 1.77-1.55 (m, 5H), 1.52-1.32 (m, 5H) ), 1.30-1.14 (m, 6H), 1.05 (dd, J = 10.3, 7.1 Hz, 3H), 0.94-0.86 (m, 1H), 0.75-0.60 (m, 1H).
实施例40：2-甲基-1-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,7,8,8a-四氢环戊基[ij]异喹啉-1(2H)-基)丙-2-醇(H-40)的制备Example 40: 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-3,7,8,8a-tetrahydrocyclopentyl[ij]isoquinoline-1(2H)-yl)propan-2-ol (H-40)
Figure PCTCN2020072851-appb-000066
Figure PCTCN2020072851-appb-000066
步骤1：将2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(300mg，1.73mmol)，溶于2，2-二甲基环氧乙烷(4ml)溶液中，加入碳酸铯(569mg，1.73mmol)，80度搅拌过夜。有机相减压浓缩，用薄层层析以洗脱剂体系A(石油醚：乙酸乙酯＝1:1)纯化所得残余物，得到产物1-(2-羟基-2-甲基丙基)-2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(140mg)，产率33％。MS m/z(ESI):246.1[M+H] +。 Step 1: Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (300mg, 1.73mmol) in 2,2-dimethylethylene oxide ( 4ml) solution, add cesium carbonate (569mg, 1.73mmol), stir at 80°C overnight. The organic phase was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography with eluent system A (petroleum ether: ethyl acetate=1:1) to obtain the product 1-(2-hydroxy-2-methylpropyl) -2,3,8,8a-tetrahydrocyclopenta[ij]isoquinolin-7(1H)-one (140mg), the yield was 33%. MS m/z (ESI): 246.1 [M+H] + .
步骤2：将化合物1a(147mg,0.57mmol)溶于1,2-二氯乙烷(10ml)溶液中，加入1-(2-羟基-2-甲基丙基)-2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(140mg,0.57mmol)和钛酸四异丙酯(0.5ml)，加热到60℃反应过夜。冷却到室温，加入硼氢化钠(65mg，1.71mmol)，室温搅拌1小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-40(79.23mg)，产率28％。MS m/z(ESI):490.1[M+H] +。 1H NMR(400MHz,DMSO-d6):δ8.51-8.49(t,J＝4Hz,1H),7.70-7.66(m,1H),7.46-7.43(t,J＝4Hz,1H),7.18-7.14(m,1H),7.02-6.98(m,1H),6.89-6.83(m,2H),4.07(s,1H),3.85-3.81(m,1H),3.58-3.56(m,2H),3.39-3.37(m,1H),3.31(s,1H),3.20-3.17(m,1H),2.73-2.70(m,1H),2.62-2.59(m,1H),2.47-2.46(t,J＝4Hz,3H),2.39-2.28(m,2H),2.09-2.01(m,1H),1.91-1.74(m,3H),1.66-1.29(m,8H),1.14-1.06(m,1H),1.03(s,3H),1.02(s,3H),0.94-0.93(m,1H). Step 2: Dissolve compound 1a (147mg, 0.57mmol) in 1,2-dichloroethane (10ml) solution, add 1-(2-hydroxy-2-methylpropyl)-2,3,8, 8a-Tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (140mg, 0.57mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (65 mg, 1.71 mmol), and stir at room temperature for 1 hour. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-40 (79.23 mg) with a yield of 28%. MS m/z (ESI): 490.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.51-8.49 (t, J = 4Hz, 1H), 7.70-7.66 (m, 1H), 7.46-7.43 (t, J = 4Hz, 1H), 7.18- 7.14(m,1H),7.02-6.98(m,1H),6.89-6.83(m,2H),4.07(s,1H),3.85-3.81(m,1H),3.58-3.56(m,2H), 3.39-3.37(m,1H),3.31(s,1H), 3.20-3.17(m,1H), 2.73-2.70(m,1H), 2.62-2.59(m,1H), 2.47-2.46(t,J ＝4Hz,3H),2.39-2.28(m,2H),2.09-2.01(m,1H),1.91-1.74(m,3H),1.66-1.29(m,8H),1.14-1.06(m,1H) ,1.03(s,3H),1.02(s,3H),0.94-0.93(m,1H).
实施例41：1-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,7,8,8a-四氢环戊[ij]异喹啉-1(2H)-基)丙-1-酮(H-41)的制备Example 41: 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-3 ,7,8,8a-Tetrahydrocyclopentan[ij]isoquinoline-1(2H)-yl)propan-1-one (H-41)
Figure PCTCN2020072851-appb-000067
Figure PCTCN2020072851-appb-000067
步骤1：将2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(100mg，0.58mmol)，溶于二氯甲烷(10ml)溶液中，在0度下加入三乙胺(118mg，1.16mmol)和丙酰氯(64mg，0.7mmol)，0度下搅拌2小时。反应液加入二氯甲烷(20ml)溶液，分别用3N盐酸溶液，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩得到目标化合物1-丙酰基-2,3,8,8a-四氢环戊烷[ij]异喹啉-7(1H)-酮(120mg)粗品。MS m/z(ESI):230.1[M+H] +。 Step 1: Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (100mg, 0.58mmol) in dichloromethane (10ml) solution at 0°C Add triethylamine (118 mg, 1.16 mmol) and propionyl chloride (64 mg, 0.7 mmol), and stir at 0°C for 2 hours. The reaction solution was added with dichloromethane (20ml) solution, washed with 3N hydrochloric acid solution, saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the target compound 1-propionyl-2,3,8,8a -Tetrahydrocyclopentane[ij]isoquinoline-7(1H)-one (120mg) crude product. MS m/z (ESI): 230.1 [M+H] + .
步骤2：将化合物1a(136mg,0.52mmol)溶于1,2-二氯乙烷(10ml)溶液中，加入1-丙酰基-2,3,8,8a-四氢环戊烷[ij]异喹啉-7(1H)-酮(120mg,0.52mmol)和钛酸四异丙酯(0.5ml)，加热到60℃反应过夜。冷却到室温，加入硼氢化钠(60mg，1.56mmol)，室温搅拌1小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-41(37.72mg)，产率15.4％。MS m/z(ESI):474.3[M+H] +。H NMR(400MHz,DMSO-d6):δ8.51-8.49(t,J＝4Hz,1H),7.72-7.67(m,1H),7.46-7.43(t,J＝4Hz,1H),7.19-6.97(m,4H),4.68-4.52(m,1H),3.96-3.94(m,1H),3.60-3.58(m,2H),3.04-3.02(m,1H),2.82-2.67(m,3H),2.46(s,3H),2.40-2.30(m,2H),1.89-1.61(m,4H),1.43-1.29(m,9H),1.03-0.98(m,5H). Step 2: Dissolve compound 1a (136mg, 0.52mmol) in 1,2-dichloroethane (10ml) solution, add 1-propionyl-2,3,8,8a-tetrahydrocyclopentane [ij] Isoquinolin-7(1H)-one (120mg, 0.52mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (60 mg, 1.56 mmol), and stir at room temperature for 1 hour. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography to obtain compound H-41 (37.72 mg) with a yield of 15.4%. MS m/z (ESI): 474.3 [M+H] + . H NMR (400MHz, DMSO-d6): δ8.51-8.49 (t, J = 4Hz, 1H), 7.72-7.67 (m, 1H), 7.46-7.43 (t, J = 4Hz, 1H), 7.19-6.97 (m, 4H), 4.68-4.52 (m, 1H), 3.96-3.94 (m, 1H), 3.60-3.58 (m, 2H), 3.04-3.02 (m, 1H), 2.82-2.67 (m, 3H) , 2.46 (s, 3H), 2.40-2.30 (m, 2H), 1.89-1.61 (m, 4H), 1.43-1.29 (m, 9H), 1.03-0.98 (m, 5H).
实施例42：环丙基(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,7,8,8a-四氢环戊[ij]异喹啉-1(2H)-基)甲酮(H-42)的制备Example 42: Cyclopropyl(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)- Preparation of 3,7,8,8a-tetrahydrocyclopenta[ij]isoquinoline-1(2H)-yl)methanone (H-42)
Figure PCTCN2020072851-appb-000068
Figure PCTCN2020072851-appb-000068
步骤1：将2,3,8,8a-四氢环戊[ij]异喹啉-7(1H)-酮(140mg，0.81mmol)，溶于二氯甲烷(10ml)溶液中，在0度下加入三乙胺(123mg，1.2mmol)和环丙烷酰氯(101mg，0.97mmol)，0度下搅拌2小时。反应液加入二氯甲烷(20ml)溶液，分别用3N盐酸溶液，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，有机相减压浓缩得到目标化合物1-(环丙烷羰基)-2,3,8,8a-四氢环戊烷[ij]异喹啉-7(1H)-酮(120mg)粗品。MS m/z(ESI):242.1[M+H] +。 Step 1: Dissolve 2,3,8,8a-tetrahydrocyclopenta[ij]isoquinoline-7(1H)-one (140mg, 0.81mmol) in dichloromethane (10ml) solution at 0°C Add triethylamine (123mg, 1.2mmol) and cyclopropane acid chloride (101mg, 0.97mmol), and stir at 0°C for 2 hours. The reaction solution was added with dichloromethane (20ml) solution, washed with 3N hydrochloric acid solution, saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the target compound 1-(cyclopropanecarbonyl)-2,3, Crude 8,8a-tetrahydrocyclopentane[ij]isoquinoline-7(1H)-one (120mg). MS m/z (ESI): 242.1 [M+H] + .
步骤2：将化合物1a(129mg,0.5mmol)溶于1,2-二氯乙烷(10ml)溶液中，加入1-(环丙烷羰基)-2,3,8,8a-四氢环戊烷[ij]异喹啉-7(1H)-酮(120mg,0.5mmol)和钛酸四异丙酯(0.5ml)，加热到60℃反应过夜。冷却到室温，加入硼氢化钠(57mg，1.5mmol)，室温搅拌1小时。加水，过滤，滤液减压浓缩，用制备液相色谱纯化所得残余物，得到化合物H-42(13.70mg)，产率5.7％。MS m/z(ESI):486.2[M+H] +。 1H NMR(400MHz,DMSO-d6):δ8.51-8.49(t,J＝4Hz,1H),7.70-7.69(m,1H),7.45-7.42(m,1H),7.15-6.99(m,4H),4.92-4.91(m,1H),4.56-4.54(m,1H),3.98-3.96(m,1H),3.60-3.58(m,2H),2.98-2.96(m,1H),2.73-2.63(m,2H),2.46(s,3H),2.40-2.29(m, 2H),1.90-1.16(m,13H),1.05-0.90(m,3H),0.76-0.58(m,2H). Step 2: Dissolve compound 1a (129mg, 0.5mmol) in 1,2-dichloroethane (10ml) solution, add 1-(cyclopropanecarbonyl)-2,3,8,8a-tetrahydrocyclopentane [ij] Isoquinoline-7(1H)-one (120mg, 0.5mmol) and tetraisopropyl titanate (0.5ml) were heated to 60°C and reacted overnight. Cool to room temperature, add sodium borohydride (57 mg, 1.5 mmol), and stir at room temperature for 1 hour. Water was added, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by preparative liquid chromatography to obtain compound H-42 (13.70 mg) with a yield of 5.7%. MS m/z (ESI): 486.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.51-8.49 (t, J = 4Hz, 1H), 7.70-7.69 (m, 1H), 7.45-7.42 (m, 1H), 7.15-6.99 (m, 4H), 4.92-4.91(m,1H), 4.56-4.54(m,1H), 3.98-3.96(m,1H), 3.60-3.58(m,2H), 2.98-2.96(m,1H), 2.73 2.63 (m, 2H), 2.46 (s, 3H), 2.40-2.29 (m, 2H), 1.90-1.16 (m, 13H), 1.05-0.90 (m, 3H), 0.76-0.58 (m, 2H).
