5-HT2A receptor inverse agonist, its preparation method and use

Abstract

The present invention relates to a novel compound as a 5-HT 2A receptor inverse agonist, a method for preparing the same, and a pharmaceutical composition. Further, non-motor symptoms (delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disorder) due to Parkinson's disease, dementia-related psychosis, major depression, or use of the above compound or pharmaceutical composition in the preparation of a drug for treating 5-HT 2A receptor-related diseases including negative symptoms of schizophrenia.

Description

Technical Field

[0001] The present invention relates to compounds as inverse agonists of 5-hydroxytryptamine 2A (5-HT 2A ), methods for their preparation, and their use in the field of 5-HT 2A receptor-related diseases.

Background Art

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

[0003] Conventionally, hallucinations and delusions in Parkinson's disease patients have mainly been clinically treated using antipsychotic drugs. First-generation antipsychotic drugs mainly inhibit dopamine D2 receptors and have severe extrapyramidal side effects. Second-generation antipsychotic drugs, in addition to inhibiting D2 receptors, more strongly inhibit specific 5-HT receptors, particularly 5-HT 2A receptors, and have higher safety, that is, they have fewer extrapyramidal side effects than first-generation antipsychotic drugs. However, since second-generation antipsychotic drugs still have inhibitory activity on D2 receptors, extrapyramidal side effects still exist, and at the same time, such drugs show side effects of weight gain to varying degrees. In 2016, the US FDA approved the sale of pimavanserin as a therapeutic drug for hallucinations and delusions associated with Parkinson's disease, becoming the first drug approved for this indication. TIFF2025525188000002.tif43170

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

[0005] 5-HT 2A receptor has intrinsic activity and can exert effects even in the absence of an agonist. Pimavanserin, a 5-HT 2A receptor inverse agonist, can inhibit the intrinsic activity of the receptor by binding to the 5-HT 2A receptor, inactivate the receptor, bring about an effect opposite to that of the agonist, and show activity even in the absence of the agonist. However, a normal 5-HT 2A receptor antagonist cannot cause a biological effect after binding to the receptor and can only show its activity by inhibiting the agonist (WO2004064738A2). Therefore, even a compound having 5-HT 2A receptor antagonistic activity does not necessarily have 5-HT 2A receptor inverse agonistic activity.

[0006] 5-HT 2A receptor inverse agonists have good prospects for use in the pharmaceutical industry as drugs, but currently only pimavanserin has been approved for sale. Therefore, in order to achieve better therapeutic effects and meet the needs of clinical patients, it is necessary to develop more 5-HT 2A receptor inverse agonists.

Summary of the Invention

[0007] In one aspect, the present invention provides a compound represented by formula (A), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000003.tif44170

[0008] wherein R1 is selected from halogen, Ring B is, TIFF2025525188000004.tif22170R2 is a hydrogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl group, independently selected, Each R3 is independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, or two R3s linked to the same carbon atom form a C 3-6 cycloalkyl group with the carbon atom to which they are linked, Ring A is, TIFF2025525188000005.tif41170X 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 is independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, C 1-3 selected from cycloalkylC n is selected from 0, 1, 2, 3.

[0009] In some embodiments of the compound of formula (A), Ring A is TIFF2025525188000006.tif23170 The other variables are as defined in the present invention.

[0010] In some embodiments of the compound of formula (A), Ring B is TIFF2025525188000007.tif21170 R3 is selected from halogen, or two R3s linked to the same carbon atom form a cycloalkyl group with the carbon atom to which they are linked, and C 3-6 form a cyclopropyl group, and R3 is preferably F, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, n is 1 or 2, and the other variables are as defined in the present invention.

[0011] In some embodiments of the compound of formula (A), R5' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 alkyl group optionally substituted with an alkyl group, C 3-6 cycloalkylC 1-3 alkyl group, and preferably, R5' is selected from 2,2,2-trifluoroethyl group, cyclopropyl group, cyclobutyl group, 3,3-difluorocyclobutyl group, cyclopropylmethyl group, 2,2-dimethylcyclopropylmethyl group, and the other variables are as defined in the present invention.

[0012] In some embodiments of the compound of formula (A), R1 is selected from halogen, Ring B is TIFF2025525188000008.tif21170R2 is a hydrogen atom, C 1-3 independently selected from an alkyl group, each R3 is a hydrogen atom, halogen, C 1-3 independently selected from an alkyl group, or two R3s linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, Ring A is, TIFF2025525188000009.tif23170R 4a , R 4b , R 4c are a hydrogen atom, halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, independently selected from each other, R5 is selected from -OR5', and R5' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 cycloalkyl C optionally substituted with an alkyl group 3-6 alkyl group, selected from 1-3 cycloalkyl C n is selected from 1, 2, 3, and the other variables are as defined in the present invention.

[0013] In another aspect of the present invention, the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000010.tif46170

[0014] Among them, R1 is selected from halogen, Ring B is, TIFF2025525188000011.tif22170R2 is a hydrogen atom, C 1-3 alkyl group, C 3-6 independently selected from a cycloalkyl group, each R3 is a hydrogen atom, halogen, C 1-3Independently selected from alkyl groups respectively, or two R3 groups linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, Ring A is, TIFF2025525188000012.tif35170X is NR 6c selected from O or S, R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c R are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 3-6 cycloalkylC 1-3 alkyl group, a C 1-3 alkyl group optionally substituted with an alkyl group of C 3-6 cycloalkylC 1-3 alkyl group, n is selected from 0, 1, 2, 3.

[0015] In some embodiments of the compound of formula (I), Ring A is, TIFF2025525188000013.tif40170 The other variables are as defined in the present invention.

[0016] In some embodiments of the compound of formula (I), Ring B is, TIFF2025525188000014.tif21170R3 is selected from a halogen, or two R3 groups linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6forms a cycloalkyl group, and R3 is preferably F, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, n is 1 or 2, and the other variables are as defined in the present invention.

[0017] In some embodiments of the compound of formula (I), R5 is selected from -OR5', and R5' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkylC 1-3 alkyl group, and preferably, R5' is selected from 2,2,2-trifluoroethyl group, cyclopropyl group, cyclobutyl group, 3,3-difluorocyclobutyl group, cyclopropylmethyl group, 2,2-dimethylcyclopropylmethyl group, and the other variables are as defined in the present invention.

[0018] In some embodiments of the compound of formula (I), R1 is selected from F, Ring B is TIFF2025525188000015.tif28170R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, each R3 is independently selected from a hydrogen atom, F, a methyl group, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, Ring A is TIFF2025525188000016.tif35170X is selected from NR 6c , O or S, R 4a , R 4b , R 6a , R 6b , R 6c , R 7a, R 7b , R 7c is independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group. Preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group. n is selected from 0, 1, 2, and 3.

[0019] In some embodiments of the compound of formula (I), R1 is selected from F, Ring B is TIFF2025525188000017.tif21170R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group, R3 is selected from a hydrogen atom, F, and a methyl group, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, Ring A is TIFF2025525188000018.tif18170selected from X is NR 6c , O, or S, R 4a , R 4b , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c is independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group, preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group, n is selected from 0, 1, 2.

[0020] In some embodiments of the compound of formula (I), R1 is selected from a halogen, Ring B is TIFF2025525188000019.tif21170R2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, Each R3 is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two R3s linked to the same carbon atom form a C 3-6 cycloalkyl group with the carbon atom to which they are linked, Ring A is TIFF2025525188000020.tif23170R 4a , R 4b , R 4c are independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is selected from a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 3-6 cycloalkylC 1-3 alkyl group, a C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, a C 1-3 cycloalkylC n is selected from 1, 2, 3, and the other variables are as defined in the present invention.

[0021] In some embodiments of the compound of formula (I), R1 is selected from F, Ring B is, TIFF2025525188000021.tif21170 R2 is selected from a hydrogen atom and a methyl group, Ring A is, TIFF2025525188000022.tif17170 X is selected from NR 6c , O or S, R 6a , R 6b , R 6c are each independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group.

[0022] In some embodiments of the compound of formula (I), R1 is selected from F, Ring B is, TIFF2025525188000023.tif21170 R2 is selected from a hydrogen atom and a methyl group, R3 is selected from a hydrogen atom, F, and a methyl group, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, Ring A is, TIFF2025525188000024.tif19170 selected from, R 4a , R 4b , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c are each independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group. Preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group. n is selected from 0, 1, 2.

[0023] In some embodiments of the compound of formula (I), R1 is selected from a halogen, Ring B is TIFF2025525188000025.tif24170R2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group. R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group. Ring A is TIFF2025525188000026.tif17170R 4a 、R 4b are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group. R5 is selected from -OR5', and R5' is selected from a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group. Preferably, R5' is selected from a C 1-6 haloalkyl group, a C 3-6Selected from cycloalkyl groups, C 3-6 halocycloalkyl groups.

[0024] In some embodiments of the compound of formula (I), R1 is selected from F, Ring B is TIFF2025525188000027.tif24170R2 is independently selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, preferably a methyl group, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h is independently selected from a hydrogen atom, F, a methyl group, or R 3a and R 3b 、R 3c and R 3d 、R 3e and R 3f 、or R 3g and R 3h form a cyclopropyl group with the carbon atom to which they are attached, Ring A is TIFF2025525188000028.tif17170R 4a and R 4b are independently selected from a hydrogen atom, F, Cl, Br, R5 is selected from -OR5', R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group, preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group.

[0025] In another aspect of the present invention, the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000029.tif49170

[0026] wherein, R1 is selected from halogen, Ring B is, TIFF2025525188000030.tif22170R2 is independently selected from a hydrogen atom, C 1-3 alkyl group, Each R3 is independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, or two R3s linked to the same carbon atom together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, Ring A is, TIFF2025525188000031.tif41170X 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 each independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, 1-3 selected from cycloalkylC n is selected from 0, 1, 2, 3.

[0027] In some embodiments of the compound of formula (II), Ring A is TIFF2025525188000032.tif23170The other variables are as defined in the present invention.

[0028] In some embodiments of the compound of formula (II), Ring B is TIFF2025525188000033.tif22170R3 is selected from halogen, or two R3's linked to the same carbon atom form, together with the carbon atom to which they are linked, a C 3-6 cycloalkyl group, and R3 is preferably F, or two R3's linked to the same carbon atom form, together with the carbon atom to which they are linked, a cyclopropyl group n is 1 or 2, and the other variables are as defined in the present invention.

[0029] In some embodiments of the compound of formula (II), R5' is a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 3-6 cycloalkylC 1-3 alkyl group, a C 1-3 C alkyl group optionally substituted with an alkyl group 3-6 cycloalkylC 1-3 alkyl group, and is preferably selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group, and the other variables are as defined in the present invention.

[0030] In some embodiments of the compound of formula (II), R1 is selected from halogen Ring B is TIFF2025525188000034.tif22170R2 is independently selected from a hydrogen atom, a C 1-3 alkyl group Each R3 is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two R3s linked to the same carbon atom form, together with the carbon atom to which they are linked, a C 3-6 cycloalkyl group, Ring A is TIFF2025525188000035.tif23170R 4a , R 4b , R 4c are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 3-6 cycloalkylC 1-3 alkyl group, a C 1-3 cycloalkylCalkyl group optionally substituted with an alkyl group, 3-6 cycloalkylC 1-3 alkyl group, n is selected from 1, 2, 3, and the other variables are as defined in the present invention.

[0031] In some embodiments of the compound of formula (II), R1 is selected from F, Ring B is TIFF2025525188000036.tif22170R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, each R3 is selected from a hydrogen atom, F, a methyl group, or two R3s linked to the same carbon atom form, together with the carbon atom to which they are linked, a cyclopropyl group, Ring A is TIFF2025525188000037.tif32170R 4a , R 4b , R 4c , R 6a , R 6b , R 6c , R7a and R 7b and R 7c is independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group. Preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group. n is selected from 0, 1, 2, and 3.

