5-HT2A receptor inverse agonist as well as preparation method and application thereof

Abstract

The invention relates to a novel compound as a 5-HT2A receptor inverse agonist, and a preparation method and a pharmaceutical composition thereof. The invention also relates to application of the compound or the pharmaceutical composition in preparation of drugs for treating 5-HT2A receptor related diseases, wherein the diseases comprise non-motor symptoms caused by Parkinson's disease, such as delusional disorder, hallusion, depression, anxiety, cognitive disorder and sleep disorder; dementia-related mental disorders; major depression; or negative symptoms of schizophrenia and the like.

Description

5-HT 2A Receptor inverse agonist and its preparation method and application Technical Field

[0001] The present invention relates to a class of 5-hydroxytryptamine 2A (5-HT 2A ) receptor inverse agonist compound and its preparation method, and its 2A Application in the field of receptor-related diseases. Background Art

[0002] Parkinson's disease (PD) is a common neurodegenerative disease with an average age of onset around 60 years old (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517.). According to data from the National Institutes of Health (NIH) in 2018, there are approximately 4 to 6 million Parkinson's patients worldwide. Among them, up to 50% of Parkinson's patients experience severe symptoms such as hallucinations or delusions during their illness, which seriously affects their quality of life and has a high morbidity and mortality rate.

[0003] For a long time, antipsychotic drugs have been used clinically to treat hallucinations and delusions in Parkinson's patients. The first generation of antipsychotic drugs mainly inhibit dopamine D2 receptors and have serious extrapyramidal side effects. In addition to inhibiting D2 receptors, the second generation of antipsychotic drugs also inhibits specific 5-HT receptors, especially 5-HT 2A Second-generation antipsychotics inhibit D2 receptors and have a better safety profile, meaning fewer extrapyramidal side effects than first-generation antipsychotics. However, because second-generation antipsychotics still have D2 receptor inhibitory activity, they still have extrapyramidal side effects and can also cause varying degrees of weight gain. In 2016, the US FDA approved pimavanserin for the treatment of hallucinations and delusions associated with Parkinson's disease, making it the first drug approved for this indication.

[0004] Pimavanserin is a 5-HT 2A 5-HT receptor inverse agonist, which can eliminate the extrapyramidal and weight gain side effects associated with dopamine receptor inhibition of first-generation and second-generation antipsychotic drugs and has better safety. 2A It is a major excitatory receptor subtype in the 5-HT receptor family and belongs to ligand-gated channels and G protein-coupled receptors. 2AThe receptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important target for antipsychotic drugs and the treatment of schizophrenia (Price, DL, et al. Behavioural Pharmacology (2012), 23(4), 426-433.).

[0005] 5-HT 2A The receptors are intrinsically active and can produce effects even in the absence of agonists. 2A Receptor inverse agonists, 5-HT 2A After binding to the receptor, it can inhibit the inherent activity of the receptor, making the receptor inactive and producing an effect opposite to that of the agonist. Even in the absence of the agonist, it can still show activity. 2A After binding to the receptor, the receptor antagonist cannot cause biological effects and can only express its activity by inhibiting the agonist (WO2004064738A2). 2A Compounds with 5-HT receptor antagonist activity, but not necessarily 5-HT 2A Receptor inverse agonist activity.

[0006] 5-HT 2A Receptor inverse agonists have good application prospects in the pharmaceutical industry, but currently only pimavanserin has been approved for marketing. Therefore, more 5-HT 2A Receptor inverse agonists to achieve better therapeutic effects and meet the needs of clinical patients.

[0007] Summary of the Invention

[0008] In one aspect, the present invention provides a compound represented by formula (A), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0009] wherein R1 is selected from halogen;

[0010] Ring B is selected from

[0011] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0012] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0013] Ring A is selected from

[0014] X is selected from NR 6c , O or S;

[0015] X1 is selected from N or CH;

[0016] R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0017] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0018] n is selected from 0, 1, 2, and 3.

[0019] In some embodiments of the compound of Formula (A):

[0020] Ring A is selected from Preferably Other variables are as defined in the present invention.

[0021] In some embodiments of the compound of formula (A):

[0022] Ring B is selected from Preferably

[0023] R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0024] n is 1 or 2; other variables are as defined in the present invention.

[0025] In some embodiments of the compound of Formula (A):

[0026] R5' is selected from C 1-6Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1- 3 alkyl-substituted C 3-6 Cycloalkyl C 1-3 Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined herein.

[0027] In some embodiments of the compound of formula (A):

[0028] R1 is selected from halogen;

[0029] Ring B is selected from Preferably

[0030] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0031] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0032] Ring A is selected from

[0033] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0034] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0035] n is selected from 1, 2, and 3; other variables are as defined in the present invention.

[0036] In another aspect of the present invention, the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0037] in,

[0038] R1 is selected from halogen;

[0039] Ring B is selected from

[0040] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0041] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0042] Ring A is selected from

[0043] X is selected from NR 6c , O or S;

[0044] R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0045] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0046] n is selected from 0, 1, 2, and 3.

[0047] In some embodiments of the compound of Formula (I):

[0048] Ring A is selected from Preferably Other variables are as defined in the present invention.

[0049] In some embodiments of the compound of Formula (I):

[0050] Ring B is selected from Preferably

[0051] R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0052] n is 1 or 2; other variables are as defined in the present invention.

[0053] In some embodiments of the compound of Formula (I):

[0054] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined herein.

[0055] In some embodiments of the compound of Formula (I):

[0056] R1 is selected from F;

[0057] Ring B is selected from Preferably

[0058] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0059] Each R3 is independently a hydrogen atom, F, a methyl group, or two R3s attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0060] Ring A is selected from

[0061] X is selected from NR 6c , O or S;

[0062] R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R7b 、R 7c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0063] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0064] n is selected from 0, 1, 2, and 3.

[0065] In some embodiments of the compound of Formula (I):

[0066] R1 is selected from F;

[0067] Ring B is selected from Preferably

[0068] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0069] R3 is selected from hydrogen, F, methyl, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0070] Ring A is selected from

[0071] X is selected from NR 6c , O or S;

[0072] R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0073] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl, preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0074] n is selected from 0, 1, and 2.

[0075] In some embodiments of the compound of Formula (I):

[0076] R1 is selected from halogen;

[0077] Ring B is selected from Preferably

[0078] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0079] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0080] Ring A is selected from

[0081] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0082] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0083] n is selected from 1, 2, and 3; other variables are as defined in the present invention.

[0084] In some embodiments of the compound of Formula (I):

[0085] R1 is selected from F;

[0086] Ring B is selected from Preferably

[0087] R2 is selected from a hydrogen atom, a methyl group;

[0088] Ring A is selected from X is selected from NR 6c , O or S;

[0089] R 6a 、R 6b 、R 6cEach is independently selected from hydrogen atom, F, Cl, Br, methyl, and trifluoromethyl.

[0090] In some embodiments of the compound of Formula (I):

[0091] R1 is selected from F;

[0092] Ring B is selected from Preferably

[0093] R2 is selected from a hydrogen atom, a methyl group;

[0094] R3 is selected from hydrogen, F, methyl, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0095] Ring A is selected from

[0096] R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0097] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0098] n is selected from 0, 1, and 2.

[0099] In some embodiments of the compound of Formula (I):

[0100] R1 is selected from halogen;

[0101] Ring B is selected from

[0102] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0103] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 alkyl;

[0104] Ring A is selected from

[0105] R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0106] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Preferably, R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0107] In some embodiments of the compound of Formula (I):

[0108] R1 is selected from F;

[0109] Ring B is selected from

[0110] R2 is independently selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; preferably methyl;

[0111] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0112] Ring A is selected from

[0113] R 4a and R 4b Each is independently selected from hydrogen atom, F, Cl, Br;

[0114] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0115] In another aspect of the present invention, the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0116] in,

[0117] R1 is selected from halogen;

[0118] Ring B is selected from

[0119] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0120] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0121] Ring A is selected from

[0122] X is selected from NR 6c , O or S;

[0123] R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0124] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C3-6 Cycloalkyl C 1-3 alkyl;

[0125] n is selected from 0, 1, 2, and 3.

[0126] In some embodiments of the compound of formula (II):

[0127] Ring A is selected from Preferably Other variables are as defined in the present invention.

[0128] In some embodiments of the compound of formula (II):

[0129] Ring B is selected from Preferably

[0130] R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0131] n is 1 or 2; other variables are as defined in the present invention.

[0132] In some embodiments of the compound of formula (II):

[0133] R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1- 3 alkyl-substituted C 3-6 Cycloalkyl C 1-3 Alkyl, preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in the present invention.

[0134] In some embodiments of the compound of formula (II):

[0135] R1 is selected from halogen;

[0136] Ring B is selected from Preferably

[0137] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0138] Each R3 is independently selected from hydrogen, halogen, C 1-3Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0139] Ring A is selected from

[0140] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0141] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0142] n is selected from 1, 2, and 3; other variables are as defined in the present invention.

[0143] In some embodiments of the compound of formula (II):

[0144] R1 is selected from F;

[0145] Ring B is selected from

[0146] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0147] Each R3 is selected from a hydrogen atom, F, a methyl group, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0148] Ring A is selected from

[0149] R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0150] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl, preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0151] n is selected from 0, 1, 2, and 3.

[0152] In some embodiments of the compound of formula (II):

[0153] R1 is selected from halogen;

[0154] Ring B is selected from

[0155] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0156] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Form C with the carbon atom to which it is connected 3-6 Cycloalkyl;

[0157] Ring A is selected from

[0158] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0159] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl.

[0160] In some embodiments of the compound of formula (II):

[0161] R1 is selected from F;

[0162] Ring B is selected from

[0163] R2 is independently selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0164] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0165] Ring A is selected from

[0166] R 4a 、R 4b 、R 4c Each is independently selected from hydrogen atom, F, Cl, Br;

[0167] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl, preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0168] In one aspect, the present invention provides a compound represented by formula (IIA), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0169] in,

[0170] R1 is selected from halogen;

[0171] Ring B is selected from

[0172] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0173] Each R3 is independently selected from hydrogen, halogen, C 1-3 alkyl;

[0174] R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0175] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, preferably, R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl;

[0176] n is selected from 0, 1, 2, and 3.

[0177] In some embodiments of the compound of Formula (IIA):

[0178] Ring B is selected from Preferably

[0179] R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0180] n is 1 or 2; other variables are as defined in the present invention.

[0181] In some embodiments of the compound of Formula (IIA):

[0182] R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1- 3 alkyl-substituted C 3-6 Cycloalkyl C 1-3Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined herein.

[0183] In some embodiments of the compound of Formula (IIA):

[0184] R1 is selected from halogen;

[0185] Ring B is selected from Preferably

[0186] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0187] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0188] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0189] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0190] n is selected from 1, 2, and 3; other variables are as defined in the present invention.

[0191] In some embodiments of the compound of Formula (IIA):

[0192] R1 is selected from F;

[0193] Ring B is selected from

[0194] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0195] Each R3 is independently a hydrogen atom, F, or a methyl group;

[0196] R 4a 、R 4bEach is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0197] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl, preferably, R5' is selected from 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0198] n is selected from 0, 1, 2, and 3.