实施例43：1-(戊基-3-基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(H-43)的制备Example 43: 1-(Pentyl-3-yl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl) Ethyl)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline-7-amine (H-43)
Figure PCTCN2020072851-appb-000069
Figure PCTCN2020072851-appb-000069
步骤1：向2,3,9,9a-四氢-1H-苯并[de]喹啉-7(8H)-酮(187mg，1mmol)的THF(20ml)溶液中加入3-戊酮(344mg，4mmol)和1M氯化锌乙醚溶液(2ml)，室温搅拌0.5小时后，加入氰基硼氢化钠(372mg，6mmol)。升温至55度，搅拌过夜。冷却至室温，用乙酸乙酯稀释，依次水洗，饱和氯化钠水溶液洗涤，干燥，浓缩。产物用硅胶柱纯化(石油醚/乙酸乙酯＝3/1)，得到1-(戊基-3-基)-2,3,9,9a-四氢-1H-苯并[de]喹啉-7(8H)-酮(167mg，黄色油状)，产率：65％。MS m/z(ESI):258.2[M+H] +。 Step 1: To 2,3,9,9a-tetrahydro-1H-benzo[de]quinoline-7(8H)-one (187mg, 1mmol) in THF (20ml) was added 3-pentanone (344mg , 4mmol) and 1M zinc chloride ether solution (2ml). After stirring at room temperature for 0.5 hours, sodium cyanoborohydride (372mg, 6mmol) was added. Warm up to 55 degrees and stir overnight. Cool to room temperature, dilute with ethyl acetate, wash with water, saturated sodium chloride aqueous solution, dry, and concentrate. The product was purified with a silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 1-(pentyl-3-yl)-2,3,9,9a-tetrahydro-1H-benzo[de]quinoline -7(8H)-one (167 mg, yellow oil), yield: 65%. MS m/z (ESI): 258.2 [M+H] + .
步骤2：将1-(戊基-3-基)-2,3,9,9a-四氢-1H-苯并[de]喹啉-7(8H)-酮(51mg，0.20mmol)和化合物1a(52mg，0.20mmol)溶解于15mL1,2-二氯乙烷中，加入1mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(30mg，0.8mmol)，50度搅拌3小时，冷却至室温，向反应液中加入2ml水，搅拌5分钟，过滤，滤液减压浓缩，用制备色谱纯化(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)，得到化合物H-43(9mg，白色固体)。MS m/z(ESI):502.4[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝4.8Hz,1H),8.18(s,2H),7.68-7.66(m,1H),7.43-7.33(m,1H),7.18-7.15(m,1H),7.09-6.95(m,2H),6.94-6.86(m,1H),3.84(s,1H),3.67-3.49(m,3H),2.96-2.88(m,1H),2.79-2.58(m,3H),2.45-2.23(m,4H),2.15(d,J＝8.4Hz,1H),2.04-1.79(m,3H),1.77-1.17(m,11H),1.13-0.88(m,3H),0.82-0.80(m,6H),0.58-0.55(m,1H). Step 2: Combine 1-(pentyl-3-yl)-2,3,9,9a-tetrahydro-1H-benzo[de]quinoline-7(8H)-one (51mg, 0.20mmol) and compound 1a (52mg, 0.20mmol) was dissolved in 15mL 1,2-dichloroethane, 1mL tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (30mg, 0.8mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 2ml of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure. Purification (preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change), to obtain compound H-43 (9 mg, white solid). MS m/z (ESI): 502.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.48(d,J=4.8Hz,1H), 8.18(s,2H), 7.68-7.66(m,1H),7.43-7.33(m,1H), 7.18- 7.15 (m, 1H), 7.09-6.95 (m, 2H), 6.94-6.86 (m, 1H), 3.84 (s, 1H), 3.67-3.49 (m, 3H), 2.96-2.88 (m, 1H), 2.79-2.58(m,3H),2.45-2.23(m,4H), 2.15(d,J=8.4Hz,1H),2.04-1.79(m,3H),1.77-1.17(m,11H),1.13- 0.88 (m, 3H), 0.82-0.80 (m, 6H), 0.58-0.55 (m, 1H).
实施例44：2-甲基-1-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)丙-2-醇(非对映异构体混合物H-44-1和非对映异构体混合物H-44-2)的制备Example 44: 2-Methyl-1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl )Amino)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)propan-2-ol (mixture of diastereomers H-44- 1 and the preparation of diastereoisomer mixture H-44-2)
Figure PCTCN2020072851-appb-000070
Figure PCTCN2020072851-appb-000070
步骤1：向50ml封管中加入1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(187mg，1mmol)，碳酸铯(326mg，1.0m mol)和10mL2,2-二甲基环氧乙烷，混合物在100度油浴中搅拌过夜，冷却至室温，用乙酸乙酯稀释，依次水洗，饱和氯化钠水溶液洗涤，干燥，浓缩。产物用硅胶柱纯化(石油醚/乙酸乙酯＝3/1)，得到1-(2-羟基-2-甲基丙基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(200mg，白色固体)，产率：77％。MS m/z(ESI):260.2[M+H] +。 Step 1: Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol), cesium carbonate (326mg, 1.0m) to 50ml sealed tube mol) and 10mL 2,2-dimethylethylene oxide, the mixture was stirred overnight in a 100°C oil bath, cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated sodium chloride aqueous solution, dried, and concentrated. The product was purified with a silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 1-(2-hydroxy-2-methylpropyl)-1,2,3,8,9,9a-hexahydro-7H -Benzo[de]quinolin-7-one (200mg, white solid), yield: 77%. MS m/z (ESI): 260.2 [M+H] + .
步骤2：将1-(2-羟基-2-甲基丙基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(100mg，0.386mmol)和化合物1a(100mg，0.386mmol)溶解于20mL1,2-二氯乙烷中，加入1mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(44mg，1.16mmol)，50度搅拌3小时，冷却至室温，向反应液中加入5mL水，搅拌5分钟，过滤，滤液减压浓缩得粗品H-44。Step 2: Add 1-(2-hydroxy-2-methylpropyl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (100mg, 0.386mmol) and compound 1a (100mg, 0.386mmol) were dissolved in 20mL of 1,2-dichloroethane, 1mL of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (44mg, 1.16mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 5 mL of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure to obtain crude H- 44.
步骤3：将粗品H-44用制备色谱(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化，分别得到非对映异构体混合物H-44-1(53mg，白色固体)；MS m/z(ESI):504.4[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.51-8.48(m,1H),7.70-7.69(m,1H),7.37-7.34(m,1H),7.16-7.13(m,1H),6.97-6.79(m,3H),3.98(s,1H),3.60-3.45(m,3H),3.41-3.26(m,2H),3.26-3.17(m,1H),2.90-2.86(m,1H),2.57-2.47(m,3H),2.40-2.20(m,3H),2.10-2.06(m,3H),1.92-1.64(m,5H),1.62-1.23(m,5H),1.14-1.10(m,1H),1.06-1.02(m,6H),0.97-0.86(m,1H),0.58-0.55(m,1H). Step 3: Purify the crude H-44 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain Diastereoisomer mixture H-44-1 (53 mg, white solid); MS m/z (ESI): 504.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.51-8.48 (m, 1H), 7.70-7.69 (m, 1H), 7.37-7.34 (m, 1H), 7.16-7.13 (m, 1H), 6.97-6.79 (m, 3H), 3.98 (s, 1H), 3.60-3.45 (m, 3H), 3.41-3.26 (m, 2H), 3.26 3.17 (m, 1H), 2.90-2.86 (m, 1H), 2.57 -2.47(m,3H),2.40-2.20(m,3H),2.10-2.06(m,3H),1.92-1.64(m,5H),1.62-1.23(m,5H),1.14-1.10(m, 1H), 1.06-1.02 (m, 6H), 0.97-0.86 (m, 1H), 0.58-0.55 (m, 1H).
和非对映异构体混合物H-44-2(13mg，白色固体)；MS m/z(ESI):504.4[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.50-8.47(m,1H),7.70-7.66(m,1H),7.46-7.42(m,1H),7.17-7.14(m,1H),7.03-6.78(m,3H),3.99(d,J＝2.2Hz,1H),3.57-2.54(m,2H),3.20-3.16(m,3H),2.83(s,1H),2.61-2.47(m,3H),2.46-2.26(m,3H),2.15-2.11(m,1H),2.05-1.13(m,14H),1.08-1.02(m,6H),0.96-0.92(m,1H),0.58-0.55(m,1H). And diastereoisomer mixture H-44-2 (13 mg, white solid); MS m/z (ESI): 504.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ 8.50-8.47 (m, 1H), 7.70-7.66 (m, 1H), 7.46-7.42 (m, 1H), 7.17-7.14 (m, 1H), 7.03-6.78 (m,3H),3.99(d,J=2.2Hz,1H),3.57-2.54(m,2H),3.20-3.16(m,3H),2.83(s,1H),2.61-2.47(m,3H) ),2.46-2.26(m,3H),2.15-2.11(m,1H),2.05-1.13(m,14H),1.08-1.02(m,6H),0.96-0.92(m,1H),0.58-0.55 (m,1H).
实施例45：1-(氧杂环丁-3-基)-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-7-胺(非对映异构体混合物H-45-1和非对映异构体混合物H-45-2)的制备Example 45: 1-(oxetan-3-yl)-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- (Base) ethyl)-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-7-amine (diastereomeric mixture H-45-1 and non-pair Preparation of mixture of enantiomers H-45-2)
Figure PCTCN2020072851-appb-000071
Figure PCTCN2020072851-appb-000071
步骤1：向1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(187mg，1mmol)的THF(20ml)溶液 中加入3-氧杂环丁酮(216mg，3mmol)和1M氯化锌乙醚溶液(2ml)，室温搅拌0.5小时后，加入氰基硼氢化钠(310mg，5mmol)。升温至55度，搅拌过夜。冷却至室温，用乙酸乙酯稀释，依次水洗，饱和氯化钠水溶液洗涤，干燥，浓缩。产物用硅胶柱纯化(石油醚/乙酸乙酯＝3/1)，得到1-(氧杂环丁-3-基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(190mg，黄色油状)，产率：78％。MS m/z(ESI):244.2[M+H] +。 Step 1: Add 3-oxo heterocycle to 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol) in THF (20ml) solution Butanone (216mg, 3mmol) and 1M zinc chloride ether solution (2ml) were stirred at room temperature for 0.5 hours, and sodium cyanoborohydride (310mg, 5mmol) was added. Warm up to 55 degrees and stir overnight. Cool to room temperature, dilute with ethyl acetate, wash with water, saturated sodium chloride aqueous solution, dry, and concentrate. The product was purified with a silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 1-(oxetan-3-yl)-1,2,3,8,9,9a-hexahydro-7H-benzene And [de]quinolin-7-one (190 mg, yellow oil), yield: 78%. MS m/z (ESI): 244.2 [M+H] + .