[0032] In some embodiments of the compound of formula (II), R1 is selected from a halogen, Ring B is TIFF2025525188000038.tif24170R2 is a hydrogen atom, C 1-3 alkyl group, C 3-6 is independently selected from a cycloalkyl group, R 3a and R 3b and R 3c and R 3d and R 3e and R 3f and R 3g and R 3h is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or R 3a and R 3b and R 3c and R 3d and R 3e and R 3f or R 3g and R 3h form a C 3-6 cycloalkyl group with the carbon atom to which they are attached, Ring A is TIFF2025525188000039.tif24170R 4a 、R 4b 、R 4c is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, respectively. R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 alkyl group optionally substituted with an alkyl group C 3-6 cycloalkyl C 1-3 alkyl group.

[0033] In some embodiments of the compound of formula (II), R1 is selected from F, Ring B is TIFF2025525188000040.tif24170R2 is independently selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h is independently selected from a hydrogen atom, F, a methyl group, or R 3a and R 3b 、R 3c and R 3d 、R 3e and R 3f 、or R 3g and R 3h form a cyclopropyl group with the carbon atom to which they are attached, Ring A is TIFF2025525188000041.tif24170R 4a 、R 4b 、R4c is independently selected from a hydrogen atom, F, Cl, and Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group. Preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group.

[0034] In one aspect, the present invention provides a compound represented by formula (IIA), a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof, TIFF2025525188000042.tif44170

[0035] Among them, R1 is selected from a halogen, Ring B is, TIFF2025525188000043.tif22170R2 is a hydrogen atom, C 1-3 an alkyl group, C 3-6 independently selected from a cycloalkyl group, Each R3 is independently selected from a hydrogen atom, a halogen, C 1-3 an alkyl group, R 4a 、R 4b is independently selected from a hydrogen atom, a halogen, C 1-3 an alkyl group, C 1-3 a haloalkyl group, R5 is selected from -OR5', and R5' is selected from C 1-6 an alkyl group, C 1-6 a haloalkyl group, C 3-6 a cycloalkyl group, C 3-6 a halocycloalkyl group, and preferably, R5' is selected from C 1-6 a haloalkyl group, C 3-6 a cycloalkyl group, C3-6 selected from halo-cycloalkyl groups, n is selected from 0, 1, 2, 3.

[0036] In some embodiments of the compound of formula (IIA), ring B is, TIFF2025525188000044.tif21170R3 is selected from halogen, or two R3s linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, and R3 is preferably F, or two R3s linked to the same carbon atom form a cyclopropyl group together with the carbon atom to which they are linked, n is 1 or 2, and the other variables are as defined in the present invention.

[0037] In some embodiments of the compound of formula (IIA), R5' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkylC 1-3 alkyl group, and preferably, R5' is selected from 2,2,2-trifluoroethyl group, cyclopropyl group, cyclobutyl group, 3,3-difluorocyclobutyl group, cyclopropylmethyl group, 2,2-dimethylcyclopropylmethyl group, and the other variables are as defined in the present invention.

[0038] In some embodiments of the compound of formula (IIA), R1 is selected from halogen, ring B is, TIFF2025525188000045.tif21170R2 is independently selected from a hydrogen atom, C 1-3 alkyl group, each R3 is a hydrogen atom, halogen, C 1-3Independently selected from alkyl groups respectively, or two R3s linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, R 4a 、R 4b 、R 4c are independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group respectively, R5 is selected from -OR5', and R5' is a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, a C 3-6 cycloalkylC 1-3 alkyl group, a C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, 1-3 selected from alkyl groups, n is selected from 1, 2, 3, and other variables are as defined in the present invention.

[0039] In some embodiments of the compound of formula (IIA), R1 is selected from F, Ring B is, TIFF2025525188000046.tif22170R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, Each R3 is independently selected from a hydrogen atom, F, and a methyl group, R 4a 、R 4b are independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, and a 3,3-difluorocyclobutyl group. Preferably, R5' is selected from a 2,2,2-trifluoroethyl group and a 3,3-difluorocyclobutyl group, n is selected from 0, 1, 2, 3.

[0040] In one aspect, the present invention provides a compound represented by formula (IIA-1) or (IIA-2), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000047.tif54170

[0041] Among them, R1 is selected from halogen, R2 is independently selected from a hydrogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl group, R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, or R 3a and R 3b R 3c and R 3d R 3e and R 3f or R 3g and R 3h form a C 3-6 cycloalkyl group with the carbon atom to which they are attached, R 4a R 4b R 4c are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group.

[0042] In some embodiments of the compound represented by formula (IIA-1) or (IIA-2), R5' is C 1-6 a haloalkyl group, C 3-6 a cycloalkyl group, C 3-6 a halocycloalkyl group, and preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, and a 3,3-difluorocyclobutyl group, and the other variables are as defined in the present invention.

[0043] In some embodiments of the compound represented by formula (IIA-1) or (IIA-2), R1 is selected from F, R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are each independently selected from a hydrogen atom, F, and a methyl group, or R 3a and R 3b 、R 3c and R 3d 、R 3e and R 3f 、or R 3g and R 3h form a cyclopropyl group with the carbon atom to which they are attached, R 4a 、R 4b 、R 4c are each independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group.

[0044] In one aspect, the present invention provides a compound represented by formula (IIB), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000048.tif41170

[0045] Among them, R1 is selected from halogen, Ring B is, TIFF2025525188000049.tif22170R2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, Each R3 is independently selected from a hydrogen atom, halogen, a C 1-3 alkyl group, R 4a 、R 4b is independently selected from a hydrogen atom, halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group, n is selected from 0, 1, 2, 3.

[0046] In some embodiments of the compound of formula (IIB), R1 is selected from F, Ring B is, TIFF2025525188000050.tif22170R2 is independently selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, Each R3 is independently selected from a hydrogen atom, F, a methyl group, R 4a 、R 4b are independently selected from a hydrogen atom, F, Cl, Br, a methyl group, a trifluoromethyl group, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, and a 3,3-difluorocyclobutyl group. n is selected from 0, 1, 2, and 3.

[0047] In another aspect, the present invention provides a compound represented by formula (III), a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof. TIFF2025525188000051.tif37170

[0048] Among them, R1 is selected from a halogen. Ring B is TIFF2025525188000052.tif22170R2 is a hydrogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl group, independently selected. Each R3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or two R3s linked to the same carbon atom form a cycloalkyl group with the carbon atom to which they are linked and C 3-6 cycloalkyl group. R 4a and R 4b are independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group. R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, C 1-3 cycloalkylC n is selected from 0, 1, 2, and 3.

[0049] In some embodiments of the compound of formula (III), Ring B is TIFF2025525188000053.tif21170R3 is selected from halogen, or two R3s linked to the same carbon atom, together with the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, and R3 is preferably F, or two R3s linked to the same carbon atom form a cyclopropyl group together with the carbon atom to which they are linked, n is 1 or 2, and the other variables are as defined in the present invention.

[0050] In some embodiments of the compound of formula (III), R5' is C 1-6 a haloalkyl group, C 3-6 a cycloalkyl group, C 3-6 a halocycloalkyl group, C 3-6 cycloalkyl C 1-3 an alkyl group, C 1-3 a C alkyl group optionally substituted with an alkyl group 3-6 cycloalkyl C 1-3 selected from an alkyl group, and preferably, R5' is selected from a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group, and the other variables are as defined in the present invention.

[0051] In some embodiments of the compound of formula (III), R1 is selected from halogen, Ring B is TIFF2025525188000054.tif21170R2 is independently selected from a hydrogen atom, C 1-3 an alkyl group, each R3 is independently selected from a hydrogen atom, halogen, C 1-3 an alkyl group, or two R3s linked to the same carbon atom form a C 3-6 cycloalkyl group, Ring A is TIFF2025525188000055.tif23170R 4a and R 4b and R 4c is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, respectively, R5 is selected from -OR5', and R5' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkyl C 1-3 alkyl group, selected from n is selected from 1, 2, 3, and the other variables are as defined in the present invention.

[0052] In some embodiments of the compound represented by formula (III), R1 is selected from a halogen, Ring B is, TIFF2025525188000056.tif19170R2 is a hydrogen atom, C 1-3 alkyl group, independently selected from each R3 is a hydrogen atom, a halogen, C 1-3 alkyl group, independently selected from each other, or two R3s linked to the same carbon atom are a cycloalkyl group with the carbon atom to which they are linked and C 3-6 to form a cycloalkyl group, R 4a and R 4b is a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, independently selected from each other, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3Alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 Cycloalkyl C 1-3 Selected from alkyl groups, n is selected from 0, 1, 2.

[0053] In some embodiments of the compound represented by formula (III), R1 is selected from F, Ring B is, TIFF2025525188000057.tif19170R2 is independently selected from a hydrogen atom and a methyl group, Each R3 is independently selected from a hydrogen atom, F, Cl, Br, and a methyl group, or two R3s linked to the same carbon atom form a cyclopropyl group with the carbon atom to which they are linked, R 4a and R 4b are independently selected from a hydrogen atom, F, Cl, Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group, n is selected from 0, 1, 2.

[0054] In some embodiments of the compound represented by formula (III), R1 is selected from a halogen, Ring B is, TIFF2025525188000058.tif22170R2 is independently selected from a hydrogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl group, Each R3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, R 4a 、R 4b are a hydrogen atom, a halogen, C 1-3An alkyl group, C 1-3 Independently selected from a haloalkyl group, respectively, R5 is selected from -OR5', and R5' is C 1-6 An alkyl group, C 1-6 A haloalkyl group, C 3-6 A cycloalkyl group, C 3-6 Selected from a halocycloalkyl group, n is selected from 0, 1, 2, 3.

[0055] In some embodiments of the compound of formula (III), R1 is selected from F, Ring B is TIFF2025525188000059.tif22170R2 is selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, Each R3 is independently selected from a hydrogen atom, F, and a methyl group, R 4a R 4b Are independently selected from a hydrogen atom, F, Cl, Br, a methyl group, and a trifluoromethyl group, respectively, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, and a 3,3-difluorocyclobutyl group, n is selected from 0, 1, 2, 3.

[0056] In some embodiments of the compound represented by formula (III), R1 is selected from a halogen, Ring B is TIFF2025525188000060.tif24170R2 is selected from a hydrogen atom, C 1-3 An alkyl group, C 3-6 Independently selected from a cycloalkyl group, R 3a R 3b R 3c R 3d R 3e R 3f R3g , R 3h is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h is a C 3-6 cycloalkyl group formed with the carbon atom to which they are attached, R 4a and R 4b are independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group.

[0057] In some embodiments of the compound represented by formula (III), R1 is selected from F, Ring B is, TIFF2025525188000061.tif24170R2 is independently selected from a hydrogen atom and a methyl group, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h is independently selected from a hydrogen atom, F, and a methyl group, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h is a cyclopropyl group formed with the carbon atom to which they are attached, R4a and R 4b is independently selected from a hydrogen atom, F, Cl, and Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group.

[0058] In another aspect, the present invention provides a compound represented by formula (IIIA) or (IIIB), a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof, TIFF2025525188000062.tif44170

[0059] wherein, R1 is selected from a halogen, R2 is selected from a hydrogen atom, C 1-3 an alkyl group, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h is independently selected from a hydrogen atom, a halogen, C 1-3 an alkyl group, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h form a C 3-6 cycloalkyl group with the carbon atom to which they are attached, R 4a and R 4b are independently selected from a hydrogen atom, a halogen, C 1-3 an alkyl group, and C 1-3 a haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6An alkyl group, C 1-6 A haloalkyl group, C 3-6 A cycloalkyl group, C 3-6 A halocycloalkyl group, C 3-6 Cycloalkyl C 1-3 An alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 Cycloalkyl C 1-3 is selected from.

[0060] In some embodiments of the compound represented by formula (IIIA) or (IIIB), R1 is selected from F, R2 is selected from a hydrogen atom and a methyl group, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h are each independently selected from a hydrogen atom, F, and a methyl group, or R 3a and R 3b 、R 3c and R 3d 、R 3e and R 3f 、or R 3g and R 3h form a cyclopropyl group with the carbon atom to which they are attached, R 4a and R 4b are each independently selected from a hydrogen atom, F, Cl, and Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group.

[0061] In another aspect, the present invention provides a compound represented by formula (IIIC), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000063.tif44170

[0062] Among them, R1 is selected from halogens, R2 is selected from a hydrogen atom, C 1-3 alkyl group, R 4a and R 4b are each independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkylC 1-3 alkyl group, C 1-3 cycloalkylC 3-6 alkyl group optionally substituted with an alkyl group, C 1-3 alkyl group.

