WO2023025276A1 - 一种钾通道调节剂、组合物及应用 - Google Patents

一种钾通道调节剂、组合物及应用 Download PDF

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WO2023025276A1
WO2023025276A1 PCT/CN2022/115057 CN2022115057W WO2023025276A1 WO 2023025276 A1 WO2023025276 A1 WO 2023025276A1 CN 2022115057 W CN2022115057 W CN 2022115057W WO 2023025276 A1 WO2023025276 A1 WO 2023025276A1
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halogenated
alkoxy
alkyl
cycloalkyl
cycloalkoxy
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French (fr)
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胡苗
吴一哲
刘兴国
周星露
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Hangzhou Healzen Therapeutics Co Ltd
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Hangzhou Healzen Therapeutics Co Ltd
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Priority to JP2023573562A priority Critical patent/JP7681132B2/ja
Priority to EP22860622.4A priority patent/EP4393907A4/en
Priority to US18/570,661 priority patent/US20240317689A1/en
Publication of WO2023025276A1 publication Critical patent/WO2023025276A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/32—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of drug synthesis and design, and in particular relates to a class of compounds regulating potassium channels or stereoisomers thereof, or pharmaceutically acceptable salts thereof, pharmaceutical compositions and applications thereof.
  • the compound has the function of regulating potassium channels and can be used for treating diseases or disorders benefiting from KCNQ channel openers.
  • central nervous system diseases have always been a difficult problem in the medical field.
  • Traditional medicine cannot prevent and treat acute and chronic central nervous system injuries, Alzheimer's disease, Parkinson's disease, epilepsy and other central nervous system diseases.
  • Ion channels are the key to regulating the excitability of neurons. Therefore, ion channels have become the most direct targets for the treatment of central nervous system diseases. Approximately more than 10% of potassium channel subtypes are known to be associated with central nervous system disorders in humans in many different ways, for example from direct control of neuronal excitability and homeostasis of the ionic environment to indirect effects through metabolism.
  • KCNQ potassium ion channel is an important branch of the potassium ion channel superfamily, and its gene mutation is related to many genetic diseases.
  • KCNQ1 KvLQT
  • KCNQ2 and KCNQ3 are the molecular basis of M-type potassium ion channels in nerve cells.
  • Benign familial neonatal convulsions BFNC
  • KCNQ4 is mostly expressed in nerve conduction pathways, nerve nuclei and inner ear hair cells related to hearing.
  • Hereditary deafness (DFNA) is related to KCNQ4 gene mutation.
  • KCNQ5 is mostly expressed in muscle tissue.
  • KCNQ potassium channel opener has become a new direction of antiepileptic drug research. Retigabine was approved by the US FDA in June 2011 for the treatment of partial seizures in refractory epilepsy. Its excellent performance in vivo and in vitro and its successful marketing prove that the KCNQ potassium channel is of great significance as a drug target. Moreover, in vivo and in vitro studies have shown that retigabine also has potential therapeutic effects on anxiety, stroke, neurodegenerative diseases, and pain. At the same time, due to the wide range of physiological functions of the KCNQ potassium channel, its opener also has very broad application prospects in the treatment of many diseases.
  • the object of the present invention is to provide a novel compound with the function of regulating potassium channels or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or its stereoisomer or its stereoisomer mixture or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a kind of above-mentioned compound or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt to be used for the preparation of the medicament for the treatment of the disease, disorder or condition benefited from the KCNQ channel opener in the application.
  • the compounds of the present invention are effective in treating and preventing diseases and conditions affected by the activity of potassium ion channels, and can be used to treat various diseases and disorders.
  • the invention provides the compound shown in formula I,
  • Ring A is a benzene ring or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O or S;
  • R 1 is selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkenyl, C 1 -C 8 alkenyl, spiroalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 -C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, C 1 -C 8 alkylthio, C 1 -C 8 Alkanoyl, C 1 -C 8 alkylsulfonyl, aminosulfonyl, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkenyloxy, halo Substituted C 3 -C 8 cycloalkyl, halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 hetero
  • R 2 are each independently selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 - C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl, Halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkyl, halogenated C 2 -C 8 heterocycloalkoxy;
  • R 2 are connected to the same atom, and the two R 2 can be different or the same, and the atoms connected to them form a 3-6-membered ring or a 3-6-membered heterocyclic ring;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 -C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy , halogenated C 3 -C 8 cycloalkyl, halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkyl, halogenated C 2 -C 8 heterocycloalkoxy, spiro alkyl;
  • n is selected from 0, 1, 2;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 and X 2 are each independently selected from -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -;
  • Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 -C 8 cycloalkyl, Halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl;
  • Z is selected from O or (CH 2 ) p , p is an integer of 1-6;
  • R 3 is C 1- C 8 alkyl, C 3- C 8 cycloalkyl, C 3- C 8 cycloalkenyl, C 2- C 8 alkenyl or C 2- C 8 alkynyl, wherein said C 1- C 8 alkyl, C 3- C 8 cycloalkyl, C 3- C 8 cycloalkenyl, C 2- C 8 alkenyl or C 2- C 8 alkynyl can be selected from one or more Halogen, nitro, cyano, amino or hydroxyl substituted.
  • Ring A is a benzene ring or a 5-8 membered heterocycle containing 1-2 heteroatoms selected from N, O or S;
  • Each R 1 is independently selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 - C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkanoyl, C 1 -C 8 alkylsulfonyl, aminosulfonyl, halogen Substituted C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl, halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 Heterocycloalkyl, halogenated C 2 -C 8 heterocycloalkoxy;
  • R 2 are each independently selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 - C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl, Halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkyl, halogenated C 2 -C 8 heterocycloalkoxy;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, C 2 -C 8 heterocycloalkyl, C 2 -C 8 heterocycloalkoxy, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl, halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkyl, halogenated C 2 -C 8 heterocycloalkoxy;
  • n is selected from 0, 1, 2;
  • n is selected from 0, 1, 2, 3, 4, 5;
  • X 1 and X 2 are each independently selected from -CRaRb, -NRa, -O-, -C(O)-, -S-, -S(O)-, -S(O) 2 -;
  • Ra and Rb are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 C 8 cycloalkyl, halogen Substituted C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkyl;
  • Z is selected from O or (CH 2 ) p , p is an integer of 1-6;
  • R 3 is C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, wherein said C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl can be selected from one or more Halogen, nitro, cyano, amino or hydroxyl substituted;
  • X 1 X 2
  • X 1 and X 2 are each independently selected from -CRa-, -N-;
  • R 1 is selected from C 1 -C 8 alkoxy, C 3 -C 8 cycloalkoxy, C 2 -C 8 heterocycloalkoxy, C 1 -C 8 alkylthio, C 1 -C 8 alkanoyl, C 1 -C 8 alkylsulfonyl, aminosulfonyl, halogenated C 1 -C 8 alkoxy, halogenated C 3 -C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkoxy;
  • n and m are greater than 1, it is multi-substituted.
  • multiple substituents can be substituted on one carbon atom, or can be substituted on multiple atoms of the corresponding ring structure; and multiple substituents Can be the same or different.
  • the two substituents and the carbon atom to which they are bonded can jointly form a C 3 -C 6 cycloalkyl group.
  • ring A is a benzene ring or a 5-membered heterocyclic ring containing 1-2 heteroatoms selected from N, O or S.
  • R 1 is selected from H, C 1- C 5 alkoxy, C 1- C 5 alkenyloxy, halogenated C 1- C 5 alkoxy, C 3- C 6 cycloalkyl, C 3- C 6 cycloalkoxy, C 3 -C 4 heterocycloalkyl, C 3 -C 4 heterocycloalkoxy, C 1- C 4 alkylthio, halogen, C 1- C 4 alkylsulfonyl, R 1 can be further replaced by one or more halogen, C 1- C 3 alkyl, halogenated C 1- C 3 alkyl, C 1- C 3 alkoxy, halogenated C 1- C 3 alkoxy, spiroane base substitution.
  • R 1 is selected from H, C 1- C 4 alkoxy, halogenated C 1- C 4 alkoxy, C 3- C 6 cycloalkyl, C 3 -C 4 heterocycloalkyl, C 1 - C 4 alkylthio, halogen, C 1- C 4 alkylsulfonyl.
  • R is further preferably H, F, Cl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, difluoromethoxy, trifluoro Methoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, hexafluoroisopropoxy, trifluorobutoxy, cyclopropanoxy, cyclobutanyloxy, cyclopentane Oxygen, cyclohexaneoxy, oxetanyloxy, methylthio, methylsulfonyl,
  • each R 2 is independently selected from hydrogen, halogen, and C 1- C 3 alkyl.
  • R 2 is H, methyl.
  • R2 is H or a methyl substituent on X1 .
  • R 2 is H or a methyl group or two methyl substituents on X 1 or two methyl groups and X 1 form a cycloalkyl group.
  • R 3 is C 1- C 5 alkyl.
  • R3 is tert-butyl.
  • each of R 4 , R 5 , R 6 and R 7 is independently H, methyl or halogen (more preferably Cl).
  • the R 4 and R 6 are H or Cl; the R 5 and R 7 are methyl.
  • Z is (CH 2 ) p , more preferably -CH 2 -.
  • preferred compounds of the present invention have structures of general formula IIa, IIb, IIc:
  • X3 is N, O, S.
  • R 1 is selected from C 1-8 alkoxy, C 3-8 cycloalkoxy, C 2 -C 8 heterocycloalkoxy, C 1- C 8 alkylthio, C 1- C 8 alkylsulfonyl , halogenated C 1-8 alkoxy, halogenated C 3-8 cycloalkoxy;
  • n is selected from 1.
  • R 1 is selected from C 1-6 alkoxy, C 3-6 cycloalkoxy, C 2 -C 6 heterocycloalkoxy, C 1- C 3 alkylthio, C 1- C 3 alkylsulfonyl , halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkoxy.
  • X 1 and X 2 is a double bond or a single bond
  • n is selected from 2;
  • R 1 is selected from: halogen, C 1- C 8 alkyl, C 1- C 8 alkoxy, C 3- C 8 cycloalkyl, C 3- C 8 cycloalkoxy, C 2 -C 8 heterocycle Alkyl, C 2 -C 8 heterocycloalkoxy, C 1- C 8 alkylthio, C 1- C 8 alkanoyl, C 1- C 8 alkylsulfonyl, aminosulfonyl, halogenated C 1- C 8 alkyl, halogenated C 1- C 8 alkoxy, halogenated C 3- C 8 cycloalkyl, halogenated C 3- C 8 cycloalkoxy, halogenated C 2 -C 8 heterocycloalkyl , Halogenated C 2 -C 8 heterocycloalkoxy.
  • R 1 is selected from halogen, C 1-8 alkoxy, C 3-8 cycloalkoxy, C 2 -C 8 heterocycloalkoxy, C 1- C 8 alkylthio, C 1- C 8 alkyl Sulfonyl, halogenated C 1-8 alkoxy, halogenated C 3-8 cycloalkoxy;
  • n is selected from 2.
  • R 1 is selected from halogen, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 2 -C 6 heterocycloalkoxy, C 1- C 3 alkylthio, C 1- C 3 alkyl Sulfonyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkoxy.
  • X 1 and X 2 are CH 2 with a single bond between them; R 4 and R 6 are H; R 5 and R 7 are methyl;
  • n is selected from 2, 3, 4, 5;
  • R2 is not selected from hydrogen.
  • R 6 is Cl; at least two of R 4 , R 5 and R 7 are not selected from hydrogen.
  • the compound has a structure shown in general formula Va:
  • R 1 ' is H, F
  • the compound is selected from the following compounds or their stereoisomers or their stereoisomer mixtures or pharmaceutically acceptable salts thereof:
  • the compound is the following compound:
  • Substituted means that a hydrogen atom is replaced by a substituent. Note that the substituents on a particular atom are restricted by its valence.
  • C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes.
  • the C, H, O, S, N, F, Cl, Br, and I involved in the groups and compounds of the present invention may optionally be substituted by one or more of their corresponding isotopes, including but not limited to Carbon isotopes 12 C, 13 C, 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O, 17 O, 18 O, sulfur isotopes 32 S, 33 S , 34 S, 36 S, nitrogen isotopes 14 N, 15 N, fluorine isotopes 17 F, 19 F, chlorine isotopes 35 Cl, 37 Cl, bromine isotopes 79 Br, 81 Br, etc.
  • alkyl used in the present invention refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 8 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl Base, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, pentyl, n-hexyl, isohexyl, neohexyl, heptyl, isoheptyl, neoheptyl, octane base, isooctyl, etc.
  • the alkyl group can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, amino Alkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 - C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, cycloalkenyl
  • Alkenyl can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halo Hydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, Amide, sulfonamide, spiroalkyl.
  • alkynyl used in the present invention refers to a straight or branched hydrocarbon chain group containing 1 to 8 carbon atoms and at least one C ⁇ C triple bond, including but not limited to ethynyl, 1-propynyl , 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3 -Methyl-1-butynyl, 4-methyl-1-butynyl, 2-methyl-3-butynyl, 1-methyl-4-butynyl, 1-hexynyl, 2 -hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2,2-di
  • the alkynyl group can be substituted by one or more substituents, and the substituents can be the same or different when multiple substitutions are made; the substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halo Hydroxyalkyl, alkylamino, haloalkylamino, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, amino, aminoalkyl, carboxyl, Amide, sulfonamide, spiroalkyl.
  • halogen and "halo" used in the present invention refer to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • cycloalkyl used in the present invention refers to a non-aromatic monovalent hydrocarbon group with 3 to 12 carbon atoms, a monocyclic or polycyclic (two monocyclic rings are connected by a chemical bond or bridged ring or spiro ring or fused) , and one or more of the chemical bonds may be double or triple bonds.
  • Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, octahydroindene, decahydronaphthalene, bicyclo[ 1.1.0] Butyl, Bicyclo [2.1.0] Pentyl, Bicyclo [2.2.0] Hexyl, Bicyclo [3.2.0] Heptyl, Bicyclo [4.2.0] Octyl, Bicyclo [ 1.1.1] pentyl, bicyclo [2.1.1] hexane, bicyclo [3.1.1] heptyl, bicyclo [2.2.1] heptyl, bicyclo [4.1.1] octane, bicyclo [ 3.2.1]octyl, bicyclo[3.2.1]octyl, bicyclo[5.1.1]non
  • the cycloalkyl group can be substituted by one or more substituents, and the substituents can be the same or different during multiple substitutions; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, Aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, cycloal
  • Cycloalkenes and cycloalkenyls can be substituted by one or more substituents, and the substituents can be the same or different when multi-substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl , aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, methylsulfone, alkylamido, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino , halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycl
  • heterocyclyl and “heterocycloalkyl” used in the present invention refer to a monocyclic or polycyclic ring with 3 to 15 ring atoms (two monocyclic rings are connected by chemical bonds or bridging rings or spiro rings or fused rings) ), saturated or unsaturated (with one or more double bonds, conjugated or incompletely conjugated) divalent cyclic hydrocarbon groups, with one or more heteroatoms selected from N, O, S.
  • Heterocyclic groups include, but are not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, thienyl, furyl, triazolyl , oxazolyl, imidazolyl, indazolyl, indolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl , Dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, pteridinyl, purinyl, pyranyl, piper Pyridy
  • the heterocyclic group can be substituted by one or more substituents, and the substituents can be the same or different when they are more substituted; the substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, Aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylate, acyl, amido, sulfonyl, alkylamide, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 hydroxyalkyl, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, halogenated C 3 -C 12 cycloalkyl, alkoxycarbony
  • spiroalkyl used in the present invention means that two carbon atoms of an alkyl group are connected to the same carbon atoms of the parent molecular group, thereby forming a 3-12 membered carbocyclic ring.
  • alkoxy refers to alkyl-O-, wherein alkyl is as defined above.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy , 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc.
  • Alkoxy also includes substituted alkoxy, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane Base, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkenyloxy refers to alkenyl-O-, wherein alkenyl is as defined above.
  • alkenyloxy also includes substituted alkenyloxy, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 hydroxyalkane Base, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • cycloalkoxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • examples of "cycloalkoxy” as used in the present invention include, but are not limited to, cyclopropanyloxy, cyclobutanyloxy, cyclopentanyloxy, cyclohexyloxy, cycloheptanyloxy, cyclooctyloxy, Bicyclo[1.1.0]butanyloxy, bicyclo[2.1.0]pentanyloxy, bicyclo[2.2.0]hexyloxy, bicyclo[1.1.1]pentanyloxy, bicyclo[2.1.1] Hexyloxy, etc.
  • Cycloalkoxy also includes substituted cycloalkoxy, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamide, spiroalkyl, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 -C 8 Hydroxyalkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl , C 5 -C 14 heteroaryl.
  • heterocycloalkoxy refers to heterocycloalkyl-O-, wherein heterocycloalkyl is as defined above.
  • heterocycloalkoxy examples include, but are not limited to, oxiraneoxy, oxetanyloxy, oxolanyloxy, oxanyloxy, azepine Propanyloxy, azetidinyloxy, azepanyloxy, azetidinyloxy and the like.
  • Heterocycloalkoxy also includes substituted heterocycloalkoxy, whose substituents can be D, halogen, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, sulfonamido, spiroalkyl , C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, halogenated C 1 -C 8 alkyl, halogenated C 1 - C 8 hydroxyalkyl, halogenated C 1 -C 8 alkoxy, halogenated C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 Aryl, C 5 -C 14 heteroaryl.
  • haloalkyl refers to straight chain or branched chain alkyl substituted by halogen (preferably fluorine, chlorine, bromine, iodine), wherein “alkyl” is as defined above.
  • halogen preferably fluorine, chlorine, bromine, iodine
  • alkyl is as defined above.