步骤2：将1-(氧杂环丁-3-基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(50mg，0.2mmol)和化合物1a(52mg，0.20mmol)溶解于15mL1,2-二氯乙烷中，加入1mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(30mg，0.8mmol)，50度搅拌3小时，冷却至室温，向反应液中加入3mL水，搅拌5分钟，过滤，滤液减压浓缩得粗品H-45。Step 2: Add 1-(oxetan-3-yl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (50mg, 0.2mmol ) And compound 1a (52mg, 0.20mmol) were dissolved in 15mL 1,2-dichloroethane, 1mL tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (30mg, 0.8mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 3 mL of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure to obtain crude H- 45.
步骤3：将粗品H-45用制备色谱(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3 H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化，分别得到非对映异构体混合物H-45-1(3mg，白色固体)；MS m/z(ESI):488.4[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.51-8.43(m,1H),7.70-7.59(m,1H),7.37-7.34(m,1H),7.16-7.13(m,2H),7.02-6.98(m,1H),6.87-6.85(m,1H),4.56-4.39(m,4H),3.70-3.67(m,1H),3.57-3.42(m,2H),3.20-3.17(m,1H),2.89-2.59(m,3H),2.40-2.13(m,4H),1.94-1.21(m,12H),1.14-1.11(m,1H),0.96-0.87(m,1H),0.56-0.53(m,1H). Step 3: Purify the crude H-45 by preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O, wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) to obtain respectively Diastereoisomer mixture H-45-1 (3 mg, white solid); MS m/z (ESI): 488.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.51-8.43 (m, 1H), 7.70-7.59 (m, 1H), 7.37-7.34 (m, 1H), 7.16-7.13 (m, 2H), 7.02-6.98 (m, 1H), 6.87-6.85 (m, 1H), 4.56-4.39 (m, 4H), 3.70-3.67 (m, 1H), 3.57-3.42 (m, 2H), 3.20-3.17 (m, 1H) ,2.89-2.59(m,3H),2.40-2.13(m,4H),1.94-1.21(m,12H),1.14-1.11(m,1H),0.96-0.87(m,1H),0.56-0.53( m,1H).
和非对映异构体混合物H-45-2(3mg，白色固体)；MS m/z(ESI):488.4[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝4.5Hz,1H),7.70-7.67(m,1H),7.43(d,J＝8.1Hz,1H),7.18-7.15(m,1H),6.99-6.96(m,1H),6.87-6.85(m,2H),4.52-4.48(m,4H),3.73-3.70(m,1H),3.62-3.49(m,2H),3.28-3.25(m,3H),3.06-3.03(m,1H),2.86-2.58(m,4H),2.46-2.17(m,4H),2.04-1.18(m,11H),0.95-0.93(m,1H),0.58-0.55(m,1H). And diastereomeric mixture H-45-2 (3 mg, white solid); MS m/z (ESI): 488.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.50(d,J=4.5Hz,1H), 7.70-7.67(m,1H), 7.43(d,J=8.1Hz,1H), 7.18-7.15(m, 1H), 6.99-6.96 (m, 1H), 6.87-6.85 (m, 2H), 4.52-4.48 (m, 4H), 3.73-3.70 (m, 1H), 3.62-3.49 (m, 2H), 3.28- 3.25(m,3H),3.06-3.03(m,1H),2.86-2.58(m,4H),2.46-2.17(m,4H),2.04-1.18(m,11H),0.95-0.93(m,1H) ), 0.58-0.55 (m, 1H).
实施例46：2-乙基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,3a,4,5-六氢环戊五[de]异喹啉-5-胺(H-46)的制备Example 46: 2-ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1, Preparation of 2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (H-46)
Figure PCTCN2020072851-appb-000072
Figure PCTCN2020072851-appb-000072
步骤1：将2-(氰甲基)苯甲酸甲酯(1.75g，10m mol)和溴乙酸叔丁酯(2.9g，15m mol)溶解于30mL干燥的N,N-二甲基甲酰胺中，冰浴下加入氢化钠(0.8g，20mmol)，室温搅拌18小时。用乙酸乙酯(100ml)稀释，水洗(50mL×2)，饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(石油醚/乙酸乙酯＝4/1)纯化，得到2-(3-(叔丁氧基)-1-氰基-3-氧丙基)苯甲酸甲酯(1.44g，黄色油状)，产率：50％。MS m/z (ESI):290.2[M+H] +。 Step 1: Dissolve methyl 2-(cyanomethyl)benzoate (1.75g, 10m mol) and tert-butyl bromoacetate (2.9g, 15m mol) in 30mL of dry N,N-dimethylformamide Sodium hydride (0.8g, 20mmol) was added under ice bath and stirred at room temperature for 18 hours. Dilute with ethyl acetate (100ml), wash with water (50mL×2), wash with saturated brine (30mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (petroleum ether). /Ethyl acetate=4/1) to obtain methyl 2-(3-(tert-butoxy)-1-cyano-3-oxopropyl)benzoate (1.44g, yellow oil), yield: 50%. MS m/z (ESI): 290.2 [M+H] + .
步骤2：2-(3-(叔丁氧基)-1-氰基-3-氧丙基)苯甲酸甲酯(1.44g，5mmol)溶解于70mL乙醇中，加入10％湿Pd/C(0.6g)，氢气置换三次，然后室温搅拌18小时。过滤，浓缩，得到2-(1-氧代-1,2,3,4-四氢异喹啉-4-基)乙酸叔丁酯(1.18g，黄色固体)，产率：91％。MS m/z(ESI):262.3[M+H] +。 Step 2: Methyl 2-(3-(tert-butoxy)-1-cyano-3-oxopropyl)benzoate (1.44g, 5mmol) was dissolved in 70mL ethanol, and 10% wet Pd/C( 0.6g), replaced with hydrogen three times, and stirred at room temperature for 18 hours. Filtered and concentrated to obtain tert-butyl 2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1.18 g, yellow solid), yield: 91%. MS m/z (ESI): 262.3 [M+H] + .
步骤3：将2-(1-氧代-1,2,3,4-四氢异喹啉-4-基)乙酸叔丁酯(1.18g，4.55m mol)溶解于25mL干燥的N,N-二甲基甲酰胺中，冰浴下加入氢化钠(0.36g，9.1mmol)，搅拌15分钟后，加入碘乙烷(0.85g，5.46m mol)，室温搅拌18小时。用乙酸乙酯(100ml)稀释，水洗(40mL×2)，饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(石油醚/乙酸乙酯＝4/1)纯化，得到2-(2-乙基-1-氧代1,2,3,4-四氢异喹啉-4-基)乙酸叔丁酯(1g，黄色油状)，产率：76％。MS m/z(ESI):290.2[M+H] +。 Step 3: Dissolve tert-butyl 2-(1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1.18g, 4.55m mol) in 25mL dry N,N -In dimethylformamide, sodium hydride (0.36g, 9.1mmol) was added under ice bath, after stirring for 15 minutes, ethyl iodide (0.85g, 5.46mmol) was added, and stirring was carried out at room temperature for 18 hours. Dilute with ethyl acetate (100ml), wash with water (40mL×2), wash with saturated brine (30mL×1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (petroleum ether) /Ethyl acetate=4/1) to obtain tert-butyl 2-(2-ethyl-1-oxo1,2,3,4-tetrahydroisoquinolin-4-yl)acetate (1g, yellow Oily), yield: 76%. MS m/z (ESI): 290.2 [M+H] + .
步骤4：向装有2-(2-乙基-1-氧代1,2,3,4-四氢异喹啉-4-基)乙酸叔丁酯(1g，3.46m mol)的圆底烧瓶中加入PPA(约30ml)，逐渐升温至140度，搅拌1小时，冷却至室温，用乙酸乙酯(100ml)稀释，水洗(50mL×2)，饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(石油醚/乙酸乙酯＝5/1)纯化，得到2-乙基-2,3,3a,4-四氢环戊[de]异喹啉-1,5-二酮(0.21g，黄色油状)，产率：28％。MS m/z(ESI):216.1[M+H] +。 Step 4: To the round bottom containing 2-(2-ethyl-1-oxo1,2,3,4-tetrahydroisoquinolin-4-yl)acetic acid tert-butyl ester (1g, 3.46m mol) Add PPA (about 30ml) to the flask, gradually increase the temperature to 140 degrees, stir for 1 hour, cool to room temperature, dilute with ethyl acetate (100ml), wash with water (50mL×2), and wash with saturated brine (30mL×1). After drying with sodium sulfate and filtering, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to obtain 2-ethyl-2,3,3a,4-tetrahydro Cyclopenta[de]isoquinoline-1,5-dione (0.21g, yellow oil), yield: 28%. MS m/z (ESI): 216.1 [M+H] + .
步骤5：将2-乙基-2,3,3a,4-四氢环戊[de]异喹啉-1,5-二酮(100mg，0.46mmol)和化合物1a(121mg，0.46mmol)溶解于20ml的1,2-二氯乙烷中，加入1.5mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(70mg，1.84mmol)，50度搅拌3小时，冷却至室温，向反应液中加入3ml水，搅拌5分钟，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(二氯甲烷/甲醇＝30/1)纯化，得到2-乙基-5-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸康-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(90mg，黄色油状)，产率：42.6％。MS m/z(ESI):460.2[M+H] +。 Step 5: Dissolve 2-ethyl-2,3,3a,4-tetrahydrocyclopenta[de]isoquinoline-1,5-dione (100mg, 0.46mmol) and compound 1a (121mg, 0.46mmol) To 20ml of 1,2-dichloroethane, 1.5ml of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (70mg, 1.84mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 3ml of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure to obtain a residue Purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain 2-ethyl-5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro [4.5]Decikang-9-yl)ethyl)amino)-3,3a,4,5-tetrahydrocyclopenta[de]isoquinolin-1(2H)-one (90mg, yellow oil), yield : 42.6%. MS m/z (ESI): 460.2 [M+H] + .
