Multi-substituted tetrahydroisoquinoline compounds and preparation methods, pharmaceutical compositions and uses

Abstract

The present invention discloses compounds containing general formula I, and methods for their preparation, pharmaceutical compositions and uses. Specifically, the present invention provides compounds having the structure shown in general formula I, and their racemic compounds, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof. The said compounds have good effects on the nuclear translocation of transcription factor EB (TFEB) and the generation of lysosomes, and are used for the prevention, treatment or adjuvant treatment of various diseases related to lysosomal dysfunction and biosynthetic deficiency, especially neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), caused by the accumulation of pathological proteins (such as β-amyloid protein, α-synuclein) in the brain.

Description

Technical Field

[0001] The present invention discloses a multi-substituted tetrahydroisoquinoline compound, a preparation method thereof, a pharmaceutical composition and uses thereof. It relates to the prevention and / or treatment of neurodegenerative diseases caused by the accumulation of pathogenic proteins in various diseases related to lysosomal dysfunction and biosynthetic defects, particularly diseases or conditions such as Alzheimer's disease and Parkinson's disease, and relates to a novel tetrahydroisoquinoline compound represented by the general formula (I), a pharmaceutically acceptable salt, isomer, solvate, metabolite, metabolic precursor, a combination of drugs containing them, and the use of such compounds.

Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by cognitive impairment and memory loss, and has become one of the major diseases affecting human health. According to the "World Alzheimer Report" released by the Alzheimer's Disease International (ADI), with the extension of the average human lifespan, one person is diagnosed with AD every about 3 seconds in the world. By 2050, the number of AD patients in the world is estimated to double every 20 years and reach 152 million, which has become a medical and social problem that needs to be urgently addressed globally. China has already entered an aging society. Dementia patients account for 25% of the world's patients. The incidence rate of AD in the general population is about 5.6%. Among the residents in urban and rural areas of China, AD is the fifth most common cause of death. The most typical pathological features of AD are senile plaques (SPs) and neurofibrillary changes (NFTs), which are respectively generated by the abnormal accumulation of β-amyloid protein (Aβ) and hyperphosphorylated Tau protein. Furthermore, the impairment of the autophagy-lysosome pathway (ALP) is also shown to be a major feature of AD. Currently, most of the drugs used in the clinical diagnosis and treatment of AD are acetylcholinesterase (AChE) inhibitors (such as donepezil) and N-methyl-D-aspartic acid receptor (NMDA) antagonists (such as memantine). These drugs can stabilize or relieve the decline of cognitive function and behavioral ability in AD patients, but cannot relieve the pathological progression. Currently, the development of new anti-AD drugs has fallen into a bottleneck period, and most drugs have ended in failure. Recently, the US FDA approved the sale of the anti-AD antibody drug aducanumab, but no significant improvement was seen in its clinical data. Many antibody drugs or drugs targeting APPγ secretase have poor effects in clinical trials, so the discovery of new target points and new drugs for improving AD has become an urgent task.

[0003] Parkinson's disease (PD), also known as Parkinsonism, is the second most common neurodegenerative disease. Its main clinical features are resting tremor, muscle rigidity, bradykinesia, and abnormal posture and gait. Its pathological features are the degeneration and loss of dopaminergic neurons in the substantia nigra of the midbrain, and the accumulation of inclusion bodies (Lewy bodies) containing α-synuclein (α-syn) in the midbrain. PD is more common in the elderly. According to statistics, the prevalence of PD is about 0.3% in the general population, 1% in people over 60 years old, and 3% in people over 80 years old. On a global scale, 1 to 2 out of every 1000 people are diagnosed with PD. It is predicted that by 2030, PD patients in China will account for half of the world's total, and PD will become a "killer" threatening the health of the elderly in China. The research on new drugs for PD has always been extremely difficult because the mechanism of apoptosis of dopamine-producing neurons has not been fully understood. All PD drugs under research and all currently marketed therapeutic drugs can only suppress symptoms and improve motor function, but cannot stop the progression of the disease itself.

[0004] A lysosome is a single-membrane, lipid globular organelle (0.2 - 0.8 μm in diameter) rich in hydrolysis (pH 4.5 - 5.0) and membrane proteins in cells. Lysosomes are involved in the process of intracellular decomposition and removal, digest substances entering the cell, recycle intracellular substances, not only regulate energy metabolism, but also decompose and remove intracellular biologically macromolecules that are not useful, such as low-density lipoprotein, Aβ protein, tau protein, and can also kill and decompose pathogens. Lysosomal dysfunction and biosynthetic defects are closely related to the occurrence of neurodegenerative diseases. Studies have shown that promoting lysosome biosynthesis and activating the autophagy-lysosome pathway (ALP) can remove toxic protein deposits in the mouse brain and improve symptoms such as AD and PD.

