Cyclic amine compound with aryl substitution and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a cyclic amine compound with an aryl substitution, and a preparation method therefor, and a use thereof. The present invention provides the use of a substance Z or a pharmaceutical composition comprising the substance Z in the preparation of a serotonin 5-HT2A receptor agonist, the substance Z being a compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated derivative thereof, or a stereoisomer thereof. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The compounds of the present invention can be used for preventing and treating depression, anxiety, cluster headaches, or neurodegenerative diseases.

Description

aryl-substituted cyclic amine compounds, their preparation methods and uses

[0001] This application claims priority to Chinese patent application 2024115764628, filed on 2024 / 11 / 6. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to aryl-substituted cyclic amine compounds, their preparation methods, and uses. Background Technology

[0003] Depression is a common mental illness, with main symptoms including low mood, loss of interest in daily activities, guilt, and sleep disturbances. A significant proportion of patients experience suicidal thoughts or behaviors. It is estimated that over 300 million people worldwide suffer from depression. Depressive symptoms are often persistent or recurrent, severely impacting patients' quality of life and creating a significant social burden.

[0004] The pathogenesis of depression is complex, involving genetics and environment. Current hypotheses regarding its pathogenesis include the monoamine hypothesis, the neuroplasticity hypothesis, and the neurotrophic imbalance hypothesis. Among these, the monoamine hypothesis provides crucial theoretical support for antidepressant drug development and neuroscience research. This hypothesis posits that a decrease in the concentration or activity of monoamine neurotransmitters such as serotonin in the brain is the cause of depressive symptoms. Currently, the most prescribed antidepressants globally primarily aim to increase monoamine neurotransmitter levels. Tricyclic antidepressants (imipramine, amitriptyline, etc.) and selective serotonin reuptake inhibitors (fluoxetine, paroxetine, citalopram, sertraline, etc.) play important roles in the clinical treatment of depression. However, these drugs have significant drawbacks, such as slow onset of action, failing to meet the clinical need for rapid symptom relief in patients with depression; and numerous side effects, including weight gain, nausea, dry mouth, and increased risk of suicidal ideation after withdrawal. Therefore, identifying new drug targets and developing novel antidepressants is urgently needed.

[0005] Recent studies have revealed the significant potential of hallucinogens in treating mental illnesses such as depression. Hallucinogens such as psilocybin (N. psilocybin) have demonstrated rapid and sustained antidepressant effects in phase II clinical trials (Duan et al., Chem Rev 2024, 124, 124-163; Carhart-Harris et al., N Engl J Med 2021, 384: 1402-1411). Hallucinogens primarily exert their pharmacological effects by activating serotonin 5-HT2A receptors in the brain. Known hallucinogens are mainly classified into three categories based on their chemical structure: tryptamines (such as psilocybin), ergotamines (such as lysergic acid diethylamide / LSD), and phenethylamines (such as mescaline) (Duan et al., Chem Rev 2024, 124, 124-163).

[0006] Besides activating the serotonin 5-HT2A receptor, most known hallucinogens exhibit poor selectivity (Duan et al., Chem Rev 2024, 124, 124-163). For example, psilocybin and LSD both activate the 5-HT2B receptor (Rouaud et al., J Psychopharmacol 2024, 38, 217–224). The 5-HT2B receptor is highly expressed in heart valves, and activation of this receptor has been found to lead to valvular heart disease (Roth, N Engl J Med 2007, 356, 6-9; Dumotier et al., J Pharmacol Toxicol Methods 2024, 128, 107542). Therefore, the US FDA published guidance on hallucinogen research in 2023, pointing out the need to pay attention to the potential toxic side effects caused by the activation of the 5-HT2B receptor by these substances (Harris, JAMA 2023, 25; 330(4), 307).

[0007] Furthermore, research has shown that, in addition to hallucinogenic substances, a few non-hallucinogenic 5-HT2A receptor agonists also possess antidepressant potential (Duan et al., Chem Rev 2024, 124, 124-163). For example, TBG (Tabernanthalog), modified from the hallucinogenic drug ibogline (Cameron et al., Nature 2021, 589, 474-479), and IHCH-7086 (Cao et al., Science 2022, 375, 403-411), modified from the antipsychotic drug lumateperone, are both antidepressant without inducing hallucinations; similarly, compound (R)-69, modified through screening a tetrahydropyridine compound library, is also antidepressant without inducing hallucinations (Kaplan et al., Nature 2022, 610, 582-591). These results demonstrate the significant potential of the 5-HT2A receptor as a novel antidepressant target. At the same time, these substances also have great potential for treating other neuropsychiatric disorders, such as anxiety disorders, cluster headaches, and neurodegenerative diseases.

[0008] However, the types of 5-HT2A agonists currently known are limited, and the known compounds generally exhibit poor selectivity for 5-HT2B receptors. Therefore, there is an urgent need to develop novel 5-HT2A receptor agonists. Summary of the Invention

[0009] To solve the problems of 5-HT in existing technologies 2A To address the limited variety of receptor agonists, this invention provides an aryl-substituted cyclic amine compound, its preparation method, and its uses. The compound of this invention can be used for the prevention and treatment of depression, anxiety, and other mental disorders. The compound of this invention is 5-HT. 2A Receptor agonists, some compounds of this invention are agonists of 5-HT 2A The receptor has full agonist activity, and some compounds are agonist-active to 5-HT. 2A The receptor has partial agonist activity, and the preferred compounds of the present invention are effective against 5-HT. 2A The receptor has agonistic activity and is effective against 5-HT. 2B The receptor has no agonistic activity.

[0010] This invention provides a substance Z or a pharmaceutical composition containing substance Z in the preparation of 5-HT 2A In the application of receptor agonists, the substance Z is a compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0011] Represents a single bond or a double bond;

[0012] R 1 It is H or C1-C4 alkyl;

[0013] R 2 H, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy or

[0014] R 3 It is H, halogen, or C1-C4 alkyl;

[0015] R 4 It is H, halogen, or C1-C4 alkyl;

[0016] R 5 It is H, halogen, or C1-C4 alkyl;

[0017] R 6 It is a C1-C4 alkyl group;

[0018] Q is C6-C 10 Aromatic ring, 4-8 membered carbon ring or 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0019] m and n are independently 0, 1, 2 or 3.

[0020] In some implementation schemes, R 1 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0021] In some implementation schemes, R 2 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0022] In some implementation schemes, R 2 In, the C 1-4 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0023] In some implementation schemes, R 2 In this context, the halogen may be fluorine, chlorine, bromine, or iodine.

[0024] In some implementation schemes, R 3 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0025] In some implementation schemes, R 4 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0026] In some implementation schemes, R 5 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0027] In some implementation schemes, R 6 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0028] In some implementations, in Q, the C6-C 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring.

[0029] In some implementations, in Q, the 4-8 member carbon ring can be a 4-membered carbon ring, a 5-membered carbon ring, a 6-membered carbon ring, a 7-membered carbon ring, or an 8-membered carbon ring.

[0030] In some implementations, in Q, the heteroatom of the 4-8 membered heterocycle is O or N.

[0031] In some implementations, in Q, the number of heterocycles in the 4-8 member is 1.

[0032] In some implementation schemes, R 1 It is H or C1-C4 alkyl.

[0033] In some implementation schemes, R 2 It can be H, halogen, hydroxyl, or amino.

[0034] In some embodiments, Q is a benzene ring, a 4-8 membered carbon ring, or a 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is N or O, and the number of heteroatoms is 1.

[0035] In some embodiments, Q is a benzene ring, a 4-8 membered carbon ring, or a 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is O, and the number of heteroatoms is 1.

[0036] In some implementations, m and n are independently 1 or 2.

[0037] In some implementation schemes, Represents a single bond or a double bond;

[0038] R 1 It is H or C1-C4 alkyl;

[0039] R 2 It can be H, halogen, hydroxyl, or amino;

[0040] R 3 For H;

[0041] R 4 For H;

[0042] R 5 For H;

[0043] Q is a benzene ring, a 4-8 membered carbon ring, or a 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is N or O, and the number of heteroatoms is 1.

[0044] m and n are independently 1 or 2.

[0045] In some embodiments, in Q, the heteroatom of the 4-8 membered heterocycle is a heteroatom of a 5-7 membered heterocycle, for example...

[0046] In some implementations, in Q, the 4-8 member heterocycle is

[0047] In some implementations, m and n are each independently 1, 2, or 3.

[0048] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0049] R 2 It can be H, hydroxyl, or amino;

[0050] R 3 For H;

[0051] R 4 For H;

[0052] R 5 For H;

[0053] m and n are each independently 1, 2 or 3;

[0054] When Q is a 4-8 member heterocyclic ring, R 1 When it is a C1-C4 alkyl group, Represents a double bond;

[0055] When Q is a 4-8 member carbon ring, R 1 It is a C1-C4 alkyl group, R 2 When it is H, Represents a single key;

[0056] When Q is a 4-8 member carbon ring, R 1 For H, R 2When H is used, n is 1.

[0057] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0058] R 2 It can be H, halogen, or hydroxyl;

[0059] R 3 For H;

[0060] R 4 For H;

[0061] R 5 For H;

[0062] Q is C6-C 10 Aromatic rings, 4-8 membered carbon rings, or 4-8 membered heterocycles; wherein the 4-8 membered heterocycle is m and n are each independently 1, 2 or 3;

[0063] When R 2 When it is halogen, m is 1.

[0064] In some implementations, when the 4-8 member heterocycle is When n is 1.

[0065] In some implementation schemes, R 2 It can be H or a hydroxyl group.

[0066] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0067] R 2 It can be H, halogen, hydroxyl, or amino;

[0068] R 3 For H;

[0069] R 4 For H;

[0070] R 5 For H;

[0071] m and n are each independently 1, 2 or 3;

[0072] When R 2 When OH is present, Q is C6-C. 10 Aromatic rings, 6-8 membered carbon rings, or 6-8 membered heterocycles;

[0073] When Q is a 6-8 member heterocyclic ring, R 2 For OH, R 1 When H is 2, Represents a single key.

[0074] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0075] R 2 It can be H, halogen, hydroxyl, or amino;

[0076] R 3 For H;

[0077] R 4 For H;

[0078] R 5 For H;

[0079] m and n are each independently 1, 2 or 3;

[0080] When Q is a 4-8 quintile heterocyclic ring, m is 1, n is 2, R 2 When it is a hydroxyl group, Represents a single key;

[0081] When m is 1 and n is 2 Represents a single bond, R 2 When Q is a hydroxyl group, it is a 7-8 membered carbon ring, a 4-8 membered heterocycle, or a C6-C ring. 10 Aromatic rings;

[0082] When m is 1 and n is 2 Represents a double bond, R 2 When Q is a hydroxyl group, it is a 6-8 membered carbon ring, a 6-8 membered heterocycle, or a C6-C ring. 10 Aromatic rings;

[0083] When m and n are 1, R 2 When Q is a hydroxyl group, it is a 6-8 membered carbon ring, a 6-8 membered heterocycle, or a C6-C ring. 10 Aromatic ring.

[0084] In some implementation schemes, for

[0085] In some implementation schemes, for

[0086] In some implementation schemes, for

[0087] In some implementation schemes, for

[0088] In some embodiments, the compound represented by Formula I may be:

[0089] The present invention provides the use of substance Z as described above or a pharmaceutical composition comprising substance Z as described above in the preparation of a medicament; said medicament is used to treat and / or prevent depression, anxiety disorders, cluster headaches or neurodegenerative diseases.

[0090] This invention provides a pharmaceutical composition containing substance Z as described above, or containing substance Z as described above, in preparation with 5-HT 2A In the context of pharmaceutical applications, the substance Z is a compound of Formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof.

[0091] In some implementations, the drug can be used to treat and / or prevent depression, anxiety disorders, cluster headaches, or neurodegenerative diseases.

[0092] This invention provides a compound of formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof:

[0093] Represents a single bond or a double bond;

[0094] R 1 It is H or C1-C4 alkyl;

[0095] R 2 H, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy or

[0096] R 3 It is H, halogen, or C1-C4 alkyl;

[0097] R 4 It is H, halogen, or C1-C4 alkyl;

[0098] R 5 It is H, halogen, or C1-C4 alkyl;

[0099] R 6 It is a C1-C4 alkyl group;

[0100] Q is a 7-8 membered carbon ring or a 7-8 membered heterocycle; the heteroatom of the 7-8 membered heterocycle is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0101] m and n are independently 0, 1, 2 or 3.

[0102] In some implementation schemes, R 1 In, the C 1-4The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0103] In some implementation schemes, R 2 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0104] In some implementation schemes, R 2 In, the C 1-4 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0105] In some implementation schemes, R 2 In this context, the halogen may be fluorine, chlorine, bromine, or iodine.

[0106] In some implementation schemes, R 3 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0107] In some implementation schemes, R 4 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0108] In some implementation schemes, R 5 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0109] In some implementation schemes, R 6 In, the C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0110] In some implementations, in Q, the 7-8 member carbon ring is a 7 member carbon ring.

[0111] In some implementations, in Q, the heteroatom of the 7-8 membered heterocycle is O or N.

[0112] In some implementations, in Q, the number of heterocycles in the 7-8 member is 1.

[0113] In some embodiments, Q is a 7-membered carbon ring or a 7-membered heterocycle; the heteroatom of the 7-membered heterocycle is N or O, and the number of heteroatoms is 1.

[0114] In some embodiments, Q is a 7-membered carbon ring or a 7-membered heterocycle; the heteroatom of the 7-membered heterocycle is O, and the number of heteroatoms is 1.

[0115] In some implementation schemes, Represents a single bond or a double bond;

[0116] R 1 It is H or C1-C4 alkyl;

[0117] R 2 It is a hydroxyl group;

[0118] R 3 For H;

[0119] R 4 For H;

[0120] R 5 For H;

[0121] Q is a 7-membered carbon ring or a 7-membered heterocycle; the heteroatom of the 7-membered heterocycle is N or O, and the number of heteroatoms is 1;

[0122] m and n are independently 1 or 2.

[0123] In some embodiments, in Q, the heteroatom of the 4-8 membered heterocycle is a heteroatom of a 7 membered heterocycle, for example...

[0124] In some implementation schemes, for

[0125] In some implementation schemes, for

[0126] In some implementation schemes, R 2 It can be H or a hydroxyl group.

[0127] In some implementations, when Q is a 7-8 member heterocyclic ring, R 1 When it is a C1-C4 alkyl group, It represents a double bond.

[0128] In some implementations, when Q is a 7-8 membered carbon ring or a 7-8 membered heterocycle; the 7-8 membered heterocycle is

[0129] In some implementations, when Q is a 7-8 member heterocyclic ring, R 2 For OH, R 1 When H is 2, Represents a single key.

[0130] In some implementations, when Q is a 7-8 member heterocyclic ring, m is 1, n is 2, and R... 2 When it is OH, Represents a single key.

[0131] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0132] R 2 It is H or hydroxyl;

[0133] R 3 For H;

[0134] R 4 For H;

[0135] R 5 For H;

[0136] m and n are each independently 1, 2 or 3;

[0137] When Q is a 7-8 member heterocyclic ring, R 1 When it is a C1-C4 alkyl group, It represents a double bond.