  • haloalkyl used in the present invention include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, 1,1,1-trifluoropropan-2-yl, etc.
  • Haloalkyl also includes substituted haloalkyl whose substituents can be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • There may be one or more halogen substituents in "haloalkyl” and the substitution may be on one atom or on different atoms.
  • haloalkoxy refers to haloalkyl-O-, wherein haloalkyl is as defined above.
  • haloalkoxy used in the present invention include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoroethoxy, difluoroethoxy, trifluoroethoxy, Monofluoropropoxy, difluoropropoxy, trifluoropropoxy, tetrafluoropropoxy, trifluoroisopropoxy, tetrafluoroisopropoxy, hexafluoroisopropoxy, monofluorobutoxy , difluorobutoxy, trifluorobutoxy, trifluoro-sec-butoxy, trifluoro-tert-butoxy, trifluoroisobutoxy, hexafluoroisobutoxy, trifluoropentyloxy, tetrafluoropentyl Oxygen, penta
  • Haloalkoxy also includes substituted haloalkoxy, whose substituents can be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aromatic group, C 5 -C 14 heteroaryl.
  • halocycloalkyl refers to a cycloalkyl group substituted by halogen, preferably fluorine, chlorine, bromine, iodine, wherein cycloalkyl is as defined above. There may be one or more halogen substituents in "halocycloalkyl", and the substitution may be on one atom or on different atoms.
  • halocycloalkoxy refers to halocycloalkyl-O-, wherein halocycloalkyl is as defined above.
  • Halocycloalkoxy also includes substituted halocycloalkoxy, whose substituents can be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroalkyl, C1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • haloheterocycloalkyl refers to a heterocycloalkyl group substituted by halogen, preferably fluorine, chlorine, bromine, iodine, wherein heterocycloalkyl is as defined above. There may be one or more halogen substituents in "haloheterocycloalkyl", and the substitution may be on one atom or on different atoms.
  • haloheterocycloalkoxy refers to haloheterocycloalkyl-O-, wherein haloheterocycloalkyl is as defined above.
  • Haloheterocycloalkoxy also includes substituted “haloheterocycloalkoxy” whose substituents can be D, oxo, amino, hydroxyl, cyano, nitro, carboxyl, amido, spiroane C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 3 -C 12 cycloalkyl, C 3 -C 12 Heterocyclyl, C 6 -C 12 aryl, C 5 -C 14 heteroaryl.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • alkanoyl refers to alkyl-C(O)-, wherein alkyl is as defined above.
  • alkylsulfonyl refers to alkyl-S(O) 2- , wherein alkyl is as defined above.
  • aminosulfonyl used in the present invention refers to amino-S(O) 2 -.
  • “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention that can be prepared by methods well known to those skilled in the art.
  • the salt may be a salt formed with an acid or a base, and the like.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, nitric, phosphoric, carbonic, formic, acetic, trifluoroacetic, propionic, oxalic, propionic Diacid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, trifluoromethanesulfonic acid, citric acid, p-toluenesulfonic acid, ethanesulfonic acid, Benzenesulfonic acid, camphorsulfonic acid, lycic acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid,
  • a preferred class of salts are the salts of the compounds of the invention with bases.
  • Bases suitable for forming salts include but are not limited to: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and other inorganic bases, ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, etc. organic base.
  • the second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any one of the above technical schemes.
  • the pharmaceutical composition of the present invention can be composed of one or more of the compounds described in any one of the above technical schemes and other compounds, or one or more of the compounds described in any of the above technical schemes composition.
  • Another object of the present invention is to provide a pharmaceutical preparation comprising one or more of the compounds described in any one of the above.
  • a pharmaceutical preparation comprising one or more of the compounds described in any one of the above.
  • tablets, powders, capsules, injections, granules, and sprays are included.
  • the present invention provides the use of the compounds described in the general formulas I to V disclosed herein or their stereoisomers or mixtures of stereoisomers or pharmaceutically acceptable salts thereof for the treatment of agonistic KCNQ Use in a disease, disorder or condition of benefit.
  • the present invention provides the use of the compounds described in the general formulas I to V disclosed herein in the preparation of drugs for diseases that are sensitive to the increase in ion flow of potassium channels, especially in the preparation of drugs for the treatment of central nervous system diseases. application.
  • the subject in need thereof suffers from cancer including epilepsy, inflammatory pain, neuropathic pain, migraine, neurodegenerative disease, anxiety disorder, stroke, complications from cocaine abuse, nicotine withdrawal syndrome , alcohol withdrawal syndrome, or tinnitus.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention has an obvious activation effect on KCNQ2/3 potassium ions.
  • the inventors of the present invention have confirmed through experiments that the present invention has the effect of significantly inducing a left shift of the half open voltage.
  • the inventors of the present invention have confirmed through experiments that the present invention can significantly inhibit the occurrence of mouse hindlimb rigidity in MES-induced epilepsy in mice.
  • the inventors of the present invention have confirmed through experiments that the compound of the present invention has better intracerebral exposure.
  • Step 1 dissolve 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (1g, 6.17mmol) in 10mL DMF, add cesium carbonate (4.02g, 12.33mmol), add iodomethane at 0°C (1.31g, 9.25mmol), reacted at 80°C for 2h.
  • the reaction was completed, cooled to room temperature, added 30mL of water, extracted with ethyl acetate, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, concentrated under reduced pressure, a large amount of white solids were precipitated, suction filtered, and the filter cake was dried to obtain the crude product.
  • Step 2 Dissolve intermediate 001-1 (1 g, 5.67 mmol) in 10 mL of concentrated hydrochloric acid, slowly add sodium azide (737.86 mg, 11.35 mmol) at 0°C, gradually return to room temperature, and react for 6 h. After the reaction is completed, slowly add saturated potassium carbonate aqueous solution to make the pH of the system around 8, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain intermediate 001-2:7 by silica gel column chromatography -Methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (0.52 mg), yield 48%.
  • Step 3 the intermediate 001-2 (250mg, 1.31mmol) was dissolved in 1mL of tetrahydrofuran, lithium aluminum tetrahydride (2.6mL, 5.23mmol, 2M in THF) was slowly added dropwise at 0°C, the temperature was raised to reflux, and the reaction was carried out for 4h. After the reaction is over, slowly add water dropwise until the system stops bubbling. After concentrating under reduced pressure, dissolve the residue with ethyl acetate and concentrate under reduced pressure to obtain intermediate 001-3: 7-methoxy-2,3,4 , 5-tetrahydro-1H-benzo[c]azepine (200mg), yield 86%.
  • Step 4 Dissolve intermediate 001-3 (100mg, 0.56mmol) in 2mL 1,4-dioxane, add N-(2,6-dimethyl-4-bromophenyl)-3 in sequence, 3-Dimethylbutanamide (252.38mg, 0.84mmol), Pd 2 (dba) 3 (25.83mg, 0.02mmol), XPhos (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl Biphenyl) (26.90mg, 0.05mmol), sodium tert-butoxide (162.66mg, 1.69mmol), after nitrogen replacement, react at 80°C for 2h.
  • Step 1 dissolve 6-hydroxy-3,4-dihydro-2H-1-naphthone (2g, 12.33mmol) in 10mL DMF, add potassium iodide (2.07g, 12.45mmol), tetrabutylammonium iodide (4.78g, 12.45mmol), sodium difluorobromoacetate (2.45g, 12.45mmol), cesium carbonate (8.04g, 24.66mmol), react overnight at 100°C.
  • Step 1 6-hydroxy-3,4-dihydro-2H-1-naphthone (0.8g, 5mmol) was dissolved in 10mL of anhydrous DMF, potassium carbonate (0.83g, 6mmol) and S-(trifluoro Methyl) dibenzothiophene trifluoromethanesulfonate (2.4g, 6mmol), stirred at room temperature for about 12 hours.
  • Step 1 dissolve 6-hydroxy-3,4-dihydro-2H-1-naphthone (2g, 12.33mmol) in 15mL DMF, add cesium carbonate (20.09g, 61.66mmol) successively, tri-toluenesulfonate Fluoroethyl ester (31.35g, 123.31mmol), react overnight at 100°C. After the reaction was completed, it was lowered to room temperature, diluted with ethyl acetate, and suction filtered. The organic phase was washed twice with saturated sodium bicarbonate, twice with saturated ammonium chloride, concentrated under reduced pressure, and obtained the product 6-(2) through silica gel column chromatography. ,2,2-trifluoroethoxy)-3,4-dihydronaphthalene-1(2H)-one (1.6g), yield 52%. LC-MS (ESI-MS): 245 [M+H] + .
  • Step 1 dissolve 6-fluoro-3,4-dihydronaphthalene-1(2H)-one (420mg, 2.56mmol) in 10mL of acetonitrile, add cesium carbonate (1.67g, 5.12mmol), trifluoroisopropyl Alcohol (583.61 mg, 5.12 mmol), reflux overnight. After the reaction was completed, it was lowered to room temperature, diluted with ethyl acetate, filtered with suction, concentrated under reduced pressure, and obtained intermediate 008-1 through silica gel column chromatography: 6-((1,1,1-trifluoropropan-2-yl)oxy base)-3,4-dihydronaphthalen-1(2H)-one (340mg), yield 51%.
  • Step 2 the intermediate 008-1 (1.47g, 5.67mmol) was dissolved in 10mL of concentrated hydrochloric acid, and sodium azide (737.86mg, 11.35mmol) was slowly added at 0°C, gradually returned to room temperature, and reacted for 6h.
  • Step 3 Dissolve intermediate 008-2 (274mg, 1.0mmol) in 1mL of tetrahydrofuran, slowly add lithium aluminum hydride (2.6mL, 5.23mmol, 2M in THF) dropwise at 0°C, raise the temperature to reflux, and react for 4h. After the reaction is completed, slowly add water dropwise until the system stops bubbling.
  • lithium aluminum hydride 2.6mL, 5.23mmol, 2M in THF
  • intermediate 008-3 7-((1,1,1-tri Fluoropropan-2-yl)oxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine, LC-MS (ESI-MS): 260[M+H] + .
  • Step 4 Dissolve intermediate 008-3 (130mg, 0.50mmol) in 2mL 4-dioxane, add N-(4-bromo-2,6-dimethylphenyl)-3,3- Dimethylbutanamide (252.38mg, 0.84mmol), Pd 2 (dba) 3 (25.83mg, 0.02mmol), X-Phos (2-dicyclohexylphosphine-2′,4′,6′-triisopropyl Biphenyl) (26.90mg, 0.05mmol), sodium tert-butoxide (162.66mg, 1.69mmol), after nitrogen replacement, react at 80°C for 2h.
  • the target compound 009 (21 mg) can be prepared by replacing methyl iodide with cyclopropane bromide, LC-MS (ESI-MS): 421[M+H] + .
  • the target compound 010 (63 mg) could be prepared by replacing methyl iodide with cyclobutane bromide, LC-MS (ESI-MS): 435[M+H] + .
  • the target compound 011 (52 mg) could be prepared by replacing methyl iodide with cyclopentyl bromide, LC-MS (ESI-MS): 449[M+H] + .
  • the target compound 012 (57 mg) could be prepared by replacing methyl iodide with cyclohexane bromide, LC-MS (ESI-MS): 463[M+H] + .
  • the target compound 013 (22 mg) could be prepared by replacing methyl iodide with 3-bromobutylene oxide, LC-MS (ESI-MS): 437[M+H] + .
  • Step 1 dissolve 6-fluoro-3,4-dihydro-2H-1-naphthone (1.6g) in 15mL of anhydrous DMSO in a reaction flask, add sodium methyl mercaptide (1.1g), and heat up to 50 The reaction was stirred at °C for about 3 hours. Add water to quench the reaction, add dichloromethane and water to extract, the separated dichloromethane phase is dried with anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography to obtain 6-(methylthio)-3,4-dihydro Naphthalene-1(2H)-one (1.1 g), LC-MS (ESI-MS): 193 [M+H] + .
  • Step 1 6-fluoro-4,4-dimethyl-3,4-dihydronaphthalene-1(2H)-one (700mg, reference Adv.Synth.Catal.2019,361,3223 -3227 synthesized) was dissolved in 7mL hydrochloric acid, sodium azide (473.46mg, 7.28mmol) was slowly added at 0°C, gradually returned to room temperature, and reacted for 4h.
  • Step 2 Dissolve intermediate 016-1 (170 mg, 0.82 mmol) in 3 mL of tetrahydrofuran, slowly add lithium aluminum hydride (1.6 mL, 3.28 mmol, 2M in THF) dropwise at 0°C, raise the temperature to reflux, and react for 4 h. After the reaction is over, slowly add water dropwise until the system stops bubbling. After concentrating under reduced pressure, dissolve the residue with ethyl acetate and concentrate under reduced pressure to obtain intermediate 016-2: 7-fluoro-5,5-dimethyl -2,3,4,5-tetrahydro-1H-benzo[c]azepine (150mg), yield 94%.
  • Step 3 N-(2,6-dimethyl-4-bromophenyl)-3,3-dimethylbutyramide (5g, 16.77mmol) was dissolved in 80mL1,4-dioxane, followed by Add pinacol diboronic acid ester (3.41g, 13.41mmol), potassium acetate (4.94g, 50.30mmol), Pd(dppf)Cl 2 (614.62mg, 0.83mmol), replace with nitrogen, and react at 90°C for 3h.
  • Step 4 the intermediate 016-3 (3g, 8.69mmol) was dissolved in 30mL of tetrahydrofuran, 10mL of water and sodium periodate (11.15g, 52.13mmol) were added successively, and reacted overnight at room temperature. After the reaction was completed, water was added until solids were precipitated, filtered, and dried to obtain intermediate 016-4: (3,5-dimethyl-4-(3,3-dimethylbutanylamino))phenylboronic acid (2.0g), Yield 87%.
  • Step 5 Dissolve Intermediate 016-2 (100mg, 0.51mmol) in 5mL of acetonitrile, add Intermediate 016-4 (204.24mg, 0.77mmol), boric acid (63.99mg, 1.03mmol), diisopropylethyl Amine (133.75mg, 1.03mmol) and copper acetate (93.98mg, 0.51mmol) were reacted at 70°C for 3h in an oxygen atmosphere. After the reaction was completed, it was lowered to room temperature, diluted with ethyl acetate, filtered with suction, and the organic phase was washed twice with saturated ammonium chloride, dried and concentrated under reduced pressure.
  • the target compound 016 (70 mg) was obtained by column chromatography with a yield of 32%.
  • the target compound 028 (23 mg) can be prepared, LC-MS (ESI-MS): 395[M+H] + .
  • Step 1 N-(2-methyl-3-fluoro-4-bromophenyl)-3,3-dimethylbutyramide (5g, 16.77mmol) was dissolved in 80mL1,4-dioxane, Add pinacol diboronic acid ester (3.41g, 13.41mmol), potassium acetate (4.94g, 50.30mmol), PdDPPFCl 2 (614.62mg, 0.83mmol) in sequence, replace with nitrogen, and react at 90°C for 3h.
  • Step 2 dissolve 7-fluoro-2,3,4,5-tetrahydro-1H-2-benzazepine (90mg, 0.54mmol) in 5mL acetonitrile, add (3-methyl-2- Fluoro-4-(3,3-dimethylbutanylamino)) phenylboronic acid pinacol ester (190mg, 0.54mmol), boric acid (70mg, 1.09mmol), copper acetate (100mg, 0.54mmol), 80°C in React in an oxygen atmosphere for 6h. After the reaction was completed, it was lowered to room temperature, diluted with ethyl acetate, filtered with suction, and the organic phase was washed twice with saturated ammonium chloride, dried and concentrated under reduced pressure.
  • Step 1 6,7-difluoro-3,4-dihydronaphthalene-1(2H)-one (2.0g, 10.98mmol) was dissolved in 30mL acetonitrile, and trifluoroisopropanol (2.5 mL, 27.45mmol), cesium carbonate (10.7g, 32.94mmol) in sealed tube, reacted at 80°C for 4h.
  • Step 2 the intermediate 034-1 (3.12g, 11.30mmol) was dissolved in 40mL of concentrated hydrochloric acid, and sodium azide (1.47g, 22.60mmol) was slowly added in an ice bath, and reacted at room temperature for 48h. After the reaction was completed, ice water and sodium carbonate aqueous solution were slowly added at low temperature to make the pH of the system alkaline, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and washed by column chromatography (PE/EA).
  • PE/EA column chromatography
  • Step 3 the intermediate 034-2 (400mg, 1.44mmol) was dissolved in 100mL of tetrahydrofuran, and lithium aluminum hydride (1mmol/mL, 13mL) was added, and reacted at 60°C for 2h.
  • Step 4 the intermediate 034-3 (230mg, 0.83mmol) was dissolved in 10mL 1,4-dioxane, and N-(4-bromo-2,6-dimethylphenyl)- 3,3-Dimethylbutanamide (370mg, 1.24mmol), sodium tert-butoxide (244mg, 2.49mmol), cesium carbonate (811mg, 2.49mmol), palladium acetate (19mg, 0.08mmol), Pd2 (dba) 3 (76mg, 0.08mmol), X-Phos (2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl) (79mg, 0.17mmol), replaced with nitrogen, reacted at 105°C for 4h.
  • Step 2 8-fluoro-7-isopropoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (540mg, 2.42mmol) was dissolved in 15mL acetonitrile, and the (4-(3,3-Dimethylbutanylamino)-3,5-dimethylphenyl)boronic acid (1.3g, 4.84mmol), copper acetate (440mg, 2.42mmol), boric acid (300mg, 4.84mmol), DIPEA (940mg, 7.26mmol), replaced with oxygen, and reacted at 60°C for 2h.