[0199] In one aspect, the present invention provides a compound represented by formula (IIA-1) or (IIA-2), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0200] in,

[0201] R1 is selected from halogen;

[0202] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0203] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Form C with the carbon atom to which it is connected 3-6 Cycloalkyl;

[0204] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0205] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0206] In some embodiments of the compound of Formula (IIA-1) or (IIA-2):

[0207] R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl; other variables are as defined herein.

[0208] In some embodiments of the compound of Formula (IIA-1) or (IIA-2):

[0209] R1 is selected from F;

[0210] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0211] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0212] R 4a 、R 4b 、R 4c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0213] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0214] In one aspect, the present invention provides a compound represented by formula (IIB), a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof:

[0215] in,

[0216] R1 is selected from halogen;

[0217] Ring B is selected from

[0218] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0219] Each R3 is independently selected from hydrogen, halogen, C 1-3 alkyl;

[0220] R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0221] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl;

[0222] n is selected from 0, 1, 2, and 3.

[0223] In some embodiments of the compound of Formula (IIB):

[0224] R1 is selected from F;

[0225] Ring B is selected from

[0226] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0227] Each R3 is independently a hydrogen atom, F, or a methyl group;

[0228] R 4a 、R 4b Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0229] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0230] n is selected from 0, 1, 2, and 3.

[0231] In another aspect, the present invention provides a compound represented by formula (III), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0232] in,

[0233] R1 is selected from halogen;

[0234] Ring B is selected from

[0235] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0236] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0237] R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0238] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0239] n is selected from 0, 1, 2, and 3.

[0240] In some embodiments of the compound of formula (III):

[0241] Ring B is selected from Preferably

[0242] R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0243] n is 1 or 2; other variables are as defined in the present invention.

[0244] In some embodiments of the compound of formula (III):

[0245] R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 alkyl-substituted C 3-6 Cycloalkyl C 1-3 Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined herein.

[0246] In some embodiments of the compound of formula (III):

[0247] R1 is selected from halogen;

[0248] Ring B is selected from Preferably

[0249] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0250] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0251] Ring A is selected from

[0252] R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0253] R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0254] n is selected from 1, 2, and 3; other variables are as defined in the present invention.

[0255] In some embodiments of the compound represented by formula (III):

[0256] R1 is selected from halogen;

[0257] Ring B is selected from

[0258] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0259] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl;

[0260] R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0261] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0262] n is selected from 0, 1, and 2.

[0263] In some embodiments of the compound represented by formula (III):

[0264] R1 is selected from F;

[0265] Ring B is selected from

[0266] R2 is independently selected from a hydrogen atom, a methyl group;

[0267] Each R3 is independently selected from a hydrogen atom, F, Cl, Br, a methyl group, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom;

[0268] R 4a and R 4b are each independently selected from hydrogen atom, hydrogen atom, F, Cl, Br;

[0269] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0270] n is selected from 0, 1, and 2.

[0271] In some embodiments of the compound represented by formula (III):

[0272] R1 is selected from halogen;

[0273] Ring B is selected from

[0274] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0275] Each R3 is independently selected from hydrogen, halogen, C 1-3 alkyl;

[0276] R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0277] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl;

[0278] n is selected from 0, 1, 2, and 3.

[0279] In some embodiments of the compound of formula (III):

[0280] R1 is selected from F;

[0281] Ring B is selected from

[0282] R2 is selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0283] Each R3 is independently a hydrogen atom, F, or a methyl group;

[0284] R 4a 、R 4b Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0285] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0286] n is selected from 0, 1, 2, and 3.

[0287] In some embodiments of the compound represented by formula (III):

[0288] R1 is selected from halogen;

[0289] Ring B is selected from

[0290] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0291] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Form C with the carbon atom to which it is connected 3-6 Cycloalkyl;

[0292] R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0293] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0294] In some embodiments of the compound represented by formula (III):

[0295] R1 is selected from F;

[0296] Ring B is selected from

[0297] R2 is independently selected from a hydrogen atom, a methyl group;

[0298] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0299] R 4a and R 4b are each independently selected from hydrogen atom, hydrogen atom, F, Cl, Br;

[0300] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0301] In another aspect, the present invention provides a compound represented by formula (IIIA) or (IIIB), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0302] in,

[0303] R1 is selected from halogen;

[0304] R2 is selected from hydrogen atom, C 1-3 alkyl;

[0305] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Form C with the carbon atom to which it is connected 3-6 Cycloalkyl;

[0306] R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0307] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl.

[0308] In some embodiments of the compound represented by formula (IIIA) or (IIIB):

[0309] R1 is selected from F;

[0310] R2 is selected from a hydrogen atom, a methyl group;

[0311] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0312] R 4a and R 4b Each is independently selected from hydrogen atom, F, Cl, Br;

[0313] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0314] In another aspect, the present invention provides a compound represented by formula (IIIC), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0315] in,

[0316] R1 is selected from halogen;

[0317] R2 is selected from hydrogen atom, C 1-3 alkyl;

[0318] R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3alkyl halide;

[0319] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl.

[0320] In some embodiments of the compound represented by formula (II):

[0321] R1 is selected from F;

[0322] R2 is selected from a hydrogen atom, a methyl group;

[0323] R 4a and R 4b are each independently selected from hydrogen atom, hydrogen atom, F, Cl, Br;

[0324] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0325] In another aspect, the present invention provides a compound represented by formula (IV), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0326] in,

[0327] R1 is selected from halogen;

[0328] R2 is selected from hydrogen atom, C 1-3 alkyl;

[0329] R 6a 、R 6b are independently selected from hydrogen atoms, halogens, C 1-3 alkyl halide;

[0330] R 6c Selected from hydrogen atoms, C 1-3 alkyl.

[0331] In some embodiments of the compound represented by formula (IV):

[0332] R1 is selected from F;

[0333] R2 is selected from a hydrogen atom, a methyl group;

[0334] R 6a 、R 6b Each is independently selected from hydrogen atom, F, trifluoromethyl;

[0335] R 6c Selected from hydrogen atom and methyl group.

[0336] In another aspect, the present invention provides a compound represented by formula (V), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0337] in,

[0338] R1 is selected from halogen;

[0339] R2 is selected from hydrogen atom, C 1-3 alkyl;

[0340] R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Halogenated alkyl.

[0341] In some embodiments of the compound represented by formula (V):

[0342] R1 is selected from F;

[0343] R2 is selected from a hydrogen atom, a methyl group;

[0344] R 7a 、R 7b 、R 7c Each is independently selected from a hydrogen atom, F, and a trifluoromethyl group.

[0345] In another aspect of the present invention, the present invention provides a compound represented by formula (VI), a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

[0346] in,

[0347] R 1a 、R 1b Each independently selected from a hydrogen atom, C 1-3 alkyl;

[0348] Ring B is selected from

[0349] R2 is independently selected from hydrogen atom, C 1-3 alkyl;

[0350] Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C3-6 Cycloalkyl;

[0351] Ring A is selected from

[0352] X is selected from NR 6c , O or S

[0353] R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0354] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl;

[0355] n is selected from 0, 1, 2, and 3.

[0356] In some embodiments of the compound of formula (VI):

[0357] R 1a 、R 1b Each independently selected from hydrogen atom, C 1-3 alkyl;

[0358] Ring B is selected from

[0359] R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl;

[0360] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen atoms, halogens, C 1-3 alkyl;

[0361] Ring A is selected from

[0362] R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide;

[0363] R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl.

[0364] In some embodiments of the compound of formula (VI):

[0365] R 1a 、R 1b are each independently selected from a hydrogen atom, a methyl group;

[0366] Ring B is selected from

[0367] R2 is independently selected from hydrogen, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0368] R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are independently selected from hydrogen, F, methyl, or R 3a With R 3b 、R 3c With R 3d 、R 3e With R 3f , or R 3g With R 3h Forming a cyclopropyl group with the carbon atom to which it is attached;

[0369] Ring A is selected from

[0370] R 4a and R 4b Each is independently selected from hydrogen atom, F, Cl, Br;

[0371] R5 is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0372] In another aspect, the present invention provides a compound as shown below, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof:

[0373] In another aspect, the present invention provides the following compounds, pharmaceutically acceptable salts or deuterated derivatives thereof, selected from:

[0374] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the aforementioned compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or a crystalline form of any of the aforementioned compounds, and a pharmaceutically acceptable carrier. The carrier includes conventional excipients in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, or wetting agents.

[0375] The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral solutions, suspensions, granules, powders, microgranules, pills, mini tablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release preparations. The pharmaceutical composition can be administered orally, transmucosally, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type.

[0376] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in dosage unit form containing a specific amount of active ingredient. For example, the pharmaceutical composition can be provided as a tablet or capsule containing an amount of active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The suitable daily dose for humans or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0377] In one aspect, the present invention provides any one of the above compounds, pharmaceutically acceptable salts or stereoisomers thereof for use in treating 5-HT 2AThe invention also relates to the use of a medicament for a receptor-related disease. The diseases or symptoms include: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tics, depression, major depressive disorder, anxiety, sleep disorder and appetite disorder, non-motor symptoms caused by Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disorder), dementia-related mental illness, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy bodies, movement disorders, dystonia, myoclonus, tremor, progressive supranuclear palsy and frontotemporal dementia; or other disease states and conditions obvious to those skilled in the art.

[0378] Definition and Description

[0379] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0380] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0381] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by reacting a compound having specific substituents discovered by the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such 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 acid salts, organic acid salts, and salts of amino acids (such as arginine, etc.), as well as salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0382] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0383] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0384] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0385] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0386] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier 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 has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0387] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0388] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0389] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with a deuterium atom. The term "optional" or "optionally" means that the event or situation described subsequently may but need not occur, and that the description includes instances where the event or situation occurs as well as instances where the event or situation does not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group may be unsubstituted or substituted with one or more deuterium atoms, i.e., includes instances where the group is unsubstituted, partially substituted, and / or fully substituted.

[0390] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0391] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0392] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 10 Indicates 1 to 10 carbons, C 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 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.

[0393] Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. The term "haloalkyl" is intended to include monohaloalkyl and polyhalogenated straight or branched chain haloalkoxy. For example, the term "C 1-10 Haloalkyl is meant to include, but is not limited to, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 2,2'-difluoroisopropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0394] Unless otherwise specified, cycloalkyl groups include any stable cyclic or polycyclic hydrocarbon radicals, all carbon atoms of which are saturated, which may be monosubstituted or polysubstituted, and which may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. The cycloalkyl groups may optionally be further substituted with halogen or C1-C3 alkyl groups.

[0395] Unless otherwise specified, "cycloalkylalkyl" refers to a C 3-6 Cycloalkyl-C 1-3 Alkyl-, cycloalkylalkyl can be substituted or unsubstituted, and its non-limiting examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, etc. The cycloalkylalkyl can be optionally further substituted by halogen or C1-C3 alkyl.

[0396] Compounds are manually or Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0397] Figure 1: The number of head shakes in SD rats 1.0-1.5 h after a single oral administration (#P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group). DETAILED DESCRIPTION

[0398] The present invention is further described below with reference to specific embodiments and test examples, but they are not intended to limit the scope of the present invention in any form.

