5-HT2A receptor inhibitors or inverse agonists, methods for preparing the same, and their uses.

Abstract

5-HT 2A This invention provides novel compounds as receptor inhibitors or inverse agonists, pharmaceutical compositions thereof, and their uses. [Solution] A compound of formula (IV), a pharmaceutically acceptable salt thereof, or a deuterated analog thereof is provided. TIFF2026065019000066.tif51170

Description

[Technical Field]

[0001] This invention relates to selective 5-hydroxytryptamine 2A (5-HT 2A ) Types of compounds used as receptor inhibitors or inverse agonists, methods for preparing them, and 5-HT 2A Regarding its use in the field of receptor-related diseases. [Background technology]

[0002] Parkinson's disease (PD) is a common neurodegenerative disease with an average age of onset of approximately 60 years (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517). According to 2018 data from the National Institutes of Health (NIH), there are approximately 4 to 6 million people worldwide with Parkinson's disease. Of these, up to 50% of Parkinson's disease patients experience severe symptoms of hallucinations or delusions during the course of the disease, which severely impacts their quality of life and leads to high morbidity and mortality rates.

[0003] In 2016, pimavanserin entered the market for the treatment of hallucinations and delusions associated with Parkinson's disease, receiving approval from the USFDA, becoming the first approved drug for treating such indications. [ka]

[0004] Pimavanserin is 5-HT 2A It acts on receptors, 5-HT 2A The receptor is a major excitatory receptor subtype in the 5-HT receptor family, and is a ligand-gated channel receptor and a G protein-coupled receptor. 2AReceptors have functions closely related to neuronal excitation, behavioral effects, learning and memory, anxiety, etc., and are therefore important targets for antipsychotic drugs and the treatment of schizophrenia (Price, DL, et al. Behavioral Pharmacology (2012), 23(4), 426-433). First-generation antipsychotics are mainly used to inhibit dopamine D2 receptors and therefore have serious extrapyramidal side effects. Second-generation antipsychotics, in addition to inhibiting D2 receptors, also target specific 5-HT receptors, particularly 5-HT receptors. 2A Second-generation antipsychotics have a higher inhibitory effect on receptors and, compared to first-generation antipsychotics, have higher safety, i.e., fewer extrapyramidal side effects. However, because second-generation antipsychotics still have inhibitory activity against D2 receptors, they still have extrapyramidal side effects. Furthermore, such drugs have the side effect of weight gain to varying degrees. [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, selective 5-HT 2A By developing receptor inhibitors or inverse agonists, extrapyramidal side effects associated with dopamine receptor inhibition, as well as weight gain side effects of first- and second-generation antipsychotics, can be eliminated. Receptor inhibitors or inverse agonists have higher safety and meet the needs of clinical patients, such as 5-HT 2A It may also be applicable to the treatment of other receptor-related diseases. [Means for solving the problem]

[0006] In one embodiment, the present invention relates to a compound of formula (I). [ka] (In the formula, At least one of X1 and X4 is N, and the other is either CR1 or N; X2 and X3 are independently selected from CR1 and N, respectively; X5 is independently CR 3a or N; X6 is independently CR 3b or N; X7 is independently CR 3c or N; X8 is independently CR 3d or N; Group B is a linear or branched C 1~6 alkyl or a 5- to 6-membered nitrogen heterocyclic group, and the linear or branched C 1~6 alkyl or 5- to 6-membered nitrogen heterocyclic group is optionally substituted with one or more deuterium atoms; Each R1 is the same or different and is independently selected from a hydrogen atom, a linear or branched C 1~10 alkyl or a halogen; Each R2 is the same or different and is independently selected from a hydrogen atom, a deuterium atom, a linear or branched C 1~10 alkyl, (linear or branched C 1~6 alkyl)2amine or a 3- to 8-membered cycloalkyl, and the linear or branched C 1~10 alkyl, (linear or branched C 1~6 alkyl)2amine or 3- to 8-membered cycloalkyl is optionally substituted with one or more deuterium atoms; R3, R 3a , R 3b , R 3c and R 3d are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a linear or branched C 1~10 alkyl, a linear or branched C 1~10 alkoxy and a linear or branched C 1~10 haloalkoxy, where the linear or branched C 1~10 alkyl and the linear or branched C 1~10 alkoxy are substituted with one or more substituents selected from a hydrogen atom, a halogen, a hydroxyl and a linear or branched C 1~10 alkoxy; or X6 is CR 3bIn this case, X6 and R3, together with the atom to which they are bonded, form a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, which is substituted with one or more identical or different R4s, each R4 independently being a hydrogen atom, a halogen, a linear or branched carbon atom 1~10 Alkyl, linear, or branched C 1~10 Alkoxy, linear, or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy contains hydrogen atoms, hydroxyl groups, and linear or branched C molecules. 1~10 Substituted with one or more substituents selected from alkoxy; X is -NH- or -(CH2) 1~4 Selected from NH-; Y is selected from either O or S; m 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) Or provide a pharmaceutically acceptable salt thereof.

[0007] In one embodiment of the compound of formula (I), at least one of X1 and X4 is N, and the other is optionally CR1; and X2 and X3 are each independently selected from CR1, preferably CH.

[0008] In one embodiment of the compound of formula (I), both X1 and X4 are N, and X2 and X3 are each independently selected from CR1.

[0009] In one embodiment of the compound of formula (I), at least one of X1 and X4 is N and the other is optionally CR1; at least one of X2 and X3 is N and the other is optionally CR1.

[0010] In one embodiment of the compound of formula (I), both X1 and X4 are N; at least one of X2 and X3 is N, and the other is optionally CR1.

[0011] In one embodiment of the compound of formula (I), at least one of X1 and X4 is N, and the other is optionally CR1; and both X2 and X3 are N.

[0012] In one embodiment of the compound of formula (I), both X1 and X4 are N, and both X2 and X3 are N.

[0013] In one embodiment of the compound of formula (I), X1 is preferably N, and X2, X3, and X4 are all CR1.

[0014] In one embodiment of the compound of formula (I), group B is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -CD2-, -(CD2)2-, -(CD2)3- or -(CD2)4-, and R2 is independently selected from dimethylamine or diethylamine, where dimethylamine or diethylamine is optionally substituted with one or more deuterium atoms; Alternatively, group B is selected from piperidinyl, where piperidinyl is optionally substituted with one or more deuterium atoms, and R2 is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms.

[0015] In one embodiment of the compound of formula (I), each R1 is the same or different and independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0016] In one embodiment of the compound of formula (I), each R2 is the same or different and independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms.

[0017] In one embodiment of the compound of formula (I), R3, R 3a , R 3b , R 3c and R 3d However, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, t Selected from difluoromethoxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH2-.

[0018] In one embodiment of the compound of formula (I), X6 is CR3b In this case, X6 and R3, together with the atoms to which they are bonded, form a ring system and are optionally substituted with one or more identical or different R4s. Here, the ring system is preferably selected from dihydrofuran, dihydropyrrole, or dihydrothiophene. Here, each R4 is either the same or different, independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0019] In a particular embodiment of the present invention, any one of the above compounds of formula (I) may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0020] Compared to pimavanserin, the compound of formula (I) provided by the present invention has a higher 5-HT 2A Antagonistic activity and 5-HT 2A It has inverse activity and / or lower cardiotoxicity. In particular, when X1 and / or X4 is N and X2 and X3 are CH, 5-HT 2A Antagonistic activity and / or 5-HT 2A The reverse action activity can be further improved.