[0138] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0139] R 2 It is H or hydroxyl;

[0140] R 3 For H;

[0141] R 4 For H;

[0142] R 5 For H;

[0143] m and n are each independently 1, 2 or 3;

[0144] When Q is a 7-8 member heterocyclic ring; the 7-8 member heterocyclic ring is

[0145] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0146] R 2 It is H or hydroxyl;

[0147] R 3 For H;

[0148] R 4 For H;

[0149] R 5 For H;

[0150] m and n are each independently 1, 2 or 3;

[0151] When Q is a 7-8 member heterocyclic ring, R 2 For OH, R 1 When H is 2, Represents a single key.

[0152] In some implementation schemes, R 1 It is H or C1-C4 alkyl;

[0153] R 2 It is H or hydroxyl;

[0154] R 3 For H;

[0155] R 4 For H;

[0156] R 5 For H;

[0157] m and n are each independently 1, 2 or 3;

[0158] When Q is a 7-8 member heterocyclic ring, m is 1, n is 2, R 2 When it is OH, Represents a single key.

[0159] In some embodiments, the compound represented by Formula II is any of the following compounds:

[0160] The present invention also provides a pharmaceutical composition comprising (i) a compound represented by Formula II above, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof; and (ii) a pharmaceutically acceptable carrier.

[0161] Terminology Definition

[0162] Unless otherwise stated, the terms used in this application have the following definitions, and the definitions of terms not referred to below are as commonly understood by those skilled in the art to which this invention pertains.

[0163] In this application, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compounds of this invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When a compound contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.

[0164] In this application, the term "multiple" refers to a natural number greater than 2, such as 2, 3, 4, or 5.

[0165] In this application, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0166] In this application, the term "hydroxyl" means –OH.

[0167] In this application, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group having a certain number of carbon atoms. 1–3 Alkyl refers to an alkyl group having 1–3 (e.g., 1, 2, 3) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, and n-butyl.

[0168] In this application, the term "alkoxy" refers to -O-alkyl, wherein the alkyl group is an alkyl group as defined above.

[0169] In this application, the term “treatment” means a therapeutic therapy. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the disease or one or more biological manifestations of the condition.

[0170] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently being" used in this application should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently being" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0171] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0172] The reagents and raw materials used in this invention are all commercially available.

[0173] The positive and progressive effects of this invention are that the compounds of this invention can be used for the prevention and treatment of depression, anxiety, cluster headaches, or neurodegenerative diseases. The compound of this invention is 5-HT. 2A Receptor agonists, some compounds of this invention are agonists of 5-HT 2A The receptor has full agonist activity, and some compounds are agonist-active to 5-HT. 2A The receptor has partial agonist activity, and the preferred compounds of the present invention are effective against 5-HT. 2A The receptor has agonistic activity and is effective against 5-HT. 2B The receptor has antagonistic activity and very weak agonistic activity. Detailed Implementation

[0174] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0175] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art.

[0176] Example 1: Preparation of 1-hydroxy-4-(1,2,5,6-tetrahydropyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-1)

[0177] Step 1: Benzyltriethylammonium chloride (20.16 g, 88.4 mmol), NaHCO3 (14.85 g, 176.8 mmol), Pd(OAc)2 (400 mg, 1.7 mmol), and compound 1-1 (25.0 g, 88.4 mmol) were added sequentially to a DMF (250 mL) solution of 5-hydroxy-1-pentene (10.66 g, 123.7 mmol). The reaction mixture was reacted at 40 °C for 24 hours. After the reaction was complete, the mixture was quenched with saturated NH4Cl aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-5% petroleum ether / ethyl acetate) to give a yellow oily intermediate 1-2 (16.0 g, yield 67%). 1H NMR(400MHz, CDCl3)δ9.78(t,J=1.5Hz,1H),7.52(d,J=7.8Hz,1H),7.26-7.18(m, 2H),7.09-7.01(m,1H),2.78-2.71(m,2H),2.51-2.45(m,2H),1.77-1.62(m,4H).

[0178] Step 2: NaClO2 (20.42 g, 226 mmol) was slowly added to a solution of compounds 1-2 (16.0 g, 66.4 mmol), NaH2PO4 (9.43 g, 66.4 mmol), 2-methyl-2-butene (20.49 g, 0.292 mol), and tert-butanol (180 mL) and water (60 mL). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the pH of the reaction system was adjusted to 2-3 with 2M hydrochloric acid, extracted with dichloromethane, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-25% petroleum ether / ethyl acetate) to give a yellow oily intermediate 1-3 (10.0 g, yield 52%). 1 H NMR (400MHz, CDCl3) δ11.16 (s, 1H), 7.52 (d, J = 7.8Hz, 1H), 7.25-7.17 (m, 2H), 7 .08-7.01(m,1H),2.81-2.70(m,2H),2.41(t,J=7.2Hz,2H),1.78-1.63(m,4H).

[0179] Step 3: A mixture of compounds 1-3 (10.0 g, 38.9 mmol) and polyphosphoric acid (230 g) was stirred at 130 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to 100 °C, and the pH was adjusted to 7 by adding 2N NaOH aqueous solution. After cooling to room temperature, the mixture was extracted with dichloromethane, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-17% petroleum ether / ethyl acetate) to give a brown oily intermediate 1-4 (5.0 g, yield 48%). The reaction was repeated once. 1 H NMR (400MHz, CDCl3) δ7.69 (dd, J=8.0, 1.2Hz, 1H), 7.54 (dd, J=7.6, 1.2Hz, 1H), 7.15 (t, J=7.8 Hz,1H),3.14-3.05(m,2H),2.74-2.67(m,2H),1.92-1.82(m,2H),1.77(dd,J=7.0,5.2Hz,2H).

[0180] Step 4: Triethylsilane (4.38 g, 37.6 mmol) was added to a trifluoroacetic acid (60 mL) solution of compounds 1-4 (6.0 g, 25.1 mmol), and the mixture was heated to 60 °C and stirred for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-5% petroleum ether / ethyl acetate) to give a gray solid intermediate 1-5 (4.0 g, yield 63%). 1 H NMR (400MHz, CDCl3) δ7.37 (dd, J=8.0, 1.2Hz, 1H), 7.02 (d, J=7.2Hz, 1H), 6.90 (t, J=7. 8Hz,1H),3.11-3.01(m,2H),2.87-2.80(m,2H),1.89-1.79(m,2H),1.69-1.57(m,4H).

[0181] Step 5: To a solution of intermediates 1-5 (4.0 g, 17.8 mmol) in 1,4-dioxane (40 mL), add bis(pinacol)diboron (6.78 g, 26.7 mmol), KOAc (3.49 g, 35.6 mmol), and Pd(dppf)Cl2 (1.3 g, 1.7 mmol) sequentially. Heat to 80 °C and stir for 16 hours. Cool to room temperature, filter, concentrate the filtrate, dilute with water, and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a dark brown oily intermediate 1-6 (4.0 g), which can be used directly in the next step.

[0182] Step 6: Under ice-water bath conditions, potassium peroxide monosulfonate (6.57 g, 10.6 mmol) was added to a 1 / 1, 40 mL mixture of acetone and water containing compounds 1-6 (4.0 g). The mixture was stirred under ice-water bath conditions for 3 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-25% petroleum ether / ethyl acetate) to give intermediates 1-7 (1.5 g, 46% yield) as a gray solid. 1 H NMR (400MHz, CDCl3) δ6.92 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 8. 0Hz,1H),4.69(s,1H),2.94-2.72(m,4H),1.92-1.77(m,2H),1.69-1.57(m,4H).

[0183] Step 7: Under ice-water bath conditions, add compound 1-8 (1.32 g, 4.6 mmol) to a DMF (15 mL) solution of intermediate 1-7 (1.5 g, 9.2 mmol) and stir at room temperature for 2 hours. After the reaction is complete, dilute with water and extract with ethyl acetate. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is purified by preparative high-performance liquid chromatography (column: Gemini 5 μm C18 150*21.2 mm, mobile phase: acetonitrile-water (0.1% TFA), gradient: 65–95%), and lyophilized to give a white solid intermediate 1-9 (1.09 g, yield 46%). 1 H NMR(400MHz, CDCl3) δ7.21(d,J=8.6Hz,1H),6.49(d,J=8.6Hz,1H),4.58(s,1H ),3.09-3.01(m,2H),2.94-2.83(m,2H),1.89-1.78(m,2H),1.68-1.57(m,4H).

[0184] Step 8: Intermediates 1-9 (0.100 g, 0.416 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.193 g, 0.624 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 6 mL). Then, Pd(PPh3)4 (0.024 g, 0.020 mmol) and Na2CO3 (0.070 g, 0.660 mmol) were added, and the mixture was heated to 100 °C and stirred for 4 hours under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure, extracted with water and dichloromethane, and the organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-04-115 (0.124 g, 87% yield). 1 H NMR (800MHz, CD3OD) δ6.71(d,J=8.2Hz,1H),6.57(d,J=8.2Hz,1H),5.60-5.56(m,1H),3.89(s,2H),3.56-3.53(m, 2H),2.90-2.87(m,2H),2.77-2.73(m,2H),2.27-2.22(m,2H),1.86-1.81(m,2H),1.61-1.55(m,4H),1.48(s,9H).

[0185] Step 9: Dissolve the intermediate LHQ-04-115 (0.040 g, 0.116 mmol) obtained in Step 8 in a 1,4-dioxane solution (2 M, 10 mL) under hydrogen chloride gas, and stir overnight at room temperature under nitrogen protection. Concentrate under reduced pressure, dissolve the residue in a small amount of methanol, and adjust to alkalinity with saturated NaHCO3 aqueous solution. Dilute with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate, and purify the remaining solid by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a white solid compound I-1 (0.018 g, 64%). 1 H NMR(500MHz,CD3OD)δ6.68(d,J=8.2Hz,1H),6.55(d,J=8.2Hz,1H),5.57-5.51(m,1H),3.29(m,2H),2.95 (t,2H),2.90-2.84(m,2H),2.80-2.75(m,2H),2.26-2.18(m,2H),1.87-1.78(m,2H),1.60-1.53(m,4H). 13 C NMR (126MHz, CD3OD) δ154.19,143.90,140.42,133.53,131.12,127.73,124.54 ,113.48,50.47,43.02,33.74,32.27,29.70,28.81,26.54,25.96.HRMS(ESI)C 16 H 22 NO + [M+H] + Calculated value: 244.1696; Measured value: 244.1697.

[0186] Example 2: Preparation of 1-hydroxy-4-(2,5-dihydro-1H-pyrrole-3-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-2)

[0187] Following the method of Example 1, the raw material 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents, and preparation methods were the same as in Example 1. A brown solid compound I-2 (0.014 g, yield 58%) was obtained. 1H NMR(500MHz,CD3OD)δ6.77(d,J=8.3Hz,1H),6.58(d,J=8.3Hz,1H),5.61-5.56(m,1H),3.89 -3.80(m,4H),2.92-2.85(m,2H),2.83-2.77(m,2H),1.88-1.80(m,2H),1.62-1.53(m,5H). 13 C NMR(126MHz,CD3OD)δ154.64,144.30,143.62,131.49,127.32,127.11,125.36,113.61,58.33,55.02,33.65,32.31,29.31,28.80,26.41.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1539.

[0188] Example 3: Preparation of 1-hydroxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-3)

[0189] Following the method of Example 1, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 1 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 1, and a pale yellow oily compound I-3 (0.023 g, yield 65%) was obtained. 1 H NMR (500MHz, CD3OD) δ6.68(d,J=8.2Hz,1H),6.55(d,J=8.2Hz,1H),5.48-5.45(m,1H),3.50-3.44(m,2H),3.08(t,J=5 .7Hz,2H),2.89-2.84(m,2H),2.78-2.71(m,2H),2.30-2.22(m,2H),1.87-1.79(m,2H),1.61-1.52(m,4H).HRMS(ESI)C 16 H 22 NO + [M+H] + Calculated value: 244.1696; Measured value: 244.1698.

[0190] Example 4: Preparation of 1-hydroxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-4)

[0191] Following the method of Example 1, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 1 was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 1, and a white solid compound I-4 (0.078 g, yield 72%) was obtained. 1 H NMR (500MHz, CD3OD) δ6.68(d,J=8.2Hz,1H),6.55(d,J=8.2Hz,1H),5.44-5.39(m,1H),3.12-3.07(m,2H),2.90-2.84(m,2H ),2.78-2.72(m,2H),2.72-2.66(m,2H),2.40(s,3H),2.37-2.29(m,2H),1.87-1.78(m,2H),1.61-1.52(m,4H).HRMS(ESI)C 17 H 24 NO + [M+H] + Calculated value: 258.1852; Measured value: 258.1861.

[0192] Example 5: Preparation of 1-hydroxy-4-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-5)

[0193] Intermediates 1-9 are described in Example 1.

[0194] Step 1: Following the method of Example 1, replace 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 1 with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods are the same as in Example 1, and a pale yellow solid compound LHQ-04-118 (0.213 g, yield 99%) is obtained. 1H NMR (800MHz, CD3OD) δ6.67(d,J=8.2Hz,1H),6.55(d,J=8.2Hz,1H),5.44-5.42(m,1H),4.00-3.97(m,2H),3.60-3.58 (m,2H),2.89-2.86(m,2H),2.73-2.69(m,2H),2.26-2.22(m,2H),1.85-1.80(m,2H),1.60-1.54(m,4H),1.49(s,9H).

[0195] Step 2: Dissolve the intermediate LHQ-04-118 (0.150 g, 0.436 mmol) obtained in Step 1 in methanol (8 mL), then add wet palladium on carbon (0.20 g, 10 wt%), and stir for 30 hours under a hydrogen atmosphere. Filter, concentrate the filtrate under reduced pressure, and purify the residual solid by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to obtain a white solid intermediate LHQ-04-138 (0.131 g, 86% yield). 1 H NMR(800MHz,CD3OD)δ6.80(d,J=8.4Hz,1H),6.58(m,J=8.4Hz,1H),4.18(m,J=13.1Hz,2H),2 .94-2.84(m,7H),1.85-1.80(m,2H),1.69(d,J=13.3Hz,2H),1.61-1.48(m,6H),1.47(s,9H).

[0196] Step 3: Dissolve the intermediate LHQ-04-138 (0.125 g, 0.362 mmol) obtained in Step 2 in a 1,4-dioxane solution of hydrogen chloride (1 M, 5 mL), under nitrogen protection, and stir overnight at room temperature. A white solid precipitates. Filter, wash the filter cake with 1,4-dioxane, and dry to obtain a white solid compound I-5 (0.080 g, yield 78%). 1 H NMR(500MHz,CD3OD)δ6.85(d,J=8.5Hz,1H),6.62(d,J=8.5Hz,1H),3.51-3.42(m,2H),3 .21-3.06(m,3H),2.92-2.83(m,4H),1.98-1.80(m,6H),1.64-1.52(m,4H).HRMS(ESI)C 16 H 24 NO + [M+H] + Calculated value: 246.1852; Measured value: 246.1861.