[0399] Example 1

[0400] Under nitrogen protection and in an ice-water bath, 2-(aminomethyl)-5-fluoropyridine (504 mg, 4.0 mmol) was dissolved in 10 ml of methanol. N-methyl-4-piperidone (452 ​​mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added. The mixture was warmed to room temperature and reacted for 15 h. Aqueous sodium bicarbonate was added to adjust the pH to alkaline. The organic phase was concentrated and extracted with dichloromethane (10 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-2 (538 mg).

[0401] 16 mL of dimethyl sulfoxide, compound 1-3 (4.00 g, 1.00 eq), trifluoroethanol (9.83 g, 3.00 eq), and cesium carbonate (16.01 g, 1.50 eq) were added sequentially to a 100 mL three-necked flask. The temperature was raised to 105°C and the reaction was maintained for 12 hours. 200 mL of water was added to the reaction solution, and the mixture was extracted twice with 200 mL of ethyl acetate each time. The organic phases were combined and washed with 200 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 1-4 (orange oil, 5.6 g).

[0402] 160 mL of tetrahydrofuran, compound 1-4 (4.0 g, 1.00 eq), di-tert-butyl dicarbonate (4.32 g, 1.0 eq), and Raney nickel (1.7 g, 1.0 eq) were added sequentially to a 500 mL hydrogenation bottle and reacted at 70°C, 50 Psi for 12 hours. The mixture was filtered and dried to obtain a crude product, which was purified by preparative chromatography to afford compound 1-5 (white solid, 2.37 g).

[0403] Ethyl acetate (5 mL), compound 1-5 (1.00 g, 1.00 eq), and HCl / EtOAc (5 mL) were added sequentially to a 100 mL single-necked bottle and stirred at 25°C for 17 hours. The reaction solution was directly spin-dried to give crude compound 1-6 (pale pink solid, 903 mg).

[0404] 2 mL of tetrahydrofuran, compound 1-6 (200 mg, 1.00 eq), and diisopropylethylamine (DIEA) (125 mg, 1.00 eq) were added sequentially to a 10 mL single-necked vial. The mixture was stirred under nitrogen for 15 minutes, then cooled to 0°C in an ice-water bath. Carbonyldiimidazole (CDI) (173 mg, 1.10 eq) was added to the reaction mixture, and the reaction was continued at 0°C for 1 hour. Compound 1-2 (216 mg, 1.0 eq) was dissolved in 1 mL of tetrahydrofuran and added to the reaction mixture. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated to dryness to obtain a crude product. The crude product was purified by thin-layer chromatography and preparative chromatography to obtain compound 1 (a yellow oil, 160 mg). 1 H NMR (400MHz, CDCl3) δ8.35(d,J=2.5Hz,1H),8.24(d,J=2.8Hz,1H),7.41-7.32(m,2H),7.24-7.20(m,1H),7.00(br d,J=2.1Hz,1H),4.50(d,J=5.4Hz,2H),4.47(s,2H),4.39(q,J=8.0Hz,2H),4.27(br s,1H),2.94(br d,J=11.6Hz,2H),2.32(s,3H),2.20-2.08(m,2H),1.82(br dd,J=3.4,12.1Hz,2H),1.73-1.61(m,2H). MS m / z(ESI):456.2[M+1].

[0405] Example 2

[0406] Compounds 2-4, 7-8, 11, 77, and 79 were obtained using a synthetic method similar to that of Example 1. The following table lists the characterization data of compounds 2-4, 7-8, 11, 77, and 79:

[0407] Example 3

[0408] 3 mL of tetrahydrofuran, compound 5-1 (300 mg, 1.00 eq), and diisopropylethylamine (282.10 mg, 1.50 eq) were added to a 100 mL single-necked flask. The temperature was cooled to 0°C and stirred under nitrogen for 15 minutes. Carbonyldiimidazole (259.55 mg, 1.10 eq) was added to the reaction solution and reacted at 0°C for 1 hour. Dissolved compound 1-2 (324.92 mg, 1.00 eq) and 2 mL of tetrahydrofuran were added to the reaction solution and reacted at 25°C for 12 hours. The mixture was filtered and dried to obtain a crude product. The crude product was purified by preparative chromatography to afford compound 5 (a yellow solid, 440 mg). 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=2.9Hz,1H),8.04(d,J=1.9Hz,1H),7.69-7.62(m,2H),7.29(dd,J=4.4,8.8Hz,1H ),7.15(t,J=5.6Hz,1H),6.93(d,J=8.5Hz,1H),4.96(q,J=9.1Hz,2H),4.46(s,2H),4.21(d,J=5.5Hz,2H),3.97(br t,J=11.4Hz,1H),2.88(br d,J=10.6Hz,2H),2.26(s,3H),2.16(br t,J=9.9Hz,2H),1.65-1.54(m,2H),1.53-1.47(m,2H). MS m / z(ESI):456.2[M+1].

[0409] Example 4

[0410] 25 mL of methylpyrrolidone and compound 6-2 (2.55 g, 1.20 eq) were added to a 100 mL three-necked flask and cooled to 0°C. Sodium hydride (1.18 g, 1.50 eq) was added to the reaction mixture in batches and stirred at 0°C for 0.5 hours. Compound 6-1 (2.40 g, 1.00 eq) was dissolved in 20 mL of methylpyrrolidone and added dropwise to the reaction mixture, stirring at 25°C for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times, each time with 200 mL. The organic phase was dried, filtered, and dried to obtain a crude product, which was purified by column chromatography to obtain compound 6-3 (white solid, 1.20 g).

[0411] Add 12 mL of tetrahydrofuran, compound 6-3 (1.20 g, 1.00 eq), di-tert-butyl dicarbonate (1.25 g, 1.00 eq), and Raney nickel (1.20 g, 2.45 eq) to a 250 mL hydrogenation bottle and react at 70°C, 50 Psi for 24 hours. Filter and spin dry to obtain a crude product, which is purified by column chromatography to yield compound 6-4 (white solid, 720 mg).

[0412] 2 mL of ethyl acetate and compound 6-4 (720 mg, 1.00 eq) were added to a 100 mL single-necked flask. Ethyl acetate hydrochloride (8 mL, 4 M) was slowly added dropwise to the reaction solution and allowed to react at 25°C for 12 hours. The mixture was then spin-dried and dissolved in 10 mL of dichloromethane. The pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution and extracted three times with 10 mL of dichloromethane each time. The organic phase was dried, filtered, and spin-dried to obtain compound 6-5 (440 mg).

[0413] 4 mL of tetrahydrofuran, compound 6-5 (390 mg, 1.00 eq), and diisopropylethylamine (352.96 mg, 1.50 eq) were added to a 100 mL single-necked flask. The temperature was cooled to 0°C and stirred under nitrogen for 15 minutes. Carbonyldiimidazole (324.73 mg, 1.10 eq) was added to the reaction solution and reacted at 0°C for 1 hour. Dissolved compound 1-2 (406.53 mg, 1.00 eq) and 2 mL of tetrahydrofuran were added to the reaction solution and reacted at 25°C for 12 hours. The mixture was filtered and dried to obtain a crude product. The crude product was purified by preparative chromatography to afford compound 6 (a yellow gum, 460 mg). 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=2.9Hz,1H),8.00(d,J=2.1Hz,1H),7.69-7.59(m,2H),7.30(dd,J=4.5,8.8Hz,1H),7.11(t,J=5.6 Hz,1H),6.81(d,J=8.5Hz,1H),5.13-5.02(m,1H),4.46(s,2H),4.19(d,J=5.5Hz,2H),3.99-3.89(m,1H),3.20-3.07(m,2H),2.81(br d,J=11.3Hz,2H),2.74-2.61(m,2H),2.19(s,3H),2.04(br t, J=10.9Hz, 2H), 1.57 (dq, J=3.4, 12.0Hz, 2H), 1.50-1.43 (m, 2H). MS m / z(ESI):464.2[M+1].

[0414] Example 5

[0415] Compound 19 was obtained by a synthetic method similar to that of Example 4. 1 H NMR (400MHz, CDCl3) δ8.30(d,J=2.4Hz,1H),7.82(d,J=2.0Hz,1H),7.41-7.33(m,4H),5.17-5.14(m,1H),4.38( s,2H),4.35-4.34(m,2H),4.32-4.28(m,1H),3.14-3.12(m,2H),2.99-2.96(m,2H),2.79-2.75(m,2H),2.52(br s,1H),2.35(s,3H),2.18-2.15(m,2H),1.91-1.87(m,2H),1.68-1.65(m,2H). MS (ESI) m / z: 482.2 [M+1].

[0416] Example 6

[0417] 5 mL of N,N-dimethylformamide, compound 9-1 (300 mg, 1.00 eq), and diisopropylethylamine (265 mg, 1.00 eq) were added sequentially to a 10 mL single-necked vial. The mixture was stirred under nitrogen for 15 minutes, then cooled to 0°C in an ice-water bath. Carbonyldiimidazole (366 mg, 1.10 eq) was added to the reaction mixture, and the reaction was continued at 0°C for 1 hour. Compound 1-2 (504 mg, 1.0 eq) was dissolved in 2 mL of DMF and added to the reaction mixture. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times, each time using 50 mL. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to yield compound 9 (a yellow oil, 310 mg). 1 HNMR(400MHz,CDCl3)δ8.38(br s,1H),8.23(d,J=2.6Hz,1H),7.52(s,1H),7.35-7.29(m,3H),7.21(t,J=2.8Hz,1H),7.11(dd,J=1.5,8.4Hz,1H),6.66(br s,1H),6.50(ddd,J=0.8,2.0,3.0Hz,1H),4.51(d,J=5.1Hz,2H),4.39(s,2H),4.34(br t,J=4.1Hz,1H),2.95(br d,J=11.5Hz,2H),2.32(s,3H),2.14(br t,J=11.1Hz,2H),1.89-1.76(m,2H),1.73-1.66(m,2H). MS m / z(ESI):396.2[M+1].

[0418] Example 7

[0419] 5 mL of N,N-dimethylformamide, compound 10-1 (300 mg, 1.00 eq), and diisopropylethylamine (245 mg, 1.00 eq) were added sequentially to a 10 mL single-necked flask. Stirred under nitrogen for 15 minutes, the temperature was then lowered to 0°C in an ice-water bath. Carbonyldiimidazole (338 mg, 1.10 eq) was added to the reaction mixture, and the reaction was allowed to react at 0°C for 1 hour. Compound 1-2 was dissolved in 2 mL of DMFN,N-dimethylformamide and added to the reaction mixture, which was then stirred at 25°C for 12 hours. 40 mL of water was added to the reaction mixture, and the mixture was extracted twice with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to yield compound 10 (yellow oil, 200 mg). 1 H NMR (400MHz, CDCl3) δ8.89 (dd, J=1.6, 4.3Hz, 1H), 8.26 (d, J=2.0Hz, 1H), 8.13-8.03 (m, 2H), 7.72 -7.63(m,2H),7.45-7.35(m,3H),4.62(d,J=5.5Hz,2H),4.44(s,2H),4.39-4.26(m,1H),2.99(br d,J=11.5Hz,2H),2.36(s,3H),2.19(br t,J=11.1Hz,2H),1.98-1.82(m,2H),1.71(br dd,J=1.9,11.8Hz,2H). MS m / z(ESI):408.2[M+1].