[0021] In another embodiment, the present invention relates to a compound of formula (II). [ka] (In the formula, X3 and X4 are independently selected from CR1 and N, respectively; X5 is independent, CR 3a or selected from N; X7 is independent, CR 3c or selected from N; X8 is independent, CR 3d or selected from N; Each R1 is the same or different, and independently comprises a hydrogen atom, a linear or branched carbon atom. 1~10 Selected from alkyl or halogen; R2 independently contains hydrogen atoms, deuterium atoms, linear or branched C atoms. 1~10 Alkyl, (linear or branched C 1~6 Selected from alkyl)2-amines or 3-8 membered cycloalkyls, in linear or branched chain form. 1~10 Alkyl, (linear or branched C 1~6 A alkyl)2-amine or a 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R3, R 3a , R 3c and R 3d However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. 1~10 Alkyl, linear, or branched C 1~10 Alkoxy and linear or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. 1~10 Substituted with one or more substituents selected from alkoxy; Alternatively, R3 and the carbon atom to which it is bonded, together with adjacent carbon atoms, form a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, which is substituted with one or more identical or different R4 atoms, each R4 atom independently being a hydrogen atom, a halogen, a linear or branched carbon atom 1~10 Alkyl, linear, or branched C 1~10 Alkoxy, linear, or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy contains hydrogen atoms, hydroxyl groups, and linear or branched C molecules. 1~10 Substituted with one or more substituents selected from alkoxy; X is -NH- or -(CH2) 1~4 Selected from NH-; Y is selected from either O or S; m and n are independently selected from 0, 1, 2, and 3; (s is independently selected from 1, 2, 3, 4, 5, and 6) Or provide a pharmaceutically acceptable salt thereof.

[0022] In one embodiment of the compound of formula (II), both X3 and X4 are CR1.

[0023] In one embodiment of the compound of formula (II), X3 is N and X4 is CR1.

[0024] In one embodiment of the compound of formula (II), X3 is CR1 and X4 is N.

[0025] In one embodiment of the compound of formula (II), each R1 is the same or different and independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0026] In one embodiment of the compound of formula (II), each R2 is the same or different and independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, a methyl, ethyl, methyl deuterated, or ethyl deuterated, more preferably methyl or methyl deuterated.

[0027] In one embodiment of the compound of formula (II), R3, R 3a , R 3c and R 3dHowever, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, t Selected from difluoromethoxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH2-.

[0028] In one embodiment of the compound of formula (II), R3 and the carbon atom to which it is bonded, together with the adjacent carbon atoms, form a ring system and are optionally substituted with one or more identical or different R4s. Here, the ring system is preferably selected from dihydrofuran, dihydropyrrole, or dihydrothiophene. Here, each R4 is either the same or different, independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0029] In a particular embodiment of the present invention, any one of the above compounds of formula (II) may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0030] Compared with pimavanserin, the compound of formula (II) provided by the present invention has higher 5-HT 2A antagonistic activity and 5-HT 2A inverse agonistic activity, and / or lower cardiotoxicity. In another aspect, the present invention relates to a compound of formula (III)

Chemical formula

[0031] In one embodiment of the compound of formula (III), both X3 and X4 are CR1.

[0032] In one embodiment of the compound of formula (III), X3 is N and X4 is CR1.

[0033] In one embodiment of the compound of formula (III), X3 is CR1 and X4 is N.

[0034] In one embodiment of the compound of formula (III), each R1 is the same or different and is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

[0035] In one embodiment of the compound of formula (III), each R2 is the same or different and independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, methyl deuterated, or ethyl deuterated, more preferably methyl or methyl deuterated.

[0036] In one embodiment of the compound of formula (III), R3, R 3a , R 3c and R 3d However, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, t Selected from difluoromethoxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH2-.

[0037] In one embodiment of the compound of formula (III), R3 and the carbon atom to which it is bonded, together with the adjacent carbon atoms, form a ring system and are optionally substituted with one or more identical or different R4 atoms. Here, the ring system is preferably selected from dihydrofuran, dihydropyrrole, or dihydrothiophene. Here, each R4 is either the same or different, independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0038] In a particular embodiment of the present invention, any one of the above compounds of formula (III) may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0039] Compared to pimavanserin, the compound of formula (III) provided by the present invention has a higher 5-HT 2A Antagonistic activity and 5-HT 2A It has reverse agonistic activity and / or lower cardiotoxicity. In another embodiment, the present invention relates to a compound of formula (IV). [ka] (In the formula, X7 is independent, CR 3c or selected from N; X8 is independent, CR 3d or selected from N; R1 independently contains hydrogen atoms, linear or branched C atoms. 1~10 Selected from alkyl or halogen; R2 independently contains hydrogen atoms, deuterium atoms, linear or branched C atoms. 1~10 Alkyl, (linear or branched C 1~6 Selected from alkyl)2-amines or 3-8 membered cycloalkyls, in linear or branched chain form. 1~10 Alkyl, (linear or branched C 1~6 A alkyl)2-amine or a 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R3, R 3c and R 3d However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. 1~10 Alkyl, linear, or branched C 1~10 Alkoxy and linear or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. 1~10 Substituted with one or more substituents selected from alkoxy; Alternatively, R3 and the carbon atom to which it is bonded, together with adjacent carbon atoms, form a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, which is substituted with one or more identical or different R4 atoms, each R4 atom independently being a hydrogen atom, a halogen, a linear or branched carbon atom 1~10 Alkyl, linear, or branched C 1~10 Alkoxy, linear, or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy contains hydrogen atoms, hydroxyl groups, and linear or branched C molecules. 1~10 Substituted with one or more substituents selected from alkoxy; (s is independently selected from 1, 2, 3, 4, 5, and 6) Or provide a pharmaceutically acceptable salt thereof.

[0040] In one embodiment of the compound of formula (IV), each R1 is the same or different and independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0041] In one embodiment of the compound of formula (IV), each R2 is the same or different and independently selected from a hydrogen atom, a deuterium atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms.

[0042] In one embodiment of the compound of formula (IV), R3, R 3c and R 3d However, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, t Selected from difluoromethoxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH2-.

[0043] In one embodiment of the compound of formula (IV), R3 and the carbon atom to which it is bonded, together with the adjacent carbon atoms, form a ring system and are optionally substituted with one or more identical or different R4s. Here, the ring system is preferably selected from dihydrofuran, dihydropyrrole, or dihydrothiophene. Here, each R4 is either the same or different, independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0044] In a particular embodiment of the present invention, any one of the above compounds of formula (IV) may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0045] Compared to pimavanserin, the compound of formula (IV) provided by the present invention has a higher 5-HT 2A Antagonistic activity and 5-HT 2A It has inverse activity and / or lower cardiotoxicity.

[0046] In another embodiment, the present invention relates to a compound of formula (V). [ka] (In the formula, X3 is independently selected from CR5 or N; X4 is independently selected from CR6 or N; X7 is independent, CR 3c or selected from N; X8 is independent, CR 3d or selected from N; R1, R5, and R6 are either the same or different, and each independently comprises a hydrogen atom, a linear or branched carbon atom. 1~10 Selected from alkyl and halogen; R2 independently contains hydrogen atoms, deuterium atoms, linear or branched C atoms. 1~10 Alkyl, (linear or branched C 1~6Selected from alkyl)2-amines or 3-8 membered cycloalkyls, in linear or branched chain form. 1~10 Alkyl, (linear or branched C 1~6 A alkyl)2-amine or a 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R3, R 3c and R 3d However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. 1~10 Alkyl, linear, or branched C 1~10 Alkoxy and linear or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. 1~10 (Substituted with one or more substituents selected from alkoxy) Or provide a pharmaceutically acceptable salt thereof.

