Polysubstituted tetrahydroisoquinoline compound, and preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a compound containing a general formula I as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention provides a compound with a structure as shown in a general formula I, and a racemate, an R-isomer, an S-isomer, a pharmaceutically acceptable salt or a mixture of the racemate, the R-isomer, the S-isomer and the pharmaceutically acceptable salt. The compound has a good effect on promoting transcription factor EB (TFEB) nuclear translocation and promoting lysosome generation, and can be used for preventing, treating or adjunctively treating various diseases related to lysosome dysfunction and insufficient biosynthesis. The compound can be used for treating neurodegenerative diseases, especially neurodegenerative diseases caused by accumulation of pathological proteins (such as beta-amyloid protein and alpha-synuclein) in the brain, such as Alzheimer's disease (AD), Parkinson's disease (PD) and the like. # imgabs0 #

Description

A class of polysubstituted tetrahydroisoquinoline compounds and preparation methods, pharmaceutical compositions and uses thereof Technical Field

[0001] The present invention discloses a class of polysubstituted tetrahydroisoquinoline compounds, their preparation methods, pharmaceutical compositions, and uses. The invention relates to novel tetrahydroisoquinoline compounds represented by general formula (I), their pharmaceutically acceptable salts, isomers, solvates, metabolites, metabolic precursors, pharmaceutical compositions containing them, and the use of such compounds in preventing and / or treating various diseases associated with lysosomal dysfunction and biosynthesis deficiency, particularly neurodegenerative diseases caused by pathological protein accumulation, such as Alzheimer's disease and Parkinson's disease. Background Art

[0002] Alzheimer's disease (AD), a degenerative disorder of the central nervous system characterized by cognitive impairment and memory loss, has become a major health concern. The World Alzheimer's Report, published by Alzheimer's Disease International (ADI), indicates that with increasing life expectancy, approximately one person worldwide develops AD every three seconds. By 2050, the global AD population is projected to double every 20 years, reaching 152 million, becoming a pressing medical and social issue. my country has entered an aging society, with dementia affecting 25% of the global population. AD, with a prevalence of approximately 5.6% in the general population, has become the fifth leading cause of death in both urban and rural my country. The most characteristic pathological features of AD are senile plaques (SPs) and neurofibrillary tangles (NFTs), formed by the abnormal accumulation of β-amyloid protein (Aβ) and hyperphosphorylated tau protein, respectively. Furthermore, impairment of the autophagy-lysosomal pathway (ALP) has also been shown to be a hallmark of AD. Currently, most of the drugs used in clinical practice for AD are acetylcholinesterase (AChE) inhibitors (such as donepezil) and N-methyl-D-aspartate receptor (NMDA) antagonists (such as memantine). Although these drugs can stabilize or slow down the decline in cognitive function and behavioral ability in AD patients, they will not slow down the rate of pathological progression. Currently, the research and development of new anti-AD drugs is at a bottleneck, and most drugs have ended in failure. Although the US FDA recently approved an anti-AD antibody drug (aducanumab) for marketing, its clinical data did not show a significant improvement effect. Many antibody drugs or drugs targeting APP gamma secretase have not shown good results in clinical trials, so there is an urgent need to reveal new targets and new drugs to improve AD.

[0003] Parkinson's disease (PD), also known as parkinsonism, is the second most common neurodegenerative disorder. Its primary clinical features are resting tremor, muscle rigidity, bradykinesia, and abnormal gait and posture. Its pathological hallmarks are the degeneration and loss of dopaminergic neurons in the substantia nigra of the midbrain, as well as the accumulation of α-synuclein (α-syn)-containing inclusions (Lewy bodies) within the midbrain. PD is particularly prevalent in the elderly. Statistics show that the prevalence of PD is approximately 0.3% in the general population, 1% in those over 60 years old, and 3% in those over 80 years old. Globally, an average of 1-2 people per 1,000 are diagnosed with PD. It is estimated that by 2030, my country will account for half of the world's PD patients, making PD a major health threat to the elderly in my country. The development of new PD drugs has been difficult due to a lack of understanding of the mechanisms of apoptosis in dopamine-producing neurons. PD drugs under development and all currently available therapeutics only manage symptoms and improve motor function but cannot halt the disease's progression.

[0004] Lysosomes are single-layered, lipid-globular organelles (0.2 to 0.8 μm in diameter) within cells, rich in hydrolases (pH 4.5-5.0) and membrane proteins. Lysosomes participate in the degradation and clearance processes within cells, not only digesting substances that enter the cell and recycling intracellular substances, regulating energy metabolism, but also degrading and clearing useless biomacromolecules from the cell, such as low-density lipoprotein, Aβ protein, and tau protein, and even killing and degrading pathogens. Lysosomal dysfunction and insufficient biosynthesis are closely associated with the development of neurodegenerative diseases. Studies have shown that promoting lysosomal biosynthesis and activating the autophagy-lysosomal pathway (ALP) can clear toxic protein deposits in the mouse brain, thereby improving AD and PD-like symptoms.

[0005] Lysosomal biogenesis is primarily regulated by the transcription factor EB (TFEB). Under normal nutrient-rich conditions, TFEB is localized in the cytoplasm. Under nutrient deficiency or stress, dephosphorylated TFEB becomes activated and enters the nucleus, where it acts as a transcription factor to activate the expression of lysosomal and autophagy-related genes, thereby promoting lysosomal biogenesis and enhancing lysosomal degradation. To date, researchers have developed numerous drug screening methods to identify small-molecule TFEB activators, among which the TFEB-GFP nuclear translocation assay is a typical one. This assay involves constructing a TFEB protein tagged with GFP (green fluorescent protein). Upon activation, TFEB translocates into the cell nucleus, allowing fluorescence microscopy to monitor changes in TFEB protein localization within the cell to determine whether TFEB is activated. Current studies have shown that mTOR inhibitors, the diterpenoid HEP14, and its derivatives can induce TFEB translocation into the nucleus, thereby promoting lysosomal biogenesis. However, these compounds are limited by their limited structural types, difficulty in synthesis, and limited natural product resources. Therefore, there is still an urgent need to find more types of small molecule compounds that can activate TFEB to enter the nucleus and promote lysosome formation, which is expected to be developed into new anti-AD or PD drugs that target the new mechanism of promoting TFEB to enter the nucleus and promote lysosome formation.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a class of compounds that can promote TFEB to enter the nucleus and induce lysosome formation.

[0008] In the first aspect of the present invention, there is provided a compound of the structure shown in general formula (I), and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof,

[0009] in,

[0010] X is selected from the group consisting of O, S, and NR 6 ;

[0011] m, n and p are each independently selected from the group consisting of 0, 1, 2, 3 or 4;

[0012] The configuration of C* can independently be S-type, R-type, or racemic;

[0013] R 1 and R 2 Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, sulfhydryl, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10Alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group;

[0014] Or, R 1 and R 2 Together with the atoms to which it is connected, it forms a substituted or unsubstituted 5-12-membered heterocyclic ring or aromatic heterocyclic ring;

[0015] R 3 Selected from the group consisting of hydrogen, substituted or unsubstituted (-C1-C6 alkyl-C6-C 10 aryl), substituted or unsubstituted (-C1~C6 alkyl-5~12 membered heteroaryl), substituted or unsubstituted (-C1~C6 alkyl-C3~C8 carbocyclic group), substituted or unsubstituted (-C1~C6 alkyl-3~12 membered heterocyclic group), substituted or unsubstituted (-C1~C6 alkyl-7~20 membered heteropolycyclic group), substituted or unsubstituted C3~C8 saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted 7-20 membered heteropolycyclic group; wherein the heteropolycyclic group includes fused ring, bridged ring and spiro ring structure;

[0016] The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5- to 12-membered heteroaryl;

[0017] R 4 and R 5 Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, C1-C6 amine, hydroxyl, hydroxymethyl, carboxyl, C1-C6 amide, thiol, -S(O)2OH, C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 3-12 membered saturated or partially unsaturated heterocyclic group;

[0018] R 6Selected from the following groups: hydrogen, C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with aryl or heteroaromatic ring, C1-C6 alkyl substituted with cycloalkane or heterocyclic hydrocarbon, C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 halogenated saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered heterocyclic group, -(CH2) q YR 7 ;

[0019] wherein q is selected from the following group: 0, 1, 2, 3 or 4;

[0020] Y is selected from the following group: O, S, NR 8 , CO or SO2;

[0021] R 7 、R 8 Each independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 amino, substituted or unsubstituted C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-C6- 10 Aryl, -C1~C6 alkyl-5~12 membered heteroaryl, -C1~C6 alkyl-C3~8 carbocyclic group, -C1~C6 alkyl-3~12 membered heterocyclic group, C3~C8 saturated or partially unsaturated carbocyclic group, C3~C8 halogenated saturated or partially unsaturated carbocyclic group, C6~C 10 Aryl, 5- to 12-membered heteroaryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group;

[0022] wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;

[0023] The substitution in the substituted or unsubstituted group means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group, and 5- to 12-membered heteroaryl;

[0024] The halogen is F, Cl, Br or I.

[0025] In another preferred embodiment, the R 4 and R 5Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, NH2, C1-C6 amine, hydroxyl, hydroxymethyl, carboxyl, C2-C6 amide, thiol, -S(O)2OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, aryl or heteroaromatic ring-substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon-substituted C1-C6 alkyl, C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 Aryl, 3-12 membered saturated or partially unsaturated heterocyclic group.

[0026] In some embodiments, R 1 and R 2 Independently selected from the following groups: substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C5~C 10 Aryl.

[0027] In another preferred embodiment, the R 1 and R 2 Independently selected from the following groups: substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3-C6 membered carbocyclic group, substituted or unsubstituted phenyl.

[0028] In some embodiments, R 1 and R 2 The atoms connected thereto together form a substituted or unsubstituted 5- to 12-membered heterocyclic ring.

[0029] In another preferred embodiment, the R 1 and R 2 The atoms connected thereto together form a substituted or unsubstituted 5- to 7-membered heterocyclic ring.

[0030] In some embodiments, R 3 Selected from the following group: hydrogen, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 3-12 membered heterocyclic group, or substituted or unsubstituted 7-20 membered heteropolycyclic group; wherein the heteropolycyclic ring includes condensed ring, bridged ring and spiro ring structure.

[0031] In some embodiments, The ring is selected from the group consisting of a benzene ring, a thiophene ring, a pyrrole ring, a furan ring, a pyridine ring, a pyrimidine ring, an indole ring, or a cyclohexyl ring.

[0032] In some embodiments, the compound is selected from the group consisting of:

[0033] In a second aspect of the present invention, a method for preparing a compound represented by general formula (I) is provided, comprising the steps of:

[0034] (1) In a mixed solvent of nitromethane and an organic acid, formula II a The compound reacts with nitromethane to produce α,β-unsaturated nitro compound II through Henry reaction. b , Formula II b The compound is then subjected to a reduction reaction to obtain Formula II c Compounds;

[0035] (2) In an alkaline solvent, in the presence of malonic acid and a base catalyst, the compound of formula Ia is reacted with malonic acid to produce a compound of formula I b Compound, Formula I b The compound is then reduced with a reducing agent to obtain formula I c Compounds;

[0036] (3) In an inert solvent, in the presence of a condensing agent, reacting a compound of formula IIc with a compound of formula Ic to obtain a compound of formula I d Compounds;

[0037] (4) In an inert solvent, d The compound undergoes Bischler–Napieralski ring closure reaction to obtain formula I e Compounds;

[0038] (5) In an inert solvent, use formula I e The compound is subjected to a reduction reaction to obtain a compound of formula If;

[0039] (6) In an inert solvent, use formula I f Compounds and Halogenated Hydrocarbons I g Carry out a substitution reaction to obtain a compound of formula (I);

[0040] Among them, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 The definitions of ,X, m, n, and p are as described above.

[0041] In some embodiments, the organic acid in step (1) is acetic acid or formic acid, and the reducing agent is LiAlH4, sodium borohydride or zinc powder.

[0042] In another preferred embodiment, the alkaline solvent in step (2) is pyridine, the alkaline catalyst is piperidine, and the reducing agent is a combination of a palladium-carbon hydrogenation catalyst and hydrogen, or a combination of a palladium-carbon hydrogenation catalyst and ammonium formate.

[0043] In another preferred embodiment, the condensing agent in step (3) is a combination of HATU or EDCI and HOBt.

[0044] In another preferred embodiment, the ring-closure reaction in step (4) uses POCl3 phosphorus oxychloride as the Lewis acid.

[0045] In another preferred embodiment, the reduction reaction in step (5) uses borohydride as a reducing agent, or uses Noyori's catalyst as an asymmetric reduction catalyst.

[0046] In another preferred embodiment, the substitution reaction in step (6) uses potassium carbonate, cesium carbonate or sodium carbonate as a base to catalyze the reaction.

[0047] In the third aspect of the present invention, a pharmaceutical composition is provided, characterized in that it comprises (1) the compound as described in the first aspect of the present invention, its racemate, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

[0048] In the fourth aspect of the present invention, there is provided a use of the compound as described in the first aspect of the present invention, its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in the third aspect of the present invention, characterized in that it is used to prevent and / or treat diseases related to lysosomal dysfunction and biosynthesis deficiency.