[0197] Example 6: Preparation of 1-hydroxy-4-(1-methylpiperidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene (compound I-6)

[0198] Referring to the method of Example 5, the 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 5 was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 5, and a white solid compound I-6 (75%) was obtained. 1 H NMR(500MHz,CD3OD)δ6.85(d,J=8.5Hz,1H),6.58(d,J=8.5Hz,1H),3.04-2.96(m,2H),2.91-2.80(m,4H),2.78-2 .65(m,1H),2.34(s,3H),2.25-2.16(m,2H),1.88-1.79(m,2H),1.75-1.68(m,4H),1.61-1.51(m,4H).HRMS(ESI)C 17 H 26 NO + [M+H] + Calculated value: 260.2009; Measured value: 260.2015.

[0199] Example 7: Preparation of 6-hydroxy-9-(1,2,5,6-tetrahydropyridin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone (compound I-7)

[0200] Step 1: Hydroxylamine hydrochloride (6.2 g, 88.8 mmol) was added to a pyridine (100 mL) solution of compound 7-1 (10.0 g, 44.4 mmol). The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid intermediate 7-2 (10.5 g, 97% yield). The reaction was repeated once. 1 H NMR (400MHz, CDCl3, ppm) δ7.90 (d, J=8.0Hz, 1H), 7.55 (dd, J=7.6, 0.8Hz, 1H), 7.07 (t,J=7.6Hz,1H),2.86(t,J=6.0Hz,2H),2.79(t,J=6.4Hz,2H),1.95-1.85(m,2H).

[0201] Step 2: To a dichloromethane solution (5.0 g, 20.8 mmol) of compound 7-2 (5.0 g, 50 mL), DIBAL-H (1 M n-hexane solution, 166 mL, 166.4 mmol) was slowly added dropwise at -10 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, potassium fluoride (24.1 g, 416 mmol) was added in portions at -10 °C. After the addition was complete, the mixture was stirred for another 30 minutes, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give a yellow solid intermediate 7-3 (2.5 g, yield 52%). The reaction was performed in four parallel batches. 1 H NMR (400MHz, CDCl3, ppm) δ7.13 (dd, J=7.6, 0.8Hz, 1H), 6.84 (t, J=8.0Hz, 1H), 6.6 8(dd,J=7.6,0.8Hz,1H),3.11-3.01(m,4H),1.83-1.77(m,2H),1.71-1.60(m,2H).

[0202] Step 3: Compound 7-3 (5.0 g, 22.1 mmol), B2Pin2 (8.4 g, 33.2 mmol), KOAc (4.3 g, 44.2 mmol), and Pd(dppf)Cl2 (1.6 g, 2.2 mmol) were added to 1,4-dioxane (50 mL), and the mixture was heated to 80 °C and stirred for 16 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Two parallel batches of the reaction were combined. A dark brown oily intermediate 7-4 (12.0 g) was obtained and used directly in the next step.

[0203] Step 4: Potassium peroxide monosulfonate (26.9 g, 43.9 mmol) was added to a 1 / 1, 100 mL solution of crude compound 7-4 (12.0 g) in acetone and water under ice-water bath conditions. The reaction mixture was stirred under ice-water bath conditions for 3 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The aqueous phase was collected and the pH was adjusted to 7-8. The mixture was then extracted three more times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give a white solid intermediate 7-5 (4.0 g, yield 55%). 1H NMR (400MHz, DMSO-d6) δ8.91 (s, 1H), 6.67 (t, J = 8.0Hz, 1H), 6.30-6.21 (m, 2H), 4.99 (s,1H),2.93-2.86(m,2H),2.70-2.62(m,2H),1.69-1.61(m,2H),1.52-1.43(m,2H).

[0204] Step 5: Under ice-water bath conditions, compound 7-6 (0.88 g, 3.1 mmol) was added to 20 mL of DMF containing compound 7-5 (1.0 g, 6.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Four parallel batches of the reaction were performed and combined. The crude product was purified by column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) and preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18 150*21.2 mm, mobile phase: acetonitrile-water (0.1% TFA), gradient: 65–95%), and lyophilized to give intermediate 7-7 (0.950 g, yield 16%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 7.05 (d, J = 8.4Hz, 1H), 6.27 (d, J = 8.8Hz, 1H), 4.64 (t, J=4.0Hz,1H),3.11-3.01(m,2H),2.78-2.70(m,2H),1.73-1.64(m,2H),1.57-1.51(m,2H).

[0205] Step 6: Intermediate 7-7 (0.100 g, 0.413 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.191 g, 0.617 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 6 mL). Then, Pd(PPh3)4 (0.024 g, 0.020 mmol) and Na2CO3 (0.070 g, 0.660 mmol) were added. Under nitrogen protection, the mixture was stirred at 100 °C for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and extracted with dichloromethane and water. The organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-05-038 (0.115 g, 80% yield). 1H NMR (800MHz, CD3OD) δ6.68(d,J=8.2Hz,1H),6.38(d,J=8.2Hz,1H),5.72-5.70(m,1H),3.94-3.91(m,2H),3.58(m, 2H),2.99-2.95(m,2H),2.85-2.81(m,2H),2.31-2.26(m,2H),1.81-1.76(m,2H),1.60-1.54(m,2H),1.48(s,9H).

[0206] Step 7: Dissolve the intermediate LHQ-05-038 (0.095 g, 0.275 mmol) obtained in Step 6 in a 1,4-dioxane solution of hydrogen chloride (0.8 M, 9 mL), under nitrogen protection, and stir overnight at room temperature. A white solid precipitates. Filter, wash the filter cake with 1,4-dioxane solution, and dry to obtain a white solid compound I-7 (0.077 g, 100% yield). 1 H NMR(800MHz,D2O)δ7.13(d,J=1.2Hz,1H),7.05(d,J=8.5Hz,1H),6.07-6.03(m,1H),3.91-3.88(m,2H),3.56-3.52( m,2H),3.50-3.46(m,2H),3.05-3.01(m,2H),2.65-2.60(m,2H),2.18-2.13(m,2H),1.80-1.75(m,2H).HRMS(ESI)C 15 H 21 N2O + [M+H] + Calculated value: 245.1648; Measured value: 245.1648.

[0207] Example 8: Preparation of 6-hydroxy-9-(1,2,3,6-tetrahydropyridin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azapyrrolidone (compound I-8)

[0208] Following the method of Example 7, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 7 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 7, and a white solid compound I-8 (0.066 g, yield 90%) was obtained. 1H NMR(800MHz,D2O)δ7.14(d,J=8.5Hz,1H),7.05(d,J=8.5Hz,1H),5.87-5.83(m,1H),3.92-3.88(m,2H),3. 57-3.52(m,4H),3.05-3.01(m,2H),2.67-2.62(m,2H),2.18-2.13(m,2H),1.80-1.75(m,2H).HRMS(ESI)C 15 H 21 N2O + [M+H] + Calculated value: 245.1648; Measured value: 245.1650.

[0209] Example 9: Preparation of 6-hydroxy-9-(1,2,5,6-tetrahydropyridin-3-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane (compound I-9)

[0210] Step 1: K₂CO₃ (47.9 g, 347 mmol) was added to a MeCN (300 mL) solution of compound 9-1 (30.0 g, 173 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, compound 9-2 (42.0 g, 347 mmol) was added, and the reaction mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Two parallel reactions were combined. The crude product was purified by column chromatography (petroleum ether) to give a colorless liquid intermediate 9-3 (70.0 g, 93% yield). 1 H NMR (400MHz, CDCl3, ppm) δ7.20-7.04(m,3H),6.86-6.83(m,1H),6.08-5.98(m,1H),5.44-5.38(m,1H),5.34-5.26(m,1H),4.55-4.49(m,2H).

[0211] Step 2: The reaction solution of compound 9-3 (5.0 g, 23.5 mmol) with N,N-diethylaniline (10 mL) was reacted at 220 °C for 6 hours. After the reaction was completed, the mixture was diluted with ethyl acetate, washed three times with 2M hydrochloric acid, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Fourteen parallel reactions were performed and combined. The crude product was purified by column chromatography (eluent: 0-5% ethyl acetate / petroleum ether) to give a yellow liquid intermediate 9-4 (30.0 g, yield 34%). 1H NMR (400MHz, CDCl3) δ7.16 (dd, J=8.0, 1.2Hz, 1H), 7.00-6.97 (m, 1H), 6.77 (dd ,J=8.0,0.8Hz,1H),6.06-5.90(m,1H),5.15-5.08(m,2H),3.64-3.62(m,2H).

[0212] Step 3: K₂CO₃ (38.9 g, 282 mmol) was added to a MeCN (300 mL) solution of compound 9-4 (30.0 g, 141 mmol). After stirring at room temperature for 30 minutes, compound 9-2 (17.0 g, 141 mmol) was added, and the reaction mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluting with petroleum ether) to give a colorless liquid intermediate 9-5 (29.0 g, yield 56%). 1 H NMR (400MHz, CDCl3, ppm) δ7.16 (dd, J=8.0, 0.8Hz, 1H), 7.04-6.99 (m, 1H), 6.79 (d, J=8.0Hz, 1H), 6.09-5.86 (m ,2H),5.48-5.37(m,1H),5.33-5.24(m,1H),5.10-4.98(m,2H),4.57-4.50(m,2H),3.61(dt,J=6.4,1.2Hz,2H).

[0213] Step 4: Grubbs' second-generation catalyst (1.0 g, 1.2 mmol) was added to a toluene (60 mL) solution of compound 9-5 (6.0 g, 23.7 mmol). The reaction mixture was then reacted at 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Five parallel reactions were performed and combined. The crude product was purified by column chromatography (petroleum ether) to give a colorless liquid intermediate 9-6 (12.0 g, 36% yield). 1 H NMR (400MHz, CDCl3) δ7.29-7.33(m,1H),7.04-7.01(m,1H),6.98-6.90(m,1H) ,5.90-5.79(m,1H),5.43-5.48(m,1H),4.64-4.56(m,2H),3.73-3.71(m,2H).

[0214] Step 5: A solution of 1,4-dioxane (40 mL) of compound 9-6 (4.0 g, 17.8 mmol), B2Pin2 (6.78 g, 26.7 mmol), KOAc (3.49 g, 35.6 mmol), and Pd(dppf)Cl2 (1.3 g, 1.7 mmol) was reacted at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Three parallel reactions were combined to give a black oily intermediate 9-7 (12.0 g), which was used directly in the next step.

[0215] Step 6: Potassium persulfate (19.0 g, 30.8 mmol) was added to a 120 mL, 1 / 1 solution of crude compound 9-7 (12.0 g) in acetone and water. The reaction mixture was reacted in an ice-water bath for 3 hours. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give intermediate 9-8 (2.5 g, 35% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.66 (s, 1H), 6.90 (t, J = 8.0Hz, 1H), 6.74-6.70 (m, 1H), 6.51 (dd, J = 8.0, 1.2Hz,1H),6.37(d,J=8.0Hz,1H),5.92-5.87(m,1H),4.13(t,J=5.2Hz,2H),2.61-2.57(m,2H).

[0216] Step 7: Add wet palladium on carbon (0.750 g, 10 wt%) to a methanol (25 mL) solution of compound 9-8 (2.5 g). The reaction mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give intermediate 9-9 (2.0 g, 76% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 6.84 (t, J = 8.0Hz, 1H), 6.53 (dd, J = 8.0, 1.2Hz, 1H), 6.37 (dd, J=8.0,1.2Hz,1H),3.86(t,J=5.2Hz,2H),2.74-2.71(m,2H),1.88-1.82(m,2H),1.60-1.55(m,2H).

[0217] Step 8: Two parallel reactions were carried out in an ice-water bath. Compound 9-10 (1.09 g, 3.8 mmol) was added to 20 mL of DMF containing compound 9-9 (1.0 g, 6.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) and preparative high-performance liquid chromatography (column: Gemini 5 μm C18 150*21.2 mm, mobile phase: acetonitrile-water (0.1% TFA), gradient: 65-95%). The product was lyophilized to give 9-11 as a white solid (920 mg, yield 30%). 1 H NMR(800MHz,DMSO-d6)δ9.64(s,1H),7.16(d,J=8.7Hz,1H),6.52(d,J=8.7Hz,1H), 3.95–3.91(m,2H),2.78–2.75(m,2H),1.89(p,J=5.6Hz,2H),1.58(p,J=6.0Hz,2H).

[0218] Step 9: Intermediate 9-11 (0.100 g, 0.411 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.191 g, 0.617 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 6 mL). Then, Pd(PPh3)4 (0.024 g, 0.020 mmol) and Na2CO3 (0.070 g, 0.660 mmol) were added, and the mixture was stirred at 100 °C for 4 h under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure, extracted with dichloromethane and water, and the organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-05-044 (0.065 g, 46% yield). 1 H NMR (800MHz, CD3OD) δ6.80(d,J=8.3Hz,1H),6.49(d,J=8.3Hz,1H),5.74-5.70(m,1H),4.16-4.14(m,2H),3.95-3.91 (m,2H),3.54-3.52(m,2H),2.86-2.82(m,2H),2.27-2.22(m,2H),1.97-1.92(m,2H),1.68-1.62(m,2H),1.48(s,9H).

[0219] Step 10: Dissolve the intermediate LHQ-05-044 (0.060 g, 0.173 mmol) obtained in Step 9 in a 1,4-dioxane solution of hydrogen chloride (0.8 M, 9 mL), under nitrogen protection, and stir overnight at room temperature. Concentrate under reduced pressure, dissolve in a small amount of methanol, and adjust to alkalinity with saturated NaHCO3 aqueous solution. Dilute with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate, and purify the remaining solid by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give brown oily compound I-9 (0.014 g, 37%). 1 H NMR (800MHz, CD3OD) δ6.82(d,J=8.3Hz,1H),6.50(d,J=8.3Hz,1H),5.80-5.77(m,1H),3.93-3.90(m,2H),3.74- 3.71(m,2H),3.12(t,J=6.1Hz,2H),2.85-2.81(m,2H),2.39-2.35(m,2H),1.96-1.91(m,2H),1.67-1.62(m,2H). 13 C NMR(201MHz,CD3OD)δ160.40,156.49,135.78,127.81,125.61,124.08,123.60,111.65,74.83,47.61,42.42,33.61,26.65,25.26,24.88.HRMS(ESI)C 15 H 20 NO2 + [M+H] + Calculated value: 246.1489; Measured value: 246.1504.

[0220] Example 10: Preparation of 6-hydroxy-9-(1,2,3,6-tetrahydropyridin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxetane (compound I-10)

[0221] Following the method of Example 9, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 9 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 9, and a white solid compound I-10 (0.066 g, yield 90%) was obtained. 1H NMR (800MHz, CD3OD) δ6.84(d,J=8.3Hz,1H),6.51(d,J=8.3Hz,1H),5.71-5.67(m,1H),3.95-3.92(m,2H),3.80- 3.77(m,2H),3.39(t,J=6.1Hz,2H),2.86-2.82(m,2H),2.76-2.72(m,2H),1.97-1.92(m,2H),1.68-1.63(m,2H). 13 C NMR(201MHz,CD3OD)δ160.43,156.75,138.02,127.38,126.15,124.30,117.66,111.53,74.89,43.38,42.40,33.60,27.10,26.61,25.27.HRMS(ESI)C 15 H 20 NO2 + [M+H] + Calculated value: 246.1489; Measured value: 246.1498.