[0063] In some embodiments of the compound represented by formula (II), R1 is selected from F, R2 is selected from a hydrogen atom, a methyl group, R 4a and R 4b are each independently selected from a hydrogen atom, F, Cl, Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group.

[0064] In another aspect, the present invention provides a compound represented by formula (IV), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000064.tif41170

[0065] Among them, R1 is selected from halogens, R2 is a hydrogen atom, C 1-3 selected from alkyl groups, R 6a , R 6b are each independently selected from a hydrogen atom, a halogen, C 1-3 haloalkyl groups, R 6c is a hydrogen atom, C 1-3 selected from alkyl groups.

[0066] In some embodiments of the compound represented by formula (IV), R1 is selected from F, R2 is selected from a hydrogen atom and a methyl group, R 6a , R 6b are each independently selected from a hydrogen atom, F, and a trifluoromethyl group, R 6c is selected from a hydrogen atom and a methyl group.

[0067] In another aspect, the present invention provides a compound represented by formula (V), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000065.tif41170

[0068] Among them, R1 is selected from halogens, R2 is a hydrogen atom, C 1-3 selected from alkyl groups, R 7a , R 7b , R 7c are each independently selected from a hydrogen atom, a halogen, C 1-3 haloalkyl groups.

[0069] In some embodiments of the compound represented by formula (V), R1 is selected from F, R2 is selected from a hydrogen atom and a methyl group, R 7a 、R 7b 、R 7c is independently selected from a hydrogen atom, F, and a trifluoromethyl group.

[0070] In another aspect of the present invention, the present invention provides a compound represented by formula (VI), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000066.tif41170

[0071] wherein, R 1a 、R 1b is independently selected from a hydrogen atom and a C 1-3 alkyl group, Ring B is TIFF2025525188000067.tif22170R2 is independently selected from a hydrogen atom and a C 1-3 alkyl group, Each R3 is independently selected from a hydrogen atom, a halogen, and a C 1-3 alkyl group, or two R3s linked to the same carbon atom form a C 3-6 cycloalkyl group with the carbon atom to which they are linked, Ring A is TIFF2025525188000068.tif32170X is selected from NR 6c 、O or S, R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, and a C 1-3 haloalkyl group, R5 is selected from -OR5', and R5' is a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group,3-6 Cycloalkyl C 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 Cycloalkyl C 1-3 selected from alkyl groups, n is selected from 0, 1, 2, 3.

[0072] In some embodiments of the compound of formula (VI), R 1a , R 1b are each independently selected from a hydrogen atom, C 1-3 alkyl groups, Ring B is TIFF2025525188000069.tif24170R2 is a hydrogen atom, C 1-3 alkyl group, C 3-6 cycloalkyl groups independently selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h are each independently selected from a hydrogen atom, a halogen, C 1-3 alkyl groups, Ring A is TIFF2025525188000070.tif17170R 4a , R 4b are each independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, C 1-3 haloalkyl groups independently selected from R5 is selected from -OR5', and R5' is C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl groups selected from.

[0073] In some embodiments of the compound of formula (VI), R 1a , R 1b are each independently selected from a hydrogen atom and a methyl group, Ring B is TIFF2025525188000071.tif24170R2 is independently selected from a hydrogen atom, a methyl group, CD3, an ethyl group, an n-propyl group, an isopropyl group, and a cyclopropyl group, R 3a 、R 3b 、R 3c 、R 3d 、R 3e 、R 3f 、R 3g 、R 3h is independently selected from a hydrogen atom, F, and a methyl group, or R 3a and R 3b 、R 3c and R 3d 、R 3e and R 3f 、or R 3g and R 3h form a cyclopropyl group with the carbon atom to which they are attached, Ring A is TIFF2025525188000072.tif17170R 4a and R 4b are independently selected from a hydrogen atom, F, Cl, and Br, R5 is selected from -OR5', and R5' is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, and a 2,2-dimethylcyclopropylmethyl group.

[0074] In another aspect, the present invention relates to a compound represented below, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, TIFF2025525188000073.tif 234170 TIFF2025525188000074.tif 218170 TIFF2025525188000075.tif 218170 TIFF2025525188000076.tif 239170 TIFF2025525188000077.tif 212170 TIFF2025525188000078.tif 139170

[0075] In another aspect, the present invention provides a compound selected from TIFF2025525188000079.tif 228170 TIFF2025525188000080.tif 244170 TIFF2025525188000081.tif 184170, a pharmaceutically acceptable salt or deuteride thereof.

[0076] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as described in any of the above, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a crystalline form of a compound as described in any of the above, and a pharmaceutically acceptable carrier. The above carrier includes conventional auxiliary components in the art such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants or wetting agents.

[0077] The above 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 film agents, nasal sprays, transdermal patches, injections, or various sustained-release preparations. The above 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 age, gender of the patient, and the type of disease.

[0078] In the case of oral administration, the above drug composition can be, for example, in the form of tablets, capsules, liquid capsules, suspensions or liquids. The above drug composition is preferably manufactured in a dosage unit form containing a specific amount of the active ingredient. For example, the above drug composition can be provided as tablets or capsules containing an amount of the active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, more preferably about 0.5 to 100 mg. The appropriate daily dose for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined using conventional methods.

[0079] In one aspect, the present invention relates to a use of a compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in any of the above in a drug for treating 5-HT 2A receptor-related diseases. The above diseases or symptoms include schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, mood disorder, dementia, anxiety disorder, sleep disorder, eating disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tic, depression, major depression, anxiety, sleep disorder and eating disorder, non-motor symptoms due to Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disorder), dementia-related psychosis, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, movement disorder, dystonia, myoclonus, tremor, progressive supranuclear palsy, and frontotemporal dementia, or other disease states and conditions apparent to those skilled in the art.

[0080] [Definitions and Explanations] Unless otherwise specified, the following terms and phrases used in this specification are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear when not specifically defined, but should be understood in its general meaning. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0081] As used herein, the term "pharmaceutically acceptable" pertains to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0082] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds found by the present invention having certain substituents together with relatively non-toxic acids or bases. When the compounds according to the present invention contain relatively acidic functional groups, the base addition salts can be obtained by contacting a neutral form of such compounds with a sufficient amount of a base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Some specific compounds according to the present invention contain both basic and acidic functional groups and can thus be converted into either base addition salts or acid addition salts.

[0083] The pharmaceutically acceptable salts according to the present invention can be synthesized from the parent compounds containing acid or base groups by conventional chemical methods. In general, the methods for preparing salts are as follows: they are prepared by reaction of these compounds in the form of free acids or free bases with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0084] Some of the compounds of the present invention can have asymmetric carbon atoms (optical centers), or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

[0085] The compounds according to the present invention may have specific geometric or steric isomeric forms. In the present invention, all such compounds include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures such as, for example, mixtures enriched in enantiomers or diastereomers, and it is hypothesized that all of these mixtures belong to the scope of the present invention. Substituents such as alkyl groups may have other asymmetric carbon atoms. All of these isomers and their mixtures are included in the scope of the present invention.

[0086] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. When attempting to obtain the enantiomers of the compounds according to the present invention, they can be prepared by asymmetric synthesis or induction with chiral auxiliaries, separating the resulting mixture of diastereomers, and assisting the decomposition of the base to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), an appropriate optically active acid or base is used to form a diastereomeric salt, and then the diastereomers are resolved by conventional methods known in the art and then recovered to obtain the pure enantiomer. Also, the separation of enantiomers and diastereomers is usually achieved by chromatography, and the chromatography uses a chiral stationary phase and is optionally combined with chemical derivatization methods (e.g., generating carbamates from amides).

[0087] The term "pharmaceutically acceptable carrier" means a representative carrier of any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and is non-toxic and has no side effects on the host or patient, and includes, but is not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0088] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a drug or pharmacologically active agent that is non-toxic but sufficient to achieve the desired effect. In the oral dosage forms of the present invention, the "effective amount" of the active substance in the composition means the amount necessary to achieve the desired effect when used in combination with other active substances in the composition. The determination of the effective amount varies from human to human, depending on the age and general condition of the recipient, as well as on the particular active substance, and the appropriate effective amount in an individual case can be determined by one of ordinary skill in the art based on conventional tests.

[0089] The present invention contemplates including all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. As common examples, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of ordinary skill in the art or by methods similar to those described herein, by using appropriate isotopically labeled reagents in place of the unlabeled reagents additionally used.

[0090] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with deuterium atoms. The terms "optional" or "optionally" mean that the event or circumstance described thereafter is possible but not essential, and the description includes both the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group is not substituted with deuterium atoms, or is substituted with one or more or a plurality of deuterium atoms, i.e., the group is not deuterated, partially deuterated, and / or fully deuterated.

[0091] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, including 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 ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on an aryl group.

[0092] If any variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition is independent in each situation. Thus, for example, if one group is substituted with 0 to 2 R's, the above group can optionally be substituted with up to 2 R's, and in each situation, each R has independent options. Also, combinations of substituents and / or their variants are only permitted if a stable compound can be formed.

[0093] Unless otherwise specified, the term "alkyl group" is used to represent a straight-chain or branched-chain saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). For example, C1-C 10 represents 1 to 10 carbons, and C 1-10 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of alkyl groups include methyl group (Me), ethyl group (Et), propyl group (e.g., n-propyl group and isopropyl group), butyl group (e.g., n-butyl group, isobutyl group, s-butyl group, t-butyl group), pentyl group (e.g., n-pentyl group, isoamyl group, neopentyl group, 1-ethylpropyl group), hexyl group (e.g., n-hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group), heptyl group, octyl group, nonyl group, decyl group, etc.

[0094] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl group" is intended to include monohaloalkyl groups and polyhalogenated straight or branched alkyl groups. For example, the term "C1-10 haloalkyl group" is intended to include, but not be limited to, fluoromethyl group, difluoromethyl group, trichloromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, tetrafluoroethyl group, pentafluoroethyl group, 3-fluoropropyl group, 3,3-difluoropropyl group, 2,2'-difluoroisopropyl group, 3,3,3-trifluoropropyl group, 4-fluorobutyl group, 4,4-difluorobutyl group, 4,4,4-trifluorobutyl group, 2-fluoro-2-methylpropyl group, 5,5,5-trifluoropentyl group, 6,6,6-trifluorohexyl group.

[0095] Unless otherwise specified, a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group in which any carbon atom is saturated and may be mono- or polysubstituted and may be monovalent, divalent, or polyvalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, norbornyl group, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc. The above cycloalkyl groups may be optionally further substituted with halogen or a C1-C3 alkyl group.

[0096] The "cycloalkylalkyl group" is, unless otherwise specified, C 3-6 cycloalkyl-C 1-3means "alkyl-", and the cycloalkylalkyl group may be substituted or unsubstituted. Non-limiting examples thereof include cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclopropylethyl group, cyclobutylethyl group, cyclopentylethyl group, cyclopropylpropyl group, cyclobutylpropyl group, cyclopentylpropyl group, and the like. The above cycloalkylalkyl group may be further optionally substituted with a halogen or a C1-C3 alkyl group.

[0097] Compounds are named manually or with ChemDraw® software, and commercially available compounds adopt the supplier's catalog name.

Brief Description of the Drawings

[0098]

Figure 1

Modes for Carrying Out the Invention

[0099] Hereinafter, the present invention will be further described with reference to specific examples and test examples, but it does not limit the scope of the present invention in any form.

[0100] Example 1 TIFF2025525188000082.tif46170

[0101] Protect with nitrogen gas. Under an ice-water bath, dissolve 2-(aminomethyl)-5-fluoropyridine (504 mg, 4.0 mmol) in 10 mL of methanol, add N-methyl-4-piperidinone (452 mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol), raise the temperature to room temperature and react for 15 h. Add an aqueous sodium bicarbonate solution to adjust the pH value to basic. After concentrating the organic phase, extract with dichloromethane (10 mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Compound 1-2 (538 mg). TIFF2025525188000083.tif47170

[0102] Add 16 mL of dimethyl sulfoxide, Compound 1-3 (4.00 g, 1.00 eq), compound trifluoroethanol (9.83 g, 3.00 eq), and cesium carbonate (16.01 g, 1.50 eq) to a 100 mL three-necked flask in sequence. Raise the temperature to 105 °C and keep the temperature for 12 h for the reaction. Add 200 mL of water to the reaction solution and extract twice with 200 mL of ethyl acetate each time. Combine the organic phases, wash the organic phases with 200 mL of saturated brine, dry the organic phases, concentrate to dryness to obtain a crude product. Purify the crude product by column chromatography to obtain Compound 1-4 (orange oil, 5.6 g).