步骤6：将2-乙基-5-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸康-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(90mg，0.196mmol)溶解于20ml干燥四氢呋喃中，冰浴下，加入氢化铝锂(15mg,0.39mmol)，升温至50度，搅拌1小时，冰浴冷却下用饱和氯化铵水溶液淬灭，过滤，浓缩，剩余物用制备色谱(制备柱：21.2X250mm C18柱，体系：10mMNH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化得到化合物H-46(3mg)，MS m/z(ESI):446.3[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.54-8.52(m,1H),7.78-7.67(m,1H),7.48-7.46(m,1H),7.24-7.14(m,1H),7.03-7.02(m,1H),6.96-6.82(m,2H),4.04-3.90(m,2H),3.62-3.59(m,2H),3.11-3.08(m,2H),2.86(s,1H),2.64-2.50(m,2H),2.48-2.22(m,4H),2.11-1.72(m,4H),1.72-1.17(m,6H),1.10-0.97(m,4H),0.97-0.94(m,2H),0.61-0.58(m,1H). Step 6: Add 2-ethyl-5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]deccan-9-yl)ethyl)amino) -3,3a,4,5-Tetrahydrocyclopenta[de]isoquinoline-1(2H)-one (90mg, 0.196mmol) was dissolved in 20ml dry tetrahydrofuran, under ice bath, added lithium aluminum hydride (15mg, 0.39mmol), heated to 50°C, stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution under ice cooling, filtered, concentrated, and used preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mMNH 4 HCO 3 H 2 O (wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) was purified to obtain compound H-46 (3 mg), MS m/z (ESI): 446.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.54-8.52 (m, 1H), 7.78-7.67 (m, 1H), 7.48-7.46 (m, 1H), 7.24-7.14 (m, 1H), 7.03-7.02 (m, 1H), 6.96-6.82 (m, 2H), 4.04-3.90 (m, 2H), 3.62-3.59 (m, 2H), 3.11-3.08 (m, 2H), 2.86 (s, 1H), 2.64 -2.50(m,2H),2.48-2.22(m,4H),2.11-1.72(m,4H),1.72-1.17(m,6H),1.10-0.97(m,4H),0.97-0.94(m, 2H), 0.61-0.58 (m, 1H).
实施例47：N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2-(2,2,2-三 氟乙基)-1,2,3,3a,4,5-六氢环戊[de]异喹啉-5-胺(H-47)的制备Example 47: N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-(2,2, Preparation of 2-trifluoroethyl)-1,2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (H-47)
Figure PCTCN2020072851-appb-000073
Figure PCTCN2020072851-appb-000073
步骤1：将2,3,3a,4-四氢环戊[de]异喹啉-1,5-二酮(100mg，0.53mmol)和化合物1a(139mg，0.53mmol)溶解于25ml的1,2-二氯乙烷中，加入1.5mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(70mg，1.84mmol)，50度搅拌3小时，冷却至室温，向反应液中加入3ml水，搅拌5分钟，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(二氯甲烷/甲醇＝30/1)纯化，得到5-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(130mg，黄色油状)，产率：57％。MS m/z(ESI):432.2[M+H] +。 Step 1: Dissolve 2,3,3a,4-tetrahydrocyclopenta[de]isoquinoline-1,5-dione (100mg, 0.53mmol) and compound 1a (139mg, 0.53mmol) in 25ml of 1, Add 1.5 mL of tetraisopropyl titanate to 2-dichloroethane, and stir and react at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (70mg, 1.84mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 3ml of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure to obtain a residue Purify by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain 5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane) -9-yl)ethyl)amino)-3,3a,4,5-tetrahydrocyclopenta[de]isoquinolin-1(2H)-one (130 mg, yellow oil), yield: 57%. MS m/z (ESI): 432.2 [M+H] + .
步骤2：将5-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(130mg，0.3mmol)溶解于25ml乙腈中，加入碳酸钾(83mg，0.6mol)和溴化苄(77mg，0.45mol)，70℃搅拌18小时。冷却至室温，用乙酸乙酯(70ml)稀释，水洗(50mL×1)，饱和食盐水洗涤(30mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物用硅胶柱色谱法(二氯甲烷/甲醇＝30/1)纯化，得到5-(苄基(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(133mg，黄色固体)，产率：85％。MS m/z(ESI):522.2[M+H] +。 Step 2: Add 5-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-3,3a, 4,5-Tetrahydrocyclopenta[de]isoquinoline-1(2H)-one (130mg, 0.3mmol) was dissolved in 25ml of acetonitrile, potassium carbonate (83mg, 0.6mol) and benzyl bromide (77mg, 0.45 mol), stirring at 70°C for 18 hours. Cooled to room temperature, diluted with ethyl acetate (70ml), washed with water (50mL×1), saturated brine (30mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column Purification method (dichloromethane/methanol=30/1) to obtain 5-(benzyl(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9) -Yl)ethyl)amino)-3,3a,4,5-tetrahydrocyclopenta[de]isoquinolin-1(2H)-one (133 mg, yellow solid), yield: 85%. MS m/z (ESI): 522.2 [M+H] + .
步骤3：将5-(苄基(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-3,3a,4,5-四氢环戊[de]异喹啉-1(2H)-酮(133mg，0.255mmol)溶解于30ml干燥四氢呋喃中，冰浴下，加入氢化铝锂(20mg,0.51mmol)，升温至50度，搅拌1小时，冰浴冷却下用饱和氯化铵水溶液淬灭，过滤，浓缩，剩余物用硅胶柱色谱法(二氯甲烷/甲醇＝30/1)纯化，得到N-苄基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,3a,4,5-六氢环戊[de]异喹啉-5-胺(90mg，黄色油状)，产率：70％。MS m/z(ESI):508.3[M+H] +。 Step 3: Add 5-(benzyl(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-3, 3a,4,5-Tetrahydrocyclopenta[de]isoquinoline-1(2H)-one (133mg, 0.255mmol) was dissolved in 30ml of dry tetrahydrofuran, and under ice bath, add lithium aluminum hydride (20mg, 0.51mmol) The temperature was raised to 50 degrees, stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution under ice cooling, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain N- Benzyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,3,3a, 4,5-Hexahydrocyclopenta[de]isoquinoline-5-amine (90mg, yellow oil), yield: 70%. MS m/z (ESI): 508.3 [M+H] + .
步骤4：将N-苄基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,3a,4,5-六氢环戊[de]异喹啉-5-胺(90mg，0.178mmol)溶解于20ml四氢呋喃中，加入碳酸钾(49mg，0.355mmol)和2,2,2-三氟乙烷磺酸三氟甲基酯(82mg，0.355mmol)，室温搅拌反应3小时，浓缩，剩余物用硅胶柱色谱法(二氯甲烷/甲醇＝30/1)纯化，得到N-苄基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2-(2,2,2-三氟乙基)-1,2,3,3a,4,5-六氢环戊[de] 异喹啉-5-胺(70mg，黄色油状)，产率：67％。MS m/z(ESI):590.3[M+H] +。 Step 4: Add N-benzyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1, 2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (90mg, 0.178mmol) was dissolved in 20ml of tetrahydrofuran, potassium carbonate (49mg, 0.355mmol) and 2,2, 2-Trifluoroethanesulfonic acid trifluoromethyl ester (82mg, 0.355mmol), stirred at room temperature for 3 hours, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to obtain N -Benzyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-(2,2, 2-Trifluoroethyl)-1,2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (70 mg, yellow oil), yield: 67%. MS m/z (ESI): 590.3 [M+H] + .
步骤5：N-苄基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-2-(2,2,2-三氟乙基)-1,2,3,3a,4,5-六氢环戊[de]异喹啉-5-胺(70mg，0.119mmol)溶解于15mL无水乙醇中，加入10％湿Pd/C(30mg)，氢气置换三次，然后室温搅拌3小时，过滤，浓缩，剩余物用制备色谱(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化，得到化合物H-47(26mg，白色固体)，产率：44％。MS m/z(ESI):500.3[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.51-8.49(m,1H),7.71-7.69(m,1H),7.45-7.43(m,1H),7.21-7.12(m,1H),7.03-7.01(m,1H),6.93-6.91(m,1H),6.84-6.82(m,1H),3.98-3.96(m,2H),3.65-3.54(m,2H),3.50-3.29(m,2H),3.16-3.14(m,1H),2.88(s,1H),2.43-2.40(m,2H),2.41-2.19(m,3H),2.10-1.13(m,12H),0.95-0.92(m,2H),0.59-0.56(m,1H). Step 5: N-benzyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-2-( 2,2,2-Trifluoroethyl)-1,2,3,3a,4,5-hexahydrocyclopenta[de]isoquinolin-5-amine (70mg, 0.119mmol) dissolved in 15mL of absolute ethanol Add 10% wet Pd/C (30mg), replace with hydrogen three times, then stir at room temperature for 3 hours, filter, concentrate, and use preparative chromatography (preparative column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) purification to obtain compound H-47 (26 mg, white solid), yield: 44%. MS m/z (ESI): 500.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.51-8.49 (m, 1H), 7.71-7.69 (m, 1H), 7.45-7.43 (m, 1H), 7.21-7.12 (m, 1H), 7.03-7.01 (m,1H),6.93-6.91(m,1H),6.84-6.82(m,1H),3.98-3.96(m,2H),3.65-3.54(m,2H),3.50-3.29(m,2H) ,3.16-3.14(m,1H),2.88(s,1H),2.43-2.40(m,2H),2.41-2.19(m,3H),2.10-1.13(m,12H),0.95-0.92(m, 2H), 0.59-0.56 (m, 1H).
实施例48：1-(7-((2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)-2,3,7,8,9,9a-六氢-1H-苯并[de]喹啉-1-基)-2-(1-(三氟甲基)环丙基)乙-1-酮(H-48)的制备Example 48: 1-(7-((2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)-2 ,3,7,8,9,9a-hexahydro-1H-benzo[de]quinolin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)ethan-1-one( H-48) Preparation
Figure PCTCN2020072851-appb-000074
Figure PCTCN2020072851-appb-000074
步骤1：向1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(187mg，1mmol)和2-(1-(三氟甲基)环丙基)乙酸(168mg，1mmol)的二氯甲烷(20ml)溶液中加入HATU(380mg，1mmol)和三乙胺(110mg，1.1mmol)，室温搅拌18小时后，反应液用水洗，干燥，浓缩。产物用硅胶柱纯化(石油醚/乙酸乙酯＝3/1)，得到1-(2-(1-(三氟甲基)环丙基)乙酰基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(236mg，黄色油状)，产率：70％。MS m/z(ESI):338.2[M+H] +。 Step 1: Add 1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinolin-7-one (187mg, 1mmol) and 2-(1-(trifluoromethyl) ring Add HATU (380mg, 1mmol) and triethylamine (110mg, 1.1mmol) to a solution of propyl)acetic acid (168mg, 1mmol) in dichloromethane (20ml). After stirring for 18 hours at room temperature, the reaction solution was washed with water, dried and concentrated. . The product was purified with a silica gel column (petroleum ether/ethyl acetate=3/1) to obtain 1-(2-(1-(trifluoromethyl)cyclopropyl)acetyl)-1,2,3,8,9 , 9a-hexahydro-7H-benzo[de]quinolin-7-one (236mg, yellow oil), yield: 70%. MS m/z (ESI): 338.2 [M+H] + .