[0047] In one embodiment of the compound of formula (V), X3 and X4 are CR5 and CR6, respectively.

[0048] In one embodiment of the compound of formula (V), X3 is N and X4 is CR6.

[0049] In one embodiment of the compound of formula (V), X3 is CR5 and X4 is N.

[0050] In one embodiment of the compound of formula (V), R1, R5, and R6 are the same or different, and each is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, preferably F, Cl, Br, or I, more preferably F.

[0051] In one embodiment of the compound of formula (V), R2 is independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, methyl deuterated, or ethyl deuterated, more preferably methyl or methyl deuterated.

[0052] In one embodiment of the compound of formula (V), R3, R 3c and R 3d However, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethoxy, t Selected from difluoromethoxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH2-.

[0053] In one embodiment of the compound of formula (V), Both X3 and X7 are CH; X4 is CR6, where R6 is a hydrogen atom or a halogen, and X4 is preferably CH or CF; X8 is CR 3d And R 3d However, it is a hydrogen atom or a halogen, preferably a hydrogen atom, F, Cl, or Br; R1 is a halogen, preferably F; R2 independently contains hydrogen atoms, deuterium atoms, or linear or branched C atoms. 1~5 Selected from alkyl groups, where linear or branched C 1~5 The alkyl group is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, or isopropyl, where the methyl, ethyl, propyl, or isopropyl group is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, methyl, or ethyl, more preferably methyl; R3 is hydroxyl, linear, or branched C 1~10 Alkyl, linear, or branched C 1~10 Alkoxy, linear, or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. 1~10 Substituted with one or more substituents selected from alkoxy; R3 is preferably a substituted or unsubstituted linear or branched C 2~5 Alkyl, substituted or unsubstituted linear or branched C 2~5 Alkoxy, or substituted or unsubstituted linear or branched C 2~5It is a haloalkoxy; R3 is more preferably ethoxy, tert-butyl, isobutyloxy, 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, 4,4,4-trifluorobutoxy, or hydroxyl.

[0054] In one embodiment of the compound of formula (V), X3, X4, X7, and X8 are all CH; R1 is a halogen, preferably F; R2 is methyl; and R3 is a linear or branched C substituted with a halogen. 1~10 Alkoxy, preferably linear or branched C 2~5 A haloalkoxy, more preferably selected from 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.

[0055] In a particular embodiment of the present invention, any one of the above compounds of formula (V) may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0056] Compared to pimavanserin, the compound of formula (V) provided by the present invention has a higher 5-HT 2A Antagonistic activity and 5-HT 2A It has reverse agonistic activity and / or lower cardiotoxicity. In particular, linear or branched C3 is substituted with a halogen. 1~10 If it is an alkoxy and X3 and X4 are CH, then 5-HT 2A Antagonistic activity and / or 5-HT 2A The reverse action activity can be further improved.

[0057] In another embodiment, the present invention relates to a compound of formula (VI). [ka] (In the formula, X3 is independently selected from CR5 or N; X4 is independently selected from CR6 or N; R1, R5, and R6 are either the same or different, and each independently comprises a hydrogen atom, a linear or branched carbon atom. 1~10 Selected from alkyl and halogen; R2 independently contains hydrogen atoms, deuterium atoms, linear or branched C atoms. 1~10 Alkyl, (linear or branched C 1~6 Selected from alkyl)2-amines or 3-8 membered cycloalkyls, in linear or branched chain form. 1~10 Alkyl, (linear or branched C 1~6 A alkyl)2-amine or a 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R 4a , R 4b and R 4c and R 4d However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. 1~10 Alkyl, linear, or branched C 1~10 Alkoxy and linear or branched C 1~10 Selected from haloalkoxys, where linear or branched C 1~10 Alkyl and linear or branched C 1~10 Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. 1~10 (Substituted with one or more substituents selected from alkoxy) Or provide a pharmaceutically acceptable salt thereof.

[0058] In one embodiment of the compound of formula (VI), X3 and X4 are CR5 and CR6, respectively.

[0059] In one embodiment of the compound of formula (VI), X3 is N and X4 is CR6.

[0060] In one embodiment of the compound of formula (VI), X3 is CR5 and X4 is N.

[0061] In one embodiment of the compound of formula (VI), R1 is independently selected from a hydrogen atom, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, preferably F, Cl, Br, or I, and more preferably F.

[0062] In one embodiment of the compound of formula (VI), R2 is the same or different and independently selected from a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, methyl deuterated, or ethyl deuterated, more preferably methyl or methyl deuterated.

[0063] In one embodiment of the compound of formula (VI), R 4a , R 4b , R 4c and R 4d However, they are the same or different, and each is independently selected from hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0064] In one embodiment of the compound of formula (VI), X3 is CH; X4 is CR6, where R6 is a hydrogen atom or a halogen, and X4 is preferably CH or CF; R1 is a halogen, preferably F; R2 independently contains hydrogen atoms, deuterium atoms, or linear or branched C atoms. 1~5 Selected from alkyl groups, where linear or branched C 1~5 The alkyl group is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, propyl, or isopropyl, where the methyl, ethyl, propyl, or isopropyl group is optionally substituted with one or more deuterium atoms, preferably a hydrogen atom, a deuterium atom, methyl, ethyl, methyl deuterated, or ethyl deuterated, more preferably methyl or methyl deuterated; R 4a and R 4b However, independently selected from hydrogen, methyl, and trifluoromethyl atoms; R 4c and R 4d That is a hydrogen atom.

[0065] In a particular embodiment of the present invention, any one of the compounds of formula (VI) above may be a deuterated analog. A deuterated analog refers to an analog formed by substituting one or more hydrogen atoms of a compound with deuterium atoms.

[0066] Compared to pimavanserin, the compound of formula (VI) provided by the present invention has a higher 5-HT 2A Antagonistic activity and / or 5-HT 2A It has inverse activity and lower cardiotoxicity.

[0067] In another embodiment, the present invention relates to the following compounds or pharmaceutically acceptable salts thereof or deuterated analogs thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] To provide.

[0068] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above compounds or its stereoisomer or a pharmaceutically acceptable salt thereof, or a crystalline form of any one of the above compounds and a pharmaceutically acceptable carrier. The carrier comprises conventional auxiliary components in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, and wetting agents.

[0069] The pharmaceutical composition may be prepared into a variety of 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 formulations. The pharmaceutical composition may be administered orally, mucosally, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal administration). The dosage may be appropriately adjusted according to the patient's age, sex, and type of disease.

[0070] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specified amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 mg to 1000 mg, preferably about 0.25 mg to 250 mg, and more preferably about 0.5 mg to 100 mg. A suitable daily dose for humans or other mammals can vary widely depending on the patient's condition and other factors, but can be determined by conventional methods.

