Heterocyclic fused gamma-carboline compound, pharmaceutical composition, preparation method and application thereof

Abstract

The invention relates to a heterocyclic fused gamma-carboline compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutical composition containing the heterocyclic fused gamma-carboline compound. The compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and pharmaceutical compositions have agonistic activity against 5-HT receptors, and can be used as 5-HT receptor agonists for the prevention or treatment of diseases or various CNS diseases or conditions related to the activity or expression level of 5-HT receptors. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to heterocyclic fused γ-carboline compounds, including their pharmaceutically acceptable salts and stereoisomers, which are selective agonists of 5-hydroxytryptamine receptors (5-HT) and can be used as therapeutic compounds, especially in the treatment and / or prevention of various CNS diseases or disorders. Background Art

[0002] Depression is a type of mental illness characterized by affective disorders. Its clinical features are significant and persistent low mood, accompanied by decreased interest, pessimism, slow thinking, and even suicidal behavior, which seriously limits psychosocial functions and reduces the quality of life. There are more than 350 million people suffering from depression worldwide, with an increase of 18% in the past decade.

[0003] Antidepressants are a recognized and effective treatment method. The main antidepressants currently include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), etc. SSRI is currently the first-line clinical treatment drug. Compared with traditional tricyclic antidepressants, it has better tolerance and higher safety. It works by inhibiting the reabsorption of the central neurotransmitter serotonin (5-HT) and increasing the concentration of 5-HT in the synaptic cleft. However, SSRIs are slow to take effect, and patients usually need to take the medicine for several weeks before it takes effect. And about 30-60% of patients do not respond adequately to the initial treatment drugs. Therefore, there is an urgent need to develop new antidepressants.

[0004] In March 2019, the US FDA approved S-ketamine as a nasal spray for the combined treatment of patients with refractory depression (Am J Psychiatry, 2019, 176(6): 428-438; JAMA Psychiatry, 2019, 76(9): 893-903.). Esketamine is the first drug approved by the FDA for depression with a new mechanism of action in 30 years. In terms of mechanism of action, esketamine is a non-selective N-methyl-D-aspartate (NMDA) receptor antagonist (Zhang et al.; Nature, 2021, 596(7871): 301-305). Esketamine has a rapid onset of action and can maintain therapeutic response with continuous use, which to some extent solves the problem of slow onset of action of traditional antidepressants. However, since it is a type of psychotropic drug, it is inconvenient to use clinically and there is a risk of sedation, cognitive impairment, dissociation and abuse. It also needs to be used in combination with first-line antidepressants to be effective, which limits its widespread use in clinical practice.

[0005] Psychedelics have great potential in treating depression, anxiety, drug addiction, post-traumatic stress disorder (PTSD) and other diseases (Nutt et al., Cell, 2020, 181(1): 24-28). Psilocybin is a tryptamine alkaloid found in Psilocybin mushrooms. In the second phase of clinical trials, it showed rapid onset and lasting relief of depression (N Engl J Med. 2022, 387(18): 1637-1648). However, psilocybin has neuropsychedelic effects and the risk of abuse, and its clinical application will be subject to many restrictions. Current studies believe that psilocybin and other hallucinogens activate 5-HT 2A Receptor activation of different signaling pathways in cells produces hallucinations or antidepressant effects. The hallucinogenic effect of hallucinogens is closely related to the simultaneous activation of the 5-HT2A-Gq and β-arrestin2 transduction pathways. By changing the binding mode of ligands to receptors, the downstream β-arrestin signal is preferentially activated, which can separate the hallucinogenic effect from the antidepressant effect, thereby retaining the antidepressant effect without producing hallucinogenic effects (Science. 2022, 375 (6579): 403-411).

[0006] Although a lot of meaningful research has been conducted in this field, there is still a need to continue researching and developing more effective small molecule 5-HT receptor agonists. Summary of the invention

[0007] The invention provides a 5-HT receptor agonist with a novel structure, and finds that the compound with such structure has good 5-HT receptor agonist activity.

[0008] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof,

[0009]

[0010] in,

[0011] X1 is selected from N-R1, or O;

[0012] X2 is selected from CH2, or CH2CH2;

[0013] R1 is selected from H, or C 1-6 alkyl;

[0014] Selected from single bonds, or double bonds

[0015] L1 is selected from a bond, -O-, or -CR 1a R 1b ;

[0016] L2 is selected from a bond, -O-, or -CR 2a R 2b ;

[0017] L3 is selected from a bond, -O-, or -CR 3a R 3b ;

[0018] L4 is selected from a bond, -O-, or -CR 4a R 4b ;

[0019] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl;

[0020] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together they form an oxo group;

[0021] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0022] or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0023] R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by one or more R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, C 3-6 Cycloalkoxy or oxo;

[0024] R6, R7, and R8 are each independently selected from H or halogen.

[0025] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, X1 is selected from N-R1, or O; R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b together to form an oxo group; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4bTogether with the carbon atom to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; the other variables are as defined herein.

[0027] In some embodiments of the present invention, in the compound of formula (I), its pharmaceutically acceptable salt or stereoisomer, R4 is selected from phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl, and the phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl is optionally substituted by R5, and the R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or oxo; other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, or 2,2,2-trichloroethoxy; other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R6, R7, R8 are each independently selected from H, F, Cl, Br, or I; other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the present invention provides a compound represented by formula (IA) or (IB), a pharmaceutically acceptable salt or stereoisomer thereof,

[0032]

[0033] in,

[0034] X1 is selected from N-R1, or O;

[0035] X2 is selected from CH2, or CH2CH2;

[0036] R1 is selected from H, or C 1-6 alkyl;

[0037] L1 is selected from a bond, -O-, or -CR 1a R 1b ;

[0038] L2 is selected from a bond, -O-, or -CR 2a R 2b ;

[0039] L3 is selected from a bond, -O-, or -CR 3a R 3b ;

[0040] L4 is selected from a bond, -O-, or -CR 4a R 4b ;

[0041] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl;

[0042] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together they form an oxo group;

[0043] or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0044] or R 1a / R 1b With R 2a / R 2b , R2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0045] R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by one or more R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, C 3-6 Cycloalkoxy or oxo;

[0046] R6, R7, and R8 are each independently selected from H or halogen.

[0047] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, X1 is selected from N-R1, or O; R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b together to form an oxo group; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; or R 1a / R1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atom to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; the other variables are as defined herein.

[0049] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, R4 is selected from phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl, and the phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl is optionally substituted by R5, and the R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or oxo; other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, or 2,2,2-trichloroethoxy; other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, in the compound represented by formula (IA) or (IB), its pharmaceutically acceptable salt or stereoisomer, R6, R7, R8 are each independently selected from H, F, Cl, Br, or I; other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt thereof,

[0054]

[0055] in,

[0056] X1 is selected from N-R1, or O;

[0057] R1 is selected from H, or C 1-6 alkyl;

[0058] L1 is selected from a bond, -O-, or -CR 1a R 1b ;

[0059] L2 is selected from a bond, -O-, or -CR 2a R 2b ;

[0060] L3 is selected from a bond, -O-, or -CR 3a R 3b ;

[0061] L4 is selected from a bond, -O-, or -CR 4a R 4b ;

[0062] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl;

[0063] R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, oxo.

[0064] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, X1 is selected from N-R1, or O; R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; other variables are as defined in the present invention.

[0065] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atom to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; the other variables are as defined herein.

[0066] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R4 is selected from phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl, and the phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl is optionally substituted by R5, and the R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0067] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, or 2,2,2-trichloroethoxy; other variables are as defined in the present invention.

[0068] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the present invention provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof,

[0070]

[0071] in,

[0072] X1 is selected from N-R1, or O;

[0073] R1 is selected from H, or C 1-6 alkyl;

[0074] L1 is selected from a bond, -O-, or -CR 1a R 1b ;

[0075] L2 is selected from a bond, -O-, or -CR 2a R 2b ;

[0076] L3 is selected from a bond, -O-, or -CR 3a R 3b ;

[0077] L4 is selected from a bond, -O-, or -CR 4a R 4b ;

[0078] R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a, R 4b Each independently selected from H, or C 1-5 alkyl;

[0079] R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, oxo.

[0080] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, X1 is selected from N-R1, or O; R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; other variables are as defined in the present invention.

[0081] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each is independently selected from H, methyl, ethyl, n-propyl, or isopropyl; other variables are as defined herein.