[0420] Example 8

[0421] 5 mL of tetrahydrofuran, compound 5-1 (400 mg, 1.00 eq), and diisopropylethylamine (376 mg, 1.50 eq) were added to a 100 mL single-necked flask. The temperature was cooled to 0°C and stirred under nitrogen for 15 minutes. Carbonyldiimidazole (346 mg, 1.10 eq) was added to the reaction solution and allowed to react at 0°C for 1 hour. Dissolved compound 39-1 (635 mg, 1.00 eq) and 4 mL of tetrahydrofuran were added to the reaction solution and allowed to react at 25°C for 12 hours. The mixture was filtered to obtain a filtrate. The filtrate was purified by preparative chromatography to obtain compound 39-2 (yellow oil, 400 mg, yield: 33.5%).

[0422] 20 mL of dichloromethane, compound 39-2 (350 mg, 1.00 eq), and trifluoroacetic acid (6 mL, 129 eq) were added to a 100 mL single-necked bottle, stirred at 25° C. for 20 minutes, and dried in a spin-drying machine to obtain a yellow oil. 20 mL of tetrahydrofuran, yellow oil, sodium cyanoborohydride (78 mg, 2.00 eq), and 37% formaldehyde aqueous solution (76 mg, 1.50 eq) were added to a 100 mL single-necked flask, stirred at 25° C. for 20 minutes, and spun off to dryness. 10 mL of methanol was added, stirred at 75° C. for 80 minutes, and spun off to dryness to obtain a crude product. The crude product was subjected to chiral separation (chromatographic column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 20%-20%) to give compound 39 (retention time: 1.778 min, yellow viscous gum, 120 mg, yield: 39.9%) and compound 41 (retention time: 1.876 min, yellow viscous gum, 130 mg, yield: 43.3%).

[0423] Compound 39: 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=2.9Hz,1H),8.02(d,J=2.0Hz,1H),7.69-7.62(m,2H),7.34(dd,J=4.5,8.8Hz,1H),7.20(t,J=5.6Hz, 1H),6.92(d,J=8.5Hz,1H),4.96(q,J=9.1Hz,2H),4.71-4.45(m,3H),4.29-4.14(m,2H),4.13-3.99(m,1H),3.13-3.04(m,1H),2.66(br d,J=10.6Hz,1H),2.18(s,3H),1.99-1.87(m,2H),1.62-1.52(m,2H). MS m / z(ESI):474.3[M+1].

[0424] Compound 41: 1H NMR (400MHz, DMSO-d6) δ8.47(d,J=2.9Hz,1H),8.03(d,J=2.0Hz,1H),7.70-7.62(m,2H),7.35(dd,J=4.5,8.8Hz,1H),7.20(t,J=5.6Hz, 1H),6.93(d,J=8.4Hz,1H),4.97(q,J=9.1Hz,2H),4.62-4.45(m,3H),4.28-4.14(m,2H),4.12-4.01(m,1H),3.13-3.06(m,1H),2.66(br d,J=11.0Hz,1H),2.18(s,3H),1.98-1.87(m,2H),1.64-1.51(m,2H). MS m / z(ESI):474.3[M+1].

[0425] Example 9

[0426] Compound 39-2 (360 mg, 1 eq) was added to 3.3 mL of ethyl acetate, followed by the addition of HCl / EtOAc (4 M, 2.41 mL, 15 eq) and the reaction mixture was allowed to react at room temperature for 12 hours. The reaction mixture was concentrated and spun down to obtain the crude product. The pH was adjusted to 7 by the addition of aqueous sodium bicarbonate solution, and the product was then concentrated and spun down to dryness. The crude product was subjected to chiral separation (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 20%-20%), followed by concentration and lyophilization to afford Compound 56A (retention time: 1.744 min, yellow oil, 95.0 mg, yield: 30.0%) and Compound 56B (retention time: 2.519 min, yellow oil, 90 mg, yield: 29.4%).

[0427] Compound 56A: 1H NMR (400MHz, CDCl3) δ1.76-1.83(m,2H),2.58-2.68(m,2H),3.03(br d,J=12.26Hz,1H),3.36-3.48(m,1H),4.27(td,J=10.66,5.19Hz,1H),4.35(br d,J=5.38Hz,2H),4.45-4.50(m,2H),4.59-4.67(m,1H),4.71-4.78(m,2H),6.54-6.69(m,1H),6.81(d,J= 8.50Hz,1H),7.35-7.43(m,2H),7.57(dd,J=8.44,2.31Hz,1H),7.97-8.06(m,1H),8.30(d,J=2.38Hz,1H). MS(ESI)m / z:460.2[M+1].

[0428] Compound 56B: 1 H NMR (400MHz, CDCl3) δ1.67(br s,2H),2.52(br d,J=3.50Hz,2H),2.86-2.98(m,1H),3.30(br s,1H),4.14(br s,1H),4.23(br s,2H),4.37(br s,2H),4.53(br s,1H),4.63(br d,J=6.13Hz,2H),6.41-6.61(m,1H),6.69(br d,J=5.88Hz,1H),7.27(br s,2H),7.37-7.52(m,1H),7.91(br s,1H),8.18(br s,1H). MS (ESI) m / z: 460.2 [M+1].

[0429] Example 10

[0430] Compounds 27-28, 42, 44, 66 / 67, 69A / 69B, and 70A / 70B were obtained using a synthesis method and / or resolution method similar to that of Example 8. The resolution conditions (chromatographic column: DAICEL CHIRALCEL OX (250 mm*50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 25%-25%) were used to obtain compounds 46A / 46B, 47A / 47B, 72A / 72B, 81A / 81B, 82A / 82B, and 83A / 83B. The following table lists the characterization data of the relevant compounds:

[0431] Example 11

[0432] Add 20 mL of tetrahydrofuran and compound 57-1 (1.80 g, 1.00 eq) to a 100 mL three-necked flask. Cool to 0°C. Add lithium aluminum tetrahydride (954 mg, 2.00 eq) in portions to the reaction mixture, and stir at 25°C for 12 hours. Add 1 mL of water, 1 mL of 15% aqueous sodium hydroxide solution, and 3 mL of water sequentially to the reaction mixture. Extract three times with ethyl acetate. The organic phase is dried, filtered, and spin-dried to obtain a crude product. The crude product is purified by preparative chromatography to afford compound 57-2 (620 mg, yield: 32.8%).

[0433] 6 mL of tetrahydrofuran, compound 57-2 (570 mg, 1.00 eq), and diisopropylethylamine (750 mg, 1.50 eq) were added to a 100 mL single-necked flask. The temperature was cooled to 0°C and stirred under nitrogen for 15 minutes. Carbonyldiimidazole (690 mg, 1.10 eq) was added to the reaction solution and reacted at 0°C for 1 hour. Compound 1-2 (864 mg, 1.00 eq) was added to the reaction solution and reacted at 25°C for 12 hours. Filtering afforded the crude product. The crude product was purified by preparative chromatography to afford compound 57 (an off-white solid, 950 mg, yield: 60.9%). 1 H NMR (400MHz, DMSO-d6) δ8.47(d,J=2.8Hz,1H),7.95(d,J=2.1Hz,1H),7.65(dt,J=2.9,8.8Hz,1H),7.52- 7.45(m,2H),7.34(dd,J=4.5,8.6Hz,1H),7.23-7.14(m,2H),6.92(d,J=1.4Hz,1H),4.49(s,2H),4.36(br d,J=5.5Hz,2H),3.96(br t,J=11.5Hz,1H),2.71(br d,J=11.1Hz,2H),2.09(s,3H),1.94-1.83(m,2H),1.61-1.50(m,2H),1.49-1.41(m,2H). MS(ESI)m / z:397.2[M+1].

[0434] Example 12

[0435] Compounds 12-13, 58-61, and 84 were obtained using a synthetic method similar to that of Example 11. The following table lists the characterization data of compounds 12-13, 58-61, and 84:

[0436] Example 13

[0437] To a 100 mL three-necked flask, add 30 mL of acetonitrile, compound 17-1 (10.0 g, 1.00 eq), and triethylamine (4.15 g, 1.00 eq) sequentially under nitrogen. Add trifluoroacetic anhydride (9.47 g, 1.10 eq) in batches. Keep the reaction temperature between 35°C and 40°C. Incubate at 40°C for half an hour. Dilute with 30 mL of water, filter, collect the filter cake, and dry under vacuum to obtain compound 17-2 (yellow oil, 11.8 g, yield: 85.3%).

[0438] Cesium carbonate (23.96 g, 2.50 eq), cuprous iodide (840 mg, 0.15 eq), and L-proline (2.27 g, 1.0 eq) were added sequentially to a 100 mL three-necked flask. 20 mL of N,N-dimethylformamide was added to the reaction flask and the mixture was allowed to react at 25°C for 15 minutes. Compound 17-2 (10 g, 1.00 eq) was dissolved in 10 mL of N,N-dimethylformamide and slowly added dropwise to the reaction mixture. The mixture was allowed to react at 25°C for 15 minutes. Tert-butyl acetoacetate (9.3 g, 2.00 eq) was added to the reaction mixture and the mixture was allowed to react at 90°C for 12 hours. After the reaction was complete, the contents of the container were cooled to 18-23°C. Water (40 mL) was added over 15 seconds, maintaining the reaction temperature below 35°C. Isopropyl acetate (40 mL), toluene (80 mL), and water (40 mL) were then added. The aqueous layer was drained and washed with saturated ammonium chloride solution (50 ml). The organic layer was then reduced to a minimum by vacuum distillation. Dichloromethane (30 ml) was added and the internal temperature was adjusted to 18°C-23°C. Trifluoroacetic acid (10 mL) was added and continued for 15 minutes. The solution was stirred overnight. The solid was filtered and washed twice with dichloromethane, each time with 20 ml. Compound 17-3 was obtained (yellow solid, 3.52 g, yield: 47.7%).

[0439] 5 mL of 1-methyl-2-pyrrolidone, 0.5 mL of water, and compound 17-3 (1.0 g, 1.00 eq) were added sequentially to a 50 mL single-necked flask. The reaction was incubated at 130°C for 12 hours. After cooling to room temperature, 30 mL of water was added and the mixture was stirred for 40 minutes. The mixture was then filtered. The filter cake was washed with water and dried under vacuum. The crude product was purified by column chromatography to afford compound 17-4 (white solid, 760 mg, yield: 46.1%).

[0440] 15 mL of N,N-dimethylformamide, compound 17-4 (750 mg, 1.00 eq), and sodium hydroxide (356.85 mg, 60% purity, 2.50 eq) were added sequentially to a 50 mL three-necked flask and allowed to react at room temperature for 30 minutes. Iodomethane (1.01 g, 2.00 eq) was added portionwise to the reaction mixture at 0°C and allowed to react at room temperature for 2 hours. 150 mL of ice water was added to the reaction mixture, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain compound 17-5 (white solid, 790 mg, yield: 92%).

[0441] 50 mL of tetrahydrofuran, compound 17-5 (790 mg, 1.00 eq), di-tert-butyl dicarbonate (769 mg, 1.00 eq), and Raney nickel (1.00 g, 3.31 eq) were added sequentially to a 200 mL hydrogenation bottle and reacted at 70°C, 50 Psi, and H2 for 16 hours. The mixture was filtered and dried to give compound 17-6 (white solid, 1.62 g, crude product).

