WO2022017440A1 - 5-ht 2a受体抑制剂或反向激动剂及其制备方法和应用 - Google Patents

5-ht 2a受体抑制剂或反向激动剂及其制备方法和应用 Download PDF

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WO2022017440A1
WO2022017440A1 PCT/CN2021/107774 CN2021107774W WO2022017440A1 WO 2022017440 A1 WO2022017440 A1 WO 2022017440A1 CN 2021107774 W CN2021107774 W CN 2021107774W WO 2022017440 A1 WO2022017440 A1 WO 2022017440A1
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straight
branched
independently selected
hydrogen atom
chain
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PCT/CN2021/107774
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English (en)
French (fr)
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张睿
叶亮
马明旭
王文艳
代玉森
田京伟
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山东绿叶制药有限公司
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Priority to CN202180006171.3A priority Critical patent/CN114728933B/zh
Priority to CN202310590636.5A priority patent/CN116730981B/zh
Priority to JP2023504487A priority patent/JP2023535926A/ja
Priority to US18/005,952 priority patent/US20230348421A1/en
Priority to EP21847375.9A priority patent/EP4186893A1/en
Publication of WO2022017440A1 publication Critical patent/WO2022017440A1/zh

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Definitions

  • the invention relates to a class of compounds as selective serotonin 2A (5-HT 2A ) receptor inhibitors or inverse agonists, a preparation method thereof, and applications in the field of diseases related to 5-HT 2A receptors.
  • Parkinson's disease is a common neurodegenerative disease with an average age of onset around 60 years old (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517.). According to the National Institutes of Health (NIH) data in 2018, there are about 4 to 6 million Parkinson's patients worldwide, and as many as 50% of Parkinson's patients will have severe hallucinations or delusions during their illness. Symptoms seriously affect the quality of life of patients and have high morbidity and mortality.
  • NASH National Institutes of Health
  • Pimavanserin acts on the 5-HT 2A receptor, a major excitatory receptor subtype in the 5-HT receptor family, which belongs to ligand-gated channels and G protein-coupled receptors.
  • 5-HT 2A receptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important target for antipsychotic drugs and schizophrenia treatment (Price, DL, et al. Behavioural Pharmacology (2012) , 23(4), 426-433.). Since the main first generation of antipsychotic drugs which inhibit dopamine D 2 receptor, we have severe extrapyramidal side effects. The second generation antipsychotics in addition to inhibiting D 2 receptors, further more specific inhibition of 5-HT receptors particularly 5-HT receptors.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • At least one of X 1 and X 4 is N, and the other is optionally CR 1 or N;
  • X 2 and X 3 are each independently selected from CR 1 and N;
  • X 5 is independently selected from CR 3a , N;
  • X 6 is independently selected from CR 3b , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Group B is a C 1-6 straight or branched chain alkyl group, a 5-6 membered aza-heterocyclic group, the C 1-6 straight or branched chain alkyl group, or a 5-6 membered aza-heterocyclic group optionally substituted with one or more deuterium atoms;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • Each R 2 is the same or different, and is independently selected from a hydrogen atom, a deuterium atom, a C 1-10 straight or branched chain alkyl group, a (C 1-6 straight chain or branched chain alkyl group) 2 amine group, 3-8 membered cycloalkyl, the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amino, or 3-8 membered cycloalkyl are any optionally substituted with one or more deuterium atoms;
  • R 3 , R 3a , R 3b , R 3c , R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or Branched alkoxy, C 1-10 straight or branched haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy The group is substituted by one or more substituents selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1 -10 linear or branched halogenated alkoxy, wherein the C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy are selected from hydrogen atom, hydroxyl, Substituted by one or more substituents in C 1-10 linear or branched alkoxy groups;
  • X is selected from -NH-, -(CH 2 ) 1-4 NH-;
  • Y is selected from O or S
  • n and n are independently selected from 0, 1, 2 and 3;
  • s is independently selected from 1, 2, 3, 4, 5 and 6;
  • y is independently selected from 0, 1, 2, 3, 4 and 5.
  • At least one of X 1 and X 4 is N, and the other is optionally CR 1 ;
  • X 2 and X 3 are each independently selected from CR 1 , preferably CH.
  • X 1 and X 4 are both N, and X 2 and X 3 are each independently selected from CR 1 .
  • At least one of X 1 and X 4 is N, the other is optionally CR 1 , at least one of X 2 , X 3 is N, and the other is optionally CR 1 .
  • X 1 and X 4 are both N, at least one of X 2 , X 3 is N, and the other is optionally CR 1 .
  • At least one of X 1 and X 4 is N, the other is optionally CR 1 , and X 2 and X 3 are both N.
  • X 1 and X 4 are both N, and X 2 and X 3 are both N.
  • X 1 is N and X 2 , X 3 and X 4 are all CR 1 .
  • the group B is -CH 2 -, - (CH 2 ) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - CD 2 -, -(CD 2 ) 2 -, -(CD 2 ) 3 -, -(CD 2 ) 4 -,
  • R 2 is independently selected from dimethylamine, diethylamine, said dimethylamine, diethylamine radicals are optionally substituted with one or more deuterium atoms;
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • R 3 , R 3a , R 3b , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy group, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluo
  • X 6 is CR 3b
  • X 6, R 3 form a ring system together with the atoms to which they are attached, and optionally substituted by one or more identical or different R 4 is substituted.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (I) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (I) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • X 1 and/or X 4 are N
  • X 2 and X 3 are CH
  • the 5-HT 2A antagonistic activity and/or the 5-HT 2A inverse agonistic activity can be further enhanced.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X 3 , X 4 are each independently selected from CR 1 , N;
  • X 5 is independently selected from CR 3a , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3a , R 3c and R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents in hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • X is selected from -NH-, -(CH 2 ) 1-4 NH-;
  • Y is selected from O or S
  • n and n are independently selected from 0, 1, 2 and 3;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • X 3 and X 4 are CR 1.
  • X 3 is N
  • X 4 is CR 1.
  • X 3 is CR 1
  • X 4 is N.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterium substituted ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3a , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1- Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butyl Oxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy,
  • R 3 and the carbon atom, form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (II) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (II) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • X 3 , X 4 are each independently selected from CR 1 , N;
  • X 5 is independently selected from CR 3a , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • Each R 1 is the same or different, and each is independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3a , R 3c and R 3d are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents in hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • R 3 and the carbon atom, with the adjacent carbon atoms form a ring system, said ring system is selected from dihydro-furan, dihydro-pyrrole, dihydro-thiophene, and substituted by one or more identical or different R 4 substitution, each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight chain haloalkoxy or branched, wherein said linear or branched C 1-10 alkyl group, C 1-10 linear or branched alkoxy group is selected from a hydrogen atom, hydroxyl, C 1- 10 substituted by one or more substituents in straight-chain or branched-chain alkoxy groups;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • X 3 and X 4 are CR 1.
  • X 3 is N
  • X 4 is CR 1.
  • X 3 is CR 1
  • X 4 is N.
  • each R 1 is the same or different, each independently selected from the group consisting of a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterium substituted ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3a , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1- Dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butyl Oxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2
  • R 3 and the carbon atom form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (III) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • R 1 is independently selected from hydrogen atom, C 1-10 straight or branched chain alkyl, halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3c and R 3d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy , C 1-10 straight or branched chain haloalkoxy, wherein said C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected from hydrogen atoms , substituted by one or more substituents in halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • R 3 and the carbon atom, with the adjacent carbon atoms form a ring system, said ring system is selected from dihydro-furan, dihydro-pyrrole, dihydro-thiophene, and substituted by one or more identical or different R 4 substitution, each R 4 is independently selected from hydrogen atom, halogen, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight chain haloalkoxy or branched, wherein said linear or branched C 1-10 alkyl group, C 1-10 linear or branched alkoxy group is selected from a hydrogen atom, hydroxyl, C 1- 10 substituted by one or more substituents in straight-chain or branched-chain alkoxy groups;
  • s is independently selected from 1, 2, 3, 4, 5 and 6.
  • each R 1 is the same or different and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl, tert-butyl.
  • each R 2 is the same or different, each independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-Butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms.
  • R 3 , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethy
  • R 3 and the carbon atom form a ring system together with the adjacent carbon atoms, and optionally substituted by one or more identical or different substituents R 4.
  • the ring system is preferably selected from dihydrofuran, dihydropyrrole, and dihydrothiophene.
  • each R 4 is the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • any one of the compounds of formula (IV) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • X 4 is independently selected from CR 6 , N;
  • X 7 is independently selected from CR 3c , N;
  • X 8 is independently selected from CR 3d , N;
  • R 1 , R 5 , and R 6 are the same or different, and are each independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 3 , R 3c and R 3d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy , C 1-10 straight or branched chain haloalkoxy, wherein said C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected from hydrogen atoms , substituted by one or more substituents in halogen, hydroxyl, C 1-10 linear or branched alkoxy;
  • X 3 and X 4 are CR 5 and CR 6.
  • X 3 is N
  • X 4 is CR 6.
  • R 1 , R 5 , R 6 are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, iso propyl, butyl, isobutyl, sec-butyl, tert-butyl; preferably F, Cl, Br or I, more preferably F.