[0082] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, R4 is selected from phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl, and the phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl is optionally substituted by R5, and the R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0083] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, or 2,2,2-trichloroethoxy; other variables are as defined in the present invention.

[0084] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, the R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; other variables are as defined in the present invention.

[0085] In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

[0086]

[0087] In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

[0088]

[0089]

[0090] In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

[0091]

[0092] The present invention provides a pharmaceutical composition, comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections or various sustained-release preparations, etc. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously or topically). The dosage can be appropriately adjusted according to the patient's age, gender and disease type, and the general daily dose is about 1-200 mg.

[0093] The present invention provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts and stereoisomers for treating and / or preventing patient diseases, and the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs. The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts and stereoisomers for treating and / or preventing diseases related to the activity or expression of 5-HT receptors. The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs, which are used to prevent or treat CNS-related diseases. The diseases associated with the activity or expression of 5-HT receptors, and / or CNS-related diseases include: refractory depression, depression, bipolar disorder, body dysmorphic disorder, anxiety, mood disorders, mania, obsessive-compulsive disorder, post-traumatic stress disorder, trauma and stress-related diseases, borderline personality disorder, cognitive disorder, burnout, opioid dependence, nicotine dependence, amphetamine dependence, alcohol dependence, substance-related disorders, pain, anorexia nervosa, binge drinking-eating disorder, sleep disorder, fibromyalgia, psychological distress, post-Lyme syndrome, perceptual disorder, limb pain, amnesia, Alzheimer's disease, migraine, cluster headache, gastroesophageal reflux disease, gastrointestinal motility disorders, chemotherapy-induced nausea, constipation, irritable bowel syndrome; or other disease states and conditions obvious to those skilled in the art.

[0094] Definition and Description

[0095] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0096] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0097] The "pharmaceutically acceptable salts" mentioned in the present invention refer to salts of the compounds of the present invention, which are prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids and bases. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; they also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic functional groups and can be converted into any acid addition salt.

[0098] Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0099] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0100] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of the salt is: in water or an organic solvent or a mixture of the two, through the reaction of these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid to prepare.

[0101] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0102] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0103] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). For example, C1-C6 means 1 to 6 carbon atoms, C 1-10 Selected from C1, C2, C3, C4, C5, C6; examples of alkyl include, but are not limited to, 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), etc.

[0104]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0105] Unless otherwise specified, the term "haloalkoxy" is used to indicate that an alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein. For example, the term "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, C6 alkoxy groups substituted with one or more halogen atoms, etc. Unless otherwise specified, examples of C1-C6 haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0106] Unless otherwise specified, the term "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or polyvalent. For example, C3-C6 cycloalkyl represents a cycloalkyl radical of 3 to 6 carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0107] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heterocyclic group preferably contains 3-14 ring atoms, and further preferably contains 5-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, dioxanyl, etc. Examples of bicyclic heterocyclyl include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

[0108] Unless otherwise specified, the term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, for example, phenyl and naphthyl.

[0109] Unless otherwise specified, the term "heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more carbocyclyls or heterocyclyls, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

[0110] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indolinyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0111] Unless otherwise specified, the term "oxo" means "=0".

[0112] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0113] The present invention is further described below in conjunction with specific embodiments and test examples, but the scope of the present invention is not limited in any form.

[0114] Example 1

[0115]

[0116] Dissolve compound 1-1 (229 mg, 1.00 mmol) in dioxane (10 mL), add triethylamine (304 mg, 3.00 mmol) and compound 1-2 (324 mg, 1.20 mmol). React at 85 °C for 8 h. Add water (30 mL) to quench, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude oil. Manually fill a silica gel column for column chromatography purification (DCM: CH3OH = 20: 1) to obtain compound 1 (210 mg, yield 50.2%, light yellow solid). LCMS = 419.2 [M+1]+ . 1 H NMR(600MHz, DOCD3)δ7.09(dt,J=8.3,1.1Hz,1H),6.64–6.57(m,2H),6.53–6.48(m,2H),6.44(dd, J=8.0,0.9Hz,1H),4.12(t,J=5.6Hz,2H),3.58–3.48(m,1H),3.39(dt,J=10.2,3.0Hz,1H),3.32–3 .29(m,1H),3.16(dd,J=8.8,5.0Hz,2H),3.00(ddd,J=11.9,4.9,1.9Hz,1H),2.91–2.87(m,2H),2. 86(s,4H),2.83–2.75(m,3H),2.59–2.53(m,2H),2.47(td,J=11.9,3.3Hz,1H),2.13–1.95(m,3H).

[0117] Compounds 2 and 4A were synthesized by a method similar to that of Compound 1 in Example 1. The structures / numbers and characterization data of the compounds are shown in the following table:

[0118]

[0119] Example 2

[0120]

[0121] Dissolve compound 3-1 (219 mg, 1.00 mmol) in dioxane (10 mL), add triethylamine (304 mg, 3.00 mmol) and compound 3-2 (234 mg, 1.20 mmol). React at 85 °C for 8 h. Add water (30 mL) to quench, extract with ethyl acetate (30 mL × 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude oil. Manually fill a silica gel column for column chromatography purification (DCM: CH3OH = 20: 1) to obtain compound 3 (144 mg, yield 38.8%, light yellow solid). LCMS = 362.2 [M + 1] + . 1H NMR(600MHz,DMSO-d6)δ10.53(s,1H),7.22–7.12(m,2H),6.95(d,J=8.0Hz ,1H),6.92–6.84(m,2H),6.80(s,1H),6.71(d,J=8.1Hz,1H),6.22(d,J=7.6 Hz,1H),3.79(s,4H),3.20–2.88(m,4H),2.75(s,1H),2.66(ddd,J=15.4,1 0.9,1.7Hz,1H),2.59(t,J=7.7Hz,2H),1.78(s,2H),1.24(d,J=5.3Hz,2H).

[0122] Example 3

[0123]

[0124] Step 1 Synthesis of Compound 5-2

[0125] Sodium hydride (2.46 g, 61.41 mmol, purity: 60%) was slowly added in batches to a solution of intermediate 5-1 (5 g, 40.94 mmol) in N,N-dimethylformamide (50 mL) under a nitrogen atmosphere at 0°C. After reacting at 0°C for 0.5 hours, (E)-methyl 4-bromo-2-butenoate (8.79 g, 49.13 mmol) was slowly added dropwise to the reaction, and the temperature was slowly raised to 25°C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into an icy ammonium chloride aqueous solution (100 mL) to quench, and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine (100 mL×3), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 5-2 (5 g, 22.70 mmol, white solid, yield: 55.4%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 10.55 (s, 1H), 7.87 (dd, J = 1.6, 7.6Hz, 1H), 7.63-7.50 (m, 1H), 7.19-7.0 5(m,2H),6.94(d,J=8.4Hz,1H),6.23(td,J=2.0,15.6Hz,1H),4.84(dd,J=2.0,4.0Hz,2H),3.78(s,3H).

[0126] Step 2 Synthesis of compound 5-3

[0127] Sodium borohydride (0.33 g, 8.72 mmol) was slowly added to a methanol (15 mL) solution of intermediate 5-2 (4 g, 18.16 mmol) at 0°C and reacted at 0°C for 1 hour. After the reaction, the reaction solution was poured into an aqueous solution of glacial ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 5-3 (4 g, 18.00 mmol, colorless oil, yield: 99.0%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.36 (dd, J = 1.6, 7.2Hz, 1H), 7.30-7.24 (m, 1H), 7.12 (td, J = 4.0, 15.6Hz, 1H) ,7.00(t,J=7.2Hz,1H),6.84(d,J=8.0Hz,1H),6.19(td,J=2.0,15.6Hz,1H),4.80-4.74(m,4H),3.77(s,3H).

[0128] Step 3 Synthesis of compound 5-4

[0129] Phosphorus tribromide (1.95 g, 7.20 mmol) was slowly added to a tetrahydrofuran (40 mL) solution of intermediate 5-3 (4 g, 18.00 mmol) at 0°C and reacted at 0°C for 1 hour. After the reaction, the reaction solution was poured into an icy sodium bicarbonate solution (100 mL) to quench, and extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 5-4 (4 g, 14.03 mmol, white solid, yield: 77.94%). 1 HNMR(400MHz,CHLOROFORM-d)δ=7.36(dd,J=1.2,7.6Hz,1H),7.32-7.27(m,1H),7.13(td,J=4.0,15.6Hz,1H),6.97(t,J =7.6Hz,1H),6.83(d,J=8.4Hz,1H),6.31(td,J=2.0,15.6Hz,1H),4.80(dd,J=2.0,3.6Hz,2H),4.60(s,2H),3.78(s,3H).