[0103] Add 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) to a 500 mL hydrogenation flask in sequence. React at 70 °C and 50 Psi for 12 h. Filter and concentrate to dryness to obtain a crude product. Purify the crude product by preparative chromatography to obtain Compound 1-5 (white solid, 2.37 g).

[0104] Ethyl acetate (5 mL), Compound 1-5 (1.00 g, 1.00 eq), and HCl / EtOAc (5 mL) were sequentially added to a 100 mL one-necked flask, and the mixture was kept at 25 °C and stirred for 17 hours. The reaction solution was directly concentrated to dryness to obtain crude Compound 1-6 (light pink solid, 903 mg). TIFF2025525188000084.tif47170

[0105] 2 mL of tetrahydrofuran, Compound 1-6 (200 mg, 1.00 eq), and diisopropylethylamine (DIEA) (125 mg, 1.00 eq) were sequentially added to a 10 mL one-necked flask. After stirring for 15 minutes under a nitrogen gas atmosphere, the temperature was lowered to 0 °C in an ice-water bath. Carbonyldiimidazole (CDI) (173 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out 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 solution, and the mixture was kept at 25 °C and stirred for 12 hours. The reaction solution 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 (yellow oil, 160 mg). 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.24 - 7.20 (m, 1H), 7.00 (br d, J= 2.1 Hz, 1H), 4.50 (d, J = 5.4 Hz, 2H), 4.47 (s, 2H), 4.39 (q, J= 8.0 Hz, 2H), 4.27 (br s, 1H), 2.94 (br d, J = 11.6 Hz, 2H), 2.32 (s, 3H), 2.20 - 2.08 (m, 2H), 1.82 (br dd, J = 3.4, 12.1 Hz, 2H), 1.73 - 1.61 (m, 2H). MS m / z(ESI): 456.2[M+1].

[0106] Example 2 Compounds 2 - 4, 7 - 8, 11, 77, 79 were obtained using the same synthesis method as in Example 1. The following table lists the characterization data of Compounds 2 - 4, 7 - 8, 11, 77, 79. TIFF2025525188000085.tif255170TIFF2025525188000086.tif91170

[0107] Example 3 TIFF2025525188000087.tif50170

[0108] 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 one - neck flask, cooled to 0 °C, and stirred for 15 minutes under nitrogen gas protection. Then, carbonyldiimidazole (259.55 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 1 - 2 (324.92 mg, 1.00 eq) dissolved in the reaction solution and 2 mL of tetrahydrofuran were added, and the reaction was carried out at 25 °C for 12 hours. The mixture was filtered and concentrated to dryness to obtain a crude product. The crude product was purified by preparative chromatography to obtain Compound 5 (yellow solid, 440 mg). 11H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.9 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.29 (dd, J = 4.4, 8.8 Hz, 1H), 7.15 (t, J = 5.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.96 (q, J = 9.1 Hz, 2H), 4.46 (s, 2H), 4.21 (d, J = 5.5 Hz, 2H), 3.97 (br t, J = 11.4 Hz, 1H), 2.88 (br d, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.16 (br t, J = 9.9 Hz, 2H), 1.65 - 1.54 (m, 2H), 1.53 - 1.47 (m, 2H). MS m / z(ESI): 456.2 [M+1].

[0109] Example 4 TIFF2025525188000088.tif73170

[0110] 25 mL of N-methylpyrrolidone and compound 6-2 (2.55 g, 1.20 eq) were added to a 100 mL three-necked flask, and the temperature was lowered to 0 °C. Sodium hydride (1.18 g, 1.50 eq) was added to the reaction solution in several portions, and the mixture was stirred at 0 °C for 0.5 h. Compound 6-1 (2.40 g, 1.00 eq) was dissolved in 20 mL of N-methylpyrrolidone and then added dropwise to the reaction solution, and the mixture was stirred at 25 °C for 12 h. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 200 mL of ethyl acetate each time. The organic phase was dried, filtered, concentrated to dryness to obtain a crude product, and the crude product was purified by column chromatography to obtain compound 6-3 (white solid, 1.20 g).

[0111] 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) were added to a 250 mL hydrogenation flask and reacted at 70 °C and 50 Psi for 24 hours. After filtration and concentration to dryness, a crude product was obtained, and the crude product was purified by column chromatography to obtain compound 6-4 (white solid, 720 mg).

[0112] 2 mL of ethyl acetate and compound 6-4 (720 mg, 1.00 eq) were added to a 100 mL single-neck flask, and hydrochloric acid in ethyl acetate (8 mL, 4 M) was slowly added dropwise to the reaction solution, followed by reaction at 25 °C for 12 hours. After concentration to dryness, 10 mL of dichloromethane was added to dissolve the product, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted three times with 10 mL of dichloromethane each time. The organic phase was dried, filtered, and concentrated to dryness to obtain compound 6-5 (440 mg).

[0113] 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-neck flask, and the temperature was lowered to 0 °C. The mixture was stirred under nitrogen protection for 15 minutes, and carbonyldiimidazole (324.73 mg, 1.10 eq) was added to the reaction solution, followed by reaction at 0 °C for 1 hour. Compound 1-2 (406.53 mg, 1.00 eq) dissolved in the reaction solution and 2 mL of tetrahydrofuran were added, and the mixture was reacted at 25 °C for 12 hours. After filtration and concentration to dryness, a crude product was obtained. The crude product was purified by preparative chromatography to obtain compound 6 (yellow gum, 460 mg). 11H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 2.9 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.30 (dd, J = 4.5, 8.8 Hz, 1H), 7.11 (t, J = 5.6 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.13 - 5.02 (m, 1H), 4.46 (s, 2H), 4.19 (d, J = 5.5 Hz, 2H), 3.99 - 3.89 (m, 1H), 3.20 - 3.07 (m, 2H), 2.81 (br d, J = 11.3 Hz, 2H), 2.74 - 2.61 (m, 2H), 2.19 (s, 3H), 2.04 (br t, J = 10.9 Hz, 2H), 1.57 (dq, J = 3.4, 12.0 Hz, 2H), 1.50 - 1.43 (m, 2H). MS m / z(ESI): 464.2 [M+1].

[0114] Example 5 TIFF2025525188000089.tif49170

[0115] Compound 19 was obtained using the same synthetic method as in Example 4. 1 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.0 Hz, 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].

[0116] Example 6 TIFF2025525188000090.tif51170

[0117] 5 mL of N,N-dimethylformamide, compound 9-1 (300 mg, 1.00 eq), and diisopropylethylamine (265 mg, 1.00 eq) were sequentially added to a 10 mL single-neck flask. After stirring for 15 minutes under a nitrogen gas atmosphere, the temperature was lowered to 0 °C in an ice-water bath. Then, carbonyldiimidazole (366 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 1-2 (504 mg, 1.0 eq) was dissolved in 2 mL of DMF and then added to the reaction solution. The mixture was kept at 25 °C and stirred for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 9 (yellow oil, 310 mg). 1 HNMR (400 MHz, CDCl3) δ 8.38 (br s, 1H), 8.23 (d, J = 2.6 Hz, 1H), 7.52 (s, 1H), 7.35 - 7.29 (m, 3H), 7.21 (t, J = 2.8 Hz, 1H), 7.11 (dd, J = 1.5, 8.4 Hz, 1H), 6.66 (br s, 1H), 6.50 (ddd, J= 0.8, 2.0, 3.0 Hz, 1H), 4.51 (d, J = 5.1 Hz, 2H), 4.39 (s, 2H), 4.34 (br t, J = 4.1 Hz, 1H), 2.95 (br d, J = 11.5 Hz, 2H), 2.32 (s, 3H), 2.14 (br t, J = 11.1 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.73 - 1.66 (m, 2H). MS m / z(ESI): 396.2[M+1].

[0118] Example 7 TIFF2025525188000091.tif53170

[0119] 5 mL of N,N-dimethylformamide, compound 10-1 (300 mg, 1.00 eq), and diisopropylethylamine (245 mg, 1.00 eq) were sequentially added to a 10 mL single-necked flask. After stirring for 15 minutes under a nitrogen gas atmosphere, the temperature was lowered to 0 °C in an ice-water bath. Carbonyldiimidazole (338 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 1-2 was dissolved in 2 mL of DMF, i.e., N,N-dimethylformamide, and then added to the reaction solution. The mixture was kept at 25 °C and stirred for 12 hours. 40 mL of water was added to the reaction solution, and extraction was performed twice with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 10 (yellow oil, 200 mg). 1 H NMR (400 MHz, CDCl3) δ 8.89 (dd, J = 1.6, 4.3 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.72 - 7.63 (m, 2H), 7.45 - 7.35 (m, 3H), 4.62 (d, J = 5.5 Hz, 2H), 4.44 (s, 2H), 4.39 - 4.26 (m, 1H), 2.99 (br d, J = 11.5 Hz, 2H), 2.36 (s, 3H), 2.19 (br t, J= 11.1 Hz, 2H), 1.98 - 1.82 (m, 2H), 1.71 (br dd, J = 1.9, 11.8 Hz, 2H). MS m / z(ESI): 408.2[M+1].

[0120] Example 8 TIFF2025525188000092.tif69170

[0121] 5 mL of tetrahydrofuran, compound 5-1 (400 mg, 1.00 eq), diisopropylethylamine (376 mg, 1.50 eq) were added to a 100 mL one-neck flask, cooled to 0 °C, stirred for 15 minutes under nitrogen gas protection, and carbonyldiimidazole (346 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 39-1 (635 mg, 1.00 eq) dissolved in the reaction solution and 4 mL of tetrahydrofuran were added, and the reaction was carried out at 25 °C for 12 hours. Filtration was performed to obtain a filtrate. The filtrate was purified by preparative chromatography to obtain compound 39-2 (yellow oil, 400 mg, yield 33.5%).

[0122] 20 mL of dichloromethane, compound 39-2 (350 mg, 1.00 eq), trifluoroacetic acid (6 mL, 129 eq) were added to a 100 mL one-neck flask, stirred at 25 °C for 20 minutes, concentrated and dried to obtain a yellow oil. 20 mL of tetrahydrofuran, the yellow oil, sodium cyanoborohydride (78 mg, 2.00 eq), 37% aqueous formaldehyde solution (76 mg, 1.50 eq) were added to a 100 mL single flask, stirred at 25 °C for 20 minutes, concentrated and dried, 10 mL of methanol was added, stirred at 75 °C for 80 minutes, concentrated and dried to obtain a crude product, and the crude product was subjected to chiral resolution (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O EtOH)], B%: 20% - 20%) to obtain compound 39 (retention time 1.778 min, yellow adhesive 120 mg, yield 39.9%) and compound 41 (retention time 1.876 min, yellow adhesive 130 mg, yield 43.3%).

[0123] Compound 39: 11H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.9 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.34 (dd, J = 4.5, 8.8 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.96 (q, J = 9.1 Hz, 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 = 10.6 Hz, 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].

[0124] Compound 41: 1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 2.9 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.35 (dd, J = 4.5, 8.8 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.97 (q, J = 9.1 Hz, 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 = 11.0 Hz, 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].

[0125] Example 9 TIFF2025525188000093.tif37170

[0126] Compound 39-2 (360 mg, 1 eq) was added to 3.3 mL of ethyl acetate, and HCl / EtOAc (4 M, 2.41 mL, 15 eq) was added. The reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated to dryness to obtain a crude product. After adding an aqueous sodium bicarbonate solution to adjust the pH value to 7, it was concentrated to dryness again. The crude product was subjected to chiral resolution (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O in ethanol)], B%: 20% - 20%), concentrated, and freeze-dried to obtain Compound 56A (retention time 1.744 min, 95.0 mg of yellow oil, yield 30.0%) and Compound 56B (retention time 2.519 min, 90 mg of yellow oil, yield 29.4%).