[0442] To a 50 mL single-necked flask, add 5 mL of ethyl acetate, compound 17-6 (1.62 g, 1.00 eq), and HCl / EtOAc (4 M, 20.0 mL, 16.21 eq). Incubate at room temperature for 2 hours. Spin dry. The crude product is purified by preparative chromatography to afford compound 17-7 (yellow oil, 297 mg, yield: 25.4%).

[0443] 4 mL of tetrahydrofuran, compound 1-2 (78.33 mg, 1.00 eq), and diisopropylethylamine (141.5 mg, 1.10 eq) were added sequentially to a 50 mL three-necked flask and allowed to react at room temperature for 15 minutes. Carbonyldiimidazole (195.39 mg, 1.10 eq) was added to the reaction mixture at 0°C and allowed to react at 0°C for one hour. After the reaction intermediate was detected, compound 17-7 (244 mg, 1.00 eq) was added to the reaction mixture and allowed to react at room temperature for 12 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted twice with 20 mL of dichloromethane each time. The organic phases were combined, washed with 20 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative chromatography to yield compound 17 (white solid, 145 mg, yield: 27.2%). 1H NMR (400MHz, CDCl3) δ8.22 (d, J = 2.5Hz, 1H), 7.59 (s, 1H), 7.44-7.37 (m, 3H), 7.33 (s, 2H), 6.89(s,1H),4.52(d,J=5.3Hz,2H),4.49-4.43(m,1H),4.41(s,2H),3.84(s,3H),3.28(br d,J=11.6Hz,2H),2.58(s,3H),2.56-2.48(m,2H),2.17(dq,J=3.2,12.6Hz,2H),1.75(br d,J=11.6Hz,2H). MS(ESI)m / z:478.2[M+1].

[0444] Example 14

[0445] Compound 30-1 (10.0 g, 1.00 eq) was slowly added dropwise to 100 mL of sulfuric acid (184 g, 35.8 eq, 75% purity) at 0°C. Stir for 10 minutes. Sodium nitrite dissolved in 81 mL of water was then slowly added dropwise at 0°C, maintaining the temperature at 5-10°C. The mixture was stirred in an ice-water bath for 3 hours. 50 mL of aqueous ammonia was added to the reaction mixture in an ice-water bath. The reaction mixture was filtered, the filter cake washed with 100 mL of water, and then concentrated to dryness to obtain compound 30-2 (yellow solid, 9.0 g, yield: 89.6%).

[0446] 40 mL of dimethyl sulfoxide, compound 30-2 (4.0 g, 1.00 eq), trifluoroiodoethane (4.93 g, 1.50 eq), and cesium carbonate (10.2 g, 2.00 eq) were added sequentially to a 250 mL three-necked flask and stirred at 100°C for 1 hour. 350 mL of water was added to the reaction solution, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and extracted twice with saturated brine each time with 100 mL of water each time. The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 25-3 (yellow solid, 1.3 g, yield: 24.6%).

[0447] 12 mL of N-methylpyrrolidone, compound 30-3 (1.20 g, 1.00 eq), and zinc cyanide (229 mg, 0.55 eq) were added sequentially to a 100 mL three-necked flask. Tetrakistriphenylphosphine palladium was added under a nitrogen atmosphere and the mixture was stirred at 130°C for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and extracted twice with saturated brine each time with 50 mL of ethyl acetate. The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 30-4 (white solid, 400 mg, yield: 47.5%).

[0448] 5 mL of tetrahydrofuran, compound 30-4 (300 mg, 1.00 eq), di-tert-butyl dicarbonate (276 mg, 1.00 eq), and Raney nickel (300 mg, 2.76 eq) were added sequentially to a 100 mL tempered glass bottle under an argon atmosphere. The mixture was stirred at 70°C at 50 psi for 12 hours under hydrogen catalysis. The reaction mixture was filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 30-5 (yellow oil, 60 mg, yield: 27.7%).

[0449] 0.5 mL of ethyl acetate, compound 30-5 (100 mg, 1.00 eq), and HCl / EtOAc (1 mL) were added sequentially to a 10 mL single-necked vial and stirred at 25°C for 6 hours. The reaction solution was concentrated to dryness to obtain crude compound 30-6 (yellow solid, 20 mg), which was used directly in the next reaction.

[0450] 1 mL of tetrahydrofuran, compound 30-6 (20 mg, 1.00 eq), and diisopropylethylamine (10.7 mg, 1.00 eq) were added sequentially to a 10 mL single-necked vial. The mixture was stirred under nitrogen for 15 minutes, then cooled to 0°C in an ice-water bath. Carbonyldiimidazole (14.8 mg, 1.10 eq) was added to the reaction mixture and allowed to react at 0°C for 1 hour. Compound 1-2 (20 mg, 1.00 eq) was dissolved in 0.5 mL of tetrahydrofuran and added to the reaction mixture. The mixture was stirred at 25°C for 12 hours. 10 mL of water was added to the reaction mixture, and the mixture was extracted twice with 5 mL of ethyl acetate. The organic phases were combined and extracted twice with saturated brine (5 mL each). The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to yield compound 30 (white solid, 10 mg, yield: 24.3%). 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),7.72(br s,1H),7.47(s,1H),7.44-7.41(m,2H),6.72(s,1H),4.57(q,J=8.6Hz,2H),4.39(s,2H),4.27(br s,1H),4.23(d,J=5.9Hz,2H),3.10(br d,J=11.6Hz,2H),2.44(s,3H),2.32(br t,J=11.4Hz,2H),2.14-2.13(m,1H),2.07(br d,J=11.4Hz,1H),1.67(br d,J=11.9Hz,2H). MS (ESI) m / z: 490.2 [M+1].

[0451] Example 15

[0452] Dichloromethane (30 mL), compound 29-1 (2.80 g, 1.00 eq) and p-fluorobenzaldehyde (4.92 g, 1.00 eq) were added sequentially to a 100 mL three-necked flask at room temperature and stirred evenly. Sodium triacetoxyborohydride (9.56 g, 2.00 eq) was then added to the reaction solution and stirred at room temperature for 16 hours. 30 mL of saturated sodium bicarbonate solution was added to the reaction solution and continued stirring for 10 minutes. The mixture was allowed to stand and the organic phase was separated. The aqueous phase was extracted three times with dichloromethane (15 mL each). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was first purified by column chromatography and then purified by preparative separation to obtain compound 29-2 (colorless oil, 1.20 g).

[0453] Tetrahydrofuran (15 mL) and compound 5-1 (1.04 g, 1.00 eq, HCl) were added sequentially to a 100 mL three-necked flask. Diisopropylethylamine (1.11 g, 2.00 eq) was added dropwise under nitrogen and stirred at 20°C for 15 minutes. The temperature was then lowered to 0°C and carbonyldiimidazole (765 mg, 1.10 eq) was added portionwise to the reaction solution. Upon reaction detection, it was determined that compound 5-1 had reacted completely. Compound 29-2 (1.40 g, 1.00 eq) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution. The mixture was stirred at 25°C for 12 hours. 100 mL of water was added to the reaction solution and extracted with ethyl acetate three times, 50 mL each time. The organic phases were combined and washed with 80 mL of saturated brine. The organic phases were dried and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 29-3 (colorless oil, 966 mg, yield: 38.8%).

[0454] Anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) were added sequentially to a 50 mL single-necked bottle and stirred at 25°C for 20 minutes. The reaction solution was dried to give crude compound 29-4 (pale yellow oil, 850 mg, yield: 91.4%).

[0455] Tetrahydrofuran (8 mL), compound 29-4 (800 mg, 1.00 eq), sodium cyanoborohydride (219 mg, 2.00 eq), and formaldehyde (212 mg, 37%, 1.50 eq) were added sequentially to a 50 mL single-necked flask. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined, washed with 40 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography and then separated by SFC (chromatographic column: DAICEL CHIRALCEL OX (250 mm*50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 25%-25%) to give compound 68A (retention time: 1.457 min, white solid, 159 mg, yield: 23.1%), compound 68B (retention time: 1.707 min, white solid, 163 mg, yield: 24.4%), compound 68C (retention time: 1.935 min, white solid, 142 mg, yield: 21.2%), and compound 68D (retention time: 2.356 min, white solid, 133 mg, yield: 19.8%).

[0456] Compound 68A: 1 H NMR (400MHz, CDCl3) δ7.87 (d, J=1.9Hz, 1H), 7.35 (dd, J=2.3, 8.5Hz, 1H), 7.17-7.08 (m, 2H), 7.00 (br t,J=8.5Hz,2H),6.75(d,J=8.5Hz,1H),5.17-4.99(m,1H),4.94(br t,J=5.1Hz,1H),4.71(d,J=8.6Hz,2H),4.56-4.43(m,2H),4.30-4.17(m,2H), 3.81-3.57(m,2H),3.22-2.91(m,2H),2.80(s,3H),2.60-2.45(m,1H),1.79(br d,J=11.8Hz,1H). MS(ESI)m / z:473.2[M+1].

[0457] Compound 68B: 1H NMR (400MHz, CDCl3) δ7.88 (d, J=2.0Hz, 1H), 7.37 (dd, J=2.3, 8.4Hz, 1H), 7.15 (dd, J= 5.3,8.4Hz,2H),7.06-6.98(m,2H),6.76(d,J=8.5Hz,1H),5.16-4.97(m,1H),4.85(br t,J=5.1Hz,1H),4.76-4.70(m,2H),4.52(br d,J=13.3Hz,2H),4.32-4.19(m,2H),3.64(br t,J=11.8Hz,1H),3.52(br d,J=10.8Hz,1H),3.08-2.80(m,2H),2.74(s,3H),2.59-2.44(m,1H),1.78(br d,J=11.5Hz,1H). MS(ESI)m / z:473.2[M+1].

[0458] Compound 68C: 1 H NMR (400MHz, CDCl3) δ7.91 (d, J=1.9Hz, 1H), 7.44 (dd, J=2.3, 8.5Hz, 1H), 7.27-7.19 (m, 2H), 7.02 (br t,J=8.5Hz,2H),6.77(d,J=8.5Hz,1H),4.76-4.70(m,3H),4.58-4.38(m,3H),4.30-4.27(m,2 H),3.24-3.21(m,1H),2.85-2.82(m,1H),2.34(s,3H),2.21-2.12(m,2H),1.82-1.80(m,2H). MS(ESI)m / z:473.2[M+1].

[0459] Compound 68D: 1 H NMR(400MHz, CDCl3) δ7.91(d,J=2.0Hz,1H),7.43(dd,J=2.3,8.4Hz,1H),7.27-7.20(m,2H),7.06-6.98(m,2H),6.77(d,J=8.5Hz,1H),4.76- 4.70(m,3H),4.58-4.38(m,3H),4.30-4.27(m,2H),3.24-3.21(m,1H), 2.85-2.82(m,1H),2.34(s,3H),2.21-2.12(m,2H),1.82-1.80(m,2H). MS(ESI)m / z:473.2[M+1].

[0460] Example 16

[0461] 30 mL of methanol, compound 50-1 (2.00 g, 1.00 eq), and ammonium acetate (1.37 g, 2.00 eq) were added sequentially to a 250 mL three-necked flask and stirred at 20°C for 1 hour. Sodium cyanoborohydride (1.12 g, 2.00 eq) was then added to the reaction mixture, and stirring continued at 60°C for 12 hours until the reaction was complete. The reaction mixture was concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 50-2 (yellow liquid, 1.80 g, yield: 89.9%).