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterated ethyl; more preferably methyl or deuterated methyl.
  • R 3 , R 3c , R 3d are the same or different and are each independently selected from hydrogen, F, Cl, Br, I, hydroxy, methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl Butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethy
  • X 3 and X 7 are both CH;
  • X 4 is CR 6 , R 6 is hydrogen atom or halogen, X 4 is preferably CH or CF;
  • X 8 is CR 3d , R 3d is hydrogen atom or halogen, R 3d is preferably hydrogen atom, F, Cl or Br;
  • R 1 is halogen, preferably F
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, C 1-5 straight-chain or branched-chain alkyl group, a C 1-5 straight-chain or branched alkyl group optionally substituted with one or more deuterium atoms ; preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl or isopropyl optionally substituted by one or more deuterium atoms; preferably hydrogen atom, methyl or ethyl; more preferably methyl;
  • R 3 is selected from hydroxyl, C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy, C 1-10 straight or branched haloalkoxy, wherein the The C 1-10 linear or branched alkyl, C 1-10 linear or branched alkoxy are selected from hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy one or more substituents; R 3 is preferably a substituted or unsubstituted C 2-5 straight-chain or branched alkyl group, a substituted or unsubstituted C 2-5 straight-chain or branched, alkoxy group, a substituted or unsubstituted C 2-5 straight-chain or branched haloalkoxy group; R 3 is more preferably an ethoxy, tert-butyl group, isobutoxy, 2-fluoroethoxy, 2 , 2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-
  • X 3, X 4, X 7 and X 8 are CH;
  • R 1 is a halogen, preferably F;
  • R 2 is methyl;
  • R 3 is selected from halo-substituted alkoxy is C 1- 10 straight chain or branched chain group, preferably C 2-5 linear or branched haloalkoxy, more preferably 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 2,2'-difluoroisopropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 4, 4-difluorobutoxy or 4,4,4-trifluorobutoxy.
  • any one of the compounds of formula (V) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compounds of formula (V) provided by the present invention have higher 5-HT 2A antagonistic activity, 5-HT 2A inverse agonistic activity, and/or lower cardiotoxicity.
  • R 3 is a C 1-10 linear or branched alkoxy group substituted by halogen, and X 3 and X 4 are CH, the antagonistic activity of 5-HT 2A and/or the anti-reaction of 5-HT 2A can be further improved. to agonistic activity.
  • the present invention provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,
  • X 3 is independently selected from CR 5 and N;
  • X 4 is independently selected from CR 6 , N;
  • R 1 , R 5 , and R 6 are the same or different, and are each independently selected from a hydrogen atom, a C 1-10 straight-chain or branched-chain alkyl group, and a halogen;
  • R 2 is independently selected from hydrogen atom, deuterium atom, C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, 3-8 membered cycloalkyl , the C 1-10 linear or branched alkyl, (C 1-6 linear or branched alkyl) 2 amine group, or 3-8 membered cycloalkyl are optionally replaced by one or more Deuterium atom substitution;
  • R 4a , R 4b , R 4c and R 4d are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, C 1-10 straight or branched alkyl, C 1-10 straight or branched Alkoxy, C 1-10 straight or branched chain haloalkoxy, wherein the C 1-10 straight or branched alkyl, C 1-10 straight or branched alkoxy are selected Substituted from one or more substituents of hydrogen atom, halogen, hydroxyl, C 1-10 linear or branched alkoxy.
  • X 3 and X 4 are CR 5, CR 6.
  • X 3 is N
  • X 4 is CR 6.
  • X 3 is CR 5
  • X 4 is N.
  • R 1 is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, tert-butyl; preferably F, Cl, Br or I, more preferably F.
  • R 2 are the same or different and are independently selected from hydrogen atoms, deuterium atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl base, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally substituted with one or more deuterium atoms; preferably hydrogen, deuterium, methyl, ethyl, deuterated methyl or deuterated ethyl ; more preferably methyl or deuterated methyl.
  • R 4a , R 4b , R 4c , R 4d are the same or different and are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl, tert-butyl.
  • X 3 is CH
  • X 4 is CR 6 , R 6 is hydrogen atom or halogen, X 4 is preferably CH or CF;
  • R 1 is halogen, preferably F
  • R 2 is independently selected from a hydrogen atom, a deuterium atom, C 1-5 straight-chain or branched-chain alkyl group, a C 1-5 straight-chain or branched alkyl group optionally substituted with one or more deuterium atoms ; preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl or isopropyl optionally substituted by one or more deuterium atoms; preferably hydrogen atom, deuterium atom, methyl, ethyl, deuterated methyl or deuterated ethyl; more preferably methyl or deuterated methyl;
  • R 4a and R 4b are independently selected from hydrogen atoms, methyl groups, and trifluoromethyl groups; R 4c and R 4d are hydrogen atoms.
  • any one of the compounds of formula (VI) described above may be a deuterated analog thereof.
  • the deuterated analogs refer to analogs in which one or more hydrogen atoms of a compound are replaced by deuterium atoms.
  • the compound of formula (VI) provided by the present invention has higher 5-HT 2A antagonistic activity and/or 5-HT 2A inverse agonistic activity, and lower cardiotoxicity.
  • the present invention provides the following compounds or pharmaceutically acceptable salts, deuterated analogs thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds or a stereoisomer or a pharmaceutically acceptable salt thereof, or a crystal of any of the above-mentioned compounds form and a pharmaceutically acceptable carrier.
  • the carrier includes conventional adjuvant ingredients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents.
  • the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, Nasal sprays, transdermal patches, injections or various sustained and controlled release preparations, etc.
  • the pharmaceutical compositions can be administered orally, transmucosally, rectally or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular and intrasternal).
  • the administered dose can be appropriately adjusted according to the patient's age, sex and disease type.
  • the pharmaceutical compositions may be in the form of, for example, tablets, capsules, liquid capsules, suspensions or liquids.
  • the pharmaceutical compositions are preferably prepared in dosage unit form containing specified quantities of active ingredients.
  • the pharmaceutical composition may be provided as a tablet or capsule containing the active ingredient in an amount ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg.
  • Suitable daily dosages for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.
  • the present invention provides the use of any one of the above-mentioned compounds, pharmaceutically acceptable salts or stereoisomers thereof in a medicament for the treatment of 5-HT 2A receptor-related diseases.
  • the diseases or symptoms include: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorders, dementia, anxiety disorders, sleep disorders, appetite disorders, bipolar disorder, secondary to hypertension psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, motor convulsions, depression, major depressive disorder, anxiety, sleep and appetite disturbances, non-motor symptoms due to Parkinson's disease, delusions, hallucinations, Depression, anxiety, cognitive impairment, sleep disturbance, dementia-related psychiatric disorders, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spondylo-cerebellar atrophy, Tourette's syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, and also salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid (see Berge et al. , “Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods.
  • salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient, including but not limited to : Binder, filler, lubricant, disintegrant, wetting agent, dispersant, solubilizer, suspending agent, etc.
  • an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
  • an "effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • the present invention is intended to include all isotopes of atoms present in the compounds of the present invention.
  • Isotopes include those atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the otherwise used non-labeled reagent.
  • deuterated analog refers to an analog of a compound in which one or more hydrogen atoms have been replaced by a deuterium atom.
  • deuterium atoms optionally substituted with one or more deuterium atoms.
  • group may be unsubstituted by deuterium atoms, or substituted with one or more deuterium atoms, i.e., includes groups that are not substituted with deuterium atoms In the case of deuterated, partially deuterated and/or fully deuterated.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable of.
  • Ketone substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl denotes a straight-chain or branched saturated hydrocarbon chain may be mono-substituted (e.g., -CH 2 F) or substituted (e.g., -CF 3), which can be mono- (e.g. methyl), divalent (eg methylene), or polyvalent (eg methine).
  • C 1- C 10 represents 1 to 10 carbons, and C 1-10 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 ;
  • alkyl groups include methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, s-butyl) , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (eg, n-hexyl, isohexyl, 1,1-dimethyl butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkoxy is intended to include monohaloalkyl and polyhalogenated straight or branched chain haloalkoxy groups.
  • haloC 1-10 alkoxy is intended to include, but not be limited to, fluoromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2 , 2-difluoroethoxy, 2,2,2-trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3,3-difluoropropoxy, 2,2'-difluoroisopropoxy, 3,3,3-trifluoropropoxy, 4-fluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutanyl oxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy.
  • Haloalkyl is intended to include monohaloalkyl and polyhalogenated straight or branched chain alkyl groups.
  • halo (C 1 -C 4) alkyl is meant to include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl and the like Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents the aforementioned alkyl groups having the specified number of carbon atoms attached through an oxygen bridge.
  • Typical alkoxy groups include C 1-10 alkoxy groups such as: C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 alkoxy groups.
  • alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S- pentyloxy, hexyloxy, 2-ethylbutoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, etc.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, may be mono- or polysubstituted, and may be monovalent, divalent or polyvalent.
  • examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane, etc.