[0222] Example 11: Preparation of 6-hydroxy-9-(1,2,5,6-tetrahydropyridin-3-yl)-1,3,4,5-tetrahydrobenzo[c]oxetine (compound I-11)

[0223] Step 1: LiBr (0.30 g, 3.4 mmol) and TsOH-H2O (0.26 g, 1.3 mmol) were added sequentially to a solution of compound 11-1 (15.0 g, 69.7 mmol) in dimethylformaldehyde 11-2 (30 mL). The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into a 2 M NaOH aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily intermediate 11-3 (18.0 g, 94% yield), which could be used directly in the next step.

[0224] Step 2: Under an ice-water bath, slowly add a solution of compound 11-3 (18 g, 69.5 mmol) in dichloromethane (50 mL) to a solution of dried AlCl3 (13.9 g, 104.2 mmol) in dichloromethane (150 mL). After the addition is complete, the reaction mixture is allowed to react under an ice-water bath for 2 hours. After the reaction is complete, the reaction mixture is poured into a 2 M NaOH aqueous solution, extracted with EtOAc, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give a yellow oily intermediate 11-4 (10.0 g, yield 56%). 1 H NMR (400MHz, DMSO-d6) δ7.51 (dd, J=8.2, 1.2Hz, 1H), 7.24-7.20 (m, 1H), 7.10-7. 03(m,1H),4.64(s,2H),3.99-3.90(m,2H),3.26-3.17(m,2H),1.76-1.65(m,2H).

[0225] Step 3: A 1,4-dioxane (100 mL) solution of compound 11-4 (10 g, 44 mmol), B2Pin2 (16.76 g, 66 mmol), KOAc (8.64 g, 88 mmol), and Pd(dppf)Cl2 (3.22 g, 4.4 mmol) was reacted at 80 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a black oily intermediate (10 g). Potassium peroxide (9.14 g, 44 mmol) was added to a 1 / 1, 100 mL solution of the intermediate (10 g) in acetone and water. The reaction mixture was reacted under an ice-water bath for 3 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-35% ethyl acetate / petroleum ether) to give a white solid intermediate 11-5 (3.0 g, yield 37%). 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 6.92-6.86 (m, 1H), 6.73 (dd, J = 8.2, 1.0Hz, 1H), 6.6 1(d,J=7.4Hz,1H),4.50(s,2H),3.96-3.85(m,2H),3.02-2.92(m,2H),1.71-1.56(m,2H).

[0226] Step 4: Under ice-water bath conditions, DBDMH (1.74 g, 6.1 mmol) was added to a DMF (20 mL) solution of compound 11-5 (2.0 g, 12.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (column: Gemini 5 μm C18 150*21.2 mm, mobile term: ACN-H2O (0.1% TFA), gradient: 65–95%), and lyophilized to give a white solid 11-6 (1.71 g, yield 56%). 1 H NMR (400MHz, DMSO) δ9.66(s,1H),7.19(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),4.78(s,2H),3.97-3.87(m,2H),3.07-2.98(m,2H),1.72-1.62(m,2H).

[0227] Step 5: Intermediate 11-6 (0.050 g, 0.206 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.096 g, 0.309 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 6 mL). Then, Pd(PPh3)4 (0.012 g, 0.010 mmol) and Na2CO3 (0.035 g, 0.330 mmol) were added. Under nitrogen protection, the mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and extracted with dichloromethane and water. The organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-04-145 (0.065 g, 92% yield). 1 H NMR (800MHz, CD3OD) δ6.78(d,J=8.1Hz,1H),6.69(d,J=8.2Hz,1H),5.64-5.60(m,1H),4.67(s,2H),4.03(t,J=5. 2Hz,2H),3.94(s,2H),3.56-3.54(m,2H),3.12-3.08(m,2H),2.28-2.23(m,2H),1.77-1.72(m,2H),1.48(s,9H).

[0228] Step 6: Dissolve the intermediate LHQ-04-145 (0.060 g, 0.173 mmol) obtained in Step 5 in a 1,4-dioxane solution of hydrogen chloride (1 M, 6 mL), under nitrogen protection, and stir overnight at room temperature. A white solid precipitates. Filter, wash the filter cake with 1,4-dioxane solution, and dry to obtain a white solid compound I-11 (0.042 g, yield 86%). 1 H NMR (600MHz, CD3OD) δ6.84(d,J=8.3Hz,1H),6.74(d,J=8.4,2.1Hz,1H),5.79-5.74(m,1H),4.68(s,2H),4.07 -4.02(m,2H),3.76-3.72(m,2H),3.40-3.34(m,2H),3.14-3.09(m,2H),2.57-2.51(m,2H),1.77-1.71(m,2H). 13 C NMR(151MHz,CD3OD)δ155.47,140.55,133.21,131.38,130.82,128.08,125.67,115.82,76.65,70.92,47.05,41.40,30.95,25.68,22.88.HRMS(ESI)C 15 H 20 NO2 + [M+H] + Calculated value: 246.1489; Measured value: 246.1495.

[0229] Example 12: Preparation of 6-hydroxy-9-(2,5-dihydro-1H-pyrrolo-3-yl)-1,3,4,5-tetrahydrobenzo[c]oxetine (compound I-12)

[0230] Following the method of Example 11, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 11, and a white solid compound I-12 (0.037 g, yield 85%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.92(d,J=8.4Hz,1H),6.76(d,J=8.3Hz,1H),5.71(t,J=1.7Hz,1H) ,4.71(s,2H),4.23(m,4H),4.05(t,J=5.2Hz,2H),3.15-3.11(m,2H),1.79-1.72(m,2H). 13C NMR (151MHz, CD3OD) δ154.61,139.61,137.47,130.44,126.23,122.90,121.48,114.43,75.12,69.35,54.40,52.56,29.48,24.20.HRMS(ESI)C 14 H 18 NO2 + [M+H] + Calculated value: 232.1332; Measured value: 232.1337.

[0231] Example 13: Preparation of 6-hydroxy-9-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,5-tetrahydrobenzo[c]oxetine (compound I-13)

[0232] Following the method of Example 11, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 11 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 11, and a white solid compound I-13 (0.029 g, yield 73%) was obtained. 1 H NMR (600MHz, CD3OD) δ6.82(d,J=8.3Hz,1H),6.72(d,J=8.3Hz,1H),5.57-5.52(m,1H),4.66(s,2H),4.04(t,J= 5.2Hz,2H),3.81-3.77(m,2H),3.43(t,J=6.1Hz,2H),3.14-3.09(m,2H),2.59-2.53(m,2H),1.78-1.71(m,2H). 13 C NMR(151MHz,CD3OD)δ155.09,139.80,138.89,133.61,131.19,127.32,119.81,115.71,76.63,71.05,43.12,42.19,30.95,29.07,25.70.HRMS(ESI)C 15 H 20 NO2 + [M+H] + Calculated value: 246.1489; Measured value: 246.1496.

[0233] Example 14: Preparation of 6-hydroxy-9-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,3,4,5-tetrahydrobenzo[c]oxetine (compound I-14)

[0234] Following the method of Example 11, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 11 was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 11, and a brown oily compound I-14 (0.089 g, yield 83%) was obtained. 1 H NMR (600MHz, CD3OD) δ6.76(d,J=8.3Hz,1H),6.67(d,J=8.3Hz,1H),5.48-5.42(m,1H),4.67(s,2H),4.02( t,J=5.2Hz,2H),3.12-3.07(m,4H),2.72-2.67(m,2H),2.40(s,3H),2.39-2.35(m,2H),1.77-1.71(m,2H). 13 C NMR(151MHz,CD3OD)δ154.41,139.76,138.06,135.24,130.79,127.45,124.35 ,115.54,76.52,71.32,55.24,53.12,45.62,33.05,30.99,25.78.HRMS(ESI)C 16 H 22 NO2 + [M+H] + Calculated value: 260.1645; Measured value: 260.1645.

[0235] Example 15: Preparation of 6-hydroxy-9-(piperidin-4-yl)-1,3,4,5-tetrahydrobenzo[c]oxetane (compound I-15)

[0236] Referring to the method of Example 5, the 1-hydroxy-4-bromo-6,7,8,9-tetrahydro-5H-benzo[7]cycloene in Example 5 was replaced with 6-hydroxy-9-bromo-1,3,4,5-tetrahydrobenzo[c]oxetine. The raw materials, reagents and preparation methods were the same as in Example 5, and a pale yellow solid compound I-15 (0.048 g, yield 91%) was obtained. 1 HNMR(600MHz,CD3OD)δ6.92(d,J=8.6Hz,1H),6.74(d,J=8.5Hz,1H),4.80(s,2H),4.05(t, J=5.2Hz,2H),3.50-3.44(m,2H),3.20-3.09(m,5H),2.04-1.84(m,4H),1.76-1.69(m,2H). 13C NMR (151MHz, CD3OD) δ152.64,138.86,132.38,130.07,123.14,114.71,75.16,67.42,44.37(2C),34.80,30.09(2C),29.57,24.22.HRMS(ESI)C 15 H 22 NO2 + [M+H] + Calculated value: 248.1645; Measured value: 248.1650.

[0237] Example 16: Preparation of 6-hydroxy-9-(1-methylpiperidin-4-yl)-1,3,4,5-tetrahydrobenzo[c]oxetane (compound I-16)

[0238] Following the method of Example 15, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 15 was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 15, and a brown oily compound I-16 (0.029 g, yield 83%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.91(d,J=8.5Hz,1H),6.70(d,J=8.5Hz,1H),4.78(s,2H),4.07-3.99(m,2H),3.21-3 .15(m,2H),3.13-3.06(m,2H),2.93-2.84(m,1H),2.58-2.45(m,5H),1.87-1.77(m,4H),1.77-1.69(m,2H). 13 C NMR(151MHz,CD3OD)δ153.71,140.19,134.60,131.23,124.66,116.02,76.52,68.86,56.81(2C),45.44,37.09,33.52(2C),30.99,25.64.HRMS(ESI)C 16 H 24 NO2 + [M+H] + Calculated value: 262.1802; Measured value: 262.1805.

[0239] Example 17: Preparation of 1-hydroxy-4-(1,2,5,6-tetrahydropyridin-3-yl)-5,6,7,8-tetrahydronaphthalene (compound I-17)

[0240] Step 1: 1-Hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene (0.500 g, 2.212 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (1.00 g, 3.318 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 25 mL). Then, Pd(PPh3)4 (0.127 g, 0.110 mmol) and Na2CO3 (0.375 g, 3.539 mmol) were added, and the mixture was stirred overnight at 85 °C under nitrogen protection. After cooling to room temperature, the mixture was concentrated under reduced pressure, extracted with dichloromethane and water, and the organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to give a yellow solid intermediate LHQ-03-107 (0.647 g, 88% yield). 1 H NMR (800MHz, CDCl3) δ6.83(d,J=8.1Hz,1H),6.61(d,J=8.1Hz,1H),5.62(m,J=3.9,1.9Hz,1H),3.94(m,J=2.4Hz,2H ),3.55(t,J=5.8Hz,2H),2.69-2.64(m,4H),2.27-2.23(m,2H),1.84-1.79(m,2H),1.76-1.71(m,2H),1.47(s,9H).

[0241] Step 2: The intermediate LHQ-03-107 (0.230 g, 0.698 mmol) obtained in Step 1 was dissolved in a 1,4-dioxane solution of hydrogen chloride (2 M, 10 mL) under nitrogen protection and stirred overnight at room temperature. The solution was concentrated under reduced pressure, dissolved in a small amount of methanol, and adjusted to alkalinity with a saturated NaHCO3 aqueous solution. The solution was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried, and concentrated. The remaining solid was purified by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a pale yellow solid compound I-17 (0.080 g, 50% yield). 1 H NMR (800MHz, CD3OD) δ6.69(d,J=8.1Hz,1H),6.52(d,J=8.1Hz,1H),5.55(m,J=3.8,1.8Hz,1H),3.31-3 .30(m,2H),2.94(t,2H),2.68-2.61(m,4H),2.24-2.19(m,2H),1.79-1.73(m,2H),1.72-1.67(m,2H). 13C NMR(201MHz,CD3OD)δ155.14,139.69,136.79,133.98,127.08,124.97,124.73,112.16,49.58,43.09,28.85,26.08,24.56,24.31,23.87.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1533.

[0242] Example 18: Preparation of 1-hydroxy-4-(2,5-dihydro-1H-pyrrole-3-yl)-5,6,7,8-tetrahydronaphthalene (compound I-18)

[0243] Following the method of Example 17, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, yielding a white solid compound I-18 (0.042 g, yield 28%). 1 H NMR (800MHz, CDCl3) δ6.88(d,J=8.2Hz,1H),6.57(d,J=8.1Hz,1H),5.78-5.75(m,1H),4.03-4.00(m,2H),3.99 -3.95(m,2H),2.73(t,J=6.2Hz,2H),2.68(t,J=6.5Hz,2H),1.84-1.78(m,2H),1.77-1.71(m,2H).HRMS(ESI)C 14 H 18 NO + [M+H] + Calculated value: 216.1383; Measured value: 216.1384.

[0244] Example 19: Preparation of 1-hydroxy-4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8-tetrahydronaphthalene (compound I-19)

[0245] In Example 17, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 17, and a white solid compound I-19 (0.083 g, yield 38%) was obtained. 1H NMR (800MHz, CD3OD) δ6.68(d,J=8.1Hz,1H),6.52(d,J=8.1Hz,1H),5.48-5.45(m,1H),3.43-3.39(m, 2H),3.03-2.99(m,2H),2.67-2.61(m,4H),2.25-2.21(m,2H),1.79-1.74(m,2H),1.72-1.67(m,2H). 13 C NMR(201MHz,CD3OD)δ154.96,139.42,136.38,135.78,126.62,124.90,124.41,112.15,45.27,43.75,31.17,28.86,24.57,24.31,23.88.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1539.

[0246] Example 20: Preparation of 1-hydroxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8-tetrahydronaphthalene (compound I-20)

[0247] In Example 17, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 17, and a white solid compound I-20 (0.174 g, yield 81%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.69(d,J=8.1Hz,1H),6.52(d,J=8.1Hz,1H),5.44-5.40(m,1H),3.11-3.06 (m,2H),2.71-2.60(m,6H),2.39(s,3H),2.38-2.32(m,2H),1.79-1.72(m,2H),1.72-1.61(m,2H). 13 C NMR(151MHz,CD3OD)δ153.63,137.39,135.05,133.77,125.23,123.55,121.92 ,110.78,53.96,51.84,44.27,30.46,27.46,23.17,22.89,22.46.HRMS(ESI)C 16 H 22 NO +[M+H] + Calculated value: 244.1696; Measured value: 244.1698.

[0248] Example 21: Preparation of 1-hydroxy-4-(piperidin-3-yl)-5,6,7,8-tetrahydronaphthalene (compound I-21)

[0249] Step 1: 1-Hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene (0.500 g, 2.212 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (1.00 g, 3.318 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 25 mL). Then, Pd(PPh3)4 (0.127 g, 0.110 mmol) and Na2CO3 (0.375 g, 3.539 mmol) were added, and the mixture was stirred overnight at 100 °C under nitrogen protection. The mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane and water. The organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to give a yellow solid intermediate LHQ-03-107 (0.647 g, 88% yield). 1 H NMR (800MHz, CDCl3) δ6.83(d,J=8.1Hz,1H),6.61(d,J=8.1Hz,1H),5.62(m,J=3.9,1.9Hz,1H),3.94(m,J=2.4Hz,2H ),3.55(t,J=5.8Hz,2H),2.69-2.64(m,4H),2.27-2.23(m,2H),1.84-1.79(m,2H),1.76-1.71(m,2H),1.47(s,9H).