[0130] Step 4 Synthesis of compound 5-5

[0131] Triphenylphosphine (5.52 mg, 21.04 mmol) was added to a solution of intermediate 5-4 (4 g, 14.03 mmol) in ethyl acetate (160 mL) and stirred at 60 ° C for 1 hour, then cesium carbonate (13.71 g, 42.09 mmol), water (631.99 g, 35.07 mmol), ethyl acetate (80 mL) were added to the reaction, and the temperature was raised to 80 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered, poured into ice water (100 mL) for dilution, and extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 5-5 (2.5 g, 12.12 mmol, colorless oil, yield: 86.41%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.15-7.07 (m, 1H), 7.03 (d, J = 7.2Hz, 1H), 6.90-6.75 (m, 2H), 4.28-4. 19(m,1H),3.94-3.84(m,1H),3.72(s,3H),3.03-2.90(m,1H),2.62-2.51(m,2H),2.50-2.28(m,2H).

[0132] Step 5 Synthesis of Compound 5-6

[0133] Under nitrogen, a tetrahydrofuran solution of lithium aluminum tetrahydride (110.42 mg, 2.1 mmol, 2.5 M, 1.16 mL) was added dropwise to a tetrahydrofuran solution of intermediate 5-5 (500 mg, 2.42 mmol) (5 mL) at 0 ° C, and the reaction was carried out at 25 ° C for 3 hours. After the reaction, the reaction solution was quenched with 3 ml of water, 3 mL of (15%) sodium hydroxide solution and 9 mL of water, then filtered and washed with ethyl acetate (50 mL), the filtrate was washed with saturated brine (50 mL × 3), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain intermediate 5-6 (370 mg, 2.08 mmol, colorless oil, yield: 85.6%). 1H NMR(400MHz,CHLOROFORM-d)δ=7.16-6.98(m,2H),6.89-6.75(m,2H),4.31-4.21(m,1H),3.89-3.77(m, 3H), 2.92 (dd, J=5.2, 16.0Hz, 1H), 2.54 (dd, J=8.8, 16.4Hz, 1H), 2.32-2.17 (m, 1H), 1.79-1.52 (m, 3H).

[0134] Step 6 Synthesis of Compound 5-7

[0135] Triphenylphosphine (816.76 mg, 3.11 mmol, purity 37%) and carbon tetrabromide (1.03 g, 3.11 mmol) were added to the intermediate 5-6 (370 mg, 2.08 mmol) in dichloromethane (5 mL) at 0 ° C, and the mixture was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into an ice sodium bicarbonate solution (50 mL) to quench, and extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain intermediate 5-7 (400 mg, 1.66 mmol, colorless oil, yield: 79.9%). 1 H NMR(400MHz, CHLOROFORM-d)δ=7.14-7.08(m,1H),7.05(d,J=7.2Hz,1H),6.90-6.84(m,1H),6.81(d,J=8.0Hz,1H),4.27-4.18(m,1H),3.88( dd,J=8.0,10.8Hz,1H),3.62-3.47(m,2H),2.96(dd,J=5.4,16.0Hz,1H),2.51(dd,J=8.0,16.0Hz,1H),2.41-2.27(m,1H),2.07-1.83(m,2H).

[0136] Step 7 Synthesis of Compound 5

[0137] At 25°C, intermediate 5-8 (235 mg, 1.02 mmol, purity 37%) and triethylamine (414.78 mg, 4.10 mmol) were added to 3-pentanone (5 mL) of intermediate 5-7 (247.10 mg, 1.02 mmol), and stirred for 12 hours at 80°C under nitrogen protection. After the reaction was completed, it was cooled to room temperature to avoid oxidation of the product due to high temperature contact with air, and then concentrated under reduced pressure. The crude product was purified by preparative Prep-HPLC separation method (Basic condition, column model: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 45%-75% Bover 10min) to obtain compound 5A (210 mg, 0.515 mmol, colorless oil, yield: 50.17%). LCMS: 390.1 [M+H] + . 1 HNMR(400MHz,CHLOROFORM-d)δ=7.13-6.99(m,2H),6.90-6.76(m,2H),6.71-6.62(m,1H),6 .53(d,J=7.2Hz,1H),6.42(d,J=8.0Hz,1H),4.33-4.18(m,1H),3.85-3.73(m,1H),3.67-3. 55(m,1H),3.40-3.21(m,3H),3.20-3.10(m,1H),2.98-2.76(m,6H),2.74-2.63(m,1H),2.5 6-2.37(m,3H),2.33-2.20(m,1H),2.15-2.03(m,1H),2.02-1.86(m,3H),1.65-1.45(m,2H).

[0138] Compound 7A was synthesized by a method similar to that of Compound 5 in Example 3. The structures / numbers and characterization data of each compound are shown in the following table:

[0139] Example 4

[0140]

[0141] Step 1 Synthesis of Compound 9-2

[0142] The reactant 9-1 (5 g, 33.75 mmol, 1 eq) was dissolved in toluene (40 mL) and replaced with nitrogen protection. DIBAL-H (diisobutylaluminum hydride, 1 M, 12.00 g, 84.37 mmol, 2.5 eq) was added at 20 ° C. The reaction solution was stirred at 20 ° C for 0.3 hours. After the reaction was complete as monitored by TLC (PE / EA = 1: 1), 1M hydrochloric acid (100 mL) was added dropwise to the reaction solution at 0 ° C to quench the reaction, and 100 mL of ethyl acetate was added. Extracted three times with 200 mL. After the organic phases were combined, they were washed with 100 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product 9-2 (3.8 g, colorless oil, yield 73.99%) was obtained.

[0143] Step 2 Synthesis of compound 9-3

[0144] Intermediate 9-2 (2.21 g, 14.55 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.75 g, 29.09 mmol) were dissolved in N,N-dimethylformamide (40 mL), and cesium carbonate (14.24 g, 43.69 mmol) was added to the mixture, and the mixture was reacted at 25°C for 1 hour. After the reaction was completed by LCMS, the reaction solution was poured into ice water (40 mL), extracted three times with 50 mL of ethyl acetate, the organic phases were combined and washed twice with saturated brine (40 mL), and the organic phases were concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain intermediate 9-3 (1.11 g, yield 32.55%, yellow oil). 1 H NMR(400MHz,CHLOROFORM-d)δ=7.25-7.17(m,2H),7.04–6.97(m,1H),6.81(d,J=8.0Hz,1H ),4.37(q,J=8.0Hz,2H),3.66(t,J=6.4Hz,2H),2.76(t,J=8.0Hz,2H),1.81-1.93(m,2H).

[0145] Step 3 Synthesis of compound 9-4

[0146] Intermediate 9-3 (906 mg, 3.87 mmol) and triphenylphosphine (2.03 g, 7.74 mmol) were dissolved in dichloromethane (27 mL) and nitrogen was replaced three times. Carbon tetrabromide (2.57 g, 7.74 mmol) was slowly added at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 25 ° C for 1 hour. TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain intermediate 9-4 (1.14 g, yield 99.19%, yellow oil). 1H NMR(400MHz,CHLOROFORM-d)δppmδ=7.25-7.19(m,2H),7.04–6.97(m,1H),6.84-6.78(m ,1H),4.37(q,J=8.4Hz,2H),3.41(t,J=6.4Hz,2H),2.82(t,J=7.2Hz,2H),2.16(m,2H).

[0147] Step 4 Synthesis of Compound 9B

[0148] Intermediate 9-4 (110 mg, 0.51 mmol) and compound 13-16 (170.76 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (3 mL) and triethylamine (154 mg, 1.52 mmol) was added dropwise. The mixture was stirred at 50°C for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was purified by reverse phase separation (0.1% formic acid system and 0-30% acetonitrile) to obtain compound 9B (95.5 mg, yellow oil, yield 98.87%). LCMS: 433.2 [M+H] + . 1 H NMR(400MHz, CHLOROFORM-d)δppmδ=7.22-7.14(m,2H),7.02–6.95(m,1H),6.79(d,J=8.4Hz,1H),6.73-6.57(m,3H),4.51-4.41(m,2H),4.36(q,J=8.0Hz ,2H),3.33-3.24(m,2H),3.23-3.14(m,1H),2.95-2.87(m,1H),2.80-2.62(m ,4H),2.47-2.34(m,2H),2.32-2.21(m,1H),2.10–1.91(m,3H),1.82(m,2H).

