5-HT 2A Receptor inverse agonists, processes for their preparation 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. It also relates to the use of the compound or the pharmaceutical composition in the manufacture of a medicament for treating 5-HT 2A receptor related diseases, including non-motor symptoms of Parkinson's disease: delusions, hallucinations, depression, anxiety, cognitive impairment, sleep disorders; dementia-related psychiatric disorders; major depressive disorder; or negative symptoms of schizophrenia, etc.

Description

TECHNICAL FIELD

[0001] The present application relates to a class of compounds as 5-hydroxytryptamine 2A (5-HT 2A ) receptor inverse agonists, and a preparation method thereof, and application thereof in the field of 5-HT 2A receptor related diseases. BACKGROUND

[0002] Parkinson's disease (PD) is a common neurodegenerative disease, with an average age of onset of about 60 years old (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517.). According to the data of the National Institutes of Health (NIH) in 2018, there are about 4-6 million Parkinson's disease patients worldwide, of which as many as 50% of Parkinson's disease patients will have hallucinations or delusions during the disease, which seriously affects the quality of life of patients and has a high incidence and mortality rate.

[0003] For a long time, antipsychotic drugs have been mainly used in the clinical treatment of hallucinations and delusions in Parkinson's disease patients. The first generation of antipsychotic drugs mainly inhibits dopamine D2 receptors, and has serious extrapyramidal side effects. The second generation of antipsychotic drugs, in addition to inhibiting D2 receptors, also more inhibits specific 5-HT receptors, especially 5-HT 2A receptors, has better safety, that is, the extrapyramidal side effects are smaller than the first generation of antipsychotic drugs. However, since the second generation of antipsychotic drugs still has D2 receptor inhibitory activity, they still have extrapyramidal side effects, and at the same time, these drugs have different degrees of weight gain side effects. In 2016, the US FDA approved Pimavanserin for marketing, which is used for the treatment of hallucinations and delusions in Parkinson's disease, and became the first drug approved for this indication.

[0004]

[0005] Pimavanserin is a 5-HT 2A receptor inverse agonist, which can eliminate the extrapyramidal and weight gain side effects related to dopamine receptor inhibition of the first and second generations of antipsychotic drugs, and has better safety. 5-HT 2A is a major excitatory receptor subtype in the 5-HT receptor family, which belongs to ligand-gated channels and G protein-coupled receptors. 5-HT 2AReceptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important target for antipsychotic drugs and treatment of schizophrenia (Price, D. L., et al. Behavioural Pharmacology (2012), 23(4), 426-433.).

[0006] 5-HT 2A Receptors have intrinsic activity, which can produce effects in the absence of an agonist. Pimavanserin is a 5-HT 2A Receptor inverse agonist, which can inhibit the intrinsic activity of the receptor after binding to the 5-HT 2A Receptor, so that the receptor does not function, and produces an effect opposite to that of the agonist, and can exhibit activity even in the absence of an agonist. A typical 5-HT 2A Receptor antagonist cannot cause a biological effect after binding to the receptor, and can only exhibit activity by inhibiting an agonist (WO2004064738A2). Therefore, even if a compound has 5-HT 2A Receptor antagonistic activity, it does not necessarily have 5-HT 2A Receptor inverse agonistic activity.

[0007] 5-HT 2A Receptor inverse agonists have good application prospects in the pharmaceutical industry as drugs, but only pimavanserin has been approved for marketing. Therefore, more 5-HT 2A Receptor inverse agonists need to be developed to achieve better therapeutic effects and meet the needs of patients in clinical practice. SUMMARY

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

[0009]

[0010] wherein R1 is selected from halogen;

[0011] ring B is selected from

[0012] R2 is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0013] each R3 is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3 connected to the same carbon atom form a C 3-6 cycloalkyl ring with the carbon atom to which they are connected;

[0014] ring A is selected from

[0015] X is selected from NR 6c , O or S;

[0016] X1is selected from N or CH;

[0017] R 4a , R 4b , R 4c , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0018] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl;

[0019] n is selected from 0, 1, 2, 3.

[0020] In some embodiments of the compound of formula (A):

[0021] Ring A is selected from preferably the other variables are as defined in the application.

[0022] In some embodiments of the compound of formula (A):

[0023] Ring B is selected from preferably

[0024] R3is selected from halogen, or two R3attached to the same carbon atom form a C 3-6 cycloalkyl; R3is preferably F, or two R3attached to the same carbon atom form a cyclopropyl;

[0025] n is 1 or 2; the other variables are as defined in the application.

[0026] In some embodiments of the compound of formula (A):

[0027] R5' is selected from C1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in this invention.

[0028] In some embodiments of the compound of formula (A):

[0029] R1 is selected from halogens;

[0030] Ring B is selected from Preferred

[0031] R2 is independently selected from hydrogen atoms, C atoms 1-3 alkyl;

[0032] Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl;

[0033] Ring A is selected from

[0034] R 4a R 4b R 4c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0035] R5 is selected from -OR5', R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl;

[0036] n is selected from 1, 2, or 3; other variables are as defined in this invention.

[0037] In another aspect of the invention, the invention provides compounds of formula (I), pharmaceutically acceptable salts thereof, stereoisomers or deuterated derivatives thereof:

[0038]

[0039] wherein

[0040] R1is selected from halogen;

[0041] Ring B is selected from

[0042] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0043] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0044] Ring A is selected from

[0045] X is selected from NR 6c , O or S;

[0046] R 4a , R 4b , 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, C 1-3 haloalkyl;

[0047] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl;

[0048] n is selected from 0, 1, 2, 3.

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

[0050] Ring A is selected from preferably the other variables are as defined in the application.

[0051] In some embodiments of the compound of formula (I):

[0052] Ring B is selected from Preferably

[0053] R3is selected from halogen, or two R3attached to the same carbon atom form a C 3-6 cycloalkyl; preferably R3is F, or two R3attached to the same carbon atom form a cyclopropyl;

[0054] n is 1 or 2; other variables are as defined in the application.

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

[0056] R5is selected from -OR5’, R5’is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl substituted with C 3-6 cycloalkyl C 1-3 alkyl; preferably R5’is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in the application.

[0057] In some embodiments of the compound of formula (I):

[0058] R1is selected from F;

[0059] Ring B is selected from Preferably

[0060] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, i-propyl, cyclopropyl;

[0061] each R3is independently a hydrogen atom, F, methyl, or two R3attached to the same carbon atom form a cyclopropyl;

[0062] Ring A is selected from

[0063] X is selected from NR 6c , O or S;

[0064] R 4a , R 4b , R 6a , R 6b , R 6c, R 7a , R 7b , R 7c each independently selected from a hydrogen atom, F, CI, Br, methyl, trifluoromethyl;

[0065] R5is selected from -OR5', R5'is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5'is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0066] n is selected from 0, 1, 2, 3.

[0067] In some embodiments of the compound of formula (I):

[0068] R1is selected from F;

[0069] Ring B is selected from preferably

[0070] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, i-propyl, cyclopropyl;

[0071] R3is selected from a hydrogen atom, F, methyl, or two R3attached on the same carbon atom form a cyclopropyl with the carbon atom to which they are attached;

[0072] Ring A is selected from

[0073] X is selected from NR 6c , O or S;

[0074] R 4a , R 4b , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c each independently selected from a hydrogen atom, F, CI, Br, methyl, trifluoromethyl;

[0075] R5is selected from -OR5', R5'is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl, preferably, R5'is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0076] n is selected from 0, 1, 2.

[0077] In some embodiments of the compound of formula (I):

[0078] R1is selected from halogen;

[0079] Ring B is selected from Preferably

[0080] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0081] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0082] Ring A is selected from

[0083] R 4a , R 4b , R 4c are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0084] R5is selected from -OR5', R5' is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, C 1-3 alkyl substituted with C 3-6 cycloalkyl C 1-3 alkyl;

[0085] n is selected from 1, 2, 3; the other variables are as defined in the application.

[0086] In some embodiments of the compound of formula (I):

[0087] R1is selected from F;

[0088] Ring B is selected from Preferably

[0089] R2is selected from a hydrogen atom, methyl;

[0090] Ring A is selected from X is selected from NR 6c , O or S;

[0091] R 6a , R 6b , R6c each independently selected from the group consisting of a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl.

[0092] In some embodiments of the compound of formula (I):

[0093] R1is selected from F;

[0094] Ring B is selected from Preferably

[0095] R2is selected from a hydrogen atom, methyl;

[0096] R3is selected from a hydrogen atom, F, methyl, or two R3attached on the same carbon atom form a cyclopropyl group with the carbon atom to which they are attached;

[0097] Ring A is selected from

[0098] R 4a , R 4b , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c each independently selected from the group consisting of a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl.

[0099] R5is selected from -OR5’, R5’is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5’is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0100] n is selected from 0, 1, 2.

[0101] In some embodiments of the compound of formula (I):

[0102] R1is selected from halogen;

[0103] Ring B is selected from

[0104] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0105] R 3a , R 3b , R 3c , R 3d , R 3e , R3f , R 3g , R 3h each independently is selected from a hydrogen atom, a halogen, a C 1-3 alkyl group;

[0106] Ring A is selected from

[0107] R 4a , R 4b each independently is selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group;

[0108] R5is selected from -OR5’, 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 3-6 cycloalkyl group, a C 3-6 halocycloalkyl group.

[0109] In some embodiments of the compound of formula (I):

[0110] R1is selected from F;

[0111] Ring B is selected from

[0112] R2is independently selected from a hydrogen atom, a methyl group, a CD3, an ethyl group, a n-propyl group, an iso-propyl group, a cyclopropyl group; preferably a methyl group;

[0113] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently is 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;

[0114] Ring A is selected from

[0115] R 4a and R 4b each independently is selected from a hydrogen atom, F, Cl, Br;

[0116] R5is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0117] In another aspect of the present application, the present application provides a compound represented by Formula (II), a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:

[0118]

[0119] wherein,

[0120] R1is selected from halogen;

[0121] Ring B is selected from

[0122] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0123] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached on the same carbon atom form a C 3-6 cycloalkyl;

[0124] Ring A is selected from

[0125] X is selected from NR 6c , O or S;

[0126] 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, C 1-3 haloalkyl;

[0127] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl1-3 alkyl, optionally substituted with C 1-3 alkyl, optionally substituted with C 3-6 cycloalkyl C 1-3 alkyl;

[0128] n is selected from 0, 1, 2, 3.