[0127] Compound 56A: 1 H NMR (400 MHz, CDCl3) δ 1.76 - 1.83 (m, 2 H), 2.58 - 2.68 (m, 2 H), 3.03 (br d, J = 12.26 Hz, 1 H), 3.36 - 3.48 (m, 1 H), 4.27 (td, J = 10.66, 5.19 Hz, 1 H), 4.35 (br d, J = 5.38 Hz, 2 H), 4.45 - 4.50 (m, 2 H), 4.59 - 4.67 (m, !) H), 4.71 - 4.78 (m, 2 H), 6.54 - 6.69 (m, 1 H), 6.81 (d, J = 8.50 Hz, 1 H), 7.35 - 7.43 (m, 2 H), 7.57 (dd, J = 8.44, 2.31 Hz, 1 H), 7.97 - 8.06 (m, 1 H), 8.30 (d, J = 2.38 Hz, 1 H). MS(ESI) m / z : 460.2[M + 1].

[0128] Compound 56B: 11H NMR (400 MHz, CDCl3) δ 1.67 (br s, 2 H), 2.52 (br d, J=3.50 Hz, 2 H), 2.86 - 2.98 (m, 1 H), 3.30 (br s, 1 H), 4.14 (br s, 1 H), 4.23 (br s, 2 H), 4.37 (br s, 2 H), 4.53 (br s, 1 H), 4.63 (br d, J=6.13 Hz, 2 H), 6.41 - 6.61 (m, 1 H), 6.69 (br d, J=5.88 Hz, 1 H), 7.27 (br s, 2 H), 7.37 - 7.52 (m, 1 H), 7.91 (br s, 1 H), 8.18 (br s, 1 H). MS(ESI) m / z : 460.2[M+1].

[0129] Example 10 Compounds 27 - 28, 42, 44, 66 / 67, 69A / 69B, 70A / 70B were obtained using the same synthesis method and / or resolution method as in Example 8, and compounds 46A / 46B, 47A / 47B, 72A / 72B, 81A / 81B, 82A / 82B, 83A / 83B were obtained using the resolution conditions (column: DAICEL CHIRALCEL OX (250 mm×50 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O EtOH)], B%: 25% - 25%). The following table lists the characterization data of such compounds. TIFF2025525188000094.tif244170TIFF2025525188000095.tif244170TIFF2025525188000096.tif244170TIFF2025525188000097.tif246170TIFF2025525188000098.tif21170

[0130] Example 11 TIFF2025525188000099.tif37170

[0131] 20 mL of tetrahydrofuran and compound 57-1 (1.80 g, 1.00 eq) were added to a 100 mL three-necked flask, and the temperature was lowered to 0 °C. Lithium aluminum tetrahydride (954 mg, 2.00 eq) was added to the reaction solution in several portions, and the mixture was stirred at 25 °C for 12 hours. 1 mL of water, 1 mL of 15% aqueous sodium hydroxide solution, and 3 mL of water were sequentially added to the reaction solution. The mixture was extracted three times with ethyl acetate. The organic phase was dried, filtered, and concentrated to dryness to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 57-2 (620 mg, yield 32.8%).

[0132] 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, and the temperature was lowered to 0 °C. The mixture was stirred for 15 minutes under nitrogen gas protection. Carbonyldiimidazole (690 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 1-2 (864 mg, 1.00 eq) was added to the reaction solution, and the reaction was carried out at 25 °C for 12 hours. The mixture was filtered to obtain a crude product. The crude product was purified by preparative chromatography to obtain compound 57 (off-white solid, 950 mg, yield 60.9%). 11H NMR (400 MHz, DMSO-d6) δ8.47 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.65 (dt, J = 2.9, 8.8 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.34 (dd, J = 4.5, 8.6 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.92 (d, J = 1.4 Hz, 1H), 4.49 (s, 2H), 4.36 (br d, J = 5.5 Hz, 2H), 3.96 (br t, J = 11.5 Hz, 1H), 2.71 (br d, J = 11.1 Hz, 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].

[0133] Example 12 Using the same synthetic method as in Example 11, Compounds 12-13, 58-61, and 84 were obtained. The following table lists the characterization data of Compounds 12-13, 58-61, and 84. TIFF2025525188000100.tif255170TIFF2025525188000101.tif41170

[0134] Example 13 TIFF2025525188000102.tif102170

[0135] 30 mL of acetonitrile, Compound 17-1 (10.0 g, 1.00 eq), and triethylamine (4.15 g, 1.00 eq) were sequentially added to a 100 mL three-necked flask and protected with N2. Trifluoroacetic anhydride (9.47 g, 1.10 eq) was added in several portions, and the reaction temperature was controlled at 35 °C to 40 °C. The reaction was allowed to proceed at 40 °C for 30 minutes. It was diluted with 30 mL of water, filtered, the filter cake was recovered, and dried under vacuum to obtain Compound 17-2 (yellow oil, 11.8 g, yield 85.3%).

[0136] Cesium carbonate (23.96 g, 2.50 eq), copper(I) iodide (840 mg, 0.15 eq), and L-proline (2.27 g, 1.0 eq) were sequentially added to a 100 mL three-necked flask. Then, 20 mL of N,N-dimethylformamide was added to the reaction flask, and the mixture was reacted 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 solution, followed by reaction at 25 °C for 15 minutes. t-Butyl acetoacetate (9.3 g, 2.00 eq) was added to the reaction solution, and the mixture was kept at 90 °C for 12 hours for a heat-retaining reaction. After complete reaction, the contents in the container were cooled to 18 - 23 °C. Water (40 mL) was added over a period exceeding 15 seconds while maintaining the reaction temperature below 35 °C. Then, isopropyl acetate (40 mL), toluene (80 mL), and water (40 mL) were added. The aqueous layer was removed, and the organic layer was washed with a saturated ammonium chloride solution (50 mL). Subsequently, the organic layer was minimized by vacuum distillation. Dichloromethane (30 mL) was added, and the internal temperature was adjusted to 18 - 23 °C. Trifluoroacetic acid (10 mL) was added for 15 minutes. The solution was stirred overnight. After filtering the solid, it was washed twice with 20 mL of dichloromethane each time. Compound 17-3 (yellow solid, 3.52 g, yield 47.7%) was obtained.

[0137] 5 mL of 1-methyl-2-pyrrolidone, 0.5 mL of water, and compound 17-3 (1.0 g, 1.00 eq) were sequentially added to a 50 mL single-necked flask. The mixture was kept at 130 °C for 12 hours for a heat-retaining reaction. After cooling to room temperature, 30 mL of water was added, and the mixture was stirred for 40 min. Then, it was filtered. The filter cake was washed with water, and the product was dried under vacuum. The crude product was purified by column chromatography to obtain compound 17-4 (white solid, 760 mg, yield 46.1%).

[0138] 15 mL of N,N-dimethylformamide, compound 17-4 (750 mg, 1.00 eq), and sodium hydride (356.85 mg, 60% purity, 2.50 eq) were successively added to a 50 mL three-necked flask and reacted at room temperature for 30 minutes. Methyl iodide (1.01 g, 2.00 eq) was added to the reaction solution in several portions at 0 °C and reacted at room temperature for 2 hours. 150 mL of ice water was added to the reaction solution, and it 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%).

[0139] 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 successively added to a 200 mL hydrogenation flask and reacted with H2 at 70 °C and 50 Psi for 16 hours. It was filtered and concentrated to dryness to obtain compound 17-6 (white solid, 1.62 g, crude product).

[0140] 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) were successively added to a 50 mL single-necked flask. It was reacted at room temperature for 2 hours. It was concentrated to dryness. The crude product was purified by preparative chromatography to obtain compound 17-7 (yellow oil, 297 mg, yield 25.4%).

[0141] 4 mL of tetrahydrofuran, compound 1-2 (78.33 mg, 1.00 eq), and diisopropylethylamine (141.5 mg, 1.10 eq) were successively added to a 50 mL three-necked flask and reacted at room temperature for 15 min. Carbonyldiimidazole (195.39 mg, 1.10 eq) was added to the reaction solution at 0 °C and reacted at 0 °C for 1 hour. After detecting the reaction intermediate, compound 17-7 (244 mg, 1.00 eq) was added to the reaction solution and reacted at room temperature for 12 hours. 20 mL of water was added to the reaction solution, and extraction was performed twice with 20 mL of dichloromethane each time. The organic phases were combined, washed with 20 mL of saturated brine, dried, concentrated to dryness, and a crude product was obtained. The crude product was purified by preparative chromatography to obtain compound 17 (white solid, 145 mg, yield 27.2%). 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 2.5 Hz, 1H), 7.59 (s, 1H), 7.44 - 7.37 (m, 3H), 7.33 (s, 2H), 6.89 (s, 1H), 4.52 (d, J = 5.3 Hz, 2H), 4.49 - 4.43 (m, 1H), 4.41 (s, 2H), 3.84 (s, 3H), 3.28 (br d, J = 11.6 Hz, 2H), 2.58 (s, 3H), 2.56 - 2.48 (m, 2H), 2.17 (dq, J = 3.2, 12.6 Hz, 2H), 1.75 (br d, J = 11.6 Hz, 2H). MS (ESI) m / z : 478.2 [M+1].

[0142] Example 14 TIFF2025525188000103.tif54170

[0143] At zero degrees, 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), stirred for 10 minutes, and then sodium nitrite dissolved in 81 mL of water at zero degrees was slowly added dropwise while maintaining the temperature control at 5 - 10°C constantly and keeping it warm in an ice-water bath and stirring for 3 hours. Under the ice-water bath, 50 mL of aqueous ammonia was added to the reaction solution, the reaction solution was filtered, the filter cake was washed with 100 mL of water, and then concentrated to dryness to obtain compound 30-2 (yellow solid, 9.0 g, yield: 89.6%).

[0144] 40 mL of dimethyl sulfoxide, compound 30-2 (4.0 g, 1.00 eq), iodoethane (4.93 g, 1.50 eq), and cesium carbonate (10.2 g, 2.00 eq) were sequentially added 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 it was extracted three times with 100 mL portions of ethyl acetate. The organic phases were combined and extracted twice with 100 mL portions of saturated brine. The organic phase was dried and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 25-3 (yellow solid, 1.3 g, yield 24.6%).

[0145] 12 mL of N-methylpyrrolidone, compound 30-3 (1.20 g, 1.00 eq), and zinc cyanide (229 mg, 0.55 eq) were sequentially added to a 100 mL three-necked flask. Under a nitrogen gas atmosphere, tetrakis(triphenylphosphine)palladium was added, and it was kept warm at 130°C and stirred for 12 hours. 100 mL of water was added to the reaction solution, and it was extracted three times with 100 mL portions of ethyl acetate. The organic phases were combined and extracted twice with 50 mL portions of saturated brine. The organic phase was dried and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 30-4 (white solid, 400 mg, yield 47.5%).

[0146] 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 sequentially added to a 100 mL reinforced bottle under an argon gas atmosphere. The mixture was kept warm at 50 Psi and 70 °C and stirred for 12 hours under a hydrogen gas catalyst. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 30-5 (yellow oil, 60 mg, yield 27.7%).

[0147] 0.5 mL of ethyl acetate, compound 30-5 (100 mg, 1.00 eq), and HCl / EtOAc (1 mL) were sequentially added to a 10 mL single-necked flask. The mixture was kept warm at 25 °C and stirred for 6 hours. The reaction solution was concentrated to dryness to obtain crude compound 30-6 (20 mg of yellow solid), which was used directly in the next reaction.

[0148] 1 mL of tetrahydrofuran, compound 30-6 (20 mg, 1.00 eq), and diisopropylethylamine (10.7 mg, 1.00 eq) were sequentially added to a 10 mL single-necked flask. After stirring for 15 minutes under a nitrogen gas atmosphere, the temperature was lowered to 0 °C in an ice water bath. Carbonyldiimidazole (14.8 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Compound 1-2 (20 mg, 1.00 eq) was dissolved in 0.5 mL of tetrahydrofuran and then added to the reaction solution. The mixture was kept warm at 25 °C and stirred for 12 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted twice with 5 mL portions of ethyl acetate. The organic phases were combined, extracted twice with 5 mL portions of saturated brine, the organic phase was dried, and concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation to obtain compound 30 (white solid, 10 mg, yield 24.3%). 11H NMR (400 MHz, CDCl3) δ 8.35 (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 = 8.6 Hz, 2H), 4.39 (s, 2H), 4.27 (br s, 1H), 4.23 (d, J = 5.9 Hz, 2H), 3.10 (br d, J = 11.6 Hz, 2H), 2.44 (s, 3H), 2.32 (br t, J = 11.4 Hz, 2H), 2.14 - 2.13 (m, 1H), 2.07 (br d, J = 11.4 Hz, 1H), 1.67 (br d, J = 11.9 Hz, 2H). MS (ESI) m / z : 490.2 [M+1].