步骤2：将1-(2-(1-(三氟甲基)环丙基)乙酰基)-1,2,3,8,9,9a-六氢-7H-苯并[de]喹啉-7-酮(67mg，0.2mmol)和化合物1a(52mg，0.20mmol)溶解于15mL1,2-二氯乙烷中，加入1mL钛酸四异丙酯，45℃搅拌反应18小时。冷却至室温，向反应液加入硼氢化钠(30mg，0.8mmol)，50度搅拌3小时，冷却至室温，向反应液中加入2ml水，搅拌5分钟，过滤，滤液减压浓缩，用制备色谱(制备柱：21.2X250mm C18柱，体系：10mM NH 4HCO 3 H 2O波长：254/214nm，梯度：30％-60％乙腈变化)纯化，得到化合物H-48(18mg，白色固体)；MS m/z(ESI):582.1[M+H] +。1H NMR(400MHz,DMSO-d6)δ8.53-8.46(m,1H),7.69-7.66(m,1H),7.46-7.43(m,1H),7.19-7.11(m,1H),7.08-6.91(m,3H),4.81(d,J＝9.8Hz,1H),4.54(s,1H),3.98(d,J＝13.4Hz,1H),3.25(s,1H),2.96-2.94(m,2H),2.64-2.63(m,4H),2.43-2.28(m,2H),2.01-2.00(m,4H),1.84-1.07(m,11H),0.89-0.87(m,5H),0.66-0.54(m,1H). Step 2: Add 1-(2-(1-(trifluoromethyl)cyclopropyl)acetyl)-1,2,3,8,9,9a-hexahydro-7H-benzo[de]quinoline -7-one (67 mg, 0.2 mmol) and compound 1a (52 mg, 0.20 mmol) were dissolved in 15 mL of 1,2-dichloroethane, 1 mL of tetraisopropyl titanate was added, and the reaction was stirred at 45°C for 18 hours. Cool to room temperature, add sodium borohydride (30mg, 0.8mmol) to the reaction solution, stir at 50°C for 3 hours, cool to room temperature, add 2ml of water to the reaction solution, stir for 5 minutes, filter, and concentrate the filtrate under reduced pressure. (Preparation column: 21.2X250mm C18 column, system: 10mM NH 4 HCO 3 H 2 O Wavelength: 254/214nm, gradient: 30%-60% acetonitrile change) Purified to obtain compound H-48 (18mg, white solid); MS m/z(ESI): 582.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.53-8.46 (m, 1H), 7.69-7.66 (m, 1H), 7.46-7.43 (m, 1H), 7.19-7.11 (m, 1H), 7.08-6.91 (m, 3H), 4.81 (d, J = 9.8 Hz, 1H), 4.54 (s, 1H), 3.98 (d, J = 13.4 Hz, 1H), 3.25 (s, 1H), 2.96-2.94 (m, 2H), 2.64-2.63 (m, 4H), 2.43-2.28 (m, 2H), 2.01-2.00 (m, 4H), 1.84-1.07 (m, 11H), 0.89-0.87 (m, 5H), 0.66- 0.54(m,1H).
实施例49至68Examples 49 to 68
化合物H-49至H-68可参照上述实施例类似的方法进行制备。Compounds H-49 to H-68 can be prepared by referring to methods similar to the above-mentioned examples.
Figure PCTCN2020072851-appb-000075
Figure PCTCN2020072851-appb-000075
Figure PCTCN2020072851-appb-000076
Figure PCTCN2020072851-appb-000076
Figure PCTCN2020072851-appb-000077
Figure PCTCN2020072851-appb-000077
Figure PCTCN2020072851-appb-000078
Figure PCTCN2020072851-appb-000078
生物测试Biological test
以下测试例所使用的细胞株为
Figure PCTCN2020072851-appb-000079
CHO-K1 OPRM1 β-Arrestin Cell Line，来源：DiscoverX，编号：93-0213C2,批号：13K0402。 The cell line used in the following test example is
Figure PCTCN2020072851-appb-000079
CHO-K1 OPRM1 β-Arrestin Cell Line, source: DiscoverX, number: 93-0213C2, batch number: 13K0402.
所使用的试剂、其供应商、货号和存储温度如下：The reagents used, their suppliers, article numbers and storage temperatures are as follows:
Assay Complete TM Cell Culture Kit 107，DiscoverX，92-3107G，-20℃； Assay Complete TM Cell Culture Kit 107, DiscoverX, 92-3107G, -20℃;
AssayComplete TM Thawing Reagent，DiscoverX，92-4002TR，-20℃； AssayComplete TM Thawing Reagent, DiscoverX, 92-4002TR, -20℃;
AssayComplete TM Cell Detachment Reagent，DiscoverX，92-0009，-20℃； AssayComplete TM Cell Detachment Reagent, DiscoverX, 92-0009, -20℃;
Assay Complete TM Cell Plating Reagent，DiscoverX，93-0563R2，-20℃； Assay Complete TM Cell Plating Reagent, DiscoverX, 93-0563R2, -20℃;
PathhunterDetection Kit，DiscoverX，93-0001，-20℃；Pathhunter Detection Kit, DiscoverX, 93-0001, -20℃;
PBS(1×)0.0067M(PO4)，Hyclone，SH30256.01，4℃；PBS(1×)0.0067M(PO4), Hyclone, SH30256.01, 4℃;
DMSO，Sigma，D5879-100ML，常温；DMSO, Sigma, D5879-100ML, room temperature;
NKH477，Sigma，1603，-20℃；NKH477, Sigma, 1603, -20°C;
IBMX，Tocris，I5879，-20℃。IBMX, Tocris, I5879, -20°C.
所使用的仪器、其型号和供应商如下：The instruments used, their models and suppliers are as follows:
Countsatr BioMed，IM1200，ALIT；Countsatr BioMed, IM1200, ALIT;
Microscope，IX51，OLYMPUS；Microscope, IX51, OLYMPUS;
Centrifuge，5804，Eppendorf；Centrifuge, 5804, Eppendorf;
Thermostatic Water Bath，DK-S420，ShanghaiShenxian thermostatic equipment factory；Thermostatic Water Bath, DK-S420, ShanghaiShenxian thermostatic equipment factory;
Cell Incubator，3111，Thermo；Cell Incubator, 3111, Thermo;
Biological Safety Cabinet，BSC-1300IIA2，AIRTECH；Biological Safety Cabinet, BSC-1300IIA2, AIRTECH;
OptiPlate-384White Opaque，6007290，Perkin Elmer；OptiPlate-384White Opaque, 6007290, Perkin Elmer;
Multimode plate Reader，Victor X5，PerkinElmer；Multimode plate Reader, Victor X5, PerkinElmer;
Culture Plate-384 White Opaque,TC-treated，6007680，PerkinElmer。Culture Plate-384 White Opaque, TC-treated, 6007680, PerkinElmer.
测试例一 HTRF-cAMP细胞实验Test Example 1 HTRF-cAMP cell experiment
实验方法和步骤Experimental methods and procedures
一、细胞复苏1. Cell Recovery
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。1. Take the resuscitation solution out of the refrigerator at 4°C and place it in a water bath at 37°C for 15 minutes.
2、从液氮罐中取出P6代细胞，将冰冻的细胞冻存管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。2. Take out the P6 generation cells from the liquid nitrogen tank, and quickly place the frozen cell cryopreservation tube in a 37°C water bath and gently shake for 30 seconds to 1 minute until you see small ice crystals or the cells are about to melt completely.
3、用70％的酒精进行彻底的消毒擦干。3. Thoroughly disinfect and wipe dry with 70% alcohol.
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。4. Centrifuge to remove the cryopreserved fluid, and resuspend the cells with pre-warmed fresh resuscitation fluid.
a、吸取3ml预先预热的细胞复苏液到15ml离心管。a. Pipette 3ml pre-warmed cell resuscitation solution into a 15ml centrifuge tube.
b、1300rpm离心3分钟。b. Centrifuge at 1300 rpm for 3 minutes.
c、去除上清冻存液，用4ml预热的复苏液重悬细胞。c. Remove the supernatant cryopreservation solution, and resuspend the cells with 4ml of pre-warmed resuscitation solution.
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO2。5. Transfer the cell suspension to a T25 cell culture flask for 24 hours, 37°C, 5% CO2.
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。6. After culturing for 24 hours, replace the resuscitation fluid in the cell culture flask with a pre-warmed cell culture medium.
二、细胞传代Second, cell passaging
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。1. When the growth density of the cells in the T25 culture flask is more than 70%, the cells are digested and subcultured with cell digestion solution.
a、吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。a. Aspirate the medium in the culture flask, add 4ml of pre-warmed PBS, gently shake to wash the cells, and aspirate the PBS.
b、吸取1ml细胞消化液加入到T25培养瓶中。b. Pipette 1ml of cell digestion solution into the T25 culture flask.
c、反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO2培养箱中5分钟。c. Shake the culture flask repeatedly to completely cover the culture flask with digestive solution, and place it in a 37°C, 5% CO2 incubator for 5 minutes.
d、取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。d. Take out the cell culture flask and observe the cells under the microscope to see if the cells are separated.
e、加入3ml预热好的细胞培养基，终止消化。e. Add 3ml of pre-warmed cell culture medium to stop the digestion.
f、用细胞培养基反复轻轻冲洗培养瓶，收集细胞悬液到15ml离心管。f. Rinse the culture flask gently with cell culture medium repeatedly, and collect the cell suspension into a 15ml centrifuge tube.
g、1300rpm离心3分钟，去除上清。g. Centrifuge at 1300 rpm for 3 minutes and remove the supernatant.
h、用3ml细胞培养基重悬。h. Resuspend with 3ml cell culture medium.
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。2. Passage the cells in a ratio of 1:3 (add 1ml of cell resuspension + 3ml of cell culture medium to each bottle and transfer to T25 bottle).
三、细胞种板Three, cell seed plate
1、重复步骤2.2.1(a-h)，直到细胞传到P8代。细胞计数，然后用2×/1mM IBMX stimulationbuffer液重悬细胞，使细胞密度为1.2*10^6/ml.1. Repeat steps 2.2.1 (a-h) until the cells reach the P8 generation. Count the cells, then resuspend the cells with 2×/1mM IBMX stimulation buffer to make the cell density 1.2*10^6/ml.
2、使用多通道移液器，将1.2*10^6/ml的细胞溶液，以每孔10ul的体积(即每孔12000个细胞)种在384孔板内。2. Using a multi-channel pipette, plant the cell solution of 1.2*10^6/ml in a 384-well plate with a volume of 10ul per well (ie 12000 cells per well).
四、c-AMP试验Four, c-AMP test
1、配置相关试剂，按药物稀释配置表，配置化合物。1. Configure related reagents and configure compounds according to the drug dilution configuration table.
a、1×Stimulation buffer液：取1ml的5×Stimulation buffer存储液加到4ml的蒸馏水中，混匀。a. 1×Stimulation buffer: Take 1ml of 5×Stimulation buffer and add it to 4ml of distilled water, and mix well.
b、2×/1mM IBMX stimulation buffer液5ml：取10ul 500mM IBMX存储液加到4990ul细胞培养基中，轻轻吹打混匀。b. 2×/1mM IBMX stimulation buffer solution 5ml: Take 10ul 500mM IBMX storage solution and add it to 4990ul cell culture medium, and gently pipette to mix.
c、阳性药吗啡的梯度稀释配置表：c. Configuration table of gradient dilution of positive drug morphine:
Figure PCTCN2020072851-appb-000080
Figure PCTCN2020072851-appb-000080
d、化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.d. Before the compound is diluted, first dissolve the compound with DMSO to make its storage concentration 10mM.