[0129] In some embodiments of the compound of formula (II):

[0130] Ring A is selected from preferably the other variables are as defined in the present application.

[0131] In some embodiments of the compound of formula (II):

[0132] Ring B is selected from preferably

[0133] R3is selected from halogen, or two R3attached to the same carbon atom form a C 3-6 cycloalkyl; preferably R3is F, or two R3attached to the same carbon atom form a cyclopropyl group;

[0134] n is 1 or 2; the other variables are as defined in the present application.

[0135] In some embodiments of the compound of formula (II):

[0136] R5’is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl, optionally substituted with C 3-6 cycloalkyl C 1-3 alkyl, preferably R5’is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; the other variables are as defined in the present application.

[0137] In some embodiments of the compound of formula (II):

[0138] R1is selected from halogen;

[0139] Ring B is selected from preferably

[0140] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0141] each R3is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two R3attached to the same carbon atom form a C 3-6 cycloalkyl group;

[0142] Ring A is selected from

[0143] R 4a , R 4b , R 4c each independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group;

[0144] R5is selected from -OR5’, 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 cycloalkyl group C 1-3 alkyl group, optionally substituted with a C 1-3 alkyl group; 3-6 cycloalkyl group C 1-3 alkyl group;

[0145] n is selected from 1, 2, 3; other variables are as defined in the application.

[0146] In some embodiments of the compound of formula (II):

[0147] R1is selected from F;

[0148] Ring B is selected from

[0149] R2is selected from a hydrogen atom, a methyl group, a CD3group, an ethyl group, a n-propyl group, an iso-propyl group, a cyclopropyl group;

[0150] each R3is selected from a hydrogen atom, a F group, a methyl group, or two R3attached to the same carbon atom form a cyclopropyl group;

[0151] Ring A is selected from

[0152] R 4a , R 4b , R 4c , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c each independently selected from a hydrogen atom, a F group, a Cl group, a Br group, a methyl group, a trifluoromethyl group;

[0153] R5is selected from -OR5', R5' is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl, preferably R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl;

[0154] n is selected from 0, 1, 2, 3.

[0155] In some embodiments of the compound of formula (II):

[0156] R1is selected from halogen;

[0157] Ring B is selected from

[0158] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0159] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently from a hydrogen atom, halogen, C 1-3 alkyl, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h form together with the carbon atom to which they are attached a C 3-6 cycloalkyl;

[0160] Ring A is selected from

[0161] R 4a , R 4b , R 4c each independently from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0162] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl.

[0163] In some embodiments of the compound of formula (II):

[0164] R1 is selected from F;

[0165] Ring B is selected from

[0166] R2 is independently selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0167] R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atom, F, methyl, or R. 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R 3g With R 3h It forms a cyclopropyl group with the attached carbon atom;

[0168] Ring A is selected from

[0169] R 4a R 4b R 4c Each is independently selected from hydrogen atoms, F, Cl, and Br;

[0170] R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl. Preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0171] In one aspect, the present invention provides compounds of formula (IIA), pharmaceutically acceptable salts thereof, stereoisomers or deuterated derivatives:

[0172]

[0173] in,

[0174] R1is selected from halogen;

[0175] Ring B is selected from

[0176] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0177] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl;

[0178] R 4a , R 4b are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0179] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, preferably R5' is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl;

[0180] n is selected from 0, 1, 2, 3.

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

[0182] Ring B is selected from preferably

[0183] R3is selected from halogen, or two R3attached to the same carbon atom form, with the carbon atom to which they are attached, a C 3-6 cycloalkyl; R3is preferably F, or two R3attached to the same carbon atom form, with the carbon atom to which they are attached, a cyclopropyl;

[0184] n is 1 or 2; the other variables are as defined in the application.

[0185] In some embodiments of the compound of formula (IIA):

[0186] R5' is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl C 3-6 cycloalkyl C 1-3alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in the application.

[0187] In some embodiments of the compound of formula (IIA):

[0188] R1is selected from halogen;

[0189] Ring B is selected from Preferably

[0190] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0191] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0192] R 4a , R 4b , R 4c are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0193] R5is selected from -OR5', R5' is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl;

[0194] n is selected from 1, 2, 3; other variables are as defined in the application.

[0195] In some embodiments of the compound of formula (IIA):

[0196] R1is selected from F;

[0197] Ring B is selected from

[0198] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, i-propyl, cyclopropyl;

[0199] each R3is independently a hydrogen atom, F, methyl;

[0200] R 4a , R 4beach independently is selected from the group consisting of a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0201] R5is selected from -OR5', R5'is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl, preferably R5'is selected from 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0202] n is selected from 0, 1, 2, 3.

[0203] In one aspect, the present application provides a compound represented by Formula (IIA-1) or (IIA-2), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0204]

[0205] wherein,

[0206] R1is selected from a halogen;

[0207] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0208] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently is selected from the group consisting of a hydrogen atom, a halogen, C 1-3 alkyl, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0209] R 4a , R 4b , R 4c each independently is selected from the group consisting of a hydrogen atom, a halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0210] R5is selected from -OR5', R5'is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl.

[0211] In some embodiments of the compound of formula (IIA-1) or (IIA-2):

[0212] R5’is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl; preferably, R5’is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl; other variables are as defined in the application.

[0213] In some embodiments of the compound of formula (IIA-1) or (IIA-2):

[0214] R1is selected from F;

[0215] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl;

[0216] 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, methyl, 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 ring with the carbon atom to which they are attached;

[0217] R 4a , R 4b , R 4c are each independently selected from a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0218] R5is selected from -OR5’, R5’is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0219] In one aspect, the present application provides a compound represented by formula (IIB), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0220]

[0221] wherein,

[0222] R1is selected from halogen;

[0223] Ring B is selected from

[0224] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0225] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl;

[0226] R 4a , R 4b are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0227] R5is selected from -OR5’, R5’is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl;

[0228] n is selected from 0, 1, 2, 3.

[0229] In some embodiments of the compound of Formula (IIB):

[0230] R1is selected from F;

[0231] Ring B is selected from

[0232] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, i-propyl, cyclopropyl;

[0233] each R3is independently a hydrogen atom, F, methyl;

[0234] R 4a , R 4b are each independently selected from a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0235] R5is selected from -OR5’, R5’is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0236] n is selected from 0, 1, 2, 3.

[0237] In another aspect, the present application provides a compound represented by Formula (III), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0238]

[0239] wherein

[0240] R1is selected from halogen;

[0241] ring B is selected from

[0242] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0243] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0244] R 4a and R 4b are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0245] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl;

[0246] n is selected from 0, 1, 2, 3.

[0247] In some embodiments of the compound of formula (III):

[0248] ring B is selected from preferably

[0249] R3is selected from halogen, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl; R3is preferably F, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a cyclopropyl group;

[0250] n is 1 or 2; the other variables are as defined in the application.

[0251] In some embodiments of the compound of formula (III):

[0252] R5' is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6haloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl, optionally substituted with C 3-6 cycloalkyl C 1-3 alkyl; preferably, R5’is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in the application.

[0253] In some embodiments of the compound of formula (III):

[0254] R1is selected from halogen;

[0255] Ring B is selected from preferably

[0256] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0257] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached on the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0258] Ring A is selected from

[0259] R 4a , R 4b , R 4c are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0260] R5is selected from -OR5’, R5’is selected from C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl, optionally substituted with C 3-6 cycloalkyl C 1-3 alkyl;

[0261] n is selected from 1, 2, 3; other variables are as defined in the application.

[0262] In some embodiments of the compound of formula (III):

[0263] R1is selected from halogen;

[0264] Ring B is selected from

[0265] R2is independently selected from a hydrogen atom, a C 1-3 alkyl group;

[0266] each R3is independently selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, or two R3attached to the same carbon atom form a C 3-6 cycloalkyl group;

[0267] 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;

[0268] R5is selected from -OR5’, 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, a C 3-6 cycloalkyl C 1-3 alkyl group, a C 1-3 alkyl group substituted with a C 3-6 cycloalkyl C 1-3 alkyl group;

[0269] n is selected from 0, 1, 2.

[0270] In some embodiments of the compound of formula (III):

[0271] R1is selected from F;

[0272] Ring B is selected from

[0273] R2is independently selected from a hydrogen atom, a methyl group;

[0274] each R3is independently selected from a hydrogen atom, F, Cl, Br, a methyl group, or two R3attached to the same carbon atom form a cyclopropyl group;

[0275] R 4a and R 4b are each independently selected from a hydrogen atom, a hydrogen atom, F, Cl, Br;

[0276] R5is selected from -OR5’, R5’is selected from a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-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;

[0277] n is selected from 0, 1, 2.

[0278] In some embodiments of the compound of formula (III):

[0279] R1is selected from halogen;

[0280] Ring B is selected from

[0281] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0282] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl;

[0283] R 4a , R 4b are each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0284] R5is selected from -OR5’, R5’is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl;

[0285] n is selected from 0, 1, 2, 3.

[0286] In some embodiments of the compound of formula (III):

[0287] R1is selected from F;

[0288] Ring B is selected from

[0289] R2is selected from a hydrogen atom, methyl, CD3, ethyl, n-propyl, i-propyl, cyclopropyl;

[0290] each R3is independently a hydrogen atom, F, methyl;

[0291] R 4a , R 4b are each independently selected from a hydrogen atom, F, Cl, Br, methyl, trifluoromethyl;

[0292] R5is selected from -OR5’, R5’is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, 3,3-difluorocyclobutyl;

[0293] n is selected from 0, 1, 2, 3.

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

[0295] R1is selected from halogen;

[0296] Ring B is selected from

[0297] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0298] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently selected from a hydrogen atom, a halogen, C 1-3 alkyl, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h form together with the carbon atom to which they are attached a C 3-6 cycloalkyl;

[0299] R 4a and R 4b each independently selected from a hydrogen atom, a halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0300] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl.