  • the target compound 036 (58 mg) could be prepared by replacing the trifluoroisopropanol in Step 1 with (S)-1,1,1-trifluoropropan-2-ol.
  • LC-MS (ESI-MS): 495 [M+H] + .
  • the target compound 037 (50 mg) could be prepared by replacing trifluoroisopropanol in step 1 with (R)-1,1,1-trifluoropropan-2-ol.
  • LC-MS (ESI-MS): 495 [M+H] + .
  • the target compound 038 (47 mg) could be prepared by replacing the trifluoroisopropanol in step 1 with methanol.
  • LC-MS (ESI-MS): 413 [M+H] + .
  • the target compound 039 (62 mg) could be prepared by replacing trifluoroisopropanol with butan-2-ol in Step 1.
  • the target compound 040 (40 mg) could be prepared by replacing the trifluoroisopropanol in Step 1 with (S)-butan-2-ol.
  • the target compound 041 (46 mg) could be prepared by replacing trifluoroisopropanol in Step 1 with (R)-butan-2-ol.
  • LC-MS (ESI-MS): 455 [M+H] + .
  • the target compound 042 (35 mg) could be prepared by replacing the trifluoroisopropanol in step 1 with cyclopropanol.
  • LC-MS (ESI-MS): 439 [M+H] + .
  • the target compound 043 (34 mg) could be prepared by replacing trifluoroisopropanol with cyclobutanol in Step 1.
  • LC-MS (ESI-MS): 453 [M+H] + .
  • the target compound 044 (41 mg) could be prepared by replacing trifluoroisopropanol with cyclopentanol in Step 1.
  • LC-MS (ESI-MS): 467 [M+H] + .
  • the target compound 045 (48 mg) could be prepared by replacing the trifluoroisopropanol in step 1 with cyclohexanol.
  • LC-MS (ESI-MS): 481 [M+H] + .
  • the target compound 048 (37 mg) can be prepared.
  • the target compound 050 can be prepared (50mg).
  • the target compound 053 (46 mg) can be prepared .
  • the target compound 054 (34 mg) could be prepared by replacing trifluoroisopropanol in Step 1 with (1-(trifluoromethyl)cyclopropyl)methanol.
  • LC-MS (ESI-MS): 503 [M+H] + .
  • the target compound 055 (49 mg) could be prepared by replacing the trifluoroisopropanol in step 1 with hexafluoroisopropanol.
  • LC-MS (ESI-MS): 531 [M+H] + .
  • the target compound 056 (62 mg) could be prepared by replacing trifluoroisopropanol in Step 1 with 2-(2,2,2-trifluoroethoxy)ethanol.
  • LC-MS (ESI-MS): 507 [M+H] + .
  • the target compound 057 (53 mg) could be prepared by replacing trifluoroisopropanol in step 1 with tetrafluoropropanol.
  • LC-MS (ESI-MS): 495 [M+H] + .
  • the target compound 058 (48 mg) could be prepared by replacing trifluoroisopropanol in step 1 with trifluoropropanol.
  • LC-MS (ESI-MS): 477 [M+H] + .
  • the target compound 059 (50 mg) can be prepared by replacing trifluoroisopropanol in step 1 with 4-(trifluoromethyl)cyclohexanol.
  • LC-MS (ESI-MS): 531 [M+H] + .
  • the target compound 060 (63 mg) could be prepared by replacing trifluorobutanol with trifluoroisopropanol in Step 1.
  • LC-MS (ESI-MS): 491 [M+H] + .
  • the target compound 063 (45 mg) could be prepared by replacing trifluoroisopropanol in step 1 with 4-fluorobutanol.
  • LC-MS (ESI-MS): 455 [M+H] + .
  • hKCNQ-CHO cells were cultured at 37°C in a humidified environment of 5% CO 2 .
  • Extracellular fluid NaCl 145, KCl 4, CaCl 2 2, MgCl 2 1, Glucose 10, HEPES 10.
  • the pH value of the extracellular fluid was adjusted to 7.4 with NaOH, and the osmotic pressure was adjusted to about 295mOsm.
  • Intracellular fluid mM (mmol/L): KOH 31.25, KCl 120, EGTA 10, MgCl 2 1.75, CaCl 2 5.374, HEPES 10, Na-ATP 4.
  • the pH value of the intracellular fluid was adjusted to 7.4 with HCl, and the osmotic pressure was adjusted to about 285mOsm.
  • the extracellular solution needs to be prepared once a week, and the intracellular solution needs to be stored at -20°C after preparation.
  • the model positive reference compound retigabine (Retigabine, RTG) was dissolved in 100% DMSO and stored as a 10 mM working solution.
  • the compounds to be tested were dissolved in 100% DMSO and stored as 10mM working solution.
  • the final concentration of DMSO in the test solution needs to be less than 0.3%.
  • the recording electrodes were pulled out and polished in a vertical puller (NARISHIGE PC-10, Japan) using a borosilicate glass capillary (GC150tF-10, Harvard Apparatus Co., UK).
  • NARISHIGE PC-10 Japan
  • GC150tF-10 Harvard Apparatus Co., UK
  • the quality control standard is an electrode resistance between 2 and 5 M ⁇ .
  • a continuous perfusion system (BT100-2J, LongerPump, China) was used to continuously perfuse extracellular fluid.
  • the perfusion system was mounted on the stage of an upright microscope (FN-S2N, Nikon, Japan), and the perfusion head was manually positioned under the microscope.
  • the voltage command for hKCNQ current amplitude detection is as follows: the cell steps from the clamping potential of -80mV to -30mV for 1500ms; then the clamping voltage drops to -120mV for 500ms; finally, the voltage returns to the clamping potential of -80mV.
  • the test voltage command is repeated every 15,000 milliseconds, and this command is continuously executed during the compound test.
  • the quality control standard for the stability of compound action is the current amplitude under 5 consecutive voltage commands, and its coefficient of variation is ⁇ 5%. If the compound has no effect on the hKCNQ current amplitude, continuous monitoring is required for 5 minutes.
  • a represents the activation activity of retigabine on KCNQ2/3 potassium ion channel at a concentration of 10 ⁇ M.
  • hKCNQ-CHO cells were cultured at 37°C in a humidified environment of 5% CO 2 .
  • Extracellular fluid (mM): NaCl 145, KCl 4, CaCl 2 2, MgCl 2 1, Glucose 10, HEPES 10.
  • the pH of the extracellular fluid was adjusted to 7.4 with NaOH, and the osmotic pressure was adjusted to about 295mOsm.
  • Intracellular fluid KOH 31.25, KCl 120, EGTA 10, MgCl 2 1.75, CaCl 2 5.374, HEPES 10, Na-ATP 4.
  • the pH of the intracellular fluid was adjusted to 7.4 with HCl, and the osmotic pressure was adjusted to about 285mOsm.
  • the model positive reference compound retigabine (Retigabine, RTG) was dissolved in 100% DMSO and stored as a 10 mM working solution.
  • the compounds to be tested were dissolved in 100% DMSO and stored as 10mM working solution.
  • the final concentration of DMSO in the test solution needs to be less than 0.3%.
  • the recording electrodes were pulled out and polished by a vertical puller (NARISHIGE PC-10, Japan) using a borosilicate glass capillary (GC150tF-10, Harvard Apparatus Co., UK).
  • NARISHIGE PC-10 NARISHIGE PC-10, Japan
  • GC150tF-10 borosilicate glass capillary
  • the quality control standard is an electrode resistance between 2 and 5 M ⁇ .
  • a continuous perfusion system (BT100-2J, LongerPump, China) was used to continuously perfuse extracellular fluid.
  • the perfusion system was mounted on the stage of an upright microscope (FN-S2N, Nikon, Japan), and the perfusion head was manually positioned under the microscope.
  • the voltage command for hKCNQ current amplitude detection is as follows: the cell is stepped from the clamping potential of -80mV to -120mV, and the voltage of each sweep is increased by 10mV to continuously clamp the cell until +60mV for 1500ms; then the clamping voltage drops to -120mV, It lasts for 500ms; finally, the voltage returns to the clamping potential -80mV.
  • the test voltage command is repeated every 15,000 milliseconds, and this command is continuously executed during the compound test.
  • the half voltage of cell hKCNQ needs to be obtained by nonlinear fitting of the current amplitude of cells at different clamping potentials (-120mV to +60mV).
  • Compound Xen-1101 is a reference compound, its structure is: (WO2008024398A2)
  • test results in Table 2 show that the compounds designed in the present invention have the effect of significantly inducing a left shift of the half open voltage.
  • the drug was formulated in proportion (solvent: 5% DMSO+5% Solutol+90% normal saline) to a solution with a concentration of 0.5 mg/mL, and the mice were administered intragastrically at 0.1 mL/10 g, and each point was paralleled 3 times. mice.
  • Example 67 MES mouse epilepsy model
  • mice (10 mice in each group) were transferred to the operation room to adapt to the environment 30 minutes in advance before the experiment.
  • test compound or positive drug sodium valproate, Valproate
  • electrical stimulation was given with ear electrodes.
  • the stimulation parameters were a square wave with a total duration of 0.8 seconds, a frequency of 50 Hz, and an amplitude of 50 mA.
  • the interval of the square wave was 10 msec.
  • test results in Table 4 show that in MES-induced epilepsy in mice, the compound can significantly inhibit the occurrence of mouse hindlimb rigidity.

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Abstract

本发明公开了一种化合物，具有通式Ⅰ所示的结构，或其立体异构体或其药学上可接受的盐或其溶剂合物。本发明同时公开了一种含有上述化合物的组合物、制剂和应用。本发明化合物对KCNQ2/3钾离子具有明显的激活作用，可用于治疗与钾通道离子流相关疾病的用途，特别是治疗中枢神经系统疾病药物方面的应用。

Description

一种钾通道调节剂、组合物及应用 技术领域
本发明属于药物合成和设计技术领域，具体是涉及一类调节钾通道的化合物或其立体异构体、或其药学上可接受的盐、药物组合物及其应用。所述的化合物具有调节钾通道功能，可用于治疗从KCNQ通道开放剂中获益的疾病或障碍。
背景技术
中枢神经系统疾病的治疗一直是医学领域的难题。传统药物无法防治急慢性中枢神经系统损伤、阿尔采末病、帕金森病、癫痫等中枢神经系统疾病。
细胞所处的化学环境跟细胞膜上的离子通道息息相关，离子通道是调节神经元兴奋性的关键，因此离子通道成为治疗中枢神经系统疾病的最直接的靶点。已知大约超过10％的钾离子通道亚型与人类的中枢神经系统疾病相关，体现在许多不同方面，例如从直接控制神经元兴奋性和离子环境的体内平衡到通过代谢的间接作用。
目前共发现KCNQ1～5五种类型，KCNQ钾离子通道是钾离子通道超家族的重要分支，其基因突变与许多遗传性疾病有关。其中，KCNQ1(KvLQT)主要分布于心肌，50％的遗传性LQT综合征与KCNQ1突变有关。KCNQ2和KCNQ3是构成神经细胞M型钾离子通道的分子基础，良性家族性新生儿惊厥症(BFNC)与KCNQ2、KCNQ3基因突变后引起的M电流下调有关。KCNQ4多表达于与听觉有关的神经传导通路、神经核团及内耳毛细胞，遗传性耳聋症(DFNA)与KCNQ4基因突变有关。KCNQ5多表达于肌肉组织。
KCNQ钾通道开放剂成为抗癫痫药物研究的新方向。瑞替加滨在2011年6月被美国FDA批准上市，作为治疗顽固性癫痫的部分发作，其体内体外的优异表现和成功上市证明KCNQ钾通道作为药物靶点具有重要意义。并且，体内外研究表明，瑞替加滨对焦虑、脑卒中、神经变性疾病、疼痛中也具有潜在的治疗作用。同时，由于KCNQ钾通道生理功能广泛，其开放剂在众多疾病的治疗领域也具有十分广阔的应用前景。
发明内容
本发明的目的是提供一种新颖的具有调节钾通道功能的化合物或其药学上可接受的盐或溶剂合物。
本发明还提供了一种包括上述化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐的药物组合物。
本发明同时提供了一种上述化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐用于制备治疗从KCNQ通道开放剂中获益的疾病、障碍或病症的药物中的应用。
本发明的所述化合物对治疗和预防受钾离子通道活性影响的疾病和病症有效果，可用于治疗多种疾病、障碍。
为实现上述目的，本发明提供了如I式所示的化合物，
Figure PCTCN2022115057-appb-000001
或其立体异构体，或其药学上可接受的盐；
其中：
环A为苯环或者含有1-2选自N、O或S杂原子的5-8元杂环；
R 1选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烯基、C 1-C 8烯氧基、螺烷基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烯氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基，所述的烷基、烷氧基、烯基、烯氧基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、烷硫基、烷酰基、烷基磺酰基、氨基磺酰基可进一步的被R 8取代；
R 2各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
或者两个R 2连接同一个原子，两个R 2可以不相同或者相同，与它们连接的原子形成3～6元环或者3～6元杂环；
R 4、R 5、R 6、R 7、R 8各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基、螺烷基；
n选自0、1、2；
m选自0、1、2、3、4、5；
X 1和X 2各自独立的选自-CRaRb、-NRa、-O-、-C(O)-、-S-、-S(O)-、-S(O) 2-；
Ra、Rb各自独立的选自氢、卤素、羟基、氨基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 8环烷基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基；
Figure PCTCN2022115057-appb-000002
表示化学键存在或者不存在；
Z选自O或者(CH 2) p，p为1-6的整数；
R 3为C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基，其中 所述的C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基可被一个或者多个选自卤素、硝基、氰基、胺基或者羟基所取代。
进一步地，本发明优选的化合物，具有通式I的结构：
或其立体异构体，或其药学上可接受的盐；
其中：
环A为苯环或者含有1-2选自N、O或S杂原子的5-8元杂环；
R 1各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
R 2各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