[0149] Example 5

[0150]

[0151] Step 1 Synthesis of compound 10-2

[0152] The raw material 10-1 (3 g, 21.19 mmol) was dissolved in methanol (100 mL), cooled to 0°C, and sodium methoxide (1.72 g, 31.79 mmol) was slowly added. The mixture was reacted at 60°C for 12 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The intermediate 10-2 (0.95 g, yellow oil, yield 32.69%) was obtained by purification by silica chromatography (petroleum ether / ethyl acetate = 0 / 1). 1H NMR (400MHz, CHLOROFORM-d) δ = 10.45 (s, 1H), 8.89 (s, 1H), 8.70-8.60 (m, 1H), 7.00-6.90 (m, 1H), 4.00 (s, 3H).

[0153] Step 2 Synthesis of compound 10-4

[0154] The raw material 10-2 (0.80 g, 5.83 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and the raw material 10-3 (2.03 g, 5.83 mmol) was slowly added. The mixture was reacted at 25°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The intermediate 10-4 (1.2 g, white solid, crude product) was obtained by purification by silica chromatography (dichloromethane / methanol = 10 / 1). LCMS: 208.0 [M+H] + .

[0155] Step 3 Synthesis of compound 10-5

[0156] The raw material 10-4 (1 g, 4.83 mmol) was dissolved in methanol (10 mL), the nitrogen was replaced three times, Pd / C (100 mg) and palladium hydroxide (100 mg) were added, the hydrogen was replaced three times, and the mixture was reacted at 25°C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain the crude product intermediate 10-5 (1 g, yellow oil). LCMS: 210.0 [M+H] + .

[0157] Step 4 Synthesis of compound 10-6

[0158] The raw material 10-5 (800 mg, 3.82 mmol) was dissolved in tetrahydrofuran (10 mL), the nitrogen was replaced three times, and lithium aluminum tetrahydride solution (2.5 M, 2.29 mL) was slowly added dropwise at 0°C, and the mixture was reacted at 25°C for 2 hours. After the reaction, the reaction solution was cooled to 0°C, 0.3 mL of H2O, 0.3 mL of 15% NaOH aqueous solution and 0.9 mL of H2O were slowly added dropwise to quench the reaction, and the crude product was dried and filtered over anhydrous sodium sulfate. The intermediate 10-6 (460 mg, colorless oil) was obtained by purification by silica chromatography (dichloromethane / methanol = 10 / 1). LCMS: 168.3 [M+H] + .

[0159] Step 5 Synthesis of compound 10-7

[0160] Oxalyl chloride (1.06 g, 8.37 mmol) was added to a dichloromethane solution (1.5 mL) to replace nitrogen three times and cooled to -60 ° C, then dimethyl sulfoxide (1.31 mL, 16.75 mmol) in dichloromethane solution (1.5 mL) was slowly added dropwise at -60 ° C, and then compound 10-6 (280 mg, 1.67 mmol) in dichloromethane solution (1.5 mL) was slowly added dropwise at -60 ° C. After the addition was completed, the mixture was reacted at -60 ° C for 1 hour. After the reaction was completed, a dichloromethane solution (2 mL) of triethylamine (1.86 g, 18.42 mmol) was slowly added dropwise at -60 ° C to quench the reaction, and extracted with dichloromethane (10 mL × 3). The separated organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 10-7 (6.00 g, yellow solid, crude product). 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.82 (s, 1H), 8.44 (d, J = 6.0Hz, 1H), 8.32 (s, 1H), 6.88 (d, J = 5.6Hz, 1H), 2.97-2.93 (m, 2H), 2.79-2.73 (m, 2H).

[0161] Step 6 Synthesis of Compound 10B

[0162] The raw material 10-7 (300.00 mg, crude product), intermediate 13-16 (314.23 mg, 1.45 mmol), sodium cyanoborohydride (570.64 mg, 9.08 mmol) and acetic acid (927.01 mg, 15.44 mmol) were dissolved in anhydrous ethanol (10 mL), and the mixture was reacted at 25 ° C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by reverse phase separation (0.1% ammonia system and 0-60% acetonitrile) to obtain product 10B (42.50 mg, yellow solid). LCMS: 366.1 [M+H] + . 1H NMR (400MHz, CHLOROFORM-d) δ = 8.36 (d, J = 5.6Hz, 1H), 8.26 (s, 1H), 6.75 (d, J = 5.6Hz, 1H), 6.72-6.67 (m, 1H), 6.66-6.60 (m, 2H), 4.51-4.41 (m 2H),3.87(s,3H),3.35-3.23(m,2H),3.22-3.13(m,1H),2.95-2.83(m,1H),2.81-2.5 8(m,4H),2.45-2.22(m,3H),2.07-1.99(m,1H),1.98-1.90(m,2H),1.86-1.76(m,2H).

[0163] Example 6

[0164]

[0165] Step 1 Synthesis of compound 11-3

[0166] Add the raw material 11-1 (2.3 g, 15.32 mmol, 1 eq) and the hydrochloride of the raw material 11-2 (2.29 g, 15.32 mmol, 1 eq, HCl) to an ethanol solution (25 mL), and slowly dropwise add a hydrochloric acid solution (12 M, 1.53 mL). The reaction solution was stirred at 90 ° C for 3 hours. After the reaction was completed by LCMS detection, the reaction solution was concentrated. The crude product was purified by reverse phase separation (0.1% hydrochloric acid system and acetonitrile: 0%-45%) and freeze-dried to obtain the intermediate 11-3 (2.1 g, yellow oil, yield 60%). LCMS: 229.1 [M+H] + .

[0167] Step 2 Synthesis of compound 11-4

[0168] The raw material 11-3 (1.6 g, 7.01 mmol, 1 eq) was added to a trifluoroacetic acid solution (20 mL), the reaction solution was cooled to 0 ° C, and sodium cyanoborohydride (1.32 g, 21.03 mmol, 3 eq) was added in batches at 0 ° C. Then stirred at 20 ° C for 1 hour. After the reaction was completed by LCMS, the reaction solution was concentrated. The crude product was purified by reverse phase separation (0.1% trifluoroacetic acid system and acetonitrile: 0%-45%). The resulting solution was adjusted to pH = 9 with sodium bicarbonate, extracted with ethyl acetate (50 mL × 3), and the separated organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 11-4 (1.5 g, yellow oil, yield 92.93%). LCMS: 231.1 [M + H] + .

[0169] Step 3 Synthesis of compound 11

[0170] Raw material 11-4 (500 mg, 2.17 mmol, 1 eq) and raw material 11-5 (497.41 mg, 2.17 mmol, 1 eq) were added to a DMF solution (5 mL), and then triethylamine (659.05 mg, 6.51 mmol, 3 eq) was added. The reaction solution was stirred at 50 ° C for 12 hours. After the reaction was completed by LCMS, the reaction solution was concentrated. The crude product was purified by reverse phase separation (0.1% trifluoroacetic acid system and acetonitrile: 0%-45%) and freeze-dried to obtain intermediate 11 (400 mg, yellow oil, yield 44.78%). LCMS: 379.2 [M+H] + .

[0171] Step 4 Synthesis of compounds 11A and 11B

[0172] The racemate 11 (400 mg) was purified by chiral preparative column chromatography (column model: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um); mobile phase: [CO2-ACN / i-PrOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode. RT1=1.532 min, RT2=1.782 min). The two peaks P1 and P2 were respectively spin-dried, and then purified by reverse phase separation (0.1% ammonia system and acetonitrile: 0%-45%) and freeze-dried to obtain compound 11A (96.7 mg, white solid). LCMS: 379.2 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.22-7.07 (m, 2H), 6.91-6.80 (m, 2H), 6.68-6.57 (m, 3H), 4.51-4.26 (m, 2H), 3.82 (s, 3H), 3.71-3.57 (m, 1H), 3.49-3.36 (m, 1H), 3.18-3.21 (m, 1H), 3.02-2.75 (m, 3H), 2.71-2.36 (m, 6H), 2.27-1.74 (m, 6H). And compound 11B (87.4 mg, white solid). LCMS: 379.2 [M+H] + . 1H NMR(400MHz,CHLOROFORM-d)δ=7.22-7.09(m,2H),6.93-6.81(m,2H),6.70-6.54(m,3H),4.49-4.31(m,2H),3.82(s,3 H),3.71-3.59(m,1H),3.47-3.37(m,1H),3.26-3.15(m,1H),2.98-2.78(m,3H),2.74-2.38(m,6H),2.24-1.77(m,6H).