[0071] In one embodiment, the present invention relates to 5-HT 2A The present invention provides the use of any one of the above compounds, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of drugs for treating receptor-related diseases. Diseases or symptoms include schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorders, dementia, anxiety disorders, sleeping disorders, anorexia, bipolar disorder, psychosis secondary to hypertension, migraines, hypertension, thrombosis, vasospasm, ischemia, motor tics, depression, major depressive disorder, anxiety disorders, sleep disturbances, eating disorders, non-motor symptoms caused by Parkinson's disease, delusions, hallucinations, cognitive impairment, dementia-related mental disorders, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxia, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, motor disorders, muscle tone disorders, myoclonus, tremors, progressive supranuclear palsy and frontotemporal dementia, or other medical conditions and pathologies that would have been obvious to those skilled in the art.

[0072] Definition and Description Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Unless otherwise defined, any particular term or phrase should not be considered ambiguous or unclear, but should be understood in its ordinary sense. Where trademarks are found herein, they are intended to refer to the corresponding goods or their active ingredients.

[0073] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues, within reasonable medical judgment, for a reasonable benefit-risk ratio, without excessive toxicity, irritation, allergic reactions or other problems or complications.

[0074] The term “pharmaceutically acceptable salt” refers to a salt of a compound of the present invention prepared from a compound having certain substituents as found in the present invention, along with a relatively non-toxic acid or base. If a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic and organic salts, and further include salts of amino acids (e.g., arginine) and salts of organic acids (e.g., glucuronic acid) (see Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.

[0075] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or base radicals by conventional chemical methods. Generally, methods for preparing such salts involve reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both to prepare the salt.

[0076] Certain compounds of the present invention may have an asymmetric carbon atom (optical center) or a double bond. Racemic compounds, diastereomers, geometric isomers, and individual isomers are included within the scope of the present invention.

[0077] The compounds of the present invention may exist as specific geometric or stereoisomers. The present invention envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically concentrated mixtures, all of which are within the scope of the present invention. Further chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are encompassed within the scope of the present invention.

[0078] Optically active (R)- and (S)-isomers and D and L isomers can be prepared using chiral synthesis, chiral reagents, or other conventional techniques. If specific enantiomers of the compounds of the present invention are desired, they can be prepared by asymmetric synthesis or derivatization with chiral auxiliary groups, where the resulting diastereomer mixture is separated, the auxiliary groups are cleaved, and the pure enantiomers of the desired type are provided. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomer salts can be formed with a suitable optically active acid or base, followed by decomposition of the diastereomer using conventional methods well known in the art, and subsequent recovery of the pure enantiomers. Furthermore, the separation of enantiomers and diastereomers is often performed by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization methods (e.g., formation of carbamates from amines).

[0079] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is toxic or adverse to the host or patient. Typical carriers include, but are not limited to, binders, packing agents, lubricants, disintegrants, wetting agents, dispersants, solubilizers, and suspending agents.

[0080] With respect to drugs or pharmacological agents, the term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of the drug or agent that is non-toxic but capable of achieving the desired effect. In the context of oral dosage forms in this invention, the "effective dose" of the active substance in the composition refers to the amount required to achieve the desired effect when such active substance is used in combination with other active substances in the composition. Determining the effective dose, which varies from person to person, depends on the recipient's age and overall health, as well as on the specific active substance. The appropriate effective dose in individual cases can be determined by those skilled in the art according to conventional testing.

[0081] The present invention is intended to include all isotopes of atoms present in the compound of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include, 13 C and 14 Contains C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeled reagent instead of the unlabeled reagent originally used.

[0082] The term “deuterated analog” refers to an analogue formed by substituting one or more hydrogen atoms of a compound with deuterium atoms. The terms “optional” or “arbitrarily” mean that the event or situation described thereafter may, but not necessarily, occur, and that this description includes cases in which such event or situation occurs and cases in which such event or situation does not occur. For example, “arbitrarily substituted with one or more deuterium atoms” means that the group may be either not substituted with deuterium atoms or may be substituted with one or more deuterium atoms, i.e., the group may be undeuterated, partially deuterated, and / or fully deuterated.

[0083] The term "substituted" means that one or more hydrogen atoms on a given atom are replaced by a substituent, and the substituent may include deuterium and hydrogen displacements, as long as the valence state of the given atom is normal and the substituted compound is stable. If the substituent is a ketone (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0084] If any variable (e.g., R) appears two or more times in the structure of a composition or compound, its definition in each case is independent. Therefore, for example, if a group is substituted with 0 to 2 Rs, the group can be arbitrarily substituted with up to 2 Rs, and in each case, R has an independent choice. Furthermore, combinations of substituents and / or their variants are acceptable only if such combinations result in a stable compound.

[0085] Unless otherwise specified, the term "alkyl" is used to describe a linear or branched saturated hydrocarbon group, which can be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3) and can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1~C 10 This represents 1 to 10 carbon atoms, C 1~10 This includes C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Selected from the following. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl and t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl and 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, and the like.

[0086] Unless otherwise specified, the terms “halo” or “halogen” mean a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent. The term “haloalkoxy” is intended to include monohaloalkoxys and linear or branched polyhaloalkoxys. For example, “C 1~10 The term “haloalkoxy” is intended to include, but is not 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, and 6,6,6-trifluorohexyloxy.

[0087] The term "haloalkyl" is intended to include monohaloalkyls and linear or branched polyhaloalkyls. For example, the term "(C1-C4) haloalkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. Unless otherwise specified, examples of haloalkyls include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0088] Unless otherwise specified, "alkoxy" refers to the alkyl group having a specific number of carbon atoms linked via oxygen crosslinking. Typical alkoxys include C 1~10 Alkoxy compounds, for example, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, C7 alkoxy, C8 alkoxy, C9 alkoxy. 10Alkoxy compounds are one example. Examples of alkoxy compounds, though not limited to them, include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, S-pentoxy, hexyloxy, 2-ethylbutoxy, heptyloxy, octyloxy, nonyloxy, and decyloxy.

[0089] Unless otherwise specified, a cycloalkyl group comprises any stable cyclic or polycyclic hydrocarbon group, where any carbon atom is saturated and can be monosubstituted or polysubstituted, and can be monovalent, divalent or polyvalent. Examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, and [4.4.0]bicyclodecane.

[0090] Compounds are named manually or by ChemDraw® software, and commercially available compounds are named according to the supplier's catalog name. [Brief explanation of the drawing]

[0091] [Figure 1] This is a comparative chart of drug-time curves for pimavanserin and compound 59 after intragastric administration. [Modes for carrying out the invention]

[0092] The present invention will be further described below with reference to specific embodiments and test examples, but the scope of the invention is not limited in any way. [Examples]

[0093] Example 1: [ka] Synthesis pathway: [ka] 1. Under nitrogen protection, 2-(aminomethyl)-5-fluoropyridine (504 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. N-methyl-4-piperidone (452 ​​mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1a (538 mg), which was used directly in the next reaction without purification.

[0094] 2. Under nitrogen protection, compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 ml of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1 (414 mg, pale yellow solid, yield: 48%). MS m / z (ESI): 429.3 [M+1]; 1 H NMR (400MHz, CDCl3)δ 8.26(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).

[0095] Compounds 2-3, 12-13, 16, 19-20, 23-31, 33-52, 58, 61, 64, 66-68, 70-72, 75-77, 80-81, and 83-101 were prepared in the same manner as in Example 1.

[0096] [Table 1]

[0097] [Table 2]

[0098] [Table 3]

[0099] [Table 4]

[0100] [Table 5]

[0101] [Table 6]

[0102] [Table 7]

[0103] [Table 8]

[0104] [Table 9]

[0105] [Table 10]

[0106] Example 2: [ka] Under nitrogen protection, 1-methylpyrazole-4-carbaldehyde (440 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. N-methyl-4-piperidone (452 ​​mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4a (617 mg).