[0301] In some embodiments of the compound of formula (III):

[0302] R1is selected from F;

[0303] Ring B is selected from

[0304] R2is independently selected from a hydrogen atom, a methyl group;

[0305] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently selected from a hydrogen atom, F, a methyl group, or R 3a and R3b R 3c R 3d R 3e R 3f R 3g R 3h with the carbon atom to which they are attached to form a cyclopropyl group;

[0306] R 4a and R 4b are each independently selected from the group consisting of a hydrogen atom, a hydrogen atom, F, Cl, Br;

[0307] R5is selected from -OR5’, R5’is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0308] In another aspect, the present application provides a compound represented by Formula (IIIA) or (IIIB), a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:

[0309]

[0310] wherein,

[0311] R1is selected from halogen;

[0312] R2is selected from a hydrogen atom, C 1-3 alkyl;

[0313] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-3 alkyl, or R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , or R 3g and R 3h form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl group;

[0314] R 4a and R 4b are each independently selected from the group consisting of a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0315] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl substituted with C 3-6 cycloalkyl C 1-3 alkyl.

[0316] In some embodiments of the compound of Formula (IIIA) or (IIIB):

[0317] R1is selected from F;

[0318] R2is selected from a hydrogen atom, a methyl group;

[0319] 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, 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;

[0320] R 4a and R 4b are each independently selected from a hydrogen atom, F, Cl, Br;

[0321] R5is selected from -OR5', R5' is selected from a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl 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.

[0322] In another aspect, the present application provides a compound of Formula (IIIC), a pharmaceutically acceptable salt, a stereoisomer, or a deuterated form thereof:

[0323]

[0324] wherein,

[0325] R1is selected from a halogen;

[0326] R2is selected from a hydrogen atom, a C1-3 alkyl;

[0327] R 4a and R 4b each independently is selected from the group consisting of a hydrogen atom, a halogen, a C 1-3 alkyl; 1-3 haloalkyl;

[0328] R5is selected from -OR5’, R5’is selected from the group consisting of a C 1-6 alkyl; 1-6 haloalkyl, C 3-6 cycloalkyl; 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl.

[0329] In some embodiments of the compound of formula (II):

[0330] R1is selected from F;

[0331] R2is selected from a hydrogen atom, a methyl;

[0332] R 4a and R 4b each independently is selected from the group consisting of a hydrogen atom, a hydrogen atom, F, Cl, Br;

[0333] R5is selected from -OR5’, R5’is selected from the group consisting of a methyl, an ethyl, an n-propyl, an iso-propyl, an n-butyl, an iso-butyl, a tert-butyl, a 2,2,2-trifluoroethyl, a cyclopropyl, a cyclobutyl, a 3,3-difluorocyclobutyl, a cyclopropylmethyl, a 2,2-dimethylcyclopropylmethyl.

[0334] In another aspect, the present application provides a compound of formula (IV), a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof:

[0335]

[0336] wherein,

[0337] R1is selected from a halogen;

[0338] R2is selected from a hydrogen atom, a C 1-3 alkyl;

[0339] R 6a , R 6b each independently is selected from the group consisting of a hydrogen atom, a halogen, a C 1-3 haloalkyl;

[0340] R 6c is selected from the group consisting of a hydrogen atom, a C 1-3alkyl.

[0341] In some embodiments of the compound of Formula (IV):

[0342] R1is selected from F;

[0343] R2is selected from a hydrogen atom, methyl;

[0344] R 6a , R 6b are each independently selected from a hydrogen atom, F, trifluoromethyl;

[0345] R 6c is selected from a hydrogen atom, methyl.

[0346] In another aspect, the present application provides a compound of Formula (V), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0347]

[0348] wherein,

[0349] R1is selected from a halogen;

[0350] R2is selected from a hydrogen atom, C 1-3 alkyl;

[0351] R 7a , R 7b , R 7c are each independently selected from a hydrogen atom, a halogen, C 1-3 haloalkyl.

[0352] In some embodiments of the compound of Formula (V):

[0353] R1is selected from F;

[0354] R2is selected from a hydrogen atom, methyl;

[0355] R 7a , R 7b , R 7c are each independently selected from a hydrogen atom, F, trifluoromethyl.

[0356] In another aspect of the present application, the present application provides a compound of Formula (VI), a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0357]

[0358] wherein,

[0359] R 1a , R 1b are each independently selected from a hydrogen atom, C 1-3 alkyl;

[0360] Ring B is selected from

[0361] R2is independently selected from a hydrogen atom, C 1-3 alkyl;

[0362] each R3is independently selected from a hydrogen atom, halogen, C 1-3 alkyl, or two R3attached to the same carbon atom form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl;

[0363] Ring A is selected from

[0364] X is selected from NR 6c , O or S

[0365] R 4a , R 4b , R 6a , R 6b , R 6c , R 7a , R 7b , R 7c each independently selected from a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 haloalkyl;

[0366] R5is selected from -OR5', R5' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl C 1-3 alkyl, optionally substituted with C 1-3 alkyl; 3-6 cycloalkyl C 1-3 alkyl;

[0367] n is selected from 0, 1, 2, 3.

[0368] In some embodiments of the compound of formula (VI):

[0369] R 1a , R 1b each independently selected from a hydrogen atom, C 1-3 alkyl;

[0370] Ring B is selected from

[0371] R2is independently selected from a hydrogen atom, C 1-3 alkyl, C 3-6 cycloalkyl;

[0372] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently is selected from a hydrogen atom, a halogen, a C 1-3 alkyl group;

[0373] Ring A is selected from

[0374] R 4a , R 4b each independently is selected from a hydrogen atom, a halogen, a C 1-3 alkyl group, a C 1-3 haloalkyl group;

[0375] R5is selected from -OR5’, 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.

[0376] In some embodiments of the compound of formula (VI):

[0377] R 1a , R 1b each independently is selected from a hydrogen atom, a methyl group;

[0378] Ring B is selected from

[0379] R2is independently selected from a hydrogen atom, a methyl group, a CD3 group, an ethyl group, a n-propyl group, an iso-propyl group, a cyclopropyl group;

[0380] R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h each independently is selected from a hydrogen atom, a F group, 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;

[0381] Ring A is selected from

[0382] R 4a and R 4b each independently is selected from the group consisting of a hydrogen atom, F, Cl, Br;

[0383] R5is selected from -OR5', R5'is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0384] In another aspect, the present application provides a compound as shown below, a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] In another aspect, the present application provides a compound as shown below, a pharmaceutically acceptable salt, stereoisomer, or deuterated form thereof:

[0393]

[0394]

[0395] In one aspect, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above-mentioned compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a crystalline form of any of the above-mentioned compounds and a pharmaceutically acceptable carrier. The carrier includes conventional adjuvant ingredients in the art, such as a filler, a binder, a diluent, a disintegrant, a lubricant, a colorant, a flavoring agent, an antioxidant, or a wetting agent, etc.

[0396] The pharmaceutical composition can be prepared into various dosage forms which are pharmaceutically available, such as tablets, capsules, oral solutions, suspensions, granules, powders, microparticles, pills, microtablets, fast dissolving films, nasal sprays, transdermal patches, injections, or various controlled release formulations, etc. The pharmaceutical composition can be administered orally, transmucosally, rectally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally). The administration dose can be appropriately adjusted depending on the age, sex, and disease type of the patient.

[0397] For oral administration, the pharmaceutical composition can be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a predetermined amount of the active ingredient. For example, the pharmaceutical composition can be provided in the form of tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. The appropriate daily dose for humans or other mammals can vary widely according to the condition of the patient and other factors, but can be determined using routine methods.

[0398] In one aspect, the present application provides any of the above-mentioned compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof for use in the treatment of 5-HT 2A receptor-related diseases. The diseases or conditions include schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tic, depression, major depressive disorder, anxiety, sleep and appetite disturbances, non-motor symptoms of Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment, or sleep disturbances), dementia-related psychosis, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar ataxia, Tourette's syndrome, Friedreich's ataxia, Machado-Joseph disease, Lewy body dementia, dyskinesia, dystonia, myoclonus, tremor, progressive supranuclear palsy, and frontotemporal dementia; or other disease states and conditions apparent to those skilled in the art.

[0399] Definitions and Descriptions

[0400] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being indefinite or unclear unless specifically defined, but should be understood according to the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0401] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0402] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application that is within the scope of sound medical judgment, of a compound of the present application having particular substituents discovered by the present inventors, is prepared from non-toxic acids or bases. Where the compound of the present application contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of the base in a suitable inert solvent or in a pure solution. Examples of pharmaceutically acceptable acid addition salts include mineral acid salts, such as hydrochloride, hydrobromide, hydroiodide, and sulfates; salts of organic acids, such as acetate, benzoate, benzenecarboxylate, citrate, cyclohexanesulfamate, fumarate, maleate, mandelate, phthalate, salicylate, and the like; salts of amino acids, such as arginate, aspartate, glutamine, glutamate, hisidinate, and the like; and salts of organic acids not being acids per se, such as glucuronate, saccharate and the like. Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, are capable of conversion into either base or acid addition salts.

[0403] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, the salt is prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.

[0404] Certain compounds of the present application can possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all intended to be within the scope of the present application.

[0405] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of the enantiomers or diastereomers, and the like. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are intended to be within the scope of this application.

[0406] Optically active (R)- and (S)-isomers and the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the diastereomeric salt separated by conventional means, and the desired enantiomer recovered by cleavage of the bond to the auxiliary group. In addition, the separation of enantiomers and diastereomers is typically accomplished by the use of chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0407] The term "pharmaceutically acceptable carrier" means any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the application, does not interfere with the biological activity of the active substance, and is nontoxic to the host or patient. Representative carriers include, but are not limited to, binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, and the like.

[0408] The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to achieve the intended result without being toxic to the recipient. With respect to oral dosage forms of the application, an "effective amount" of one active substance in a composition means the amount required to achieve the intended result in combination with another active substance in the composition. The determination of an effective amount will vary from subject to subject, depending on the age and general condition of the recipient, as well as the particular active substance, and an appropriate effective amount for a given subject can be determined by one of ordinary skill in the art using routine testing.

[0409] The present application is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14 C. Isotopically-labeled compounds of the application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0410] The term "deuterated analog" refers to an analog of a compound in which one or more hydrogen atoms are replaced by deuterium atoms. The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with one or more deuterium atoms" means that the group can be unsubstituted with deuterium atoms, or substituted with one or more deuterium atoms, i.e., includes groups that are not deuterated, partially deuterated, and / or fully deuterated.