[0173] Example 7

[0174]

[0175] Step 1 Synthesis of compound 12-2

[0176] The raw material 12-1 (25 g, 187.76 mmol) was dissolved in acetone (300 mL), and potassium carbonate (64.87 g, 469.41 mmol) and ethyl bromoacetate (40.76 g, 244.09 mmol) were added to the mixture in sequence. The reaction solution was stirred at 25 ° C for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a normal phase chromatography column (Welch Ultimate XB-CN 250mm×100mm×10um,

[0177] [Hexane-EtOH] 5-45% ethanol). After concentration, intermediate 12-2 (39.85 g, yellow solid, yield 96.81%) was obtained.

[0178] LCMS: 220.0 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ=8.23(br s,1H),7.15-7.12(t,J=2.8Hz,1H),7.12-7.05(m,2H),6.74(t,J=2.8Hz,1H),6.47-6 .42(dd,J=2.0,6.4Hz,1H),4.79(s,2H),4.30(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).

[0179] Step 2 Synthesis of compound 12-3

[0180] Intermediate 12-2 (39.85 g, 181.77 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL). Then, sodium hydride (9.45 g, 236.36 mmol, 60% purity) was added to the mixture in batches at 0°C under nitrogen protection. After the reaction solution was stirred at 0°C for 0.5 hours, (trimethylsilyl)ethoxymethyl chloride (36.37 g, 218.12 mmol) was added to the reaction solution. The reaction solution was stirred at 25°C for 10 hours. After the reaction was completed by LCMS detection, the reaction solution was poured into an ice-saturated ammonium chloride solution (300 mL) for quenching, diluted with water (200 mL), and then extracted with ethyl acetate (400 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain intermediate 12-3 (28.25 g, yellow oil, yield 44.47%). LCMS: 350.1 [M+H] + .

[0181] Step 3 Synthesis of compound 12-4

[0182] Intermediate 12-3 (28.25 g, 80.83 mmol) was dissolved in methanol (200 mL) and water (200 mL). Sodium hydroxide (16.15 g, 403.82 mmol) was then added to the mixture. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed by LCMS, the reaction solution was concentrated under reduced pressure to remove methanol, and the residue was adjusted to pH 3 with 1M hydrochloric acid aqueous solution (420 mL), and then extracted with ethyl acetate (400 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was passed through a reverse phase chromatography column (C18 column, 0.1% formic acid system and 50-80% acetonitrile). Lyophilization gave intermediate 12-4 (19.92 g, white solid, yield 76.67%). LCMS: 322.2 [M+H] + .

[0183] Step 4 Synthesis of compound 12-5

[0184] Intermediate 12-4 (19.92 g, 61.97 mmol) and N,O-dimethylhydroxylamine hydrochloride were dissolved in anhydrous dichloromethane (400 mL). Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.61 g, 76.22 mmol) and 4-dimethylaminopyridine (760 mg, 6.22 mmol) were added to the mixture at 0°C. The reaction solution was stirred at 0°C for 10 minutes, and then N,N-diisopropylethylamine (24.03 g, 185.91 mmol) was added to the mixture. The reaction solution was stirred at 25°C for 12 hours. After the reaction was completed by LCMS, the reaction solution was concentrated under reduced pressure to remove dichloromethane, the residue was diluted with water (200 mL), and then extracted with ethyl acetate (300 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to obtain intermediate 12-5 (14 g, yellow oil, yield 61.98%). LCMS: 365.2 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ=7.17-7.07(m,3H),6.72(d,J=3.2Hz,1H),6.54(dd,J=2.4,6.0Hz,1H),5 .46(s,2H),4.96(s,2H),3.78(s,3H),3.50-3.43(m,2H),3.27(s,3H),0.92-0.84(m,2H),-0.05(s,9H).

[0185] Step 5 Synthesis of compound 12-6

[0186] Intermediate 12-5 (14 g, 38.41 mmol) was dissolved in N,N-dimethylformamide (280 mL). Then N-bromosuccinimide (6.84 g, 38.41 mmol) was added to the mixture in batches at 0°C. The reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed by LCMS detection, the reaction solution was poured into ice water (300 mL) and extracted with ethyl acetate (300 mL×3). The combined organic phases were washed with saturated sodium sulfite aqueous solution (200 mL), 5% potassium carbonate aqueous solution (200 mL), and saturated brine (200 mL×3) in turn, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Intermediate 6 was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-3 / 1) to obtain intermediate 12-6 (16.12 g, yellow oil, yield 94.65%). LCMS: 445.1 [M+H] + . 1H NMR (400MHz, CHLOROFORM-d) δ = 7.20-7.06 (m, 3H), 6.60 (dd, J = 1.6, 6.4Hz, 1H), 5.40 (s, 2H), 4.95(s,2H),3.79(s,3H),3.53-3.42(m,2H),3.27(s,3H),0.96-0.82(m,2H),-0.05(s,9H).

[0187] Step 6 Synthesis of compound 12-7

[0188] Intermediate 12-6 (16.12 g, 36.35 mmol) was dissolved in anhydrous tetrahydrofuran (4 L). Then, n-butyl lithium (2.5 M, 26.18 mL) was slowly added dropwise to the mixture under a nitrogen atmosphere at -70 °C. The reaction solution was stirred at -70 °C for 1 hour. After the reaction was completed by LCMS, it was poured into an ice-cold saturated ammonium chloride solution (500 mL) for quenching, diluted with water (1500 mL), and then extracted with ethyl acetate (800 mL×3). The organic phases were combined and washed with saturated brine (500 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase chromatography (C 18 Column, 0.1% formic acid system and 60-80% acetonitrile). Lyophilization gave intermediate 12-7 (1.75 g, yellow oil, yield 15.87%). LCMS: 304.1 [M+H] + . 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.67 (s, 1H), 7.24 (d, J = 8.0Hz, 1H), 7.10 (d, J = 8.4Hz, 1H), 6.75 ( d,J=8.0Hz,1H),5.56(s,2H),4.85(s,2H),3.56-3.49(m,2H),0.96-0.89(m,2H),-0.03(s,9H).

[0189] Step 7 Synthesis of compound 12-9

[0190] Intermediate 12-7 (800 mg, 2.64 mmol) and intermediate 12-8 (1.20 g, 7.91 mmol mmol) were dissolved in anhydrous methanol (24 mL). Acetic acid (640.00 mg, 10.66 mmol) and sodium cyanoborohydride (829 mg, 13.19 mmol) were then added to the mixture in sequence. The reaction solution was stirred at 60 ° C for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was passed through a reverse phase chromatography column (C18 column, 0.1% trifluoroacetic acid system and 30-60% acetonitrile). After freeze-drying, intermediate 12-9 (790 mg, white solid, yield 68.31%) was obtained. LCMS: 439.2 [M+H] + . 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.03 (brs, 1H), 7.21-7.12 (m, 3H), 7.08-7.02 (m, 2H), 6.83 (t ,J=7.2Hz,1H),6.71(d,J=8.0Hz,1H),6.62(d,J=7.6Hz,1H),5.49-5.33(m,2H),4.96(d,J=12 .4Hz,1H),4.84(s,1H),4.31(dd,J=2.8,12.8Hz,1H),3.67(s,3H),3.50(dt,J=2.4,8.4Hz,2H ),3.38-3.28(m,1H),3.24-3.14(m,1H),3.07-2.89(m,2H),1.01-0.80(m,2H),-0.05(s,9H).