[0107] Under nitrogen protection, compound 4a (208 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (5 mL). * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 4 (172 mg, yield: 43%). MS m / z (ESI): 414.3 [M+1]; 1H NMR (400MHz, CDCl3)δ 7.38(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).

[0108] Compounds 5, 8, and 22 were prepared in the same manner as compound 4.

[0109] [Table 11]

[0110] Example 3: [ka] N-Boc-bromoethylamine (2.23 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 mL of water was added, and then the resulting solution was dissolved in dichloromethane (60 mL). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6a (1.97 g).

[0111] Under nitrogen protection, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. Compound 6a (968 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. *3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6b (912 mg).

[0112] Under nitrogen protection, compound 6b (702 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 6c (467 mg).

[0113] Under nitrogen protection, compound 6c (278 mg, 0.5 mmol) was dissolved in 5 mL of dichloromethane. Trifluoroacetic acid (285 mg, 2.5 mmol) was added, and the resulting mixture was reacted at room temperature for 2 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (5 mL) was added. * Extraction was performed as described in 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6 (201 mg, yield: 88%). MS m / z(ESI): 457.2[M+1]; 1 H NMR (400MHz, CDCl3)δ 7.25-7.23(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).

[0114] Example 4: [ka] 1-(2-bromoethyl)imidazolidine-2-one (1.93 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was dissolved in dichloromethane (60 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7a (1.56 g).

[0115] Under nitrogen protection, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. Compound 7a (844 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * The compound was extracted in step 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 7b (812 mg).

[0116] Under nitrogen protection, compound 7b (640 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). *Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 7 (494 mg, yield: 47%). MS m / z (ESI): 526.3 [M+1]; 1 H NMR (400MHz, CDCl3)δ 7.24-7.22(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).

[0117] Example 5: [ka] Tert-butyldimethylbromoethoxysilane (2.38 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was dissolved in dichloromethane (60 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9a (1.72 g).

[0118] Under nitrogen protection, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. Compound 9a (1028 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9b (812 mg).

[0119] Under nitrogen protection, compound 9b (732 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 9c (327 mg).

[0120] Under nitrogen protection, compound 9c (286 mg, 0.5 mmol) was dissolved in 5 ml of THF. A 1 M solution of tetrabutylammonium tetrahydrofuran fluoride (1 ml, 1.0 mmol) was added, and the resulting mixture was reacted at room temperature for 2 hours. The organic phase was concentrated, and then dichloromethane (5 mL) was added. * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9 (118 mg, yield: 52%). MS m / z(ESI): 458.3[M+1]; 1H NMR (400MHz, CDCl3)δ 7.23-7.20(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).

[0121] Example 6: [ka] 2-Bromo-N,N-dimethylacetamide (1.66 g, 10.0 mmol) was dissolved in 20 ml of DMF. It was then dissolved in 4-piperidone (0.99 g, 10.0 mmol), potassium carbonate (2.07 g, 15.0 mmol) was added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was dissolved in dichloromethane (60 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10a (1.15 g).

[0122] Under nitrogen protection, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. Compound 10a (736 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10b (832 mg).

[0123] Under nitrogen protection, compound 10b (586 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (546 mg, 2.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 10 (535 mg, yield: 54%). MS m / z (ESI): 499.3 [M+1]; 1 H NMR (400MHz, CDCl3)δ 7.20-7.13(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), 3.6 6(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).

[0124] Example 7: [ka] 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone (2.98 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was dissolved in dichloromethane (60 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11a (2.26 g).

[0125] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. Compound 11a (1.26 g, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. An aqueous solution of NaHCO3 was added to adjust the pH value to alkaline. The organic phase was concentrated, and then extracted with dichloromethane (10 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 11b (1.03 g).

[0126] Under nitrogen protection, Compound 11b (425 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60 °C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (10 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 11 (311 mg, yield: 49%); MS m / z (ESI): 631.3 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.96 (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).

[0127] Example 8: [Chemical Formula] Under nitrogen protection, in an ice-water bath, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol. N,N-dimethyl-1,3-diaminopropane (408 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. An aqueous solution of NaHCO3 was added to adjust the pH value to alkaline. The organic phase was concentrated, and then extracted with dichloromethane (10 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 14a (587 mg).

[0128] Under nitrogen protection, Compound 14a (210 mg, 1.0 mmol) was dissolved in 5 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60 °C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was extracted with dichloromethane (5 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 13 (202 mg, yield: 48%); MS m / z (ESI): 416.3 [M+1]; 1 H NMR (400 MHz, CDCl3) δ 7.26 - 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).

[0129] Example 9: [ka] (2-bromomethyl)dimethylamine (1.52 g, 10.0 mmol) was dissolved in 20 ml of DMF. 4-piperidone (0.99 g, 10.0 mmol) and potassium carbonate (2.07 g, 15.0 mmol) were added, and the resulting mixture was heated to 80°C and reacted with stirring for 8 hours. The reaction solution was cooled to room temperature. 60 ml of water was added, and then the resulting solution was dissolved in dichloromethane (60 ml). * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 15a (1.17 g).

[0130] Under nitrogen protection, 4-fluorobenzylamine (500 mg, 4.0 mmol) was dissolved in 10 ml of methanol in an ice bath. Compound 15a (680 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (10 ml) was added. * 3) Extraction was performed. The organic phase was combined, dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 15b (611 mg).

[0131] Under nitrogen protection, compound 15b (279 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-formamide (273 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 mL of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). *Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 15 (287 mg, yield: 59%). MS m / z (ESI): 485.3 [M+1]; 1 H NMR (400MHz, CDCl3)δ 7.22-7.16(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,2 H), 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).

[0132] Example 10: [ka] Under nitrogen protection, compound 3 (372 mg, 1.0 mmol) was dissolved in 10 ml of acetonitrile. 1-bromo-3-fluoropropane (211 mg, 1.5 mmol) and cesium carbonate (652 mg, 2.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 5 hours. The reaction solution was cooled to room temperature and filtered. 10 ml of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 17 (238 mg, yield: 54%). MS m / z(ESI): 433.2[M+1]; 1H NMR (400MHz, CDCl3)δ 8.22(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).

[0133] Compounds 18, 55-57, 59-60, 62, 65, 69, 73-74, 78, and 82 were prepared in the same manner as compound 17.

[0134] [Table 12]

[0135] [Table 13]

[0136] [Table 14]

[0137] Example 11: [ka] Under nitrogen protection, compound 1a (446 mg, 2.0 mmol) was dissolved in 10 ml of acetonitrile. Compound 32a (440 mg, 2.0 mmol), HATU (760 mg, 2.0 mmol), and diisopropylethylamine (387 mg, 3.0 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature and filtered. 20 ml of water was added to the filtrate, and then the resulting solution was dissolved in dichloromethane (10 ml). *It was extracted in (3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain Compound 32 (561 mg, yield: 66%). MS m / z (ESI): 426.2 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (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).

[0138] Compounds 53 and 54 were prepared in the same manner as Compound 32.

[0139]

Table 15

[0140] Example 12:

Chem.

Chem.