[0049] In another preferred embodiment, the disease is a neurodegenerative disease caused by accumulation of pathological proteins.

[0050] In another preferred embodiment, the disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.

[0051] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0052] After extensive and in-depth research, the inventors unexpectedly discovered a series of compounds of general formula (I). A series of biological activity tests revealed that these compounds have demonstrated excellent activity in inducing lysosomal biogenesis and activating the autophagy-lysosomal pathway to degrade pathological protein deposits in the brain. This led to the completion of the present invention.

[0053] definition

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0055] In this document, unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms on a group being replaced by a substituent selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, halogen, hydroxy, carboxyl, cyano, C1-C8 alkyl, C2 ... 10 Aldehyde, C2~C6 acyl, C2~C 10 Ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group with 1-3 substituents, the substituents are selected from: halogen, C1~C 10 Alkyl, cyano, hydroxy, nitro, C3-C8 cycloalkyl, C1-C8 alkoxy, amino.

[0056] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

[0057] As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example, C1-C6 alkyl groups represent straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0058] As used herein, the term "alkoxy" refers to a group having an alkyl-oxy structure. For example, "C1-C6 alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0059] As used herein, the term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3-10 ring atoms), wherein 1-3 atoms are heteroatoms selected from N, S, and O. It can be a monocyclic, bicyclic, or polycyclic ring, such as a bridged ring or a spirocyclic ring. Specific examples include oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, and pyrrolidinyl.

[0060] As used herein, the term "aryl" refers to a cyclic aromatic group having a specific number of carbon atoms. For example, "C6-C 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, or the like.

[0061] As used herein, the term "aryl" refers to a cyclic aromatic group having a specified number of ring atoms, wherein 1 to 3 atoms are heteroatoms selected from N, S, and O. The aryl group may be a single ring or a fused ring. For example, a "5-12 membered aryl" group refers to an aryl group having 5 to 12 carbon atoms, such as pyrrolyl, pyridyl, thienyl, furanyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridinyl, quinolinyl, or the like.

[0062] As used herein, the term "acyl" refers to a -C(=O)R group having a specific number of carbon atoms. For example, C2-6 acyl refers to a -C(=O)R group having 2 to 6 carbon atoms, such as -C(=O)CH3, -C(=O)C2H5, -C(=O)C3H7, -C(=O)C4H9, or the like.

[0063] As used herein, the term "ester group" refers to a ROC(=O)- group having a specific number of carbon atoms. For example, a C2-6 acyl group refers to a ROC(=O)- group having 2 to 6 carbon atoms, such as -C(=O)OCH3, -C(=O)OC2H5, -C(=O)OC3H7, -C(=O)OC4H9, or the like.

[0064] As used herein, the term "alkenyl" refers to an alkenyl group having a specific number of carbon atoms, including straight or branched alkenyl groups. For example, C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0065] As used herein, the term "alkynyl" refers to an alkynyl group having a specific number of carbon atoms, including straight or branched chain alkynyl groups. For example, a C2-C6 alkynyl group refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

[0066] As used herein, the term "amino group" refers to a -NR group having 0 to 6 carbon atoms. 1 R 2 Groups such as -NH2, -NHCH3, -NHC(=O)CH3, -NHCH2CH3, -N(CH3)2, or similar groups. As used herein, amine groups are intended to include amino groups, i.e., -NH2.

[0067] As used herein, the term "amido" refers to a -C(=O)NR group having a specified number of carbon atoms. 1 R 2 groups such as -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, or similar groups.

[0068] As used herein, the term "sulfonamido" refers to a -S(=O)2NR group having a specified number of carbon atoms. 1 R2 group. For example, C1-C6 sulfonamide refers to a sulfonamide group having 1 to 6 carbon atoms, such as -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, or the like.

[0069] As used herein, the term "sulfonyl" refers to a -S(=O)2- group.

[0070] As used herein, the term "sulfinyl" refers to a -S(=O)- group.

[0071] As used herein, the term "halogen" refers to F, Cl, Br, and I.

[0072] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds and (Z), (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformers) are all within the scope of the present invention.

[0073] The term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, and 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0074] Herein, the form "C1-C6" indicates that the group may have 1 to 6 carbon atoms, for example 1, 2, 3, 4, 5 or 6.

[0075] The main advantages of the present invention include:

[0076] (1) The compounds of the present invention have good activity in inducing lysosomal biosynthesis and activating the autophagy-lysosomal pathway to degrade pathological protein deposits in the brain.

[0077] (2) The preparation method of the compound of the present invention is simple.

[0078] (3) The compounds of the present invention have good pharmacokinetic properties and good drugability.

[0079] Specific embodiments

[0080] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. The starting materials used in the present invention are commercially available unless otherwise specified.

[0081] Example 1: 5-(2-(1H-indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A1)

[0082] 1.1 Synthesis of Intermediate 1-3: The starting material 1-2 (3-indolepropionic acid, 2.08 g, 11.0 mmol) was dissolved in 100 mL of dichloromethane. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 5.70 g, 15.0 mmol), N,N-diisopropylethylamine (DIPEA, 5.22 mL, 30.0 mmol), and a dichloromethane solution of 1-1 (pepperethylamine, 1.65 g, 10.0 mmol) were added sequentially, and the mixture was stirred at room temperature for 4 h. After completion of the reaction as monitored by TLC (thin-layer chromatography), the reaction mixture was diluted with dichloromethane and washed sequentially with 1N dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography using petroleum ether / ethyl acetate (1:1) to obtain 3.02 g of the product 1-3 as an off-white solid in a 90% yield. 1 H NMR (500MHz, CDCl3) δ8.18(s,1H),7.58(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.20( ddd,J=8.2,7.0,1.2Hz,1H),7.12(ddd,J=7.9,7.0,1.1Hz,1H),6.98–6.94(m,1H),6.6 2(d,J=7.9Hz,1H),6.53(d,J=1.7Hz,1H),6.38(dd,J=7.9,1.7Hz,1H),5.91(s,2H),5. 42(s,1H),3.38(q,J=6.6Hz,2H),3.09(t,J=7.3Hz,2H),2.54(dt,J=17.6,7.1Hz,4H). 13C NMR (126MHz, DMSO) δ172.7,147.7,146.1,136.3,132.5,127.1,122.0,121.8,121. 5,119.3,118.7,114.8,111.2,109.0,108.3,100.8,40.7,37.4,35.2,21.3.ESI-MS m / z 336.2[M+H] + .

[0083] 1.2 Synthesis of Intermediate 1-4: Intermediate 1-3 (2.70 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, and phosphorus oxychloride (4.46 mL, 48.0 mmol) was added. Under argon, the mixture was stirred at reflux for 1.5 h. After completion of the reaction, as monitored by TLC, the mixture was evaporated to dryness under reduced pressure. Ice-cold saturated sodium bicarbonate was added to adjust the mixture to a weak alkaline state. The mixture was extracted with dichloromethane and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product 1-4 was purified by column chromatography using dichloromethane / methanol = 20:1 to obtain 2.03 g of a yellow solid, in an 80% yield. ESI-MS m / z 319.1 [M+H] + .

[0084] 1.3 Synthesis of Compound A1: Intermediate 1-4 (2.04 g, 6.4 mmol) was dissolved in 50 mL of a methanol / dichloromethane (v / v = 2:1) mixed solvent. Sodium borohydride (1.46 g, 38.4 mmol) was added portionwise under ice-cooling and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated ammonium chloride solution. The organic solvent was evaporated under reduced pressure and extracted with dichloromethane. The mixture was washed sequentially with saturated sodium bicarbonate and saturated sodium chloride solutions. The organic layer was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by column chromatography using dichloromethane / methanol = 15:1 to afford 1.82 g of product A1 as a white solid in an 89% yield. 1 H NMR (500MHz, CDCl3) δ7.87(s,1H),7.61(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.18(dd,J=15.0,7.4Hz,2H),7.11(t,J=7.5Hz ,1H),6.54(s,1H),6.45(s,1H),5.92–5.85(m,2H),4.23(s,1H),3.50(dd,J=6.4,4.7Hz,1H),3.24–3.17(m,1H),2.98–2.86(m, 1H),2.82–2.65(m,4H),2.25–2.06(m,2H). 13C NMR (150MHz, CDCl3) δ146.3,145.3,136.3,130.9,127.5,126.8,122.0,121.3,119 .2,118.7,116.7,111.5,108.4,106.7,100.3,63.0,47.9,35.7,26.0,21.1.ESI-MS m / z 321.3[M+H] + .

[0085] Example 2: (S)-5-(2-(1H-indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((S)-A1)

[0086] The synthesis of intermediate 1-4 was performed as described in Example 1. 1-4 (0.95 g, 3.0 mmol) was dissolved in 10 mL of anhydrous DMF. The catalyst, RuCl[(R,R)-TsDPEN(p-cymene)] (57 mg, 0.09 mmol), was added under argon at room temperature. A mixed solution of formic acid and triethylamine (v / v = 5 / 2, 1.1 mL) was then added, and the mixture was stirred at room temperature overnight. After TLC monitoring of the reaction, the reaction solution was neutralized with saturated NaHCO₃ solution to a weakly alkaline pH. Five volumes of ice water were then added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with NaHCO₃ solution and once with NaCl solution, and dried over Na₂SO₄. The organic solvent was evaporated to dryness, and the product (S)-A1 was purified by column chromatography using dichloromethane / methanol (15:1) to obtain 1.82 g of the white solid product (S)-A1 in an 89% yield. The optical purity was 96:4er (chromatographic conditions: chiral IA (4.6 mm×250 mm), n-hexane / isopropanol / triethylamine = 80 / 20 / 0.1, 0.8 mL / min, 254 nm UV, room temperature). 1 H NMR (500MHz, CDCl3) δ7.87(s,1H),7.61(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.18(dd,J=15.0,7.4Hz,2H),7.11(t,J=7.5Hz,1H),6.54(s,1H),6. 45(s,1H),5.92–5.85(m,2H),4.23(s,1H),3.50(dd,J=6.4,4.7Hz,1H),3. 24–3.17(m,1H),2.98–2.86(m,1H),2.82–2.65(m,4H),2.25–2.06(m,2H). 13C NMR (150MHz, CDCl3) δ146.3,145.3,136.3,130.9,127.5,126.8,122.0,121.3,119 .2,118.7,116.7,111.5,108.4,106.7,100.3,63.0,47.9,35.7,26.0,21.1.ESI-MS m / z 321.3[M+H] + .

[0087] Example 3: (R)-5-(2-(1H-indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((R)-A1)

[0088] The synthesis of intermediate 1-4 was performed as described in Example 1. 1-4 (0.95 g, 3.0 mmol) was dissolved in 10 mL of anhydrous DMF. The catalyst, RuCl[(R,R)-TsDPEN(p-cymene)] (57 mg, 0.09 mmol), was added under argon at room temperature. A mixed solution of formic acid and triethylamine (v / v = 5 / 2, 1.1 mL) was then added, and the mixture was stirred at room temperature overnight. After TLC monitoring of the reaction, the reaction solution was neutralized with saturated NaHCO₃ solution to a weakly alkaline pH. Five volumes of ice water were then added, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed once with NaHCO₃ solution and once with NaCl solution, and dried over Na₂SO₄. The organic solvent was evaporated to dryness, and the mixture was purified by column chromatography using dichloromethane / methanol (15:1) to afford 1.78 g of the product (R)-A1 as a white solid in an 87% yield. The optical purity was 95:5er (chromatographic conditions: chiral IA (4.6 mm×250 mm), n-hexane / isopropanol / triethylamine = 80 / 20 / 0.1, 0.8 mL / min, 254 nm UV, room temperature). 1 H NMR (500MHz, CDCl3) δ7.87(s,1H),7.61(d,J=7.9Hz,1H),7.32(d,J=8.1Hz,1H),7.18(dd,J=15.0,7.4Hz,2H),7.11(t,J=7.5Hz,1H),6.54(s,1H),6. 45(s,1H),5.92–5.85(m,2H),4.23(s,1H),3.50(dd,J=6.4,4.7Hz,1H),3. 24–3.17(m,1H),2.98–2.86(m,1H),2.82–2.65(m,4H),2.25–2.06(m,2H). 13C NMR (150MHz, CDCl3) δ146.3,145.3,136.3,130.9,127.5,126.8,122.0,121.3,119 .2,118.7,116.7,111.5,108.4,106.7,100.3,63.0,47.9,35.7,26.0,21.1.ESI-MS m / z 321.3[M+H] + .

[0089] Example 4: 1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (A2)

[0090] Referring to the synthetic route of A1, 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) was used to replace the raw material 1-1 in Example 1 to obtain compound A2 with a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.63(d,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H) ,7.24(d,J=2.3Hz,1H),7.07(t,J=7.5Hz,1H),6.98(t,J=7.6Hz,1H),6.77(s,1H), 6.67(s,1H),4.36(t,J=6.1Hz,1H),3.72(s,3H),3.63(s,3H),3.47–3.36(m,1H),3 .26–3.15(m,1H),3.07–2.91(m,3H),2.96–2.81(m,1H),2.32(q,J=7.8,7.1Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ148.4,148.0,136.8,127.4,125.7,124.9,123.1,121.4,119.0 ,118.6,113.7,112.2,111.9,110.1,55.98,55.95,54.3,49.1,34.9,25.4,21.7.ESI-MS m / z 337.2[M+H] + .