  • Figure 1 Comparison of drug-time curves after oral administration of pimavanserin and compound 59
  • compound 14a (210 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile, N-(4-isobutoxybenzyl)-1H-imidazole-carboxamide (273 mg, 1.0 mmol), potassium carbonate (207 mg, 1.5 mmol), the temperature was raised to 60 °C and the reaction was stirred for 12 h.
  • compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile, 32a (440 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol), diisopropylethylamine (387 mg, 3.0 mmol) were added and the temperature was raised to The reaction was stirred at 60°C for 12h.
  • 63b (1.49 g, 7.63 mmol) was dissolved in 20 ml of methanol, and (5-fluoropyridin-2methyl)amine (962.4 mg, 7.63 mmol), sodium triacetoxyborohydride (1.972 g, 9.31 mmol) were added. mmol), warmed to room temperature and reacted for 15h, added NaHCO 3 aqueous solution to adjust the pH value to basic, concentrated the organic phase, then extracted with dichloromethane (50mL*3), combined the organic phases, dried with anhydrous sodium sulfate, filtered, reduced Concentration column chromatography gave 63c (217 mg).
  • DMEM+10% FBS purchased from GBICO
  • Logarithmic growth phase NIH 3 T3-5HT 2A R cells at a density of 1000 cells per well were seeded in white wall clear bottom 96-well plates, 37 °C, 5% CO 2 incubator overnight The next day, to be The test compound was added to the cells, and the highest concentration of the test compound was 10 uM, which was diluted with PBS at 3.16-fold concentration gradient to 9 concentrations, and each concentration was set up in double wells. PBS was used as the negative control group, and pimavanserin with the same concentration was used as the positive control group. After adding the drug, continue to incubate at 37°C in a 5% CO 2 incubator for 120 hours.
  • Cell culture medium DMEM/F12+10% FBS (purchased from GBICO)
  • CHO-K1/5-HT 2A cells in logarithmic growth phase were seeded in a 384-well plate at a density of 10,000 cells per well, cultured at 37°C in a 5% CO 2 incubator for 16-24 hours, and centrifuged to remove the cell culture plate medium, adding the dye, into 37 °C, 5% CO 2 incubator incubation continued for 1h. Place the cell culture plate on the FLIPR, add the compound to be tested, and detect the Ca 2+ signal.
  • the highest concentration of the compound to be tested is 10uM, and 10 concentrations of the compound to be tested are diluted with 3-fold concentration gradient with PBS.
  • Inhibition rate (%) 100%-[(signal value of compound to be tested-signal value of detection solution)/(maximum signal value-signal value of detection solution)] ⁇ 100%
  • CHO-hERG cell line Choinese hamster ovary cells stably expressing hERG channels
  • CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, placed in an incubator at 37°C and 5% CO2, and passaged at a ratio of 1:5 every 48 hours.
  • the cell culture medium was aspirated, rinsed with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added, and digested at room temperature for 3-5 minutes. The digestion solution was aspirated, and the cells were resuspended in extracellular fluid and transferred to the experimental dish for electrophysiological recording.
  • Cisapride Take 10 ⁇ L of 150 ⁇ M Cisapride DMSO stock solution, transfer it to 4990 ⁇ L extracellular fluid, and dilute 500 times to obtain the final concentration to be tested, 300 nM.
  • hERG potassium channel currents were recorded by whole-cell patch-clamp technique at room temperature.
  • the glass microelectrode is drawn from the glass electrode blank (BF150-86-10, Sutter) by a drawing machine.
  • the tip resistance after filling the electrode liquid is about 2-5M ⁇ . Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier. Clamp voltages and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz.
  • the cells were clamped at -80mV and the step voltage evoked hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s then back to -80mV. This voltage stimulation was given every 10 s, and the dosing process was started after it was determined that the hERG potassium current was stable (1 min). Compounds were administered for at least 1 minute at each concentration tested and at least 2 cells were tested at each concentration (n > 2).
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after drug addition and before drug addition, respectively.
  • Test Example 3 In vitro stability evaluation of pimavanserin and compound 59 in liver microsomes
  • liver microsome working solution Dilute liver microsomes to 0.56 mg/ml with 100 mM phosphate buffer;
  • NADPH reduced nicotinamide adenine dinucleotide phosphate
  • Stop solution configuration Dilute tolbutamide to 20ng/mL with acetonitrile, as stop solution containing internal standard.
  • Pimavanserin purchased from MCE Company.
  • Eight SD rats weighing about 220 grams were randomly divided into 2 groups, 4 rats in each group, fasted for 12 hours before administration, and administered pimavanserin and compound 59 by intragastric administration at a dose of 46.7 ⁇ mol/kg, respectively.
  • Vehicles were all 20% Solutol.
  • Blood was collected before administration and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration, respectively. The blood was placed in a heparinized EP tube, and the plasma was centrifuged to separate the plasma. Plasma concentrations of compounds were determined by LC-MS/MS, and pharmacokinetic parameters were calculated.

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Abstract

本发明涉及一种作为5-HT 2A受体抑制剂或反向激动剂的新化合物及其制备方法和药物组合物。还涉及含有所述化合物或药物组合物在制备治疗5-HT 2A受体相关疾病的药物中的应用，所述疾病包括帕金森病引起的非运动症状：妄想、幻觉、抑郁、焦虑、认知障碍、睡眠障碍；痴呆相关的精神疾病；重度抑郁症；或精神分裂的阴性症状等。

Description

5-HT 2A受体抑制剂或反向激动剂及其制备方法和应用 技术领域
本发明涉及一类作为选择性5-羟色胺2A(5-HT 2A)受体抑制剂或反向激动剂的化合物及其制备方法，及其在与5-HT 2A受体相关疾病领域的应用。
背景技术
帕金森症(Parkinson’s disease，PD)是一种常见的神经系统变性疾病，平均发病年龄为60岁左右(Degirmenci,Yildiz.Cumhuriyet Medical Journal(2017),39(3),509-517.)。据2018年美国国立卫生研究院(NIH)数据显示，全球范围内大约有400万～600万帕金森症患者，其中，多达50％的帕金森症患者患病期间会产生幻觉或妄想的严重症状，严重影响患者的生活质量，并且具有较高的发病率和死亡率。
2016年，美国FDA批准匹莫范色林(Pimavanserin)上市，用于治疗帕金森病伴发的幻觉和妄想症状，成为首个获批该适应症的药物。
Figure PCTCN2021107774-appb-000001
匹莫范色林