[0141] Under nitrogen protection, compound 63b (1.49 g, 7.63 mmol) was dissolved in 20 ml of methanol. (5-Fluoropyridine-2-methyl)amine (962.4 mg, 7.63 mmol) and sodium triacetoxyborohydride (1.972 g, 9.31 mmol) were added, and the resulting mixture was heated to room temperature and reacted for 15 hours. The pH was adjusted to alkaline by adding an aqueous solution of NaHCO3. The organic phase was concentrated, and then dichloromethane (50 mL) was added. * The compound was extracted using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain compound 63c (217 mg).

[0142] Under nitrogen protection, compound 63c (217 mg, 0.71 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-1-formamide (194 mg, 0.710 mmol) and potassium carbonate (107.9 mg, 0.781 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was then mixed with dichloromethane (30 mL). * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 63 (50.5 mg, pale yellow oily liquid, yield: 14%). MS m / z (ESI): 511.69 [M+1] 1H NMR (600MHz, CDCl3)δ 8.24(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).

[0143] Example 13: [ka] Synthesis pathway: [ka] Under nitrogen protection, compound 79a (200 mg, 0.75 mmol) was dissolved in 10 ml of acetonitrile. N-(4-isobutyloxybenzyl)-1H-imidazole-1-formamide (207 mg, 0.75 mmol) and potassium carbonate (105 mg, 0.75 mmol) were added, and the resulting mixture was heated to 60°C and reacted with stirring for 5 hours. The reaction solution was cooled to room temperature, filtered, and then the filtrate was mixed with dichloromethane (20 mL). * Extraction was performed using method 3). The organic phase was combined, dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (dichloromethane:methanol = 10:1) to obtain compound 79 (166 mg, pale yellow oily liquid, yield: 47%). MS m / z (ESI): 471.2 [M+1] 1H NMR (600MHz, CDCl3)δ 7.20(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).

[0144] Test Example 1.5-HT 2A In vitro activity testing of receptors 1.5-HT 2A Screening for reverse activity 1.1 Test materials: Cell line: Adherent cell NIH3T3-5-HT 2A R Cell culture medium: DMEM + 10% FBS (purchased from GBICO) Cell culture plate: White-walled, transparent-bottomed 96-well plate (purchased from Perkin Elmer) Detection kit: Bright-Glo® Luciferase (purchased from Promega) Detection equipment: BioTek multifunction microplate reader

[0145] 1.2 Test drug Pimavanserin: Purchased from MCE Corporation Other compounds: Prepared according to the previous examples.

[0146] 1.3 Test Method: NIH3T3-5HT during the logarithmic growth phase 2AR cells were seeded at a density of 1000 cells per well in a white-walled, clear-bottomed 96-well plate and cultured overnight in a 37°C, 5% CO2 incubator. The following day, the compound to be tested was added to the cells, and the compound to be tested was subjected to a 3.16-fold gradient dilution with PBS to obtain nine concentrations, the highest of which was 10 μM. Double replication wells were prepared for each concentration; PBS was used as the negative control, and pimavanserin at the same concentration was used as the positive control. After addition, the cells were cultured for a further 120 hours in a 37°C, 5% CO2 incubator. On day 6, an equal volume of Bright-Glo® luciferase reagent to the cell sorbate was added to the cells, and the cells were incubated in the dark at room temperature for 20 minutes. The plate was shaken every 5 minutes using a plate shaker, and the luminescence intensity was detected by a microplate reader to calculate the cell inhibition rate. The data was processed using GraphPad Prism 7.0 to obtain cell inhibition rate curves, and IC 50 The calculation was performed. The test results are shown in Table 5. Cell inhibition rate (%) = [100 - (Lum test drug - Lum culture solution) / (Lum cell control - Lum culture solution) × 100]%

[0147] 2. Testing of 5-HT2A antagonistic activity (i.e., calcium ion antagonistic activity) 2.1 Test materials: Cell line: CHO-K1 / 5-HT 2A (Chempartner) Cell culture medium: DMEM / F12 + 10% FBS (purchased from GBICO) Cell culture plate: 384-well assay plate (purchased from Corning) Detection kit: FLIPR® Calcium-4 Assay Kit (purchased from Molecular Devices)

[0148] 2.2 Test drug Pimavanserin: Purchased from MCE Corporation Other compounds: Prepared according to the previous examples.

[0149] 2.3 Test Method: CHO-K1 / 5-HT during the logarithmic growth phase 2A Cells were seeded in a 384-well plate at a density of 10,000 cells per well and cultured in a 37°C, 5% CO2 incubator for 16–24 hours. The culture medium was then removed from the cell culture plate by centrifugation. The dye was added, and the cells were incubated for a further 1 hour in a 37°C, 5% CO2 incubator. The cell culture plate was placed on a FLIPR. The compound to be tested was added, and Ca 2+ The signal was detected, and the compound under test was subjected to a 3-fold gradient dilution with PBS to obtain 10 concentrations, the highest of which was 10 μM, and a double replication well was prepared. 100 nM α-methyl-5-HT was added after 15 minutes, and Ca 2+ The signal was detected again, and the value obtained by adding only 100 nM α-methyl-5-HT was taken as the maximum signal. Risperidone was used as a positive control to determine the stability of the test. The data were processed with GraphPad Prism 7.0 to obtain cell inhibition rate curves and IC50. 50 The calculation was performed. The test results are shown in Table 5. Inhibition rate (%) = 100% - [(Signal value of the compound being tested - Signal value of the test solution) / (Maximum signal value - Signal value of the test solution)] × 100%

[0150] Test Example 2. hERG inhibitory activity 1. Test materials and equipment 1.1 Positive control compounds Name: Cisapride

[0151] 1.2 Solvent Name: Dimethyl sulfoxide (DMSO)

[0152] 1.3 Cells Species and strain: CHO-hERG cell line (Chinese hamster ovary cells that stably express hERG channels) Culture medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, and 100 μg / mL hygromycin B Culture conditions: 5% CO2, incubator at 37°C Freezing conditions: Liquid nitrogen

[0153] 1.4 Test equipment Patch clamp amplifiers (Axoclamp 200B, Multiclamp 700B, Axon, US) Digital-to-analog converters (DigiData 1440A, DigiData 1550B, Axon, US) Inverted microscope (IX51, IX71, Olympus, Japan) High-speed drug delivery system (RSC-200, Bio-Logic, France) Micromanipulator (MX7600R, Syskiyou, US) Electrode puller (P-97, Sutter, US) Glass electrode (BF150-86-10, Sutter, US) Vibration isolation table and shield mesh (63-534, TMC, US) Data acquisition and analysis software (pClamp 10, Axon, US) Carbon dioxide incubator (HERacell 150i, Thermo, US) Biological safety cabinet (MODEL 1384, Thermo, US) Water purifier (Milli Q, Millipores, US)

[0154] 2. Test Method 2.1 Cell culture and processing CHO cells stably expressing hERG were cultured in a 35 mm diameter cell culture dish in a 5% CO2 incubator at 37°C and subcultured at a 1:5 ratio every 48 hours. On the day of the experiment, the cell culture solution was pipettered, the cells were rinsed once with extracellular fluid, and then a 0.25% trypsin-EDTA (Invitrogen) solution was added. Digestion was performed at room temperature for 3-5 minutes. The digested fluid was pipettered, the cells were resuspended in extracellular fluid, and transferred to a laboratory dish for electrophysiological recording for later use.

[0155] 2.2 Compound preparation On the day of the test, the compound was diluted with DMSO to an intermediate concentration. 10 μL of the intermediate concentration compound was taken and transferred to 4990 μL of extracellular solution, and then diluted 500-fold to obtain the final concentration to be tested.