R 4、R 5、R 6、R 7各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
n选自0、1、2；
m选自0、1、2、3、4、5；
X 1和X 2各自独立的选自-CRaRb、-NRa、-O-、-C(O)-、-S-、-S(O)-、-S(O) 2-；
Ra、Rb各自独立的选自氢、卤素、羟基、氨基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3C 8环烷基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基；
Figure PCTCN2022115057-appb-000003
表示化学键存在或者不存在；
Z选自O或者(CH 2) p，p为1-6的整数；
R 3为C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基，其中所述的C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基可被一个或者多个选自卤素、硝基、氰基、胺基或者羟基所取代；
当
Figure PCTCN2022115057-appb-000004
表示为X 1＝X 2，X 1、X 2各自独立的选自-CRa-、-N-；
当
Figure PCTCN2022115057-appb-000005
表示为X 1-X 2，且当R 4、R 5、R 6、R 7均不选自氯，且当X 1为CH或O，R 2为H，且当A环为苯环，R 1选自C 1-C 8烷氧基、C 3-C 8环烷氧基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷氧基；
当
Figure PCTCN2022115057-appb-000006
表示为X 1-X 2，且当R 4、R 5、R 6、R 7均不选自氯，且当A环为噻吩环，m选自2、3、4、5，R 2不选自氢。
本发明中，n、m大于1时，为多取代，此时多个取代基可以在一个碳原子上取 代，也可以在对应环结构的多个原子上取代；且多取代时多个取代基可以相同，也可以不相同。当两个取代基连接在同一个碳原子上时，两个取代基与它们结合的碳原子可以共同形成C 3-C 6环烷基。
作为优选，环A为苯环或者含有1-2选自N、O或S杂原子的5元杂环。
作为优选，R 1选自H、C 1-C 5烷氧基、C 1-C 5烯氧基、卤代C 1-C 5烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、C 3-C 4杂环烷基、C 3-C 4杂环烷氧基、C 1-C 4烷硫基、卤素、C 1-C 4烷基磺酰基，R 1可进一步被一个或多个卤素、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷氧基、螺烷基取代。优选为，R 1选自H、C 1-C 4烷氧基、卤代C 1-C 4烷氧基、C 3-C 6环烷基、C 3-C 4杂环烷基、C 1-C 4烷硫基、卤素、C 1-C 4烷基磺酰基。R 1进一步优选为H、F、Cl、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、三氟丙氧基、三氟异丙氧基、六氟异丙氧基、三氟丁氧基、环丙烷氧基、环丁烷氧基、环戊烷氧基、环己烷氧基、氧杂环丁烷氧基、甲硫基、甲磺酰基、
Figure PCTCN2022115057-appb-000007
Figure PCTCN2022115057-appb-000008
作为优选，R 2各自独立的选自氢、卤素、C 1-C 3烷基。作为进一步优选，R 2为H、甲基。作为更进一步优选，R 2为H或在X 1上的甲基取代基。作为更具体的优选，R 2为H或在X 1上的一个甲基或两个甲基取代基或两个甲基与X 1形成环烷基。
作为优选，R 3为C 1-C 5烷基。作为进一步优选，R 3为叔丁基。
作为优选，所述R 4、R 5、R 6、R 7各自独立的H、甲基、卤素(进一步优选为Cl)。作为进一步优选，所述R 4、R 6为H或Cl；所述R 5、R 7为甲基。
作为优选，Z为(CH 2) p，进一步优选为-CH 2-。
更进一步地，本发明优选地化合物，具有通式Ⅱa、IIb、IIc的结构：
Figure PCTCN2022115057-appb-000009
或其立体异构体或其药学上可接受的盐；
上述通式中X 1、X 2之间为双键或者单键。
作为优选，X 3为N、O、S。
进一步地，本发明优选的化合物，具有通式III的结构：
Figure PCTCN2022115057-appb-000010
或其立体异构体或其药学上可接受的盐或其溶剂合物；
R 1选自C 1-8烷氧基、C 3-8环烷氧基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷基磺酰基、卤代C 1-8烷氧基、卤代C 3-8环烷氧基；
n选自1。
更进一步地，本发明优选的化合物，通式IV中：
Figure PCTCN2022115057-appb-000011
或其立体异构体或其药学上可接受的盐；
R 1选自C 1-6烷氧基、C 3-6环烷氧基、C 2-C 6杂环烷氧基、C 1-C 3烷硫基、C 1-C 3烷基磺酰基、卤代C 1-6烷氧基、卤代C 3-6环烷氧基。
进一步地，本发明优选的化合物，通式IIc-2中：
Figure PCTCN2022115057-appb-000012
或其立体异构体或其药学上可接受的盐；
X 1、X 2之间为双键或者单键；
n选自2；
R 1选自：卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基。
进一步地，本发明优选的化合物，通式III中：
Figure PCTCN2022115057-appb-000013
或其立体异构体或其药学上可接受的盐；
R 1选自卤素、C 1-8烷氧基、C 3-8环烷氧基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷基磺酰基、卤代C 1-8烷氧基、卤代C 3-8环烷氧基；
n选自2。
进一步地，本发明优选的化合物，具有通式V所示的结构：
Figure PCTCN2022115057-appb-000014
或其立体异构体或其药学上可接受的盐；
R 1选自卤素、C 1-6烷氧基、C 3-6环烷氧基、C 2-C 6杂环烷氧基、C 1-C 3烷硫基、C 1-C 3烷基磺酰基、卤代C 1-6烷氧基、卤代C 3-6环烷氧基。
更进一步地，本发明优选的化合物，通式Ⅱa～IIc或IIc-2中：
X 1、X 2为CH 2，两者之间为单键；R 4和R 6为H；R 5和R 7为甲基；
m选自2、3、4、5；
R 2不选自氢。
进一步地，本发明优选的化合物，通式Ⅱa～IIc或IIc-2中：
R 6为Cl；R 4、R 5、R 7至少两个不选自氢。
作为优选，所述化合物具有通式Va所示的结构：
Figure PCTCN2022115057-appb-000015
R 1’为H、F；
R 1为
Figure PCTCN2022115057-appb-000016
作为优选，所述的化合物选自下列化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐：
Figure PCTCN2022115057-appb-000017
Figure PCTCN2022115057-appb-000018
Figure PCTCN2022115057-appb-000019
或其立体异构体、或其药学上可接受的盐。
作为优选，所述化合物为如下化合物：
N-(4-(7-甲氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(001)
N-(4-(7-乙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(002)
N-(4-(7-异丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(003)
N-(4-(7-(仲丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(004)
N-(4-(7-(二氟甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(005)
N-(2,6-二甲基-4-(7-(三氟甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(006)
N-(2,6-二甲基-4-(7-(2,2,2-三氟乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯 基)-3,3-二甲基丁酰胺(007)
N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(008)
N-(4-(7-环丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(009)
N-(4-(7-环丁氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(010)
N-(4-(7-(环戊氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(011)
N-(4-(7-(环己基氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(012)
N-(2,6-二甲基-4-(7-(氧杂环丁烷-3-基-氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(013)
N-(2,6-二甲基-4-(7-(甲硫基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(014)
N-(2,6-二甲基-4-(7-(甲基磺酰基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(015)
N-(4-(7-氟-5,5-二甲基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(016)
N-(4-(5,5-二甲基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(017)
N-(4-(2-氯-8,8-二甲基-4,6,7,8-四氢-5H-噻吩并[3,2-c]氮杂卓-5-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(018)
N-(4-(8,8-二甲基-4,6,7,8-四氢-5H-噻吩并[3,2-c]氮杂卓-5-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(019)
N-(4-(2-氯-4,4-二甲基-4,5,6,8-四氢-7H-噻吩并[2,3-c]氮杂卓-7-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(020)
N-(4-(4,4-二甲基-4,5,6,8-四氢-7H-噻吩并[2,3-c]氮杂卓-7-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(021)
N-(4-(7-氟-3,4-二氢螺环[苯并[c]氮杂卓-5,1'-环丙烷]-2(1H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(022)
N-(4-(8-氟-1,2,3,5-四氢-4H-苯并[e][1,4]二氮杂卓-4-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(023)
N-(4-(8-氟-1-甲基-1,2,3,5-四氢-4H-苯并[e][1,4]二氮杂卓-4-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(024)
N-(4-(8-氟-2,3-二氢苯并[f][1,4]硫氮杂卓-4(5H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(025)
N-(4-(8-氟-1,1-二氧代-2,3-二氢苯并[f][1,4]硫氮杂卓-4(5H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(026)
N-(4-(7-氟-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(027)
N-(4-(7-氟-5-甲基-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(028)
N-(3-氟-4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2-甲基苯基)-3,3-二甲基丁酰胺(029)
N-(4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,3,6-三甲基苯基)-3,3-二甲基丁酰胺(030)
N-(3-氯-4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(031)
(R)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(032)
(S)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(033)
(R)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(032)
(S)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(033)
N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(034)
N-(4-(8-氟-7-异丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(035)
(S)-N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(036)
(R)-N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(037)
N-(4-(8-氟-7-甲氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(038)
N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3，3-二甲基丁酰胺(039)
(S)-N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(040)
(R)-N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(041)
N-(4-(7-环丙氧基-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3- 二甲基丁酰胺(042)
N-(4-(7-环丁氧基-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(043)
N-(4-(7-(环戊氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(044)
N-(4-(7-(环己氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(045)
N-(4-(7,8-二氟-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(046)
N-(4-(7,8-二氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(047)
N-(3-氯-4-(7,8-二氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(048)
N-(4-(7,8-二氟-3,4-二氢螺环[苯并[c]氮杂卓-5,1'-环丙烷]-2(1H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(049)
(E)-N-(2,6-二甲基-4-(7-((4,4,4-三氟丁-2-烯-1-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(050)
N-(4-(7-((3-(二氟甲基)双环[1.1.1]戊烷-1-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(051)
N-(2,6-二甲基-4-(7-(2,2,2-三氟-1-甲氧基乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(052)
N-(2,6-二甲基-4-(7-(3,3,3-三氟-2-甲基丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(053)
N-(2,6-二甲基-4-(7-((1-(三氟甲基)环丙基)甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(054)
N-(4-(7-((1,1,1,3,3,3-六氟丙-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(055)
N-(2,6-二甲基-4-(7-(2-(2,2,2-三氟乙氧基)乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(056)
N-(2,6-二甲基-4-(7-(2,2,3,3-四氟丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(057)
N-(2,6-二甲基-4-(7-(3,3,3-三氟丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(058)
N-(2,6-二甲基-4-(7-((4-(三氟甲基)环己基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(059)
N-(2,6-二甲基-4-(7-(4,4,4-三氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(060)
N-(2,6-二甲基-4-(7-((4,4,5,5,5-五氟戊基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(061)
N-(2,6-二甲基-4-(7-(2,2,4,4,4-五氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(062)
N-(4-(7-(4-氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(063)
术语说明
除非另有定义，本发明使用的所有技术和科学术语与该领域专业人员通常理解的含义相同。除非另有说明，本发明参考的所有专利文献、公开披露的资料等全文纳入参考文献。如本发明中同一术语有多个定义，以本节中的定义为准。
需要理解的是，前文的一般描述和后文的详细描述仅仅是示范性的和解释性的，对任何权利要求都无限制性。需要注意的是，说明书和所附权利要求书中，除非文中另有说明，单数形式指代如“一”、“一个”、“这个”，包含复数指代。还需注意的是，除非另有说明，“或”代表“和/或”。此外，“包含”、“包括”等类似术语不是限制性的。
“取代”是指氢原子被取代基取代。需要注意的是，特定原子上的取代基是被其价态限制的。在定义部分，“C i-C j”、“C i- j”包括起点和终点的范围，其中i和j都是整数，表示碳原子的数目。例如，C 1-C 4，C 1-C 8，C 3-C 8，C 1-6，C 3-6等。
本发明所述基团和化合物中所涉及的C、H、O、S、N、F、Cl、Br、I等均包括它们的同位素情况。同时，本发明所述基团和化合物中所涉及的C、H、O、S、N、F、Cl、Br、I可任选的被一个或多个它们对应的同位素取代，包括但不限于碳的同位素 12C、 13C、 14C，氢的同位素氕(H)、氘(D)、氚(T)，氧的同位素 16O、 17O、 18O，硫的同位素 32S、 33S、 34S、 36S，氮的同位素 14N、 15N，氟的同位素 17F、 19F，氯的同位素 35Cl、 37Cl，溴的同位素 79Br、 81Br等。
本发明所用术语“烷基”是指含有1至8个碳原子的直链或支链的饱和烃基，包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、特戊基、正己基、异己基、新己基、庚烷基、异庚烷基、新庚烷基、辛基、异辛基等。烷基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“烯基”、“链烯基”是指含有1至8个碳原子且含至少一个C＝C双键的直链或支链的烃链基团，包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、 1-甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、1-甲基-2-己烯基、2-甲基-2-己烯基、2-甲基-3-己烯基、3,5-二甲基-2-己烯基、3,3-二甲基-1-戊烯基、3-甲基-2-乙基-1-丁烯基、1-辛烯基、2-辛烯基等。烯基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、烷氨基、卤代烷氨基、环烷基、卤代环烷基、杂环基、芳基、杂芳基、羟基、卤素、氰基、硝基、氨基、氨基烷基、羧基、酰胺基、磺酰胺基、螺烷基。
本发明所用术语“炔基”是指含有1至8个碳原子且含至少一个C≡C叁键的直链或支链的烃链基团，包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、3-甲基-1-丁炔基、4-甲基-1-丁炔基、2-甲基-3-丁炔基、1-甲基-4-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、1-甲基-4-戊炔基、2-甲基-3-戊炔基、2,2-二甲基-4-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、5-庚炔基、2-甲基-3-己炔基、3-甲基-1-己炔基、3,3-二甲基-1-己炔基、4-甲基-1-己炔基等。炔基可被一个或者多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤代羟烷基、烷氨基、卤代烷氨基、环烷基、卤代环烷基、杂环基、芳基、杂芳基、羟基、卤素、氰基、硝基、氨基、氨基烷基、羧基、酰胺基、磺酰胺基、螺烷基。
本发明所用术语“卤素”、“卤代”是指氟、氯、溴和碘，优选氟、氯和溴。
本发明所用术语“环烷基”是指具有3至12个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基，且可有一个或多个化学键为双键或三键。“环烷基”包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、八氢茚、十氢萘、双环[1.1.0]丁烷基、双环[2.1.0]戊烷基、双环[2.2.0]己烷基、双环[3.2.0]庚烷基、双环[4.2.0]辛烷基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[4.1.1]辛烷基、双环[3.2.1]辛烷基、双环[3.2.1]辛烷基、双环[5.1.1]壬烷基、双环[4.2.1]壬烷基、双环[4.3.1]壬烷基、双环[3.2.2]壬烷基、双环[5.2.1]癸烷基、双环[4.2.2]癸烷基、螺环[2.2]戊烷基、螺环[2.3]己烷基、螺环[2.4]庚烷基、螺环[2.5]辛烷基、螺环[2.6]壬烷基、螺环[3.5]壬烷基、螺环[3.4]辛烷基、螺环[3.3]庚烷基、螺环[4.5]癸烷基、螺环[4.4]壬烷基等。环烷基可被一个或多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。
本发明所用术语“环烯基”是指具有3至12个碳原子且至少含有一个C＝C双键的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基，包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环烯基、螺[2.2]戊-1-烯基、螺[2.2]戊-1,4-二烯基、螺[2.3]己-1-烯基、螺[2.3]己-1,4-二烯基、螺[3.3]庚-1-烯基、螺[3.3]庚-1,5-二烯基、螺[3.4]辛-1-烯基、螺[3.4]辛-1,6-二烯基、螺[3.4]辛-5-烯基、螺[3.4]辛-6-烯基、螺[3.4]辛-1-烯基、双环[2.1.1]己-1-烯基、双环[2.1.1]己-2-烯基、双环[3.1.1]庚-1-烯基、双环[3.1.1]庚-2-烯基、双环[2.2.1]庚-1-烯基、双环[2.2.1]庚-2-烯基等。环烯、环烯基可被一个或多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、环烯基、环炔基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 12杂芳基、C 3-C 12杂环基。