匹莫范色林作用于5-HT 2A受体，是5-HT受体家族中的一种主要兴奋性受体亚型，属于配体门控通道和G蛋白耦联受体。5-HT 2A受体功能与神经元兴奋、行为效果、学习记忆和焦虑等密切相关，是抗精神病药物及精神分裂症治疗的重要作用靶点(Price,D.L.,et al.Behavioural Pharmacology(2012),23(4),426-433.)。由于第一代抗精神病药物主要是抑制多巴胺D 2受体，有着严重的锥体外束副作用。第二代抗精神病药物除抑制D 2受体外，还更多抑制特定的5-HT受体特别是5-HT 2A受体，具有更好的安全性，即锥体外束副作用比第一代抗精神病药物更小。但是，由于第二代抗精神病药物仍然具有D 2受体的抑制活性，因此仍然有锥体外束副作用，同时该类药物出现不同程度的体重增加的副作用。
因此，开发选择性5-HT 2A受体抑制剂或反向激动剂，可消除第一代和第二代抗精神病药物多巴胺受体抑制相关的锥体外束和体重增加副作用，具有更好的安全性，并且还可应用于其它与5-HT 2A体相关的疾病治疗，以满足临床患者的需求。
发明内容
在一个方面中，本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000002
其中，
X 1和X 4中的至少一个为N，另一个任选为CR 1或N；
X 2、X 3各自独立选自CR 1、N；
X 5独立选自CR 3a、N；
X 6独立选自CR 3b、N；
X 7独立选自CR 3c、N；
X 8独立选自CR 3d、N；
基团B为C 1-6直链或支链的烷基，5-6元氮杂环基，所述C 1-6直链或支链的烷基、或5-6元氮杂环基任选地被一个或多个氘原子取代；
每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
每个R 2相同或不同，各自独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 3、R 3a、R 3b、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
或者当X 6为CR 3b时，X 6、R 3与它们所连接的原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
X选自-NH-、-(CH 2) 1-4NH-；
Y选自O或S；
m和n独立地选自0、1、2和3；
s独立地选自1、2、3、4、5和6；
y独立地选自0、1、2、3、4和5。
在式(I)化合物的一个实施方案中，X 1和X 4中的至少一个为N，另一个任选为CR 1；X 2、X 3各自独立选自CR 1，优选为CH。
在式(I)化合物的一个实施方案中，X 1和X 4均为N，X 2、X 3各自独立选自CR 1。
在式(I)化合物的一个实施方案中，X 1和X 4中的至少一个为N，另一个任选为CR 1，X 2、X 3中的至少一个为N，另一个任选为CR 1。
在式(I)化合物的一个实施方案中，X 1和X 4均为N，X 2、X 3中的至少一个为N，另一个任选为CR 1。
在式(I)化合物的一个实施方案中，X 1和X 4中的至少一个为N，另一个任选为CR 1，X 2、X 3中均为N。
在式(I)化合物的一个实施方案中，X 1和X 4均为N，X 2、X 3均为N。
在式(I)化合物的一个实施方案中，优选X 1为N，X 2、X 3和X 4均为CR 1。
在式(I)化合物的一个实施方案中，基团B为-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-(CH 2) 4-、-CD 2-、-(CD 2) 2-、-(CD 2) 3-、-(CD 2) 4-，R 2独立地选自二甲胺基、二乙胺基，所述二甲胺基、二乙胺基 任选被一个或多个氘原子取代；
或者基团B为选自哌啶基，所述哌啶基任选地被一个或多个氘原子取代，R 2独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代。
在式(I)化合物的一个实施方案中，每个R 1相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在式(I)化合物的一个实施方案中，每个R 2相同或不同，各自独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代。
在式(I)化合物的一个实施方案中，R 3、R 3a、R 3b、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基-3-羟基-丁基、i-Pr-O-CH 2-。
在式(I)化合物的一个实施方案中，或者当X 6为CR 3b时，X 6、R 3与它们所连接的原子一起形成环系，并且任选地被一个或多个相同或不同的R 4取代。
其中，所述环系优选自二氢呋喃、二氢吡咯、二氢噻吩。
其中，每个R 4相同或不同，各自独立地选自自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在本发明的一个具体实施方式中，上述任一所述式(I)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(I)化合物具有更高的5-HT 2A拮抗活性、5-HT 2A反向激动活性，和/或更低的心脏毒性。尤其是当X 1和/或X 4为N，X 2和X 3为CH时，可进一步提高5-HT 2A拮抗活性和/或5-HT 2A反向激动活性。
在另一个方面中，本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000003
其中，
X 3、X 4各自独立选自CR 1、N；
X 5独立选自CR 3a、N；
X 7独立选自CR 3c、N；
X 8独立选自CR 3d、N；
每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1- 10直链或支链的烷氧基中的一个或多个取代基所取代；
X选自-NH-、-(CH 2) 1-4NH-；
Y选自O或S；
m和n独立地选自0、1、2和3；
s独立地选自1、2、3、4、5和6。
在式(II)化合物的一个实施方案中，X 3和X 4均为CR 1。
在式(II)化合物的一个实施方案中，X 3为N，X 4为CR 1。
在式(II)化合物的一个实施方案中，X 3为CR 1，X 4为N。
在式(II)化合物的一个实施方案中，每个R 1相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在式(II)化合物的一个实施方案中，每个R 2相同或不同，各自独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、氘代甲基或氘代乙基；更优选为甲基或氘代甲基。
在式(II)化合物的一个实施方案中，R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基 -3-羟基-丁基、i-Pr-O-CH 2-。
在式(II)化合物的一个实施方案中，R 3、及其相连碳原子、与相邻的碳原子一起形成环系，并且任选地被一个或多个相同或不同的R 4取代。
其中，所述环系优选自二氢呋喃、二氢吡咯、二氢噻吩。
其中，每个R 4相同或不同，各自独立地选自自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在本发明的一个具体实施方式中，上述任一所述式(II)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(II)化合物具有更高的5-HT 2A拮抗活性、5-HT 2A反向激动活性，和/或更低的心脏毒性。在另一个方面中，本发明提供了式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000004
其中，
X 3、X 4各自独立选自CR 1、N；
X 5独立选自CR 3a、N；
X 7独立选自CR 3c、N；
X 8独立选自CR 3d、N；
每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1- 10直链或支链的烷氧基中的一个或多个取代基所取代；
s独立地选自1、2、3、4、5和6。
在式(III)化合物的一个实施方案中，X 3和X 4均为CR 1。
在式(III)化合物的一个实施方案中，X 3为N，X 4为CR 1。
在式(III)化合物的一个实施方案中，X 3为CR 1，X 4为N。
在式(III)化合物的一个实施方案中，每个R 1相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在式(III)化合物的一个实施方案中，每个R 2相同或不同，各自独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、氘代甲基或氘代乙基；更优选为甲基或氘代甲基。
在式(III)化合物的一个实施方案中，R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基-3-羟基-丁基、i-Pr-O-CH 2-。
在式(III)化合物的一个实施方案中，R 3、及其相连碳原子、与相邻的碳原子一起形成环系，并且任选地被一个或多个相同或不同的R 4取代。
其中，所述环系优选自二氢呋喃、二氢吡咯、二氢噻吩。
其中，每个R 4相同或不同，各自独立地选自自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在本发明的一个具体实施方式中，上述任一所述式(III)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(III)化合物具有更高的5-HT 2A拮抗活性、5-HT 2A反向激动活性，和/或更低的心脏毒性。在另一个方面中，本发明提供了式(IV)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000005
其中，
X 7独立选自CR 3c、N；
X 8独立选自CR 3d、N；
R 1独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1- 10直链或支链的烷氧基中的一个或多个取代基所取代；
s独立地选自1、2、3、4、5和6。
在式(IV)化合物的一个实施方案中，每个R 1相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在式(IV)化合物的一个实施方案中，每个R 2相同或不同，各自独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代。
在式(IV)化合物的一个实施方案中，R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基-3-羟基-丁基、i-Pr-O-CH 2-。
在式(IV)化合物的一个实施方案中，R 3、及其相连碳原子、与相邻的碳原子一起形成环系，并且任选地被一个或多个相同或不同的R 4取代。
其中，所述环系优选自二氢呋喃、二氢吡咯、二氢噻吩。
其中，每个R 4相同或不同，各自独立地选自自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在本发明的一个具体实施方式中，上述任一所述式(IV)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(IV)化合物具有更高的5-HT 2A拮抗活性、5-HT 2A反向激动活性，和/或更低的心脏毒性。
在另一个方面中，本发明提供了式(V)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000006
其中，
X 3独立选自CR 5、N；
X 4独立选自CR 6、N；
X 7独立选自CR 3c、N；
X 8独立选自CR 3d、N；
R 1、R 5、R 6相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
在式(V)化合物的一个实施方案中，X 3和X 4分别为CR 5和CR 6。
在式(V)化合物的一个实施方案中，X 3为N，X 4为CR 6。
在式(V)化合物的一个实施方案中，X 3为CR 5，X 4为N。
在式(V)化合物的一个实施方案中，R 1、R 5、R 6相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基；优选为F、Cl、Br或I，更优选为F。
在式(V)化合物的一个实施方案中，R 2独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、氘代甲基或氘代乙基；更优选为甲基或氘代甲基。
在式(V)化合物的一个实施方案中，R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基-3-羟基 -丁基、i-Pr-O-CH 2-。
在式(V)化合物的一个实施方案中，
X 3和X 7均为CH；
X 4为CR 6，R 6为氢原子或卤素，X 4优选为CH或CF；
X 8为CR 3d，R 3d为氢原子或卤素，R 3d优选为氢原子、F、Cl或Br；
R 1为卤素，优选为F；
R 2独立地选自氢原子、氘原子、C 1-5直链或支链的烷基，所述C 1-5直链或支链的烷基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、丙基或异丙基，所述甲基、乙基、丙基或异丙基任选地被一个或多个氘原子取代；优选为氢原子、甲基或乙基；更优选为甲基；
R 3选自羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；R 3优选为取代或未被取代的C 2-5直链或支链的烷基、取代或未被取代的C 2-5直链或支链的烷氧基、取代或未被取代的C 2-5直链或支链的卤代烷氧基；R 3更优选为乙氧基、叔丁基、异丁氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基或羟基。
在式(V)化合物的一个实施方案中，