阳性药TRV130和各化合物稀释配置表：The dilution configuration table of the positive drug TRV130 and each compound:
Figure PCTCN2020072851-appb-000081
Figure PCTCN2020072851-appb-000081
Figure PCTCN2020072851-appb-000082
Figure PCTCN2020072851-appb-000082
e、50uM NK477 1ml：取1ul 50mM NKH477存储液加到999ul 1×Stimulation buffer液中，震荡混匀。e. 50uM NK477 1ml: Take 1ul 50mM NKH477 storage solution and add it to 999ul 1×Stimulation buffer solution, shake and mix well.
f、检测试剂f. Detection reagents
A.cAMP-Cryptate(供体，冻干的)反应液：取1ml 5×cAMP-Cryptate存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。A. cAMP-Cryptate (donor, lyophilized) reaction solution: Take 1ml of 5×cAMP-Cryptate stock solution and add it to 4ml of 1×Lysis&Detection Buffer, and mix gently.
B.Anti-cAMP-d2(受体，冻干的)反应液：取1ml 5×Anti-cAMP-d2存储液加到4ml 1×Lysis & Detection Buffer液中，轻轻混匀。B. Anti-cAMP-d2 (receptor, lyophilized) reaction solution: Take 1ml of 5×Anti-cAMP-d2 storage solution and add it to 4ml of 1×Lysis&Detection Buffer, and mix gently.
2、cAMP试验步骤2. cAMP test procedure
a、种12000个细胞在10μl含2xIBMX stimulation缓冲液种，每孔。a. Seed 12,000 cells in 10μl containing 2xIBMX stimulation buffer, per well.
b、在每孔细胞中加入8μl的化合物样品稀释液。b. Add 8 μl of compound sample dilution to each well of cells.
c、每孔中加入配置好的2μl的10xNKH477液。c. Add 2μl of 10xNKH477 solution to each well.
d、37℃孵育45mins。d. Incubate at 37°C for 45mins.
e、加入10μl cAMP-d2和10μl抗cAMP Cryptate反应液。e. Add 10μl cAMP-d2 and 10μl anti-cAMP Cryptate reaction solution.
f、室温避光孵育60mins。f. Incubate in the dark at room temperature for 60 minutes.
g、HTRF读板。g, HTRF plate reading.
3、RFU检测读板3. RFU detection and reading
孵育60分钟后，所有的样品将通过均相时间分辨荧光的方法检测读板。After 60 minutes of incubation, all samples will be detected and read by a homogeneous time-resolved fluorescence method.
数据分析data analysis
将数据从多功能读板仪连接的电脑中对应软件导出，包括665nm和620nm两个信号值。比率的计算公式为：比率＝665nm信号值/620nm信号值×10000。用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品比率-空白孔比率)/TOP×100(注：TOP值是吗啡样品比率-空白孔比率后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表1所示：Export the data from the corresponding software in the computer connected to the multi-function plate reader, including two signal values of 665nm and 620nm. The calculation formula of the ratio is: ratio=665nm signal value/620nm signal value×10000. Use GraphPad Prism software to analyze the data. The best fit curve is log (agonist) vs. response. The EC50 value of the compound is determined by the non-linear regression analysis of the computer-assisted dose-response curve; PEC50 = -logEC50 (the unit of the EC50 value is moles); the maximum of% morphine Effect value = (compound sample ratio-blank hole ratio)/TOP×100 (Note: TOP value is the morphine sample ratio-blank hole ratio and then analyzed and fitted the curve Top value by the software Graphpad Prism). The results are shown in Table 1:
表1 化合物对cAMP的活性Table 1 The activity of compounds on cAMP
Figure PCTCN2020072851-appb-000083
Figure PCTCN2020072851-appb-000083
测试例二 β-Arrestin细胞实验Test Example 2 β-Arrestin cell experiment
实验方法和步骤Experimental methods and procedures
一、细胞复苏1. Cell Recovery
1、将复苏液从4℃冰箱中取出放37℃水浴锅中预热15分钟。1. Take the resuscitation solution out of the refrigerator at 4°C and place it in a water bath at 37°C for 15 minutes.
2、从液氮罐中取出P6代细胞，将冰冻的细胞培养管迅速放在37℃水浴锅中轻轻晃动30秒到1分钟，直到看见小冰晶或细胞即将完全融化。2. Take out the P6 generation cells from the liquid nitrogen tank, quickly place the frozen cell culture tube in a 37°C water bath and gently shake for 30 seconds to 1 minute until small ice crystals or the cells are about to melt completely.
3、用70％的酒精进行彻底的消毒擦干。3. Thoroughly disinfect and wipe dry with 70% alcohol.
4、离心去除冻存液，用预先预热的新鲜复苏液重悬细胞。4. Centrifuge to remove the cryopreserved fluid, and resuspend the cells with pre-warmed fresh resuscitation fluid.
a、吸取3ml预先预热的细胞复苏液到15ml离心管。a. Pipette 3ml pre-warmed cell resuscitation solution into a 15ml centrifuge tube.
b、1300rpm离心3分钟。b. Centrifuge at 1300 rpm for 3 minutes.
c、去除上清，用4ml预热的复苏液重悬细胞。c. Remove the supernatant and resuspend the cells with 4ml of pre-warmed resuscitation fluid.
5、将细胞混悬液转移到T25细胞培养瓶中培养24小时，37℃，5％CO2。5. Transfer the cell suspension to a T25 cell culture flask for 24 hours, 37°C, 5% CO2.
6、培养24小时后，将细胞培养瓶中的复苏液换成预热好的细胞培养基。6. After culturing for 24 hours, replace the resuscitation fluid in the cell culture flask with a pre-warmed cell culture medium.
二、细胞传代Second, cell passaging
1、当细胞在T25培养瓶中的生长密度>70％时,用细胞消化液对细胞进行消化传代培养。1. When the growth density of the cells in the T25 culture flask is more than 70%, the cells are digested and subcultured with cell digestion solution.
a.吸出培养瓶中的培养基，加入4ml预先预热的PBS，轻轻晃动润洗细胞，吸弃PBS。a. Aspirate the medium in the culture flask, add 4ml of pre-warmed PBS, gently shake to wash the cells, and aspirate the PBS.
b.吸取1ml细胞消化液加入到T25培养瓶中。b. Pipette 1ml of cell digestion solution into T25 culture flask.
c.反复摇晃培养瓶使消化液彻底覆盖培养瓶，放在37℃,5％CO2培养箱中5分钟。c. Shake the culture flask repeatedly to completely cover the culture flask with digestive solution, and place it in a 37°C, 5% CO2 incubator for 5 minutes.
d.取出细胞培养瓶，在显微镜下观察细胞，看细胞是否被分离。d. Take out the cell culture flask and observe the cells under the microscope to see if the cells are separated.
e.加入3ml预热好的细胞培养基，终止消化。e. Add 3ml of pre-warmed cell culture medium to stop the digestion.
f.用细胞培养基反复轻轻冲洗培养瓶，最后将细胞悬液转移到15ml离心管。f. Wash the culture flask repeatedly with cell culture medium, and finally transfer the cell suspension to a 15ml centrifuge tube.
g.1300rpm离心3分钟，去除上清。g. Centrifuge at 1300 rpm for 3 minutes and remove the supernatant.
h.用3ml细胞培养基重悬。h. Resuspend with 3ml cell culture medium.
2、按1：3的比例进行细胞传代(每瓶加入1ml的细胞重悬液+3ml的细胞培养基，传至T25瓶)。2. Passage the cells in a ratio of 1:3 (add 1ml of cell resuspension + 3ml of cell culture medium to each bottle and transfer to T25 bottle).
3、重复步骤2.2.1(a-h)，直到细胞传到P8代。3. Repeat steps 2.2.1 (a-h) until the cells reach the P8 generation.
三、细胞种板Three, cell seed plate
1、用移液器取20ul的细胞悬液用细胞计数仪测量细胞数。1. Take 20ul of cell suspension with a pipette and measure the number of cells with a cell counter.
2、1300rpm离心3分钟，沉淀细胞。2. Centrifuge at 1300 rpm for 3 minutes to pellet the cells.
3、去除上清，加入相应细胞铺板液使细胞浓度为2×10^5/ml。3. Remove the supernatant and add the corresponding cell plating solution to make the cell concentration 2×10^5/ml.
4、使用多通道移液器，根据实验设计，将2×10^5/ml的细胞溶液，以每孔20ul的体积(即每孔4000个细胞)种在384孔板内。4. Using a multi-channel pipette, according to the experimental design, plant 2×10^5/ml cell solution in a 384-well plate with a volume of 20ul per well (ie 4000 cells per well).
5、将种好细胞的384孔板放到37℃,5％CO2培养箱中培养24h。5. Place the 384-well plate with the seeded cells in a 37°C, 5% CO2 incubator for 24 hours.
四、β-arrestin试验Four, β-arrestin test
1、按照下列稀释表配置化合物。1. Prepare the compound according to the following dilution table.
a.阳性药吗啡的梯度稀释配置表：a. Configuration table of gradient dilution of positive drug morphine:
Figure PCTCN2020072851-appb-000084
Figure PCTCN2020072851-appb-000084
b.化合物稀释之前，先将化合物用DMSO溶解，使其存储浓度为10mM.b. Before the compound is diluted, the compound is dissolved in DMSO to a storage concentration of 10mM.
阳性药TRV130和各化合物稀释配置表：The dilution configuration table of the positive drug TRV130 and each compound:
Figure PCTCN2020072851-appb-000085
Figure PCTCN2020072851-appb-000085
2、取5ul上述配置好的各化合物样品稀释液加到384孔板中。2. Take 5ul of each compound sample dilution prepared above and add it to a 384-well plate.
3、加完样后，将384孔板放回37℃,5％CO2培养箱中培养90分钟。3. After adding the sample, put the 384-well plate back into the 37°C, 5% CO2 incubator and incubate for 90 minutes.
五、RLU检测Five, RLU detection
1、化合物孵育结束前，按下列比例配置Working Detection溶液(注意避光)。然后每孔加入12.5ul，避光、常温、摇床孵育1h。1. Before the completion of the compound incubation, configure the Working Detection solution according to the following ratio (be careful to avoid light). Then add 12.5ul to each well, and incubate for 1h in a shaker at room temperature in the dark.
Figure PCTCN2020072851-appb-000086
Figure PCTCN2020072851-appb-000086
2、化合物孵育结束，每孔加入12.5ul上述工作液，避光、常温、80rpm摇床孵育1h。2. At the end of the compound incubation, add 12.5ul of the above working solution to each well, and incubate for 1h in the dark, room temperature, 80rpm shaker.
3、孵育结束，运用多功能读板仪进行读板。3. At the end of the incubation, use a multi-function plate reader to read the plate.