[0462] 20 mL of dichloromethane, compound 50-2 (1.80 g, 1.00 eq), and p-fluoropyridinecarboxaldehyde (999 mg, 1.00 eq) were added sequentially to a 100 mL three-necked flask under nitrogen atmosphere. Stirring was continued at 30°C for 6 hours. Sodium triacetate borohydride (3.37 g, 2.00 eq) was added and stirring continued at 30°C for 13 hours. The temperature was lowered to room temperature, quenched with water (10 mL), and extracted twice with dichloromethane (10 mL each). The organic phases were combined and washed twice with 10 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was separated by high-performance liquid chromatography to yield compound 50-3 (yellow liquid, 1.30 g).

[0463] 15 mL of tetrahydrofuran, 1-trifluoroethoxy-4-pyridinemethylamine (800 mg, 1.00 eq), and N,N-diisopropylethylamine (1.00 g, 2.00 eq) were added sequentially to a 100 mL round-bottom flask and reacted at 20°C under nitrogen for 15 minutes. The reaction temperature was lowered to 0°C, and carbonyldiimidazole (754 mg, 1.20 eq) was added. Stirring continued for 0.5 hours. 10 mL of tetrahydrofuran and a solution of compound 50-3 (1.30 g, 1.00 eq) were added. The reaction mixture was heated to 80°C and stirred for 24 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (30 mL each). The organic phases were combined, washed with 60 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by HPLC to obtain compound 50-4 (yellow liquid, 900 mg, yield: 40.9%).

[0464] 8 mL of dichloromethane, compound 50-4 (900 mg, 1.00 eq), and trifluoroacetic acid (6.14 g, 33.9 eq) were added sequentially to a 100 mL three-necked flask under nitrogen atmosphere and reacted at 10°C for 1 hour. The reaction mixture was concentrated overnight to dryness to afford compound 50-5 (yellow liquid, 910 mg, crude trifluoroacetate salt), which was used directly in the next step.

[0465] 20 mL of dichloromethane, compound 50-5 (950 mg, 1.00 eq, trifluoroacetate salt), formaldehyde solution (200 mg, 1.51 eq), and sodium cyanoborohydride (205 mg, 2.00 eq) were added sequentially to a 100 mL three-necked flask and stirred at 25°C for 13 hours. The reaction mixture was cooled to 0°C and quenched by the addition of aqueous sodium bicarbonate (20 mL). The mixture was then extracted twice with dichloromethane (30 mL each). The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by HPLC and chiral preparative chromatography (chromatographic column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​IPA)]; B%: 25%-25%) to give compounds 50A (retention time: 1.259 min, yellow liquid, 90.0 mg, yield: 11.2%) and 50B (retention time: 1.460 min, yellow liquid, 120 mg, yield: 14.8%).

[0466] Compound 50A: 1 H NMR (400MHz, CDCl3) δ8.29(d,J=2.8Hz,1H),8.03(d,J=2.0Hz,1H),7.60(dd,J1=2.4Hz J2=8.4Hz,1H),7.38-7.37(m,1H),7.25-7.23(m,1H),6.82(d,J=8.8Hz,1H),6.53(br,1H),4.79-4.72(m,2H),4.44-4.26(m,5H),2.99-2. 92(m,1H),2.55-2.54(m,1H)2.27(s,3H),2.20-2.17(m,1H),2.07-2.03(m,2H),1.73-1.70(m,1H),0.57-0.45(m,3H),0.26-0.24(m,1H). MS(ESI)m / z:482.2[M+1].

[0467] Compound 50B: 1H NMR (400MHz, CDCl3) δ8.29(d,J=2.8Hz,1H),8.03(d,J=2.0Hz,1H),7.60(dd,J1=2.4Hz J2=8.4Hz,1H),7.38-7.37(m,1H),7.26-7.23(m,1H),6.82(d,J=8.8Hz,1H),6.54(br,1H),4.79-4.72(m,2H),4.48-4.19(m,5H),3.00-2. 92(m,1H),2.58-2.54(m,1H)2.28(s,3H),2.20-2.18(m,1H),2.11-2.04(m,2H),1.73-1.70(m,1H),0.52-0.47(m,3H),0.27-0.25(m,1H). MS(ESI)m / z:482.2[M+1].

[0468] Example 17

[0469] Compounds 49A / 49B and 83A / 83B were obtained using a similar synthesis and resolution method as in Example 16. The following table lists the characterization data of compounds 49A / 49B and 83A / 83B:

[0470] Example 18

[0471] Dichloromethane (110 mL), compound 85-1 (22.0 g, 1.00 eq), and p-fluorophenylethylamine (14.0 g, 1.10 eq) were added sequentially to a 250 mL three-necked flask and stirred at 20°C for 6 hours. After the reaction was complete, sodium triacetoxyborohydride (32.3 g, 1.50 eq) was added and stirring continued at 20°C for 12 hours. After the reaction was complete, 80 mL of water was added to the reaction solution, and the mixture was extracted twice with 80 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude product 85-2 (yellow oil, 33.5 g, crude product).

[0472] Dichloromethane (670 mL), compound 85-2 (33.5 g, 1.00 eq), triethylamine (28.6 mL, 2.00 eq), trifluoroacetic anhydride (17.1 mL, 1.20 eq), and 4-dimethylaminopyridine (6.27 g, 0.50 eq) were added sequentially to a 1 L three-necked flask and stirred at 20°C for 1 hour. After the reaction was complete, the mixture was washed with water twice, each time with 400 mL of water. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 85-3 (yellow oil, 37.5 g, yield: 69.2%).

[0473] Dichloromethane (187 mL), compound 85-3 (37.5 g, 1.00 eq), and trifluoroacetic acid (33.0 mL, 5.00 eq) were added sequentially to a 500 mL three-necked flask and stirred at 20°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to dryness to obtain crude compound 85-4 (yellow oil, 28.6 g, yield: 100%).

[0474] Tetrahydrofuran (286 mL), compound 85-4 (28.6 g, 1.00 eq), and aqueous formaldehyde (33.1 mL, 37% purity, 5.00 eq) were added sequentially to a 500 mL three-necked flask. Sodium cyanoborohydride (11.2 g, 2.00 eq) was added portionwise and stirred at 20°C for 1.5 hours. After the reaction was complete, the pH was adjusted to 8 with saturated aqueous sodium carbonate solution, and the product was extracted twice with dichloromethane (100 mL each). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude product 85-5 (yellow oil, 34.5 g, yield: 87.7%).

[0475] Water (217 mL), compound 85-5 (32.5 g, 1.00 eq), and concentrated hydrochloric acid (325 mL, 12.0 M, 40.4 eq) were added sequentially to a 1-L three-necked flask and stirred at 100°C for 12 hours. After the reaction was complete, the pH was adjusted to 8-9 with 156 g of sodium hydroxide, and the mixture was extracted twice with dichloromethane, each containing 400 mL. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. Chiral separation of the crude product afforded compound 85-6 (yellow oil, 2.19 g, crude product).

[0476] (1-Methyl-1H-indol-5-yl)methanamine (333 mg, 1.00 eq) was added to 5 mL of tetrahydrofuran, followed by diisopropylethylamine (672 mg, 906 μL, 2.50 eq). The reaction mixture was cooled to 0°C, carbonyldiimidazole (371 mg, 1.10 eq) was added, and stirring continued for one hour. Compound 85-6 (500 mg, 1.00 eq) dissolved in 3 mL of tetrahydrofuran was added, and the reaction mixture was heated to 70°C and allowed to react for 12 hours. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative separation to yield compound 85 (white solid, 760 mg, yield: 85.6%). The product was then separated by SFC (chromatographic column: DAICEL CHIRALCEL OX (250 mm*50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 25%-25%) to give compound 85A (retention time: 2.018 min, white solid, 266 mg, yield: 41.7%) and compound 85B (retention time: 2.461 min, white solid, 235 mg, yield: 36.3%).

[0477] Compound 85A: 1 H NMR (400MHz, CDCl3) δ7.24 (s, 1H), 7.22-7.15 (m, 3H), 7.04 (d, J = 3.0Hz, 1H), 6.98 (t, J = 8.6Hz, 2H), 6.95-6.91 (m, 1H), 6.39 (d,J=2.9Hz,1H),5.04-4.86(m,1H),4.68-4.61(m,2H),4.57(s,1H),4.49(s,1H),4.45-4.41(m,2H),3.77(s,3H),3.19(br t,J=11.9Hz,1H),3.03-2.95(m,1H),2.40(br d,J=13.3Hz,1H),2.34(s,3H),2.24-2.16(m,2H),1.66-1.61(m,1H).MS(ESI)m / z:427.2[M+1].

[0478] Compound 85B: 1H NMR (400MHz, CDCl3) δ7.24(s,1H),7.21-7.15(m,3H),7.05-7.03(m,1H),7.01-6.96(m,2H),6. 94-6.91(m,1H),6.39(d,J=2.9Hz,1H),5.04-4.86(m,1H),4.68-4.61(m,2H),4.59-4.56(m,1H ),4.52-4.48(m,1H),4.45-4.41(m,2H),3.77(s,3H),3.24-3.14(m,1H),3.02-2.95(m,1H),2. 43-2.37(m,1H),2.35(s,3H),2.26-2.19(m,2H),1.67-1.62(m,1H).MS(ESI)m / z:427.2[M+1].

[0479] Example 19

[0480] Compound 86A, Compound 86B, and Compound 87A / Compound 87B were obtained using a similar synthesis and resolution method as in Example 18. The following table lists the characterization data of Compounds 86A, 86B, 87A, and 87B:

[0481] Example 20

[0482] Compound 88-1 (8 g, 41.88 mmol, 1 eq) was added to hydrochloric acid (6 M, 120 mL, 17.2 eq) in a 500 mL round-bottom flask at 0°C. A solution of sodium nitrite (2.89 g, 41.88 mmol, 1 eq) in water (10 mL) was then added, and the reaction was stirred at 38°C for 8 hours. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound 88-2 (3.5 g, 18.23 mmol, 43.5% yield) as a white solid.

[0483] To a mixture of compound 88-2 (2.8 g, 14.58 mmol, 1 eq) and cesium carbonate (9.50 g, 29.17 mmol, 2 eq) in xylidine (28 mL) was added trifluoroethyl trifluoromethanesulfonate (10.16 g, 43.75 mmol, 3 eq). The mixture was stirred at 50°C for 1 hour. The reaction mixture was filtered and washed with ethyl acetate (100 mL*3). The organic layer was washed with saturated sodium chloride aqueous solution (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 88-3 (3 g, 10.95 mmol, yield 75.1%) as a colorless oil.

[0484] Compound 88-3 (700 mg, 2.55 mmol, 1 eq), potassium N-aminomethyltrifluoroborate (726.75 mg, 3.07 mmol, 1.2 eq), potassium phosphate (1.63 g, 7.66 mmol, 3 eq), and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium(II) (93.02 mg, 0.128 mmol, 0.05 eq) were dissolved in dioxane (10 mL) and water (2 mL). The atmosphere was replaced with nitrogen three times and then stirred at 80°C under nitrogen for 1 hour. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phases were washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 88-4 (0.7 g, 2.16 mmol, yield 84.5%) as a light yellow solid.