[0411] The term "substituted" means that any one or more hydrogen atoms on the designated atom is / are replaced with a substituent group, which can include heavy hydrogen and variations of hydrogen, as long as the valency of the designated atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

[0412] When any variable (e.g., R) occurs more than one time in a compound or substituent, "each occurrence" is treated as independent of the other occurrences. Therefore, for example, if a group is substituted with 0-2 R groups, the group can optionally be substituted with up to two R groups, and each occurrence of R is independently selected. Also, combinations of substituents and / or variations of substituents are permissible only if such combinations result in stable compounds.

[0413] Unless otherwise specified, the term "alkyl" is used to mean straight or branched chain saturated hydrocarbon groups, which can be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), and which can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). For example, C1-C10alkyl includes methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, and the like. 10 represents 1 to 10 carbons, C 1-10 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, and the like.

[0414] Unless otherwise specified, the term "halogen" or "halo" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" is intended to include mono-halo and poly-halo, straight- chain or branched halogenated alkyl groups. For example, the term "C 1-10Haloalkyl is intended to include, but not be limited to, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 2,2'-difluoroisopropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl.

[0415] Unless otherwise specified, cycloalkyl includes any stable cyclic or polycyclic hydrocarbon radical in which any carbon atom is saturated, can be mono- or polysubstituted, and can be univalent, divalent, or multivalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like. The cycloalkyl groups can be optionally further substituted with halogen, or C1-C3 alkyl.

[0416] Unless otherwise specified, "cycloalkylalkyl" means a C 3-6 Cycloalkyl-C 1-3 Alkyl-, cycloalkylalkyl can be substituted or unsubstituted, non-limiting examples of which include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, and the like. The cycloalkylalkyl groups can be optionally further substituted with halogen, or C1-C3 alkyl.

[0417] The compounds are named by hand or Software naming, commercially available compounds use the vendor catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0418] Figure 1 : The number of head-throwing times of SD rats at 1.0-1.5 h after single gavage administration (wherein, #P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group). DETAILED DESCRIPTION

[0419] The present application is further illustrated by the following specific examples and test examples, but the scope of the present application is not limited in any form by the examples.

[0420] Example 1

[0421]

[0422] Compound 1-2 (538mg) was obtained by dissolving 2-(aminomethyl)-5-fluoropyridine (504mg, 4.0mmol) in 10ml of methanol under nitrogen protection and ice water bath, and then adding N-methyl-4-piperidone (452mg, 4.0mmol), sodium triacetoxyborohydride (933mg, 4.4mmol), and then allowing to react at room temperature for 15h. The pH value was adjusted to alkaline by adding aqueous sodium bicarbonate solution, the organic phase was concentrated, then extracted with dichloromethane (10ml*3), the combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-2 (538mg).

[0423]

[0424] Compound 1-4 (orange oil, 5.6g) was obtained by sequentially adding 16mL of dimethyl sulfoxide, compound 1-3 (4.00g, 1.00eq), compound trifluoroethanol (9.83g, 3.00eq), and cesium carbonate (16.01g, 1.50eq) into a 100mL three-necked flask, and then allowing to react at 105°C for 12h. 200mL of water was added to the reaction solution, and then extracted twice with 200mL of ethyl acetate. The organic phase was combined, washed with 200mL of saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound 1-4 (orange oil, 5.6g).

[0425] Compound 1-5 (white solid, 2.37g) was obtained by sequentially adding 160mL of tetrahydrofuran, compound 1-4 (4.0g, 1.00eq), di-tert-butyl dicarbonate (4.32g, 1.0eq), and Raney nickel (1.7g, 1.0eq) into a 500mL hydrogenation flask, and then allowing to react at 70°C under 50Psi for 12h. Filtration and spin-drying were performed to obtain a crude product, and the crude product was purified by preparative chromatography to obtain compound 1-5 (white solid, 2.37g).

[0426] Compound 1-6 (light pink solid, 903mg) was obtained by sequentially adding ethyl acetate (5mL), compound 1-5 (1.00g, 1.00eq), and HCl / EtOAc (5mL) into a 100mL single-necked flask, and then allowing to react at 25°C for 17h. The reaction solution was directly spin-dried to obtain a crude compound 1-6 (light pink solid, 903mg).

[0427]

[0428] Into a 10 mL single necked flask, 2 mL tetrahydrofuran, compound 1-6 (200 mg, 1.00 eq), diisopropylethylamine (DIEA) (125 mg, 1.00 eq) were added successively, stirred for 15 min under nitrogen atmosphere, then cooled to 0 °C with ice water bath, carbonyldiimidazole (CDI) (173 mg, 1.10 eq) was added into the reaction solution, 0 °C for 1 h, compound 1-2 (216 mg, 1.0 eq) was dissolved in 1 mL tetrahydrofuran and added into the reaction solution, 25 °C for 12 h. The reaction solution was concentrated to dryness to give a crude product. The crude product was purified by thin layer chromatography and preparative chromatography to give compound 1 (yellow oil, 160 mg). 1 H NMR (400 MHz, CDC13) 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+l].

[0429] Example 2

[0430] Compounds 2-4, 7-8, 11, 77, 79 were obtained using synthetic methods similar to those of Example 1. The following table lists the characterization data of compounds 2-4, 7-8, 11, 77, 79:

[0431]

[0432]

[0433] Example 3

[0434]

[0435] Into a 100 mL three-necked flask, 3 mL tetrahydrofuran, compound 5-1 (300 mg, 1.00 eq), diisopropylethylamine (282.10 mg, 1.50 eq) were added, and the mixture was stirred at 0 °C for 15 min under nitrogen. To the reaction mixture, carbonyldiimidazole (259.55 mg, 1.10 eq) was added, and the mixture was stirred at 0 °C for 1 h. To the reaction mixture, compound 1-2 (324.92 mg, 1.00 eq) dissolved in 2 mL tetrahydrofuran was added, and the mixture was stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by preparative chromatography to give compound 5 (yellow solid, 440 mg). 1 H 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+l].

[0436] Example 4

[0437]

[0438] Into a 100 mL three-necked flask, 3 mL tetrahydrofuran, compound 5-1 (300 mg, 1.00 eq), diisopropylethylamine (282.10 mg, 1.50 eq) were added, and the mixture was stirred at 0 °C for 15 min under nitrogen. To the reaction mixture, carbonyldiimidazole (259.55 mg, 1.10 eq) was added, and the mixture was stirred at 0 °C for 1 h. To the reaction mixture, compound 1-2 (324.92 mg, 1.00 eq) dissolved in 2 mL tetrahydrofuran was added, and the mixture was stirred at 25 °C for 12 h. The mixture was filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by preparative chromatography to give compound 5 (yellow solid, 440 mg).

[0439] Into a 250 mL hydrogenation bottle was placed 12 mL of tetrahydrofuran, compound 6-3 (1.20 g, 1.00 eq), di-tert-butyl dicarbonate (1.25 g, 1.00 eq), Raney nickel (1.20 g, 2.45 eq), and the reaction was stirred at 70 °C, 50 Psi for 24 hours. The reaction was filtered and dried to give a crude product. The crude product was purified by column chromatography to give compound 6-4 (white solid, 720 mg).

[0440] Into a 100 mL single neck flask was placed 2 mL of ethyl acetate, compound 6-4 (720 mg, 1.00 eq), and the reaction was stirred at 25 °C. To the reaction was slowly added ethyl acetate hydrochloride (8 mL, 4 M) dropwise. The reaction was stirred at 25 °C for 12 hours. The reaction was dried and dissolved in 10 mL of dichloromethane. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The reaction was extracted with dichloromethane three times, 10 mL each time. The organic phase was dried, filtered, and dried to give compound 6-5 (440 mg).

[0441] Into a 100 mL single neck flask was placed 4 mL of tetrahydrofuran, compound 6-5 (390 mg, 1.00 eq), and diisopropylethylamine (352.96 mg, 1.50 eq). The reaction was stirred at 0 °C for 15 minutes under nitrogen protection. To the reaction was added carbonyldiimidazole (324.73 mg, 1.10 eq) at 0 °C. The reaction was stirred at 0 °C for 1 hour. To the reaction was added compound 1-2 (406.53 mg, 1.00 eq) dissolved in 2 mL of tetrahydrofuran. The reaction was stirred at 25 °C for 12 hours. The reaction was filtered and dried to give a crude product. The crude product was purified by preparative chromatography to give compound 6 (yellow gum, 460 mg). 1 H 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+l].

[0442] Example 5

[0443]

[0444] Compound 19 was obtained using a similar synthetic procedure to Example 4. 1 H NMR (400 MHz, CDC13) 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).

[0445] MS (ESI) m / z: 482.2 [M + 1].

[0446] Example 6

[0447]

[0448] Into a 10 mL single necked flask, 5 mL of N,N-dimethylformamide, compound 9-1 (300 mg, 1.00 eq), diisopropylethylamine (265 mg, 1.00 eq) were added successively, stirred for 15 minutes under nitrogen atmosphere, then reduced to 0°C with ice water bath, carbonyldiimidazole (366 mg, 1.10 eq) was added to the reaction solution, 0°C reaction for 1 hour, compound 1-2 (504 mg, 1.0 eq) was dissolved in 2 mL of DMF and added to the reaction solution, 25°C incubation and stirring for 12 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate three times, 50 mL each time. The organic phase was combined, dried, concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 9 (yellow oil, 310 mg). 1H NMR (400 MHz, CDC13) 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+l].

[0449] Example 7

[0450]

[0451] Compound 10-1 (300 mg, 1.00 eq), diisopropylethylamine (245 mg, 1.00 eq) were added into a 10 mL single neck flask, stirred for 15 minutes under nitrogen atmosphere, then cooled to 0 °C with ice water bath, carbonyldiimidazole (338 mg, 1.10 eq) was added into the reaction solution, reacted for 1 hour at 0 °C, compound 1-2 was dissolved in 2 mL DMF N,N-dimethylformamide and added into the reaction solution, stirred for 12 hours at 25 °C. 40 mL water was added into the reaction solution, extracted with ethyl acetate twice, 50 mL each time. The organic phase was combined, dried, concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 10 (yellow oil, 200 mg). 1 H NMR (400 MHz, CDC13) 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+l].