数据分析data analysis
将数据从多功能读板仪连接的电脑中对应软件导出，用GraphPad Prism软件对数据进行分析。最佳拟合曲线选用log(agonist)vs.response.利用计算机辅助剂量-反应曲线的非线性回归分析方式确定化合物的EC50值；PEC50＝-logEC50(EC50值的单位是摩尔)；％吗啡的最大效应值＝(化合物样品的RLU值-空白孔的RLU值)/TOP×100(注：TOP值是吗啡样品的RLU值-空白孔的RLU值后通过软件Graphpad Prism分析拟合的曲线Top值)。结果如表2所示：Export the data from the corresponding software in the computer connected to the multi-function plate reader, and analyze the data with GraphPad Prism software. The best fit curve is log(agonist) vs.response. The EC50 value of the compound is determined by the non-linear regression analysis method of the computer-assisted dose-response curve; PEC50=-logEC50 (the unit of the EC50 value is mole); the maximum of% morphine Effect value = (RLU value of the compound sample-RLU value of the blank well)/TOP×100 (Note: TOP value is the RLU value of the morphine sample-the RLU value of the blank well, after analyzing the fitted curve Top value by the software Graphpad Prism) . The results are shown in Table 2:
表2 化合物对β-arrestin的测试结果Table 2 Test results of compounds on β-arrestin
Figure PCTCN2020072851-appb-000087
Figure PCTCN2020072851-appb-000087
从表1和表2可以看出，本发明代表性化合物对cAMP具有较高的抑制活性，以及较高的Emax值。此外本发明的化合物对β-arrestin具有较低的Emax值，偏向性好。It can be seen from Table 1 and Table 2 that the representative compound of the present invention has a higher inhibitory activity against cAMP and a higher Emax value. In addition, the compound of the present invention has a lower Emax value for β-arrestin, and has a good bias.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that, after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (28)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体或溶剂化物：A compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:
    Figure PCTCN2020072851-appb-100001
    Figure PCTCN2020072851-appb-100001
    式中，In the formula,
    R a为取代或未取代的C 6-10芳基、或取代或未取代的5或6元单环杂芳基； R a is a substituted or unsubstituted C 6-10 aryl group, or a substituted or unsubstituted 5 or 6-membered monocyclic heteroaryl group;
    R b为氢或取代或未取代的C 1-10烷基； R b is hydrogen or substituted or unsubstituted C 1-10 alkyl;
    W 1为一个键，或C(R cR d)； W 1 is a bond, or C(R c R d );
    W 2为C(R eR f)、NR g或O； W 2 is C(R e R f ), NR g or O;
    R c、R d、R e、R f各自独立地选自氢、羟基、卤素、氰基、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基或NR 11R 12； R c, R d, R e , R f are each independently selected from hydrogen, hydroxy, halo, cyano, a substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, or NR 11 R 12 ;
    R g为氢、取代或未取代的C 1-10烷基、-COC 1-10烷基、-CONR 11R 12、或-SO 2C 1-10烷基； R g is hydrogen, substituted or unsubstituted C 1-10 alkyl, -COC 1-10 alkyl, -CONR 11 R 12 , or -SO 2 C 1-10 alkyl;
    Z 1为N或CR 1； Z 1 is N or CR 1 ;
    Z 2为NR 2、O或C(R 3R 4)； Z 2 is NR 2 , O or C (R 3 R 4 );
    Z 3为C(R 5R 6)、NR 7或O； Z 3 is C(R 5 R 6 ), NR 7 or O;
    Z 4为C(R 8R 9)、NR 10或O； Z 4 is C(R 8 R 9 ), NR 10 or O;
    W 2、Z 1、Z 2、Z 3、Z 4不同时含杂原子，且W 2、Z 1不同时含杂原子，Z 1、Z 2不同时含杂原子，Z 2、Z 3、Z 4不同时含两个或以上的杂原子； W 2 , Z 1 , Z 2 , Z 3 , Z 4 do not contain heteroatoms at the same time, and W 2 , Z 1 do not contain heteroatoms at the same time, Z 1 , Z 2 do not contain heteroatoms at the same time, Z 2 , Z 3 , Z 4 Do not contain two or more heteroatoms at the same time;
    R 1为氢或取代或未取代的C 1-10烷基； R 1 is hydrogen or substituted or unsubstituted C 1-10 alkyl;
    R 2、R 7、R 10各自独立地为氢、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、取代或未取代的C 3-8环烷基或-(CR 21R 22) p-L 1；L 1为C 3-8环烷基、C 1-10烷氧基、-COC 1-10烷基、-COC 3-8环烷基、-CONR 11R 12、-C(O)OC 1-10烷基、-SO 2C 1-10烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-CO-(CR 21R 22) u-(CR 23R 24)C 1-10烷基、-(CR 23R 24)C 1-10烷基、-(CR 23R 24)CN、-(CR 23R 24)OH或-(CR 23R 24)C 1-10烷氧基(； R 2 , R 7 , and R 10 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1-10 alkoxy, substituted or unsubstituted C 3-8 cycloalkyl or -(CR 21 R 22 ) p -L 1 ; L 1 is C 3-8 cycloalkyl, C 1-10 alkoxy -COC 1-10 alkyl, -COC 3-8 cycloalkyl, -CONR 11 R 12 , -C(O)OC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring, -CO-(CR 21 R 22 ) u -(CR 23 R 24 )C 1-10 alkyl, -(CR 23 R 24 )C 1 -10 alkyl, -(CR 23 R 24 )CN, -(CR 23 R 24 )OH or -(CR 23 R 24 )C 1-10 alkoxy(;
    R 3、R 4各自独立地为氢、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、取代或未取代的C 3-8环烷基或-(CR 31R 32) q-L 2；L 2为C 3-8环烷基、C 1-10烷氧基、-COC 1-10烷基、-CONR 11R 12、-C(O)OC 1-10烷基、-SO 2C 1-10烷基、-SO 2NR 11R 12、4 至6元饱和或不饱和单杂环、-(CR 33R 34)C 1-10烷基、-(CR 33R 34)CN、-(CR 33R 34)OH或-(CR 33R 34)C 1-10烷氧基；或者R 3、R 4与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基、C 1-10烷基、卤代C 1-10烷基； R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1- 10 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl or -(CR 31 R 32 ) q -L 2 ; L 2 is C 3-8 cycloalkyl, C 1-10 alkoxy,- COC 1-10 alkyl, -CONR 11 R 12 , -C(O)OC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or not Saturated single heterocyclic ring, -(CR 33 R 34 )C 1-10 alkyl, -(CR 33 R 34 )CN, -(CR 33 R 34 )OH or -(CR 33 R 34 )C 1-10 alkoxy Group; or R 3 , R 4 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring; the 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring It is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy, C 1-10 alkyl, and halogenated C 1-10 alkyl;
    R 5、R 6各自独立地为氢、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、取代或未取代的C 3-8环烷基或-(CR 51R 52) r-L 3；L 3为C 3-8环烷基、C 1-10烷氧基、-COC 1-10烷基、-CONR 11R 12、-C(O)OC 1-10烷基、-SO 2C 1-10烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 53R 54)C 1-10烷基、-(CR 53R 54)CN、-(CR 53R 54)OH或-(CR 53R 54)C 1-10烷氧基(；或者R 5、R 6与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基、C 1-10烷基、卤代C 1-10烷基； R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1- 10 alkoxy group, a substituted or unsubstituted C 3-8 cycloalkyl or - (CR 51 R 52) r -L 3; L 3 is a C 3-8 cycloalkyl group, C 1-10 alkoxy, - COC 1-10 alkyl, -CONR 11 R 12 , -C(O)OC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or not Saturated single heterocyclic ring, -(CR 53 R 54 )C 1-10 alkyl, -(CR 53 R 54 )CN, -(CR 53 R 54 )OH or -(CR 53 R 54 )C 1-10 alkoxy Group (; or R 5 , R 6 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring; the 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring The ring is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy, C 1-10 alkyl, and halogenated C 1-10 alkyl;
    R 8、R 9各自独立地为氢、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、卤代C 1-10烷氧基、取代或未取代的C 3-8环烷基或-(CR 81R 82) m-L 4；L 4为C 3-8环烷基、C 1-10烷氧基、-COC 1-10烷基、-CONR 11R 12、-C(O)OC 1-10烷基、-SO 2C 1-10烷基、-SO 2NR 11R 12、4至6元饱和或不饱和单杂环、-(CR 83R 84)C 1-10烷基、-(CR 83R 84)CN、-(CR 83R 84)OH或-(CR 83R 84)C 1-10烷氧基；或者R 8、R 9与相连的碳原子共同形成3至6元饱和单杂环或3至6元饱和单环；所述3至6元饱和单杂环或3至6元饱和单环为未取代的或被1-3个选自下组的取代基取代：卤素、C 1-10烷氧基、C 1-10烷基、卤代C 1-10烷基； R 8 and R 9 are each independently hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1-10 alkyl, halogenated C 1- 10 Alkoxy, substituted or unsubstituted C 3-8 cycloalkyl or -(CR 81 R 82 ) m -L 4 ; L 4 is C 3-8 cycloalkyl, C 1-10 alkoxy,- COC 1-10 alkyl, -CONR 11 R 12 , -C(O)OC 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 NR 11 R 12 , 4 to 6-membered saturated or not Saturated single heterocyclic ring, -(CR 83 R 84 )C 1-10 alkyl, -(CR 83 R 84 )CN, -(CR 83 R 84 )OH or -(CR 83 R 84 )C 1-10 alkoxy Group; or R 8 , R 9 and the connected carbon atoms together form a 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring; the 3 to 6-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring It is unsubstituted or substituted by 1-3 substituents selected from the group consisting of halogen, C 1-10 alkoxy, C 1-10 alkyl, and halogenated C 1-10 alkyl;
    R 01、R 02、R 03、R 04各自独立地为氢、羟基、氰基、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基； R 01 , R 02 , R 03 , and R 04 are each independently hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogen Substitute C 1-10 alkyl;
    R 21、R 22相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、-NR 11R 12、-NR 13COC 1-10烷基或-NR 13SO 2R 0； R 21 and R 22 are the same or different, and are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1- 10 alkyl group, -NR 11 R 12 , -NR 13 COC 1-10 alkyl group or -NR 13 SO 2 R 0 ;
    R 31、R 32相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、-NR 11R 12、-NR 13COC 1-10烷基或-NR 13SO 2R 0； R 31 and R 32 are the same or different, and are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1- 10 alkyl group, -NR 11 R 12 , -NR 13 COC 1-10 alkyl group or -NR 13 SO 2 R 0 ;
    R 51、R 52相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、-NR 11R 12、-NR 13COC 1-10烷基或-NR 13SO 2R 0； R 51 and R 52 are the same or different, and are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1- 10 alkyl group, -NR 11 R 12 , -NR 13 COC 1-10 alkyl group or -NR 13 SO 2 R 0 ;
    R 81、R 82相同或不同，且各自独立地为氢、羟基、卤素、取代或未取代的C 1-10烷基、取代或未取代的C 1-10烷氧基、卤代C 1-10烷基、-NR 11R 12、-NR 13COC 1-10烷基或-NR 13SO 2R 0； R 81 and R 82 are the same or different, and are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 1-10 alkoxy, halogenated C 1- 10 alkyl group, -NR 11 R 12 , -NR 13 COC 1-10 alkyl group or -NR 13 SO 2 R 0 ;
    R 23、R 24与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 23 , R 24 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
    R 33、R 34与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 33 , R 34 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
    R 53、R 54与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未取代的3至6元饱和或不饱和单环； R 53 , R 54 and the connected carbon atom form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
    R 83、R 84与相连的碳原子形成取代或未取代的3至6元饱和或不饱和单杂环、或取代或未 取代的3至6元饱和或不饱和单环； R 83 , R 84 and the connected carbon atoms form a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring, or a substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic ring;
    R 0为取代或未取代的C 1-10烷基、NR 11R 12、或取代或未取代的C 3-8环烷基； R 0 is substituted or unsubstituted C 1-10 alkyl, NR 11 R 12 , or substituted or unsubstituted C 3-8 cycloalkyl;
    R 11、R 12各自独立地为氢、C 1-10烷基、卤代C 1-10烷基、取代或未取代的3至6元饱和或不饱和单杂环；或者R 11、R 12与相连的氮原子形成取代或未取代的4至6元饱和或不饱和单杂环； R 11 and R 12 are each independently hydrogen, C 1-10 alkyl, halogenated C 1-10 alkyl, substituted or unsubstituted 3 to 6-membered saturated or unsaturated monocyclic heterocyclic ring; or R 11 , R 12 Form a substituted or unsubstituted 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring with the connected nitrogen atom;