X 3、X 4、X 7和X 8均为CH；R 1为卤素，优选为F；R 2为甲基；R 3选自被卤素取代的C 1- 10直链或支链的烷氧基，优选为C 2-5直链或支链的卤代烷氧基，更优选为2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基或4，4，4-三氟丁氧基。
在本发明的一个具体实施方式中，上述任一所述式(V)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(V)化合物具有更高的5-HT 2A拮抗活性、5-HT 2A反向激动活性，和/或更低的心脏毒性。尤其是当R 3为被卤素取代的C 1-10直链或支链的烷氧基，X 3和X 4为CH时，可进一步提高5-HT 2A拮抗活性和/或5-HT 2A反向激动活性。
在另一个方面中，本发明提供了式(VI)所示化合物或其药学上可接受的盐，
Figure PCTCN2021107774-appb-000007
其中，
X 3独立选自CR 5、N；
X 4独立选自CR 6、N；
R 1、R 5、R 6相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
R 4a、R 4b、R 4c、R 4d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代。
在式(VI)化合物的一个实施方案中，X 3和X 4分别为CR 5、CR 6。
在式(VI))化合物的一个实施方案中，X 3为N，X 4为CR 6。
在式(VI)化合物的一个实施方案中，X 3为CR 5，X 4为N。
在式(VI)化合物的一个实施方案中，R 1独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基；优选为F、Cl、Br或I，更优选为F。
在式(VI)化合物的一个实施方案中，R 2相同或不同，独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、氘代甲基或氘代乙基；更优选为甲基或氘代甲基。
在式(VI)化合物的一个实施方案中，R 4a、R 4b、R 4c、R 4d相同或不同，各自独立地选自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
在式(VI)化合物的一个实施方案中，
X 3为CH；
X 4为CR 6，R 6为氢原子或卤素，X 4优选为CH或CF；
R 1为卤素，优选为F；
R 2独立地选自氢原子、氘原子、C 1-5直链或支链的烷基，所述C 1-5直链或支链的烷基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、丙基或异丙基，所述甲基、乙基、丙基或异丙基任选地被一个或多个氘原子取代；优选为氢原子、氘原子、甲基、乙基、氘代甲基或氘代乙基；更优选为甲基或氘代甲基；
R 4a、R 4b独立地选自氢原子、甲基、三氟甲基；R 4c、R 4d为氢原子。
在本发明的一个具体实施方式中，上述任一所述式(VI)化合物可以是其氘代类似物。所述氘代类似物指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。
相对于匹莫范色林，本发明提供的式(VI)化合物具有更高的5-HT 2A拮抗活性和/或5-HT 2A反向激动活性，更低的心脏毒性。
在另一个方面中，本发明提供了如下所示化合物或其药学上可接受的盐、氘代类似物：
Figure PCTCN2021107774-appb-000008
Figure PCTCN2021107774-appb-000009
Figure PCTCN2021107774-appb-000010
Figure PCTCN2021107774-appb-000011
Figure PCTCN2021107774-appb-000012
Figure PCTCN2021107774-appb-000013
Figure PCTCN2021107774-appb-000014
Figure PCTCN2021107774-appb-000015
Figure PCTCN2021107774-appb-000016
在一个方面中，本发明提供了一种药物组合物，包括治疗有效量的上述任一所述化合物或其立体异构体或其药学上可接受的盐，或上述任一所述化合物的结晶形式以及药学上可接受的载体。所述载体，包括本领域中常规的辅料成分，例如、填充剂、粘合剂、稀释剂、崩解剂、润滑剂、着色剂、调味剂、抗氧化剂和润湿剂等。
所述药物组合物可以制备成药学上可接受的各种剂型，如片剂、胶囊剂、口服液剂、混悬液、颗粒剂、粉剂、微粒剂、丸剂、微型片剂、速溶膜剂、鼻喷雾剂、透皮贴剂、注射剂或各种缓控释制剂等。所述药物组合物可以经口服、经粘膜、经直肠或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌肉内和胸骨内)给药。给药剂量可根据患者的年龄、性别和疾病类型进行适当调整。
对于口服给药，所述药物组合物可呈例如片剂、胶囊、液体胶囊、悬浮液或液体形式。所述药物组合物优选以含有特定量活性成分的剂量单位形式制得。例如，所述药物组合物可以包含约0.1至1000mg，优选约0.25至250mg，且更优选约0.5至100mg范围内的量的活性成分的片剂或胶囊提供。用于人类或其它哺乳动物的适合日剂量可根据患者的病况及其它因素而广泛变化，但可使用常规方法确定。
在一个方面中，本发明提供了上述任一所述化合物、其药学上可接受的盐或其立体异构体用于治疗5-HT 2A受体相关疾病的药物中的应用。所述疾病或症状包括：精神分裂症、精神病、分裂情感性障碍、躁狂症、精神病性抑郁症、情感障碍、痴呆、焦虑症、睡眠障碍、食欲障碍、双相性精神障碍、高血压继发的精神病、偏头痛、高血压、血栓形成、血管痉挛、局部 缺血、运动性抽搐、抑郁、重度抑郁症、焦虑、睡眠紊乱和食欲紊乱、帕金森病引起的非运动症状、妄想、幻觉、抑郁、焦虑、认知障碍、睡眠障碍、痴呆相关的精神疾病、精神分裂的阴性症状、帕金森氏病、亨延顿舞蹈病、阿耳茨海默病、脊椎小脑萎缩症、图雷特氏综合征、弗里德赖希共济失调、马查多-约瑟夫病、路易体痴呆、运动障碍、肌张力障碍、肌阵挛、震颤、进行性核上性麻痹和额颞叶痴呆；或其它对本领域技术人员而言显而易见的其他疾病状态和状况。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的酸加成盐的实例包括无机酸盐、有机酸盐，还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，盐的制备方法为：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生 物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体，包括但不限于：粘合剂、填充剂、润滑剂、崩解剂、润湿剂、分散剂、增溶剂、助悬剂等。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。作为一般实例且非限制性地，氢的同位素包括氘和氚。碳的同位素包括 13C和 14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所述的方法，使用适当同位素标记试剂代替另外使用的非标记试剂来制备。
术语“氘代类似物”指的是化合物的一个或多个氢原子被氘原子替代所产生的类似物。术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。例如，“任选地被一个或多个氘原子取代”是指所述基团可以是未被氘原子取代的情况、或者被一个或多个氘原子取代的情况，即包括了基团未被氘代、部分氘代和/或全部氘代的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。例如如C 1-C 10表示1至10个碳，C 1-10选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9和C 10；烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基，1-乙基丙基)，己基(如，n-己基，异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基)，庚基，辛基，壬基，癸基等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。术语“卤代烷氧基”意在包括单卤代烷基和多卤代直链或支链的卤代烷氧基。例如，术语“卤代C 1-10烷氧基意在包括但不仅限于氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基。
“卤代烷基”意在包括单卤代烷基和多卤代直链或支链的烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
除非另有规定，“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。典型的 烷氧基包括C 1-10烷氧基，例如：C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10的烷氧基。烷氧基的例子包括但不限于：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、正戊氧基、S-戊氧基、己氧基、2-乙基丁氧基、庚氧基、辛氧基、壬氧基，癸氧基等
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
化合物经手工或者
Figure PCTCN2021107774-appb-000017
软件命名，市售化合物采用供应商目录名称。
附图说明
图1：匹莫范色林及化合物59灌胃给药后药时曲线对比图
具体实施方式
下面结合具体实施例和试验例，进一步阐述本发明，但不以任何形式限制本发明的范围。
实施例1：
Figure PCTCN2021107774-appb-000018
合成路线：
Figure PCTCN2021107774-appb-000019
1、氮气保护，冰水浴下，将2-(氨甲基)-5-氟吡啶(504mg，4.0mmol)溶于10ml甲醇中，加入N-甲基-4哌啶酮(452mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物1a(538mg)，不经纯化直接用于下一步反应。
2、氮气保护，将化合物1a(446mg，2.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(546mg，2.0mmol)、碳酸钾(414mg，3.0mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物1(414mg，淡黄色固体)，产率：48％。MS m/z(ESI)：429.3[M+1]； 1H NMR(400MHz,CDCl 3)δ8.26(d,1H),7.38-7.32(m,1H),7.31-7.28(m,1H),7.18-7.14(m,2H),6.85-6.80(m, 2H),6.64-6.58(m,1H),4.37(s,2H),4.34(d,2H),3.70(d,2H),2.93-2.87(m,2H),2.28(s,3H),2.13-1.98(m,4H),1.81-1.64(m,4H),1.02(d,6H).
采用与实施例1类似的方式制备化合物2-3、12-13、16、19-20、23-31、33-52、58、61、64、66-68、70-72、75-77、80-81、83-101。
表1：化合物2-3、12-13、16、19-20、23-31、33-52、58、61、64、66-68、70-72、75-77、80-81、83-101结构和表征数据
Figure PCTCN2021107774-appb-000020
Figure PCTCN2021107774-appb-000021
Figure PCTCN2021107774-appb-000022
Figure PCTCN2021107774-appb-000023
Figure PCTCN2021107774-appb-000024
Figure PCTCN2021107774-appb-000025
Figure PCTCN2021107774-appb-000026
Figure PCTCN2021107774-appb-000027
Figure PCTCN2021107774-appb-000028
Figure PCTCN2021107774-appb-000029
实施例2：
Figure PCTCN2021107774-appb-000030
氮气保护，冰水浴下，将1-甲基吡唑-4-甲醛(440mg，4.0mmol)溶于10ml甲醇中，加入N-甲基-4哌啶酮(452mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升 至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物4a(617mg)。
氮气保护，将化合物4a(208mg，1.0mmol)溶于5ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(273mg，1.0mmol)、碳酸钾(207mg，1.5mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水10ml，然后用二氯甲烷萃取(5mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物4(172mg，产率：43％)。MS m/z(ESI)：414.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.38(s,1H),7.17(s,1H),7.12-7.07(m,2H),6.82-6.77(m,2H),4.69(m,1H),4.30-4.25(m,2H),4.23-4.20(m,2H),3.78(s,3H),3.69-3.64(d,2H),2.98-2.88(m,2H),2.32(s,3H),2.18-2.02(m,3H),1.80-1.65(m,4H),1.04-0.99(d,6H).