本发明所用术语“杂环基”、“杂环烷基”是指具有3至15个环原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)、饱和或不饱和的(具有一个或多个双键，共轭或不完全共轭)的二价环烃基，具有一个及以上选自N、O、S的杂原子。杂环基包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、异恶唑基、异噻唑基、吡唑基、噻唑基、噻吩基、呋喃基、三唑基、恶唑基、咪唑基、吲唑基、吲嗪基、吲哚基、二氢吲哚基、异吲哚啉基、喹啉基、异喹啉基、喹喔啉基、喹唑啉基、二氢喹啉基、四氢喹啉基、二氢异喹啉基、二氢异喹啉基、四氢异喹啉基、噌啉基、蝶啶基、嘌呤基、吡喃基、哌啶基、哌嗪基、吗啉基、二氧六环基、氧杂环丙基、氧杂环丁基、氧杂环己基、氧杂环庚基、氧杂环辛基、氮杂环丙基、氮杂环丁基、氮杂环戊基、氮杂环庚基、氮杂环辛基、硫杂环丁烷基、硫杂环丙烷基、氮杂环辛烷基、氧氮杂
Figure PCTCN2022115057-appb-000020
基、二氮杂
Figure PCTCN2022115057-appb-000021
基、硫氮杂
Figure PCTCN2022115057-appb-000022
基、二氢呋喃基、二氢噻吩基、二氢吡喃基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢噻唑基、四氢咪唑基、六氢哒嗪基、六氢嘧啶基、噻吩并氮杂卓、苯并氮杂卓、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并三唑基、苯并三嗪基、苯并噁二唑基、苯并噁唑基、苯并异噁唑基、咪唑并吡啶基、咪唑并噻唑基、吡咯并吡啶基、噻吩并吡咯基、噻吩并噻吩基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、吡咯并吡咯基、吡咯并嘧啶基、吡咯并哒嗪基、1-氮杂螺[2.2]戊烷基、1-氮杂螺[2.3]己烷基、4-氮杂螺[2.3]己烷基、5-氮杂螺[2.3]己烷基、2-氮杂螺[3.3]庚烷基、2,6-二氮杂螺[3.3]庚烷基、2-氧杂-6-氮杂螺[3.3]庚烷、1-氮杂螺[2.5]辛烷基、2-氮杂螺[3.4]辛烷基、6-氮杂螺[3.4]辛烷基、2,6-二氮杂螺[3.4]辛烷基、2-氮杂螺[3.5]壬烷基、6-氮杂螺[3.5]壬烷基、7-氮杂螺[3.5]壬烷基、2,7-二氮杂螺[3.5]壬烷基、2-氧杂-7-氮杂螺[3.5]壬烷基、1-氮杂螺[4.4]壬烷基、2-氮杂螺[4.4]壬烷基、8-氮杂螺[4.5]癸烷基、2,8-二氮杂螺[4.5]癸烷基、1-氧杂螺[2.2]戊烷基、1-氧杂螺[2.3]己烷基、4-氧杂螺[2.3]己烷基、5-氧杂螺[2.3]己烷基、2-氧杂螺[3.3]庚烷基、 1-氧杂螺[2.5]辛烷基、2-氧杂螺[3.4]辛烷基、6-氧杂螺[3.4]辛烷基、2-氧杂螺[3.5]壬烷基、6-氧杂螺[3.5]壬烷基、7-氧杂螺[3.5]壬烷基、1-氧杂螺[4.4]壬烷基、2-氧杂螺[4.4]壬烷基、8-氧杂螺[4.5]癸烷基、十氢喹啉基、十氢异喹啉基、2-氮杂双环[1.1.1]戊烷基、2-氧杂双环[1.1.1]戊烷基、氮杂双环[2.1.1]己烷基、氧杂双环[2.1.1]己烷基、氮杂双环[3.1.1]庚烷基、氧杂双环[3.1.1]庚烷基、氮杂双环[2.2.1]庚烷基、氮杂双环[4.1.1]辛烷基、氮杂双环[3.2.1]辛烷基、氮杂双环[3.2.1]辛烷基等。杂环基可被一个或多个取代基取代，多取代时取代基可以相同也可以不同；所述取代基独立为D(氘)、氧代、卤素、氰基、硝基、羟基、氨基、氨基烷基、烯基、炔基、羧基、羧酸酯基、酰基、酰胺基、甲砜基、烷基酰胺基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8羟烷基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、卤代C 3-C 12环烷基、烷氧羰基、烷硫基、烷基磺酰基、羟烷基酰胺基、磺酰胺基、螺烷基、C 6-C 12芳基、C 5-C 14杂芳基、C 3-C 12杂环基。根据本文定义，术语“杂环基”可以包括具有至少一个杂原子的芳香族杂环或非芳香族杂环基或脂肪族杂环基。
本发明所用术语“螺烷基”是指烷基的两个碳原子与母体分子基团的同一个个碳原子连接，从而形成3-12元的碳环。
本发明所用术语“烷氧基”是指烷基-O-，其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等。“烷氧基”还包括取代烷氧基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“烯氧基”是指烯基-O-，其中烯基如上所定义。“烯氧基”还包括取代烯氧基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“环烷氧基”是指环烷基-O-，其中环烷基如上所定义。本发明所用“环烷氧基”的实例包括但不限于环丙烷氧基、环丁烷氧基、环戊烷氧基、环己烷氧基、环庚烷氧基、环辛烷氧基、双环[1.1.0]丁烷氧基、双环[2.1.0]戊烷氧基、双环[2.2.0]己烷氧基、双环[1.1.1]戊烷氧基、双环[2.1.1]己烷氧基等。“环烷氧基”还包括取代环烷氧基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“杂环烷氧基”是指杂环烷基-O-，其中杂环烷基如上所定义。本 发明所用“杂环烷氧基”的实例包括但不限于氧杂环丙烷氧基、氧杂环丁烷氧基、氧杂环戊烷氧基、氧杂环己烷氧基、氮杂环丙烷氧基、氮杂环丁烷氧基、氮杂环戊烷氧基、氮杂环己烷氧基等。“杂环烷氧基”还包括取代杂环烷氧基，其取代基可为D、卤素、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、磺酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、卤代C 1-C 8烷基、卤代C 1-C 8羟烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“卤代烷基”是指被卤素(优选为氟、氯、溴、碘)取代的直链或支链烷基，其中“烷基”如上所定义。本发明所用“卤代烷基”的实例包括但不限于氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、2-氟乙基、2-氯乙基、四氟乙基、五氟乙基、1,1,1-三氟丙-2-基等。“卤代烷基”还包括取代的卤代烷基，其取代基可为D、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。“卤代烷基”中卤素取代基可以是一个或多个，可以在一个原子上进行取代，也可以在不同的原子上进行取代。
本发明所用术语“卤代烷氧基”是指卤代烷基-O-，其中卤代烷基如上所定义。本发明所用“卤代烷氧基”的实例包括但不限于一氟甲氧基、二氟甲氧基、三氟甲氧基、一氟乙氧基、二氟乙氧基、三氟乙氧基、一氟丙氧基、二氟丙氧基、三氟丙氧基、四氟丙氧基、三氟异丙氧基、四氟异丙氧基、六氟异丙氧基、一氟丁氧基、二氟丁氧基、三氟丁氧基、三氟仲丁氧基、三氟叔丁氧基、三氟异丁氧基、六氟异丁氧基、三氟戊氧基、四氟戊氧基、五氟戊氧基、三氟异戊氧基、一氯甲氧基、二氯甲氧基、一氯乙氧基、二氯乙基、氯丙基等。“卤代烷氧基”还包括取代的卤代烷氧基，其取代基可为D、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“卤代环烷基”是指被卤素(优选为氟、氯、溴、碘)取代的环烷基基团，其中环烷基如上所定义。“卤代环烷基”中卤素取代基可以是一个或多个，可以在一个原子上进行取代，也可以在不同的原子上进行取代。
本发明所用术语“卤代环烷氧基”是指卤代环烷基-O-，其中卤代环烷基如上所定义。“卤代环烷氧基”还包括取代的卤代环烷氧基，其取代基可为D、氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“卤代杂环烷基”是指被卤素(优选为氟、氯、溴、碘)取代的杂环烷基基团，其中杂环烷基如上所定义。“卤代杂环烷基”中卤素取代基可以是一个或多个，可以在一个原子上进行取代，也可以在不同的原子上进行取代。
本发明所用术语“卤代杂环烷氧基”是指卤代杂环烷基-O-，其中卤代杂环烷基如上所定义。“卤代杂环烷氧基”还包括取代的“卤代杂环烷氧基”，其取代基可为D、 氧代、氨基、羟基、氰基、硝基、羧基、酰胺基、螺烷基、C 1-C 8烷基、C 1-C 8羟烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 12环烷基、C 3-C 12杂环基、C 6-C 12芳基、C 5-C 14杂芳基。
本发明所用术语“烷硫基”是指烷基-S-，其中烷基如上所定义。烷硫基包括但不限于甲硫基、乙硫基、丙硫基、丁硫基等。
本发明所用术语“烷酰基”是指烷基-C(O)-，其中烷基如上所定义。
本发明所用术语“烷基磺酰基”是指烷基-S(O) 2-，其中烷基如上所定义。
本发明所用术语“氨基磺酰基”是指氨基-S(O) 2-。
“药学上可接受的盐”是指采用本领域技术人员所熟知的方法可以制备本发明所述化合物的盐。所述的盐可以是与酸或碱形成的盐等。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、氢碘酸、硫酸、硝酸、磷酸、碳酸等无机酸，甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、三氟甲磺酸、枸橼酸、对甲苯磺酸、乙磺酸、苯磺酸、樟脑磺酸、枸杞酸、异烟酸、水杨酸、抗坏血酸、龙胆酸、葡萄糖酸、丙酮酸、萘磺酸、硬脂酸、苯乙酸、对氨基苯磺酸、羟乙磺酸、双羟萘酸，丹宁酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于：氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱，氨水、三乙胺、二乙胺、哌嗪、胍、二乙醇胺等有机碱。
本发明的第二个目的是提供一种药物组合物，包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述的化合物中的一种或多种与其他化合物组成，或者上述任意一项技术方案所述的化合物中的一种或多种组成。
本发明的另一个目的是提供一种药物制剂，包括上述任意一项所述的化合物的一种或多种。作为优选，包括片剂、粉剂、胶囊、注射制剂、颗粒制剂、喷雾剂。另一方面，本发明提供的是使用本文公开的通式I～通式V所述的化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐治疗从激动KCNQ中获益的疾病、障碍或病症中的应用。
另一方面，本发明提供的是使用本文公开的通式I～通式V所述的化合物在制备治疗对钾通道离子流增加敏感的疾病药物、特别是在制备治疗中枢神经系统疾病药物方面的应用。
在一些实施方式中，有需要的受治疗者罹患癌症包括癫痫、炎症性疼痛、神经性疼痛、偏头痛、神经变性疾病、焦虑障碍、脑卒中、可卡因滥用引起的并发症、尼古丁戒断综合征、酒精戒断综合征或耳鸣。
本发明发明人通过实验证实，本发明化合物对KCNQ2/3钾离子具有明显的激活作用。
本发明发明人通过实验证实，本发明具有显著诱导半数开放电压左移的效应。
本发明发明人通过实验证实，本发明在MES诱导的小鼠癫痫中，可显著性的抑制小鼠后肢强直性的发生。
本发明发明人通过实验证实，本发明化合物具有较好的脑内暴露。
具体实施方式
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围。
实施例1：N-(4-(7-甲氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(001)
Figure PCTCN2022115057-appb-000023
步骤1，将6-羟基-3,4-二氢萘-1(2H)-酮(1g,6.17mmol)溶于10mL DMF中，加入碳酸铯(4.02g,12.33mmol)，0℃加碘甲烷(1.31g,9.25mmol)，80℃反应2h。反应结束，冷却至室温，加入30mL水，用乙酸乙酯萃取，有机相用饱和碳酸氢钠水溶液洗两次，减压浓缩后有大量白色固体析出，抽滤，滤饼干燥得到粗品产物，经硅胶柱层析纯化，得到中间体001-1：6-甲氧基-3,4-二氢萘-1(2H)-酮(1.06g)，收率96％。LC-MS(ESI-MS):177[M+H] +。直接用于下一步。
步骤2，将中间体001-1(1g,5.67mmol)溶于10mL浓盐酸中，0℃缓慢加入叠氮化钠(737.86mg,11.35mmol)，逐渐恢复至室温，反应6h。反应结束，缓慢加入饱和碳酸钾水溶液，使体系pH值在8左右，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经硅胶柱层析得到中间体001-2：7-甲氧基-2,3,4,5-四氢-1H-苯并[c]氮杂卓-1-酮(0.52mg)，收率48％。LC-MS(ESI-MS):192[M+H] +。
步骤3，将中间体001-2(250mg,1.31mmol)溶于1mL四氢呋喃中，0℃缓慢滴加四氢铝锂(2.6mL,5.23mmol,2M in THF)，升温至回流，反应4h。反应结束，缓慢滴加水，至体系不再冒泡止，减压浓缩后，用乙酸乙酯溶解残留物，减压浓缩后得到中间体001-3：7-甲氧基-2,3,4,5-四氢-1H-苯并[c]氮杂卓(200mg)，收率86％。LC-MS(ESI-MS):178[M+H] +。
步骤4，将中间体001-3(100mg,0.56mmol)溶于2mL 1,4-二氧六环中，依次加入N-(2，6-二甲基-4-溴苯基)-3，3-二甲基丁酰胺(252.38mg,0.84mmol)，Pd 2(dba) 3(25.83mg,0.02mmol)，XPhos(2-二环己基磷-2′,4′,6′-三异丙基联苯)(26.90mg,0.05mmol)，叔丁醇钠(162.66mg,1.69mmol)，氮气置换后，80℃反应2h。反应结束，降至室温，抽滤，乙酸乙酯洗涤固体残留物，之后用饱和氯化铵溶液洗三次，浓缩有机相，经硅胶柱层析得到目标化合物001(90mg)，收率40％。LC-MS(ESI-MS):395[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.18(d,J＝8.2Hz,1H),6.67(d,J＝2.4Hz,1H),6.62(dd,J＝8.1,2.6Hz,1H),6.48(s,2H),6.40(brs,1H),4.49(s,2H),3.75(s,3H),3.73–3.70(m,2H),2.95–2.88(m,2H),2.23(s,2H),2.15(s,6H),1.88–1.82(m,2H), 1.12(s,9H).
实施例2：N-(4-(7-乙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(002)
Figure PCTCN2022115057-appb-000024
参考实施例1的合成路线和方法，将碘甲烷替换为溴乙烷，可制备得到目标化合物002(35mg)，LC-MS(ESI-MS):409[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.16(d,J＝8.2Hz,1H),6.66(d,J＝2.5Hz,1H),6.61(dd,J＝8.2,2.6Hz,1H),6.49(d,J＝6.1Hz,2H),6.39(brs,1H),4.48(s,2H),3.97(q,J＝7.0Hz,2H),3.73–3.68(m,2H),2.93–2.87(m,2H),2.23(s,2H),2.14(s,6H),1.88–1.82(m,2H),1.37(t,J＝7.0Hz,3H),1.12(s,9H).
实施例3：N-(4-(7-异丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(003)
Figure PCTCN2022115057-appb-000025
参考实施例1的合成路线和方法，将碘甲烷替换为2-溴丙烷，可制备得到目标化合物003(46mg)，LC-MS(ESI-MS):423[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.15(d,J＝8.2Hz,1H),6.65(d,J＝2.4Hz,1H),6.60(dd,J＝8.2,2.5Hz,1H),6.48(s,2H),6.42(brs,1H),4.51–4.44(m,3H),3.71(d,J＝4.6Hz,2H),2.92–2.85(m,2H),2.23(s,2H),2.14(s,6H),1.85(d,J＝4.3Hz,2H),1.30(d,J＝6.1Hz,6H),1.12(s,9H).
实施例4：N-(4-(7-(仲丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(004)
Figure PCTCN2022115057-appb-000026
参考实施例1的合成路线和方法，将碘甲烷替换为2-溴丁烷，可制备得到目标化合物004(60mg)，LC-MS(ESI-MS):437[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.15(d,J＝8.2Hz,1H),6.65(d,J＝2.4Hz,1H),6.60(dd,J＝8.2,2.5Hz,1H),6.49(d,J＝7.5Hz,2H),6.42(brs,1H),4.49(s,2H),4.22(dd,J＝12.1,6.1Hz,1H),3.75–3.68(m,2H),2.93–2.86(m,2H),2.23(s,2H),2.15(s,6H),1.88–1.80(m,2H),1.75–1.68(m,2H),1.25(s,3H),1.12(s,9H),0.95–0.92(m,3H).
实施例5：N-(4-(7-(二氟甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(005)
Figure PCTCN2022115057-appb-000027
步骤1，将6-羟基-3,4-二氢-2H-1-萘酮(2g,12.33mmol)溶于10mL DMF中，依次加入碘化钾(2.07g,12.45mmol)，四丁基碘化铵(4.78g,12.45mmol)，二氟溴乙酸钠(2.45g,12.45mmol)，碳酸铯(8.04g,24.66mmol)，100℃反应过夜。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和碳酸氢钠洗2次，用饱和氯化铵洗2次，减压浓缩，经硅胶柱层析得到产物6-(二氟甲氧基)-3,4-二氢萘-1(2H)-酮(1.4g)，收率53％。LC-MS(ESI-MS):213[M+H] +。
后续步骤参考实施例1的合成路线和方法，将6-甲氧基-3,4-二氢萘-1(2H)-酮替换为6-(二氟甲氧基)-3,4-二氢萘-1(2H)-酮(1.4g)，可制备得到目标化合物005(28mg)，LC-MS(ESI-MS):431[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.24(d,J＝8.2Hz,1H),6.90–6.83(m,2H),6.47(s,2H),6.44(s,1H),6.41(s,1H),4.53(s,2H),3.77–3.71(m,2H),2.97–2.91(m,2H),2.23(s,2H),2.15(s,6H),1.86(dd,J＝9.9,5.7Hz,2H),1.12(s,9H).
实施例6：N-(2,6-二甲基-4-(7-(三氟甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(006)
Figure PCTCN2022115057-appb-000028
步骤1，将6-羟基-3,4-二氢-2H-1-萘酮(0.8g,5mmol)溶于10mL无水DMF中，加入碳酸钾(0.83g,6mmol)和S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(2.4g,6mmol)，在室温下搅拌反应约12小时。反应完之后加入水和乙酸乙酯萃取，有机相饱和食盐水洗涤后用无水硫酸钠干燥，然后减压浓缩，经硅胶柱层析纯化得到产物6-(三氟甲氧基)-3,4-二氢萘-1(2H)-酮(0.52g)，收率45％，LC-MS(ESI-MS):231[M+H] +。
后续步骤参考实施例1的合成路线和方法，将6-甲氧基-3,4-二氢萘-1(2H)-酮替换为6-(三氟甲氧基)-3,4-二氢萘-1(2H)-酮，可制备得到目标化合物006(22mg)，LC-MS(ESI-MS):449[M+H] +。
实施例7：N-(2,6-二甲基-4-(7-(2,2,2-三氟乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(007)
Figure PCTCN2022115057-appb-000029
步骤1，将6-羟基-3,4-二氢-2H-1-萘酮(2g,12.33mmol)溶于15mL DMF中，依次加入碳酸铯(20.09g,61.66mmol)，对甲苯磺酸三氟乙基酯(31.35g,123.31mmol)，100℃ 反应过夜。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和碳酸氢钠洗2次，用饱和氯化铵洗2次，减压浓缩，经硅胶柱层析得到产物6-(2,2,2-三氟乙氧基)-3,4-二氢萘-1(2H)-酮(1.6g)，收率52％。LC-MS(ESI-MS):245[M+H] +。
后续步骤参考实施例1的合成路线和方法，将6-甲氧基-3,4-二氢萘-1(2H)-酮替换为6-(2,2,2-三氟乙氧基)-3,4-二氢萘-1(2H)-酮，可制备得到目标化合物007(50mg)，LC-MS(ESI-MS):463[M+H] +。
实施例8：N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(008)
Figure PCTCN2022115057-appb-000030
步骤1，将6-氟-3,4-二氢萘-1(2H)-酮(420mg,2.56mmol)溶于10mL乙腈中，依次加入碳酸铯(1.67g,5.12mmol)，三氟异丙醇(583.61mg,5.12mmol)，回流过夜。反应结束，降至室温，乙酸乙酯稀释，抽滤，减压浓缩，经硅胶柱层析得到中间体008-1：6-((1,1,1-三氟丙烷-2-基)氧基)-3,4-二氢萘-1(2H)-酮(340mg)，收率51％。LC-MS(ESI-MS):259[M+H] +。
步骤2，将中间体008-1(1.47g,5.67mmol)溶于10mL浓盐酸中，0℃缓慢加入叠氮化钠(737.86mg,11.35mmol)，逐渐恢复至室温，反应6h。反应结束，缓慢加入饱和碳酸钾水溶液，使体系pH值在8左右，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经硅胶柱层析得到中间体008-2：7-((1,1,1-三氟丙烷-2-基)氧基)-2,3,4,5-四氢-1H-苯并[c]氮杂卓-1-酮。LC-MS(ESI-MS):274[M+H] +。
步骤3，将中间体008-2(274mg,1.0mmol)溶于1mL四氢呋喃中，0℃缓慢滴加四氢铝锂(2.6mL,5.23mmol,2M in THF)，升温至回流，反应4h。反应结束，缓慢滴加水，至体系不再冒泡止，减压浓缩后，用乙酸乙酯溶解残留物，减压浓缩后得到中间体008-3：7-((1,1,1-三氟丙烷-2-基)氧基)-2,3,4,5-四氢-1H-苯并[c]氮杂卓，LC-MS(ESI-MS):260[M+H] +。
步骤4，将中间体008-3(130mg,0.50mmol)溶于2mL 4-二氧六环中，依次加入N-(4-溴-2,6-二甲基苯基)-3，3-二甲基丁酰胺(252.38mg,0.84mmol)，Pd 2(dba) 3(25.83mg,0.02mmol)，X-Phos(2-二环己基磷-2′,4′,6′-三异丙基联苯)(26.90mg,0.05mmol)，叔丁醇钠(162.66mg,1.69mmol)，氮气置换后，80℃反应2h。反应结束，降至室温，抽滤，乙酸乙酯洗涤固体残留物，之后用饱和氯化铵溶液洗三次，浓缩有机相，经硅胶柱层析得到目标化合物008(90mg)。LC-MS(ESI-MS):477[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.19(d,J＝8.2Hz,1H),6.73(d,J＝2.6Hz,1H),6.67(dd,J＝8.2,2.6Hz,1H),6.47(s,2H),6.41(s,1H),4.61–4.53(m,1H),4.49(s,2H),3.72(s,2H),2.96–2.88(m,2H),2.23(s,2H),2.15(s,6H),1.90–1.81(m,2H),1.46(d,J＝6.4Hz,3H),1.12(s,9H).