[0149] Example 15 TIFF2025525188000104.tif163170

[0150] Dichloromethane (30 mL), compound 29-1 (2.80 g, 1.00 eq) and p-fluorobenzaldehyde (4.92 g, 1.00 eq) were sequentially added to a 100 mL three-necked flask at room temperature and stirred uniformly. Further, sodium triacetoxyborohydride (9.56 g, 2.00 eq) was added to the reaction solution, and the reaction was carried out with stirring at room temperature for 16 hours. 30 mL of saturated sodium bicarbonate solution was added to the reaction solution, and stirring was continued for 10 minutes. The mixture was allowed to stand for phase separation, the organic phase was separated, and the aqueous phase was extracted three times with 15 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. First, the crude product was purified by column chromatography and further purified by preparative separation to obtain compound 29-2 (colorless oil, 1.20 g).

[0151] Add tetrahydrofuran (15 mL) and compound 5-1 (1.04 g, 1.00 eq, HCl) to a 100 mL three-necked flask in sequence. Under nitrogen gas conditions, add diisopropylethylamine (1.11 g, 2.00 eq) dropwise, and stir at 20 °C for 15 minutes. Further cool the temperature to 0 °C, and add carbonyldiimidazole (765 mg, 1.10 eq) to the reaction solution in several portions. When the reaction was detected, the reaction of compound 5-1 was completed. Dissolve compound 29-2 (1.40 g, 1.00 eq) in tetrahydrofuran (5 mL), slowly add it dropwise to the reaction solution, keep the temperature at 25 °C and stir for 12 hours. Add 100 mL of water to the reaction solution, and extract it three times with 50 mL of ethyl acetate each time. Combine the organic phases, wash the organic phase with 80 mL of saturated brine, dry the organic phase, concentrate it to dryness, and obtain a crude product. Purify the crude product by column chromatography to obtain compound 29-3 (colorless oily substance, 966 mg, yield 38.8%).

[0152] Add anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) to a 50 mL single-necked flask in sequence. Keep the temperature at 25 °C and stir for 20 minutes. Concentrate and dry the reaction solution to obtain crude compound 29-4 (pale yellow oily substance, 850 mg, yield 91.4%).

[0153] 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 sequentially added to a 50 mL one-neck flask. The mixture was kept at 25 °C and stirred for 12 h. 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, washed with 40 mL of saturated brine, dried, concentrated to dryness, and a crude product was obtained. First, the crude product was purified by column chromatography, and further separated by SFC (column: DAICEL CHIRALCEL OX (250 mm × 50 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O in EtOH)], B%: 25% - 25%) to obtain Compound 68A (retention time 1.457 min, 159 mg of white solid, yield 23.1%), Compound 68B (retention time 1.707 min, 163 mg of white solid, yield 24.4%), Compound 68C (retention time 1.935 min, 142 mg of white solid, yield 21.2%), and Compound 68D (retention time 2.356 min, 133 mg of white solid, yield 19.8%).

[0154] Compound 68A: 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 2.3, 8.5 Hz, 1H), 7.17 - 7.08 (m, 2H), 7.00 (br t, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 5.17 - 4.99 (m, 1H), 4.94 (br t, J = 5.1 Hz, 1H), 4.71 (d, J = 8.6 Hz, 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 = 11.8 Hz, 1H). MS(ESI) m / z : 473.2[M+1].

[0155] Compound 68B: 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 2.3, 8.4 Hz, 1H), 7.15 (dd, J = 5.3, 8.4 Hz, 2H), 7.06 - 6.98 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 5.16 - 4.97 (m, 1H), 4.85 (br t, J = 5.1 Hz, 1H), 4.76 - 4.70 (m, 2H), 4.52 (br d, J= 13.3 Hz, 2H), 4.32 - 4.19 (m, 2H), 3.64 (br t, J = 11.8 Hz, 1H), 3.52 (br d, J = 10.8 Hz, 1H), 3.08 - 2.80 (m, 2H), 2.74 (s, 3H), 2.59 - 2.44 (m, 1H), 1.78 (br d, J = 11.5 Hz, 1H). MS(ESI) m / z : 473.2[M+1].

[0156] Compound 68C: 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 2.3, 8.5 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.02 (br t, J= 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 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].

[0157] Compound 68D: 11H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 2.3, 8.4 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.06 - 6.98 (m, 2H), 6.77 (d, J= 8.5 Hz, 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].

[0158] Example 16 TIFF2025525188000105.tif87170

[0159] 30 mL of methanol, compound 50-1 (2.00 g, 1.00 eq), and ammonium acetate (1.37 g, 2.00 eq) were sequentially added to a 250 mL three-necked flask, stirred at 20 °C for 1 hour, sodium cyanoborohydride (1.12 g, 2.00 eq) was added to the reaction solution, and then stirred at 60 °C for 12 hours until the reaction was complete. The reaction solution 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%).

[0160] 20 mL of dichloromethane, compound 50-2 (1.80 g, 1.00 eq), p-pyridinecarboxaldehyde (999 mg, 1.00 eq) were sequentially added to a 100 mL three-necked flask, protected with nitrogen gas, and stirred at 30 °C for 6 hours. Sodium triacetoxyborohydride (3.37 g, 2.00 eq) was added, and stirring was continued at 30 °C for 13 hours. The temperature was lowered to room temperature, water (10 mL) was added to quench, and extraction was performed twice with 10 mL of dichloromethane each time. The organic phases were combined, the organic phase was washed twice with 10 mL of saturated brine, the organic phase was dried, concentrated to dryness, and a crude product was obtained. Compound 50-3 (yellow liquid, 1.30 g) was obtained from the crude product by high-performance liquid separation.

[0161] 15 mL of tetrahydrofuran, 1-trifluoroethoxy-4-pyridinemethylamine (800 mg, 1.00 eq), N,N-diisopropylethylamine (1.00 g, 2.00 eq) were sequentially added to a 100 mL round-bottom flask, and the reaction was carried out at 20 °C for 15 minutes under nitrogen gas conditions. The reaction was cooled to 0 °C, carbonyldiimidazole (754 mg, 1.20 eq) was added, and stirring was continued for 0.5 hour. Then, a solution of 10 mL of tetrahydrofuran and compound 50-3 (1.30 g, 1.00 eq) was added, and the reaction was heated to 80 °C and stirred for 24 hours until the reaction was complete. 20 mL of water was added to the reaction solution, and extraction was performed twice with 30 mL of ethyl acetate each time. The organic phases were combined, the organic phase was washed with 60 mL of saturated brine, the organic phase was dried, concentrated to dryness, and a crude product was obtained. The crude product was purified by high-performance liquid separation to obtain compound 50-4 (yellow liquid, 900 mg, yield 40.9%).

[0162] 8 mL of dichloromethane, compound 50-4 (900 mg, 1.00 eq), trifluoroacetic acid (6.14 g, 33.9 eq) were sequentially added to a 100 mL three-necked flask, and the reaction was carried out at 10 °C for 1 hour under nitrogen gas protection. The reaction solution was concentrated to dryness to obtain compound 50-5 (yellow liquid, 910 mg, trifluoroacetate crude product), which was used directly in the next step.

[0163] 20 mL of dichloromethane, compound 50-5 (950 mg, 1.00 eq, trifluoroacetate), formaldehyde solution (200 mg, 1.51 eq), and sodium cyanoborohydride (205 mg, 2.00 eq) were successively added to a 100 mL three-necked flask and stirred at 25 °C for 13 h. The reaction was cooled to 0 °C, quenched by adding an aqueous sodium bicarbonate solution (20 mL), and extracted twice with 30 mL of dichloromethane each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by high-performance liquid chromatography and chiral preparation (column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O IPA)], B%: 25% - 25%) to obtain compound 50A (retention time 1.259 min, 90.0 mg of yellow liquid, yield 11.2%) and 50B (retention time 1.460 min, 120 mg of yellow liquid, yield 14.8%).

[0164] Compound 50A: 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.60 (dd, J1 = 2.4 Hz J2 = 8.4 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.25 - 7.23 (m, 1H), 6.82 (d, J = 8.8 Hz, 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].

[0165] Compound 50B: 11H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.60 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.26 - 7.23 (m, 1H), 6.82 (d, J = 8.8 Hz, 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].

[0166] Example 17 Using the same synthesis and resolution methods as in Example 16, compounds 49A / 49B and compounds 83A / 83B were obtained. The following table lists the characterization data of compounds 49A / 49B and 83A / 83B. TIFF2025525188000106.tif220170

[0167] Example 18 TIFF2025525188000107.tif88170

[0168] Dichloromethane (110 mL), compound 85-1 (22.0 g, 1.00 eq), and p-fluorophenethylamine (14.0 g, 1.10 eq) were sequentially added to a 250 mL three-necked flask and stirred at 20 °C for 6 hours. After complete reaction, sodium triacetoxyborohydride (32.3 g, 1.50 eq) was added, and stirring was continued at 20 °C for 12 hours. After complete reaction, 80 mL of water was added to the reaction solution, and extraction was performed twice with 80 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and crude product 85-2 (yellow oil, 33.5 g, crude product) was obtained.

[0169] 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 sequentially added to a 1 L three-necked flask and stirred at 20 °C for 1 hour. After complete reaction, washing was performed twice with 400 mL of water each time. The organic phases were combined, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 85-3 (yellow oil, 37.5 g, yield 69.2%).

[0170] Dichloromethane (187 mL), compound 85-3 (37.5 g, 1.00 eq), and trifluoroacetic acid (33.0 mL, 5.00 eq) were sequentially added to a 500 mL three-necked flask and stirred at 20 °C for 12 hours. After complete reaction, the reaction solution was directly concentrated to dryness to obtain crude compound 85-4 (yellow oil, 28.6 g, yield 100%).

[0171] Tetrahydrofuran (286 mL), compound 85-4 (28.6 g, 1.00 eq), aqueous formaldehyde solution (33.1 mL, 37% purity, 5.00 eq) were sequentially added to a 500 mL three-necked flask. Sodium cyanoborohydride (11.2 g, 2.00 eq) was added in several portions, and the mixture was stirred at 20 °C for 1.5 h. After the reaction was complete, the pH value was adjusted to 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted twice with 100 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated to dryness to obtain crude product 85-5 (yellow oil, 34.5 g, yield 87.7%).

[0172] Water (217 mL), compound 85-5 (32.5 g, 1.00 eq), concentrated hydrochloric acid (325 mL, 12.0 M, 40.4 eq) were sequentially added to a 1 L three-necked flask, and the mixture was stirred at 100 °C for 12 h. After the reaction was complete, the pH value was adjusted to 8 - 9 with 156 g of sodium hydroxide, and the mixture was extracted twice with 400 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated to dryness to obtain a crude product. The crude product was subjected to chiral separation to obtain compound 85-6 (yellow oil, 2.19 g, crude product).

[0173] (1-Methyl-1H-indol-5-yl)methanamine (333 mg, 1.00 eq) was added to 5 mL of tetrahydrofuran, and diisopropylethylamine (672 mg, 906 μL, 2.50 eq) was added. The reaction mixture was cooled to 0 °C, and carbonyldiimidazole (371 mg, 1.10 eq) was added, and stirring was continued for 1 hour. Compound 85-6 (500 mg, 1.00 eq) dissolved in 3 mL of tetrahydrofuran was added, the reaction mixture was heated to 70 °C, and reacted for 12 hours. After complete reaction, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by preparative separation to obtain compound 85 (white solid, 760 mg, yield 85.6%). Further, by SFC separation (column: DAICEL CHIRALCEL OX (250 mm × 50 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O EtOH)], B%: 25% - 25%), 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%) were obtained.