[0485] To a solution of compound 88-4 (300 mg, 0.925 mmol, 1 eq) in dichloromethane (10 mL) were added 2-chloropyridine (315.14 mg, 2.78 mmol, 3 eq) and trifluoroacetic anhydride (391.53 mg, 1.39 mmol, 1.5 eq). The mixture was then stirred at 20°C for 1 hour, followed by the addition of 3-fluoro-N-[(4-fluorophenyl)methyl]-1-methyl-piperidin-4-amine (489.07 mg, 2.04 mmol, 2.2 eq) at 20°C. The resulting mixture was stirred at 20°C for an additional hour. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (dichloromethane / methanol = 1 / 0 to 10 / 1) and separated by SFC (chromatographic column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​MeOH)]; B%: 15%-15%) to afford compound 88A (retention time: 1.025 min, 123 mg, yield 26.3%) as a white solid, and compound 88B (retention time: 1.231 min, 116 mg, yield 25.1%) as a white solid.

[0486] Compound 88A: 1 H NMR (400MHz, DMSO-d6) δ7.76-7.64(m,1H),7.25-7.15(m,2H),7.15-7.05(m,2H),6. 99(t,J=5.6Hz,1H),6.87(d,J=8.0Hz,1H),4.92(q,J=9.2Hz,2H),4.82-4.59(m,2H), 4.41(d,J=17.6Hz,1H),4.29-4.08(m,3H),2.97(t,J=12.0Hz,1H),2.83-2.70(m,1H) ,2.24-2.04(m,4H),2.02-1.86(m,2H),1.41-1.22(m,1H).MS(ESI)m / z:491.3[M+1].

[0487] Compound 88B: 1H NMR(400MHz,DMSO-d6)δ7.70(t,J=8.8Hz,1H),7.25-7.15(m,2H),7.14-7.04(m,2H) ,7.03-6.93(m,1H),6.87(d,J=8.0Hz,1H),4.92(q,J=8.8Hz,2H),4.82-4.58(m,2H), 4.41(d,J=18.0Hz,1H),4.30-4.05(m,3H),2.97(t,J=11.6Hz,1H),2.82-2.70(m,1H) ,2.24-2.04(m,4H),2.02-1.85(m,2H),1.41-1.20(m,1H).MS(ESI)m / z:491.3[M+1].

[0488] Example 21

[0489] Using a synthesis method and resolution method similar to Example 20, compound 89A (retention time: 0.994 min, white solid) and compound 89B (retention time: 1.055 min, white solid) were obtained.

[0490] Compound 89A: 1 H NMR (400MHz, CDCl3) δ8.03 (d, J = 3.3Hz, 1H), 7.56 (s, 1H), 7.14-7.07 (m, 3H), 6.96 (br t,J=8.5Hz,2H),4.92-4.74(m,1H),4.66-4.56(m,2H),4.54-4.34(m,3H),4.13(br s,3H),4.08-4.02(m,1H),3.08(br dd,J=7.9,12.8Hz,1H),2.76-2.66(m,2H),2.29-2.23(m,4H),2.20-2.09(m,2H),1.41-1.22(m,1H).MS(ESI)m / z:499.2[M+1].

[0491] Compound 89B: 1H NMR (400MHz, CDCl3) δ8.11 (d, J = 3.3Hz, 1H), 7.67-7.61 (m, 1H), 7.23-7.11 (m, 2H), 7.09-6.95 (m, 3H), 5.01-4.8 1(m,1H),4.70(s,1H),4.66-4.42(m,3H),4.33-4.21(m,3H),3.39(t,J=7.1Hz,1H),3.26-3.05(m,3H),3.02(br dd,J=1.9,3.9Hz,1H),2.89-2.71(m,2H),2.20-2.09(m,4H),1.41-1.22(m,1H).MS(ESI)m / z:499.2[M+1].

[0492] Example 22

[0493] Tetrahydrofuran (15 mL) and compound 5-1 (1.04 g, 1.00 eq, HCl) were added sequentially to a 100 mL three-necked flask. Diisopropylethylamine (1.11 g, 2.00 eq) was added dropwise under nitrogen, and the mixture was stirred at 20°C for 15 minutes. The temperature was then lowered to 0°C, and N,N'-carbonyldiimidazole (765 mg, 1.10 eq) was added portionwise to the reaction mixture. Upon reaction monitoring, the reaction of compound 5-1 was complete. Compound 68-1 (1.40 g, 1.00 eq) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at 25°C for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times, each time using 50 mL. The organic phases were combined, washed with 80 mL of saturated brine, dried, and concentrated to yield the crude product. The crude product was purified by column chromatography to obtain compound 68-2 (colorless oil, 966 mg, yield: 38.8%).

[0494] Anhydrous dichloromethane (27 mL), compound 68-2 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) were added sequentially to a 50 mL single-necked bottle and stirred at 25°C for 20 minutes. The reaction mixture was dried to give crude compound 68-3 (pale yellow oil, 850 mg, yield: 91.4%).

[0495] Tetrahydrofuran (8 mL), compound 68-3 (800 mg, 1.00 eq), sodium cyanoborohydride (219 mg, 2.00 eq), and formaldehyde (212 mg, 37%, 1.50 eq) were added sequentially to a 50 mL single-necked flask. The mixture was stirred at 25°C for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined and washed with 40 mL of saturated brine, dried, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 68A (white solid, 643 mg, yield: 78.1%). 1 H NMR (400MHz, CDCl3) δ7.87 (d, J=1.9Hz, 1H), 7.35 (dd, J=2.3, 8.5Hz, 1H), 7.17-7.08 (m, 2H), 7.00 (br t,J=8.5Hz,2H),6.75(d,J=8.5Hz,1H),5.17-4.99(m,1H),4.94(br t,J=5.1Hz,1H),4.71(d,J=8.6Hz,2H),4.56-4.43(m,2H),4.30-4.17(m,2H), 3.81-3.57(m,2H),3.22-2.91(m,2H),2.80(s,3H),2.60-2.45(m,1H),1.79(br d,J=11.8Hz,1H). MS(ESI)m / z:473.2[M+1].

[0496] Test Example 1.5-HT 2A Receptor inverse agonist activity assay

[0497] 1.1 Experimental Materials:

[0498] Cell line: adherent cells NIH3T3-5-HT 2A R

[0499] Cell culture medium: DMEM + 10% FBS (purchased from GBICO)

[0500] Cell culture plate: 96-well plate with white wall and transparent bottom (purchased from Perkin Elmer)

[0501] Detection kit: Bright-Glo TM Luciferase (purchased from Promega)

[0502] Detection instrument: BioTek multifunctional microplate reader

[0503] 1.2 Trial Drugs

[0504] Pimavanserin: purchased from MCE

[0505] Other compounds: prepared according to the above examples

[0506] 1.3 Experimental methods:

[0507] NIH3T3-5HT cells in the logarithmic growth phase 2A R cells were seeded in a 96-well plate with a white wall and transparent bottom at a density of 1000 cells per well and cultured in a 37°C, 5% CO2 incubator overnight. On the second day, the test compound was added to the cells. The highest concentration of the test compound was 10uM. The compound was diluted with PBS at a concentration gradient of 3.16 times to 9 concentrations, with duplicate wells for each concentration. PBS was used as the negative control group, and the same concentration of pimavanserin was used as the positive control group. After adding the drug, the cells were cultured in a 37°C, 5% CO2 incubator for 120 hours. On the sixth day, Bright-Glo was added to the cells at an equal volume to the cell fluid. TM Luciferase reagent was added to the cells and incubated at room temperature in the dark for 20 min. The plate was shaken every 5 min. The luminescence intensity was measured by a microplate reader and the cell inhibition rate was calculated. The data were processed using GraphPad Prism 7.0 to obtain the cell inhibition rate curve and calculate the IC 50 , the test results are shown in Table 1.

[0508] Cell inhibition rate (%) = [100-(Lum test drug-Lum culture medium) / (Lum cell control-Lum culture medium) × 100]%

[0509] Test Example 2. hERG Inhibitory Activity

[0510] 1. Test materials and instruments

[0511] 1.1 Positive control compound

[0512] Name: Cisapride

[0513] 1.2 Solvent

[0514] Name: DMSO (dimethyl sulfoxide)

[0515] 1.3 Cells

[0516] Species & Strain: CHO-hERG cell line (Chinese hamster ovary cells stably expressing the hERG channel)

[0517] Culture medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, 100 μg / mL Hygromycin B

[0518] Culture conditions: 5% CO2, 37°C incubator

[0519] Freezing conditions: liquid nitrogen

[0520] 1.4 Experimental Instruments

[0521] Patch clamp amplifier (Axoclamp 200B, Multiclamp 700B, Axon, USA)

[0522] Digital-to-analog converter (DigiData 1440A, DigiData 1550B, Axon, USA)

[0523] Inverted microscope (IX51, IX71, Olympus, Japan)

[0524] Rapid drug delivery system (RSC-200, Bio-Logic, France)

[0525] Micromanipulator (MX7600R, Syskiyou, USA)

[0526] Electrode pulling apparatus (P-97, Sutter, USA)

[0527] Glass electrode (BF150-86-10, Sutter, USA)

[0528] Anti-vibration table and shielding net (63-534, TMC, USA)

[0529] Data acquisition and analysis software (pClamp 10, Axon, USA)

[0530] CO2 incubator (HERAcell 150i, Thermo, USA)

[0531] Biological safety cabinet (MODEL 1384, Thermo, USA)

[0532] Water purifier (Milli Q, Millipore, USA)

[0533] 2. Experimental Methods

[0534] 2.1 Cell culture and treatment

[0535] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator, and passaged every 48 hours at a 1:5 ratio. On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed with extracellular fluid, and then digested with 0.25% Trypsin-EDTA (Invitrogen) solution at room temperature for 3-5 minutes. The digestion solution was aspirated, the cells were resuspended in the extracellular fluid, and transferred to a dish for electrophysiological recording.

[0536] 2.2 Compound preparation

[0537] On the day of testing, dilute the compound to an intermediate concentration with DMSO. Transfer 10 μL of the intermediate concentration compound to 4990 μL of extracellular fluid and dilute 500-fold to the final concentration to be tested.

[0538] Preparation of the positive control compound Cisapride: 10 μL of 150 μM Cisapride DMSO stock solution was transferred to 4990 μL of extracellular fluid and diluted 500-fold to obtain the final concentration of 300 nM to be tested.

[0539] 2.3 Electrophysiological recording process

[0540] CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusion of the electrode solution was approximately 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0541] 2.4 Data Processing and Analysis

[0542] Data were analyzed using pClamp 10 and GraphPad Prism 5.0 software.

[0543] The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated as follows: Inhibition% = [1–(I / Io)] × 100%

[0544] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0545] Compound IC 50The results were calculated using the following equation using GraphPad Prism 5 software. The experimental results are shown in Table 1: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0546] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0547] 3. Test results

[0548] Table 1 In vitro test results of the compounds of the present invention

[0549] The results showed that the 5-HT 2A The inverse agonist activity is better than that of pimavanserin and the cardiotoxicity is lower.