实施例9：N-(4-(7-环丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯 基)-3,3-二甲基丁酰胺(009)
Figure PCTCN2022115057-appb-000031
参考实施例1的合成路线和方法，将碘甲烷替换为溴代环丙烷，可制备得到目标化合物009(21mg)，LC-MS(ESI-MS):421[M+H] +。
实施例10：N-(4-(7-环丁氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(010)
Figure PCTCN2022115057-appb-000032
参考实施例1的合成路线和方法，将碘甲烷替换为溴代环丁烷，可制备得到目标化合物010(63mg)，LC-MS(ESI-MS):435[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.13(d,J＝8.2Hz,1H),6.59(d,J＝2.4Hz,1H),6.52(dd,J＝8.1,2.6Hz,1H),6.48(d,J＝6.6Hz,2H),6.40(s,1H),4.57(t,J＝7.2Hz,1H),4.48(d,J＝10.8Hz,2H),3.70(d,J＝4.8Hz,2H),2.93–2.84(m,2H),2.45–2.36(m,2H),2.23(s,2H),2.15(s,6H),1.88–1.77(m,4H),1.25(s,2H),1.12(s,9H).
实施例11：N-(4-(7-(环戊氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(011)
Figure PCTCN2022115057-appb-000033
参考实施例1的合成路线和方法，将碘甲烷替换为溴代环戊烷，可制备得到目标化合物011(52mg)，LC-MS(ESI-MS):449[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.14(d,J＝8.2Hz,1H),6.63(d,J＝2.5Hz,1H),6.58(dd,J＝8.2,2.6Hz,1H),6.48(s,2H),6.40(brs,1H),4.71–4.65(m,1H),4.47(s,2H),3.75–3.67(m,2H),2.93–2.86(m,2H),2.23(s,2H),2.15(s,6H),1.89–1.81(m,6H),1.62–1.54(m,4H),1.12(s,9H).
实施例12：N-(4-(7-(环己基氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(012)
Figure PCTCN2022115057-appb-000034
参考实施例1的合成路线和方法，将碘甲烷替换为溴代环己烷，可制备得到目标化合物012(57mg)，LC-MS(ESI-MS):463[M+H] +。
实施例13：N-(2,6-二甲基-4-(7-(氧杂环丁烷-3-基-氧基)-1,3,4,5-四氢-2H-苯并[c] 氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(013)
Figure PCTCN2022115057-appb-000035
参考实施例1的合成路线和方法，将碘甲烷替换为3-溴环氧丁烷，可制备得到目标化合物013(22mg)，LC-MS(ESI-MS):437[M+H] +。
实施例14：N-(2,6-二甲基-4-(7-(甲硫基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(014)
Figure PCTCN2022115057-appb-000036
步骤1，在反应瓶中将6-氟-3,4-二氢-2H-1-萘酮(1.6g)溶解于15mL无水DMSO中，加入甲硫醇钠(1.1g)，升温至50℃搅拌反应约3小时。加水淬灭反应，加入二氯甲烷和水萃取，分离的二氯甲烷相用无水硫酸钠干燥之后浓缩，然后通过硅胶柱层析纯化得到6-(甲硫基)-3,4-二氢萘-1(2H)-酮(1.1g)，LC-MS(ESI-MS):193[M+H] +。
后续步骤参考实施例1的合成路线和方法，将6-甲氧基-3,4-二氢萘-1(2H)-酮替换为6-(甲硫基)-3,4-二氢萘-1(2H)-酮，可制备得到目标化合物014(78mg)，LC-MS(ESI-MS):411[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.18(d,J＝7.6Hz,1H),7.00(d,J＝8.2Hz,2H),6.47(s,2H),6.41(s,1H),4.50(s,2H),3.74–3.69(m,2H),2.95–2.89(m,2H),2.44(s,3H),2.23(s,2H),2.14(s,6H),1.88–1.83(m,2H),1.12(s,9H).
实施例15：N-(2,6-二甲基-4-(7-(甲基磺酰基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(015)
Figure PCTCN2022115057-appb-000037
在反应瓶中将化合物014(30mg)溶解于3mL二氯甲烷中，加入mCPBA(35mg)(3-氯过氧苯甲酸)，在室温下搅拌反应约1小时。然后用亚硫酸钠水溶液淬灭反应，加入二氯甲烷和水萃取，分离的二氯甲烷相用无水硫酸钠干燥之后浓缩，然后通过硅胶柱层析纯化得到化合物015(26mg)，LC-MS(ESI-MS):443[M+H] +。
实施例16：N-(4-(7-氟-5,5-二甲基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(016)
Figure PCTCN2022115057-appb-000038
步骤1，在反应瓶中将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮(700mg,参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)溶于7mL盐酸中，0℃下缓慢加入叠氮化钠(473.46mg,7.28mmol)，逐渐恢复至室温，反应4h。反应结束，缓慢加入饱和碳酸钾水溶液，使体系PH在8左右，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经硅胶柱层析得到中间体016-1：7-氟-5,5-二甲基-2,3,4,5-四氢-1H-苯并[c]氮杂卓-1-酮(360mg)，收率36％。LC-MS(ESI-MS):208[M+H] +。
步骤2，将中间体016-1(170mg,0.82mmol)溶于3mL四氢呋喃中，0℃缓慢滴加四氢铝锂(1.6mL,3.28mmol,2M in THF)，升温至回流，反应4h。反应结束，缓慢滴加水，至体系不再冒泡止，减压浓缩后，用乙酸乙酯溶解残留物，减压浓缩后得到中间体016-2：7-氟-5,5-二甲基-2,3,4,5-四氢-1H-苯并[c]氮杂卓(150mg)，收率94％。LC-MS(ESI-MS):194[M+H] +。
步骤3，将N-(2，6-二甲基-4-溴苯基)-3，3-二甲基丁酰胺(5g,16.77mmol)溶于80mL1，4-二氧六环中，依次加入联硼酸频哪醇酯(3.41g,13.41mmol)，醋酸钾(4.94g,50.30mmol)，Pd(dppf)Cl 2(614.62mg,0.83mmol)，氮气置换，90℃反应3h。反应结束，乙酸乙酯稀释，过滤，有机相用饱和氯化钠水溶液洗1次，干燥并减压浓缩经柱层析得到中间体016-3：(3，5-二甲基-4-(3，3-二甲基丁酰胺基))苯硼酸频哪醇酯(4.30g)，收率74％。LC-MS(ESI-MS):346[M+H] +。
步骤4，将中间体016-3(3g,8.69mmol)溶于30mL四氢呋喃中，依次加入10mL水，高碘酸钠(11.15g,52.13mmol)，室温反应过夜。反应结束，加水至有固体析出，过滤，干燥得到中间体016-4：(3，5-二甲基-4-(3，3-二甲基丁酰胺基))苯硼酸(2.0g)，收率87％。LC-MS(ESI-MS):264[M+H] +。
步骤5，将中间体016-2(100mg,0.51mmol)溶于5mL乙腈中，依次加入中间体016-4(204.24mg,0.77mmol)，硼酸(63.99mg,1.03mmol)，二异丙基乙胺(133.75mg,1.03mmol)，醋酸铜(93.98mg,0.51mmol)，70℃在氧气氛围中反应3h。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和氯化铵洗2次，干燥并减压浓缩，经柱层析得到目标化合物016(70mg)，收率32％。LC-MS(ESI-MS):411[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.22–7.17(m,1H),7.07(dd,J＝11.7,2.6Hz,1H),6.82(td,J＝8.0,2.6Hz,1H),6.43–6.38(m,3H),4.56(s,2H),3.61–3.55(m,2H),2.23(s,2H),2.14(s,6H),2.05–1.98(m,2H),1.33(d,J＝4.0Hz,6H),1.12(s,9H).
实施例17：N-(4-(5,5-二甲基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(017)
Figure PCTCN2022115057-appb-000039
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为4,4-二甲基-3,4-二氢萘-1(2H)-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成 得到)，可制备得到目标化合物017(52mg)，LC-MS(ESI-MS):393[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.39(d,J＝7.0Hz,1H),7.24–7.08(m,3H),6.42(d,J＝5.9Hz,3H),4.59(s,2H),3.60–3.54(m,2H),2.23(s,2H),2.14(s,6H),2.05(t,J＝5.9Hz,2H),1.33(s,6H),1.12(s,9H).
实施例18：N-(4-(2-氯-8,8-二甲基-4,6,7,8-四氢-5H-噻吩并[3,2-c]氮杂卓-5-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(018)
Figure PCTCN2022115057-appb-000040
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为2-氯-7,7-二甲基-6,7-二氢苯并[b]噻吩-4(5H)-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)，可制备得到目标化合物018(28mg)，LC-MS(ESI-MS):433[M+H] +, 1H NMR(400MHz,CDCl 3)δ6.71(s,1H),6.45–6.40(m,3H),4.37(s,2H),3.76–3.70(m,2H),2.25(s,2H),2.16(s,6H),1.90–1.84(m,2H),1.33(s,6H),1.13(s,9H).
实施例19：N-(4-(8,8-二甲基-4,6,7,8-四氢-5H-噻吩并[3,2-c]氮杂卓-5-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(019)
Figure PCTCN2022115057-appb-000041
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为7,7-二甲基-6,7-二氢苯并[b]噻吩-4(5H)-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)，可制备得到目标化合物019(41mg)，LC-MS(ESI-MS):399[M+H] +, 1H NMR(400MHz,CDCl 3)δ6.97(d,J＝5.1Hz,1H),6.90(d,J＝5.1Hz,1H),6.47(s,2H),6.42(brs,1H),4.48(s,2H),3.81–3.76(m,2H),2.24(s,2H),2.15(s,6H),1.91–1.86(m,2H),1.38(s,6H),1.12(s,9H).
实施例20：N-(4-(2-氯-4,4-二甲基-4,5,6,8-四氢-7H-噻吩并[2,3-c]氮杂卓-7-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(020)
Figure PCTCN2022115057-appb-000042
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为2-氯-4,4-二甲基-5,6-二氢苯并[b]噻吩-7(4H)-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)，可制备得到目标化合物020(29mg)，LC-MS(ESI-MS):433[M+H] +, 1H NMR(400MHz,CDCl 3)δ6.73(s,1H),6.49(s,2H),6.44(brs,1H),4.44(s,2H),3.72–3.68(m,2H),2.25(s,2H),2.17(s,6H),1.89–1.83(m,2H),1.24(s,6H),1.13(s,9H).
实施例21：N-(4-(4,4-二甲基-4,5,6,8-四氢-7H-噻吩并[2,3-c]氮杂卓-7-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(021)
Figure PCTCN2022115057-appb-000043
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为4,4-二甲基-5,6-二氢苯并[b]噻吩-7(4H)-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)，可制备得到目标化合物021(18mg)，LC-MS(ESI-MS):399[M+H] +, 1H NMR(400MHz,CDCl 3)δ6.98(d,J＝5.2Hz,1H),6.91(d,J＝5.2Hz,1H),6.53(s,2H),6.42(brs,1H),4.57(s,2H),3.77–3.72(m,2H),2.24(s,2H),2.16(s,6H),1.92–1.88(m,2H),1.28(s,6H),1.12(s,9H).
实施例22：N-(4-(7-氟-3,4-二氢螺环[苯并[c]氮杂卓-5,1'-环丙烷]-2(1H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(022)
Figure PCTCN2022115057-appb-000044
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为7'-氟-2'，3'-二氢-4'H-螺环[环丙烷-1,1'-萘]-4'-酮(参考文献Adv.Synth.Catal.2019,361,3223–3227合成得到)，可制备得到目标化合物022(33mg)，LC-MS(ESI-MS):409[M+H] +, 1H NMR(400MHz,DMSO)δ8.72(s,1H),7.48(dd,J＝8.1,6.2Hz,1H),6.93(ddd,J＝11.0,9.5,2.6Hz,2H),6.54(s,2H),4.67(s,2H),3.78(s,2H),2.15(s,2H),2.05(s,6H),1.65–1.46(m,2H),1.05(s,9H),0.96–0.83(m,4H).
实施例23：N-(4-(8-氟-1,2,3,5-四氢-4H-苯并[e][1,4]二氮杂卓-4-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(023)
Figure PCTCN2022115057-appb-000045
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为7-氟-2,3-二氢喹啉-4(1H)-酮(参考文献Bioorganic Chemistry，2020，99，103800合成得到)，可制备得到目标化合物023(44mg)，LC-MS(ESI-MS):384[M+H] +, 1H NMR(400MHz,CDCl 3)δ7.16(dd,J＝8.2,6.5Hz,1H),6.53–6.49(m,2H),6.48(s,2H),6.39(dd,J＝10.3,2.4Hz,1H),4.46(s,2H),3.71–3.66(m,2H),3.26–3.21(m,2H),2.22(s,2H),2.13(s,6H),1.11(s,9H).
实施例24：N-(4-(8-氟-1-甲基-1,2,3,5-四氢-4H-苯并[e][1,4]二氮杂卓-4-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(024)
Figure PCTCN2022115057-appb-000046
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为 7-氟-1-甲基-2,3-二氢喹啉-4(1H)-酮，可制备得到目标化合物024(52mg)，LC-MS(ESI-MS):398[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.16(dd,J＝8.9,6.8Hz,1H),6.56(s,1H),6.55–6.50(m,3H),6.44(brs,1H),4.44(s,2H),3.66–3.61(m,2H),3.15(dd,J＝5.9,3.7Hz,2H),2.88(s,3H),2.24(s,2H),2.16(s,6H),1.12(s,9H).
实施例25：N-(4-(8-氟-2,3-二氢苯并[f][1,4]硫氮杂卓-4(5H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(025)
Figure PCTCN2022115057-appb-000047
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为7-氟硫代色满-4-酮，可制备得到目标化合物025(47mg)，LC-MS(ESI-MS):401[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.33(dd,J＝8.2,5.9Hz,1H),7.23(dd,J＝8.8,2.5Hz,1H),6.86(td,J＝8.3,2.5Hz,1H),6.49–6.41(m,3H),4.71(s,2H),4.03–3.96(m,2H),2.97–2.91(m,2H),2.23(s,2H),2.15(s,6H),1.11(s,9H).
实施例26：N-(4-(8-氟-1,1-二氧代-2,3-二氢苯并[f][1,4]硫氮杂卓-4(5H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(026)
Figure PCTCN2022115057-appb-000048
在反应瓶中将化合物025(25mg)溶解于2mL二氯甲烷中，加入mCPBA(30mg)，在室温下搅拌反应约1小时。然后用亚硫酸钠水溶液淬灭反应，加入二氯甲烷和水萃取，分离的二氯甲烷相用无水硫酸钠干燥之后浓缩，然后通过硅胶柱层析纯化得到目标化合物026(21mg)，LC-MS(ESI-MS):433[M+H] +。
实施例27：N-(4-(7-氟-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(027)
Figure PCTCN2022115057-appb-000049
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为6-氟萘-1(2H)-酮，可制备得到目标化合物027(37mg)，LC-MS(ESI-MS):381[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.25–7.20(m,1H),6.83(t,J＝8.0Hz,2H),6.47(s,2H),6.42–6.33(m,2H),6.03–5.96(m,1H),4.49(s,2H),4.27(s,2H),2.23(s,2H),2.13(s,6H),1.12(s,9H).
实施例28：N-(4-(7-氟-5-甲基-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(028)
Figure PCTCN2022115057-appb-000050
参考实施例16的合成路线和方法，将6-氟-4,4-二甲基-3,4-二氢萘-1(2H)-酮替换为6-氟-4-甲基萘-1(2H)-酮，可制备得到目标化合物028(23mg)，LC-MS(ESI-MS):395[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.34–7.31(m,1H),7.11(dd,J＝ 10.2,2.6Hz,1H),6.97(td,J＝8.3,2.7Hz,1H),6.60(s,2H),6.53(s,1H),6.07(t,J＝5.8Hz,1H),4.18(s,2H),3.66(d,J＝6.3Hz,2H),2.31(s,2H),2.24(s,6H),2.20(s,3H),1.19(s,9H).
实施例29：N-(3-氟-4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2-甲基苯基)-3,3-二甲基丁酰胺(029)
Figure PCTCN2022115057-appb-000051
步骤1，将N-(2-甲基-3-氟-4-溴苯基)-3，3-二甲基丁酰胺(5g,16.77mmol)溶于80mL1，4-二氧六环中，依次加入联硼酸频哪醇酯(3.41g,13.41mmol)，醋酸钾(4.94g,50.30mmol)，PdDPPFCl 2(614.62mg,0.83mmol)，氮气置换，90℃反应3h。反应结束，乙酸乙酯稀释，过滤，有机相用饱和氯化钠水溶液洗1次，干燥并减压浓缩经柱层析得到油状(3-甲基-2-氟-4-(3，3-二甲基丁酰胺基))苯硼酸频哪醇酯(4g)，收率69％。LC-MS(ESI-MS):350[M+H] +。
步骤2，将7-氟-2,3,4,5-四氢-1H-2-苯并氮杂卓(90mg,0.54mmol)溶于5mL乙腈中，依次加入(3-甲基-2-氟-4-(3，3-二甲基丁酰胺基))苯硼酸频哪醇酯(190mg,0.54mmol)，硼酸(70mg,1.09mmol)，醋酸铜(100mg,0.54mmol)，80℃在氧气氛围中反应6h。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和氯化铵洗2次，干燥并减压浓缩，经柱层析得到目标化合物029(36mg)，收率17％。,LC-MS(ESI-MS):387[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.23(d,J＝8.8Hz,1H),7.17–7.11(m,1H),6.85(dd,J＝9.6,2.3Hz,1H),6.82–6.70(m,3H),4.35(s,2H),3.60–3.55(m,2H),3.00–2.94(m,2H),2.23(s,2H),2.15(d,J＝2.2Hz,3H),1.98–1.91(m,2H),1.11(s,9H).