[0005] Currently, lysosome biogenesis is mainly controlled by transcription factor EB (TFEB). Under normal conditions with sufficient nutrients, TFEB is localized in the cytoplasm. Under nutrient-deprived or stress conditions, dephosphorylated TFEB is activated and enters the cell nucleus. As a transcription factor, it initiates the expression of lysosome- and autophagy-related genes, thereby promoting lysosome production and enhancing the degradation function of lysosomes. So far, researchers have developed many drug screening methods to identify small molecule TFEB activators. Here, TFEB-GFP nuclear translocation detection is one of the representative methods, and its principle is to construct a TFEB protein containing a GFP (green fluorescent protein) label. When TFEB is activated, TFEB translocates to the cell nucleus. Therefore, to determine whether the TFEB protein is activated, the localization change of the TFEB protein in the cell can be observed with a fluorescence microscope. Current studies have shown that mTOR inhibitors, diterpenoid compound HEP14 and its derivatives, etc. can induce TFEB to enter the nucleus and promote lysosome biogenesis. However, these compounds have limitations such as a single structural type, difficult synthesis, and limitations of natural resources. Therefore, it is still urgently necessary to discover more types of small molecule compounds that can activate TFEB and promote its entry into the nucleus to promote lysosome biogenesis, and to develop new anti-AD or anti-PD drugs targeting the new mechanism of promoting TFEB nuclear entry and lysosome biogenesis.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] An object of the present invention is to provide a class of compounds that can promote the nuclear entry of TFEB and induce lysosome biogenesis.