[0250] Step 2: Dissolve the intermediate LHQ-03-107 (0.400 g, 1.215 mmol) obtained in Step 1 in methanol (25 mL), then add wet palladium on carbon (0.400 g, 10 wt%), and stir at room temperature for 30 hours under a hydrogen balloon. Filter, concentrate the filtrate under reduced pressure, and purify the residual solid by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to obtain a white solid intermediate LHQ-03-113 (0.292 g, 72% yield). 1H NMR(800MHz,CD3OD)δ6.87(d,J=8.3Hz,1H),6.56(d,J=8.3Hz,1H),4.15-4.09(m,1H),4 .01-3.96(m,1H),2.93-2.42(m,7H),1.83-1.72(m,7H),1.59-1.52(m,1H),1.47(s,9H).

[0251] Step 3: Add the intermediate LHQ-03-113 (0.280 g, 0.845 mmol) obtained in Step 2 to the reaction flask, then add 10 mL of a 1,4-dioxane solution of hydrogen chloride. Under nitrogen protection, stir overnight at room temperature. Concentrate under reduced pressure, dissolve the residue in a small amount of methanol, and adjust to alkalinity with saturated NaHCO3 aqueous solution. Dilute with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate. The remaining solid is purified by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a white solid compound I-21 (0.073 g, yield 37%). 1 H NMR (800MHz, CD3OD) δ6.83(d,J=8.3Hz,1H),6.54(d,J=8.3Hz,1H),3.06-3.02(m,1H),2.94-2.85(m,1H),2.88- 2.82(m,1H),2.73(t,J=6.4Hz,2H),2.64-2.59(m,3H),2.55-2.50(m,1H),1.83-1.72(m,6H),1.68-1.56(m,2H). 13 C NMR (201MHz, CD3OD) δ152.80,135.07,133.00,123.84,122.64,111.10,52.49,45.68,37.46,31.53,26.45,25.96,23.45,23.05,22.18.HRMS(ESI)C 15 H 22 NO + [M+H] + Calculated value: 232.1696; Measured value: 232.1690.

[0252] Example 22: Preparation of 1-H-4-(pyrrolidine-3-yl)-5,6,7,8-tetrahydronaphthalene (compound I-22)

[0253] In Example 21, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 21, and a brown solid compound I-22 (0.042 g, yield 28%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.90(d,J=8.3Hz,1H),6.58(d,J=8.3Hz,1H),3.47-3.38(m,1H),3.31-3.24(m,1H),3.20 -3.13(m,1H),3.10-3.02(m,1H),2.79-2.66(m,3H),2.66-2.61(m,2H),2.21-2.13(m,1H),1.86-1.70(m,5H). 13 C NMR (151MHz, CD3OD) δ154.47,137.21,132.21,125.43,123.63,112.65,53.84,47.22,40.79,34.18,27.87,24.82,24.42,23.55.HRMS(ESI)C 14 H 20 NO + [M+H] + Calculated value: 218.1539; Measured value: 218.1536.

[0254] Example 23: Preparation of 1-hydroxy-4-(piperidin-4-yl)-5,6,7,8-tetrahydronaphthalene (compound I-23)

[0255] In Example 21, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 21, and a white solid compound I-23 (0.022 g, yield 57%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.86(d,J=8.4Hz,1H),6.55(d,J=8.3Hz,1H),3.14-3.08(m,2H),2.83 -2.75(m,1H),2.75-2.67(m,4H),2.65-2.60(m,2H),1.81-1.70(m,4H),1.67-1.54(m,4H). 13C NMR (151MHz, CD3OD) δ153.98,136.41,136.02,125.07,123.97,112.58,47.87(2C),38.11,34.69(2C),27.24,24.87,24.46,23.61.HRMS(ESI)C 15 H 22 NO + [M+H] + Calculated value: 232.1696; Measured value: 232.1696.

[0256] Example 24: Preparation of 1-hydroxy-4-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydronaphthalene (compound I-24)

[0257] In Example 21, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 21, and a white solid compound I-24 (0.021 g, yield 31%) was obtained. 1 H NMR(600MHz,CD3OD)δ6.86(d,J=8.3Hz,1H),6.55(d,J=8.3Hz,1H),3.01-2.95 (m,2H),2.72-2.60(m,5H),2.32(s,3H),2.19-2.11(m,2H),1.81-1.65(m,8H). 13 C NMR(151MHz,CD3OD)δ154.05,136.23,135.66,125.14,123.82,112.57,57.55(2C),46.44,37.13,33.77(2C),27.25,24.86,24.45,23.59.HRMS(ESI)C 16 H 24 NO + [M+H] + Calculated value: 246.1852; Measured value: 246.1852.

[0258] Example 25: Preparation of 1-hydroxy-4-(2,5,6,7-tetrahydro-1H-aza-4-yl)-5,6,7,8-tetrahydronaphthalene (compound I-25)

[0259] In Example 17, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-2,3,4,7-tetrahydro-1H-azacycloheptane-1-carboxylic acid tert-butyl ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a white solid compound I-25 (0.073 g, yield 64%) was obtained. 1 H NMR(500MHz,DMSO-d6)δ9.00(s,1H),6.62(d,J=8.1Hz,1H),6.50(d,J=1.9Hz,1H),5.68-5.47(m,1H),3.26(d,J=5.4Hz,1 H),2.93(t,J=5.7Hz,1H),2.78-2.69(m,3H),2.57-2.50(m,4H),2.38-2.30(m,2H),2.26-2.19(m,1H),1.72-1.58(m,5H). 13 C NMR(151MHz,CD3OD)δ145.32,137.85,129.36,126.37,120.84,117.14,115.40 ,102.53,43.54,38.42,29.41,25.95,22.59,20.00,19.81,19.69.HRMS(ESI)C 16 H 22 NO + [M+H] + Calculated value: 242.1696; Measured value: 244.1699.

[0260] Example 26: Preparation of 5-(4-methoxy-5,6,7,8-tetrahydronaphth-1-yl)-1,2,3,6-tetrahydropyridine (compound I-26)

[0261] In Example 17, 4-bromo-5,6,7,8-tetrahydronaphthalene-1-ol was replaced with 5-bromo-1,2,3,4-tetrahydro-8-methoxynaphthalene. The other raw materials, reagents and preparation methods were the same as in Example 17, and a white solid compound I-26 (0.047 g, 96%) was obtained. 1H NMR(800MHz, CDCl3)δ6.90(d,J=8.2Hz,1H),6.64(d,J=8.3Hz,1H),5.63-5.59(m,1H),3.80(s,3H),3.4 4-3.41(m,2H),3.04-3.00(m,2H),2.71-2.65(m,4H),2.23-2.18(m,2H),1.79-1.69(m,4H).HRMS(ESI)C 16 H 22 NO + [M+H] + Calculated value: 244.1696; Measured value: 244.1696.

[0262] Example 27: Preparation of 5-hydroxy-8-(1,2,5,6-tetrahydropyridin-3-yl)chromium (compound I-27)

[0263] Step 1: Dissolve 44.6 g (198.8 mmol) of ethyl triethylphosphonoethyl in 300 mL of dry THF and cool to 0 °C in an ice-water bath. Slowly add sodium hydride (8.0 g, 198.8 mmol, 60 wt%) to the reaction system and stir at 0 °C for 30 minutes. Add reactant 27-1 (20 g, 99.4 mmol) dropwise to the above system, remove the ice bath, and slowly stir to room temperature overnight. Quench the reaction with saturated ammonium chloride solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous Na₂SO₄, and concentrate the filtrate to obtain crude pale yellow oily compound 27-2 (30.0 g).

[0264] Step 2: Compound 27-2 (30.0 g), sodium acetate (23.6 g, 288 mmol), and p-toluenesulfonyl hydrazine (35.8 g, 192 mmol) were reacted overnight at 80 °C in a mixed solvent of tetrahydrofuran and water (1 / 1, 1 L). After the reaction was monitored by LCMS, the mixture was cooled to room temperature, and the reaction system was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and the residue was concentrated and subjected to column chromatography (eluent: 0-50% methanol / dichloromethane) to give a colorless oily compound 27-3 (24.0 g, 88% two-step yield). 1 H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 7.06-6.91 (m, 2H), 6.81 (dd, J = 7.6, 1.6Hz, 1H) ,4.07(q,J=7.2Hz,2H),3.01-2.88(m,2H),2.47-2.37(m,2H),1.18(t,J=7.2Hz,3H).

[0265] Step 3: Under ice-water bath conditions, lithium aluminum hydride (96.6 mL, 96.6 mmol, 1 mol / L in THF) was slowly added dropwise to a tetrahydrofuran (500 mL) solution of compound 27-3 (24.0 g, 87.8 mmol), maintaining the reaction temperature below 10°C. The reaction system was slowly raised to room temperature and reacted for 1 hour. After the reaction was monitored by LCMS, sodium sulfate decahydrate was added to quench the reaction. The filtrate was concentrated, and the residue was subjected to column chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to give a colorless oily compound 27-4 (19.2 g, yield 94%). 1 H NMR(400MHz, DMSO-d6)δ9.76(s,1H),6.99(dd,J=8.0,1.2Hz,1H),6.79(dd,J=8.0,1.2Hz ,1H),4.47(t,J=5.2Hz,1H),3.43(q,J=6.8Hz,2H),2.80-2.62(m,2H),1.72-1.51(m,2H).

[0266] Step 4: Compound 27-4 (19.2 g, 83.0 mmol) and triphenylphosphine (32.6 g, 124.4 mmol) were dissolved in tetrahydrofuran (600 mL), purged with nitrogen, and cooled to 0 °C in an ice-water bath. Diisopropyl azodicarbonate (DIAD) (33.4 g, 166.0 mmol) was slowly added to the solution. After the addition was complete, the ice bath was removed, the reaction system was slowly raised to room temperature, and the reaction was stirred overnight. The reaction was monitored by LCMS until complete. The reaction was diluted with ethyl acetate and extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and the residue was concentrated and subjected to column chromatography (eluent: petroleum ether) to give a colorless oily compound 27-5 (13.9 g, 78% yield). 1 H NMR (400MHz, DMSO-d6) δ7.13 (dd, J=8.0, 1.2Hz, 1H), 7.02 (t, J=8.0Hz, 1H), 6.78 (d d,J=8.4,1.2Hz,1H),4.19-4.04(m,2H),2.67(t,J=6.8Hz,2H),2.02-1.89(m,2H).

[0267] Step 5: Compound 27-5 (9.0 g, 42.2 mmol), dried potassium acetate (8.3 g, 84.4 mmol), pinacol diboronate (16.1 g, 63.3 mmol), and Pd(dppf)Cl2 (1.54 g, 2.1 mmol) in a 1,4-dioxane (100 mL) solution were reacted at 80 °C for 2 hours. After the reaction was monitored by LCMS, ethyl acetate was added to dilute the reaction mixture and the mixture was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the filtrate was concentrated to obtain a black, oily crude product. The crude product was redissolved in acetone (100 mL) and cooled to 0 °C in an ice-water bath. Oxone (18.2 g, 29.6 mmol) was added in portions. After the addition was complete, the ice bath was removed, and the reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was monitored by LCMS, ethyl acetate was added to dilute the reaction mixture and extract it. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and the residue was concentrated and subjected to column chromatography (eluent: 0-35% ethyl acetate / petroleum ether) to give a white solid compound 27-6 (3.6 g, yield 56%). 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),6.82(t,J=8.0Hz,1H),6.32(dd,J=8.0,1.2Hz,1H) ,6.18(dd,J=8.4,1.2Hz,1H),4.16-3.91(m,2H),2.56-2.51(m,2H),1.92-1.75(m,2H).

[0268] Step 6: Under ice-water bath conditions, dibromohydantoin (3.4 g, 12.0 mmol) was added in portions to a DMF (100 mL) solution of compound 27-6 (3.6 g, 24.0 mmol). After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous Na2SO4, and the filtrate was concentrated. The residue was purified by column chromatography (eluent: 0-80% ethyl acetate / petroleum ether) followed by C18 reversed-phase column chromatography (MeCN / H2O (0.1% TFA) = 45%-55%) to give compound 27-7 (1.1 g, 20% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.61 (s, 1H), 7.11 (d, J = 8.8Hz, 1H), 6.32 (d, J = 8.8Hz, 1H), 4.17-4.11 (m, 2H), 2.55 (t, J = 6.4Hz, 2H), 1.92-1.84 (m, 2H).

[0269] Step 7: Intermediate 27-7 (0.100 g, 0.436 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.202 g, 0.654 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 12 mL). Then, Pd(PPh3)4 (0.025 g, 0.021 mmol) and Na2CO3 (0.070 g, 0.654 mmol) were added. Under nitrogen protection, the mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and extracted with dichloromethane and water. The organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-05-030 (0.093 g, 64% yield). 1 H NMR (800MHz, CD3OD) δ6.74(d,J=8.2Hz,1H),6.28(d,J=8.2Hz,1H),5.71(m,1H),4.14(s,2H),4.12-4.10( m,2H),3.51(s,2H),2.64(t,J=6.6Hz,2H),2.23(m,J=5.7,2.7Hz,2H),1.95(m,J=6.3Hz,2H),1.48(s,9H).

[0270] Step 8: Dissolve the intermediate LHQ-05-030 (0.080 g, 0.241 mmol) obtained in Step 7 in a 1,4-dioxane solution of hydrogen chloride (0.8 M, 9 mL), under nitrogen protection, and stir overnight at room temperature. Concentrate under reduced pressure, dissolve in a small amount of methanol, and adjust to alkalinity with saturated NaHCO3 aqueous solution. Dilute with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate. The remaining solid is purified by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a brown oily compound I-27 (0.005 g, 9%). 1 H NMR (800MHz, CD3OD) δ6.78(d,J=8.2Hz,1H),6.30(d,J=8.2Hz,1H),5.81-5.77(m,1H),4.12-4.09(m,2H),3.79-3. 74(m,2H),3.15(t,J=6.1Hz,2H),2.63(t,J=6.6Hz,2H),2.42-2.37(m,2H),1.97-1.91(m,2H),1.32-1.27(m,2H). 13C NMR(201MHz,CD3OD)δ155.58,152.94,133.95,126.61,121.84,119.65,109.78,105.86,65.69,45.53,40.91,23.12,21.51,19.06.HRMS(ESI)C 14 H 18 NO2 + [M+H] + Calculated value: 232.1332; Measured value: 232.1334.