[0191] Step 8 Synthesis of compound 12

[0192] The intermediate 12-9 (200 mg, 455.96 μmol) was dissolved in N, N-dimethylformamide (6 mL), and then tetramethylethylenediamine (533 mg, 4.59 mmol) and tetrabutylammonium fluoride (1 M, 4.56 mL) were added to the mixture. The reaction solution was stirred at 50 ° C for 12 hours. Tetramethylethylenediamine (265 mg, 2.28 mmol) was added to the mixture, and the reaction solution was stirred at 70 ° C for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was poured into ice saturated ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was passed through a reverse phase column (C18 column, 0.1% ammonia system and 28-58% acetonitrile). After freeze-drying, the final product 12 (30.7 mg, off-white solid, yield 21.50%) was obtained. LCMS: 309.3 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ = 10.78 (s, 1H), 7.20-7.13 (m, 2H), 7.04 (d, J = 1.6 Hz, 1H), 6.96-6.82 (m, 4H), 6.33 (d, J = 7.2 Hz, 1H), 4.25 (dd, J = 3.6, 10.8 Hz, 1H), 4.13-4.03 (m, 2H), 3.77 (s, 3H), 2.86-2.65 (m, 4H), 1.87-1.79 (m, 1H). Example 8

[0193]

[0194] Step 1 Synthesis of compound 5-3

[0195] 13-1 (18.00 g, 96.24 mmol), palladium acetate (216.06 mg, 0.96 mmol), 1,3-bis(diphenylphosphino)propane (793.87 mg, 1.92 mmol) and 3-butyl-1-methyl-1H-imidazol-3-ium tetrafluoroborate (109.25 g, 481.20 mmol) were added to dimethyl sulfoxide (150 mL), nitrogen was replaced three times and stirred at 25 ° C for 10 minutes, then 13-2 (13.88 g, 192.48 mmol) and triethylamine (14.61 g, 144.36 mmol) were slowly added and nitrogen was replaced three times, and the temperature was raised to 115 ° C for 24 hours. After the reaction was completed, it was diluted with saturated brine (150 mL) for quenching and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase separation (0.1% formic acid system and 0-30% acetonitrile) to give 13-3 (7.60 g, yellow oil, yield 44.31%). 1 H NMR(400MHz,CHLOROFORM-d)δ7.63-7.57(m,1H),7.48-7.43(m,1H),7.31-7.20(m,2H),5.63-5.58(m ,1H),5.46(d,J=2.0Hz,1H),4.16(s,3H),3.92(t,J=6.0Hz,2H),3.05(t,J=6.0Hz,2H),2.10(s,1H).

[0196] Step 2 Synthesis of compound 13-4

[0197] 13-3 (7.60 g, 42.64 mmol), acetic anhydride (8.71 g, 85.28 mmol) and 4-dimethylaminopyridine (15.63 g, 127.93 mmol) were added to a dichloromethane solution (150 mL) and stirred at 25 ° C for 1 hour. After the reaction was completed, it was diluted with water (100 mL) and quenched, and extracted with dichloromethane (100 mL × 3). The organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-5 / 1) gave 13-4 (7.6 g, colorless oil, yield 80.90%). 1 H NMR(400MHz,CHLOROFORM-d)δ7.30-7.24(m,1H),7.16-7.12(m,1H),6.96-6.85(m,2H),5.22-5.19(m ,1H),5.11(d,J=1.6Hz,1H),4.09(t,J=7.2Hz,2H),3.83(s,3H),2.84(t,J=6.8Hz,2H),1.99(s,3H).

[0198] Step 3 Synthesis of compound 13-5

[0199] Diethylzinc (2M, 86.26 mL) was added to dichloromethane (86 mL) to replace nitrogen and cooled to 0°C, and then a dichloromethane (10 mL) solution of trifluoroacetic acid (22.03 g, 193.22 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at 0°C for 20 minutes. A dichloromethane (10 mL) solution of diiodomethane (50.83 g, 189.77 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at 0°C for 20 minutes, and then a dichloromethane (10 mL) solution of 13-4 (7.60 g, 34.50 mmol) was slowly added dropwise at 0°C, and the mixture was reacted at 20°C for 2 hours. The reaction solution was slowly dropped with water (200 mL) and hydrochloric acid (1M, 50 mL) at 0°C to quench, and then extracted with dichloromethane (100 mL×3). The separated organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and then the crude product was concentrated under reduced pressure. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-10 / 1) gave 13-5 (6.00 g, yellow oil, yield 74.22%). 1H NMR (400MHz, CHLOROFORM-d) δ7.24-7.16 (m, 2H), 6.89-6.81 (m, 2H), 4.00 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 1.94 (s, 3H), 1.88 (t, J = 7.2 Hz, 2H), 0.77-0.70 (m, 4H). Step 4 Synthesis of compound 13-6

[0200] 13-5 (3 g, 12.80 mmol) was dissolved in tetrahydrofuran (30 mL), and an aqueous solution (30 mL) of lithium hydroxide monohydrate (5.37 g, 128.05 mmol) was added at 0°C. The reaction solution was stirred at 50°C for 12 hours. The reaction mixture was extracted with ethyl acetate (30 mL × 3), and the separated organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-3 / 1) gave 13-6 (1.8 g, yellow oil, yield 73.12%).

[0201] Step 5 Synthesis of Compound 13-7

[0202] 13-6 (1.8 g, 9.36 mmol) and triphenylphosphine (3.19 g, 12.17 mmol) were added to dichloromethane (30 mL), the nitrogen was replaced and the mixture was cooled to 0°C, and carbon tetrabromide (6.21 g, 18.73 mmol) was slowly added at 0°C, and the reaction solution was stirred at 30°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 0) to obtain 13-7 (1.84 g, colorless oil, yield 77.04%). 1 H NMR (400MHz, CHLOROFORM-d) δ7.26-7.19(m,2H),6.95-6.82(m,2H),3.86(s,3H),3.28(t,J=8.0Hz,2H),2.11(t,J=8.0Hz,2H),0.81-0.73(m,4H).

[0203]

[0204] Step 6 Synthesis of compound 13-9

[0205] To a solution of 13-8 (10 g, 73.98 mmol, 1 eq) in ethanol (80 mL) was added a solution of sodium nitrite (6.13 g, 88.78 mmol, 1.2 eq) in water (30 mL) at 0°C. Then concentrated hydrochloric acid (12 M, 7.7 mL, 1.25 eq) was added to the solution at 0°C. The reaction solution was stirred at 0°C for 30 minutes. After the reaction was completed by TLC, the reaction solution was diluted with 250 mL of water and then extracted with ethyl acetate (250 mL×3). The organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 13-9 (13 g, brown oil).

[0206] Step 7 Synthesis of Compound 13-10

[0207] Dissolve 13-9 (23 g, 140.11 mmol) in tetrahydrofuran (115 mL) and lithium aluminum tetrahydride (112.1 mL, 2.5 N, 280.2 mmol). The two solutions were co-dropped at a flow rate of 5 mL / min at 25°C through a coil (22.8 mL) reactor. The reaction solution flowing out of the coil was cooled to 0°C. The reaction solution was kept at 0°C and quenched with water / 15% sodium hydroxide aqueous solution / water = 15 mL / 15 mL / 45 mL, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-2 / 1) gave 13-10 (16 g, reddish brown oil, crude product).

[0208] Step 8 Synthesis of compound 13-12

[0209] 13-10 (10 g) and 13-11 (10.23 g, 66.59 mmol) were added to an ethanol solution (133 mL), and a hydrochloric acid solution (12 M, 6.66 mL) was slowly added dropwise, and stirred at 90°C for 3 hours. The reaction mixture was filtered, and the filter cake was rinsed with petroleum ether to obtain the filter cake 13-12 (14 g, brown solid, crude product). 1 H NMR (400MHz, DMSO-d6) δ = 9.76 (s, 2H), 7.36 (t, J = 10.4Hz, 2H), 7.15-7.05 (m, 1H), 6.88 (t, J = 8.0Hz, 2H ),6.60-6.50(m,1H),4.46(t,J=4.4Hz,2H),4.25-4.13(m,2H),3.52-3.41(m,2H),3.12-3.01(m,2H).

[0210] Step 9 Synthesis of compound 13-13

[0211] 13-12 (6 g) was added to trifluoroacetic acid (60 mL) to replace nitrogen protection and cooled to 0°C, and then sodium cyanoborohydride (4.51 g, 71.79 mmol) was added at 0°C, and the mixture was reacted at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure and adjusted to pH = 12 with 5% potassium carbonate aqueous solution, and then extracted with diethyl ether (100 mL×3). The separated organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 13-13 (6.5 g, brown solid). LCMS: 217.1 [M+H] + .

[0212] Step 10 Synthesis of Compound 13-14

[0213] 13-13 (13 g, 60.11 mmol) was added to methanol (150 mL), and Boc2O (13.12 g, 60.11 mmol) and DIEA (9.32 g, 72.13 mmol) were slowly added. The reaction solution was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, diluted with water (200 mL), extracted with ethyl acetate (200 mL×3), and the separated organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) gave 13-14 (5 g, yellow solid, yield 26.29%). LCMS: 317.1 [M+H] + .

[0214] Step 11 Synthesis of Compounds 13-15

[0215] 13-14 (5 g, 15.80 mmol) was subjected to SFC chiral separation and then concentrated under reduced pressure. The crude product was purified by reverse phase separation (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 um); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 12%, isocratic elution mode) to obtain 13-15 (2 g, yellow solid, yield 40%). LCMS: 317.1 [M+H] + .