[0156] Preparation of the positive control compound cisapride: 10 μL of 150 μM cisapride DMSO mother liquor was taken, transferred to 4990 μL of extracellular fluid, and subjected to a 500-fold dilution to obtain the final concentration of 300 nM to be tested.

[0157] 2.3 Electrophysiological Recording Process CHO (Chinese hamster ovary) cells stably expressing hERG potassium channels were collected, and the hERG potassium channel current was recorded at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were formed by pulling a glass electrode blank (BF150-86-10, Sutter) with a glass microelectrode puller. The tip resistance was approximately 2–5 MΩ after perfusion with pipette solution. The glass microelectrode could be connected to a patch-clamp amplifier by inserting the glass microelectrode into an amplifier probe. Limiting voltage and data recording were controlled and recorded by computer using pClamp 10 software at a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After whole-cell recording was obtained, the cells were clamped at -80 mV, and the hERG potassium current (I hERGA step voltage inducing ) was changed from -80mV to +20mV by applying a depolarizing voltage for 2 seconds, then repolarized to -50mV over 1 second, and returned to -80mV. Such voltage stimulation was applied every 10 seconds, and the administration process was started after it was determined that the hERG potassium current had stabilized (1 minute). The compound at each test concentration was administered for at least 1 minute, and at least 2 cells (n≧2) were tested for each concentration.

[0158] 2.4 Data Processing and Analysis Data analysis was performed using pClamp 10 and GraphPad Prism 5.0 software.

[0159] The formula for calculating the inhibition of various compound concentrations on the hERG potassium current (the peak value of the hERG tail current induced at -50mV) is: Inhibition % = [1 - (I / Io)] × 100% Here, inhibition% represents the percentage of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitudes of the hERG potassium current before and after administration, respectively.

[0160] Compound IC 50 This was calculated using GraphPad Prism 5 software by applying it to the following formula, and the test results are shown in Table 5: Y = bottom + (top - bottom) / (1 + 10^((LogIC) 50 -X) * Hill gradient)) Here, X is the logarithm of the test concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and the bottom and top are the minimum and maximum inhibition percentages, respectively.

[0161] Test results

[0162] [Table 16]

[0163] [Table 17]

[0164] The results showed that the compound of the present invention is superior to that of pimavanserin in terms of 5-HT 2A Antagonistic activity and / or 5-HT 2A It was shown to have inverse activity and lower cardiotoxicity.

[0165] Test Example 3. In vitro stability evaluation of pimavanserin and compound 59 in liver microsomes. 1 Solution formulation 1) Preparation of the standard solution for the test sample: Dilute the test sample with methanol to 100 μM; 2) Preparation of liver microsome standard solution: Dilute liver microsomes to 0.56 mg / ml with 100 mM phosphate buffer; 3) Preparation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) standard solution: Weigh an appropriate amount of NADPH, dilute it to 20 mM with phosphate buffer, and then add an equal volume of 60 mM MgCl2 solution; 4) Preparation of stop solution: Tolbutamide was diluted with acetonitrile to 20 ng / mL to be used as a stop solution containing an internal standard.

[0166] 2. Incubation Process 1) Prepare an anti-adsorption EP tube for incubation, and label it with the species, test sample, reference substance (testosterone and dextromethorphan), time point (0 min, 5 min, 10 min, 20 min, 30 min, 60 min, blank 60, and NCF60), etc. 2) Add 2 μL of the test sample or reference substance standard solution and 178 μL of the liver microsome standard solution to each tube, and instead of the test sample, add 2 μL of acetonitrile to the blank tube, and pre-incubate the mixture in a 37°C water bath kettle for about 10 minutes, at which point each sample will be divided into triplicate aliquots; 3) After completing the pre-incubation, add 20 μL of NADPH standard solution to each tube except for 0 min and NCF60 to initiate the reaction, and add 20 μL of phosphate buffer (containing 30 mM MgCl2) to the NCF60 tube, where in the incubation system the test sample or reference substance has a final concentration of 1 μM, liver microsomes have a final concentration of 0.5 mg / mL, NADPH has a final concentration of 1 mM, and MgCl2 has a final concentration of 3 mM; 4) Add 600 μL of stop solution to the sample at 0 minutes, followed by the NADPH standard solution, incubate each sample for the corresponding period, and then add 600 μL of stop solution to stop the reaction; 5) After stopping the reaction, vortex each sample for 30 seconds, then centrifuge at 13500 rpm for 10 minutes; add 100 μL of supernatant to an EP tube, add 100 μL of Milli-Q water, vortex the resulting mixture until homogeneous; perform LC-MS / MS analysis using the method shown in Table 6; 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0167] [Table 18]

[0168] 3. Data Analysis The remaining percentage of the test sample was tested after 60 minutes. The test results are shown in Table 7.

[0169] [Table 19]

[0170] The results indicate that compound 59 exhibits significantly superior stability compared to pimavanserin in canine and human liver microsomes in vitro, suggesting better drug discovery potential.

[0171] Test Example 4. In vivo pharmacokinetic study of pimavanserin and compound 59 in rats. 1. Test drug Pimavanserin: Purchased from MCE Corporation. Compound 59: Prepared according to the previous example.

[0172] 2. Test Method Eight SD rats, weighing approximately 220g, were randomly divided into two groups of four rats each. The rats were fasted for 12 hours prior to administration. Each group received a dose of 46.7 μmol / kg of pimavanserin and compound 59 intragastricly, with both groups using 20% ​​Solutol as the vehicle. Blood samples were collected before administration and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The blood was placed in heparinized EP tubes and centrifuged. After plasma pretreatment, the concentration of the compounds in the plasma was determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The test results are shown in Figure 1 and Table 8.

[0173] [Table 20]

[0174] The result was that compound 59's T 1 / 2 However, it is higher than that of pimavanserin; compound 59 C max However, it is twice that of pimavanserin; the AUC of compound 59 last However, this is four times that of pimavanserin; indicating that the in vivo pharmacokinetic properties of compound 59 are clearly better than those of pimavanserin.

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, X １ and X ４ At least one of them is N, and the other is arbitrarily CR １ or N; X ２ and X ３ Each of them operates independently, CR １ and selected from N; X ５ However, CR became independent. ３ａ or selected from N; X ６ is independently selected from CR ３ｂ or N; X ７ However, CR became independent. ３ｃ or selected from N; X ８ However, CR became independent. ３ｄ or selected from N; Base B is linear or branched C １～６ Alkyl or 5-6 membered nitrogen heterocyclic group, and the linear or branched C １～６ The alkyl or the aforementioned 5-6 membered nitrogen heterocyclic group is optionally substituted with one or more deuterium atoms; Each R １ However, they may be the same or different, and independently, hydrogen atoms, linear or branched C １～１０ Selected from alkyl or halogen; Each R ２ However, whether the same or different, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ３ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ Substituted with one or more substituents selected from alkoxy; or X ６ CR ３ｂ If X ６ and R ３ However, together with the atoms to which they are bonded, they form a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, with the same or different R ４ Replaced by one or more of the following, each R ４ However, independently, hydrogen atoms, halogens, linear or branched C １～１０ Alkyl, linear, or branched C １～１０ Alkoxy, linear, or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy is a hydrogen atom, hydroxyl, and linear or branched C １～１０ Substituted with one or more substituents selected from alkoxy; X is -NH- or -(CH ２ ) １～４ Selected from NH-; Y is selected from O or S; m 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) or a pharmaceutically acceptable salt thereof.