[0452] Example 8

[0453]

[0454] Into a 100 mL single-necked flask was placed 5 mL of tetrahydrofuran, compound 5-1 (400 mg, 1.00 eq), diisopropylethylamine (376 mg, 1.50 eq), and the mixture was stirred for 15 minutes at 0°C under nitrogen. To the reaction mixture was added carbonyldiimidazole (346 mg, 1.10 eq), and the mixture was stirred for 1 hour at 0°C. To the reaction mixture was added compound 39-1 (635 mg, 1.00 eq) dissolved in 4 mL of tetrahydrofuran, and the mixture was stirred for 12 hours at 25°C. 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%).

[0455] Into a 100 mL single-necked flask was placed 20 mL of dichloromethane, compound 39-2 (350 mg, 1.00 eq), and trifluoroacetic acid (6 mL, 129 eq), and the mixture was stirred for 20 minutes at 25°C. Rotary evaporation was performed to obtain a yellow oil. Into a 100 mL single-necked flask was placed 20 mL of tetrahydrofuran, the yellow oil, sodium cyanoborohydride (78 mg, 2.00 eq), and 37% aqueous formaldehyde solution (76 mg, 1.50 eq), and the mixture was stirred for 20 minutes at 25°C. Rotary evaporation was performed, 10 mL of methanol was added, and the mixture was stirred for 80 minutes at 75°C. Rotary evaporation was performed to obtain a crude product. The crude product was subjected to chiral separation (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 gum, 120 mg, yield: 39.9%) and compound 41 (retention time: 1.876 min, yellow gum, 130 mg, yield: 43.3%).

[0456] Compound 39: 1H 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+l].

[0457] Compound 41: 1 H 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+l].

[0458] Example 9

[0459]

[0460] 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 and reacted at room temperature for 12 hours. The reaction solution was concentrated and dried to obtain a crude product, and the pH was adjusted to 7 by adding sodium bicarbonate aqueous solution, and then concentrated and dried. The crude product was subjected to chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O EtOH)]; B%: 20%-20%), and concentrated and lyophilized to obtain compound 56A (retention time: 1.744 min, yellow oil, 95.0 mg, yield: 30.0%) and compound 56B (retention time: 2.519 min, yellow oil, 90 mg, yield: 29.4%).

[0461] Compound 56A: 1 H NMR (400 MHz, CDCl3) δ 1.76-1.83 (m, 2H), 2.58-2.68 (m, 2H), 3.03 (br d, J = 12.26 Hz, 1H), 3.36-3.48 (m, 1H), 4.27 (td, J = 10.66, 5.19 Hz, 1H), 4.35 (br d, J = 5.38 Hz, 2H), 4.45-4.50 (m, 2H), 4.59-4.67 (m, 1H), 4.71-4.78 (m, 2H), 6.54-6.69 (m, 1H), 6.81 (d, J = 8.50 Hz, 1H), 7.35-7.43 (m, 2H), 7.57 (dd, J = 8.44, 2.31 Hz, 1H), 7.97-8.06 (m, 1H), 8.30 (d, J = 2.38 Hz, 1H). MS (ESI) m / z: 460.2 [M+1].

[0462] Compound 56B: 1 H NMR (400 MHz, CDCl3) δ 1.67 (br s, 2H), 2.52 (br d, J = 3.50 Hz, 2H), 2.86-2.98 (m, 1H), 3.30 (br s, 1H), 4.14 (br s, 1H), 4.23 (br s, 2H), 4.37 (br s, 2H), 4.53 (br s, 1H), 4.63 (br d, J = 6.13 Hz, 2H), 6.41-6.61 (m, 1H), 6.69 (br d, J = 5.88 Hz, 1H), 7.27 (br s, 2H), 7.37-7.52 (m, 1H), 7.91 (br s, 1H), 8.18 (br s, 1H). MS (ESI) m / z: 460.2 [M+1].

[0463] Example 10

[0464] Compounds 27-28, 42, 44, 66 / 67, 69A / 69B, 70A / 70B were obtained using similar synthetic and / or resolution methods as Example 8, compounds 46A / 46B, 47A / 47B, 72A / 72B, 81A / 81B, 82A / 82B, 83A / 83B were obtained using resolution conditions (column: DAICEL CHIRALCEL OX (250mm*50mm, 10μm); mobile phase: [A: CO2, B: (0.1% NH3H2O EtOH)]; B%: 25%-25%), the following table lists the characterization data of the relevant compounds:

[0465]

[0466]

[0467]

[0468]

[0469] Example 11

[0470]

[0471] Into a 100 mL flask, 20 mL of tetrahydrofuran, compound 57-1 (1.80 g, 1.00 eq) was added, and the reaction solution was cooled to 0 °C. Lithium aluminum hydride (954 mg, 2.00 eq) was added in batches, and the reaction solution was stirred at 25 °C for 12 hours. 1 mL of water, 1 mL of 15% sodium hydroxide aqueous solution and 3 mL of water were added in turn, and the reaction solution was extracted with ethyl acetate three times. The organic phase was dried, filtered and rotary evaporated to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 57-2 (620 mg, yield: 32.8%).

[0472] Into a 100 mL flask, 6 mL of tetrahydrofuran, compound 57-2 (570 mg, 1.00 eq), diisopropylethylamine (750 mg, 1.50 eq) was added, and the reaction solution was cooled to 0 °C. After stirring for 15 minutes under nitrogen 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. Filtration was carried out to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 57 (white solid, 950 mg, yield: 60.9%). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (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+l].

[0473] Example 12

[0474] Compounds 12-13, 58-61, 84 were obtained using similar synthetic methods as Example 11. The characterization data of compounds 12-13, 58-61, 84 are listed in the following table:

[0475]

[0476]

[0477] Example 13

[0478]

[0479] Into a 100 mL three-necked flask, 30 mL acetonitrile, compound 17-1 (10.0 g, 1.00 eq), triethylamine (4.15 g, 1.00 eq) were added successively under N2 protection. Trifluoroacetic anhydride (9.47 g, 1.10 eq) was added in batches, and the reaction temperature was controlled at 35-40 °C. The reaction was incubated at 40 °C for half an hour. Diluted with 30 mL water, filtered, collected the filter cake, vacuum dried to obtain compound 17-2 (yellow oil, 11.8 g, yield: 85.3%).

[0480] Cesium carbonate (23.96 g, 2.50 eq), cuprous iodide (840 mg, 0.15 eq), L-proline (2.27 g, 1.0 eq) were added sequentially to a 100 mL three-necked flask, and 20 mL of N,N-dimethylformamide was added to the reaction flask and allowed to react at 25 °C for 15 minutes. Compound 17-2 (10 g, 1.00 eq) was dissolved in 10 mL of N,N-dimethylformamide and added slowly dropwise to the reaction solution, and allowed to react at 25 °C for 15 minutes. tert-Butyl acetoacetate (9.3 g, 2.00 eq) was added to the reaction solution, and allowed to react at 90 °C for 12 hours. After the reaction was completed, the contents of the vessel were cooled to 18-23 °C. Water (40 mL) was added over 15 seconds, maintaining the reaction temperature below 35 °C. Isopropyl acetate (40 mL), toluene (80 mL), and water (40 mL) were then added. The aqueous layer was drained and washed with saturated ammonium chloride solution (50 mL). The organic layer was then reduced to a minimum by vacuum distillation. Dichloromethane (30 mL) was added, and the internal temperature was adjusted to 18-23 °C. Trifluoroacetic acid (10 mL) was added and the addition was continued for 15 minutes. The solution was stirred overnight. The solid was filtered and washed twice with dichloromethane (20 mL each time). Compound 17-3 (yellow solid, 3.52 g, yield: 47.7%) was obtained.

[0481] 5 mL of 1-methyl-2-pyrrolidinone, 0.5 mL of water, compound 17-3 (1.0 g, 1.00 eq) were sequentially added to a 50 mL three-necked flask. The reaction was allowed to proceed at 130 °C for 12 hours. After cooling to room temperature, 30 mL of water was added and stirred for 40 minutes. It was then filtered. The filter cake was washed with water, and the product was dried under vacuum. Compound 17-4 (white solid, 760 mg, yield: 46.1%) was obtained by purifying the crude product by column chromatography.

[0482] 15 mL of N,N-dimethylformamide, compound 17-4 (750 mg, 1.00 eq), sodium hydride (356.85 mg, 60% purity, 2.50 eq) were sequentially added to a 50 mL three-necked flask and allowed to react at room temperature for 30 minutes. Iodomethane (1.01 g, 2.00 eq) was added to the reaction solution in portions at 0 °C, and the reaction was allowed to proceed at room temperature for 2 hours. 150 mL of ice water was added to the reaction solution, and it was extracted with ethyl acetate three times, 100 mL each time. The organic phase was combined, dried, and concentrated to dryness to obtain compound 17-5 (white solid, 790 mg, yield: 92%).

[0483] Into a 50 mL flask, 4 mL of tetrahydrofuran, compound 17-5 (790 mg, 1.00 eq), di-tert-butyl dicarbonate (769 mg, 1.00 eq), Raney nickel (1.00 g, 3.31 eq) were added sequentially, 70 °C, 50 Psi, H2, reaction for 16 hours. Filtration, rotary evaporation to give compound 17-6 (white solid, 1.62 g, crude).

[0484] Into a 50 mL flask, 4 mL of tetrahydrofuran, compound 17-5 (790 mg, 1.00 eq), di-tert-butyl dicarbonate (769 mg, 1.00 eq), Raney nickel (1.00 g, 3.31 eq) were added sequentially, 70 °C, 50 Psi, H2, reaction for 16 hours. Filtration, rotary evaporation to give compound 17-6 (white solid, 1.62 g, crude).

[0485] Into a 50 mL flask, 4 mL of tetrahydrofuran, compound 17-5 (790 mg, 1.00 eq), di-tert-butyl dicarbonate (769 mg, 1.00 eq), Raney nickel (1.00 g, 3.31 eq) were added sequentially, 70 °C, 50 Psi, H2, reaction for 16 hours. Filtration, rotary evaporation to give compound 17-6 (white solid, 1.62 g, crude). 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].

[0486] Example 14

[0487]

[0488] Compound 30-1 (10.0 g, 1.00 eq) was slowly added dropwise to 100 mL of sulfuric acid (184 g, 35.8 eq, 75% purity) at 0°C, and stirred for 10 minutes. Sodium nitrite dissolved in 81 mL of water was then slowly added dropwise at 0°C, maintaining the temperature between 5 and 10°C throughout the process. The mixture was stirred and kept in an ice-water bath for 3 hours. Then, 50 mL of ammonia was added to the reaction mixture in an ice-water bath. The reaction mixture was filtered, and the filter cake was washed with 100 mL of water and concentrated to dryness to obtain compound 30-2 (yellow solid, 9.0 g, yield: 89.6%).