[0271] Example 28: Preparation of 5-hydroxy-8-(1,2,3,6-tetrahydropyridin-4-yl)chromium (compound I-28)

[0272] Following the method of Example 27, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 27 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 27, and a brown oily compound IHCH-1422 (0.029 g, yield 52%) was obtained. 1 H NMR(800MHz,CD3OD)δ6.75(d,J=8.2Hz,1H),6.28(d,J=8.2Hz,1H),5.67-5.64(m,1H),4.10-4.06(m,2H) ,3.51-3.48(m,2H),3.08(t,J=5.8Hz,2H),2.64(t,J=6.6Hz,2H),2.52-2.48(m,2H),1.96-1.91(m,2H). 13 C NMR (201MHz, CD3OD) δ156.40,154.32,137.77,127.46,123.57,121.84,111.13,106.94,66.95,44.98,43.42,29.02,22.97,20.57.HRMS(ESI)C 14 H 18 NO2 + [M+H] + Calculated value: 232.1332; Measured value: 232.1339.

[0273] Example 29: Preparation of 1-hydroxy-4-(1,2,5,6-tetrahydropyridin-3-yl)naphthalene (compound I-29)

[0274] In Example 17, 4-bromo-5,6,7,8-tetrahydronaphthyl-1-ol was replaced with 4-bromonaphthyl-1-ol. The other required raw materials, reagents and preparation methods were the same as in Example 17, and brown solid compound I-29 (0.059 g, yield 42%) was obtained. 1 H NMR(600MHz,CD3OD)δ8.24-8.18(m,1H),7.98-7.93(m,1H),7.46-7.36(m,2H),7.07(d,J=7.6Hz,1H), 6.76(d,J=7.7Hz,1H),5.82-5.77(m,1H),3.56-3.50(m,2H),3.07(t,J=5.9Hz,2H),2.38-2.31(m,2H). 13 C NMR(151MHz,CD3OD)δ154.06,138.28,133.97,131.82,127.04,126.83,126.5 4,126.27,126.21,125.36,123.54,108.24,49.96,43.08,25.97.HRMS(ESI)C 15 H 16 NO + [M+H] + Calculated value: 226.1226; Measured value: 222.1228.

[0275] Example 30: Preparation of 1-hydroxy-4-(2,5-dihydro-1H-pyrrolo-3-yl)naphthalene (compound I-30)

[0276] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-hydroxy-4-bromonaphthalene, and 1-BOC-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-BOC-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a brown oily compound I-30 (0.047 g, yield 40%) was obtained. 1 H NMR(800MHz,CD3OD)δ8.28(d,1H),8.06(d,J=8.5Hz,1H),7.54-7.50(m,1H),7.49-7.44(m,1H),7.2 6(d,J=7.8Hz,1H),6.82(d,J=7.8Hz,1H),6.03-5.99(m,1H),4.41-4.38(m,2H),4.32-4.29(m,2H). 13C NMR(201MHz,CD3OD)δ155.52,138.54,133.61,127.96,127.56,126.72,125.85,125.49,123.96,123.06,122.44,108.10,55.48,54.07.HRMS(ESI)C 14 H 14 NO + [M+H] + Calculated value: 212.1070; Measured value: 212.1078.

[0277] Example 31: Preparation of 1-hydroxy-4-(1,2,3,6-tetrahydropyridin-4-yl)naphthalene (compound I-31)

[0278] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-hydroxy-4-bromonaphthalene, and 1-BOC-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a purple-red solid compound I-31 (0.150 g, yield 90%) was obtained. 1 H NMR (600MHz, CD3OD) δ8.22(d,1H),7.91(d,1H),7.46-7.37(m,2H),7.08(d,J=7.6Hz,1H),6.77( d,J=7.6Hz,1H),5.74-5.69(m,1H),3.63-3.59(m,2H),3.22(t,J=5.8Hz,2H),2.53-2.47(m,2H). 13 C NMR(151MHz,CD3OD)δ154.01,138.36,133.54,133.20,127.06,126.53,126.3 3,126.13,125.39,124.42,123.59,108.25,44.82,43.45,30.92.HRMS(ESI)C 15 H 16 NO + [M+H] + Calculated value: 226.1226; Measured value: 226.1225.

[0279] Example 32: Preparation of 1-hydroxy-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)naphthalene (compound I-32)

[0280] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-hydroxy-4-bromonaphthalene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a brown solid compound I-32 (0.053 g, yield 24%) was obtained. 1 H NMR (600MHz, CD3OD) δ8.23-8.18(m,1H),7.94-7.89(m,1H),7.46-7.36(m,2H),7.07(d,J=7.6Hz,1H),6.76(d ,J=7.8Hz,1H),5.70-5.65(m,1H),3.23-3.18(m,2H),2.80(t,J=5.8Hz,2H),2.58-2.52(m,2H),2.46(s,3H). 13 C NMR(151MHz,CD3OD)δ153.82,137.72,133.66,133.26,126.96,126.51,126.24,1 26.23,125.34,124.85,123.53,108.24,55.45,53.33,45.71,32.55.HRMS(ESI)C 16 H 18 NO + [M+H] + Calculated value: 240.1383; Measured value: 240.1383.

[0281] Example 33: Preparation of 1-amino-4-(1,2,5,6-tetrahydropyridin-3-yl)naphthalene (compound I-33)

[0282] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-amino-4-bromonaphthalene. The other raw materials, reagents and preparation methods were the same as in Example 17, and a brown oily compound I-33 (0.115 g, yield 66%) was obtained. 1 H NMR (800MHz, CD3OD) δ8.03(d,J=8.2Hz,1H),7.94(d,J=8.2Hz,1H),7.50-7.43(m,2H),7.14(m,J=7.8,2.3Hz, 1H), 6.80 (m, J = 7.7, 2.3Hz, 1H), 5.98-5.94 (m, 1H), 3.91-3.88 (m, 2H), 3.49-3.45 (m, 2H), 2.66-2.61 (m, 2H). 13C NMR(201MHz,CD3OD)δ145.16,133.32,133.10,127.89,127.51,127.27,126.1 0,126.00,125.63,125.28,123.28,109.72,46.84,41.58,23.10.HRMS(ESI)C 15 H 17 N2 + [M+H] + Calculated value: 225.1386; Measured value: 225.1381.

[0283] Example 34: Preparation of 1-amino-4-(2,5-dihydro-1H-pyrrolo-3-yl)naphthalene (compound I-34)

[0284] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-amino-4-bromonaphthalene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a brown solid compound I-34 (0.157 g, yield 99%) was obtained. 1 H NMR(800MHz,CD3OD)δ8.16-7.97(m,2H),7.53-7.43(m,2H),7.30-7.13(m,1H) ,6.83-6.70(m,1H),6.06-5.94(m,1H),4.43-4.39(m,2H),4.35-4.31(m,2H). 13 C NMR(201MHz,CD3OD)δ146.35,138.50,133.25,127.98,127.57,126.00,125.64,125.13,123.39,121.78,120.16,109.04,55.33,54.06.HRMS(ESI)C 14 H 15 N2 + [M+H] + Calculated value: 211.1230; Measured value: 221.1236.

[0285] Example 35: Preparation of 5-(4-chloronaphth-1-yl)-1,2,3,6-tetrahydropyridine (compound I-35)

[0286] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-bromo-4-chloronaphthalene. The other raw materials, reagents and preparation methods were the same as in Example 17, and a yellow oily compound I-35 (0.049 g, yield 58%) was obtained. 1 H NMR (600MHz, CD3OD) δ8.28-8.23(m,1H),8.14-8.09(m,1H),7.64-7.52(m,3H),7.25-7. 20(m,1H),5.89-5.83(m,1H),3.56-3.51(m,2H),3.11-3.06(m,2H),2.39-2.32(m,2H). 13 C NMR (151MHz, CD3OD) δ140.54,137.60,134.02,132.10,131.91,128.11,127.8 8,127.52,127.22,126.77,126.54,125.46,49.73,42.99,25.93.HRMS(ESI)C 15 H 15 ClN + [M+H] + Calculated value: 244.0888; Measured value: 244.0895.

[0287] Example 36: Preparation of 3-(4-chloronaphth-1-yl)-2,5-dihydro-1H-pyrrole (compound I-36)

[0288] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 1-bromo-4-chloronaphthalene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a yellow oily compound I-36 (0.025 g, yield 12%) was obtained. 1 H NMR(600MHz,CD3OD)δ8.28(d,J=1.6Hz,1H),8.17(d,1H),7.66-7.53(m,3H), 7.36-7.29(m,1H),6.08-6.03(m,1H),4.12-4.06(m,2H),4.04-3.98(m,2H). 13C NMR (151MHz, CD3OD) δ140.51,134.32,133.81,132.41,132.14,129.23,128.25,128.12,126.99,126.75,126.21,125.59,57.88,55.47.HRMS(ESI)C 14 H 13 ClN + [M+H] + Calculated value: 230.0731; Measured value: 230.0725.

[0289] Example 37: Preparation of 4-hydroxy-7-(1,2,5,6-tetrahydropyridin-3-yl)-2,3-dihydro-1H-indene (compound I-37)

[0290] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene. The other raw materials, reagents and preparation methods were the same as in Example 17, and a brown solid compound I-37 (0.084 g, yield 61%) was obtained. 1 H NMR(800MHz,CD3OD)δ6.87(d,J=8.3Hz,1H),6.59(d,J=8.2Hz,1H),5.90-5.87(m,1H),3.87-3.84(m,2H) ,3.37-3.33(m,2H),2.91(t,J=7.4Hz,2H),2.83(t,J=7.3Hz,2H),2.56-2.52(m,2H),2.06-2.01(m,2H). 13 C NMR(201MHz,CD3OD)δ153.13,143.38,131.61,130.26,126.48,126.03,122.16,112.69,44.28,40.16,32.61,28.84,24.94,21.63.HRMS(ESI)C 14 H 18 NO + [M+H] + Calculated value: 216.1383; Measured value: 216.1383.

[0291] Example 38: Preparation of 4-hydroxy-7-(2,5-dihydro-1H-pyrrolo-3-yl)-2,3-dihydro-1H-indene (compound I-38)

[0292] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a brown solid compound I-38 (0.069 g, yield 38%) was obtained. 1 H NMR (800MHz, CD3OD) δ6.95(d,J=8.3Hz,1H),6.62(d,J=8.3Hz,1H),5.95-5.92(m,1H),4.41-4. 38(m,2H),4.24-4.21(m,2H),3.02(t,J=7.4Hz,2H),2.86(t,J=7.5Hz,2H),2.13-2.07(m,2H). 13 C NMR(201MHz,CD3OD)δ153.95,144.26,136.69,130.90,126.29,119.87,117.07,112.64,52.59,33.97,28.58,24.40,21.77.HRMS(ESI)C 13 H 16 NO + [M+H] + Calculated value: 202.1226; Measured value: 202.1224.

[0293] Example 39: Preparation of 4-hydroxy-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-indene (compound I-39)

[0294] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a yellow-brown solid compound I-39 (0.058 g, yield 57%) was obtained. 1H NMR(500MHz,CD3OD)δ6.84(d,J=8.1Hz,1H),6.54(d,J=8.1Hz,1H),5.67-5.62(m,1H),3.45-3.40(m,2H), 3.01(t,J=5.7Hz,2H),2.90(t,J=7.3Hz,2H),2.81(t,J=7.3Hz,2H),2.40-2.32(m,2H),2.05-1.95(m,2H). 13 C NMR(201MHz,CD3OD)δ152.03,142.69,136.60,130.83,129.68,125.61,122.34,112.39,44.01,42.44,32.92,28.81,28.56,25.03.HRMS(ESI)C 14 H 18 NO + [M+H] + Calculated value: 216.1383; Measured value: 216.1388.

[0295] Example 40: Preparation of 4-hydroxy-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1H-indene (compound I-40)

[0296] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a yellow-brown solid compound I-40 (0.020 g, yield 47%) was obtained. 1 H NMR (500MHz, CD3OD) δ6.85(d,J=8.2Hz,1H),6.54(d,J=8.2Hz,1H),5.64-5.58(m,1H),3.13-3.07(m,2H),2.90(t ,J=7.3Hz,2H),2.81(t,J=7.4Hz,2H),2.68(t,J=5.8Hz,2H),2.52-2.44(m,2H),2.38(s,3H),2.05-1.95(m,2H). 13C NMR(201MHz,CD3OD)δ153.49,144.15,137.34,131.57,131.12,127.04,122.50,113.79,55.47,53.29,45.65,34.36,30.60,30.20,26.42.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1539.

[0297] Example 41: Preparation of 4-hydroxy-7-(piperidin-3-yl)-2,3-dihydro-1H-indene (compound I-41)

[0298] In Example 21, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene. The other raw materials, reagents and preparation methods were the same as in Example 21, and a white solid compound I-41 (0.053 g, yield 39%) was obtained. 1 H NMR (500MHz, CD3OD) δ6.82(d,J=8.2Hz,1H),6.53(d,J=8.2Hz,1H),3.06-2.93(m,2H),2.89(t,J=7.3Hz,2H),2.82(t,2 H),2.76-2.66(m,1H),2.65-2.49(m,2H),2.09-1.99(m,2H),1.90-1.81(m,1H),1.81-1.71(m,1H),1.69-1.55(m,2H). 13 C NMR(201MHz,CD3OD)δ152.78,145.03,132.49,130.70,125.25,114.09,53.60,47.01,41.28,32.50,32.48,30.43,27.67,25.82.HRMS(ESI)C 14 H 20 NO + [M+H] + Calculated value: 218.1539; Measured value: 218.1542.

[0299] Example 42: Preparation of 4-hydroxy-7-(pyrrolidone-3-yl)-2,3-dihydro-1H-indene (compound I-42)

[0300] In Example 21, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 21, and a reddish-brown solid compound I-42 (0.049 g, yield 35%) was obtained. 1 H NMR (500MHz, CD3OD) δ6.89(d,J=8.2Hz,1H),6.56(d,J=8.2Hz,1H),3.28(m,J=9.0,6.6Hz,2H),3.19-3.11(m,1H),3.10-3.01( m,1H),2.91-2.86(m,2H),2.83(t,J=7.4Hz,2H),2.80-2.71(m,1H),2.22-2.12(m,1H),2.10-2.00(m,2H),1.90-1.79(m,1H). 13 C NMR(201MHz,CD3OD)δ153.00,145.55,130.83,130.17,125.11,114.26,53.71,47.29,42.97,33.97,32.86,30.40,25.81.HRMS(ESI)C 13 H 18 NO + [M+H] + Calculated value: 204.1383; Measured value: 204.1882.

[0301] Example 43: Preparation of 4-hydroxy-7-(piperidin-4-yl)-2,3-dihydro-1H-indene (compound I-43)

[0302] In Example 21, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 21, and a white solid compound I-43 (0.049 g, yield 60%) was obtained. 1H NMR(500MHz,CD3OD)δ6.86(d,J=8.2Hz,1H),6.57(d,J=8.2Hz,1H),3.51-3.44(m, 2H),3.17-3.08(m,2H),2.94-2.80(m,5H),2.11-2.01(m,2H),2.01-1.82(m,4H). 13 C NMR(201MHz,CD3OD)δ153.18,144.87,132.12,131.04,124.89,114.29,45.88(2C),37.90,32.38,30.63(2C),30.39,25.85.HRMS(ESI)C 14 H 20 NO + [M+H] + Calculated value: 218.1539; Measured value: 218.1539.