[0174] Compound 85A: 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.22 - 7.15 (m, 3H), 7.04 (d, J = 3.0 Hz, 1H), 6.98 (t, J = 8.6 Hz, 2H), 6.95 - 6.91 (m, 1H), 6.39 (d, J= 2.9 Hz, 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 = 11.9 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.40 (br d, J = 13.3 Hz, 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].

[0175] Compound 85B: 1 H NMR (400 MHz, CDCl3) δ 7.24 (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 = 2.9 Hz, 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].

[0176] Example 19 Compound 86A, Compound 86B, Compound 87A / Compound 87B were obtained using the same synthesis method and resolution method as in Example 18. The following table lists the characterization data of Compounds 86A, 86B, 87A, and 87B. TIFF2025525188000108.tif231170

[0177] Example 20 TIFF2025525188000109.tif75170

[0178] 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. Next, an aqueous solution of sodium nitrite (2.89 g, 41.88 mmol, 1 eq) in water (10 mL) was added, and the reaction was carried out with stirring 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, yield 43.5%) as a white solid.

[0179] Trifluoroethyl triflate (10.16 g, 43.75 mmol, 3 eq) was added to a mixed solution 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). 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 aqueous sodium chloride 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.

[0180] 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), [N-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (93.02 mg, 0.128 mmol, 0.05 eq) were dissolved in dioxane (10 mL) and water (2 mL), and the mixture was purged with nitrogen gas three times. The reaction was then carried out with stirring at 80 °C under a nitrogen gas atmosphere 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, 84.5% yield) as a pale yellow solid.

[0181] 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). Subsequently, the mixture was stirred at 20 °C for 1 hour, and then 3-fluoro-N-[(4-fluorophenyl)methyl]-1-methyl-piperidin-4-amine (489.07 mg, 2.04 mmol, 2.2 eq) was added at 20 °C. The resulting mixture was stirred at 20 °C for an additional 1 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 then by SFC resolution (column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 μm), mobile phase: [A: CO2, B: (0.1% NH3H2O MeOH)], B%: 15% - 15%) to give compound 88A as a white solid (retention time 1.025 min, 123 mg, yield 26.3%) and compound 88B as a white solid (retention time 1.231 min, 116 mg, yield 25.1%).

[0182] Compound 88A: 11H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.64 (m, 1H), 7.25 - 7.15 (m, 2H), 7.15 - 7.05 (m, 2H), 6.99 (t, J = 5.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.92 (q, J = 9.2 Hz, 2H), 4.82 - 4.59 (m, 2H), 4.41 (d, J= 17.6 Hz, 1H), 4.29 - 4.08 (m, 3H), 2.97 (t, J = 12.0 Hz, 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].

[0183] Compound 88B: 1 1H NMR (400 MHz, DMSO-d6) δ 7.70 (t, J = 8.8 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.14 - 7.04 (m, 2H), 7.03 - 6.93 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.92 (q, J = 8.8 Hz, 2H), 4.82 - 4.58 (m, 2H), 4.41 (d, J= 18.0 Hz, 1H), 4.30 - 4.05 (m, 3H), 2.97 (t, J = 11.6 Hz, 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].

[0184] Example 21 TIFF2025525188000110.tif47170

[0185] Compound 89A (retention time 0.994 min, white solid) and compound 89B (retention time 1.055 min, white solid) were obtained using the same synthesis method and separation method as in Example 20.

[0186] Compound 89A: 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 3.3 Hz, 1H), 7.56 (s, 1H), 7.14 - 7.07 (m, 3H), 6.96 (br t, J= 8.5 Hz, 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, 12.8 Hz, 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].

[0187] Compound 89B: 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 3.3 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.23 - 7.11 (m, 2H), 7.09 - 6.95 (m, 3H), 5.01 - 4.81 (m, 1H), 4.70 (s, 1H), 4.66 - 4.42 (m, 3H), 4.33 - 4.21 (m, 3H), 3.39 (t, J = 7.1 Hz, 1H), 3.26 - 3.05 (m, 3H), 3.02 (br dd, J= 1.9, 3.9 Hz, 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].

[0188] Example 22 TIFF2025525188000111.tif81170

[0189] Add tetrahydrofuran (15 mL) and compound 5-1 (1.04 g, 1.00 eq, HCl) to a 100 mL three-necked flask in sequence. Under nitrogen gas conditions, add diisopropylethylamine (1.11 g, 2.00 eq) dropwise, and stir at 20 °C for 15 minutes. Further cool down to 0 °C, and add N,N'-carbonyldiimidazole (765 mg, 1.10 eq) to the reaction solution in several portions. When the reaction was detected, the reaction of compound 5-1 was completed. Dissolve compound 68-1 (1.40 g, 1.00 eq) in tetrahydrofuran (5 mL), slowly add it dropwise to the reaction solution, keep the temperature at 25 °C and stir for 12 hours. Add 100 mL of water to the reaction solution, and extract it 3 times with 50 mL of ethyl acetate each time. Combine the organic phases, wash the organic phase with 80 mL of saturated brine, dry the organic phase, concentrate it to dryness, and obtain a crude product. Purify the crude product by column chromatography to obtain compound 68-2 (colorless oily, 966 mg, yield 38.8%).

[0190] Add anhydrous dichloromethane (27 mL), compound 68-2 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) to a 50 mL single-necked flask in sequence. Keep the temperature at 25 °C and stir for 20 minutes. Concentrate the reaction solution to dryness to obtain crude compound 68-3 (light yellow oily substance, 850 mg, yield 91.4%).

[0191] 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 sequentially added to a 50 mL one-neck flask. The mixture was kept at 25 °C and stirred 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, washed with 40 mL of saturated brine, dried, concentrated to dryness, 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 (400 MHz, CDCl3) δ 7.87 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 2.3, 8.5 Hz, 1H), 7.17 - 7.08 (m, 2H), 7.00 (br t, J= 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 5.17 - 4.99 (m, 1H), 4.94 (br t, J = 5.1 Hz, 1H), 4.71 (d, J = 8.6 Hz, 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 = 11.8 Hz, 1H). MS(ESI) m / z : 473.2[M+1].

[0192] Test Example 1. 5-HT 2A Receptor inverse agonist activity test 1.1 Experimental materials: Cell line: adherent cell NIH3T3-5-HT 2A R Cell medium: DMEM + 10% FBS (purchased from GBICO) Cell culture plate: white wall transparent bottom 96-well plate (purchased from Perkin Elmer) Detection kit: Bright-Glo 商標Luciferase (purchased from Promega) Detection instrument: BioTek multifunctional microplate reader 1.2 Test drugs Pimavanserin: purchased from MCE Other compounds: prepared according to the above examples 1.3 Experimental method: NIH3T3-5HT 2A R cells in the logarithmic growth phase were inoculated into a white-wall transparent-bottom 96-well plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and the next day, the test compound was added to the cells. The highest concentration of the test compound was 10 μM, and it was diluted to 9 concentrations with a 3.16-fold concentration gradient in PBS, and duplicate wells were set up for each concentration. PBS was used as the negative control group, and pimavanserin at the same concentration was used as the positive control group. After adding the drug, the cells were continuously cultured in a 37°C, 5% CO2 incubator for 120 h. On the 6th day, an equal volume of Bright-Glo 商標 Luciferase reagent was added to the cells, cultured in the dark at room temperature for 20 min, shaken with a plate shaker every 5 min, the luminescence intensity was detected with a microplate reader, the cell inhibition rate was calculated, the data was processed with GraphPad Prism 7.0, a cell inhibition rate curve was obtained, and IC 50 was calculated, and the test results are shown in Table 1. Cell inhibition rate (%) = [100 - (Lum test drug - Lum culture medium) / (Lum cell control - Lum culture medium) × 100]%

[0193] Test Example 2. hERG inhibition activity 1. Test materials and equipment 1.1 Positive control compound Name: Cisapride 1.2 Solvent Name: DMSO (dimethyl sulfoxide) 1.3 Cells Species & strain: CHO-hERG cell line (Chinese hamster ovary cells stably expressing the hERG channel) Medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, 100 μg / mL Hygromycin B Culture conditions: 5% CO2, incubator at 37°C Cryopreservation conditions: liquid nitrogen 1.4 Experimental equipment Patch clamp amplifier (Axoclamp 200B, Multiclamp 700B, Axon, USA) Digital - analog converter (DigiData 1440A, DigiData 1550B, Axon, USA) Inverted microscope (IX51, IX71, Olympus, Japan) High - speed administration system (RSC - 200, Bio - Logic, France) Micromanipulator (MX7600R, Syskiyou, USA) Electrode puller (P - 97, Sutter, USA) Glass electrode (BF150 - 86 - 10, Sutter, USA) Vibration - isolation table and shielding net (63 - 534, TMC, USA) Data acquisition and analysis software (pClamp 10, Axon, USA) Carbon dioxide incubator (HERAcell 150i, Thermo, USA) Biological safety cabinet (MODEL 1384, Thermo, USA) Pure water meter (Milli Q, Millipore, USA)

[0194] 2. Experimental methods 2.1 Cell culture and treatment CHO cells stably expressing hERG were cultured in a 35 - mm - diameter cell culture dish, placed in an incubator at 37°C and 5% CO2, and sub - cultured at a ratio of 1:5 every 48 hours. On the day of the test, the cell culture medium was aspirated, the cells were rinsed once with extracellular fluid, then 0.25% trypsin - EDTA (Invitrogen) solution was added and digested at room temperature for 3 - 5 minutes. The digestive solution was aspirated, the cells were resuspended with extracellular fluid, and transferred to an experimental dish for electrophysiological recording for use.

[0195] 2.2 Preparation of Compounds On the day of the test, the compound was diluted with DMSO to an intermediate concentration. 10 μL of the compound at the intermediate concentration was taken and transferred to 4990 μL of extracellular fluid, and diluted 500-fold to obtain the final concentration required for the test. Preparation of the positive control compound Cisapride: 10 μL of a 150 μM Cisapride DMSO stock solution was taken and transferred to 4990 μL of extracellular fluid, and diluted 500-fold to obtain the final concentration of 300 nM required for the test.

[0196] 2.3 Electrophysiological Recording Process In Chinese Hamster Ovary (CHO) cells stably expressing the hERG potassium channel, the hERG potassium channel current was recorded at room temperature using the whole-cell patch-clamp technique. The glass microelectrode was pulled out with a microelectrode puller from a glass electrode blank (BF150-86-10, Sutter), and the tip resistance after injecting the electrode internal solution was about 2 - 5 MΩ. The glass microelectrode can be connected to the patch-clamp amplifier by inserting it into the amplifier probe. The clamp voltage and data recording were controlled, recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and a single 2 s depolarizing voltage from -80 mV to +20 mV was applied to induce the hERG potassium current (I hERG ), then repolarized to -50 mV, lasted for 1 s, and then returned to -80 mV. This voltage stimulation was applied every 10 s. After confirming that the hERG potassium current was stable (after 1 minute), the administration process was started. The compound was administered for at least 1 minute per test concentration, and at least 2 cells (n≥2) were tested per concentration.

[0197] 2.4 Data Processing and Analysis Data analysis was performed using pClamp 10 and GraphPad Prism 5.0 software. The calculation formula for the degree of inhibition of hERG potassium current at different compound concentrations (the peak of the hERG tail current induced at -50 mV) is as follows. Inhibition% = [1 - (I / Io)] × 100% Among them, Inhibition% represents the inhibition rate of hERG potassium current by the compound, and I and Io represent the amplitudes of hERG potassium current after and before administration, respectively. Using GraphPad Prism 5 software, the compound IC 50 was calculated by fitting the following formula, and the test results are shown in Table 1. Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - X) × HillSlope)) Among them, X is the Log value of the test article detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum inhibition percentage and the maximum inhibition percentage, respectively.

[0198] 3. Test Results As can be seen from the results of TIFF2025525188000112.tif251170, the 5-HT 2A inverse agonistic activities of the multiple compounds of the present invention are all superior to pimavanserin and have lower cardiotoxicity.

[0199] Test Example 3. In Vitro Stability Evaluation of Liver Microsomes 1. Solution Preparation 1) Preparation of the test article working solution: Dilute the test article to 100 μM with methanol, 2) Preparation of the liver microsome working solution: Dilute the liver microsomes to 0.56 mg / mL with 100 mM phosphate buffer, 3) Preparation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH, dilute it to 20 mM with phosphate buffer, and further add an equal volume of 60 mM MgCl2 solution, 4) Preparation of the stop solution: As the stop solution containing the internal standard substance, dilute tolbutamide to 20 ng / mL with acetonitrile.