实施例30：N-(4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,3,6-三甲基苯基)-3,3-二甲基丁酰胺(030)
Figure PCTCN2022115057-appb-000052
将7-氟-2,3,4,5-四氢-1H-2-苯并氮杂卓(100mg,0.60mmol)溶于5mL乙腈中，依次加入(2,3,5-三甲基-4-(3，3-二甲基丁酰胺基))苯硼酸频哪醇酯(260mg,0.72mmol)，硼酸(75mg,1.21mmol)，醋酸铜(109mg,0.60mmol)，吡啶(50μL,1.21mmol)，80℃在氧气氛围中反应6h。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和氯化铵洗2次，干燥并减压浓缩，经柱层析得到目标化合物030(38mg)，收率16％。LC-MS(ESI-MS):397[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.02(dd,J＝8.2,5.8Hz,1H),6.89–6.85(m,2H),6.79(td,J＝8.4,2.6Hz,1H),6.58(brs,1H),4.01(s,2H),3.26–3.21(m,2H),2.96–2.90(m,2H),2.30(s,2H),2.22(s,3H),2.15(s,6H),1.94–1.87(m,2H),1.16(s,9H).
实施例31：N-(3-氯-4-(7-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(031)
Figure PCTCN2022115057-appb-000053
将7-氟-2,3,4,5-四氢-1H-2-苯并氮杂卓(100mg,0.60mmol)溶于5mL乙腈中，依次加入(2-氯-3,5-二甲基-4-(3，3-二甲基丁酰胺基))苯硼酸频哪醇酯(282mg,0.66mmol)(可由类似实施例16的方法合成)，硼酸(75mg,1.21mmol)，醋酸铜(110mg,0.60mmol)，吡啶(50μL,1.21mmol)，80℃在氧气氛围中反应6h。反应结束，降至室温，乙酸乙酯稀释，抽滤，有机相用饱和氯化铵洗2次，干燥并减压浓缩，经柱层析得到目标化合物031(52mg)，收率20％。LC-MS(ESI-MS):417[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.14(dd,J＝8.3,5.9Hz,1H),6.89–6.85(m,2H),6.80(td,J＝8.5,2.7Hz,1H),6.63(brs,1H),4.13(s,2H),3.41–3.36(m,2H),2.98–2.92(m,2H),2.32–2.27(m,2H),2.30(s,3H),2.19(s,3H),1.99–1.92(m,2H),1.15(s,9H).
实施例32：(R)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(032)
Figure PCTCN2022115057-appb-000054
参考实施例8的合成路线和方法，将三氟异丙醇替换为(R)-1,1,1-三氟丙烷-2-醇，可制备得到目标化合物032(50mg)。LC-MS(ESI-MS):477[M+H] +. 1H NMR(400MHz,Chloroform-d)δ7.19(d,J＝8.2Hz,1H),6.72-6.73(m,1H),6.65-6.68(m,1H),6.46-6.48(m,2H),6.41(brs,1H),4.53-4.59(m,1H),4.49(s,2H),3.71-3.73(m,2H),2.89-2.92(m,2H),2.22(s,2H),2.14(s,6H),1.83-1.86(m,2H),1.46(d,J＝6.5Hz,3H),1.12(s,9H).
实施例33：(S)-N-(2,6-二甲基-4-(7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(033)
Figure PCTCN2022115057-appb-000055
参考实施例8的合成路线和方法，将三氟异丙醇替换为(S)-1,1,1-三氟丙烷-2-醇,可制备得到目标化合物033(63mg)。LC-MS(ESI-MS):477[M+H] +. 1H NMR(400MHz,Chloroform-d)δ7.19(d,J＝8.2Hz,1H),6.72-6.73(m,1H),6.65-6.68(m,1H),6.46-6.49(m,2H),6.42(brs,1H),4.52-4.60(m,1H),4.49(s,2H),3.71-3.73(m,2H),2.90-2.93(m,2H),2.22(s,2H),2.14(s,6H),1.82-1.88(m,2H),1.45-1.46(m,3H),1.12(s,9H).
实施例34：N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(034)
Figure PCTCN2022115057-appb-000056
步骤1，将6,7-二氟-3,4-二氢萘-1(2H)-酮(2.0g，10.98mmol)溶于30mL乙腈中，向体系中依次加入三氟异丙醇(2.5mL，27.45mmol)，碳酸铯(10.7g，32.94mmol)于封管，80℃反应4h。反应结束，浓缩除去乙腈，加乙酸乙酯、水溶解，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，得中间体034-1：7-氟-6-((1,1,1-三氟丙烷-2-基)氧基)-3,4-二氢萘-1(2H)-酮(3.12g)，收率：94％。直接进行下一步反应。ESI-MS(M+H) +＝277。 1H-NMR(400MHz,CCl3D)δ7.76(d,J＝11.6Hz,1H),6.89(d,J＝7.5Hz,1H),4.66-4.74(m,1H),2.88-2.91(m,2H),2.58-2.61(m,2H),2.09-2.15(m,2H),1.57(dd,J＝6.5,0.9Hz,3H).
步骤2，将中间体034-1(3.12g，11.30mmol)溶于40mL浓盐酸中，在冰浴下缓慢加入叠氮化钠(1.47g，22.60mmol),室温反应48h。反应结束，低温缓慢加入冰水、碳酸钠水溶液，使体系pH至调制碱性，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(PE/EA洗脱)得中间体034-2：8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-2,3,4,5-四氢-1H-苯并[c]氮杂卓-1-酮(750mg)收率：23％。ESI-MS(M+H) +＝292。
步骤3，将中间体034-2(400mg，1.44mmol)溶于100mL的四氢呋喃中，加入氢化铝锂(1mmol/mL，13mL)，60℃反应2h。反应结束，加水淬灭(至不再有气泡产生)，减压浓缩除水后，乙酸乙酯(1g产物1L EA)溶解混合物，抽滤，无水硫酸钠干燥，滤液减压浓缩，得中间体034-3：8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-2,3,4,5-四氢-1H-苯并[c]氮杂卓350mg，收率：92％。ESI-MS(M+H)+＝278。
步骤4，将中间体034-3(230mg，0.83mmol)溶于10mL 1,4-二氧六环中，向体系依次加入N-(4-溴-2,6-二甲基苯基)-3,3-二甲基丁酰胺(370mg，1.24mmol)，叔丁醇钠(244mg，2.49mmol)，碳酸铯(811mg，2.49mmol)，醋酸钯(19mg，0.08mmol)，Pd 2(dba) 3(76mg，0.08mmol)，X-Phos(2-二环己基磷-2′,4′,6′-三异丙基联苯)(79mg，0.17mmol)，氮气置换，105℃反应4h。反应结束，减压除去二氧六环，加入二氯甲烷、水溶解混合物，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(PE/EA洗脱)得目标化合物034(170mg)，收率：41％。ESI-MS(M+H) +＝495。 1H-NMR(400MHz,CCl 3D)δ7.02(d,J＝11.2Hz,1H),6.82(d,J＝8.1Hz,1H),6.43-6.47(m,3H),4.45-4.49(m,3H),3.67-3.75(m,2H),2.87-2.90(m,2H),2.23(s,2H),2.16(s,6H),1.82-1.85(m,2H),1.50(d,J＝6.5Hz,3H),1.12(s,9H).
实施例35：N-(4-(8-氟-7-异丙氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(035)
Figure PCTCN2022115057-appb-000057
步骤1，参考实施例34的步骤1、2、3的合成路线和方法，把三氟异丙醇替换为 异丙醇，可制备得到8-氟-7-异丙氧基-2,3,4,5-四氢-1H-苯并[c]氮杂卓，ESI-MS(M+H) +＝224。
步骤2，将8-氟-7-异丙氧基-2,3,4,5-四氢-1H-苯并[c]氮杂卓(540mg，2.42mmol)溶于15mL乙腈中，向体系依次加入(4-(3,3-二甲基丁酰胺基)-3,5-二甲基苯基)硼酸(1.3g，4.84mmol)，醋酸铜(440mg，2.42mmol)，硼酸(300mg，4.84mmol)，DIPEA(940mg，7.26mmol)，氧气置换，60℃反应2h。反应结束，加入饱和氯化铵的水溶液洗涤，用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析(PE/EA洗脱)得到目标化合物035(150mg)，收率：14％。ESI-MS(M+H) +＝441。 1H-NMR(400MHz,CCl 3D)δ6.97-7.00(m,1H),6.71-6.74(m,1H),6.42-6.48(m,3H),4.40-4.45(m,3H),3.67-3.73(m,2H),2.85-2.89(m,2H),2.21(s,2H),2.14(s,6H),1.81-1.85(m,2H),1.32(d,J＝6.1Hz,6H),1.12(s,9H).
实施例36.(S)-N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(036)
Figure PCTCN2022115057-appb-000058
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为(S)-1,1,1-三氟丙烷-2-醇，可制备得到目标化合物036(58mg)。LC-MS(ESI-MS):495[M+H] +。
实施例37.(R)-N-(4-(8-氟-7-((1,1,1-三氟丙烷-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(037)
Figure PCTCN2022115057-appb-000059
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为(R)-1,1,1-三氟丙烷-2-醇，可制备得到目标化合物037(50mg)。LC-MS(ESI-MS):495[M+H] +。
实施例38.N-(4-(8-氟-7-甲氧基-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(038)
Figure PCTCN2022115057-appb-000060
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为甲醇，可制备得到目标化合物038(47mg)。LC-MS(ESI-MS):413[M+H] +。
实施例39.N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3，3-二甲基丁酰胺(039)
Figure PCTCN2022115057-appb-000061
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为丁烷-2-醇，可制备得到目标化合物039(62mg)。LC-MS(ESI-MS):455[M+H] +。
实施例40.(S)-N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(040)
Figure PCTCN2022115057-appb-000062
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为(S)-丁烷-2-醇，可制备得到目标化合物040(40mg)。LC-MS(ESI-MS):455[M+H] +。
实施例41.(R)-N-(4-(7-(仲丁氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(041)
Figure PCTCN2022115057-appb-000063
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为(R)-丁烷-2-醇，可制备得到目标化合物041(46mg)。LC-MS(ESI-MS):455[M+H] +。
实施例42.N-(4-(7-环丙氧基-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(042)
Figure PCTCN2022115057-appb-000064
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为环丙醇，可制备得到目标化合物042(35mg)。LC-MS(ESI-MS):439[M+H] +。
实施例43.N-(4-(7-环丁氧基-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(043)
Figure PCTCN2022115057-appb-000065
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为环丁醇，可制备得到目标化合物043(34mg)。LC-MS(ESI-MS):453[M+H] +。
实施例44.N-(4-(7-(环戊氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(044)
Figure PCTCN2022115057-appb-000066
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为环戊醇，可制备得到目标化合物044(41mg)。LC-MS(ESI-MS):467[M+H] +。
实施例45.N-(4-(7-(环己氧基)-8-氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(045)
Figure PCTCN2022115057-appb-000067
参考实施例34的合成路线和方法，将步骤1中的三氟异丙醇替换为环己醇，可制备得到目标化合物045(48mg)。LC-MS(ESI-MS):481[M+H] +。
实施例46.N-(4-(7,8-二氟-1,3-二氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(046)
Figure PCTCN2022115057-appb-000068
参考实施例34步骤2、3、4的合成路线和方法，，将7-氟-6-((1,1,1-三氟丙烷-2-基)氧基)-3,4-二氢萘-1(2H)-酮替换为6,7-二氟萘-1(2H)-酮，可制备得到目标化合物046(38mg)。LC-MS(ESI-MS):399[M+H] +。
实施例47.N-(4-(7,8-二氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(047)
Figure PCTCN2022115057-appb-000069
参考实施例34步骤2、3、4的合成路线和方法，将步骤2中的7-氟-6-((1,1,1-三氟丙烷-2-基)氧基)-3,4-二氢萘-1(2H)-酮替换为6,7-二氟-3,4-二氢萘-1(2H)-酮，可制备得到目标化合物047(63mg)。LC-MS(ESI-MS):401[M+H] +。
实施例48.N-(3-氯-4-(7,8-二氟-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(048)
Figure PCTCN2022115057-appb-000070
参考实施例31的合成路线和方法，将7-氟-2,3,4,5-四氢-1H-2-苯并氮杂卓替换为7,8-二氟-2,3,4,5-四氢-1H-苯并[c]氮杂卓，可制备得到目标化合物048(37mg)。LC-MS(ESI-MS):435[M+H] +。
实施例49.N-(4-(7,8-二氟-3,4-二氢螺环[苯并[c]氮杂卓-5,1'-环丙烷]-2(1H)-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(049)
Figure PCTCN2022115057-appb-000071
参考实施例34步骤2、3、4的合成路线和方法，，将7-氟-6-((1,1,1-三氟丙烷-2-基)氧基)-3,4-二氢萘-1(2H)-酮替换为6'，7'-二氟-2'，3'-二氢-4'H-螺环[环丙烷-1,1'-萘]-4'-酮，可制备得到目标化合物049(38mg)。LC-MS(ESI-MS):427[M+H] +。
实施例50.(E)-N-(2,6-二甲基-4-(7-((4,4,4-三氟丁-2-烯-1-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(050)
Figure PCTCN2022115057-appb-000072
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为(E)-4,4,4-三氟丁-2-烯-1-醇，可制备得到目标化合物050(50mg)。LC-MS(ESI-MS):489[M+H] +。
实施例51.N-(4-(7-((3-(二氟甲基)双环[1.1.1]戊烷-1-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(051)
Figure PCTCN2022115057-appb-000073
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为3-(二氟甲基)双环[1.1.1]戊-1-醇，可制备得到目标化合物051(42mg)。LC-MS(ESI-MS):497[M+H] +。
实施例52.N-(2,6-二甲基-4-(7-(2,2,2-三氟-1-甲氧基乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(052)
Figure PCTCN2022115057-appb-000074
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为2,2,2-三氟-1-甲氧基乙烷-1-醇，可制备得到目标化合物052(52mg)。LC-MS(ESI-MS):493[M+H] +。
实施例53.N-(2,6-二甲基-4-(7-(3,3,3-三氟-2-甲基丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(053)
Figure PCTCN2022115057-appb-000075
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为3,3,3-三氟-2-甲基丙-1-醇，可制备得到目标化合物053(46mg)。LC-MS(ESI-MS):491[M+H] +。
实施例54.N-(2,6-二甲基-4-(7-((1-(三氟甲基)环丙基)甲氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(054)
Figure PCTCN2022115057-appb-000076
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为(1-(三氟甲基)环丙基)甲醇，可制备得到目标化合物054(34mg)。LC-MS(ESI-MS):503[M+H] +。
实施例55.N-(4-(7-((1,1,1,3,3,3-六氟丙-2-基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(055)
Figure PCTCN2022115057-appb-000077
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为六氟异丙醇，可制备得到目标化合物055(49mg)。LC-MS(ESI-MS):531[M+H] +。
实施例56.N-(2,6-二甲基-4-(7-(2-(2,2,2-三氟乙氧基)乙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(056)
Figure PCTCN2022115057-appb-000078
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为2-(2,2,2-三氟乙氧基)乙醇，可制备得到目标化合物056(62mg)。LC-MS(ESI-MS):507[M+H] +。
实施例57.N-(2,6-二甲基-4-(7-(2,2,3,3-四氟丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(057)
Figure PCTCN2022115057-appb-000079
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为四氟丙醇，可制备得到目标化合物057(53mg)。LC-MS(ESI-MS):495[M+H] +。
实施例58.N-(2,6-二甲基-4-(7-(3,3,3-三氟丙氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(058)
Figure PCTCN2022115057-appb-000080
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为三氟丙醇，可制备得到目标化合物058(48mg)。LC-MS(ESI-MS):477[M+H] +。