    R 13各自独立地为氢、取代或未取代的C 1-10烷基或卤代C 1-10烷基； R 13 is each independently hydrogen, substituted or unsubstituted C 1-10 alkyl or halo C 1-10 alkyl;
    u为0、1或2；u is 0, 1 or 2;
    p、q、r、m各自独立地为0、1、2或3；p, q, r, and m are each independently 0, 1, 2 or 3;
    t为0或1；t is 0 or 1;
    n为1、2或3；n is 1, 2 or 3;
    所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代；The "substitution" means that 1, 2, or 3 hydrogen atoms in the group are replaced by substituents each independently selected from Group A;
    所述L 1、L 2、L 3、L 4中的环烷基、烷氧基、烷基或4至6元饱和或不饱和单杂环为未取代的或被1、2或3个各自独立地选自A组的取代基所取代； The cycloalkyl, alkoxy, alkyl or 4- to 6-membered saturated or unsaturated monocyclic heterocyclic ring in said L 1 , L 2 , L 3 , and L 4 is unsubstituted or is each of 1, 2 or 3 Substituted by substituents independently selected from Group A;
    所述A组取代基选自：氰基、乙酰基、羟基、羟甲基、羟乙基、羧基、卤代C 1-8烷基、卤素、硝基、C 6-10芳基、5或6元单环杂芳基、C 1-10烷基、C 1-10烷氧基、C 3-8环烷基、C 3-8环烷氧基、C 2-10烯基、C 2-10炔基、-CONR a0R b0、-C(O)OC 1-10烷基、-CHO、-OC(O)C 1-10烷基、-SO 2C 1-10烷基、-SO 2C 6-10芳基、-COC 6-10芳基、4至6元饱和或不饱和单杂环或4至6元饱和或不饱和单环，其中R a0、R b0各自独立地为氢或C 1-3烷基。 The group A substituents are selected from: cyano, acetyl, hydroxyl, hydroxymethyl, hydroxyethyl, carboxyl, halogenated C 1-8 alkyl, halogen, nitro, C 6-10 aryl, 5 or 6-membered monocyclic heteroaryl, C 1-10 alkyl, C 1-10 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, C 2-10 alkenyl, C 2- 10 alkynyl, -CONR a0 R b0 , -C(O)OC 1-10 alkyl, -CHO, -OC(O)C 1-10 alkyl, -SO 2 C 1-10 alkyl, -SO 2 C 6-10 aryl, -COC 6-10 aryl, 4 to 6-membered saturated or unsaturated monocyclic heterocyclic ring or 4 to 6-membered saturated or unsaturated monocyclic ring, wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R a为取代或未取代的吡啶；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R a is substituted or unsubstituted pyridine; the "substituted" refers to the group 1, 2, or 3 hydrogen atoms of are replaced by substituents each independently selected from Group A.
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R a为取代或未取代的苯基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R a is a substituted or unsubstituted phenyl group; the "substituted" refers to a group 1, 2, or 3 hydrogen atoms in are replaced by substituents each independently selected from Group A.
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R c、R d各自独立地为氢、羟基、卤素、氰基、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或NR 11R 12；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R c and R d are each independently hydrogen, hydroxy, halogen, cyano, substituted or Unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ; the "substituted" means that 1, 2 or 3 hydrogen atoms in the group are each independently Is substituted with a substituent selected from Group A.
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R e、R f各自独立地为氢、羟基、卤素、氰基、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或NR 11R 12；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R e and R f are each independently hydrogen, hydroxyl, halogen, cyano, substituted or Unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or NR 11 R 12 ; the "substituted" means that 1, 2 or 3 hydrogen atoms in the group are each independently Is substituted with a substituent selected from Group A.
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，R b为氢。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R b is hydrogen.
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特 征在于，R 01、R 02、R 03、R 04各自独立地为氢、羟基、氰基、卤素、取代或未取代的C 1-3烷基、取代或未取代的C 1-3烷氧基或卤代C 1-3烷基；所述“取代”是指基团中的1、2或3个氢原子被各自独立地选自A组的取代基所取代。 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein R 01 , R 02 , R 03 , and R 04 are each independently hydrogen, hydroxyl, or cyanide Group, halogen, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy or halogenated C 1-3 alkyl; the “substituted” refers to 1 in the group , 2 or 3 hydrogen atoms are replaced by substituents each independently selected from Group A.
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，所述式(I)化合物为式(Ⅱ)所示结构：The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound of formula (I) has a structure represented by formula (II):
    Figure PCTCN2020072851-appb-100002
    Figure PCTCN2020072851-appb-100002
  9. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；t为0；n为1、2或3。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C( R 5 R 6 ); t is 0; n is 1, 2 or 3.
  10. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，Z 1为N；Z 2为CR 3R 4；Z 3为NR 7或O；Z 4为C(R 8R 9)；t为0或1；n为1。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is NR 7 Or O; Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1.
  11. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为NR 10或O；t为1；n为1、2或3。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C( R 5 R 6 ); Z 4 is NR 10 or O; t is 1; n is 1, 2 or 3.
  12. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3.
  13. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n为1、2或3。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C (R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
  14. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为一个键，或C(R cR d)；W 2为C(R eR f)。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W 1 is a bond, or C(R c R d ); W 2 is C(R e R f ).
  15. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为一个键，或C(R cR d)；W 2为C(R eR f)；Z 1、Z 2、Z 3、Z 4、t、n为选自下组的一种： The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W 1 is a bond, or C(R c R d ); W 2 is C(R e R f ); Z 1 , Z 2 , Z 3 , Z 4 , t, n are one selected from the following group:
    (ⅰ)Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；t为0；n为1、2或3； (I) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
    (ⅱ)Z 1为N；Z 2为CR 3R 4；Z 3为NR 7或O；Z 4为C(R 8R 9)；t为0或1；n为1； (Ii) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is NR 7 or O; Z 4 is C(R 8 R 9 ); t is 0 or 1; n is 1;
    (ⅲ)Z 1为N；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为NR 10或O；t为1；n为1、2或3； (Iii) Z 1 is N; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is NR 10 or O; t is 1; n is 1, 2 or 3;
    (ⅳ)Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3； (Iv) Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
    (ⅴ)Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n 为1、2或3。 (Ⅴ) Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
  16. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为一个键，或C(R cR d)；W 2为NR g或O。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W 1 is a bond, or C(R c R d ); W 2 is NR g or O.
  17. 如权利要求1或8所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，W 1为一个键，或C(R cR d)；W 2为NR g或O；Z 1、Z 2、Z 3、Z 4、t、n为选自下组的一种： The compound of claim 1 or 8, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein W 1 is a bond, or C(R c R d ); W 2 is NR g or O; Z 1 , Z 2 , Z 3 , Z 4 , t, n are one selected from the following group:
    (ⅰ)Z 1为CR 1；Z 2为NR 2；Z 3为C(R 5R 6)；t为0；n为1、2或3； (I) Z 1 is CR 1 ; Z 2 is NR 2 ; Z 3 is C(R 5 R 6 ); t is 0; n is 1, 2 or 3;
    (ⅱ)Z 1为CR 1；Z 2为CR 3R 4；Z 3为C(R 5R 6)；Z 4为C(R 8R 9)、NR 10或O；t为0或1；n为1、2或3。 (Ii) Z 1 is CR 1 ; Z 2 is CR 3 R 4 ; Z 3 is C(R 5 R 6 ); Z 4 is C(R 8 R 9 ), NR 10 or O; t is 0 or 1; n is 1, 2 or 3.
  18. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，其特征在于，所述化合物选自表A或表B。The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, wherein the compound is selected from Table A or Table B.
  19. 一种药物组合物，所述药物组合物包括权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物；以及药学可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof; and a pharmaceutically acceptable carrier.
  20. 如权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如权利要求19所述药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 19 is used in the preparation of the prevention and/or treatment of MOR Receptor agonist-mediated drug use in related diseases.
  21. 如权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如权利要求19所述药物组合物在制备预防和/或治疗疼痛和疼痛相关疾病的药物中的用途。The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 19 is used in the preparation of the prevention and/or treatment of pain Use in medicine for pain-related diseases.
  22. 如权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物、或如权利要求19所述药物组合物在制备激动或拮抗MOR受体的药物中用途。The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or the pharmaceutical composition according to claim 19 in the preparation of agonistic or antagonistic MOR receptor Use in medicine.
  23. 如权利要求20所述的用途，其特征在于，所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病。The use according to claim 20, wherein the related diseases mediated by the MOR receptor agonist are selected from the group consisting of pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, and cardiovascular diseases. Diseases and respiratory diseases.
  24. 如权利要求23所述的用途，其特征在于，所述MOR受体激动剂介导的相关疾病为疼痛。The use according to claim 23, wherein the related disease mediated by the MOR receptor agonist is pain.
  25. 如权利要求21所述的用途，其特征在于，所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。The use according to claim 21, wherein the pain is selected from the group consisting of postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  26. 如权利要求24所述的用途，其特征在于，所述癌症选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。The use according to claim 24, wherein the cancer is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia, and leukemia.
  27. 一种预防和/或治疗MOR受体激动剂介导的相关疾病的方法，包括给予所需患者治疗有效量的权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如权利要求19所述药物组合物。A method for preventing and/or treating related diseases mediated by MOR receptor agonists, comprising administering to a patient a therapeutically effective amount of the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable compound thereof Salt, stereoisomer or solvate, or the pharmaceutical composition of claim 19.
  28. 一种预防和/或治疗疼痛和疼痛相关疾病的方法，包括给予所需患者治疗有效量的权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体或溶剂化物，或如权利要求19所述药物组合物。A method for preventing and/or treating pain and pain-related diseases, comprising administering to a patient a therapeutically effective amount of the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof Body or solvate, or the pharmaceutical composition of claim 19.
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