以与化合物4类似的方式制备化合物5、8、22。
表2：化合物5、8、22结构和表征数据
Figure PCTCN2021107774-appb-000031
实施例3：
Figure PCTCN2021107774-appb-000032
Figure PCTCN2021107774-appb-000033
将N-Boc-溴乙胺(2.23g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物6a(1.97g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入6a(968mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物6b(912mg)。
氮气保护，将化合物6b(702mg，2.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(546mg，2.0mmol)、碳酸钾(414mg，3.0mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物6c(467mg)。
氮气保护，将化合物6c(278mg，0.5mmol)溶于5ml二氯甲烷中，加入三氟乙酸(285mg，2.5mmol)，在室温下反应2h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(5ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物6(201mg，产率：88％)。MS m/z(ESI)：457.2[M+1]； 1H NMR(400MHz,CDCl 3)δ7.25-7.23(m,2H),7.02-6.98(m,4H),6.78-6.75(m,2H),4.48-4.27(m,5H),3.62-3.59(m,2H),3.51-3.29(m,2H),2.94-2.89(m,2H),2.84-2.80(m,2H),2.47-2.41(m,2H),2.18-2.02(m,3H),1.75-1.68(m,4H),1.02-0.98(d,6H).
实施例4：
Figure PCTCN2021107774-appb-000034
Figure PCTCN2021107774-appb-000035
将1-(2-溴乙基)咪唑烷-2-酮(1.93g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物7a(1.56g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入7a(844mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物7b(812mg)。
氮气保护，将化合物7b(640mg，2.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(546mg，2.0mmol)、碳酸钾(414mg，3.0mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物7(494mg，产率：47％)。MS m/z(ESI)：526.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.24-7.22(m,2H),7.02-6.98(m,4H),6.78-6.75(m,2H),4.60-4.54(m,2H),4.32-4.26(m,4H),3.72-3.62(m,4H),3.51-3.44(m,2H),3.41-3.32(m,2H),3.30-3.26(m,2H),2.98-2.92(m,2H),2.47-2.41(m,2H),2.18-2.02(m,3H),1.74-1.65(m,4H),1.02-0.99(d,6H).
实施例5：
Figure PCTCN2021107774-appb-000036
将叔丁基二甲基溴乙氧基硅烷(2.38g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降 至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物9a(1.72g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入9a(1028mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物9b(812mg)。
氮气保护，将化合物9b(732mg，2.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(546mg，2.0mmol)、碳酸钾(414mg，3.0mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物9c(327mg，)。
氮气保护，将化合物9c(286mg，0.5mmol)溶于5ml THF中，加入1M的四丁基氟化铵四氢呋喃溶液(1ml，1.0mmol)，在室温下反应2h。浓缩有机相，然后用二氯甲烷萃取(5ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物9(118mg，产率：52％)。MS m/z(ESI)：458.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.23-7.20(m,2H),7.02-6.98(m,4H),6.81-6.76(m,2H),4.70-4.50(m,2H),4.38-4.27(m,4H),3.78-3.69(m,4H),3.41-3.19(m,2H),2.84-2.74(m,2H),2.67-2.51(m,2H),2.18-2.02(m,2H),1.81-1.58(m,3H),1.02-0.98(d,6H).
实施例6：
Figure PCTCN2021107774-appb-000037
将2-溴-N,N-二甲基乙酰胺(1.66g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物10a(1.15g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入10a(736mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物10b(832mg)。
氮气保护，将化合物10b(586mg，2.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(546mg，2.0mmol)、碳酸钾(414mg，3.0mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物10(535mg，产率：54％)。MS m/z(ESI)：499.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.20-7.13(m,2H),7.02-6.95(m,4H),6.77-6.73(m,2H),4.48-4.43(m,1H),4.38-4.27(m,3H),4.26-4.23(m,2H),3.66(d,2H),3.15(d,2H),3.02-2.88(m,8H),2.30-2.20(m,2H),2.10-2.00(m,1H),1.80-1.65(m,4H),1.01-0.96(d,6H).
实施例7：
Figure PCTCN2021107774-appb-000038
将7-(4-溴丁氧基)-3,4-二氢-2(1H)-喹啉酮(2.98g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物11a(2.26g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入11a(1.26g，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物11b(1.03g)。
氮气保护，将化合物11b(425mg，1.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基 苄基)-1H-咪唑-甲酰胺(273mg，1.0mmol)、碳酸钾(207mg，1.5mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物11(311mg，产率：49％)。MS m/z(ESI)：631.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.96(s,1H),7.20-7.15(m,2H),7.04-6.96(m,4H),6.79-6.75(m,2H),6.50-6.43(m,1H),6.32-6.28(m,1H),4.70-4.52(m,2H),4.48-4.43(m,2H),4.31-4.27(m,2H),3.98-3.90(m,2H),3.64(d,2H),3.50-3.20(d,2H),2.82-2.58(m,4H),2.56-2.44(m,4H),2.10-2.00(m,2H),1.90-1.65(m,7H),1.02-0.97(d,6H).
实施例8：
Figure PCTCN2021107774-appb-000039
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入N,N-二甲基-1,3-二氨基丙烷(408mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物14a(587mg)。
氮气保护，将化合物14a(210mg，1.0mmol)溶于5ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(273mg，1.0mmol)、碳酸钾(207mg，1.5mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水10ml，然后用二氯甲烷萃取(5ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物13(202mg，产率：48％)。MS m/z(ESI)：416.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.26-7.20(m,4H),7.02-6.97(m,2H),6.81-6.76(m,2H),4.47(s,2H),4.38-4.35(m,2H),3.71(s,2H),3.30-3.24(m,2H),2.35-2.25(m,2H),2.15-2.00(m,7H),1.65-1.58(m,2H),1.02-0.98(d,6H).
实施例9：
Figure PCTCN2021107774-appb-000040
将(2-溴甲基)二甲胺(1.52g，10.0mmol)溶于20ml DMF中，加入4-哌啶酮(0.99g，10.0mmol)、碳酸钾(2.07g，15.0mmol)，升温至80℃搅拌反应8h。反应液降至室温，加入60ml水，然后用二氯甲烷萃取(60ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物15a(1.17g)。
氮气保护，冰水浴下，将4-氟苄胺(500mg，4.0mmol)溶于10ml甲醇中，加入15a(680mg，4.0mmol)、三乙酰氧基硼氢化钠(933mg，4.4mmol)，升至室温反应15h。加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩得化合物15b(611mg)。
氮气保护，将化合物15b(279mg，1.0mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-甲酰胺(273mg，1.0mmol)、碳酸钾(207mg，1.5mmol)，升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物15(287mg，产率：59％)。MS m/z(ESI)：485.3[M+1]； 1H NMR(400MHz,CDCl 3)δ7.22-7.16(m,2H),7.02-6.95(m,4H),6.77-6.75(m,2H),4.55-4.46(m,1H),4.38-4.32(m,2H),4.26-4.23(m,2H),3.67(d,2H),3.19(d,1H),2.98-2.68(m,6H),2.61(s,6H),2.45-2.35(m,2H),2.10-2.00(m,2H),1.80-1.65(m,2H),1.01-0.96(d,6H).
实施例10：
Figure PCTCN2021107774-appb-000041
Figure PCTCN2021107774-appb-000042
氮气保护，将化合物3(372mg，1.0mmol)溶于10ml乙腈中，加入1-溴-3-氟丙烷(211mg，1.5mmol)、碳酸铯(652mg，2.0mmol)，升温至60℃搅拌反应5h。冷却至室温，过滤，滤液加水10ml，然后用二氯甲烷萃取(10ml*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物17(238mg，产率：54％)。MS m/z(ESI)：433.2[M+1]； 1H NMR(400MHz,CDCl 3)δ8.22(s,1H),7.45-7.35(m,2H),7.22-7.14(m,2H),7.15-7.07(m,1H),6.85-6.81(m,2H),4.67(t,1H),4.60(t,1H),4.44-4.34(m,3H),4.34(d,2H),4.07(t,2H),3.12(d,2H),2.46(s,3H),2.40-2.32(m,2H),2.19-2.05(m,4H),1.75-1.67(m,2H).
以与化合物17类似的方式制备化合物18、55-57、59-60、62、65、69、73-74、78、82。
表3：化合物18、55-57、59-60、62、65、69、73-74、78、82结构和表征数据
Figure PCTCN2021107774-appb-000043
Figure PCTCN2021107774-appb-000044
Figure PCTCN2021107774-appb-000045
实施例11：
Figure PCTCN2021107774-appb-000046
氮气保护，将化合物1a(446mg，2.0mmol)溶于10ml乙腈中，加入32a(440mg，2.0mmol)、HATU(760mg，2.0mmol)，二异丙基乙基胺(387mg，3.0mmol)升温至60℃搅拌反应12h。冷却至室温，过滤，滤液加水20ml，然后用二氯甲烷萃取(10mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物32(561mg，产率：66％)。MS m/z(ESI)：426.2[M+1]； 1H NMR(400MHz,DMSO-d 6)δ8.50(s,1H),7.72-7.64(m,1H),7.26-7.20(m,1H),6.99-6.87(m,2H),6.62-6.50(m,1H),4.53(s,2H),4.38-4.24(m,1H),2.97-2.92(m,2H),2.80-2.61(m,5H),2.55-2.52(m,1H),2.12(s,3H),1.98-1.88(m,2H),1.65-1.30(m,10H).