[0200] 2. Incubation Process 1) Prepare adsorption-resistant EP tubes for incubation, label the species, test articles, control articles (testosterone, dextromethorphan), time points (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc., 2) Add 2 μL of the test article or control article working solution and 178 μL of the liver microsome working solution to each tube. Add 2 μL of acetonitrile instead of the test article to the Blank tube, and pre-incubate in a 37°C water bath for about 10 min. Prepare three parallel samples for each, 3) After the pre-incubation, except for the 0 min and NCF60 samples, add 20 μL of the NADPH working solution to each tube to initiate the reaction. Add 20 μL of the phosphate buffer (containing 30 mM MgCl2) to the NCF60 tube. The final concentration of the test article or control article in the incubation system is 1 μM, the final concentration of the liver microsome is 0.5 mg / mL, the final concentration of NADPH is 1 mM, and the final concentration of MgCl2 is 3 mM. 4) First, add the 0 min sample to 600 μL of the stop solution, then add the NADPH working solution. After incubating each sample for the corresponding time, add 600 μL of the stop solution to stop the reaction. 5) After stopping the reaction of each sample, vortex for 30 s, then centrifuge at 13500 rpm for 10 min. Take 100 μL of the supernatant and put it into an EP tube. Add 100 μL of Milli-Q water, vortex to mix evenly, and then analyze by LC-MS / MS. 6) Use testosterone and dextromethorphan as positive control articles and detect the stability and reliability of the system under the same conditions.

[0201] 3. Data Analysis Measure the remaining percentage of the test article after 60 min and show the test results in Table 2. As can be seen from the results of TIFF2025525188000113.tif203170, the multiple compounds of the present invention have better stability than pimavanserin in dog and human liver microsomes in vitro and have better drug discovery potential.

[0202] Test Example 4. In Vivo Pharmacodynamic Evaluation 1. Experimental Protocol Based on the in vivo pharmacokinetic data of a series of compounds, after a single intragastric administration to SD rats, the drug reaches C at 1.0 - 1.5 h. max At this time point, 4-iodo-2,5-dimethoxy-A-methyl-phenylethylamine hydrochloride (i.e., DOI, a 5-HT 2A receptor agonist) was intraperitoneally injected into SD rats at a dose of 2.5 mg / kg to induce and model the head-twitch behavior of SD rats. The low-dose group, medium-dose group, and high-dose group of Compound 68A were set corresponding to 0.22, 0.66, and 2.0 mg / kg, respectively. Pimavanserin tartrate (Pim-T) was 0.7 mg / kg. The administration routes of Compound 68A and Pim-T were both oral intragastric administration.

[0203] 2. Experiment Grouping and Administration The compound was dissolved in DMSO:20% solutol (5%:95%). SD rats (200 g - 250 g) were randomly divided into 6 groups according to body weight: a solvent control (Control) group, a model (Model) group, a 0.7 mg / kg group of Pim-T, and 0.22, 0.66, and 2.0 mg / kg groups of Compound 68A, with 7 animals in each group. The animal grouping and administration information are shown in detail in Table 3. Note in TIFF2025525188000114.tif52170: The dosages of Pim-T (pimavanserin tartrate) and Compound 68A were both calculated as free bases.

[0204] 3. Experimental Operations Rats were fasted at 17:00 on the day before the test. On the test day, the animals were acclimated in the test laboratory for at least 1 h. Rats in each group were administered a single dose intragastrically at the doses shown in Table 3. One hour after administration, except for the Control group, DOI at 2.5 mg / kg was intraperitoneally injected into all other groups, and an equal volume of physiological saline was administered to the Control group. The behavior of the rats was observed immediately after injection. The observer performed a random double-blind test to eliminate interference due to artificial factors. The number of head shakes of the rats was observed and recorded within 1.0 - 1.5 h after administration of the rats. The test data are shown as mean ± standard error (Mean ± SEM). The differences between groups at each time point were compared using SPSS statistics 20.0 software and one-way analysis of variance ANOVA. All tests were two-sided tests, and P < 0.05 indicated statistical significance.

[0205] 4. Data analysis Compared with the Control group, the number of head shakes of the rats in the Model group was significantly increased (P < 0.05). Compared with the Model group, the number of head shakes of the rats in the 0.7 mg / kg group of Pim-T was significantly decreased (P < 0.05), and the number of head shakes of the rats in the 0.22, 0.66, and 2.0 mg / kg groups of Compound 68A was significantly decreased (P < 0.01). At equimolar doses, the number of head shakes of the rats in the 0.66 mg / kg group of Compound 68A was lower than that in the 0.7 mg / kg group of Pim-T. The specific results are shown in Table 4 and Figure 1. TIFF2025525188000115.tif54170 Note: Compared with the Control group, # P < 0.05, compared with the Model group, *P < 0.05, **P < 0.01. As can be seen from the results, within 1.0 - 1.5 h after a single intragastric administration to SD rats, Compound 68A can significantly inhibit the number of head shakes of rats within the dose range of 0.22 - 2.0 mg / kg, and the starting dose of action is 0.22 mg / kg. At equimolar doses, Compound 68A was superior to Pim-T in pharmacodynamic effects.

[0206] Test Example 5. Evaluation of in vivo tissue distribution 1. Experimental protocol Compound 68A was administered intragastrically once to Sprague-Dawley rats (200 g - 250 g) at a dose of 11 mg / kg. Plasma and brain, heart, liver, and lung tissues were collected at 0.25 h, 1 h, and 6 h after administration, and there were 3 animals at each time point.

[0207] 2. Experimental operation The rats were fasted at around 18:00 on the day before the experiment, and were allowed to drink water freely during that time. On the day of the test, the rats were weighed, randomly divided into 3 groups according to their body weight, and one animal group was assigned to each time point. The compound was dissolved in DMSO:20% solutol (5%:95%), and Compound 68A was administered intragastrically once to the rats at a dose of 11 mg / kg, a dosing volume of 5 mL / kg, and a drug solution concentration of 2.2 mg / mL. At each sampling time point, the animals were anesthetized with ether, about 1 mL of blood was taken from the heart, put into a heparinized EP tube, centrifuged at 10000 rpm for 10 min to separate the plasma. Then, after perfusing the heart to remove the blood, the brain, heart, liver, and lung tissues were collected, the blood was completely blotted with filter paper, weighed separately, wrapped in paper after weighing, and stored at -80 °C in preparation for measurement.

[0208] 3. Sample measurement and data analysis After pretreatment, LC-MS / MS analysis was performed on plasma samples and each tissue homogenate (the homogenate of each tissue was prepared at a weight-to-volume ratio of 1:4), and the concentrations of the test substance in plasma and each tissue were measured. The experimental data were shown as Mean ± Standard Deviation (Mean ± SD), and the specific results are shown in Table 5. As can be seen from the results of TIFF2025525188000116.tif122170, at 0.25 h, 1 h, and 6 h after a single intragastric administration to Sprague-Dawley rats, the concentrations of Compound 68A in the tissues were all higher than that in plasma, indicating that Compound 68A has good permeability. In particular, the distribution in the brain tissue was high, the brain-blood ratio could reach 9.51 - 10.5, and the brain concentration was stable between 0.25 - 6 h.

Claims

1. A compound represented by formula (A), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein Among them, R 1 is selected from halogen, Ring B is R 2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two Rs linked to the same carbon atom 3 form a cycloalkyl group with the carbon atom to which they are linked and C 3-6 ​ Ring A is X is NR 6c or selected from S, X 1 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 each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group, R 5 is -OR 5 ' selected from, R 5 ' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 alkyl group optionally substituted with C 3-6 cycloalkyl C 1-3 alkyl group selected from, n is selected from 0, 1, 2, 3 the compound, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

2. A compound represented by formula (I), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen, Ring B is R 2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or two Rs linked to the same carbon atom 3 form a cycloalkyl group with the carbon atom to which they are linked and C 3-6 ​ Ring A is X is NR 6c or selected from S, R 4a 、R 4b 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, and a C 1-3 haloalkyl group. R 5 is -OR 5 ', C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkyl C 1-3 selected from alkyl groups, n is selected from 0, 1, 2, 3 the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

3. A compound represented by formula (II), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen and Ring B is R 2 is independently selected from a hydrogen atom, C 1-3 alkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two Rs linked to the same carbon atom 3 form a cycloalkyl group with the carbon atom to which they are linked and C 3-6 ​ Ring A is X is NR 6c or selected from S, R 4a 、R 4b 、R 4c 、R 6a 、R 6b 、R 6c 、R 7a 、R 7b 、R 7c is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, and a C 1-3 haloalkyl group, respectively R 5 is -OR 5 ' selected from, R 5 ' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 alkyl group optionally substituted with C 3-6 cycloalkyl C 1-3 selected from alkyl groups, n is selected from 0, 1, 2, 3 the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

4. A compound represented by formula (IIA), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen, Ring B is R 2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, respectively R 4a and R 4b are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, and a C 1-3 haloalkyl group. R 5 is -OR 5 ' selected from, R 5 ' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 selected from halo cycloalkyl groups, n is selected from 0, 1, 2, 3 the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

5. A compound represented by formula (III), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen and Ring B is R 2 is independently selected from a hydrogen atom, a C 1-3 alkyl group, a C 3-6 cycloalkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or two Rs linked to the same carbon atom 3 form a cycloalkyl group with the carbon atom to which they are linked and C 3-6 and R 4a and R 4b are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group R 5 is -OR 5 ' selected from, R 5 ' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkyl C 1-3 selected from alkyl groups, n is selected from 0, 1, 2, 3 the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

6. Ring B is R 3 is selected from halogen or two Rs linked to the same carbon atom 3 and the carbon atom to which they are linked and C 3-6 form a cycloalkyl group, and R 3 is preferably F or two Rs linked to the same carbon atom 3 form a cyclopropyl group with the carbon atom to which they are linked n is 1 or 2 the compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

7. R 5 ' is C 1-6 a haloalkyl group, C 3-6 a cycloalkyl group, C 3-6 a halocycloalkyl group, C 3-6 cycloalkyl C 1-3 an alkyl group, C 1-3 C optionally substituted with an alkyl group 3-6 cycloalkyl C 1-3 selected from alkyl groups, preferably a 2,2,2-trifluoroethyl group, a cyclopropyl group, a cyclobutyl group, a 3,3-difluorocyclobutyl group, a cyclopropylmethyl group, a 2,2-dimethylcyclopropylmethyl group the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

8. R 1 is selected from halogen, Ring B is R 2 is independently selected from a hydrogen atom, C 1-3 alkyl group, Each R 3 is independently selected from a hydrogen atom, a halogen, C 1-3 alkyl group, or two Rs linked to the same carbon atom 3 are a C 3-6 cycloalkyl group with the carbon atom to which they are linked, Ring A is R 4a 、R 4b 、R 4c are each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, and a C 1-3 haloalkyl group R 5 is -OR 5 ' selected from, R 5 ' is C 1-6 haloalkyl group, C 3-6 cycloalkyl group, C 3-6 halocycloalkyl group, C 3-6 cycloalkyl C 1-3 alkyl group, C 1-3 alkyl group optionally substituted with C 3-6 cycloalkyl C 1-3 selected from alkyl groups, n is selected from 1, 2, 3 the compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

9. A compound represented by formula (IV), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen and R 2 is selected from a hydrogen atom, C 1-3 alkyl group, R 6a and R 6b are each independently selected from a hydrogen atom, a halogen, C 1-3 haloalkyl group, R 6c is selected from a hydrogen atom, C 1-3 alkyl group, the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

10. A compound represented by formula (V), a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, wherein among them R 1 is selected from halogen and R 2 is selected from a hydrogen atom, C 1-3 alkyl group, R 7a 、R 7b 、R 7c are each independently selected from a hydrogen atom, a halogen, a C 1-3 haloalkyl group the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

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

12. The following compound, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, selected from the compound according to claim 1, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof.

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

14. Use of a compound according to any one of claims 1 to 12, a pharmaceutically acceptable salt, stereoisomer or deuteride thereof, or the pharmaceutical composition according to claim 13, for the preparation of a medicament for treating 5-HT 2A receptor-related diseases Use.

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

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