[0216] Step 12 Synthesis of Compounds 13-16

[0217] 13-15 (2 g, 6.32 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL), and the mixture was stirred at 25°C for 0.5 hours. After the reaction, the reaction solution was adjusted to pH = 11 with 5% potassium carbonate aqueous solution, extracted with ethyl acetate (40 mL × 3), and the separated organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 13-16 (1.03 g, yellow solid, yield 75.70%). LCMS: 217.0 [M+H] + . 1 H NMR(400MHz,CHLOROFORM-d)δ6.74-6.61(m,3H),4.51-4.41(m,2H),3.63(s,1H),3.39-3 .26(m,2H),3.23-3.09(m,2H),3.05-2.93(m,2H),2.84-2.65(m,2H),2.03-1.83(m,2H).

[0218]

[0219] Step 13 Synthesis of Compound 13B

[0220] Compound 13-7 (217 mg, 1.00 mmol) was dissolved in dioxane (10 mL), and triethylamine (304 mg, 3.00 mmol) and compound 13-16 (305 mg, 1.20 mmol) were added. The mixture was reacted at 85 °C for 8 h. Water (30 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude oil. The mixture was manually filled with a silica gel column for column chromatography purification (DCM: CH3OH = 20:1) to obtain compound 13B (198 mg, light yellow solid, yield 50.7%). LCMS: 390.23 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ7.18(td,J=7.8,1.8Hz,1H),7.11(dd,J=7.4,1.7Hz,1H),6.93(dd,J=8.2,1.1Hz,1H),6.82 (td,J=7.4,1.1Hz,1H),6.63(d,J=7.1Hz,1H),6.53(t,J=7.6Hz,1H),6.51–6.46(m,1H),4.38(dt,J=11.2,2.7Hz,1 H),4.25(ddd,J=11.1,9.9,2.3Hz,1H),3.80(s,3H),3.30(t,J=2.1Hz,3H),3.15–3.09(m,1H),2.97(d,J=10.1Hz,1 H),2.59(td,J=10.5,2.8Hz,1H),2.24–2.00(m,3H),1.84(d,J=13.9Hz,1H),1.78–1.61(m,4H),0.67–0.56(m,4H).

[0221] Example 9

[0222]

[0223] Step 1 Synthesis of compound 14B

[0224] Compound 14-1 (30 mg, 199.77 μmol, 27.55 μL, 1 eq), compound 13-16 (43.21 mg, 199.77 μmol, 1 eq) and paraformaldehyde (12.00 mg, 399.54 μmol, 2 eq) were dissolved in ethanol (1 mL), and then boron trifluoride etherate (28.35 mg, 199.77 μmol, 24.57 μL, 1 eq) was added. The reaction solution was stirred at 80 ° C under a nitrogen atmosphere for 12 hours. After the reaction was completed by LCMS detection, the reaction solution was concentrated under reduced pressure under vacuum. The crude product was purified by reverse phase separation (0.1% hydrochloric acid system and acetonitrile) and lyophilized to obtain compound 14B (7.1 mg, white solid, yield: 9.33%). LCMS: 379.1 [M + H] + . 1H NMR(400MHz,CHLOROFORM-d)δ=8.10(br s,1H),7.82(dd,J=7.8,1.8Hz,1H),7.58-7.49(m,1H),7.06-6.97(m,2H),6.92-6.85(m,1H),6.84-6.73( m,2H),4.72-4.42(m,2H),4.01(s,3H),3.87-3.47(m,10H),3.04-2.85(m,2H),2.73-2.59(m,1H),2.32(br d,J=15.6Hz,1H).

[0225] Example 10

[0226]

[0227]

[0228] Step 1 Synthesis of compound 15-2

[0229] 15-1 (500 mg, 3.26 mmol) was dissolved in ethanol (15 mL), and then sodium nitrite (270 mg, 3.91 mmol) dissolved in water (5.7 mL) was added to the mixture, and then concentrated hydrochloric acid (12 M, 340.07 μL) was slowly added to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 0.5 hours. After the reaction was completed by TLC detection, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (50 mL × 3), the organic phases were combined and washed with saturated brine (40 mL × 2), and then the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 15-2 (580 mg, yellow solid, yield 97.53%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.95-7.81 (m, 1H), 7.11-6.94 (m, 2H), 4.33 (t, J = 4.8Hz, 2H), 4.08 (t, J = 4.8Hz, 2H).

[0230] Step 2 Synthesis of compound 15-3

[0231] 15-2 (553 mg, 3.04 mmol) was dissolved in tetrahydrofuran (20 mL). Then, lithium aluminum tetrahydride (2.5 M, 2.43 mL) was slowly added to the mixture at 5 ° C under a nitrogen atmosphere. The reaction solution was stirred at 5 ° C for 0.5 hours. After the reaction was completed by TLC detection, the reaction solution was quenched with water / 15% sodium hydroxide aqueous solution / water = 0.23 mL / 0.23 mL / 0.69 mL at 0 ° C, filtered and washed with 50 mL of ethyl acetate to obtain a filtrate. The filtrate was concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (silica gel column, petroleum ether / ethyl acetate = 3 / 1-1 / 1) gave 15-3 (350 mg, yellow solid, yield 68.55%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 6.94-6.86 (m, 1H), 6.82-6.74 (m, 1H), 6.63-6.55 (m, 1H), 4.47-4.40 (m, 2H), 3.49-3.42 (m, 2H).

[0232] Step 3 Synthesis of compound 15-4

[0233] 15-3 (334 mg, 1.99 mmol) and piperidine-4,4-diol hydrochloride (336 mg, 2.19 mmol) were dissolved in ethanol (9 mL), and hydrochloric acid solution (12 M, 198.61 μL) was slowly added to the mixture, and the reaction solution was stirred at 90 ° C for 3 hours. After the reaction was completed by LCMS detection, the reaction mixture was filtered, the filter cake was rinsed with petroleum ether, and the filter cake was dried to obtain 15-4 (430 mg, brown solid, yield 93.22%). LCMS: 233.2 [M + H] + . 1 HNMR (400MHz, DMSO-d6) δ = 7.02 (dd, J = 3.6, 8.4Hz, 1H), 6.88 (dd, J = 8.8, 12.0Hz, 1H), 4.53 (t, J = 4.4Hz, 2H), 4.34-4.19 (m, 4H), 3.47 (br d,J=4.0Hz,2H),3.05(br t,J=5.8Hz,2H).

[0234] Step 4 Synthesis of compound 15-5

[0235] 15-4 (427 mg, 1.84 mmol) was dissolved in trifluoroacetic acid (13 mL), sodium cyanoborohydride (300 mg, 4.77 mmol) was slowly added to the mixture in batches at 0°C, and the reaction solution was stirred at 20°C for 2 hours. After the reaction was completed by LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase chromatography (C 18Column, 0.1% formic acid system and 50-60% acetonitrile). After freeze-drying, 15-5 (430 mg, brown solid, yield 99.84%) was obtained. LCMS: 235.2 [M+H] + .

[0236] Step 5 Synthesis of Compound 15

[0237] 15-5 (400 mg, 1.71 mmol) and 15-6 (336 mg, 2.05 mmol) were dissolved in ethanol (13 mL), and acetic acid (1.03 g, 17.07 mmol) and sodium cyanoborohydride (643 mg, 10.23 mmol) were added to the mixture at 0 ° C, and the reaction solution was stirred at 20 ° C for 2 hours. After the reaction was completed by LCMS, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was successively purified by reverse phase chromatography (C 18 column, 0.1% trifluoroacetic acid system and 20-50% acetonitrile) and reverse phase chromatography column (C 18 Column, 0.1% ammonia system and 53-83% acetonitrile). After freeze-drying, 15 (200 mg, colorless oil, yield 30.63%) was obtained.