[0091] Example 5: (S)-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((S)-A2)

[0092] Referring to the synthetic route of (S)-A1, the raw material 1-1 in Example 2 was replaced by 3,4-dimethoxyphenethylamine (CAS: 120-20-7) to obtain compound (S)-A2.1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.63(d,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H) ,7.24(d,J=2.3Hz,1H),7.07(t,J=7.5Hz,1H),6.98(t,J=7.6Hz,1H),6.77(s,1H), 6.67(s,1H),4.36(t,J=6.1Hz,1H),3.72(s,3H),3.63(s,3H),3.47–3.36(m,1H),3 .26–3.15(m,1H),3.07–2.91(m,3H),2.96–2.81(m,1H),2.32(q,J=7.8,7.1Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ148.4,148.0,136.8,127.4,125.7,124.9,123.1,121.4,119.0 ,118.6,113.7,112.2,111.9,110.1,55.98,55.95,54.3,49.1,34.9,25.4,21.7.ESI-MS m / z 337.2[M+H] + .

[0093] Example 6: (R)-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((R)-A2)

[0094] Referring to the synthetic route of (R)-A1, the raw material 1-1 in Example 3 was replaced with 3,4-dimethoxyphenethylamine (CAS: 120-20-7) to obtain compound (R)-A2. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),7.63(d,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H) ,7.24(d,J=2.3Hz,1H),7.07(t,J=7.5Hz,1H),6.98(t,J=7.6Hz,1H),6.77(s,1H), 6.67(s,1H),4.36(t,J=6.1Hz,1H),3.72(s,3H),3.63(s,3H),3.47–3.36(m,1H),3 .26–3.15(m,1H),3.07–2.91(m,3H),2.96–2.81(m,1H),2.32(q,J=7.8,7.1Hz,2H). 13C NMR(100MHz,DMSO-d6)δ148.4,148.0,136.8,127.4,125.7,124.9,123.1,121.4,119.0 ,118.6,113.7,112.2,111.9,110.1,55.98,55.95,54.3,49.1,34.9,25.4,21.7.ESI-MS m / z 337.2[M+H] + .

[0095] Example 7: 1-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A3)

[0096] Synthesis of intermediate 2-3: The starting material 2-1 (4.84 g, 20.0 mmol) was dissolved in nitromethane (21.5 mL, 400 mmol), and ammonium acetate (3.08 g, 40.0 mmol) and glacial acetic acid (11.4 mL, 200 mmol) were added sequentially. The mixture was heated and stirred at 80°C for 2 h. After the reaction was completed as monitored by TLC, the organic solvent was evaporated and saturated sodium bicarbonate was slowly added and stirred at room temperature to adjust the pH to neutral. The precipitated solid was filtered, washed once with saturated sodium bicarbonate and water, and dried to obtain 4.62 g of bright yellow intermediate 2-2 with a yield of 81%, which was directly used in the next step. 2-2 (4.56 g, 16.0 mmol) was dissolved in ultra-dry tetrahydrofuran solution and set aside. In a -5°C ice bath, 50 mL of ultra-dry tetrahydrofuran was added to a 250 mL two-necked round-bottom flask. Lithium aluminum tetrahydride (1.82 g, 48.0 mmol) was added in three batches. In an ice bath and under argon protection, the 2-2 solution was added dropwise to the reaction flask using a dropping funnel. After the addition was complete, the dropping funnel was removed, a condenser was installed and protected with argon, and the mixture was moved to an oil bath and heated under reflux for 2 h. After the reaction was complete as monitored by TLC, the reaction flask was moved to a -5°C ice bath with stirring, and ice water was added dropwise to quench until there were no bubbles. The insoluble solid was then filtered off and washed with ethyl acetate. The filtrate was collected, and the organic solvent was dried by spin drying, extracted with water and ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. After purification by column chromatography with dichloromethane / methanol / ammonia water = 10:1:0.1, 2.88 g of brown liquid product 2-3 was obtained in a yield of 70%. 1 H NMR(400MHz,DMSO-d6)δ7.44-7.33(m,5H),6.89(br.d,J=8.8Hz,1H),6.76(dd,J=8.4,2 .0Hz,1H),5.04(s,2H),3.72(s,3H),2.73t,J=6.8Hz,2H),2.53t,J=6.8Hz,2H).ESI-MS m / z258.1[M+H] +.

[0097] Synthesis of Intermediate 3-3: Dissolve starting materials 3-1 (5-methoxyindole-3-carboxaldehyde, 3.50 g, 20 mmol) and malonic acid (4.08 g, 40 mmol) in 50 mL of pyridine. Add piperidine (340 mg, 4 mmol) under argon and react at 100°C for 3 h. After evaporation of the solvent, the reaction mixture was moved to 0°C in an ice bath and 20 mL of 6N hydrochloric acid was added dropwise. Stir for 30 min, filter, and wash with water to obtain 3.12 g of a white solid 3-2 in 72% yield, which was used directly in the next step. Dissolve 3-2 (2.17 g, 10 mmol) in 40 mL of methanol, add 217 mg of palladium-on-carbon hydrogenation catalyst (containing 10% water), and heat at 55°C under 1-2 bar of hydrogen to react overnight. After the reaction was completed as monitored by TLC, the mixture was filtered, the filtrate was collected, concentrated, and purified by column chromatography using dichloromethane / methanol = 30:1 to obtain 1.93 g of white solid product 3-3 with a yield of 88%. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),10.62(s,1H),7.22(d,J=8.5Hz,1H),7.07(d,J=2.0Hz,1H),6.99(d,J =2.5Hz,1H),6.71(dd,J=8.5,2.5Hz,1H),3.76(s,3H),2.89(2H,t,J=7.5Hz),2.58(2H,t,J=7.5Hz).ESI-MS m / z 218.0[MH] - .

[0098] Synthesis of intermediate 3-4: Referring to the synthetic route of A1, the raw material 1-1 in Example 1 was replaced by 2-3, and the raw material 1-2 in Example 1 was replaced by 3-3 to obtain a white solid product 3-4. 1 H NMR (500MHz, CDCl3) δ8.18(s,1H),7.57(d,J=7.9Hz,1H),7.45-7.33(m,5H),7.37(d,J=8.1 Hz,1H),7.22(ddd,J=8.2,7.0,1.2Hz,1H),7.12(ddd,J=7.9,7.0,1.1Hz,1H),6.62(d,J=7. 9Hz,1H),6.53(d,J=1.7Hz,1H),6.38(dd,J=7.9,1.7Hz,1H),5.44(s,1H),5.10(s,2H),3.8 0(s,3H),3.37(q,J=6.6Hz,2H),3.09(t,J=7.1Hz,2H),2.54(dt,J=17.5,7.0Hz,4H).ESI-MS m / z 459.2[M+H] +.

[0099] Synthesis of Intermediate 3-5: Intermediate 3-4 (3.66 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, and phosphorus oxychloride (4.46 mL, 48.0 mmol) was added. Under argon, the mixture was stirred at reflux for 1.5 h. After completion of the reaction, as monitored by TLC, the mixture was evaporated to dryness under reduced pressure. Ice-cold saturated sodium bicarbonate was added to adjust the solution to a weak base. The mixture was extracted with dichloromethane and washed with saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The product 3-5 was purified by column chromatography using a dichloromethane / methanol ratio of 20:1 to obtain 2.71 g of a yellow solid, in a 77% yield. ESI-MS m / z 441.2 [M+H] + .

[0100] Synthesis of Compound A3: Intermediate 3-5 (2.64 g, 6.0 mmol) was dissolved in 50 mL of a methanol / dichloromethane (v / v = 2:1) mixed solvent. Sodium borohydride (1.37 g, 36.0 mmol) was added portionwise under ice-cooling and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated ammonium chloride solution. The organic solvent was evaporated under reduced pressure and extracted with dichloromethane. The mixture was washed sequentially with saturated sodium bicarbonate and saturated sodium chloride solutions. The organic layer was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by column chromatography using dichloromethane / methanol = 15:1 to afford 2.22 g of product A1 as a white solid in an 84% yield. 1 H NMR (500MHz, CDCl3) δ7.88(s,1H),7.60(d,J=7.9Hz,1H),7.48-7.36(m,5H),7.32(d,J=8.1Hz,1H),7.16(dd,J=15.0,7.4Hz,2H),7.11(t,J= 7.5Hz,1H),6.52(s,1H),5.21(s,2H),4.23(s,1H),3.50(s,3H),3.24– 3.17(m,1H),2.82–2.65(m,4H),2.58–2.31(m,2H),2.25–2.06(m,2H). 13 C NMR (150MHz, CDCl3) δ146.3,145.3,136.3,130.9,127.5,126.8,122.0,121.3,119 .2,118.7,116.7,111.5,108.4,106.7,100.3,63.0,47.9,35.7,26.0,21.1.ESI-MS m / z 443.3[M+H] + .

[0101] Example 8: 6-(Benzyloxy)-1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A4)

[0102] Referring to the synthetic route of A3, the raw material 3-1 in Example 7 was replaced by 5-fluoroindole-3-carboxaldehyde (CAS: 2338-71-8) to obtain compound A4. 1 H NMR (500MHz, CDCl3) δ7.92 (s, 1H), 7.65 (d, J = 7.9Hz, 1H), 7.47-7.36 (m, 5H), 7.30 (d, J = 8.0Hz, 1H), 7.15 (dd, J = 15.0, 7.4Hz, 2H), 7.10 (t,J=7.5Hz,1H),6.52(s,1H),5.21(s,2H),4.23(s,1H),3.24–3.17(m,1H),2.82–2.65(m,4H),2.55–2.31(m,2H),2.25–2.08(m,2H). 13 C NMR (150MHz, CDCl3) δ146.3,145.3,136.3,130.9,127.5,126.8,122.0,121.3,1 19.2,118.7,116.7,111.5,108.4,106.7,100.3,47.9,35.7,26.0,21.1.ESI-MS m / z 431.2[M+H] + .

[0103] Example 9: 1-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A5)

[0104] Referring to the synthetic route of A3, intermediate 3-3 in Example 7 was replaced by 3-indolepropionic acid (CAS: 830-96-6) to obtain compound A5. 1 H NMR (500MHz, CDCl3) δ8.05(s,1H),7.75(d,J=7.9Hz,1H),7.46-7.36(m,5H),7.30(d,J=8.0Hz,1H),7.13(dd,J=15.0,7.4Hz,2H),7.11(t,J= 7.5Hz,1H),6.72(s,1H),6.50(s,1H),5.21(s,2H),4.23(s,1H),3.24– 3.17(m,1H),2.82–2.65(m,4H),2.55–2.31(m,2H),2.25–2.08(m,2H). 13C NMR (150MHz, CDCl3) δ146.8,145.3,137.3,130.9,127.3,126.8,122.1,121.3,1 19.0,118.7,116.7,111.5,107.4,106.5,100.3,48.0,35.7,26.2,20.8.ESI-MS m / z 413.2[M+H] + .

[0105] Example 10: 5-(2-(1H-indol-3-yl)ethyl)-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A12)

[0106] Product A1 from Example 1 was used as the starting material for this step. A1 (1.60 g, 5.0 mmol) and bromomethylcyclohexane (CAS: 2550-36-9) (1.32 g, 7.5 mmol) were dissolved in 50 mL of acetonitrile. Potassium carbonate (3.45 g, 25.0 mmol) was added, and the mixture was stirred and refluxed for 24 hours. After TLC monitoring, the solvent was evaporated and the mixture was purified by column chromatography using dichloromethane / methanol (20:1) to obtain 1.35 g of a yellow solid A12, with a yield of 65%. 1 H NMR (500MHz, CDCl3) δ8.10(s,1H),7.62(d,J=7.9Hz,1H),7.32(d,J=7.9Hz,1H ),7.25–7.11(m,2H),6.95(d,J=2.1Hz,1H),6.55(d,J=9.3Hz,2H),5.88(s,2H) ,3.96–3.90(m,2H),3.61(dd,J=8.0,4.4Hz,1H),3.35(m,2H),3.32–3.21(m,1H ),2.45–2.25(m,2H),2.23–2.00(m,5H),1.69–1.46(m,5H),1.41–1.24(m,4H). 13 C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116.4,111.0,108.3,107.4,100.3,68.0,59.9,50.1, 43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 417.3[M+H] + .

[0107] Example 11: (S)-5-(2-(1H-indol-3-yl)ethyl)-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((S)-A12)

[0108] Referring to the synthetic route of A12, the raw material A1 in Example 1 was replaced by (S)-A1 to obtain a yellow solid product (S)-A12. 1 H NMR(500MHz, CDCl3)δ8.10(s,1H),7.62(d,J=7.9Hz,1H),7.32(d,J=7.9Hz,1H ),7.25–7.11(m,2H),6.95(d,J=2.1Hz,1H),6.55(d,J=9.3Hz,2H),5.88(s,2H) ,3.96–3.90(m,2H),3.61(dd,J=8.0,4.4Hz,1H),3.35(m,2H),3.32–3.21(m,1H ),2.45–2.25(m,2H),2.23–2.00(m,5H),1.69–1.46(m,5H),1.41–1.24(m,4H). 13 C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116. 4,111.0,108.3,107.4,100.3,68.0,59.9,50.1,43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 417.3[M+H] + .