以与化合物32类似的方式制备化合物53、54。
表4：化合物53、54结构和表征数据
Figure PCTCN2021107774-appb-000047
实施例12:
Figure PCTCN2021107774-appb-000048
合成路线：
Figure PCTCN2021107774-appb-000049
氮气保护，将63a(1.212g，11.3mmol)溶于10ml乙腈中，加入溴甲基环己烷(2g，11.3mmol)、碳酸钾(4.68g，33.9mmol)，升温至60℃搅拌反应12h，冷却至室温，过滤，然后用二氯甲烷萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得63b(1.49g，淡黄色油状液体)。
氮气保护，将63b(1.49g，7.63mmol)溶于20ml甲醇中，加入(5-氟吡啶-2甲基)胺(962.4mg，7.63mmol)、三乙酰氧基硼氢化钠(1.972g，9.31mmol)，升至室温反应15h，加入NaHCO 3水溶液调pH值至碱性，浓缩有机相，然后用二氯甲烷萃取(50mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩柱层析得63c(217mg)。
氮气保护，将63c(217mg，0.71mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-1-甲酰胺(194mg，0.710mmol)、碳酸钾(107.9mg，0.781mmol)，升温至60℃搅拌反应12h，冷却至室温，过滤，然后用二氯甲烷萃取(30mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物63(50.5mg，淡黄色油状液体)，收率：14％。MS m/z(ESI)：511.69[M+1] 1H NMR(600MHz,CDCl 3)δ8.24(d,1H),7.37(d,2H),7.17(d,2H),6.90-6.75(m,2H),4.42(s,2H),4.33(d,2H),3.70(d,2H),3.11(s,2H),2.41-2.14(m,1H),2.11-2.01(m,2H),1.85-1.63(m,10H),1.46-1.36(m,2H),1.31(d,2H),1.24(d,2H),1.16(s,2H),1.02(s,3H),1.01(s,3H).
实施例13：
Figure PCTCN2021107774-appb-000050
合成路线：
Figure PCTCN2021107774-appb-000051
氮气保护，将79a(200mg，0.75mmol)溶于10ml乙腈中，加入N-(4-异丁氧基苄基)-1H-咪唑-1-甲酰胺(207mg，0.75mmol)、碳酸钾(105mg，0.75mmol)，升温至60℃搅拌反应5h。冷却至室温，过滤，然后用二氯甲烷萃取(20mL*3)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩有机相，用柱层析分离(二氯甲烷：甲醇＝10:1)，得化合物79(166mg，淡黄色油状液体)，收率：47％。MS m/z(ESI)：471.2[M+1] 1H NMR(600MHz,CDCl 3)δ7.20(m,2H),7.01(m,4H),6.92(s,1H),6.81-6.74(m,2H),5.40(s,1H),4.44(t,1H),4.34(s,3H),4.27(d,2H),3.68(d,2H),2.98(s,2H),2.94-2.87(m,2H),2.31(m,2H),2.06(m,1H),1.80-1.74(m,2H),1.66(m,2H),1.01(d,J＝6.7Hz,6H).
试验例1. 5-HT 2A受体的体外活性测试
1. 5-HT 2A反向激动活性筛选
1.1实验材料：
细胞系：贴壁细胞NIH3T3-5-HT 2A R
细胞培养基：DMEM+10％FBS(购自GBICO)
细胞培养板：白壁透底96孔板(购自Perkin Elmer)
检测试剂盒：Bright-Glo TMLuciferase(购自Promega)
检测仪器：BioTek多功能酶标仪
1.2试验药物
匹莫范色林：购自MCE公司
其他化合物：按照前述实施例制备得到
1.3实验方法：
将对数生长期的NIH 3T3-5HT 2A R细胞，以每孔1000个细胞的密度接种于白壁透底96孔板中，37℃，5％CO 2培养箱培养过夜，第二天，将待测化合物加入细胞中，待测化合物最高浓度为10uM，用PBS以3.16倍浓度梯度稀释9个浓度，每个浓度设双复孔。以PBS为阴性对照组，以相同浓度的匹莫范色林为阳性对照组。加入药物后，继续37℃，5％CO 2培养箱培养120h，第六天，将与细胞液等体积的Bright-Glo TMLuciferase试剂加入细胞中，室温避光孵育20min，每5min震板仪震动一次，酶标仪检测发光强度，计算细胞抑制率，用GraphPad Prism 7.0处理数据，得出细胞抑制率曲线并计算IC 50，试验结果见表5。
细胞抑制率(％)＝[100-(Lum待测药-Lum培养液)/(Lum细胞对照-Lum培养液)×100]％
2. 5-HT2A拮抗活性(即钙离子拮抗作用)试验
2.1试验材料：
细胞系：CHO-K1/5-HT 2A(Chempartner)
细胞培养基：DMEM/F12+10％FBS(购自GBICO)
细胞培养板：384-well Assay Plate(购自Corning)
检测试剂盒：
Figure PCTCN2021107774-appb-000052
Calcium 4 Assay Kit(购自Molecular Devices)
2.2试验药物
匹莫范色林：购自MCE公司
其他化合物：按照前述实施例制备得到
2.3试验方法：
将对数生长期的CHO-K1/5-HT 2A细胞，以每孔10000个细胞的密度接种于384孔板中，37℃，5％CO 2培养箱培养16-24h后，离心去除细胞培养板中的培养基，加入染料，放入37℃，5％CO 2培养箱中继续孵育1h。将细胞培养板置于FLIPR上，加入待测化合物，检测Ca 2+信号，待测化合物最高浓度10uM，用PBS以3倍浓度梯度稀释10个浓度，设双复孔，15min后加入100nM a-methyl-5-HT，再次检测Ca 2+信号，以只加入100nM a-methyl-5-HT的数值为最大信号。为了确定检测稳定性，以利培酮作为阳性对照。用GraphPad Prism7.0处理数据，得出细胞抑制率曲线并计算IC 50，试验结果见表5。
抑制率(％)＝100％-[(待测化合物信号值-检测液信号值)/(最大信号值-检测液信号值)]×100％
试验例2. hERG抑制活性
1.试验材料和仪器
1.1阳性对照化合物
名称：Cisapride(西沙比利)
1.2溶媒
名称：DMSO(二甲亚砜)
1.3细胞
种属&品系：CHO-hERG细胞系(稳定表达hERG通道的中国仓鼠卵巢细胞)
培养基：90％F12，10％胎牛血清，100μg/mL G418，100μg/mL Hygromycin B
培养条件：5％CO2，37℃培养箱
冻存条件：液氮
1.4实验仪器
膜片钳放大器(Axoclamp 200B,Multiclamp 700B,Axon,美国)
数模转换器(DigiData 1440A,DigiData 1550B,Axon,美国)
倒置显微镜(IX51,IX71,Olympus,日本)
快速给药系统(RSC-200,Bio-Logic,法国)
微操作器(MX7600R,Syskiyou,美国)
电极拉制仪(P-97,Sutter,美国)
玻璃电极(BF150-86-10,Sutter,美国)
防震台与屏蔽网(63-534,TMC,美国)
数据采集与分析软件(pClamp 10,Axon,美国)
二氧化碳培养箱(HERAcell 150i,Thermo,美国)
生物安全柜(MODEL 1384,Thermo,美国)
纯水仪(Milli Q,Millipore,美国)
2.实验方法
2.1细胞培养和处理
稳定表达hERG的CHO细胞培养于直径35mm的细胞培养皿中，置于37℃，5％CO2的培养箱培养，每48小时按1:5比例进行传代。试验当天，吸走细胞培养液，用细胞外液淋洗一遍后加入0.25％Trypsin-EDTA(Invitrogen)溶液，室温下消化3-5分钟。吸走消化液，细胞外液重悬细胞并转移到用于电生理记录的实验皿中备用。
2.2化合物准备
测试当天，将化合物用DMSO稀释成中间浓度。取10μL中间浓度化合物转移至4990μL细胞外液中，500倍稀释得到需要测试的最终浓度。
阳性对照化合物Cisapride准备：取150μM的Cisapride DMSO母液10μL，转移至4990μL细胞外液中，500倍稀释得到需要测试的最终浓度300nM。
2.3电生理记录过程
稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。
2.4数据处理和分析
采用pClamp 10和GraphPad Prism 5.0软件进行数据分析。
不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度计算公式为：
Inhibition％＝[1–(I/Io)]×100％
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。
化合物IC 50使用GraphPad Prism 5软件通过以下方程拟合计算得出，试验结果见表5：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。
试验结果
表5本发明化合物体外试验结果
Figure PCTCN2021107774-appb-000053
Figure PCTCN2021107774-appb-000054
结果显示：
本发明多个化合物的5-HT 2A拮抗活性和/或5-HT 2A反向激动活性均优于匹莫范色林，且心脏毒性更低。
试验例3.匹莫范色林与化合物59体外肝微粒体稳定性评价
1溶液配置
1)供试品工作液配置：将供试品用甲醇稀释至100μM；
2)肝微粒体工作液配置：将肝微粒体用100mM磷酸盐缓冲液稀释至0.56mg/ml；
3)还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)工作液配置：称取适量NADPH用磷酸盐缓冲液稀释至20mM，再加入等体积的60mM的MgCl 2溶液；
4)终止液配置：用乙腈将甲苯磺丁脲稀释至20ng/mL，作为含内标的终止液。
2孵育过程
1)准备孵育抗吸附EP管，标记种属、供试品、对照品(睾酮、右美沙芬)、时间点(0、5、10、20、30、60min、Blank60、NCF60)等；
2)各管中加入2μL的供试品或对照品工作液和178μL肝微粒体工作液，Blank管中加入2μL乙腈代替供试品，放入37℃水浴锅中预孵育约10min，每样本平行3份；
3)预孵育结束后，除0min及NCF60外，每管中加入20μLNADPH工作液启动反应，NCF60管中加入20μL磷酸盐缓冲液(含30mM的MgCl 2)，孵育体系中供试品或对照品终浓度为1μM、肝微粒体终浓度为0.5mg/mL，NADPH终浓度为1mM，MgCl 2终浓度为3mM；
4)0min样品先加入600μL终止液后再加NADPH工作液，各样品孵育相应时间后加入600μL终止液终止反应；
5)各样品终止反应后涡旋30s，然后13500rpm离心10min，取100μL上清液于EP管中加入100μL Milli-Q水涡旋混匀后，采用表6的方法进行LC-MS/MS分析。
