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WO2020147848A1 - Dérivé d'oxaspiro substitué tricyclique, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé d'oxaspiro substitué tricyclique, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
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
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group
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Chinese (zh)
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胡斌
刘力锋
石晓永
杨文�
关慧平
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Yangtze River Pharmaceutical Group Co Ltd
Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Priority to CN202080003464.1A priority Critical patent/CN112334465B/zh
Publication of WO2020147848A1 publication Critical patent/WO2020147848A1/fr
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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.

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Abstract

L'invention concerne un dérivé d'oxaspiro substitué tricyclique, un procédé de préparation associé, et une utilisation pharmaceutique de celui-ci. En particulier, l'invention concerne des composés de formule (I) et de formule (II) ou des sels, stéréoisomères, ou solvates pharmaceutiquement acceptables de ceux-ci, leurs procédés de préparation et leurs utilisations.
PCT/CN2020/072851 2019-01-17 2020-01-17 Dérivé d'oxaspiro substitué tricyclique, son procédé de préparation et son utilisation pharmaceutique Ceased WO2020147848A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN117263956A (zh) * 2022-01-19 2023-12-22 天地恒一制药股份有限公司 阿片受体激动剂及其制备方法和用途

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WO2012129495A1 (fr) * 2011-03-23 2012-09-27 Trevena, Inc. Ligands de récepteurs opïoides, et leurs procédés d'utilisation et de production
WO2017063509A1 (fr) * 2015-10-15 2017-04-20 江苏恒瑞医药股份有限公司 Dérivé oxa spiro, son procédé de préparation, et ses applications dans des médicaments
WO2017106306A1 (fr) * 2015-12-14 2017-06-22 Trevena, Inc. Procédés de traitement de l'hyperalgésie
WO2018188641A1 (fr) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un agoniste du mor et un agoniste du kor, et ses utilisations
WO2019109937A1 (fr) * 2017-12-06 2019-06-13 江苏恒瑞医药股份有限公司 Utilisation d'un agoniste de kor en combinaison avec un agoniste de mor dans la préparation d'un médicament pour le traitement de la douleur
WO2019205983A1 (fr) * 2018-04-28 2019-10-31 四川科伦博泰生物医药股份有限公司 Composé oxa-spiro, son procédé de préparation et ses utilisations

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Publication number Priority date Publication date Assignee Title
WO2012129495A1 (fr) * 2011-03-23 2012-09-27 Trevena, Inc. Ligands de récepteurs opïoides, et leurs procédés d'utilisation et de production
WO2017063509A1 (fr) * 2015-10-15 2017-04-20 江苏恒瑞医药股份有限公司 Dérivé oxa spiro, son procédé de préparation, et ses applications dans des médicaments
WO2017106306A1 (fr) * 2015-12-14 2017-06-22 Trevena, Inc. Procédés de traitement de l'hyperalgésie
WO2018188641A1 (fr) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un agoniste du mor et un agoniste du kor, et ses utilisations
WO2019109937A1 (fr) * 2017-12-06 2019-06-13 江苏恒瑞医药股份有限公司 Utilisation d'un agoniste de kor en combinaison avec un agoniste de mor dans la préparation d'un médicament pour le traitement de la douleur
WO2019205983A1 (fr) * 2018-04-28 2019-10-31 四川科伦博泰生物医药股份有限公司 Composé oxa-spiro, son procédé de préparation et ses utilisations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117263956A (zh) * 2022-01-19 2023-12-22 天地恒一制药股份有限公司 阿片受体激动剂及其制备方法和用途

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