[0109] Example 12: (R)-5-(2-(1H-indol-3-yl)ethyl)-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((R)-A12)

[0110] Referring to the synthetic route of A12, the raw material A1 in Example 1 was replaced by (R)-A1 to obtain a yellow solid product (R)-A12. 1H NMR (500MHz, CDCl3) δ8.10(s,1H),7.62(d,J=7.9Hz,1H),7.32(d,J=7.9Hz,1H ),7.25–7.11(m,2H),6.95(d,J=2.1Hz,1H),6.55(d,J=9.3Hz,2H),5.88(s,2H) ,3.96–3.90(m,2H),3.61(dd,J=8.0,4.4Hz,1H),3.35(m,2H),3.32–3.21(m,1H ),2.45–2.25(m,2H),2.23–2.00(m,5H),1.69–1.46(m,5H),1.41–1.24(m,4H). 13 C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116. 4,111.0,108.3,107.4,100.3,68.0,59.9,50.1,43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 417.2[M+H] + .

[0111] Example 13: 5-(2-(1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A13)

[0112] Referring to the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and a substitution reaction was carried out with compound A1 to obtain A13. 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.65(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7 .23–7.09(m,2H),6.96(d,J=2.2Hz,1H),6.54(d,J=9.4Hz,2H),5.88(s,2H),3.98– 3.92(m,2H),3.59(dd,J=8.3,4.5Hz,1H),3.37(m,2H),3.30–3.21(m,1H),2.98–2 .79(m,4H),2.49(m,1H),2.23–2.00(m,2H),1.69–1.46(m,5H),1.41–1.24(m,2H). 13C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116. 4,111.0,108.3,107.4,100.3,68.0,59.9,50.1,43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 419.1[M +H] + .

[0113] Example 14: (S)-5-(2-(1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((S)-A13)

[0114] Referring to the synthetic route of (S)-A12, 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 11, and a substitution reaction was carried out with compound (S)-A1 to obtain (S)-A13. 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.65(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7 .23–7.09(m,2H),6.96(d,J=2.2Hz,1H),6.54(d,J=9.4Hz,2H),5.88(s,2H),3.98– 3.92(m,2H),3.59(dd,J=8.3,4.5Hz,1H),3.37(m,2H),3.30–3.21(m,1H),2.98–2 .79(m,4H),2.49(m,1H),2.23–2.00(m,2H),1.69–1.46(m,5H),1.41–1.24(m,2H). 13 C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116. 4,111.0,108.3,107.4,100.3,68.0,59.9,50.1,43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 419.1[M+H] + .

[0115] Example 15: (R)-5-(2-(1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((R)-A13)

[0116] Referring to the synthetic route of (R)-A12, 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 12, and a substitution reaction was carried out with compound (R)-A1 to obtain (R)-A13. 1 H NMR (500MHz, CDCl3) δ8.11(s,1H),7.65(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7 .23–7.09(m,2H),6.96(d,J=2.2Hz,1H),6.54(d,J=9.4Hz,2H),5.88(s,2H),3.98– 3.92(m,2H),3.59(dd,J=8.3,4.5Hz,1H),3.37(m,2H),3.30–3.21(m,1H),2.98–2 .79(m,4H),2.49(m,1H),2.23–2.00(m,2H),1.69–1.46(m,5H),1.41–1.24(m,2H). 13 C NMR (125MHz, CDCl3) δ145.6,145.5,136.3,131.7,127.3,127.3,121.6,121.0,119.0,118.8,116. 4,111.0,108.3,107.4,100.3,68.0,59.9,50.1,43.1,36.3,35.0,33.1,32.8,24.0,22.2.ESI / MS m / z 419.1[M+H] + .

[0117] Example 16: tert-Butyl-4-((5-(2-(1H-indol-3-yl)ethyl)-7,8-dihydro-[1,3]dioxazolo[4,5-g]isoquinolin-6(5H)-yl)methyl)piperidine-1-carboxylate (A14)

[0118] Referring to the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6), and a substitution reaction was carried out with compound A1 to obtain A14. 1H NMR (500MHz, CDCl3) δ8.18(s,1H),7.60(s,1H),7.36(d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H ),4.09(s,2H),3.52(dd,J=8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.6 4(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H). 13 C NMR(125MHz, CDCl3)δ161.5,146.1,145.8,136.6,132.0,127.6,127.2,121.6,121.0,119.0,118.8,116.8,111 .1,108.3,107.5,101.3,78.8,68.0,59.9,50.1,45.1,38.3,36.1,33.1,32.5,26.0,25.4.ESI / MS m / z 518.3[M+H] + .

[0119] Example 17: (S)-tert-Butyl-4-((5-(2-(1H-indol-3-yl)ethyl)-7,8-dihydro-[1,3]dioxazolo[4,5-g]isoquinolin-6(5H)-yl)methyl)piperidine-1-carboxylate ((S)-A14)

[0120] Referring to the synthetic route of (S)-A12, 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6) was used to replace the bromomethylcyclohexane in Example 11, and a substitution reaction was carried out with compound (S)-A1 to obtain (S)-A14. 1 H NMR (500MHz, CDCl3) δ8.18(s,1H),7.60(s,1H),7.36(d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H ),4.09(s,2H),3.52(dd,J=8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.6 4(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H). 13C NMR (125MHz, CDCl3) δ161.5,146.1,145.8,136.6,132.0,127.6,127.2,121.6,121.0,119.0,118.8,116 .8,111.1,108.3,107.5,101.3,78.8,68.0,59.9,50.1,45.1,38.3,36.1,33.1,32.5,26.0,25.4.ESI / MS m / z 518.3[M+H] + .

[0121] Example 18: (R)-tert-Butyl-4-((5-(2-(1H-indol-3-yl)ethyl)-7,8-dihydro-[1,3]dioxazolo[4,5-g]isoquinolin-6(5H)-yl)methyl)piperidine-1-carboxylate ((R)-A14)

[0122] Referring to the synthetic route of (R)-A12, 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6) was used to replace the bromomethylcyclohexane in Example 12, and a substitution reaction was carried out with compound (R)-A1 to obtain (R)-A14. 1 H NMR (500MHz, CDCl3) δ8.18(s,1H),7.60(s,1H),7.36(d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H ),4.09(s,2H),3.52(dd,J=8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.6 4(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H). 13 C NMR (125MHz, CDCl3) δ161.5,146.1,145.8,136.6,132.0,127.6,127.2,121.6,121.0,119.0,118.8,116 .8,111.1,108.3,107.5,101.3,78.8,68.0,59.9,50.1,45.1,38.3,36.1,33.1,32.5,26.0,25.4.ESI / MS m / z 518.3[M+H] + .

[0123] Example 19: 5-(2-(1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A15)

[0124] 1.0 mL of A14 was dissolved in 20 mL of a mixed solvent of dichloromethane / trifluoroacetic acid (v / v = 5:1) and stirred at room temperature for 1 h. After the reaction of the raw material was completed as monitored by TLC, a saturated sodium carbonate solution was added to the reaction solution, and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography using dichloromethane / methanol = 10:1 to obtain A15 as a yellow solid. 1 H NMR(500MHz, CDCl3)δ8.18(s,1H),7.60(s,1H),7.36 (d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H),4.09(s,2H),3.52(dd,J =8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.64(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H). 13 C NMR (125MHz, CDCl3) δ146.0,145.5,136.1,132.3,127.5,127.1,121.5,121.1,119.2,118.7,1 16.5,111.0,108.2,107.4,101.3,78.8,68.0,59.8,50.1,45.1,36.3,33.1,32.5,25.4.ESI / MS m / z418.2[M+H] + .

[0125] Example 20: (S)-5-(2-(1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((S)-A15)

[0126] 1.0(S)-A14 was dissolved in 20 mL of a mixed solvent of dichloromethane / trifluoroacetic acid (v / v = 5:1) and stirred at room temperature for 1 h. After the reaction of the raw material was completed as monitored by TLC, a saturated sodium carbonate solution was added to the reaction solution and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography using dichloromethane / methanol = 10:1 to obtain a yellow solid (S)-A15. 1H NMR (500MHz, CDCl3) δ8.18(s,1H),7.60(s,1H),7.36(d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H ),4.09(s,2H),3.52(dd,J=8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.6 4(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H). 13 C NMR (125MHz, CDCl3) δ146.0,145.5,136.1,132.3,127.5,127.1,121.5,121.1,119.2,118.7,1 16.5,111.0,108.2,107.4,101.3,78.8,68.0,59.8,50.1,45.1,36.3,33.1,32.5,25.4.ESI / MS m / z 418.2[M+H] + .

[0127] Example 21: (R)-5-(2-(1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((R)-A15)

[0128] 1.0 (R)-A14 was dissolved in 20 mL of a mixed solvent of dichloromethane / trifluoroacetic acid (v / v = 5:1) and stirred at room temperature for 1 h. After the reaction of the raw material was completed as monitored by TLC, a saturated sodium carbonate solution was added to the reaction solution and the pH was adjusted to 8-9. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography using dichloromethane / methanol = 10:1 to obtain a yellow solid (R)-A15. 1 H NMR (500MHz, CDCl3) δ8.18(s,1H),7.60(s,1H),7.36(d,J=8.1Hz,1H),7.21–7.12(m,2H),7.05(t,J=7.4Hz,1H),6.55(d,J=9.4Hz,2H),5.46(s,2H ),4.09(s,2H),3.52(dd,J=8.9,4.1Hz,1H),3.31–3.23(m,1H),2.99–2.6 4(m,6H),2.52–2.34(m,3H),1.82(m,2H),1.74–1.60(m,5H),1.46(s,9H).13 C NMR (125MHz, CDCl3) δ146.0,145.5,136.1,132.3,127.5,127.1,121.5,121.1,119.2,118.7,1 16.5,111.0,108.2,107.4,101.3,78.8,68.0,59.8,50.1,45.1,36.3,33.1,32.5,25.4.ESI / MS m / z 418.2[M+H] + .

[0129] Example 22: 5-(2-(1H-indol-3-yl)ethyl)-6-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A16)

[0130] 1.0 mg of A15 was dissolved in 20 mL of acetonitrile, and 510 mg of iodomethane and 1.65 g of potassium carbonate were added sequentially. The reaction was refluxed for 24 hours. After TLC monitoring, the organic solvent was dried, and water and ethyl acetate were added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was purified by column chromatography using dichloromethane / methanol = 15:1 to obtain A16 as a yellow solid. ESI-MS m / z 432.2 [M+H] + .

[0131] Example 23: 5-(2-(1H-indol-3-yl)ethyl)-6-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A17)

[0132] Referring to the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 3-bromomethyltetrahydrofuran (CAS: 165253-29-2) to undergo a substitution reaction with compound A1 to obtain A17. ESI-MS m / z 405.1 [M+H] +

[0133] Example 24: 5-(2-(1H-indol-3-yl)ethyl)-6-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A18)

[0134] Referring to the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromoethyltetrahydropyran (CAS: 4677-20-7), and a substitution reaction was carried out with compound A1 to obtain A18. 1H NMR (400MHz, CDCl3) δ8.08(s,1H),7.61(d,J=7.8Hz,1H),7.35(d,J=8.1Hz,1H),7.25–7.17(m ,1H),7.15–7.10(m,1H),7.02(s,1H),6.59(s,1H),6.49(s,1H),4.07–3.97(m,2H),3.87(s,3 H),3.79(s,3H),3.57(s,1H),3.41(td,J=11.4,4.4Hz,2H),3.32(dd,J=19.4,10.0Hz,1H),3. 02–2.77(m,4H),2.59–2.37(m,2H),2.04–2.17(m,2H),1.76–1.85(m,2H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ147.4,136.5,130.9,127.0,125.6,122.0,121.0,119.1,119.0,117.0,111.4 ,111.1,110.7,68.1,61.4,60.1,55.9,55.8,44.0,36.8,32.8,32.0,29.7,24.7,23.8,22.5.ESI / MS m / z 433.1[M+H] + .

[0135] Example 25: 5-(2-(1H-indol-3-yl)ethyl)-6-benzyl-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A23)

[0136] Referring to the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with benzyl bromide, and a substitution reaction occurred with compound A1 to obtain A23. ESI / MS m / z 411.2 [M+H] + .

[0137] Example 26: 5-(2-(1H-indol-3-yl)ethyl)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A24)

[0138] Following the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethylpyridine (CAS: 54751-01-8) to undergo a substitution reaction with compound A1 to obtain A24. ESI / MS m / z 412.2 [M+H] + .

[0139] Example 27: 5-(2-(1H-indol-3-yl)ethyl)-6-(pyrimidin-5-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A25)

[0140] Following the synthetic route of A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 5-(bromomethyl)pyrimidine (CAS: 25198-96-3) to undergo a substitution reaction with compound A1 to obtain A25. ESI / MS m / z 413.2 [M+H] + .