[0238] Step 6 Synthesis of compounds 15A and 15B

[0239] Compound 15 (200 mg, 522.92 μmol) was purified by SFC chiral column chromatography (column model: DAICELCHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode) to give 15A (RT = 0.728 min) and 15B (RT = 0.924 min). 15A and 15B were diluted with acetonitrile (2 mL), water (2 mL), and 1M HCl / H2O (0.29 mL), respectively, and lyophilized to give the hydrochloride of 15A (98.9 mg, white solid, yield 45.15%). LCMS: 383.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.26 (br s, 1H), 7.26-7.12 (m, 2H), 7.03-6.83 (m, 2H), 6.72 (dd, J = 4.0, 8.0Hz, 1H), 6.53 (dd, J = 8.4, 12.0Hz, 1H), 4.58 (br d, J = 11.2 Hz, 1H), 4.37-4.24 (m, 1H), 3.83-3.74 (m, 3H), 3.62-3.54 (m, 1H), 3.52-3.37 (m, 4H), 3.17-2.93 (m, 3H), 2.72 (td, J = 2.4, 10.8 Hz, 1H), 2.65-2.54 (m, 3H), 2.35-2.15 (m, 2H), 1.97 (m, 2H). Hydrochloride of 15B (97.1 mg, white solid, yield 44.21%). LCMS: 383.2 [M+H] + . HNMR (400MHz, DMSO-d6) δ = 10.53 (br s, 1H), 7.24-7.14 (m, 2H), 7.02-6.85 (m, 2H), 6.73 (dd, J = 4.0, 8.0Hz, 1H), 6.53 (dd, J = 8.0, 12.0Hz, 1H), 4.58 (br d,J=11.2Hz,1H),4.42-4.25(m,1H),3.82-3.75(m,3H),3.62-3.54(m,1H),3.52-3.46(m,2H),3.42-3.35( m,2H),3.25-2.97(m,3H),2.72(td,J=2.8,11.2Hz,1H),2.65-2.53(m,3H),2.30-2.18(m,2H),1.98(m,2H).

[0240] Test Example 1.5-HT 2A Functional activity test of receptors

[0241] 1. Test methods:

[0242] (1) FLIPR analysis

[0243] a. To detect 5-HT 2A Receptor-mediated downstream G q -PLC β After activation of the Ca-PI cascade, 2+ The release of 5-HT 2A The recipient HEK293 cells were diluted to 20,000 cells / 20 μL with DMEM medium and inoculated into 384-well poly-lysine-coated cell plates and cultured at 37° C., 5% CO 2 for 16-20 hours.

[0244] b. Use Echo to dilute the positive drug and the test compound to the corresponding concentrations, and transfer 750 nL to the corresponding compound plate. ; Add 30 μL of FLIPR buffered saline solution (HBSS+HEPE+0.5% BSA) for experiment to the corresponding compound plate, and centrifuge at 1000 rpm for 1 minute.

[0245] c. Take the cell plate prepared the day before out of the incubator, discard the culture medium, add 20 μL FLIPR buffer (HBSS+HEPE+0.5% BSA) and 20 μL 2×Fluo-4 Direct TM Buffer, total volume is 40 μL. Incubate in 5% CO2, 37°C incubator for 50 minutes, then place at room temperature for 10 minutes.

[0246] d. Place the compound plate, cell plate and pipette tip into the instrument, run the FLIPR instrument software, add 10 μL of the test compound and reference compound of the established concentration to the cell plate according to the set program, and read the fluorescence signal. After reading, export the data and calculate it through the "Max-Min", "Read 1 to Maximum allowed" method in the software. Activation% = (RLU-DMSO) / (HC-DMSO) * 100

[0247] (2) β-arrestin analysis

[0248] a. To detect 5-HT 2A Receptor-mediated downstream β-arrestin signaling agonist activity, using transfected 5-HT 2A -β-arrestin 2 in HEK

[0249] 293 cell line. Dilute the cells to 0.75×10 6 cells / mL, 40 μL / well seeded in 384-well cell plates, 37°C, 5%

[0250] Incubate overnight in CO2.

[0251] b. Dilute the test compound using an Echo gradient, transfer 250 nL to the compound plate, and add 50 μL of DMEM medium.

[0252] c. Dilute the Promega-N2013 detection reagent to the specified concentration using DMEM medium and add 5 μL / well to the cell plate.

[0253] d. Use Bravo to transfer 5 μL of compound to the cell plate, incubate at room temperature in the dark for 30 minutes, and read.

[0254] Activation% = (Signal-LC) / (HC-LC)*100

[0255] (3) Test results: The compounds of the present invention have an effect on 5-HT 2A The functional activity tests of the receptors are shown in Table 1.

[0256] Table 1 Effect of the compounds of the present invention on 5-HT 2A Functional activity test of receptors

[0257]

[0258] Note: + indicates maximum agonist activity (Emax) <20%; ++ indicates maximum agonist activity (Emax) of 21-40%; +++ indicates maximum agonist activity (Emax) of 41-60%; ++++ indicates maximum agonist activity (Emax) of 61-80%; +++++ indicates maximum agonist activity (Emax) of 81-100%.

[0259] From the data in Table 1, it can be seen that the compounds of the present invention have an effect on 5-HT 2A The receptor has a certain agonist activity, and compound 10B has a certain agonist activity on 5-HT 2A Receptor-mediated activation of β-arrestin2 signaling is selective.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, in, X1 is selected from N-R1, or O; X2 is selected from CH2, or CH2CH2; R1 is selected from H, or C 1-6 alkyl; Selected from single bonds, or double bonds L1 is selected from a bond, -O-, or -CR 1a R 1b ; L2 is selected from a bond, -O-, or -CR 2a R 2b ; L3 is selected from a bond, -O-, or -CR 3a R 3b ; L4 is selected from a bond, -O-, or -CR 4a R 4b ; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together they form an oxo group; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl; or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl; R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by one or more R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Halogenated alkoxy, C 3-6 Cycloalkoxy or oxo; R6, R7, and R8 are each independently selected from H or halogen.

2. A compound represented by formula (IA) or (IB), a pharmaceutically acceptable salt or stereoisomer thereof, in, X1 is selected from N-R1, or O; X2 is selected from CH2, or CH2CH2; R1 is selected from H, or C 1-6 alkyl; L1 is selected from a bond, -O-, or -CR 1a R 1b ; L2 is selected from a bond, -O-, or -CR 2a R 2b ; L3 is selected from a bond, -O-, or -CR 3a R 3b ; L4 is selected from a bond, -O-, or -CR 4a R 4b ; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together they form an oxo group; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl; or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atoms to which they are attached, they form C 3-6 Cycloalkyl; R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by one or more R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Halogenated alkoxy, C 3-6 Cycloalkoxy or oxo; R6, R7, and R8 are each independently selected from H or halogen.

3. A compound represented by formula (II), or a pharmaceutically acceptable salt thereof, in, X1 is selected from N-R1, or O; R1 is selected from H, or C 1-6 alkyl; L1 is selected from a bond, -O-, or -CR 1a R 1b ; L2 is selected from a bond, -O-, or -CR 2a R 2b ; L3 is selected from a bond, -O-, or -CR 3a R 3b ; L4 is selected from a bond, -O-, or -CR 4a R 4b ; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl; R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, oxo.

4. A compound represented by formula (III), or a pharmaceutically acceptable salt thereof, in, X1 is selected from N-R1, or O; R1 is selected from H, or C 1-6 alkyl; L1 is selected from a bond, -NH-, -O-, or -CR 1a R 1b ; L2 is selected from a bond, -O-, or -CR 2a R 2b ; L3 is selected from a bond, -O-, or -CR 3a R 3b ; L4 is selected from a bond, -O-, or -CR 4a R 4b ; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each independently selected from H, or C 1-5 alkyl; R4 is selected from phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the phenyl, 5-10 membered heterocyclyl, or 5-10 membered heteroaryl is optionally substituted by R5, wherein R5 is selected from C 1-5 Alkoxy, C 1-5 Haloalkoxy, oxo.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X1 is selected from N-R1, or O; R1 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b Each is independently selected from H, methyl, ethyl, n-propyl, or isopropyl; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together they form an oxo group; or R 1a and R 1b , R 2a and R 2b , R 3a and R 3b , R 4a and R 4b Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; or R 1a / R 1b With R 2a / R 2b , R 2a / R 2b With R 3a / R 3b , R 3a / R 3b With R 4a / R 4b Together with the carbon atoms to which they are attached, they form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group; R4 is selected from phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl, wherein the phenyl, 1,2,3,4-tetrahydroquinolyl, 3,4-dihydrobenzopyranyl, or pyridinyl is optionally substituted with R5, wherein R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo; R6, R7, and R8 are each independently selected from H, F, Cl, Br, or I.

6. The compound according to claim 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: The R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, or 2,2,2-trichloroethoxy; Alternatively, said R4 is selected from The R5 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, or oxo.

7. The following compounds, pharmaceutically acceptable salts or stereoisomers thereof, selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease associated with the activity or expression of a 5-HT receptor.

10. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing CNS-related diseases.

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