[0303] Example 44: Preparation of 4-hydroxy-7-(1-methylpiperidin-4-yl)-2,3-dihydro-1H-indene (compound I-44)

[0304] In Example 21, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-hydroxy-7-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 21, and a pale yellow solid compound I-44 (0.048 g, yield 23%) was obtained. 1 H NMR(500MHz,CD3OD)δ6.84(d,J=8.2Hz,1H),6.54(d,J=8.2Hz,1H),3.04-2.96(m,2H),2.90-2.79 (m,4H),2.59-2.49(m,1H),2.34(s,3H),2.24-2.12(m,2H),2.09-1.99(m,2H),1.78-1.70(m,4H). 13 CNMR(201MHz,CD3OD)δ152.61,144.75,133.73,130.67,125.06,114.10,57.34(2C),46.35,39.46,33.33(2C),32.36,30.38,25.86.HRMS(ESI)C 15 H 22 NO + [M+H] +Calculated value: 232.1696; Measured value: 232.1698.

[0305] Example 45: Preparation of 4-hydroxy-7-(1,2,5,6-tetrahydropyridin-3-yl)-2,3-dihydrobenzofuran (compound I-45)

[0306] Step 1: Three parallel reactions were performed. Compound 45-2 (1.04 g, 3.7 mmol) was added to a DMF (20 mL) solution of compound 45-1 (1.0 g, 7.3 mmol) under ice-water bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: 0-25% ethyl acetate / petroleum ether) and preparative high-performance liquid chromatography (column: Gemini 5 μm C18 150*21.2 mm, mobile phase: acetonitrile-water (0.1% TFA), gradient: 65–95%), and lyophilized to give 45-3 (1.135 g, yield 24%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),7.05(d,J=8.6Hz,1H),6.27(d,J=8.6Hz,1H),4.57(t,J=8.8Hz,2H),3.14(t,J=8.8Hz,2H).

[0307] Step 2: Intermediate 45-3 (0.100 g, 0.467 mmol) and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester (0.217 g, 0.701 mmol) were dissolved in a mixed solvent of water and 1,4-dioxane (1 / 5, 12 mL). Then, Pd(PPh3)4 (0.027 g, 0.023 mmol) and Na2CO3 (0.079 g, 0.747 mmol) were added. Under nitrogen protection, the mixture was stirred at 100 °C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and extracted with dichloromethane and water. The organic phases were combined, dried, and concentrated. The mixture was purified by silica gel column chromatography (eluent: 0-15% ethyl acetate / petroleum ether) to give a white solid intermediate LHQ-05-034 (0.104 g, 70% yield). 1H NMR(800MHz,CD3OD)δ6.86(d,1H),6.28(d,J=8.4Hz,1H),6.07(m,1H),4.54(t,J=8.7Hz,2H), 4.24-4.22(m,2H),3.52-3.50(m,2H),3.09(t,J=8.7Hz,2H),2.28-2.23(m,2H),1.48(s,9H).

[0308] Step 3: Dissolve the intermediate LHQ-05-034 (0.095 g, 0.299 mol) from Step 2 in a 1,4-dioxane solution of hydrogen chloride (0.8 M, 9 mL), under nitrogen protection, and stir overnight at room temperature. Concentrate under reduced pressure, dissolve in a small amount of methanol, and adjust to alkalinity with saturated NaHCO3 aqueous solution. Dilute with water, extract three times with ethyl acetate, combine the organic phases, dry and concentrate. The remaining solid is purified by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a brown oily compound I-45 (0.028 g, 43%). 1 H NMR (800MHz, CD3OD) δ6.83(d,J=8.4Hz,1H),6.26(d,J=8.4Hz,1H),6.10-6.06(m,1H),4.51(t,J =8.7Hz,2H),3.64-3.61(m,2H),3.07(t,J=8.7Hz,2H),2.94(t,J=5.9Hz,2H),2.28-2.23(m,2H). 13 C NMR(201MHz,CD3OD)δ159.71,154.90,134.84,127.81,123.13,116.01,113.99,109.00,72.29,47.34,43.06,27.87,26.15.HRMS(ESI)C 13 H 16 NO2 + [M+H] + Calculated value: 218.1176; Measured value: 218.1179.

[0309] Example 46: Preparation of 4-hydroxy-7-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran (compound I-46)

[0310] Referring to Example 45, 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester in Example 45 was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 45, and a yellow solid compound I-46 (0.026 g, yield 55%) was obtained. 1 H NMR(800MHz,CD3OD)δ6.96(d,J=8.5Hz,1H),6.32(d,J=8.5Hz,1H),6.22-6.18(m,1H),4.57(t,J =8.8Hz,2H),3.82-3.77(m,2H),3.40(t,J=6.2Hz,2H),3.10(t,J=8.7Hz,2H),2.81-2.77(m,2H). 13 C NMR(201MHz,CD3OD)δ160.08,155.41,134.19,127.61,116.46,115.21,114.33,109.05,72.67,43.44,42.37,27.70,25.28.HRMS(ESI)C 13 H 16 NO2 + [M+H] + Calculated value: 218.1176; Measured value: 218.1177.

[0311] Example 47: Preparation of 5-(2,3,4,5-tetrahydrobenzo[b]oxetane-9-yl)-1,2,3,6-tetrahydropyridine (compound I-47)

[0312] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 9-bromo-2,3,4,5-tetrahydrobenzo[b]oxetane. The other raw materials, reagents and preparation methods were the same as in Example 17, and a colorless oily compound I-47 (0.083 g, yield 50%) was obtained. 1 H NMR (800MHz, CD3OD) δ7.05(d,J=1.9Hz,1H),6.98(d,J=1.8Hz,1H),6.90(t,1H),5.80-5.76(m,1H),3.92-3.88(m,2H ),3.58-3.55(m,2H),2.98-2.94(m,2H),2.80-2.76(m,2H),2.28-2.23(m,2H),1.97-1.91(m,2H),1.71-1.66(m,2H). 13C NMR(201MHz,CD3OD)δ158.91,138.37,137.63,135.66,130.56,128.66,124.99,124.57,74.85,43.07,35.40(2C),33.65,27.48,26.27.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1541.

[0313] Example 48: Preparation of 3-(2,3,4,5-tetrahydrobenzo[b]oxetane-9-yl)-2,5-dihydro-1H-pyrrole (compound I-48)

[0314] In Example 17, 4-bromo-5,6,7,8-tetrahydronaphthyl-1-ol was replaced with 9-bromo-2,3,4,5-tetrahydrobenzo[b]oxetane, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, yielding a yellow oily compound I-48 (0.089 g, yield 64%). 1 H NMR (800MHz, CD3OD) δ7.26(d,J=1.6Hz,1H),7.18(d,J=1.6Hz,1H),7.00(t,J=7.6Hz,1H),6.36-6.32(m,1H),4. 48-4.45(m,2H),4.21-4.18(m,2H),4.00-3.95(m,2H),2.84-2.80(m,2H),2.02-1.96(m,2H),1.75-1.70(m,2H). 13 C NMR (201MHz, CD3OD) δ159.46,138.43,132.33,127.67,125.72,124.89,124.72,122.06,74.63,54.36,53.21,35.30,33.35,27.26.HRMS(ESI)C 14 H 18 NO + [M+H] + Calculated value: 216.1383; Measured value: 216.1378.

[0315] Example 49: Preparation of 4-(2,3,4,5-tetrahydrobenzo[b]oxetane-9-yl)-1,2,3,6-tetrahydropyridine (compound I-49)

[0316] In Example 17, 4-bromo-5,6,7,8-tetrahydronaphthyl-1-ol was replaced with 9-bromo-2,3,4,5-tetrahydrobenzo[b]oxetane, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, yielding a white oily compound I-49 (0.088 g, yield 68%). 1 H NMR (800MHz, CD3OD) δ7.04(d,J=1.8Hz,1H),6.98(d,J=1.8Hz,1H),6.90(t,J=7.5Hz,1H),5.87-5.58(m,1H),3.92-3.89( m,2H),3.47-3.44(m,2H),3.05-3.01(m,2H),2.80-2.77(m,2H),2.48-2.44(m,2H),1.97-1.92(m,2H),1.72-1.67(m,2H). 13 C NMR(201MHz,CD3OD)δ158.86,137.75,137.72,136.99,130.40,128.33,124.54,124.48,74.82,45.40,43.66,35.41,33.67,30.14,27.49.HRMS(ESI)C 15 H 20 NO + [M+H] + Calculated value: 230.1539; Measured value: 230.1537.

[0317] Example 50: Preparation of 1-methyl-4-(2,3,4,5-tetrahydrobenzo[b]oxetane-9-yl)-1,2,3,6-tetrahydropyridine (compound I-50)

[0318] In Example 17, 4-bromo-5,6,7,8-tetrahydronaphthyl-1-ol was replaced with 9-bromo-2,3,4,5-tetrahydrobenzo[b]oxetane, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, yielding a brown oily compound I-50 (0.458 g, yield 99%).1 H NMR (500MHz, CD3OD) δ7.12(d,J=1.7Hz,1H),7.03(d,1H),6.95(t,J=7.5Hz,1H),5.75-5.69(m,1H),3.96-3.91(m, 2H),3.83-3.77(m,2H),3.43-3.37(m,2H),2.92(s,3H),2.86-2.77(m,4H),2.00-1.92(m,2H),1.75-1.67(m,2H). 13 C NMR (201MHz, CD3OD) δ158.90,137.91,137.65,134.65,131.42,128.17,124.68 ,119.26,74.94,53.53,52.07,43.06,35.36,33.56,28.01,27.35.HRMS(ESI)C 16 H 22 NO + [M+H] + Calculated value: 244.1696; Measured value: 244.1699.

[0319] Example 51: Preparation of 1-methyl-4-(5,6,7,8-tetrahydronaphth-1-yl)-1,2,3,6-tetrahydropyridine (compound I-51)

[0320] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 5-bromo-1,2,3,4-tetrahydronaphthalene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a yellow oily compound I-51 (0.391 g, 91%) was obtained. 1 H NMR(500MHz,CD3OD)δ7.00(t,J=7.5Hz,1H),6.93(d,J=1.3Hz,1H),6.83(d,J=1.4Hz,1H),5.50-5.44(m,1H),3.12- 3.07(m,2H),2.77(t,J=6.0Hz,2H),2.72-2.66(m,4H),2.40(s,3H),2.39-2.34(m,2H),1.82-1.70(m,J=5.8Hz,4H). 13C NMR (201MHz, CD3OD) δ143.85,138.70,138.27,135.18,128.99,126.47,126.24 ,123.54,55.28,53.15,45.72,31.61,30.84,28.17,24.58,24.23.HRMS(ESI)C 16 H 22 N + [M+H] + Calculated value: 228.1747; Measured value: 228.1747.

[0321] Example 52: Preparation of 4-(2,3-dihydro-1H-inden-4-yl)-1-methyl-1,2,3,6-tetrahydropyridine (compound I-52)

[0322] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 4-bromo-2,3-dihydro-1H-indene, and 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester was replaced with 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 17, and a brown oily compound I-52 (0.516 g, yield 99%) was obtained. 1 H NMR(500MHz,CD3OD)δ7.12-7.03(m,2H),6.97(d,1H),5.70(m,J=3.4,1.7Hz,1H),3.15-3.10(m,2 H),2.95-2.86(m,4H),2.71(t,J=5.8Hz,2H),2.55-2.48(m,2H),2.40(s,3H),2.06-1.96(m,2H). 13 C NMR(201MHz,CD3OD)δ145.79,142.02,139.85,137.58,127.30,125.60,123.95,123.80,55.40,53.19,45.66,33.94,33.77,30.44,26.68.HRMS(ESI)C 15 H 20 N + [M+H] + Calculated value: 214.1590; Measured value: 214.1589.

[0323] Example 53: Preparation of 5-(bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-1,2,3,6-tetrahydropyridine (compound I-53)

[0324] In Example 17, 1-hydroxy-4-bromo-5,6,7,8-tetrahydronaphthalene was replaced with 2-bromobicyclo[4.2.0]octa-1,3,5-triene. The other raw materials, reagents and preparation methods were the same as in Example 17, and a pale yellow solid compound I-53 (0.025 g, yield 30%) was obtained. 1 H NMR(600MHz,CD3OD)δ7.16-7.08(m,2H),6.88(d,J=6.9Hz,1H),6.29-6.24(m,1H),3.68- 3.64(m,2H),3.29-3.25(m,2H),3.17-3.12(m,2H),2.99-2.93(m,2H),2.34-2.27(m,2H). 13 C NMR(151MHz,CD3OD)δ145.64,141.25,133.68,133.42,127.15,122.97,121.72,120.56,45.13,41.56,30.60,28.74,24.80.HRMS(ESI)C 13 H 16 N + [M+H] + Calculated value: 186.1277; Measured value: 186.1277.

[0325] Example 54: Preparation of 5-(5,6,7,8-tetrahydronaphth-1-yl)-1,2,3,6-tetrahydropyridine (compound I-54)

[0326] In Example 51, 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 51, and a pale yellow oily substance I-54 (0.063 g, yield 31%) was obtained. 1 H NMR (600MHz, CD3OD) δ7.01(t,J=7.5Hz,1H),6.95(d,J=1.4Hz,1H),6.85(d,J=1.4Hz,1H),5.64-5.59(m,1H),3.43-3. 38(m,2H),3.02(t,J=5.9Hz,2H),2.77(t,J=6.0Hz,2H),2.71(t,J=5.8Hz,2H),2.32-2.24(m,2H),1.81-1.72(m,4H). 13C NMR(151MHz,CD3OD)δ142.25,138.84,138.39,135.57,129.27,126.93,126.27,124.81,48.79,42.83,30.83,28.18,25.52,24.58,24.20.HRMS(ESI)C 15 H 20 N + [M+H] + Calculated value: 214.1590; Measured value: 214.1590.

[0327] Example 55: Preparation of 3-(5,6,7,8-tetrahydronaphth-1-yl)-2,5-dihydro-1H-pyrrole (compound I-55)

[0328] In Example 51, 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 1-Boc-2,5-dihydropyrrole-3-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 51, and a brown solid compound (0.016 g, 24%) was obtained. 1 H NMR (600MHz, CD3OD) δ7.13-7.05(m,2H),7.04-6.98(m,1H),5.90-5.85(m,1H),4.31-4. 27(m,2H),4.27-4.22(m,2H),2.87-2.78(m,2H),2.78-2.70(m,2H),1.84-1.76(m,4H). 13 C NMR (151MHz, CD3OD) δ139.29,139.09,136.31,133.43,130.86,126.79,126.60,123.47,55.20,54.01,30.89,29.06,24.48,23.89.HRMS(ESI)C 14 H 18 N + [M+H] + Calculated value: 200.1434; Measured value: 200.1436.

[0329] Example 56: Preparation of 4-(5,6,7,8-tetrahydronaphth-1-yl)-1,2,3,6-tetrahydropyridine (compound I-56)

[0330] In Example 51, 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 51, and a white oily substance I-56 (0.078 g, 63%) was obtained. 1 H NMR (800MHz, CD3OD) δ7.00(t,J=7.5Hz,1H),6.93(d,J=7.6Hz,1H),6.83(d,J=1.4Hz,1H),5.52-5.46(m,1H),3.46- 3.42(m,2H),3.07-3.02(m,2H),2.76(t,J=6.2Hz,2H),2.69(t,J=6.0Hz,2H),2.29-2.24(m,2H),1.80-1.72(m,4H). 13 C NMR(201MHz,CD3OD)δ144.24,139.35,138.26,135.12,128.95,126.47,126.25,124.32,45.09,43.61,30.85,30.69,28.17,24.59,24.23.HRMS(ESI)C 15 H 20 N + [M+H] + Calculated value: 214.1590; Measured value: 214.1594.