2. Compound of formula (II) 【Chemistry 2】 (In the formula, X ３ and X ４ Each of them operates independently, CR １ and selected from N; X ５ However, CR became independent. ３ａ or selected from N; X ７ However, CR became independent. ３ｃ or selected from N; X ８ However, CR became independent. ３ｄ or selected from N; Each R １ However, they may be the same or different, and independently, hydrogen atoms, linear or branched C １～１０ Selected from alkyl or halogen; R ２ However, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ３ , R ３ａ , R ３ｃ and R ３ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ Substituted with one or more substituents selected from alkoxy; or R ３ And the carbon atom to which it is bonded, together with the adjacent carbon atoms, forms a ring system selected from dihydrofuran, pyrroline, or dihydrothiophene, the same or different R ４ Replaced by one or more of the following, each R ４ However, independently, hydrogen atoms, halogens, linear or branched C １～１０ Alkyl, linear, or branched C １～１０ Alkoxy, linear, or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy is a hydrogen atom, hydroxyl, and linear or branched C １～１０ Substituted with one or more substituents selected from alkoxy; X is -NH- or -(CH ２ ) １～４ Selected from NH-; Y is selected from O or S; m and n are independently selected from 0, 1, 2, and 3; (s is independently selected from 1, 2, 3, 4, 5, and 6) or a pharmaceutically acceptable salt thereof.

3. Compound of formula (III) 【Transformation 3】 (In the formula, X ３ and X ４ are each independently selected from CR １ and N; X ５ However, CR became independent. ３ａ or selected from N; X ７ However, CR became independent. ３ｃ or selected from N; X ８ is independently selected from CR ３ｄ or N; Each R １ However, they may be the same or different, and independently, hydrogen atoms, linear or branched C １～１０ Selected from alkyl or halogen; R ２ However, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ３ , R ３ａ , R ３ｃ and R ３ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ Substituted with one or more substituents selected from alkoxy; or R ３ And the carbon atom to which it is bonded, together with the adjacent carbon atoms, forms a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, the same or different R ４ Replaced by one or more of the following, each R ４ However, independently, hydrogen atoms, halogens, linear or branched C １～１０ Alkyl, linear, or branched C １～１０ Alkoxy, linear, or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy is a hydrogen atom, hydroxyl, and linear or branched C １～１０ Substituted with one or more substituents selected from alkoxy; (s is independently selected from 1, 2, 3, 4, 5, and 6) or a pharmaceutically acceptable salt thereof.

4. Compound of formula (IV) 【Chemistry 4】 (In the formula, X ７ However, CR became independent. ３ｃ or selected from N; X ８ However, CR became independent. ３ｄ or selected from N; R １ However, independently, hydrogen atoms, linear or branched C １～１０ Selected from alkyl or halogen; R ２ However, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ３ , R ３ｃ and R ３ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ Substituted with one or more substituents selected from alkoxy; or R ３ And the carbon atom to which it is bonded, together with the adjacent carbon atoms, forms a ring system selected from dihydrofuran, dihydropyrrole, or dihydrothiophene, the same or different R ４ Replaced by one or more of the following, each R ４ However, independently, hydrogen atoms, halogens, linear or branched C １～１０ Alkyl, linear, or branched C １～１０ Alkoxy, linear, or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy is a hydrogen atom, hydroxyl, and linear or branched C １～１０ Substituted with one or more substituents selected from alkoxy; (s is independently selected from 1, 2, 3, 4, 5, and 6) or a pharmaceutically acceptable salt thereof.

5. Compound of formula (V) 【Transformation 5】 (In the formula, X ３ However, CR became independent. ５ or selected from N; X ４ However, CR became independent. ６ or selected from N; X ７ However, CR became independent. ３ｃ or selected from N; X ８ However, CR became independent. ３ｄ or selected from N; R １ , R ５ and R ６ However, they may be the same or different, and each may be independently a hydrogen atom, a linear or branched C atom. １～１０ Selected from alkyl and halogen; R ２ However, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ３ , R ３ｃ and R ３ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ (Substituted with one or more substituents selected from alkoxys) or a pharmaceutically acceptable salt thereof.

6. Compound of formula (VI) 【Transformation 6】 (In the formula, X ３ However, CR became independent. ５ or selected from N; X ４ However, CR became independent. ６ or selected from N; R １ , R ５ and R ６ However, they may be the same or different, and each may be independently a hydrogen atom, a linear or branched C atom. １～１０ Selected from alkyl and halogen; R ２ However, independently, hydrogen atoms, deuterium atoms, linear or branched C atoms １～１０ Alkyl, (linear or branched C １～６ Alkyl) ２ A selected amine or 3- to 8-membered cycloalkyl group, the linear or branched C １～１０ Alkyl, the above (linear or branched C １～６ Alkyl) ２ The amine or the 3- to 8-membered cycloalkyl group is optionally substituted with one or more deuterium atoms; R ４ａ , R ４ｂ and R ４ｃ and R ４ｄ However, they may be the same or different, and each may be independently a hydrogen atom, halogen, hydroxyl, linear or branched C. １～１０ Alkyl, linear, or branched C １～１０ Alkoxy and linear or branched C １～１０ Selected from haloalkoxys, where the linear or branched C １～１０ Alkyl and the linear or branched C １～１０ Alkoxy includes hydrogen atoms, halogens, hydroxyls, and linear or branched C atoms. １～１０ (Substituted with one or more substituents selected from alkoxys) or a pharmaceutically acceptable salt thereof.

7. R １ , R ５ and R ６ However, they may be the same or different, and each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl; Base B is -CH ２ -, - (CH ２ ) ２ -, - (CH ２ ) ３ -, - (CH ２ ) ４ -, -CD ２ -, - (CD) ２ ) ２ -, - (CD) ２ ) ３ - or - (CD) ２ ) ４ - and R ２ However, independently selected from dimethylamine or diethylamine, wherein the dimethylamine or diethylamine is optionally substituted with one or more deuterium atoms; Alternatively, group B is selected from piperidinyl, where the piperidinyl is optionally substituted with one or more deuterium atoms, R ２ However, independently selected from hydrogen atoms, deuterium atoms, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, where the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with one or more deuterium atoms; R ３ , R ３ａ , R ３ｂ , R ３ｃ and R ３ｄ However, they are the same or different, and each independently, hydrogen atom, F, Cl, Br, I, hydroxyl, 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, 2-ethylbutyl, oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, fluoromethoxy, difluoromethoxy, trichloromethyl Toxy, 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-trifluorobutoxy, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, 2-methyl-3-hydroxybutyl, and i-Pr-O-CH ２ - Selected from; R ４ and / or R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ The compounds described in any one of claims 1 to 6, or pharmaceutically acceptable salts thereof, which are the same or different, and which are independently selected from a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, respectively.

8. The following: 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 A compound or a pharmaceutically acceptable salt thereof or a deuterated analog thereof, selected from the above.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the preparation of a drug for treating 5-HT receptor-related disorders, wherein the 5-HT receptor-related disorder is preferably schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety disorder, sleep disorder, anorexia, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, or motor thrombosis. Use in: depression, major depressive disorder, anxiety, sleep disorders, eating disorders, non-motor symptoms caused by Parkinson's disease, delusions, hallucinations, cognitive impairment, dementia-related mental disorders, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxia, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, motor disorders, muscle tone abnormalities, myoclonus, tremor or progressive supranuclear palsy and frontotemporal dementia.

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