[0141] Example 28: 1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A26)

[0142] Referring to the synthetic routes of A3 and A12, 2-3 and 3-3 in Example 7 were replaced by 3,4-dimethoxyphenylethylamine and 3-indolepropionic acid, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A26. ESI / MS m / z 413.2 [M+H] + .Pale yellow solid, 1 H NMR(400MHz, CDCl3)δ8.06(brs,1H),7.63(d,J=7.8Hz,1H),7.38(d,J=8.1Hz,1H),7.24–7.18 (m,1H),7.16–7.10(m,1H),7.02(s,1H),6.59(s,1H),6.49(s,1H),4.07–3.97(m,2H),3.87(s, 3H),3.79(s,3H),3.57(s,1H),3.41(td,J=11.4,4.4Hz,2H),3.32(dd,J=19.4,10.0Hz,1H),3 .02–2.77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13C NMR (125MHz, CDCl3): δ147.2,136.5,130.9,127.6,126.6,122.0,121.0,119.1,119.0,117.0,111.4 ,111.1,110.7,68.1,61.4,60.1,55.9,55.8,44.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 435.0

[0143] Example 29: 5-(2-(1H-indol-3-yl)ethyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline (A27)

[0144] Referring to the synthetic routes of A3 and A12, 1,4-benzodioxane-6-carbaldehyde (CAS: 29668-44-8) and 3-indolepropionic acid were used to replace 2-1 and 3-3 in Example 7, respectively, and 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 10 to obtain A27 as a white solid. 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.35(d,J=8.3Hz,1H),7.25–7.11(m,1H),7.09(s,1H),6.44(s,1H),6.50(s,1H),6.44(s,1H) ,6.36–6.16(m,2H),4.77(s,2H),4.51(t,J=13.7Hz,2H),3.33–3.05(m,1H),3.00–2.61(m,4H),4.12(s,3H),2.32–2.17(m,2H). 13 C NMR (125MHz, CDCl3) δ160.9,150.8,147.3,135.8,128.1,126.5,125.4,124.4,121.8,122 .7,121.8,119.0,118.3,115.1,114.6,108.9,92.7,70.9,53.7,43.2,33.5,25.4.ESI-MS m / z 433.2.

[0145] Example 30: 1-(2-(1H-indol-3-yl)ethyl)-7-(benzyloxy)-6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A28)

[0146] Following the synthetic routes of A3 and A12, 2-1 and 3-3 in Example 7 were replaced with 4-benzyloxy-3-methoxybenzaldehyde (CAS: 2426-87-1) and 3-indolepropionic acid, respectively. The bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to afford A28. ESI-MS m / z 511.3.

[0147] Example 31: 1-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A29)

[0148] Following the synthetic routes of A3 and A12, 2-1 and 3-3 in Example 7 were replaced with 3-benzyloxy-4-methoxybenzaldehyde (CAS: 6346-05-0) and 3-indolepropionic acid, respectively. The bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to afford A29. ESI-MS m / z 511.3.

[0149] Example 32: 1-(2-(1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol (A30)

[0150] Compound A26 (1.30 g, 3.0 mmol) was dissolved in ultra-dry dichloromethane. A 4N solution of boron tribromide in dichloromethane (7.5 mL, 30 mmol) was added dropwise at -15°C, and the mixture was stirred at room temperature for 4 h. After completion of the reaction as monitored by TLC, an excess of water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed once with saturated sodium bicarbonate and once with saturated sodium chloride. The phase was concentrated and purified by column chromatography using dichloromethane / methanol (15:1) to afford 0.91 g of A30 as a yellow solid in a 75% yield. 1H NMR(400MHz, CDCl3) δ8.06(brs,1H),7.68(d,J=7.8Hz,1H),7.28(d,J=8.1Hz,1H),7.16 –7.11(m,1H),7.05–7.01(m,1H),6.95(s,1H),6.49(s,1H),6.30(s,1H),4.08–3.97(m, 2H),3.57(s,1H),3.41(td,J=11.4,4.4Hz,2H),3.32(dd,J=19.4,10.0Hz,1H),3.02–2. 77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ145.2,137.5,131.9,125.6,123.5,122.0,121.0,119.1,119.0,117.0, 111.4,111.1,110.7,62.1,55.9,55.8,42.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 405.1[MH] - .

[0151] Example 33: 5-(2-(1H-indol-3-yl)ethyl)-2-propyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A31)

[0152] Compound A30 (0.81 g, 2.0 mmol), n-butyraldehyde (173 mg, 2.4 mmol), and p-toluenesulfonic acid (34 mg, 0.2 mmol) were dissolved in 10 mL of toluene and heated under reflux at 110°C for 24 h. After completion of the reaction, as monitored by TLC, water and ethyl acetate were added for extraction. The organic phase was collected, washed once with saturated sodium chloride solution, concentrated, and purified by column chromatography using dichloromethane / methanol = 40:1 to obtain 0.62 g of A31, a 67% yield, as a light yellow solid. ESI / MS m / z 461.2 [M+H] + .

[0153] Example 34: 5-(2-(1H-indol-3-yl)ethyl)-2-((1-methylpiperidin-4-yl)methyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A32)

[0154] Referring to the synthetic route of A31, the reaction reagent n-butyraldehyde in Example 33 was replaced with 1-methyl-4-piperidinecarboxaldehyde (CAS: 50675-21-3) to obtain A32. ESI / MS m / z 530.3 [M+H] + .

[0155] Example 35: 5-(2-(1H-indol-3-yl)ethyl)-2-phenyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A33)

[0156] Referring to the synthetic route of A31, benzaldehyde was used to replace the n-butyraldehyde in Example 33 to obtain A33. ESI / MS m / z 495.0 [M+H] + .

[0157] Example 36: 5-(2-(1H-indol-3-yl)ethyl)-2-benzyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A34)

[0158] Referring to the synthetic route of A31, the reaction reagent n-butyraldehyde in Example 43 was replaced with phenylacetaldehyde to obtain A34. ESI / MS m / z 509.2 [M+H] + .

[0159] Example 37: 7-(2-(1H-indol-3-yl)ethyl)-8-((tetrahydro-2H-pyran-4-yl)methyl)-3,4,7,8,9,10-hexahydro-2H-[1,4]dioxepino[2,3-g]isoquinoline (A35)

[0160] Compound A30 (0.81 g, 2.0 mmol) and 1,3-dibromopropane (0.81 g, 4 mmol) were dissolved in 20 mL of acetonitrile, followed by the addition of potassium carbonate (2.2 g, 16 mmol) and heating under reflux at 85°C for 48 h. After TLC monitoring of the reaction, the mixture was filtered, the filter cake washed with ethyl acetate, and the filtrate collected and concentrated. The filtrate was then purified by column chromatography using dichloromethane / methanol = 40:1 to obtain 0.52 g of A35 in a 58% yield as a pale yellow solid. ESI / MS m / z 447.1 [M+H] + .

[0161] Example 38: 1-(2-(1H-indol-3-yl)ethyl)-6,7-bis(2-methoxyethoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A36)

[0162] Referring to the synthetic route of A35, the reaction reagent 1,3-dibromopropane in Example 37 was replaced with 2-bromoethyl methyl ether (CAS: 6482-24-2) to obtain A36. ESI / MS m / z 523.3 [M+H] + .

[0163] Example 39: 12-(2-(1H-indol-3-yl)ethyl)-13-((tetrahydro-2H-pyran-4-yl)methyl)-2,3,5,6,8,9,12,13,14,15-decahydro-[1,4,7,10]tetraoxadododeca[2,3-g]isoquinoline (A37)

[0164] Referring to the synthetic route of A35, the reaction reagent 1,3-dibromopropane in Example 37 was replaced with 1,14-dibromo-3,6,9,12-tetraoxatetradecane (CAS: 57602-02-5) to obtain A37. ESI / MS m / z 521.2 [M+H] + .

[0165] Example 40: 1-(2-(1H-indol-3-yl)ethyl)-6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (A38)

[0166] Compound A28 (1.0 g, 2.0 mmol) was dissolved in 20 mL of methanol, followed by the addition of 100 mg of Pd / C catalyst (containing 10% water) and ammonium formate (1.26 g, 20 mmol). The mixture was heated and stirred at 55°C for 12 h. After completion of the reaction as monitored by TLC, the filtrate was collected by suction and the solvent evaporated to dryness. The filtrate was then purified by column chromatography using dichloromethane / methanol (20:1) to afford 0.70 g of A38, a yield of 83%, as a yellow solid. ESI / MS m / z 420.2 [M+H] + .

[0167] Example 41: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-ol (A39)

[0168] Compound A29 (1.0 g, 2.0 mmol) was dissolved in 20 mL of methanol, followed by the addition of 100 mg of Pd / C catalyst (containing 10% water) and ammonium formate (1.26 g, 20 mmol). The mixture was heated and stirred at 55°C for 12 h. After completion of the reaction as monitored by TLC, the filtrate was collected by suction and the solvent evaporated to dryness. The filtrate was then purified by column chromatography using dichloromethane / methanol (20:1) to afford 0.71 g of A39, an 85% yield, as a yellow solid. ESI / MS m / z 420.2 [M+H] + .

[0169] Example 42: 1-(2-(1H-indol-3-yl)ethyl)-6-ethoxy-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A40)

[0170] Compound A39 (1.05 g, 2.5 mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of iodoethane (0.58 g, 3.75 mmol) and potassium carbonate (1.04 g, 7.5 mmol). The mixture was stirred at reflux at 85°C for 12 h. After completion of the reaction, as monitored by TLC, the filtrate was collected by suction and the solvent evaporated to dryness. The filtrate was then purified by column chromatography using dichloromethane / methanol = 30:1 to afford 0.87 g of A40, a 78% yield, as a yellow solid. ESI / MS m / z 449.2 [M+H] + .

[0171] Example 43: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-6-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroisoquinoline (A41)

[0172] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 52 was replaced with 2-iodo-1,1,1-trifluoroethane (CAS: 353-83-3) to obtain A41. ESI / MS m / z 503.2 [M+H] + .

[0173] Example 44: 1-(2-(1H-indol-3-yl)ethyl)-6-(cyclopropylmethoxy)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A42)

[0174] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 42 was replaced with (iodomethyl)cyclopropane (CAS: 33574-02-6) to obtain A42. ESI / MS m / z 475.3 [M+H] + .

[0175] Example 45: 1-(2-(1H-indol-3-yl)ethyl)-6-(cyclopentylmethoxy)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A43)

[0176] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 42 was replaced with (iodomethyl)cyclopropane (CAS: 27935-87-1) to obtain A43. ESI / MS m / z 503.2 [M+H] + .

[0177] Example 46: Ethyl 2-((1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)acetate (A44)

[0178] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 42 was replaced with ethyl bromoacetate to obtain A44. ESI / MS m / z 507.2 [M+H] + .

[0179] Example 47: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A45)

[0180] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 42 was replaced with 1-(2-bromoethyl)-4-methylpiperazine (CAS: 801152-34-1) to obtain A45. ESI / MS m / z 547.4 [M+H] + .

[0181] Example 48: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-6-((4-methylbenzyl)oxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A46)

[0182] Referring to the synthetic route of A40, 4-methylbenzyl bromide (CAS: 104-81-4) was used to replace the iodoethane in Example 42 to obtain A46. ESI / MS m / z 525.4 [M+H] + .

[0183] Example 49: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-6-(pyridin-4-ylmethoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A47)

[0184] Referring to the synthetic route of A40, 4-methylbenzyl bromide (CAS: 104-81-4) was used to replace the iodoethane in Example 42 to obtain A47. ESI / MS m / z 525.4 [M+H] + .

[0185] Example 50: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-6-(pyrimidin-5-ylmethoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A48)

[0186] Referring to the synthetic route of A40, the reaction reagent iodoethane in Example 42 was replaced with 4-bromomethylpyrimidine (CAS: 25198-96-3) to obtain A48. ESI / MS m / z 513.3 [M+H] + .

[0187] Example 51: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl 2,2,2-trifluoroacetate (A49)

[0188] Compound A39 (1.05 g, 2.5 mmol) was dissolved in 20 mL of dichloromethane at 0°C, followed by trifluoroacetic anhydride (0.79 g, 3.75 mmol), triethylamine (0.45 g, 4.5 mmol), and N,N-dimethylaminopyridine (DMAP, 30.5 mg, 0.25 mmol). The mixture was stirred at room temperature for 6 h. After completion of the reaction, as monitored by TLC, the mixture was extracted with water and ethyl acetate. The organic phase was collected, concentrated, and purified by column chromatography using dichloromethane / methanol = 30:1 to obtain 1.04 g of A49, an 81% yield, as a yellow solid. ESI / MS m / z 517.2 [M+H] + .

[0189] Example 52: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonic acid (A50)

[0190] Referring to the synthetic route of A49, trifluoromethanesulfonic anhydride was used to replace the trifluoroacetic anhydride in Example 51 to obtain A50. ESI / MS m / z 553.2 [M+H] + .

[0191] Example 53: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-ylbenzenesulfonate (A51)

[0192] Referring to the synthetic route of A49, the trifluoroacetic anhydride in Example 51 was replaced with benzenesulfonyl chloride to obtain A51. ESI / MS m / z 561.2 [M+H] + .

[0193] Example 54: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl 4-(trifluoromethyl)benzenesulfonate (A52)

[0194] Referring to the synthetic route of A49, 4-trifluoromethylbenzenesulfonyl chloride (CAS: 2991-42-6) was used to replace the trifluoroacetic anhydride in Example 51 to obtain A52. ESI / MS m / z 629.2 [M+H] + .