[0331] Example 57: Preparation of 5-(2,3-dihydro-1H-inden-4-yl)-1,2,3,6-tetrahydropyridine (compound I-57)

[0332] In Example 52, 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with 1-Boc-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester. The other raw materials, reagents and preparation methods were the same as in Example 52, and a yellow oil (0.148 g, 93%) was obtained. 1 H NMR (600MHz, CD3OD) δ7.18(d,J=7.4Hz,1H),7.13(t,J=7.5Hz,1H),7.00(d,J=7.5Hz,1H),5.99-5.94(m, 1H),3.92-3.88(m,2H),3.38(t,J=6.2Hz,2H),2.96-2.88(m,4H),2.60-2.54(m,2H),2.09-2.00(m,2H). 13C NMR (151MHz, CD3OD) δ146.40,142.62,136.35,133.16,127.69,125.90,125.11,124.83,45.37,41.43,33.94,33.45,26.63,23.02.HRMS(ESI)C 14 H 18 N + [M+H] + Calculated value: 200.1434; Measured value: 200.1434.

[0333] Example 58: Preparation of 4-(2,3-dihydro-1H-inden-4-yl)-1,2,3,6-tetrahydropyridine (compound I-58)

[0334] In Example 52, 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was replaced with N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester. The other required raw materials, reagents and preparation methods were the same as in Example 52, and a brown oily substance (0.050 g, 32%) was obtained. 1 H NMR (800MHz, CD3OD) δ7.08 (m, J=14.8, 7.4Hz, 2H), 6.97 (d, J=7.3Hz, 1H), 5.74-5.71 (m, 1H), 3.49-3.45 (m, 2H),3.07-3.03(m,2H),2.92(t,J=7.3Hz,2H),2.88(t,J=7.4Hz,2H),2.43-2.39(m,2H),2.04-1.98(m,2H). 13 C NMR(201MHz,CD3OD)δ145.77,141.97,140.32,138.24,127.31,125.58,124.65,123.91,45.24,43.66,33.95,33.73,29.58,26.68.HRMS(ESI)C 14 H 18 N + [M+H] + Calculated value: 200.1434; Measured value: 200.1434.

[0335] Biological Assay Example 1: Testing of the Functional Activity of the Compounds of the Invention on 5-Hydroxytryptamine Receptors

[0336] Methods: BRET method was used to determine the functional activity of compounds on serotonin receptors: This method was used to detect 5-HT... 2A receptors or 5-HT 2BReceptor-mediated G protein signaling pathway (Gq bystander system): On day 1, 6cm culture dishes containing 70% density HEK-293T cells (ATCC, CRL-11268) were inoculated with 0.4μg 5-HT. 2A receptors or 5-HT 2B Receptor plasmid, 1 μg Gαq, 0.04 μg G protein-coupled receptor kinase 2RH domain (GRK2) containing C-terminal phycolucantase. RH -Rluc)Gβ3, 1μg kras containing N-terminal green fluorescent protein CAAX (GFP-kras CAAX 1.56 μg of vector pcDNA3.1 and 16 μL of PEI (Polysciences) were transfected. This was for the detection of 5-HT. 2A receptors or 5-HT 2B The receptor-mediated β-arrestin2 signaling pathway was used on day 1. 6cm culture dishes containing 70% HEK-293T cells (ATCC, CRL-11268) were inoculated with 500μg of 5-HT containing C-terminal phycolucant enzyme. 2A receptors or 5-HT 2B Receptor plasmid (5-HT) 2A -Rluc or 5-HT 2B Transfected cells with 500 μg of Rluc, 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin2 containing N-terminal green fluorescent protein (GFP2-ARRB2), and 16 μL of PEI. The next day, cells were digested and seeded into a single 96-well plate (6 cm culture dish volume). Each well contained 100 μL of culture medium (DMEM + 2% dialyzed fetal bovine serum) and was incubated at 37°C with continuous 5% CO2 circulation. On the third day, the culture medium was removed from the 96-well plate, and 40 μL of the substrate coelomic 400a (final concentration 5 μM) was added to each well. Immediately afterwards, 20 μL of different drug concentrations were added sequentially from left to right, ensuring a final drug concentration of 10 from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11M and OM were each treated in duplicate, followed by detection using a Tristar 3 Multimode Reader. Rluc was read for fluorescence signals at 410nm-480nm, and GFP for fluorescence signals at 515nm-540nm. The ratio of the machine's GFP / Rluc readings reflects the activation of intracellular G proteins and the membrane status of β-arrestin2; an increased ratio indicates receptor activation. Therefore, various compounds can be used to detect 5-HT... 2A receptors or 5-HT 2B The agonistic effect of the receptor can be characterized. After processing the data using the Graphpad Prism formula "log(agonist) vs. response -- variable slope (four parameters)," the effects of different compounds on 5-HT were obtained. 2A receptors or 5-HT 2B EC activated by receptor G protein signaling or β-arrestin2 signaling pathway 50 value.

[0337] Results: The compounds of this invention have a positive effect on 5-HT 2A Receptor activity is shown in Table 1 ("NA" indicates no agonist activity).

[0338] Table 1

[0339] Result 2: The compounds of this invention have an effect on 5-HT 2B Receptor activities are shown in Table 2 (antagonist activities are listed separately, and the data provided are IC50 values). 50 The data provided by agonists are for EC 50 and Emax(%)).

[0340] Table 2

[0341] As can be seen from the data in Table 2, the compounds of this invention have a positive effect on 5-HT. 2B The receptor exhibits antagonistic activity against Gq signaling and antagonistic or very weak partial agonist activity against β-arrestin2 signaling (Emax ranges from 7% to 34%).

Claims

1. A substance Z or a pharmaceutical composition containing substance Z in the preparation of serotonin 5-HT 2A In the application of receptor agonists, the substance Z is a compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof; the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Represents a single bond or a double bond; R 1 It is H or C1-C4 alkyl; R 2 H, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy or R 3 It is H, halogen, or C1-C4 alkyl; R 4 It is H, halogen, or C1-C4 alkyl; R 5 It is H, halogen, or C1-C4 alkyl; R 6 It is a C1-C4 alkyl group; Q is C6-C 10 Aromatic ring, 4-8 membered carbon ring or 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; m and n are independently 0, 1, 2 or 3.

2. The application according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 1 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (2)R 2 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (3)R 2 In, the C 1-4 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (4)R 2 In this context, the halogen is fluorine, chlorine, bromine, or iodine; (5)R 3 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (6)R 4 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (7)R 5 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (8)R 6 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (9) In Q, the C6-C 10 The aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring; (10) In Q, the 4-8 member carbon ring is a 4-membered carbon ring, a 5-membered carbon ring, a 6-membered carbon ring, a 7-membered carbon ring or an 8-membered carbon ring; (11) In Q, the heteroatom of the 4-8 membered heterocycle is O or N; (12) In Q, the number of heterocycles in the 4-8 member is 1; In (13)Q, the heteroatom of the 4-8 membered heterocycle is a heteroatom of a 5-7 membered heterocycle, for example...

3. The application according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 1 It is H or C1-C4 alkyl; (2)R 2 It can be H, halogen, hydroxyl, or amino; (3) Q is a benzene ring, a 4-8 membered carbon ring, or a 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is N or O, and the number of heteroatoms is 1; preferably, the heteroatom of the 4-8 membered heterocycle is O; (4) m and n are independently 1 or 2.

4. The application according to claim 1, characterized in that, It is any of the following schemes: Option 1: Represents a single bond or a double bond; R 1 It is H or C1-C4 alkyl; R 2 It can be H, halogen, hydroxyl, or amino; R 3 For H; R 4 For H; R 5 For H; Q is a benzene ring, a 4-8 membered carbon ring, or a 4-8 membered heterocycle; the heteroatom of the 4-8 membered heterocycle is N or O, and the number of heteroatoms is 1. m and n are independently 1 or 2; Option 2: R 1 It is H or C1-C4 alkyl; R 2 It can be H, hydroxyl, or amino; R 3 For H; R 4 For H; R 5 For H; m and n are each independently 1, 2 or 3; When Q is a 4-8 member heterocyclic ring, R 1 When it is a C1-C4 alkyl group, Represents a double bond; When Q is a 4-8 member carbon ring, R 1 It is a C1-C4 alkyl group, R 2 When it is H, Represents a single key; When Q is a 4-8 member carbon ring, R 1 For H, R 2 When H is the integer, n is 1; Option 3: R 1 It is H or C1-C4 alkyl; R 2 It can be H, halogen, or hydroxyl; R 3 For H; R 4 For H; R 5 For H; Q is C6-C 10 Aromatic rings, 4-8 membered carbon rings, or 4-8 membered heterocycles; wherein the 4-8 membered heterocycle is m and n are each independently 1, 2 or 3; When R 2 When it is halogen, m is 1; Option 4: R 1 It is H or C1-C4 alkyl; R 2 It can be H, halogen, hydroxyl, or amino; R 3 For H; R 4 For H; R 5 For H; m and n are each independently 1, 2 or 3; When R 2 When OH is present, Q is C6-C. 10 Aromatic rings, 6-8 membered carbon rings, or 6-8 membered heterocycles; When Q is a 6-8 member heterocyclic ring, R 2 For OH, R 1 When H is 2, Represents a single key; Option 5: R 1 It is H or C1-C4 alkyl; R 2 It can be H, halogen, hydroxyl, or amino; R 3 For H; R 4 For H; R 5 For H; m and n are each independently 1, 2 or 3; When Q is a 4-8 quintile heterocyclic ring, m is 1, n is 2, R 2 When it is a hydroxyl group, Represents a single key; When m is 1 and n is 2 Represents a single bond, R 2 When Q is a hydroxyl group, it is a 7-8 membered carbon ring, a 4-8 membered heterocycle, or a C6-C ring. 10 Aromatic rings; When m is 1 and n is 2 Represents a double bond, R 2 When Q is a hydroxyl group, it is a 6-8 membered carbon ring, a 6-8 membered heterocycle, or a C6-C ring. 10 Aromatic rings; When m and n are 1, R 2 When Q is a hydroxyl group, it is a 6-8 membered carbon ring, a 6-8 membered heterocycle, or a C6-C ring. 10 Aromatic ring.

5. The application according to claim 1, characterized in that, It satisfies one or two of the following conditions: (1) for and (2) for 6. The application according to claim 1, characterized in that, The compound shown in Formula I is:

7. The use of substance Z as described in any one of claims 1-6 or a pharmaceutical composition comprising substance Z as described in any one of claims 1-6 in the preparation of a medicament; said medicament being used to treat and / or prevent depression, anxiety disorders, cluster headaches, or neurodegenerative diseases.

8. A pharmaceutical composition comprising substance Z as described in any one of claims 1-6, or comprising substance Z as described in any one of claims 1-6, in the preparation of serotonin 5-HT 2A Application in receptor-related drugs, wherein the substance Z is a compound of formula I, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof; the drug may be used to treat and / or prevent depression, anxiety disorders, cluster headaches, or neurodegenerative diseases.

9. A compound of Formula II, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof: Represents a single bond or a double bond; R 1 It is H or C1-C4 alkyl; R 2 H, halogen, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy or R 3 It is H, halogen, or C1-C4 alkyl; R 4 It is H, halogen, or C1-C4 alkyl; R 5 It is H, halogen, or C1-C4 alkyl; R 6 It is a C1-C4 alkyl group; Q is a 7-8 membered carbon ring or a 7-8 membered heterocycle; the heteroatom of the 7-8 membered heterocycle is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; m and n are independently 0, 1, 2 or 3.

10. The compound of formula II according to claim 9, its pharmaceutically acceptable salt, its prodrug, its solvate, its deuterated derivative, or its stereoisomer, characterized in that, It satisfies one or more of the following conditions: (1)R 1 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (2)R 2 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (3)R 2 In, the C 1-4 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (4)R 2 In this context, the halogen is fluorine, chlorine, bromine, or iodine; (5)R 3 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (6)R 4 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (7)R 5 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (8)R 6 In, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (9) In Q, the 7-8 member carbon ring is a 7 member carbon ring; (10) In Q, the heteroatom of the 7-8 membered heterocycle is O or N; (11) In Q, the number of heterocycles in the 7-8 member is 1; In (12)Q, the heteroatom of the 7-8 membered heterocycle is a heteroatom of a 7 membered heterocycle, for example...

11. The compound of formula II according to claim 9, its pharmaceutically acceptable salt, its prodrug, its solvate, its deuterated derivative, or its stereoisomer, characterized in that, It is any of the following schemes: Option 1: Represents a single bond or a double bond; R 1 It is H or C1-C4 alkyl; R 2 It is a hydroxyl group; R 3 For H; R 4 For H; R 5 For H; Q is a 7-membered carbon ring or a 7-membered heterocycle; the heteroatom of the 7-membered heterocycle is N or O, and the number of heteroatoms is 1; m and n are independently 1 or 2; Option 2: R 1 It is H or C1-C4 alkyl; R 2 It is H or hydroxyl; R 3 For H; R 4 For H; R 5 For H; m and n are independently 1, 2, or 3; When Q is a 7-8 member heterocyclic ring, R 1 When it is a C1-C4 alkyl group, Represents a double bond; Option 3: R 1 It is H or C1-C4 alkyl; R 2 It is H or hydroxyl; R 3 For H; R 4 For H; R 5 For H; m and n are independently 1, 2, or 3; When Q is a 7-8 member heterocyclic ring; the 7-8 member heterocyclic ring is Option 4: R 1 It is H or C1-C4 alkyl; R 2 It is H or hydroxyl; R 3 For H; R 4 For H; R 5 For H; m and n are independently 1, 2, or 3; When Q is a 7-8 member heterocyclic ring, R 2 For OH, R 1 When H is 2, Represents a single key; Option 5: R 1 It is H or C1-C4 alkyl; R 2 It is H or hydroxyl; R 3 For H; R 4 For H; R 5 For H; m and n are independently 1, 2, or 3; When Q is a 7-8 member heterocyclic ring, m is 1, n is 2, R 2 When it is OH, Represents a single key.

12. The compound of formula II according to claim 9, its pharmaceutically acceptable salt, its prodrug, its solvate, its deuterated derivative, or its stereoisomer, characterized in that, It satisfies one or two of the following conditions: (1) for (2)Q is a 7-membered carbon ring or a 7-membered heterocycle; the heteroatom of the 7-membered heterocycle is N or O, and the number of heteroatoms is 1; preferably, the heteroatom of the 7-membered heterocycle is O; preferably, for 13. The compound of formula II according to claim 9, its pharmaceutically acceptable salt, its prodrug, its solvate, its deuterated derivative, or its stereoisomer, characterized in that, The compound represented by Formula II is any of the following compounds:

14. A pharmaceutical composition, characterized in that, It comprises (i) a compound of Formula II as described in any one of claims 9-13, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated thereof, or a stereoisomer thereof; and (ii) a pharmaceutically acceptable carrier.

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