[0489] 40 mL of dimethyl sulfoxide, compound 30-2 (4.0 g, 1.00 eq), trifluoroiodoethane (4.93 g, 1.50 eq), and cesium carbonate (10.2 g, 2.00 eq) were 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 mixture, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The combined organic phases were extracted twice with 100 mL of saturated brine each time. The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 25-3 (yellow solid, 1.3 g, yield: 24.6%).

[0490] 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. Tetraphenylphosphine palladium was added under a nitrogen atmosphere, and the mixture was stirred at 130 °C for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The combined organic phases were extracted twice with 50 mL of saturated brine each time. The organic phase was dried and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 30-4 (white solid, 400 mg, yield: 47.5%).

[0491] 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 tempered glass flask under an argon atmosphere. The mixture was stirred at 50 Psi and 70 °C for 12 hours under hydrogen catalysis. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 30-5 (yellow oil, 60 mg, yield: 27.7%).

[0492] 0.5 mL of ethyl acetate, compound 30-5 (100 mg, 1.00 eq), and HCl / EtOAc (1 mL) were added sequentially to a 10 mL single-necked flask, and the mixture was stirred at 25 °C for 6 hours. The reaction solution was concentrated to dryness to obtain crude compound 30-6 (yellow solid, 20 mg), which was used directly in the next reaction step.

[0493] Into a 10 mL single-necked flask, 1 mL of tetrahydrofuran, compound 30-6 (20 mg, 1.00 eq), diisopropylethylamine (10.7 mg, 1.00 eq) were added in turn, stirred for 15 minutes under nitrogen atmosphere, and then cooled to 0°C with 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 added to the reaction solution, and the reaction was carried out at 25°C for 12 hours. 10 mL of water was added to the reaction solution, and the extraction was carried out twice with 5 mL of ethyl acetate each time. The organic phase was combined and extracted twice with 5 mL of saturated brine each time. The organic phase was dried, concentrated, and dried to obtain a crude product. The crude product was purified by preparative separation to obtain compound 30 (white solid, 10 mg, yield: 24.3%). 1 H 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].

[0494] Example 15

[0495]

[0496]

[0497] Into a 100 mL three-necked flask, dichloromethane (30 mL), compound 29-1 (2.80 g, 1.00 eq), and p-fluorobenzaldehyde (4.92 g, 1.00 eq) were added in turn at room temperature, and stirred uniformly. Sodium triacetoxyborohydride (9.56 g, 2.00 eq) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. 30 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the stirring was continued for 10 minutes. After the separation of the organic phase, the aqueous phase was extracted with dichloromethane three times, 15 mL each time. The combined organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography, and then by preparative separation to obtain compound 29-2 (colorless oil, 1.20 g).

[0498] Compound 29-3 (colorless oil, 966 mg, yield: 38.8%) was obtained by the following procedure. Anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 eq), trifluoroacetic acid (15.4 g, 78.0 eq) were sequentially added to a 50 mL single-neck flask, and stirred at 25 °C for 20 minutes. The reaction solution was rotary dried to obtain a crude compound 29-4 (pale yellow oil, 850 mg, yield: 91.4%).

[0499] Compound 29-3 (colorless oil, 966 mg, yield: 38.8%) was obtained by the following procedure. Anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 eq), trifluoroacetic acid (15.4 g, 78.0 eq) were sequentially added to a 50 mL single-neck flask, and stirred at 25 °C for 20 minutes. The reaction solution was rotary dried to obtain a crude compound 29-4 (pale yellow oil, 850 mg, yield: 91.4%).

[0500] Compound 29-3 (colorless oil, 966 mg, yield: 38.8%) was obtained by the following procedure. Anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 eq), trifluoroacetic acid (15.4 g, 78.0 eq) were sequentially added to a 50 mL single-neck flask, and stirred at 25 °C for 20 minutes. The reaction solution was rotary dried to obtain a crude compound 29-4 (pale yellow oil, 850 mg, yield: 91.4%).

[0501] Compound 68A: 1H NMR (400 MHz, CDC13) 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+l].

[0502] Compound 68B: 1 H NMR (400 MHz, CDC13) 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+l].

[0503] Compound 68C: 1H NMR (400 MHz, CDC13) 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+l].

[0504] Compound 68D: 1 H NMR (400 MHz, CDC13) 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+l].

[0505] Example 16

[0506]

[0507] Into a 250 mL three-necked flask, 30 mL of methanol, compound 50-1 (2.00 g, 1.00 eq), ammonium acetate (1.37 g, 2.00 eq) were added successively, stirred at 20 °C for 1 hour, sodium cyanoborohydride (1.12 g, 2.00 eq) was added to the reaction, and the temperature was continued to be stirred at 60 °C for 12 hours until the reaction was completed. 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%).

[0508] Into a 100 mL three-necked flask, 20 mL of dichloromethane, compound 50-2 (1.80 g, 1.00 eq), 4-fluoropicolinic aldehyde (999 mg, 1.00 eq) were added successively, and stirred at 30 °C for 6 hours under nitrogen protection. Sodium borohydride (3.37 g, 2.00 eq) was added, and the stirring was continued at 30 °C for 13 hours. The temperature was lowered to room temperature, and water (10 mL) was added to quench the reaction. The mixture was extracted with dichloromethane twice, 10 mL each time. The organic phase was combined, washed with 10 mL of saturated brine twice, dried, and concentrated to dryness to obtain a crude product. The crude product was separated by high performance liquid chromatography to obtain compound 50-3 (yellow liquid, 1.30 g).

[0509] Into a 100 mL round-bottom flask, 15 mL of tetrahydrofuran, 1-trifluoroethoxy-4- pyridinylmethylamine (800 mg, 1.00 eq), N,N-diisopropylethylamine (1.00 g, 2.00 eq) were added successively, and reacted at 20 °C for 15 minutes under nitrogen protection. The reaction was lowered to 0 °C, and carbonyldiimidazole (754 mg, 1.20 eq) was added, followed by stirring for 0.5 hours. A solution of 10 mL of tetrahydrofuran, 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 completed. To the reaction mixture, 20 mL of water was added, and the mixture was extracted with ethyl acetate twice, 30 mL each time. The organic phase was combined, washed with 60 mL of saturated brine, dried, and concentrated to dryness to obtain a crude product. The crude product was separated and purified by high performance liquid chromatography to obtain compound 50-4 (yellow liquid, 900 mg, yield: 40.9%).

[0510] Into a 100 mL three-necked flask, 8 mL of dichloromethane, compound 50-4 (900 mg, 1.00 eq), trifluoroacetic acid (6.14 g, 33.9 eq) were added successively, and reacted at 10 °C for 1 hour under nitrogen protection. The reaction was concentrated to dryness to obtain compound 50-5 (yellow liquid, 910 mg, crude trifluoroacetate salt), which was directly used in the next step.

[0511] Into a 100 mL three-necked flask, 20 mL of dichloromethane, compound 50-5 (950 mg, 1.00 eq, trifluoroacetate salt), formaldehyde solution (200 mg, 1.51 eq), sodium cyanoborohydride (205 mg, 2.00 eq) were added sequentially, stirred at 25 °C for 13 hours. The reaction was quenched by adding aqueous sodium bicarbonate solution (20 mL) at 0 °C, extracted with dichloromethane twice, 30 mL each time. The organic phases were combined, dried, concentrated to dryness to give the crude product. The crude product was subjected to high performance liquid chromatography and chiral preparation (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 pm); mobile phase: [A: CO2, B: (0.1% NH3H2O IPA)]; B%: 25%-25%) to give compound 50A (retention time: 1.259 min, yellow liquid, 90.0 mg, yield: 11.2%) and 50B (retention time: 1.460 min, yellow liquid, 120 mg, yield: 14.8%).

[0512] Compound 50A: 1 H NMR (400 MHz, CDC13) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.60 (dd, Ji = 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+l].

[0513] Compound 50B: 1H NMR (400 MHz, CDC13) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.60 (dd, Ji = 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+l].

[0514] Example 17

[0515] Compounds 49A / 49B, 83A / 83B were obtained using similar synthetic and resolution procedures as described in Example 16. The following table lists the characterization data for compounds 49A / 49B, 83A / 83B:

[0516]

[0517] Example 18

[0518]

[0519] Dichloromethane (110 mL), compound 85-1 (22.0 g, 1.00 eq), compound p-fluorophenethylamine (14.0 g, 1.10 eq) were added into a 250 mL three-necked flask in turn, stirred at 20 °C for 6 hours. After the reaction was completed, sodium triacetoxyborohydride (32.3 g, 1.50 eq) was added, and the stirring was continued at 20 °C for 12 hours. After the reaction was completed, 80 mL of water was added to the reaction solution, and dichloromethane was extracted twice, 80 mL each time. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain the crude product 85-2 (yellow oil, 33.5 g, crude).

[0520] Into a 1 L three-necked flask, 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), 4-dimethylaminopyridine (6.27 g, 0.50 eq) were added sequentially at 20 °C and stirred for 1 h. After completion of the reaction, it was washed with water twice, 400 mL each time. The organic phase was combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 85-3 (yellow oil, 37.5 g, yield: 69.2%).

[0521] Into a 500 mL three-necked flask, dichloromethane (187 mL), compound 85-3 (37.5 g, 1.00 eq), trifluoroacetic acid (33.0 mL, 5.00 eq) were added sequentially at 20 °C and stirred for 12 h. After completion of the reaction, it was concentrated to dryness to obtain the crude compound 85-4 (yellow oil, 28.6 g, yield: 100%).

[0522] Into a 500 mL three-necked flask, tetrahydrofuran (286 mL), compound 85-4 (28.6 g, 1.00 eq), formaldehyde aqueous solution (33.1 mL, 37% purity, 5.00 eq) were added sequentially, sodium cyanoborohydride (11.2 g, 2.00 eq) was added in portions at 20 °C and stirred for 1.5 h. After completion of the reaction, it was adjusted to pH 8 with saturated sodium carbonate aqueous solution and extracted with dichloromethane twice, 100 mL each time. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound 85-5 (yellow oil, 34.5 g, yield: 87.7%).