[0195] Example 55: 1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-6-phenoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A53)

[0196] Compound A39 (0.63 g, 1.5 mmol), iodobenzene (0.37 g, 1.8 mmol), cuprous bromide dimethyl sulfide (0.31 g, 1.5 mmol), and cesium carbonate (1.47 g, 4.5 mmol) were dissolved in 15 mL of pyridine and heated at 120°C under argon for 24 h. After completion of the reaction, as monitored by TLC, the mixture was filtered and washed with ethyl acetate. The filtrate was collected and washed three times with an equal volume of water. The organic phase was concentrated and purified by column chromatography using dichloromethane / methanol = 40:1 to obtain 0.32 g of A53, a 43% yield, as a yellow solid. ESI / MS m / z 497.3 [M+H] + .

[0197] Example 56: 2-((1-(2-(1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)ethan-1-amine (A54)

[0198] As shown in the figure above, compound A39 (0.63 g, 1.5 mmol), N-Boc-ethanolamine (0.48 g, 3 mmol), and triphenylphosphine (1.18 g, 4.5 mmol) were dissolved in 30 mL of tetrahydrofuran. Diisopropyl azodicarboxylate (DIAD, 1.04 g, 7.5 mmol) was added dropwise with stirring at 0°C. After complete addition, the mixture was transferred to room temperature and stirred for 6 hours. After completion of the reaction, water and ethyl acetate were added for extraction. The organic phase was collected, concentrated, and further dissolved in 10 mL of dichloromethane / trifluoroacetic acid (v / v = 5:1). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to neutralize the trifluoroacetic acid, and the pH was adjusted to 8. The mixture was extracted with dichloromethane. The organic phase was collected, concentrated, and purified by column chromatography using dichloromethane / methanol (10:1). The yield for the two steps was 47%, yielding 0.32 g of A54 as a yellow oil. ESI / MS m / z 464.3[M+H] + .

[0199] Example 57: 5-(2-(5-methoxy-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A55)

[0200] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine and 5-methoxyindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A55. ESI / MS m / z 449.3 [M+H] + .

[0201] Example 58: 6,7-dimethoxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A56)

[0202] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced by 3,4-dimethoxyphenethylamine and 5-methoxyindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran to obtain A56. 1H NMR(500MHz, CDCl3)δ7.94(s,1H),7.28(s,1H),7.09–6.97(m,2H),6.87(dd,J =8.7,2.5Hz,1H),6.59(s,1H),6.48(s,1H),3.99(dd,J=10.5,4.2Hz,2H),3.87 (d,J=2.4Hz,6H),3.57(s,3H),3.57(s,1H),3.36(dd,J=30.6,19.6Hz,3H),2.9 6–2.75(m,4H),2.47(s,3H),2.26–1.98(m,2H),1.79(dd,J=32.5,13.5Hz,5H). 13 C NMR (125MHz, CDCl3) δ153.8,146.7,131.7,127.9,122.0,111.9,111.8,111. 4,110.6,101.1,68.1,61.3,56.0,55.9,55.8,43.9,31.9,31.7,22.2.ESI / MS m / z 465.2[M+H] + .

[0203] Example 59: 5-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A57)

[0204] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced by piperidine and 5-fluoroindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran to obtain A57. 1 H NMR (500MHz, CDCl3) δ7.99 (s, 1H), 7.26 (d, J = 3.9 Hz, 1H), 7.20 (dd, J = 9.7, 2. 5Hz,1H),7.03(s,1H),6.93(td,J=9.0,2.5Hz,1H),6.53(d,J=21.4Hz,2H),5. 88(s,2H),3.99–3.93(m,2H),3.51(s,1H),3.41–3.19(m,3H),2.83(t,J=7.9 Hz,4H),2.41(d,J=25.7Hz,3H),2.13–1.93(m,2H),1.81–1.63(m,5H).ESI / MS m / z 437.1[M+H] + .

[0205] Example 60: 1-1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A58)

[0206] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 5-fluoroindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A58. ESI / MS m / z 437.1 [M+H] + .

[0207] Example 61: 5-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A59)

[0208] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine and 5-chloroindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A59. ESI / MS m / z 453.2 [M+H] + .

[0209] Example 62: 1-(2-(5-chloro-1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A60)

[0210] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 5-chloroindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A60. ESI / MS m / z 469.1 [M+H] + .

[0211] Example 63: 1-(2-(5-bromo-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A61)

[0212] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 5-bromoindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A61. ESI / MS m / z 513.1 [M+H]+ .

[0213] Example 64: 5-(2-(5-methyl-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A62)

[0214] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine and 5-methylindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A62. ESI / MS m / z 449.1 [M+H] + .

[0215] Example 65: 6,7-dimethoxy-1-(2-(5-methyl-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A63)

[0216] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 5-methylindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A63. ESI / MS m / z 449.1 [M+H] + .

[0217] Example 66: 6,7-dimethoxy-1-(2-(7-methyl-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A64)

[0218] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 7-methylindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A64. ESI / MS m / z 449.1 [M+H] + .

[0219] Example 67: 5-(2-(5-(Benzyloxy)-1H-indol-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A65)

[0220] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine and 5-benzyloxyindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A65. ESI / MS m / z 525.2 [M+H] + .

[0221] Example 68: 1-(2-(5-(Benzyloxy)-1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A66)

[0222] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine and 5-benzyloxyindole-3-carboxaldehyde, respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran to obtain A66. ESI / MS m / z 541.3 [M+H] + .

[0223] Example 69: 3-(2-(6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinolin-5-yl)ethyl)-1H-indole-5-ol (A67)

[0224] A65 (262 mg, 0.5 mmol) was dissolved in 10 mL of methanol, and 26 mg of palladium-carbon catalyst (containing 10% water) and ammonium formate (315 mg, 5 mmol) were added. The mixture was heated at 55°C overnight, filtered, and the filtrate was collected. After concentration, it was purified by column chromatography using dichloromethane / methanol = 20:1 to obtain A67 as a yellow solid. ESI / MS m / z 435.2 [M+H] + .

[0225] Example 70: 3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indole-5-ol (A68)

[0226] Referring to the synthetic route of A67, the raw material A65 in Example 69 was replaced with A66 to obtain A68. ESI / MS m / z 450.1 [M+H] + .ESI / MS m / z 451.1[M+H] + .

[0227] Example 71: 6,7-Dimethoxy-1-(2-(1-methyl-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A69)

[0228] Compound A26 (1.30 g, 3.0 mmol) was dissolved in ultra-dry DMF at 0°C in an ice bath. Sodium hydride (1.5 equivalents) was added and stirring continued for 15 min in an ice bath. A solution of iodomethane in tetrahydrofuran was then added dropwise to the reaction system. After the addition was complete, argon was applied to protect the reaction mixture. The mixture was then transferred to room temperature and stirred for 4 h.

[0229] After the reaction was completed as monitored by TLC, excess water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed once with saturated sodium bicarbonate and once with saturated sodium chloride solution, concentrated, and purified by column chromatography using dichloromethane / methanol = 20:1 to obtain 1.13 g of A69 (yield 85%) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ7.58(d,J=7.8Hz,1H),7.18(d,J=8.1Hz,1H),7.15–7.11(m,1H), 7.05–7.01(m,1H),6.95(s,1H),6.49(s,1H),6.30(s,1H),4.08–3.97(m,2H),3.57(s,1 H),3.41(td,J=11.4,4.4Hz,2H),3.32(dd,J=19.4,10.0Hz,1H),3.35(s,3H),3.02–2. 77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ145.2,137.5,131.9,125.6,123.5,122.0,121.0,119.1,119.0,117.0,11 1.4,111.1,110.7,62.1,55.9,55.8,47.5,42.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 449.3[M+H] + .

[0230] Example 72: (2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)methanol (A70)

[0231] Compound A21 (130 mg, 0.3 mmol) was dissolved in 5 mL of a mixed solvent of formic acid and 40% formaldehyde (v / v = 3:2) under an ice bath. The mixture was stirred at 90°C under argon for 2 h. After completion of the reaction as monitored by TLC, an excess of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography using dichloromethane / methanol (20:1) to afford 1.13 g of A70 (73% yield) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ7.58(d,J=7.8Hz,1H),7.18(d,J=8.1Hz,1H),7.16–7.10(m,1H), 7.05–7.01(m,1H),6.95(s,1H),6.49(s,1H),6.30(s,1H),4.18–3.97(m,2H),3.55(s,1 H),3.40(td,J=11.4,4.4Hz,2H),3.37(d,2H),3.32(dd,J=19.4,10.0Hz,1H),3.02–2. 77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ145.2,137.5,131.9,125.6,123.5,122.0,121.0,119.1,119.0,117.0,11 1.4,111.1,110.7,62.1,55.9,55.8,47.5,42.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 465.1[M+H] + .

[0232] Example 73: Ethyl 2-(3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)acetate (A71)

[0233] Referring to the synthetic route of A69, ethyl 2-bromoacetate was used to replace methyl iodide in Example 71 to obtain A71. ESI / MS m / z 521.1 [M+H] + .

[0234] Example 74: 2-(3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)acetic acid (A72)

[0235] 100 mg of compound A71 was dissolved in 10 mL of a mixed solution of EtOH / 2N NaOH (v / v = 1:1) and stirred at room temperature for 1 h. After the reaction of the raw material was completed, the organic solvent was dried by TLC, and the pH was adjusted to 4-5 with 1N HCl. The product was extracted with dichloromethane and concentrated, and then recrystallized from ethyl acetate and n-hexane to obtain A72.

[0236] Example 75: 2-(3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)acetamide (A73)

[0237] 100 mg of compound A72 was dissolved in 10 mL of 1,4-dioxane, 1 mL of pyridine (5 equiv.), 1.2 mL of tert-butyl dicarbonate (2 equiv.), and 2.1 g of ammonium bicarbonate (10 equiv.), and heated at 50 degrees for 12 h. After the reaction of the raw material was completed, 50 mL of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The mixture was purified by column chromatography using dichloromethane / methanol = 20:1 to obtain A73.

[0238] Example 76: 2-(3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)ethan-1-ol (A74)

[0239] Referring to the synthetic route of A69, 2-iodoethanol (CAS: 624-76-0) was used to replace the iodomethane in Example 71 to obtain A74. ESI / MS m / z 521.1 [M+H] + .

[0240] A74 was obtained by replacing the iodomethane in the synthesis example of A65 with 2-iodoethanol (CAS: 624-76-0) and following the synthesis route of A65. Purification by column chromatography using dichloromethane / methanol = 20:1 resulted in a white solid. ESI / MS m / z 479.3 [M+H] + .

[0241] Example 77: 6,7-dimethoxy-1-(2-(1-(2-(methylsulfonyl)ethyl)-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A75)

[0242] Referring to the synthetic route of A69, 1-bromo-2-(methylsulfonyl)ethane (CAS: 16523-02-7) was used to replace the iodomethane in Example 71 to obtain A75. ESI / MS m / z 541.3 [M+H] + .

[0243] Example 78: 2-(3-(2-(6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-1-yl)-N,N-dimethylethane-1-amine (A76)

[0244] Referring to the synthetic route of A69, (2-bromomethyl)dimethylamine (CAS: 5459-68-7) was used to replace the iodomethane in Example 71 to obtain A76. ESI / MS m / z 506.1 [M+H] + .

[0245] Example 79: 6,7-dimethoxy-1-(2-(2-methyl-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A77)

[0246] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced by 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 2-methylindole-3-carbaldehyde (CAS: 5416-80-8), respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A77. ESI / MS m / z 449.1 [M+H] + .

[0247] Example 80: 1-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A78)

[0248] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced by 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 7-azaindole-3-carboxaldehyde (CAS: 4649-09-6), respectively, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A78. ESI / MS m / z 436.2 [M+H] + .

[0249] Example 81: 1-(2-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A79)

[0250] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced by 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 4-azaindole-3-carboxaldehyde (CAS: 276862-85-2), respectively, and the bromomethylcyclohexane in Example 10 was replaced by 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A79. ESI / MS m / z 436.2 [M+H] + .

[0251] Example 82: 5-(2-(Benzo[b]thiophen-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A80)

[0252] Referring to the synthetic routes of A3 and A12, piperidine (CAS: 1484-85-1) and 2-thiophenecarboxaldehyde (CAS: 98-03-3) were used to replace 2-3 and 3-1 in Example 7, respectively, and 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 10 to obtain A80. ESI / MS m / z 436.1 [M+H] + .

[0253] Example 83: 6-(Benzyloxy)-7-methoxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A81)

[0254] Referring to the synthetic routes of A3 and A12, the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to undergo a substitution reaction with A3 to obtain A81. ESI / MS m / z 541.1 [M+H] + .

[0255] Example 84: 6-(Benzyloxy)-1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A82)

[0256] Referring to the synthetic routes of A3 and A12, 3-1 in Example 7 was replaced with 5-fluoroindole-3-carboxaldehyde, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to participate in the final substitution reaction to obtain A82. ESI / MS m / z 529.2 [M+H] + .