MEANS FOR SOLVING THE PROBLEMS

[0007] A first aspect of the present invention provides a compound having a structure represented by general formula (I), and its racemic compound, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof. [Chemical formula] Here, X is selected from the group consisting of O, S, or NR 6 and is selected from the group consisting of 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 are each independently hydrogen, deuterium, tritium, halogen, cyano group, nitro group, hydroxy group, sulfhydryl group, carboxy group, -S(O)2OH, substituted or unsubstituted C1-C 10 linear or branched alkyl group, substituted or unsubstituted C1-C 10 alkoxy group, C2-C6 linear or branched alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted saturated or partially unsaturated C3-C 10 membered carbocyclic group, substituted or unsubstituted C6-C 10 aryl group, substituted or unsubstituted saturated or partially unsaturated 5-12 membered heterocyclic group, substituted or unsubstituted 5-12 membered heteroaryl group, 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 alternatively, R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted 5-12 membered heterocyclic or aromatic heterocyclic ring, R 3 is hydrogen, substituted or unsubstituted (-C1-C6 alkyl-C6-C 10an aryl group), a substituted or unsubstituted (-C1-C6 alkyl-5-12-membered heteroaryl group), a substituted or unsubstituted (-C1-C6 alkyl-C3-C8 carbocyclic group), a substituted or unsubstituted (-C1-C6 alkyl-3-12-membered heterocyclic group), a substituted or unsubstituted (-C1-C6 alkyl-7-20-membered heteropolycyclic group), a substituted or unsubstituted C3-C8 saturated or partially unsaturated carbocyclic group, a substituted or unsubstituted C6-C 10 selected from the group consisting of an aryl group, a substituted or unsubstituted 3-12-membered heterocyclic group, and a substituted or unsubstituted 7-20-membered heteropolycyclic group, wherein the heteropolycyclic group includes a fused ring, a bridged ring, and a spiro ring structure, [Chemical formula] the ring is selected from the group consisting of a substituted or unsubstituted 3-12-membered heterocyclic group, a substituted or unsubstituted C6-C 10 selected from the group consisting of an aryl group, a substituted or unsubstituted 5-12-membered heteroaryl group, R 4 and R 5 are each independently hydrogen, deuterium, tritium, halogen, cyano group, nitro group, amino group, C1-C6 amine group, hydroxy group, hydroxymethyl group, carboxy group, C1-C6 amide, sulfhydryl group, -S(O)2OH, C1-C6 alkylsulfonyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C6-C 10 selected from the group consisting of an aryl group, a substituted or unsubstituted 3-12-membered saturated or partially unsaturated heterocyclic group, R 6 is hydrogen, a C1-C6 alkylsulfonyl group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, an aryl group or a heteroaryl-substituted C1-C6 alkyl group, a cycloalkane or a heterocyclic hydrocarbon-substituted C1-C6 alkyl group, a C3-C8 saturated or partially unsaturated carbocyclic group, a C3-C8 halogenated saturated or partially unsaturated carbocyclic group, a C6-C 10 selected from the group consisting of an aryl group, a 3-12-membered heterocyclic group, -(CH2)qYR 7 and Here, q is selected from the group consisting of 0, 1, 2, 3, or 4, Y is selected from the group consisting of O, S, NR 8 , CO, or SO2, R 7 , R 8 are each independently hydrogen, a hydroxy group, an amino group, a C1-C6 amine group, a substituted or unsubstituted C1-C6 alkoxy group, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, -C1-C6 alkyl-C6-10 aryl group, -C1-C6 alkyl-5-12 membered heteroaryl group, -C1-C6 alkyl-C3-8 carbocyclic group, -C1-C6 alkyl-3-12 membered heterocyclic group, a C3-C8 saturated or partially unsaturated carbocyclic group, a C3-C8 halogenated saturated or partially unsaturated carbocyclic group, a C6-C 10 aryl group, a 5-12 membered heteroaryl group, a 3-12 membered saturated or partially unsaturated heterocyclic group selected from the group consisting of, wherein the heteroaryl group or heterocyclic group each independently contains 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, The substitution in the substituted or unsubstituted means that the group is substituted by 1-3 substituents selected from the group consisting of halogen, cyano group, nitro group, amino group, hydroxy group, hydroxymethyl group, carboxy group, sulfhydryl group, C1-C6 alkyl group, C1-C6 halogenated alkyl group, C1-C6 alkoxy group, C1-C6 alkoxycarbonyl group, C1-C6 halogenated alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkylsulfonyl group, C3-C8 saturated or partially unsaturated carbocyclic group, C6-C 10 aryl group, a 3-12 membered saturated or partially unsaturated heterocyclic group, and a 5-12 membered heteroaryl group, wherein the halogen is F, Cl, Br, or I. In another preferred example, the R 4 and R 5are each independently hydrogen, deuterium, tritium, a halogen, a cyano group, a nitro group, an amino group, NH2, a C1-C6 amine group, a hydroxy group, a hydroxymethyl group, a carboxy group, a C2-C6 amide, a sulfhydryl group, -S(O)2OH, a C1-C6 alkylsulfonyl group, a C1-C6 alkyl group, a halogen-substituted C1-C6 alkyl group, an aryl group or a heteroaryl-substituted C1-C6 alkyl group, a cycloalkane or a heterocyclic hydrocarbon-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, an aryl group or a heteroaryl-substituted C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C3-C8 cycloalkyl group, a C3-C8 halogenated cycloalkyl group, a C6-C 10 are selected from the group consisting of an aryl group and a 3- to 12-membered saturated or partially unsaturated heterocyclic group.

[0008] In some embodiments, R 1 and R 2 are independently selected from the group consisting of a substituted or unsubstituted C1-C 10 linear or branched alkyl group, a substituted or unsubstituted saturated or partially unsaturated C3-C 10 member carbocyclic group, and a substituted or unsubstituted C5-C 10 aryl group. In another preferred example, said R 1 and R 2 are independently selected from the group consisting of a substituted or unsubstituted C1-C6 linear or branched alkyl group, a substituted or unsubstituted saturated or partially unsaturated C3-C6 member carbocyclic group, and a substituted or unsubstituted phenyl group.

[0009] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted 5- to 12-membered heterocyclic ring.

[0010] In another preferred example, said R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocyclic ring.

[0011] In some embodiments, R 3 is selected from the group consisting of hydrogen, a substituted or unsubstituted C6-C 10 aryl group, a substituted or unsubstituted 3- to 12-membered heterocyclic group, or a substituted or unsubstituted 7- to 20-membered hetero polycyclic group, wherein the hetero polycyclic group includes fused ring, bridged ring, and spiro ring structures.

[0012] In some embodiments,

Chemical Structure

[0013] In some embodiments, the compound is selected from the group consisting of the following.