[0523] Into a 1 L three-necked flask, water (217 mL), compound 85-5 (32.5 g, 1.00 eq), concentrated hydrochloric acid (325 mL, 12.0 M, 40.4 eq) were added sequentially at 100 °C and stirred for 12 h. After completion of the reaction, it was adjusted to pH 8-9 with sodium hydroxide 156 g and extracted with dichloromethane twice, 400 mL each time. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was separated by chiral separation to obtain compound 85-6 (yellow oil, 2.19 g, crude).

[0524] (1 -Methyl- 1 H-indol-5-yl)methanamine (333 mg, 1.00 eq) was added to 5 ml tetrahydrofuran, diisopropylethylamine (672 mg, 906 μL, 2.50 eq) was added. The reaction was cooled to 0 °C, carbonyldiimidazole (371 mg, 1.10 eq) was added, and stirring was continued for one hour. Compound 85-6 (500 mg, 1.00 eq) dissolved in 3 ml tetrahydrofuran was added, the reaction was warmed to 70 °C, and reacted for 12 hours. After the reaction was complete, water was added, and extraction was performed with dichloromethane. The organic phases were combined, dried, concentrated, and dried to obtain a crude product. The crude product was purified by preparative separation to obtain compound 85 (white solid, 760 mg, yield: 85.6%). 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 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%).

[0525] 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].

[0526] Compound 85B: 1H NMR (400 MHz, CDC13) 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+l].

[0527] Example 19

[0528] Using similar synthetic methods and resolution methods as Example 18 to obtain compound 86A, compound 86B; compound 87A / compound 87B. The following table lists the characterization data of compound 86A, 86B; 87A, 87B:

[0529]

[0530]

[0531] Example 20

[0532]

[0533] To hydrochloric acid (6 M, 120 mL, 17.2 eq) in a 500 mL round-bottom flask was added compound 88-1 (8 g, 41.88 mmol, 1 eq) at 0 °C. Then a solution of sodium nitrite (2.89 g, 41.88 mmol, 1 eq) in water (10 mL) was added and the reaction was stirred at 38 °C for 8 h. 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 ~ 3 / 1) to obtain compound 88-2 (3.5 g, 18.23 mmol, 43.5% yield) as a white solid.

[0534] To a mixture of compound 88-2 (2.8 g, 14.58 mmol, 1 eq) and cesium carbonate (9.50 g, 29.17 mmol, 2 eq) in dimethylformamide (28 mL) was added trifluoroethyl triflate (10.16 g, 43.75 mmol, 3 eq). The mixture was stirred at 50 °C for 1 h. 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 give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 88-3 (3 g, 10.95 mmol, 75.1% yield) as colorless oil.

[0535] To a mixture of 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), [racemic- butyldi(1-adamantyl)phosphine]methanesulfonate palladium(II) (2-amino-1,1'- biphenyl-2-yl) (93.02 mg, 0.128 mmol, 0.05 eq) in dioxane (10 mL) and water (2 mL) was purged with nitrogen for 3 times, then the reaction was stirred at 80 °C under nitrogen for 1 h. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was 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 light yellow solid.

[0536] To a solution of compound 88-4 (300 mg, 0.925 mmol, 1 eq) in dichloromethane (10 mL) was added 2-chloropyridine (315.14 mg, 2.78 mmol, 3 eq) and trifluoroacetic anhydride (391.53 mg, 1.39 mmol, 1.5 eq). The mixture was then stirred at 20 °C for 1 h, then 3-fluoro-N-[(4-fluorophenyl)methyl]-l-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 another 1 h. 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 ~ 10 / 1) and then by SFC (Chromatographic column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 pm); Mobile phase: [A: CO2, B: (0.1% NH3H2O MeOH)]; B%: 15% - 15%) to give compound 88A (retention time: 1.025 min, 123 mg, yield 26.3%) as a white solid and compound 88B (retention time: 1.231 min, 116 mg, yield 25.1%) as a white solid.

[0537] Compound 88A: 1 H NMR (400 MHz, DMSO-d6) d 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+l].

[0538] Compound 88B: 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+l].

[0539] Example 21

[0540]

[0541] Using a similar synthetic and resolution method as Example 20, compound 89A (retention time: 0.994 min, white solid) and compound 89B (retention time: 1.055 min, white solid) were obtained.

[0542] 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+l].

[0543] Compound 89B: 1H NMR (400 MHz, CDC13) 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+l].

[0544] Example 22

[0545]

[0546] Compound 5-1 (1.04 g, 1.00 eq, HC1) was added into a 100 mL three-neck flask, diisopropylethylamine (1.11 g, 2.00 eq) was added dropwise under nitrogen condition, and the mixture was stirred at 20 °C for 15 min. The reaction solution was cooled to 0 °C, and N, N'- carbonyldiimidazole (765 mg, 1.10 eq) was added portionwise. The reaction was detected to find that compound 5-1 had been completely reacted. Compound 68-1 (1.40 g, 1.00 eq) was dissolved in tetrahydrofuran (5 mL) and added slowly dropwise into the reaction solution, which was stirred at 25 °C for 12 h. The reaction solution was added with 100 mL water, and extracted with ethyl acetate for three times, 50 mL each time. The organic phase was combined, washed with 80 mL saturated brine, dried, and concentrated to dryness to obtain a crude product. The crude product was purified by column chromatography to obtain compound 68-2 (colorless oil, 966 mg, yield: 38.8%).

[0547] Anhydrous dichloromethane (27 mL), compound 68-2 (966 mg, 1.00 eq), and trifluoroacetic acid (15.4 g, 78.0 eq) were added into a 50 mL single-neck flask in sequence, and the mixture was stirred at 25 °C for 20 min. The reaction solution was rotary evaporated to dryness to obtain a crude compound 68-3 (pale yellow oil, 850 mg, yield: 91.4%).

[0548] Into a 50 mL single-neck flask, tetrahydrofuran (8 mL), compound 68-3 (800 mg, 1.00 eq), sodium cyanoborohydride (219 mg, 2.00 eq), formaldehyde (212 mg, 37%, 1.50 eq) were added successively. The reaction was stirred at 25 °C for 12 hours. To the reaction solution, 50 mL of water was added, and the organic phase was extracted with ethyl acetate three times, 30 mL each time. The organic phase was combined and washed with 40 mL of saturated brine, and the organic phase was 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, CDC13) 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].

[0549] Test Example 1. 5-HT 2A Receptor inverse agonist activity test

[0550] 1.1 Experimental materials:

[0551] Cell line: adherent cell NIH3T3-5-HT 2A R

[0552] Cell culture medium: DMEM + 10% FBS (purchased from GBICO)

[0553] Cell culture plate: white wall transparent bottom 96-well plate (purchased from Perkin Elmer)

[0554] Detection kit: Bright-Glo TM Luciferase (purchased from Promega)

[0555] Detection instrument: BioTek multifunctional enzyme marker

[0556] 1.2 Test drug

[0557] Pimavanserin: purchased from MCE company

[0558] Other compounds: prepared according to the foregoing examples

[0559] 1.3 Experimental Methods:

[0560] The logarithmic growth phase of NIH 3T3-5HT 2A R cells were seeded at a density of 1000 cells per well in 96-well plates with a clear white background and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the test compound was added to the cells at a maximum concentration of 10 μM. Nine concentrations were serially diluted 3.16-fold with PBS, with each concentration in duplicate. PBS served as the negative control, and pimozide at the same concentration served as the positive control. After drug addition, the cells were incubated at 37°C in a 5% CO2 incubator for 120 hours. On the sixth day, an equal volume of Bright-Glo... TM Luciferase reagent was added to the cells and incubated at room temperature in the dark for 20 min. The cells were shaken every 5 min, and the luminescence intensity was detected using a microplate reader. The cell inhibition rate was calculated, and the data were processed using GraphPadPrism 7.0 to obtain the cell inhibition rate curve and calculate the IC50. 50 The experimental results are shown in Table 1.

[0561] Cell inhibition rate (%) = [100 - (Lum test drug - Lum culture medium) / (Lum cell control - Lum culture medium) × 100]%

[0562] Experimental Example 2. hERG Inhibitory Activity

[0563] 1. Experimental materials and instruments

[0564] 1.1 Positive control compound

[0565] Name: Cisapride

[0566] 1.2 Solvent

[0567] Name: DMSO (Dimethyl sulfoxide)

[0568] 1.3 Cells

[0569] Species & Strain: CHO-hERG cell line (Chinese hamster ovary cells stably expressing the hERG channel)

[0570] Culture medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, 100 μg / mL Hygromycin B

[0571] Culture conditions: 5% CO2, 37℃ incubator

[0572] Freezing condition: liquid nitrogen

[0573] 1.4 Experimental instruments

[0574] Axopatch amplifier (Axoclamp 200B, Multiclamp 700B, Axon, USA)

[0575] D / A converter (DigiData 1440A, DigiData 1550B, Axon, USA)

[0576] Inverted microscope (IX51, IX71, Olympus, Japan)

[0577] Fast drug delivery system (RSC-200, Bio-Logic, France)

[0578] Micro manipulator (MX7600R, Syskiyou, USA)

[0579] Electrode puller (P-97, Sutter, USA)

[0580] Glass electrode (BF150-86-10, Sutter, USA)

[0581] Anti-vibration table and shielding net (63-534, TMC, USA)

[0582] Data acquisition and analysis software (pClamp 10, Axon, USA)

[0583] CO2 incubator (HERAcell 150i, Thermo, USA)

[0584] Bio-safety cabinet (MODEL 1384, Thermo, USA)

[0585] Milli-Q water system (Milli Q, Millipore, USA)

[0586] 2. Experimental methods

[0587] 2.1 Cell culture and treatment

[0588] CHO cells stably expressing hERG were cultured in 35 mm cell culture dishes in a 37 °C, 5% CO2 incubator and passaged at a ratio of 1:5 every 48 hours. On the day of experiment, the cell culture medium was aspirated and the cells were rinsed once with extracellular solution before the addition of 0.25% Trypsin-EDTA (Invitrogen) solution for 3-5 minutes at room temperature. The trypsin solution was aspirated and the cells were resuspended in extracellular solution and transferred to experimental dishes for electrophysiological recording.

[0589] 2.2 Compound preparation

[0590] On the day of the test, the compounds were diluted in DMSO to an intermediate concentration. 10 μL of the intermediate concentration of compound was transferred to 4990 μL of extracellular solution to give a 500-fold dilution to the final concentration required for testing.