[0257] Example 85: 6-(Benzyloxy)-1-(2-(5-chloro-1H-indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A83)

[0258] Referring to the synthetic routes of A3 and A12, 3-1 in Example 7 was replaced with 5-chloroindole-3-carboxaldehyde, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to participate in the final substitution reaction to obtain A83. ESI / MS m / z 545.3 [M+H] + .

[0259] Example 86: 6-(Benzyloxy)-7-methoxy-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A84)

[0260] Referring to the synthetic routes of A3 and A12, 3-1 in Example 7 was replaced with 5-methoxyindole-3-carboxaldehyde, and the bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A84 was obtained. ESI / MS m / z 540.3 [M+H] + .

[0261] Example 87: 6-(Benzyloxy)-1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-7-methoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A85)

[0262] Referring to the synthetic routes of A3 and A12, 3-1 in Example 7 was replaced with 5-fluoroindole-3-carboxaldehyde, and the bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A85 was obtained. ESI / MS m / z 528.1 [M+H] + .

[0263] Example 88: 1-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A86)

[0264] Referring to the synthetic routes of A3 and A12, 3-indolepropionic acid was used to replace 3-3 in Example 7, and 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 10 to participate in the substitution reaction. After the final hydrolysis step, A86 was obtained. ESI / MS m / z 510.0 [M+H] + .

[0265] Example 89: 1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A87)

[0266] Referring to the synthetic routes of A3 and A12, 2-3 and 3-3 in Example 7 were replaced with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 3-indolepropionic acid, respectively. The bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A87 was obtained. ESI / MS m / z 434.4 [M+H] + .

[0267] Example 90: 5-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A88)

[0268] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine (CAS: 120-20-7) and 5-fluoroindole-3-carboxaldehyde, respectively. The bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A88 was obtained. ESI / MS m / z 436.1 [M+H] + .

[0269] Example 91: 5-(2-(5-methoxy-1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A89)

[0270] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine (CAS: 120-20-7) and 5-methoxyindole-3-carboxaldehyde, respectively. The bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A89 was obtained. ESI / MS m / z 448.2 [M+H] + .

[0271] Example 92: 5-(2-(5-chloro-1H-indol-3-yl)ethyl)-6-(piperidin-4-ylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A90)

[0272] Referring to the synthetic routes of A3 and A12, 2-3 and 3-1 in Example 7 were replaced with piperidine (CAS: 120-20-7) and 5-chloroindole-3-carboxaldehyde, respectively. The bromomethylcyclohexane in Example 10 was replaced with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction. After the final hydrolysis step, A90 was obtained. ESI / MS m / z 452.2 [M+H] + .

[0273] Example 93: (S)-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline ((S)-A26)

[0274] Referring to the synthetic route of A12, (S)-A2 was used as the starting material, and 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 11. A substitution reaction was carried out with compound (S)-A2 to obtain (S)-A26. A light yellow solid was obtained. 1 H NMR (400MHz, CDCl3) δ8.06(brs,1H),7.63(d,J=7.8Hz,1H),7.38(d,J=8.1Hz,1H),7.24–7.18(m,1H),7.16–7.10(m,1H),7.0 2(s,1H),6.59(s,1H),6.49(s,1H),4.07–3.97(m,2H),3.87(s,3H),3.79(s,3H),3.57(s,1H),3.41(td,J=11.4,4.4Hz,2H), 3.32(dd,J=19.4,10.0Hz,1H),3.02–2.77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ147.2,136.5,130.9,127.6,126.6,122.0,121.0,119.1,119.0,117.0,111.4 ,111.1,110.7,68.1,61.4,60.1,55.9,55.8,44.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 435.3[M+H] + .

[0275] Example 94: (R)-1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline ((R)-A26)

[0276] Referring to the synthetic route of A12, (R)-A2 was used as the starting material, and 4-bromomethyltetrahydropyran (CAS: 125552-89-8) was used to replace the bromomethylcyclohexane in Example 12. A substitution reaction was carried out with compound (R)-A2 to obtain (R)-A26. A light yellow solid, 1H NMR(400MHz, CDCl3)δ8.06(brs,1H),7.63(d,J=7.8Hz,1H),7.38(d,J=8.1Hz,1H),7.24–7.18 (m,1H),7.16–7.10(m,1H),7.02(s,1H),6.59(s,1H),6.49(s,1H),4.07–3.97(m,2H),3.87(s, 3H),3.79(s,3H),3.57(s,1H),3.41(td,J=11.4,4.4Hz,2H),3.32(dd,J=19.4,10.0Hz,1H),3 .02–2.77(m,4H),2.59–2.37(m,3H),2.04–2.17(m,2H),1.76–1.85(m,3H),1.36–1.26(m,2H). 13 C NMR (125MHz, CDCl3): δ147.2,136.5,130.9,127.6,126.6,122.0,121.0,119.1,119.0,117.0,111.4 ,111.1,110.7,68.1,61.4,60.1,55.9,55.8,44.0,36.8,33.8,32.0,31.7,29.7,23.7,22.1.ESI / MS m / z 435.3[M+H] + .

[0277] Example 95: 1-(2-(1H-indol-3-yl)ethyl)-2-((3-oxaspiro[5.5]undec-9-yl)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (A93)

[0278] Following the synthetic route of A12, 3-oxaspiro[5.5]undecan-9-one (4-1, CAS: 1159280-53-1) and A2 were used as starting materials. Methyltriphenylphosphonium bromide (12 mmol) was dissolved in 50 mL of tetrahydrofuran, evacuated under argon protection, and potassium tert-butoxide solution (1 mol / L) was slowly added dropwise at 0°C. After complete addition, the mixture was kept at 0°C and stirred for 1 hour. Then, a tetrahydrofuran solution of 3-oxaspiro[5.5]undecan-9-one was slowly added dropwise to the above solution. After complete addition, the mixture was allowed to react at room temperature overnight. After completion of the reaction, as monitored by TLC, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. The mixture was filtered through celite and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, concentrated, and chromatographed on a PE / EA (10 / 1) column to obtain intermediate 4-2. Intermediate 4-2 (6 mmol) was dissolved in tetrahydrofuran. Borane-dimethyl sulfide solution (9 mmol) was slowly added dropwise at 0°C under argon. The mixture was allowed to react at room temperature for 4 h. NaOH solution was then added dropwise until bubbles disappeared to quench the reaction. After stirring for 15 min, 30% H₂O₂ was added and the mixture was allowed to react at room temperature for another 2 h. After TLC monitoring of the reaction, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and chromatographed on a PE / EA (5 / 1) column to obtain Intermediate 4-3. Intermediate 4-3 (5 mmol) was dissolved in 20 mL of a 48% hydrogen bromide / ethanol (v / v = 1:1) mixture and heated at 90°C for 2 h. After TLC monitoring of the reaction, the mixture was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and chromatographed on a PE / EA (10 / 1) column to obtain Intermediate 4-4. A2 (3 mol) was dissolved in 15 mL of acetonitrile, 4-4 (4.5 mol) and potassium carbonate (15 mol) were added, and the mixture was heated under reflux for 24 h. After the reaction was complete as monitored by TLC, the filtrate was collected by suction, concentrated, and purified by column chromatography using DCM / MeOH (30 / 1) to obtain compound A93. ESI / MS m / z 503.4 [M+H] + .

[0279] Example 96: 9-((1-(2-(1H-indol-3-yl)ethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-azaspiro[5.5]undecane (A94)

[0280] Following the synthetic route of A93, A94 was obtained using 3-azaspiro[5.5]-9-undecanone (CAS: 1056629-32-3) and A2 as starting materials. ESI / MS m / z 502.4 [M+H] + .

[0281] Example 97: 1-(2-(1H-indol-3-yl)ethyl)-2-(((1R,5S)-8-oxabicyclo[3.2.1]octan-3-yl)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (A95)

[0282] Following the synthetic route of A93, A95 was obtained using 8-oxabicyclo[3.2.1]octan-3-one (CAS: 77745-32-5) and A2 as starting materials. ESI / MS m / z 461.3 [M+H] + .

[0283] Example 98: 1-(2-(1H-indol-3-yl)ethyl)-2-(((1R,5S)-8-oxabicyclo[3.2.1]octan-3-yl)methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (A96)

[0284] Following the synthetic route of A93, A96 was obtained using nortropinone (CAS: 5632-84-8) and A2 as starting materials. ESI / MS m / z 460.4 [M+H] + .

[0285] Example 99: 1-(2-(1-Benzyl-1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A97)

[0286] Compound A26 was used as a synthetic intermediate, and following the synthetic route of A69, methyl iodide was replaced by benzyl bromide, and a substitution reaction occurred at the indole 1 position to obtain A97. ESI / MS m / z 525.3[M+H] + .

[0287] Example 100: 1-(2-(1-(4-fluorobenzyl)-1H-indol-3-yl)ethyl)-6,7-dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A98)

[0288] Compound A26 was used as a synthetic intermediate, and following the synthetic route of A69, 4-fluorobenzyl bromide was used to replace iodomethane, and a substitution reaction occurred at the indole 1 position to obtain A98. ESI / MS m / z 543.3[M+H] + .

[0289] Example 101: 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-6-((4-fluorobenzyl)oxy)-7-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroisoquinoline (A99)

[0290] Using compound A4 as a synthetic intermediate, A4 (430 mg, 1.0 mmol) was dissolved in 50 mL of tetrahydrofuran, and trifluoroacetic anhydride (420 mg, 2.0 mmol) was slowly added dropwise at room temperature. After complete addition, the mixture was transferred to 60°C and stirred for 2 h. After TLC monitoring of the complete reaction of the raw materials, a saturated sodium bicarbonate solution was slowly added dropwise to the above solution until no bubbles were generated. After completion of the dropwise addition, the mixture was transferred to a separatory funnel, extracted twice with ethyl acetate and water, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated without column chromatography to obtain compound 5-1 (500 mg, yield 95%).

[0291] 5-1 (500 mg, 0.95 mmol) was dissolved in 50 mL of methanol, and 50 mg of palladium carbon (containing 10% water) and ammonium formate (599 mg, 9.5 mmol) were added. The reaction was heated at 60 degrees under argon protection for 4 hours. After the reaction was completed as monitored by TLC, the palladium carbon was filtered off, and then water and ethyl acetate were added to extract twice, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated without column chromatography to obtain compound 5-2 (348 mg, yield 84%).

[0292] 5-2 (348 mg, 0.8 mmol) was dissolved in 40 mL of DMF, and 4-fluorobenzyl bromide (181 mg, 0.96 mmol) and potassium carbonate (552 mg, 4.0 mmol) were added. The reaction was heated at 60°C for 2 hours. After the reaction was completed as monitored by TLC, water and ethyl acetate were added, extracted twice, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate / petroleum ether (1 / 2, v / v) to give the yellow compound 5-3 (381 mg, yield 88%).

[0293] 5-3 (381 mg, 0.7 mmol) was dissolved in 40 mL of ultra-dry dichloromethane, and 1.0 M BBr3 solution (4.2 mL, 4.2 mmol) was slowly added dropwise at -20 ° C. Then, the reaction was stirred at this temperature for 2 hours. After the reaction was completed as monitored by TLC, water was slowly added to quench the reaction, and water and dichloromethane were added to extract twice, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and classified by ethyl acetate / petroleum ether (1 / 3, v / v) column chromatography to obtain yellow compound 5-4 (267 mg, yield 72%).

[0294] 5-4 (267 mg, 0.5 mmol) was dissolved in 30 mL of DMF, and 2-iodo-1,1,1-trifluoroethane (158 mg, 0.75 mmol) and potassium carbonate (345 mg, 2.5 mmol) were added. The reaction was heated at 60°C for 2 hours. After the reaction was completed as monitored by TLC, water and ethyl acetate were added, extracted twice, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate / petroleum ether (1 / 2, v / v) to give a yellow compound 5-5 (257 mg, yield 84%).

[0295] 5-5 (257 mg, 0.42 mmol) was dissolved in 15 mL of MeOH and 15 mL of H2O, and potassium carbonate (290 mg, 2.1 mmol) was added. The mixture was heated at 80°C for 2 hours. After completion of the reaction as monitored by TLC, the mixture was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with methanol / dichloromethane (1 / 30, v / v) to give yellow compound A99 (206 mg, 95% yield). 1 H NMR (600MHz, CDCl3) δ8.75 (s, 1H), 7.44 (dd, J = 8.3, 5.4Hz, 2H), 7.28 (dd, J = 9 .6,2.5Hz,1H),7.22(dd,J=8.8,4.3Hz,1H),7.10(t,J=8.6Hz,2H),7.04(s,1H ),6.96(s,1H),6.73(d,J=6.2Hz,2H),5.05(s,2H),4.02(dd,J=8.9,3.5Hz,1H ),3.09–2.78(m,6H),2.72(dt,J=16.2,5.7Hz,1H),2.27–2.09(m,2H).ESI / MS m / z 517.2[M+H] + .