实施例59.N-(2,6-二甲基-4-(7-((4-(三氟甲基)环己基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(059)
Figure PCTCN2022115057-appb-000081
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为4-(三氟甲基)环己醇，可制备得到目标化合物059(50mg)。LC-MS(ESI-MS):531[M+H] +。
实施例60.N-(2,6-二甲基-4-(7-(4,4,4-三氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(060)
Figure PCTCN2022115057-appb-000082
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换三氟丁醇，可制备得到目标化合物060(63mg)。LC-MS(ESI-MS):491[M+H] +。
实施例61.N-(2,6-二甲基-4-(7-((4,4,5,5,5-五氟戊基)氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(061)
Figure PCTCN2022115057-appb-000083
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为4,4,5,5,5-五氟戊醇(49mg)。LC-MS(ESI-MS):541[M+H] +。
实施例62.N-(2,6-二甲基-4-(7-(2,2,4,4,4-五氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)苯基)-3,3-二甲基丁酰胺(062)
Figure PCTCN2022115057-appb-000084
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为2,2,4,4,4-五氟丁醇(57mg)。LC-MS(ESI-MS):527[M+H] +。
实施例63.N-(4-(7-(4-氟丁氧基)-1,3,4,5-四氢-2H-苯并[c]氮杂卓-2-基)-2,6-二甲基苯基)-3,3-二甲基丁酰胺(063)
Figure PCTCN2022115057-appb-000085
参考实施例8的合成路线和方法，将步骤1中的三氟异丙醇替换为4-氟丁醇，可制备得到目标化合物063(45mg)。LC-MS(ESI-MS):455[M+H] +。
生物试验
实施例64：KCNQ2/3钾离子通道激活试验
步骤
1.细胞培养
hKCNQ-CHO细胞在5％CO 2的湿润环境下，37℃培养。
2.溶液
2.1.细胞外液(mM)：NaCl 145,KCl 4,CaCl 2 2,MgCl 2 1,Glucose 10,HEPES 10。细胞外液的pH值使用NaOH调至7.4，渗透压调至295mOsm左右。
2.2.细胞内液(mM(mmol/L))：KOH 31.25,KCl 120,EGTA 10,MgCl 2 1.75,CaCl 2 5.374,HEPES 10,Na-ATP 4。细胞内液的pH值使用HCl调至7.4，渗透压调至285mOsm左右。
2.3.细胞外液需要每周配备一次，细胞内液配备之后需要在-20℃进行保存。
3.工作液的准备
模型阳性参照化合物瑞替加宾(Retigabine,RTG)使用100％DMSO进行溶解，配置为10mM工作液保存。待测化合物使用100％DMSO进行溶解，配置为10mM工作液保存。测试溶液中DMSO终浓度需小于0.3％。
4.全细胞电压钳记录
全细胞膜片钳在室温下进行钳制。使用EPC 10USB放大器(HEKA Elektronik,德国)记录到的电信号通过3kHz低通滤波后，最后记录在PatchMaster 2×90.5软件(HEKA Elektronik,德国)中。在此步骤，质控标准为细胞高阻封接大于500MOhms，检测电流大于0.4nA。
记录电极使用硼硅酸盐玻璃毛细管(GC150tF-10,Harvard Apparatus Co.,英国)通过垂直拉制仪(NARISHIGE PC-10,日本)中拉出并抛光。在此步骤，质控标准为电极电阻2～5MΩ之间。
全细胞膜片钳在记录过程中，会使用连续灌流系统(BT100-2J,LongerPump,中国)持续灌注细胞外液。灌注系统安装在立式显微镜(FN-S2N,尼康,日本)的载物台上，在显微镜下人工定位灌注头。
hKCNQ电流幅度检测的电压指令如下：细胞从-80mV的钳制电位，阶跃至-30mV，持续1500ms；然后钳制电压降至-120mv，持续500ms；最后，电压回到钳制电位-80mV。检测电压指令每15000毫秒重复一次，该指令在化合物测试期间持续执行。化合物作用稳定性的质控标准为连续5次电压指令下的电流幅度，其变异系数＜5％。如果化合物对hKCNQ电流幅度无任何作用，需要持续监测5分钟。
5.数据分析
数据分析使用PatchMaster 2×90.5软件(HEKA Elektronik,德国)和Excel 2013(微软,美国)软件进行分析。每一个细胞的膜片钳记录，需得出测试化合物浓度所对应的hKCNQ通道电流幅度(Itest)。Itest减去细胞本来的通道电流(Icontrol)为增强的通道电流，除以Icontrol之后可以得到电流增强倍数。即电流增强倍数(Enhancment％)＝(Itest-Icontrol)/Icontrol*100％。实验结果见表1
表1 化合物对KCNQ2/3钾离子通道激活活性
Figure PCTCN2022115057-appb-000086
Figure PCTCN2022115057-appb-000087
表中：“0.05μM”“3μM”表示待测化合物的测试浓度。A>100％,50％<B<100％，C<50％。“-”表示没有进行对应测试。
其中化合物a为对照化合物，其结构为
Figure PCTCN2022115057-appb-000088
a表示瑞替加滨在10μM浓度下对KCNQ2/3钾离子通道激活活性。
表1结果表明，化合物a在3μM浓度下和瑞替加滨在10μM浓度下对KCNQ2/3钾离子通道激活活性低于50％，本发明的化合物在3μM浓度下对KCNQ2/3钾离子通道激活活性大于50％。
实施例65：半数开放电压左移试验
步骤
1.细胞培养
hKCNQ-CHO细胞在5％CO 2的湿润环境下，37℃培养。
2.溶液
a)细胞外液(mM)：NaCl 145,KCl 4,CaCl 2 2,MgCl 2 1,Glucose 10,HEPES 10。细胞外液的pH使用NaOH调至7.4，渗透压调至295mOsm左右。
b)细胞内液(mM)：KOH 31.25,KCl 120,EGTA 10,MgCl 2 1.75,CaCl 2 5.374,HEPES 10,Na-ATP 4。细胞内液的pH使用HCl调至7.4，渗透压调至285mOsm左右。
c)细胞外液需要每周配备一次，细胞内液配备之后需要分装后在-20℃进行保存。
3.工作液的准备
模型阳性参照化合物瑞替加宾(Retigabine,RTG)使用100％DMSO进行溶解，配置为10mM工作液保存。待测化合物使用100％DMSO进行溶解，配置为10mM工作液保存。测试溶液中DMSO终浓度需小于0.3％。
4.全细胞电压钳记录
全细胞膜片钳在室温下进行钳制。使用EPC 10USB放大器(HEKA Elektronik,德国)记录到的电信号通过3kHz低通滤波后，最后记录在PatchMaster 2×90.5软件(HEKA Elektronik,德国)中。在此步骤，质控标准为细胞高阻封接大于500MOhms，检测电流大于0.4nA。
记录电极使用硼硅酸盐玻璃毛细管(GC150tF-10,Harvard Apparatus Co.,英国)通过垂直拉制仪(NARISHIGE PC-10,日本)拉出并抛光。在此步骤，质控标准为电极电阻2～5MΩ之间。
全细胞膜片钳在记录过程中，会使用连续灌流系统(BT100-2J,LongerPump,中国)持续灌注细胞外液。灌注系统安装在立式显微镜(FN-S2N,尼康,日本)的载物台上，在显微镜下人工定位灌注头。
hKCNQ电流幅度检测的电压指令如下：细胞从-80mV的钳制电位，阶跃至-120mV，以每一个sweep增加10mV的电压对细胞持续钳制直至+60mV，持续1500ms；然后钳制电压降至-120mv，持续500ms；最后，电压回到钳制电位-80mV。检测电压指令每15000毫秒重复一次，该指令在化合物测试期间持续执行。细胞hKCNQ的半数电压需要通过细胞在不同钳制电位(-120mV到+60mV)的电流幅度非线性拟合而来。
5.数据分析
数据分析使用PatchMaster 2×90.5软件(HEKA Elektronik,德国)和Excel 2013(微软,美国)软件进行分析。每一个细胞的膜片钳记录，需得出测试化合物浓度所对应的hKCNQ的半数电压(V1/2-test)。V1/2-test减去化合物作用前hKCNQ的半数电压(V1/2-control)为左移的半数电压值ΔV1/2(V 1/2Shift(mV))。
实验结果见表2：
表2 化合物对KCNQ2/3半数开放电压左移效应
Figure PCTCN2022115057-appb-000089
表中：“50nM”、“300nM”为待测化合物的测试浓度。“-”表示没有进行对应测试。
化合物Xen-1101为对照化合物，其结构为：
Figure PCTCN2022115057-appb-000090
(WO2008024398A2)
表2的测试结果表明，本发明设计的化合物具有显著诱导半数开放电压左移的效 应。
实施例66：小鼠过脑实验
实验步骤
1.药物配制
给药剂量5mg/kg
将药物按比例(溶剂：5％DMSO+5％Solutol+90％生理盐水)配制成浓度为0.5mg/mL的溶液，按0.1mL/10g对小鼠进行灌胃给药，每个点平行3只小鼠。
2.定点取脑组织
待小鼠给药后，将小鼠麻醉后用生理盐水进行心脏灌注，解剖取脑组织，经生理盐水清洗后吸干水分，称重后转移至2mLEP管，按脑组织：生理盐水＝1：1(g/mL)加入生理盐水，每管3颗钢珠上组织研磨机，60HZ，60s进行匀浆，15000rpm，4℃离心10min取上清液即为脑组织匀浆液。
3.样品处理
3.1.标准曲线和质控样本配制处理
取药物储备液(0.5mg/mL)用乙腈稀释成浓度分别为50、100、200、500、1000、2000、5000、10000、20000ng/mL的标准曲线工作液，100、2000、10000ng/mL的质控工作液。分别取47.5uL空白基质中加入2.5μL的标准曲线工作液和质控工作液，配置成浓度为2.5、5、10、25、50、100、250、500、1000ng/mL的标准曲线样本和浓度为5、100、500ng/mL的质控样本，分别加入200μL的乙腈(含内标氯雷他定5ng/mL)，涡旋振荡3min后，15000rpm，4℃离心10min，取上清液进行LC-MS/MS分析，得标准曲线。
3.2样本配制处理
取脑组织匀浆液样品50μL，加入200μL的乙腈(含内标氯雷他定5ng/mL)，涡旋振荡3min后，15000rpm，4℃离心10min，取上清液进行LC-MS/MS分析，结合标准曲线，得到对应脑内浓度。
实验结果见表3：
表3 化合物经灌胃给药后脑内浓度
Figure PCTCN2022115057-appb-000091
表3的测试结果表明，小鼠经灌胃给药后，化合物脑内浓度有一定的提升。
实施例67：MES小鼠癫痫模型
实验步骤：
1.实验前提前30min将小鼠(每组10只小鼠)转入操作间适应环境。
2.在特定时间给予待测化合物或阳性药(丙戊酸钠，Valproate)。Valproate给药后30min或待测化合物给药后30min，用耳电极给予电刺激，刺激参数为总时长为 0.8秒，频率50Hz、幅度50mA的方波，方波的间隔为10msec。
3.记录电刺激完成后1分钟内，动物出现后肢强直的次数及发作时间，以及有可能出现的死亡及死亡时间。
4.给药后并观察记录药物可能诱导的副作用，分为四个级别：
·无:正常
·轻度镇静(Mild sedation)
·中度镇静(Moderate sedation)
·重度镇静(Severe sedation)
实验结果见表4：
表4 化合物对MES诱导的小鼠癫痫的保护作用(mpk：mg/kg)
化合物编号 剂量 强直保护率
实施例003 5mpk 100％
实施例008 5mpk 90％
实施例011 5mpk 90％
实施例032 5mpk 100％
实施例033 5mpk 100％
实施例035 5mpk 100％
表4的测试结果表明，在MES诱导的小鼠癫痫中，化合物可显著性的抑制小鼠后肢强直性的发生。

Claims (16)

  1. 一种化合物，其特征在于，具有通式Ⅰ所示的结构：
    Figure PCTCN2022115057-appb-100001
    或其立体异构体或其药学上可接受的盐；
    其中：
    环A为苯环或者含有1-2选自N、O或S杂原子的5-8元杂环；
    R 1选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烯基、C 1-C 8烯氧基、螺烷基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 1-C 8烯氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基，所述的烷基、烷氧基、烯基、烯氧基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、烷硫基、烷酰基、烷基磺酰基、氨基磺酰基可进一步的被R 8取代；
    每一个R 2任选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
    或者两个R 2连接同一个原子，两个R 2可以不相同或者相同，与它们连接的原子形成3～6元环或者3～6元杂环；
    R 4、R 5、R 6、R 7、R 8各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基、螺烷基；
    n选自0、1、2；
    m选自0、1、2、3、4、5；
    X 1和X 2各自独立的选自-CRaRb、-NRa、-O-、-C(O)-、-S-、-S(O)-、-S(O) 2-；
    Ra、Rb各自独立的选自氢、卤素、羟基、氨基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 8环烷基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基；
    Figure PCTCN2022115057-appb-100002
    表示化学键存在或者不存在；
    Z选自O或者(CH 2) p，p为1-6的整数；
    R 3为C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基，其中所述的C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基可被一个 或者多个选自卤素、硝基、氰基、氨基或者羟基所取代。
  2. 根据权利要求1所示的化合物，其特征在于，具有通式Ⅰ所示的结构：
    Figure PCTCN2022115057-appb-100003
    或其立体异构体或其药学上可接受的盐；
    其中：
    环A为苯环或者含有1-2选自N、O或S杂原子的5-8元杂环；
    R 1各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
    R 2各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
    R 4、R 5、R 6、R 7各自独立的选自氢、卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基；
    n选自0、1、2；
    m选自0、1、2、3、4、5；
    X 1和X 2各自独立的选自-CRaRb、-NRa、-O-、-C(O)-、-S-、-S(O)-、-S(O) 2-；
    Ra、Rb各自独立的选自氢、卤素、羟基、氨基、C 1-C 8烷基、C 1-C 8烷氧基、C 1-C 8烷氨基、C 3-C 8环烷基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基；
    Figure PCTCN2022115057-appb-100004
    表示化学键存在或者不存在；
    Z选自O或者(CH 2) p，p为1-6的整数；
    R 3为C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基，其中所述的C 1-C 8烷基、C 3-C 8环烷基、C 3-C 8环烯基，C 2-C 8链烯基或C 2-C 8炔基可被一个或者多个选自卤素、硝基、氰基、胺基或者羟基所取代；
    当
    Figure PCTCN2022115057-appb-100005
    表示为X 1＝X 2，X 1、X 2各自独立的选自-CRa-、-N-；
    当
    Figure PCTCN2022115057-appb-100006
    表示为X 1-X 2，且当R 4、R 5、R 6、R 7均不选自氯，且当X 1为CH或O，R 2为H，且当A环为苯环，R 1选自C 1-C 8烷氧基、C 3-C 8环烷氧基、C 2-C 8杂环烷氧基、 C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷氧基；
    当
    Figure PCTCN2022115057-appb-100007
    表示为X 1-X 2，且当R 4、R 5、R 6、R 7均不选自氯，且当A环为噻吩环，m选自2、3、4、5，R 2不选自氢。
  3. 根据权利要求2所述的化合物，其特征在于，具有通式IIa～IIc所示的结构：
    Figure PCTCN2022115057-appb-100008
    或其立体异构体或其药学上可接受的盐；
    X 1、X 2之间为双键或者单键；
    X 3选自N、O、S。
  4. 根据权利要求3所述的化合物，其特征在于，具有通式III所示的结构：
    Figure PCTCN2022115057-appb-100009
    或其立体异构体或其药学上可接受的盐；
    R 1选自C 1-8烷氧基、C 3-8环烷氧基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷基磺酰基、卤代C 1-8烷氧基、卤代C 3-8环烷氧基；
    n选自1。
  5. 根据权利要求4所述的化合物，其特征在于，具有通式IV所示的结构：
    Figure PCTCN2022115057-appb-100010
    或其立体异构体或其药学上可接受的盐；
    R 1选自C 1-6烷氧基、C 3-6环烷氧基、C 2-C 6杂环烷氧基、C 1-C 3烷硫基、C 1-C 3烷基磺酰基、卤代C 1-6烷氧基、卤代C 3-6环烷氧基。
  6. 根据权利要求1所述的化合物，其特征在于，具有通式Ⅱc所示的结构：
    Figure PCTCN2022115057-appb-100011
    或其立体异构体或其药学上可接受的盐；
    X 1、X 2之间为双键或者单键；
    n选自2；
    R 1选自：卤素、C 1-C 8烷基、C 1-C 8烷氧基、C 3-C 8环烷基、C 3-C 8环烷氧基、C 2-C 8杂环烷基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷酰基、C 1-C 8烷基磺酰基、氨基磺酰基、卤代C 1-C 8烷基、卤代C 1-C 8烷氧基、卤代C 3-C 8环烷基、卤代C 3-C 8环烷氧基、卤代C 2-C 8杂环烷基、卤代C 2-C 8杂环烷氧基。
  7. 根据权利要求6所述的化合物，其特征在于，具有通式III所示的结构：
    Figure PCTCN2022115057-appb-100012
    或其立体异构体或其药学上可接受的盐；
    R 1选自卤素、C 1-8烷氧基、C 3-8环烷氧基、C 2-C 8杂环烷氧基、C 1-C 8烷硫基、C 1-C 8烷基磺酰基、卤代C 1-8烷氧基、卤代C 3-8环烷氧基；
    n选自2。
  8. 根据权利要求7所述的化合物，其特征在于，具有通式V所示的结构：
    Figure PCTCN2022115057-appb-100013
    或其立体异构体或其药学上可接受的盐；
    R 1选自卤素、C 1-6烷氧基、C 3-6环烷氧基、C 2-C 6杂环烷氧基、C 1-C 3烷硫基、C 1-C 3烷基磺酰基、卤代C 1-6烷氧基、卤代C 3-6环烷氧基。
  9. 根据权利要求3所述的化合物，其特征在于，通式IIa～IIc中：
    X 1、X 2为CH 2，两者之间为单键；R 4和R 6为H；R 5和R 7为甲基；
    m选自2、3、4、5；
    R 2不选自氢。
  10. 根据权利要求3所述的化合物，其特征在于，通IIa～IIc中：
    R 6为Cl；R 4、R 5、R 7至少两个不选自氢。
  11. 根据权利要求1所述的化合物，其特征在于，具有通式Va所示的结构：
    Figure PCTCN2022115057-appb-100014
    R 1’为H、F；
    R 1为
    Figure PCTCN2022115057-appb-100015
  12. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2022115057-appb-100016
    Figure PCTCN2022115057-appb-100017
    Figure PCTCN2022115057-appb-100018
    Figure PCTCN2022115057-appb-100019
    或其立体异构体或其药学上可接受的盐。
  13. 一种药物组合物，其特征在于，包括如权利要求1～12中任意一项所述的化合物一种或多种
  14. 一种药物制剂，其特征在于，包括权利要求1～12中任意一项所述的化合物的一种或多种。
  15. 一种如权利要求1-12中任一项所述的化合物或其药学上可接受的盐在制备治疗从钾离子通道激活中获益的疾病、特别是在制备治疗中枢神经系统疾病药物方面的应用。
  16. 根据权利要15所述的应用，其特征在于，所述疾病选自：癫痫、炎症性疼痛、神经性疼痛、偏头痛、神经变性疾病、焦虑障碍、抑郁、脑卒中、可卡因滥用引起的并发症、尼古丁戒断综合症、酒精戒断综合症或耳鸣。
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