6)相同条件下用睾酮和右美沙芬作为阳性对照品，以检测体系的稳定性和可靠性。
表6 LC-MS-MS分析方法
Figure PCTCN2021107774-appb-000055
Figure PCTCN2021107774-appb-000056
3数据分析
测试60min后供试品的剩余百分比，试验结果见表7。
表7本发明化合物在人和大鼠肝微粒体中的试验数据
Figure PCTCN2021107774-appb-000057
结果显示：化合物59在体外犬和人肝微粒体稳定性明显优于匹莫范色林，具有更好的成药特性。
试验例4.匹莫范色林及化合物59大鼠体内药代动力学实验
1试验药物
匹莫范色林：购自MCE公司。
化合物59，按照前述实施例制备得到。
2试验方法
8只体重为220克左右的SD大鼠随机分为2组，每组4只，给药前禁食12小时，按照46.7μmol/kg剂量分别灌胃给药匹莫范色林、化合物59，溶媒均为20％Solutol。分别于给药前及给药后0.25、0.5、1、2、3、4、6、8、12、24小时采血，血液置于肝素化的EP管中，离心分离血浆，血浆经前处理后至LC-MS/MS测定血浆中化合物的浓度，并计算药代动力学参数。
试验结果见图1和表8。表8匹莫范色林及化合物59灌胃给药后药代动力学参数对比
Figure PCTCN2021107774-appb-000058
结果显示：化合物59的T 1/2高于匹莫范色林，化合物59的C max是匹莫范色林的2倍，化合物59的AUC last是匹莫范色林的4倍，化合物59的体内药代动力学性质明显优于匹莫范色林。

Claims (10)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100001
    其中，
    X 1和X 4中的至少一个为N，另一个任选为CR 1或N；
    X 2、X 3各自独立选自CR 1、N；
    X 5独立选自CR 3a、N；
    X 6独立选自CR 3b、N；
    X 7独立选自CR 3c、N；
    X 8独立选自CR 3d、N；
    基团B为C 1-6直链或支链的烷基，5-6元氮杂环基，所述C 1-6直链或支链的烷基、或5-6元氮杂环基任选地被一个或多个氘原子取代；
    每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    每个R 2相同或不同，各自独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1- 6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 3、R 3a、R 3b、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1- 10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    或者当X 6为CR 3b时，X 6、R 3与它们所连接的原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    X选自-NH-、-(CH 2) 1-4NH-；
    Y选自O或S；
    m和n独立地选自0、1、2和3；
    s独立地选自1、2、3、4、5和6；
    y独立地选自0、1、2、3、4和5。
  2. 式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100002
    其中，
    X 3、X 4各自独立选自CR 1、N；
    X 5独立选自CR 3a、N；
    X 7独立选自CR 3c、N；
    X 8独立选自CR 3d、N；
    每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、吡咯啉、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    X选自-NH-、-(CH 2) 1-4NH-；
    Y选自O或S；
    m和n独立地选自0、1、2和3；
    s独立地选自1、2、3、4、5和6。
  3. 式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100003
    其中，
    X 3、X 4各自独立选自CR 1、N；
    X 5独立选自CR 3a、N；
    X 7独立选自CR 3c、N；
    X 8独立选自CR 3d、N；
    每个R 1相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 3、R 3a、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    s独立地选自1、2、3、4、5和6。
  4. 式(IV)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100004
    其中，
    X 7独立选自CR 3c、N；
    X 8独立选自CR 3d、N；
    R 1独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    或者R 3、及其相连碳原子、与相邻的碳原子一起形成环系，所述环系选自二氢呋喃、二氢吡咯、二氢噻吩，并且被一个或多个相同或不同的R 4取代，每个R 4各自独立地选自氢原子、卤素、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代；
    s独立地选自1、2、3、4、5和6。
  5. 式(V)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100005
    其中，
    X 3独立选自CR 5、N
    X 4独立选自CR 6、N；
    X 7独立选自CR 3c、N；
    X 8独立选自CR 3d、N；
    R 1、R 5、R 6相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 3、R 3c、R 3d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代。
  6. 式(VI)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021107774-appb-100006
    其中，
    X 3独立选自CR 5、N；
    X 4独立选自CR 6、N；
    R 1、R 5、R 6相同或不同，各自独立地选自氢原子、C 1-10直链或支链的烷基、卤素；
    R 2独立地选自氢原子、氘原子、C 1-10直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、3-8元环烷基，所述C 1-6直链或支链的烷基、(C 1-6直链或支链的烷基) 2胺基、或3-8元环烷基任选地被一个或多个氘原子取代；
    R 4a、R 4b、R 4c、R 4d相同或不同，各自独立地选自氢原子、卤素、羟基、C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基、C 1-10直链或支链的卤代烷氧基，其中所述的C 1-10直链或支链的烷基、C 1-10直链或支链的烷氧基被选自氢原子、卤素、羟基、C 1-10直链或支链的烷氧基中的一个或多个取代基所取代。
  7. 根据权利要求1-6中任意一项所述的化合物或其药学上可接受的盐，其中，
    R 1、R 5、R 6相同或不同，各自独立地选自氢原子、F、Cl、Br、I、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基；
    基团B为-CH 2-、-(CH 2) 2-、-(CH 2) 3-、-(CH 2) 4-、-CD 2-、-(CD 2) 2-、-(CD 2) 3-、-(CD 2) 4-，R 2独立地选自二甲胺基、二乙胺基，所述二甲胺基、二乙胺基任选被一个或多个氘原子取代；
    或者基团B为选自哌啶基，所述哌啶基任选地被一个或多个氘原子取代，R 2独立地选自氢原子、氘原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基，所述甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基任选地被一个或多个氘原子取代。
    R 3、R 3a、R 3b、R 3c、R 3d相同或不同，各自独立地选自氢原子、F、Cl、Br、I、羟基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1，1-二甲基丁基、2，2-二甲基丁基、3，3-二甲基丁基和2-乙基丁基、氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基、氟甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基、2-氟乙氧基、2，2-二氟乙氧基、2，2，2-三氟乙氧基、四氟乙氧基、五氟乙氧基、3-氟丙氧基、3，3-二氟丙氧基、2，2'-二氟异丙氧基、3，3，3-三氟丙氧基、4-氟丁氧基、4，4-二氟丁氧基、4，4，4-三氟丁氧基、2-氟-2-甲基丙基、5，5，5-三氟戊氧基、6，6，6-三氟己氧基、2-甲基-3-羟基-丁基、i-Pr-O-CH 2-。
    每个R 4和/或R 4a、R 4b、R 4c、R 4d相同或不同，各自独立地选自氢原子、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基。
  8. 下述化合物或其药学上可接受的盐、氘代类似物，其选自：
    Figure PCTCN2021107774-appb-100007
    Figure PCTCN2021107774-appb-100008
    Figure PCTCN2021107774-appb-100009
    Figure PCTCN2021107774-appb-100010
    Figure PCTCN2021107774-appb-100011
    Figure PCTCN2021107774-appb-100012
  9. 一种药物组合物，包括权利要求1-8任一所述化合物或其药学上可接受的盐和药学上可接受的载体。
  10. 权利要求1-8任一所述化合物或其药学上可接受的盐或权利要求9所述药物组合物在 制备治疗5-HT受体相关疾病的药物中的应用；优选所述5-HT受体相关疾病包括：精神分裂症、精神病、分裂情感性障碍、躁狂症、精神病性抑郁症、情感障碍、痴呆、焦虑症、睡眠障碍、食欲障碍、双相性精神障碍、高血压继发的精神病、偏头痛、高血压、血栓形成、血管痉挛、局部缺血、运动性抽搐、抑郁、重度抑郁症、焦虑、睡眠紊乱和食欲紊乱、帕金森病引起的非运动症状、妄想、幻觉、抑郁、焦虑、认知障碍、睡眠障碍、痴呆相关的精神疾病、精神分裂的阴性症状、帕金森氏病、亨延顿舞蹈病、阿耳茨海默病、脊椎小脑萎缩症、图雷特氏综合征、弗里德赖希共济失调、马查多-约瑟夫病、路易体痴呆、运动障碍、肌张力障碍、肌阵挛、震颤或进行性核上性麻痹和额颞叶痴呆。
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