[0591] Positive control compound Cisapride preparation: 10 μL of 150 μM Cisapride DMSO stock was transferred to 4990 μL of extracellular solution to give a 500-fold dilution to the final concentration of 300 nM required for testing.

[0592] 2.3 Electrophysiological recording procedure

[0593] CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium currents using the whole-cell patch-clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode capillaries (BF150-86-10, Sutter) using a micropipette puller and had a tip resistance of 2-5 MΩ after being filled with internal solution. The glass microelectrode was inserted into the amplifier probe to connect to the patch-clamp amplifier. The voltage-clamp and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV and the step voltage to induce hERG potassium current (I hERG ) was given a 2 s depolarization from -80 mV to +20 mV, repolarization to -50 mV for 1 s, and then back to -80 mV. This voltage stimulation was given every 10 s, and after the hERG potassium current was determined to be stable (1 min), the drug administration process was started. Each test concentration of compound was given for at least 1 min, and at least 2 cells were tested for each concentration (n≥2).

[0594] 2.4 Data processing and analysis

[0595] Data analysis was performed using pClamp 10 and GraphPad Prism 5.0 software.

[0596] The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different concentrations of compounds was calculated according to the following formula:

[0597] Inhibition% = [1 - (I / Io)] x 100%

[0598] Where Inhibition% represents the percentage inhibition of hERG potassium current by the compound, and I and Io represent the amplitudes of hERG potassium current after and before drug administration, respectively.

[0599] Compound IC 50The test results are shown in Table 1: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))

[0600] wherein X is the Log value of the test sample detection concentration, Y is the percentage of inhibition at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0601] 3. Test results

[0602] Table 1: In vitro test results of the compounds of the present application

[0603]

[0604] The results show that the 5-HT 2A reverse agonistic activity of the compounds of the present application is better than that of pimavanserin, and the cardiotoxicity is lower.

[0605] Test Example 3: In vitro liver microsomal stability evaluation

[0606] 1. Solution preparation

[0607] 1) Preparation of test sample working solution: dilute the test sample with methanol to 100 μM;

[0608] 2) Preparation of liver microsomal working solution: dilute the liver microsomes with 100 mM phosphate buffer to 0.56 mg / ml;

[0609] 3) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: weigh an appropriate amount of NADPH and dilute with phosphate buffer to 20 mM, and then add an equal volume of 60 mM MgCl2solution;

[0610] 4) Preparation of termination solution: dilute tolbutamide with acetonitrile to 20 ng / mL as the termination solution containing an internal standard.

[0611] 2. Incubation process

[0612] 1) Prepare the incubation anti-absorption EP tube, and label the species, test sample, control (testosterone, dextromethorphan), time point (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc.

[0613] 2) Add 2 μL of test sample or control working solution and 178 μL of liver microsomal working solution to each tube, and add 2 μL of acetonitrile instead of the test sample to the Blank tube, and place it in a 37°C water bath for pre-incubation for about 10 min, with 3 replicates for each sample;

[0614] 3) After the pre-incubation, 20 μL NADPH working solution was added to each tube to start the reaction, except for 0 min and NCF60, 20 μL phosphate buffer (containing 30 mM MgCl2) was added to NCF60 tube, the final concentration of test compound or control was 1 μM, the final concentration of liver microsomes was 0.5 mg / mL, the final concentration of NADPH was 1 mM, and the final concentration of MgCl2 was 3 mM;

[0615] 4) 600 μL stop solution was added to 0 min sample first, then NADPH working solution was added, after the corresponding incubation time, 600 μL stop solution was added to each sample to stop the reaction;

[0616] 5) After the reaction was stopped, each sample was vortexed for 30 s, then centrifuged at 13500 rpm for 10 min, 100 μL supernatant was taken to an EP tube, 100 μL Milli-Q water was added, vortexed, and then LC-MS / MS analysis was performed.

[0617] 6) Testosterone and dextromethorphan were used as positive control under the same conditions to detect the stability and reliability of the system.

[0618] 3. Data analysis

[0619] The remaining percentage of test compound after 60 min of testing was determined, and the results are shown in Table 2.

[0620] Table 2 Test data of compounds of the present application in human and rat liver microsomes

[0621]

[0622]

[0623] The results show that the in vitro canine and human liver microsomal stability of the compounds of the present application is better than that of pimavanserin, and the compounds have better drug-making properties.

[0624] Test Example 4. In vivo pharmacodynamic evaluation

[0625] 1. Experimental scheme

[0626] According to the in vivo pharmacokinetic data of the series of compounds, 1.0-1.5 h after a single gavage administration to SD rats, the drug reached C max At this time point, SD rats were induced to shake their heads by intraperitoneal injection of 4-iodo-2,5-dimethoxy-α-methyl-phenethylamine hydrochloride (i.e., DOI, a 5-HT 2A receptor agonist) at a dose of 2.5 mg / kg, and modeling was performed.

[0627] The low, medium and high dose groups of compound 68A were set to 0.22, 0.66, 2.0 mg / kg respectively. Pimavanserin tartrate (Pim-T) was set to 0.7 mg / kg. The administration routes of compound 68A and Pim-T were both oral gavage.

[0628] 2. Experimental grouping and administration

[0629] Compound 68A was dissolved in DMSO:20% solutol (5%:95%). SD rats (200-250 g) were randomly divided into 6 groups according to body weight: Control group, Model group, Pim-T 0.7 mg / kg group, compound 68A 0.22, 0.66, 2.0 mg / kg group, 7 animals in each group. The animal grouping and administration information is shown in Table 3.

[0630] Table 3: Animal grouping and administration

[0631]

[0632] Note: The doses of Pim-T (pimavanserin tartrate) and compound 68A are calculated as free base.

[0633] 3. Experimental operation

[0634] The rats were fasted at 17:00 the day before the test. On the test day, the animals were acclimated in the test laboratory for at least 1 h. The rats in each group were administered a single gavage dose according to Table 3. One hour after administration, all groups except the Control group were injected intraperitoneally with 2.5 mg / kg DOI, and the Control group was given an equal volume of normal saline. The rats were observed immediately after injection. The observation was randomized and double-blinded to exclude human interference. The number of head shakes in rats was recorded within 1.0-1.5 h after administration.

[0635] The test data were expressed as mean ± standard error (Mean ± SEM). Single factor variance analysis ANOVA was used to compare the differences between groups at each time point using SPSS statistics 20.0 software. All tests were two-tailed, and P<0.05 was considered statistically significant.

[0636] 4. Data analysis

[0637] The number of head shaking of the model group was significantly increased compared with the Control group (P<0.05). The number of head shaking of the Pim-T 0.7 mg / kg group was significantly reduced compared with the model group (P<0.05), and the number of head shaking of the compound 68A 0.22, 0.66, 2.0 mg / kg groups was extremely significantly reduced (P<0.01). At the equimolar dose, the number of head shaking of the compound 68A 0.66 mg / kg group was lower than that of the Pim-T 0.7 mg / kg group. The specific results are shown in Table 4 and Figure 2. Figure 1 .

[0638] Table 4: Number of head shaking of SD rats 1.0-1.5 h after single gavage administration

[0639]

[0640] Note: # P<0.05, compared with the Control group; *P<0.05, **P<0.01, compared with the Model group.

[0641] The results showed that the compound 68A could significantly inhibit the number of head shaking of rats in the dose range of 0.22-2.0 mg / kg 1.0-1.5 h after single gavage administration, and the effective dose was 0.22 mg / kg. At the equimolar dose, the compound 68A was superior to Pim-T in terms of drug efficacy.

[0642] Test Example 5: Evaluation of in vivo tissue distribution

[0643] 1. Experimental scheme

[0644] SD rats (200-250 g) were administered with the compound 68A by single gavage, and the administration dose was 11 mg / kg. At 0.25 h, 1 h, and 6 h after administration, blood plasma and brain, heart, liver, and lung tissues were taken, and there were 3 animals at each time point.

[0645] 2. Experimental operation

[0646] The rats were fasted at about 18 o'clock the day before the experiment, and water was allowed freely during the period. On the test day, the rats were weighed and randomly divided into 3 groups according to the body weight, and there was one group of animals at each time point. The compound was dissolved in DMSO:20% solutol (5%:95%), and the rats were administered with the compound 68A by single gavage, and the administration dose was 11 mg / kg, the administration volume was 5 mL / kg, and the concentration of the drug solution was 2.2 mg / mL. At each collection time point, the animals were anesthetized with ether, about 1 mL of blood was taken from the heart and placed in a heparinized EP tube, centrifuged at 10,000 rpm for 10 min, and the blood plasma was separated. Then, the brain, heart, liver, and lung tissues were taken after blood perfusion, the blood stains were absorbed with filter paper, and then weighed, and the paper was weighed and stored at -80°C for testing.

[0647] 3. Sample determination and data analysis

[0648] The plasma samples and each tissue homogenate (1:4 weight volume ratio for each tissue water homogenate) were pretreated and analyzed by LC-MS / MS to determine the concentration of the test substance in the plasma and each tissue. The experimental data were expressed as mean ± standard deviation (Mean ± SD), and the specific results are shown in Table 5.

[0649] Table 5: Concentration of compound 68A in plasma and each tissue after single gavage administration in SD rats

[0650]

[0651]

[0652] The results show that the concentration of compound 68A in the tissues is higher than that in the plasma at 0.25 h, 1 h, and 6 h after single gavage administration in SD rats, indicating that compound 68A has good permeability; in particular, the distribution in the brain tissue is relatively high, and the brain-blood ratio can reach 9.51-10.5, and the concentration in the brain is stable between 0.25-6 h.

Claims

1. A compound having the structure shown below, a pharmaceutically acceptable salt, or a stereoisomer thereof:

2. A pharmaceutical composition comprising a compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier.

3. Use of a compound of claim 1, a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition of claim 2 in the manufacture of a medicament for the treatment of a 5-HT 2A receptor-related disorder.

4. The use according to claim 3, wherein the 5-HT 2A The 5-HT receptor-related disease is dementia.

5. Use according to claim 3, wherein the 5-HT 2A The disease associated with the 5-HT receptor is a mental disease associated with dementia.

6. Use according to claim 3, wherein the 5-HT 2A The 5-HT receptor-related disease is Alzheimer's disease.

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