Chemical Structure

[0014]

Chemical Structure

[0015]

Chemical Structure

[0016]

Chemical Structure

[0017]

Chemical Structure

[0018]

Chemical Structure

[0019] [Chemical]

[0020] The second aspect of the present invention provides a method for preparing a compound represented by the general formula (I), (1) In a mixed solvent of nitromethane and an organic acid, the compound of formula II a is subjected to a Henry reaction with nitromethane to obtain an α,β-unsaturated nitro group compound II b , and the compound of formula II b is subjected to a reduction reaction to obtain a compound of formula II c , and [Chemical] (2) In a basic solvent, in the presence of malonic acid and a base catalyst, the compound of formula I a is subjected to a Knoevenagel reaction with malonic acid to obtain a compound of formula I b , and the compound of formula I b is reduced with a reducing agent to obtain a compound of formula I c , and [Chemical] (3) In an inert solvent, in the presence of a condensing agent, the compound of formula II c is reacted with the compound of formula I c to obtain a compound of formula I d , and [Chemical] (4) In an inert solvent, the compound of formula I d is used for a Bischler-Napieralski cyclization reaction to obtain a compound of formula I e , and [Chemical] (5) In an inert solvent, the compound of formula I e is used for a reduction reaction to obtain a compound of formula I f , and [Chemical] (6) In an inert solvent, a compound of formula I f is subjected to a substitution reaction with a halogenated hydrocarbon I g to obtain a compound of formula (I), and

Chemical formula

[0021] In some embodiments, the organic acid described in step (1) is acetic acid or formic acid, and the reducing agent is LiAlH4, sodium borohydride or zinc powder.

[0022] In another preferred example, the basic solvent described in step (2) is pyridine, the base catalyst is piperidine, and the reducing agent is a combination of a palladium-carbon hydrogenation catalyst and hydrogen gas, or a combination of a palladium-carbon hydrogenation catalyst and ammonium formate.

[0023] In another preferred example, the condensing agent described in step (3) is HATU or a combination of EDCI and HOBt.

[0024] In another preferred example, for the ring-closing reaction described in step (4), POCl3 (phosphorus oxychloride) is used as a Lewis acid.

[0025] In another preferred example, for the reduction reaction described in step (5), a borohydride is used as a reducing agent, or Noyori's catalyst is used as an asymmetric reduction catalyst.

[0026] In another preferred example, for the substitution reaction described in step (6), potassium carbonate, cesium carbonate or sodium carbonate is used as the base for the catalytic reaction.

[0027] The third aspect of the present invention provides a pharmaceutical composition comprising: (1) the compound according to the first aspect of the present invention, its racemic compound, R-isomer, S-isomer, or its pharmaceutically acceptable salt; and (2) a pharmaceutically acceptable carrier.

[0028] The fourth aspect of the present invention provides the use of the compound according to the first aspect of the present invention, its racemic compound, R-isomer, S-isomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to the third aspect of the present invention, which is characterized by being used for the prevention and / or treatment of diseases related to lysosomal dysfunction and biosynthetic deficiency.

[0029] In another preferred example, the disease is a neurodegenerative disease caused by the accumulation of pathological proteins.

[0030] In another preferred example, the disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease.

Advantages of the Invention

[0031] It should be understood that within the scope of the present invention, by combining each of the above technical features of the present invention with the technical features specifically described below (for example, in the examples), new or preferred technical solutions can be constituted. Due to space limitations, it will not be repeated here.

Modes for Carrying Out the Invention

[0032] As a result of extensive and thorough research, the present inventors discovered a series of compounds represented by the general formula (I), and conducted a series of biological activity tests on them, and found that they have excellent activity in favorably inducing lysosomal biosynthesis, activating the autophagy-lysosome pathway, and decomposing pathological protein deposits in the brain. Based on this, the present invention was completed.

[0033] Definition Unless otherwise defined, 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. As used herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on the group are substituted by a substituent selected from the group consisting of a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C1-C8 alkoxy group, a halogen, a hydroxy group, a carboxy group, a cyano group, and a C1-C 10 aldehyde group, a C2-C6 acyl group, a C2-C 10 ester group, an amino group, and a phenyl group, wherein the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents, and the substituents are selected from a halogen, a C1-C 10 alkyl group, a cyano group, a hydroxy group, a nitro group, a C3-C8 cycloalkyl group, a C1-C8 alkoxy group, and an amino group.

[0034] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration, the S configuration, or a mixture of the R and S configurations.

[0035] As used herein, the term "alkyl group" includes straight-chain or branched-chain alkyl groups. For example, a C1-C6 alkyl group represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, etc.

[0036] As used herein, the term "alkoxy group" refers to a group having an alkyl-oxy group structure. For example, a "C1-C6 alkoxy group" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy group, etc.

[0037] As used herein, the term "heterocyclic group" or "heterocycloalkyl group" refers to a saturated or partially saturated cyclic group having a specific number of ring atoms (e.g., 3 to 10 ring atoms), and 1 to 3 of which are heteroatoms selected from N, S, and O. It can be monocyclic or can also be bicyclic or polycyclic in the form of, for example, a bridged ring or a spiro ring. Specific examples can include an oxetanyl group, an azetidinyl group, a tetrahydro-2H-pyranyl group, a piperidine group, a tetrahydrofuranyl group, a morpholinyl group, a pyrrolidinyl group, and the like.