[0296] Example 102: 1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-6-((4-fluorobenzyl)oxy)-2-methyl-7-(2,2,2-trifluoroethoxy)-1,2,3,4-tetrahydroisoquinoline (A100)

[0297] Compound A99 was used as a synthetic intermediate. A99 (103 mg, 0.2 mmol) was dissolved in 15 mL of 1,2-dichloroethane, and paraformaldehyde (12 mg, 0.4 mmol), sodium cyanoborohydride (24 mg, 0.4 mmol), anhydrous magnesium sulfate (24 mg, 0.2 mmol) and trifluoroacetic acid (9 mg, 0.1 mmol) were added sequentially. The mixture was heated at 60°C for 2 hours. After completion of the reaction as monitored by TLC, the mixture was extracted twice with water and dichloromethane, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using methanol / dichloromethane (1 / 30, v / v) to give yellow compound A100 (69 mg, 65% yield). 1 H NMR (600MHz, CDCl3) δ9.01(s,1H),7.52(dd,J=8.2,5.4Hz,2H),7.39(dd,J=9.6,2.5Hz,1H),7.31(dd,J=8.9,4.3Hz,1H),7.26(t,J=8.7Hz,2H),7.17(s ,1H),6.99(s,1H),6.80(d,J=6.1Hz,2H),5.17(s,2H),4.43–4.08(m,1H),3 .31(s,3H),3.09–2.78(m,6H),2.81–2.60(m,1H),2.27–2.09(m,2H).ESI / MS m / z 531.2[M+H]+.

[0298] Example 103: 1-(2-(1H-indol-3-yl)ethyl)-6-((4-fluorobenzyl)oxy)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A101)

[0299] Compound A39 was used as a synthetic intermediate. A39 (42 mg, 0.1 mmol) was dissolved in 5 mL of DMF, and 4-fluorobenzyl bromide (23 mg, 0.12 mmol) and potassium carbonate (69 mg, 0.5 mmol) were added. The reaction was heated at 60°C for 2 hours. After completion of the reaction as monitored by TLC, the product was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate / petroleum ether (1 / 2, v / v) to afford the pale yellow compound A101 (46 mg, 87% yield). ESI / MS m / z 529.3 [M+H]+.

[0300] Example 104: 1-(2-(5-Fluoro-1H-indol-3-yl)ethyl)-6-((4-fluorobenzyl)oxy)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (A102)

[0301] Compound A82 was used as a synthetic intermediate. A82 (106 mg, 0.2 mmol) was dissolved in 10 mL of methanol. 11 mg of palladium carbon (containing 10% water) and ammonium formate (126 mg, 2 mmol) were added. The reaction was heated at 60°C under argon for 4 hours. After completion of the reaction as monitored by TLC, the palladium carbon was filtered off. The mixture was then extracted twice with water and ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 6-1, which was directly subjected to the next step without column chromatography. Intermediate 6-1 was dissolved in 5 mL of DMF, and 4-fluorobenzyl bromide (212 mg, 0.24 mmol) and potassium carbonate (138 mg, 1.0 mmol) were added. The reaction was heated at 60°C for 2 hours. After completion of the reaction as monitored by TLC, the product was extracted twice with water and ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate / petroleum ether (1 / 2, v / v) to give a pale yellow compound A102 (67 mg, 61% yield). ESI / MS m / z 547.2 [M+H]+.

[0302] Pharmacological activity and pharmacokinetics test examples

[0303] Example 1: Test experiment for promoting TFEB nuclear entry activity

[0304] The experimental steps are as follows: 1. Cultivation of Hela cells. This experiment requires the cultivation of a HeLa cell line that can stably express TFEB-EGFP fluorescent protein, and then screening the activity of the compound. 2. Screening of small molecule compounds that induce TFEB-EGFP nuclear entry and lysosome formation. When the cell density of the TFEB-EGFP stably transfected cell line in a 96-well plate is about 85%, treat with 30μM and 50μM compound concentrations or Torin 1 (1μM). After 3 hours, 6 hours and 9 hours of treatment, the nuclear entry of TFEB was observed by fluorescence microscopy (Nikon) and the nuclear entry rate was counted. During this process, the experimenter performed screening in a double-blind manner.

[0305] The experimental results are shown in Table 1.

[0306] Table 1 Activity data of some compounds a,b

[0307] aTorin 1 (1 μM) was used as the positive control group, and DMSO was used as the blank control group. b “ / ” indicates that the compound has already promoted TFEB nuclear entry at a high rate under the previous condition, so there is no need to evaluate the current condition.

[0308] Experimental conclusion: From the above experimental results, it can be seen that multiple compounds have a significant inducing effect on TFEB nuclear entry in cells. Compounds A16, A24, A26, A55, A59, A62, A64, A66, A82, A83, A88 and A89 promoted the TFEB nuclear entry rate to 80% to 90% at a concentration of 30 μM and a time point of 3 h. Compounds A3, A4, A5, A15, A29, A56, A57, A58, A60, A61, A63, A84, A85, A86, A90, A98, A99, A100 and A101 promoted the TFEB nuclear entry rate to 90% to 100% at a concentration of 30 μM and a time point of 3 h. These compounds have the potential to induce lysosomal biogenesis and activate the autophagy-lysosomal pathway to degrade pathological protein deposits in the brain, providing a good option for developing into therapeutic drugs for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0309] Example 2: Tissue distribution data of compound A26 in mice

[0310] The drug concentrations in plasma or cerebrospinal fluid were measured at 15 minutes and 30 minutes after oral administration (20 mg / kg), intraperitoneal injection (10 mg / kg), and intravenous injection (5 mg / kg). The experimental results are shown in Table 2.

[0311] Table 2 Tissue distribution data of compound A26 in mice a

[0312] a An average of 3 mice were included per dose.

[0313] Experimental conclusion: At the 15-minute time point, the preferred compound A26 achieved brain-to-plasma drug concentration ratios of 3.4 times, 2.12 times, and 3.3 times through oral, intraperitoneal, and intravenous administration, respectively. This indicates that compound A26 has good blood-brain barrier penetration and brain targeting, which suggests that the compound has the advantage of being developed into a drug for the treatment of brain diseases.

[0314] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of the structure represented by general formula (I), and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, in, X is selected from the group consisting of O, S, and NR 6 ; m, n and p are each independently selected from the group consisting of 0, 1, 2, 3 or 4; The configuration of C* can independently be S-type, R-type, or racemic; R 1 and R 2 Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, hydroxyl, sulfhydryl, carboxyl, -S(O)2OH, substituted or unsubstituted C1-C 10 Straight chain or branched alkyl, substituted or unsubstituted C1~C 10 Alkoxy, C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C2-C6 acyl group, substituted or unsubstituted C2-C6 ester group, substituted or unsubstituted C0-C6 amino group, substituted or unsubstituted C1-C6 amide group, substituted or unsubstituted C1-C6 alkyl-sulfonyl group or substituted or unsubstituted C1-C6 alkyl-sulfinyl group; Or, R 1 and R 2 Together with the atoms to which it is connected, it forms a substituted or unsubstituted 5- to 12-membered heterocyclic ring or aromatic heterocyclic ring; R 3 Selected from the group consisting of hydrogen, substituted or unsubstituted (-C1-C6 alkyl-C6-C 10 aryl), substituted or unsubstituted (-C1~C6 alkyl-5~12 membered heteroaryl), substituted or unsubstituted (-C1~C6 alkyl-C3~C8 carbocyclic group), substituted or unsubstituted (-C1~C6 alkyl-3~12 membered heterocyclic group), substituted or unsubstituted (-C1~C6 alkyl-7~20 membered heteropolycyclic group), substituted or unsubstituted C3~C8 saturated or partially unsaturated carbocyclic group, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted 7-20 membered heteropolycyclic group; wherein the heteropolycyclic group includes fused ring, bridged ring and spiro ring structure; The ring is selected from the following groups: substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5- to 12-membered heteroaryl; R 4 and R 5 Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, C1-C6 amine, hydroxyl alkyl, hydroxymethyl, carboxyl, C1-C6 amide, mercapto, -S(O)2OH, C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 3-12 membered saturated or partially unsaturated heterocyclic group; R 6 Selected from the following groups: hydrogen, C1-C6 alkylsulfonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with aryl or heteroaromatic ring, C1-C6 alkyl substituted with cycloalkane or heterocyclic hydrocarbon, C3-C8 saturated or partially unsaturated carbocyclic group, C3-C8 halogenated saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered heterocyclic group, -(CH2) q YR 7 ; wherein q is selected from the following group: 0, 1, 2, 3 or 4; Y is selected from the following group: O, S, NR 8 , CO or SO2; R 7 、R 8 Each independently selected from the following groups: hydrogen, hydroxyl, amino, C1-C6 amino, substituted or unsubstituted C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 alkyl-C6- 10 Aryl, -C1~C6 alkyl-5~12 membered heteroaryl, -C1~C6 alkyl-C3~8 carbocyclic group, -C1~C6 alkyl-3~12 membered heterocyclic group, C3~C8 saturated or partially unsaturated carbocyclic group, C3~C8 halogenated saturated or partially unsaturated carbocyclic group, C6~C 10 Aryl, 5- to 12-membered heteroaryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group; wherein the heteroaryl or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; The substitution in the substituted or unsubstituted group means that the group is substituted by 1 to 3 substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkylsulfonyl, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group, and 5- to 12-membered heteroaryl; The halogen is F, Cl, Br or I. In another preferred embodiment, the R 4 and R 5 Each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, nitro, amino, NH2, C1-C6 amine, hydroxyl, hydroxymethyl, carboxyl, C2-C6 amide, thiol, -S(O)2OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, aryl or heteroaromatic ring-substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon-substituted C1-C6 alkyl, C1-C6 alkoxy, aryl or heteroaromatic ring-substituted C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C 10 Aryl, 3- to 12-membered saturated or partially unsaturated heterocyclic group.

2. The compound according to claim 1, and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 and R 2 Independently selected from the following groups: substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3-C 10 Membered carbocyclic group, substituted or unsubstituted C5~C 10 Aryl. In another preferred embodiment, the R 1 and R 2 Independently selected from the following groups: substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted saturated or partially unsaturated C3-C6 membered carbocyclic group, substituted or unsubstituted phenyl.

3. The compound according to claim 1, and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 and R 2 The atoms connected thereto together form a substituted or unsubstituted 5- to 12-membered heterocyclic ring. In another preferred embodiment, the R 1 and R 2 The atoms connected thereto together form a substituted or unsubstituted 5- to 7-membered heterocyclic ring.

4. The compound according to claim 1, and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, characterized in that: R 3 Selected from the following group: hydrogen, substituted or unsubstituted C6~C 10 Aryl, substituted or unsubstituted 3-12 membered heterocyclic group, or substituted or unsubstituted 7-20 membered heteropolycyclic group; wherein the heteropolycyclic ring includes condensed ring, bridged ring and spiro ring structure.

5. The compound according to claim 1, and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, characterized in that: The ring is selected from the group consisting of a benzene ring, a thiophene ring, a pyrrole ring, a furan ring, a pyridine ring, a pyrimidine ring, an indole ring, or a cyclohexyl ring.

6. The compound according to claim 1, and its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following group:

7. A method for preparing a compound represented by general formula (I), comprising the steps of: (1) In a mixed solvent of nitromethane and an organic acid, formula II a The compound reacts with nitromethane to produce α,β-Unsaturated nitro compounds II b , Formula II b The compound is then subjected to a reduction reaction to obtain Formula II c Compounds; (2) In an alkaline solvent, in the presence of malonic acid and a base catalyst, the compound of formula Ia is reacted with malonic acid to produce a compound of formula I b Compound, Formula I b The compound is then reduced with a reducing agent to obtain formula I c Compounds; (3) In an inert solvent, in the presence of a condensing agent, reacting a compound of formula IIc with a compound of formula Ic to obtain a compound of formula I d Compounds; (4) In an inert solvent, d The compound undergoes Bischler–Napieralski ring closure reaction to obtain formula I e Compounds; (5) In an inert solvent, e The compound is subjected to a reduction reaction to obtain a compound of formula If; (6) In an inert solvent, use formula I f Compounds and Halogenated Hydrocarbons I g Carry out a substitution reaction to obtain a compound of formula (I); in, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , X, m, n, p are defined as described in claim 1.

8. The preparation method according to claim 7, wherein The organic acid in step (1) is acetic acid or formic acid, and the reducing agent is LiAlH4, sodium borohydride or zinc powder. In another preferred embodiment, the alkaline solvent in step (2) is pyridine, the alkaline catalyst is piperidine, and the reducing agent is a combination of a palladium-carbon hydrogenation catalyst and hydrogen, or a combination of a palladium-carbon hydrogenation catalyst and ammonium formate. In another preferred embodiment, the condensing agent in step (3) is a combination of HATU or EDCI and HOBt. In another preferred embodiment, the ring-closure reaction in step (4) uses POCl3 phosphorus oxychloride as the Lewis acid. In another preferred embodiment, the reduction reaction in step (5) uses borohydride as a reducing agent, or uses Noyori's catalyst as an asymmetric reduction catalyst. In another preferred embodiment, the substitution reaction in step (6) uses potassium carbonate, cesium carbonate or sodium carbonate as a base to catalyze the reaction.

9. A pharmaceutical composition, characterized in that The invention comprises (1) the compound according to any one of claims 1 to 6, its racemate, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof; and (2) a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 6, its racemate, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, characterized in that: Used to prevent and / or treat diseases related to lysosomal dysfunction and insufficient biosynthesis. In another preferred embodiment, the disease is a neurodegenerative disease caused by accumulation of pathological proteins. In another preferred embodiment, the disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.

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