[0550] Test Example 3. In vitro liver microsome stability evaluation

[0551] 1. Solution Preparation

[0552] 1) Preparation of test sample working solution: dilute the test sample to 100 μM with methanol;

[0553] 2) Preparation of liver microsome working solution: Dilute liver microsomes to 0.56 mg / ml with 100 mM phosphate buffer;

[0554] 3) Prepare the reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH and dilute it to 20 mM with phosphate buffer. Then add an equal volume of 60 mM MgCl2 solution.

[0555] 4) Preparation of stop solution: dilute tolbutamide to 20 ng / mL with acetonitrile as the stop solution containing internal standard.

[0556] 2. Incubation process

[0557] 1) Prepare incubation anti-adsorption EP tubes and label the species, test substance, reference substance (testosterone, dextromethorphan), time point (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc.

[0558] 2) Add 2 μL of test sample or control working solution and 178 μL of liver microsome working solution to each tube. Add 2 μL of acetonitrile to the blank tube instead of the test sample. Pre-incubate in a 37°C water bath for approximately 10 minutes. Each sample should be repeated in triplicate.

[0559] 3) After the preincubation, 20 μL of NADPH working solution was added to each tube except for 0 min and NCF60 to start the reaction. 20 μL of phosphate buffer (containing 30 mM MgCl2) was added to the NCF60 tube. The final concentration of the test or control in the incubation system was 1 μM, the final concentration of liver microsomes was 0.5 mg / mL, the final concentration of NADPH was 1 mM, and the final concentration of MgCl2 was 3 mM.

[0560] 4) For the 0 min sample, add 600 μL of stop solution first, then add NADPH working solution. After incubating each sample for the corresponding time, add 600 μL of stop solution to terminate the reaction;

[0561] 5) After terminating the reaction, each sample was vortexed for 30 seconds and then centrifuged at 13500 rpm for 10 minutes. 100 μL of the supernatant was placed in an EP tube, 100 μL of Milli-Q water was added, and vortexed to mix thoroughly before LC-MS / MS analysis.

[0562] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0563] 3. Data Analysis

[0564] The remaining percentage of the test sample after 60 minutes of testing is shown in Table 2.

[0565] Table 2 Experimental data of the compounds of the present invention in human and rat liver microsomes

[0566] The results showed that the compounds of the present invention were more stable than pimavanserin in canine and human liver microsomes in vitro and had better drug-forming properties.

[0567] Test Example 4. In vivo pharmacodynamic evaluation

[0568] 1. Experimental Plan

[0569] According to the in vivo pharmacokinetic data of a series of compounds, the drug reaches C 1.0 to 1.5 h after a single oral administration in SD rats. max At this time point, SD rats were intraperitoneally injected with 4-iodo-2,5-dimethoxy-α-methyl-phenylethylamine hydrochloride (DOI, 5-HT 2A Receptor agonist) at a dose of 2.5 mg / kg was used to induce head shaking behavior in SD rats to establish the model.

[0570] The low, medium, and high doses of compound 68A were set at 0.22, 0.66, and 2.0 mg / kg, respectively. Pimavanserin tartrate (Pim-T) was set at 0.7 mg / kg. Both compound 68A and Pim-T were administered via oral gavage.

[0571] 2. Experimental Grouping and Drug Administration

[0572] The compound was dissolved in DMSO:20% solutol (5%:95%). SD rats (200-250 g) were randomly divided into six groups based on body weight: solvent control, model, Pim-T 0.7 mg / kg, and compound 68A 0.22, 0.66, and 2.0 mg / kg groups, with seven animals per group. Animal grouping and dosing information are detailed in Table 3.

[0573] Table 3: Animal grouping and dosing Note: The dosages of Pim-T (Pimavanserin tartrate) and Compound 68A were calculated based on the free base.

[0574] 3. Experimental Operation

[0575] Rats were fasted at 5:00 PM on the day before the experiment. On the day of the experiment, animals were acclimated to the testing laboratory for at least 1 hour. Each group of rats received a single oral gavage of the drug according to the dosage in Table 3. One hour after administration, all groups except the control group received an intraperitoneal injection of 2.5 mg / kg DOI. The control group received an equal volume of saline. The rats' behavior was immediately observed after injection. The observations were randomized, double-blind, and no human factors were involved. The number of head shakes observed within 1.0 to 1.5 hours after administration was recorded.

[0576] The experimental data were expressed as mean ± standard error (Mean ± SEM). SPSS statistics 20.0 software was used to perform one-way analysis of variance (ANOVA) to compare the differences between the groups at each time point. All tests were two-sided, and P < 0.05 indicated statistical significance.

[0577] 4. Data Analysis

[0578] Compared with the control group, the number of head shakes in the model group rats was significantly increased (P < 0.05). Compared with the model group, the number of head shakes in the Pim-T 0.7 mg / kg group rats was significantly reduced (P < 0.05), and the number of head shakes in the compound 68A 0.22, 0.66, and 2.0 mg / kg groups rats was extremely significantly reduced (P < 0.01). At equimolar doses, the number of head shakes in the compound 68A 0.66 mg / kg group rats was lower than that in the Pim-T 0.7 mg / kg group. Specific results are shown in Table 4 and Figure 1.

[0579] Table 4: Number of head shakes in SD rats 1.0-1.5 h after single oral administration Note: #P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group.

[0580] Results showed that compound 68A significantly inhibited head shaking in SD rats within a dose range of 0.22-2.0 mg / kg 1.0-1.5 hours after a single oral administration, with the onset of efficacy at 0.22 mg / kg. At equimolar doses, compound 68A exhibited superior pharmacodynamics to Pim-T.

[0581] Test Example 5. Evaluation of in vivo tissue distribution

[0582] 1. Experimental Plan

[0583] SD rats (200 g-250 g) were given compound 68A by oral gavage at a dose of 11 mg / kg. Plasma and brain, heart, liver, and lung tissues were collected 0.25 h, 1 h, and 6 h after administration, with 3 animals at each time point.

[0584] 2. Experimental Operation

[0585] The rats were fasted at around 18:00 the day before the experiment, with free access to water. On the day of the experiment, the rats were weighed and randomly divided into 3 groups according to body weight, with one group of animals at one time point. The compound was dissolved in DMSO:20% solutol (5%:95%), and the rats were given a single oral administration of compound 68A at a dose of 11 mg / kg, a dosing volume of 5 mL / kg, and a drug concentration of 2.2 mg / mL. At each collection time point, the animals were anesthetized with ether, and about 1 mL of blood was collected from the heart and placed in a heparinized EP tube. The tube was centrifuged at 10,000 rpm for 10 minutes to separate the plasma, and then the brain, heart, liver, and lung tissues were collected after the blood was removed by cardiac perfusion. The blood stains were absorbed with filter paper and weighed separately. The weighing paper was wrapped and stored at -80°C for testing.

[0586] 3. Sample Measurement and Data Analysis

[0587] Plasma samples and tissue homogenates (each tissue was homogenized in water at a weight-to-volume ratio of 1:4) were pretreated and then analyzed by LC-MS / MS to determine the concentrations of the analytes in plasma and tissues. The experimental data are expressed as mean ± standard deviation (Mean ± SD). The specific results are shown in Table 5.

[0588] Table 5: Plasma and tissue concentrations of compound 68A in SD rats after single oral administration

[0589] The results showed that 0.25h, 1h, and 6h after a single oral administration to SD rats, the concentration of compound 68A in tissues was higher than that in plasma, indicating that compound 68A has good permeability; especially in brain tissue, the distribution was high, with a brain-to-blood ratio of 9.51 to 10.5, and the concentration in the brain was stable between 0.25 and 6h.

Claims

1. A compound represented by formula (A), or a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof: in, R1 is selected from halogen; Ring B is selected from R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl groups, or two groups attached to the same carbon atom R3 forms a C with the carbon atom to which it is connected 3-6 Cycloalkyl; Ring A is selected from X is selected from NR 6c , O or S; X1 is selected from N or CH; R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, which is a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, R1 is selected from halogen; Ring B is selected from R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; Ring A is selected from X is selected from NR 6c , O or S; R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1- 3 haloalkyl; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, which is a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, R1 is selected from halogen; Ring B is selected from R2 is independently selected from hydrogen atom, C 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; Ring A is selected from X is selected from NR 6c , O or S; R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof, which is a compound represented by formula (IIA), or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof: in, R1 is selected from halogen; Ring B is selected from R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 alkyl; R 4a 、R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl; n is selected from 0, 1, 2, and 3.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, which is a compound represented by formula (III), or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof: in, R1 is selected from halogen; Ring B is selected from R2 is independently selected from hydrogen atom, C 1-3 Alkyl, C 3-6 Cycloalkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R 4a and R 4b are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: Ring B is selected from Preferably R3 is selected from halogen, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; R3 is preferably F, or two R3 attached to the same carbon atom form a cyclopropyl group with the attached carbon atom; n is 1 or 2.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, optionally C 1- 3 alkyl-substituted C 3-6 Cycloalkyl C 1-3 Alkyl; preferably 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, wherein: R1 is selected from halogen; Ring B is selected from Preferably R2 is independently selected from hydrogen atom, C 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, C 1-3 Alkyl, or two R3 connected to the same carbon atom form a C 3-6 Cycloalkyl; Ring A is selected from R 4a 、R 4b 、R 4c are independently selected from hydrogen atoms, halogens, C 1-3 Alkyl, C 1-3 alkyl halide; R5 is selected from -OR5', R5' is selected from C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 Cycloalkyl C 1- 3 alkyl, optionally C 1-3 Alkyl substituted C 3-6 Cycloalkyl C 1-3 alkyl; n is selected from 1, 2, and 3.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof, which is a compound represented by formula (IV), or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof: in, R1 is selected from halogen; R2 is selected from hydrogen atom, C 1-3 alkyl; R 6a 、R 6b , are each independently selected from hydrogen atom, halogen, C 1-3 alkyl halide; R 6c Selected from hydrogen atoms, C 1-3 alkyl.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof, which is a compound represented by formula (V), or a pharmaceutically acceptable salt, stereoisomer, or deuterated substance thereof: in, R1 is selected from halogen; R2 is selected from hydrogen atom, C 1-3 alkyl; R 7a 、R 7b 、R 7c are independently selected from hydrogen atoms, halogens, C 1-3 Halogenated alkyl.

11. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof, selected from the following compounds, or a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof:

12. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated substance thereof, which is selected from the following compounds, or a pharmaceutically acceptable salt or deuterated substance thereof:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt, stereoisomer or deuterated substance thereof and a pharmaceutically acceptable carrier.

14. The compound according to any one of claims 1 to 12, its pharmaceutically acceptable salt, stereoisomer or deuterated substance, or the pharmaceutical composition according to claim 13 for the preparation of a pharmaceutical composition for treating 5-HT 2A Application of drugs in the treatment of receptor-related diseases.

15. The use according to claim 14, wherein the 5-HT 2A Receptor-related diseases include: Schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety disorder, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tics, depression, major depressive disorder, anxiety, sleep disturbance and appetite disturbance, non-motor symptoms due to Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disturbance), dementia-related psychotic disorder, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, dementia with Lewy bodies, movement disorders, dystonia, myoclonus, tremor or progressive supranuclear palsy and frontotemporal dementia.

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