[0038] As used herein, the term "aryl group" refers to a cyclic aromatic group having a specific number of carbon atoms. For example, "C6-C 10 aryl group" refers to an aryl group having 6 to 10 carbon atoms such as, for example, a phenyl group, a naphthyl group, or a similar group.

[0039] As used herein, the term "aryl group" refers to a cyclic aromatic group having a specific number of ring atoms, and 1 to 3 of which are heteroatoms selected from N, S, and O. It can be monocyclic or can also be in a fused ring form. For example, "5- to 12-membered aryl group" refers to an aryl group having 5 to 12 carbon atoms such as, for example, a pyrrolyl group, a pyridyl group, a thienyl group, a furanyl group, an imidazolyl group, a pyrimidinyl group, a benzothienyl group, an indolyl group, an imidazopyridinyl group, a quinolinyl group, or a similar group.

[0040] As used herein, the term "acyl group" refers to a -C(=O)R group having a specific number of carbon atoms. For example, C 2-6 acyl group refers to a -C(=O)R group having 2 to 6 carbon atoms such as, for example, -C(=O)CH3, -C(=O)C2H5, -C(=O)C3H7, -C(=O)C4H9, or a similar group.

[0041] As used herein, the term "ester group" refers to R-O-C(=O)-yl having a specific number of carbon atoms. For example, C 2-6The acyl group refers to R - O - C(=O)-yl having 2 to 6 carbon atoms such as, for example, -C(=O)OCH3, -C(=O)OC2H5, -C(=O)OC3H7, -C(=O)OC4H9, or similar groups.

[0042] As used herein, the term "alkenyl group" refers to an alkenyl group having a specific number of carbon atoms, including linear or branched alkenyl groups. For example, a C2-C6 alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms such as, for example, a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, or similar groups.

[0043] As used herein, the term "alkynyl group" refers to an alkynyl group having a specific number of carbon atoms, including linear or branched alkynyl groups. For example, a C2-C6 alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms such as, for example, an ethynyl group, a propynyl group, a butynyl group, or similar groups.

[0044] As used herein, the term "amine group" refers to -NR having 0 to 6 carbon atoms such as, for example, -NH2, -NHCH3, -NHC(=O)CH3, -NHCH2CH3, -N(CH3)2, or similar groups. 1 R 2 In this specification, the amine group shall include the amino group, i.e., -NH2.

[0045] As used herein, the term "amide group" refers to -C(=O)NR having a specific number of carbon atoms such as, for example, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, or similar groups. 1 R 2 group.

[0046] As used herein, the term "sulfonamide group" refers to -S(=O)2NR having a specific number of carbon atoms. 1 R 2Refers to a group. For example, a C1-C6 sulfonamide group 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 a similar group.

[0047] As used herein, the term "sulfonyl group" refers to a -S(=O)2- group.

[0048] As used herein, the term "sulfinyl group" refers to a -S(=O)- group.

[0049] As used herein, the term "halogen" refers to F, Cl, Br, and I.

[0050] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms, such as the R and S configurations including chiral centers, the (Z) and (E) isomers of double bonds, and the (Z) and (E) conformational isomers, etc. (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)). Accordingly, a single stereochemical isomer of a compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) is within the scope of the present invention.

[0051] The term "tautomer" represents that structural isomers of different energies can interconvert across a low energy barrier. For example, proton tautomers (i.e., proton transfer) include interconversions by proton transfer such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, and valence tautomers include interconversions by recombination of some bonding electrons. In this specification, the form "C1-C6" indicates that the group can have 1 to 6 carbon atoms, such as 1, 2, 3, 4, 5, or 6 carbon atoms.

[0052] The main advantages of the present invention are as follows. (1) All the compounds of the present invention can induce lysosome biosynthesis, activate the autophagy-lysosome pathway, and have good activity to degrade pathological protein deposits in the brain. (2) The preparation method of the compounds of the present invention is simple. (3) The compounds of the present invention have good pharmacokinetic properties and drug discovery potential.

[0053] Specific Examples Hereinafter, the present invention will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, experimental methods without specific conditions are usually in accordance with conventional conditions or conditions proposed by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight. Starting materials used in the present invention are all purchased as commercially available products unless otherwise specified.

[0054] Example 1: 5-(2-(1H-Indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A1)

Chemical Structure

[0055] 1.2 Synthesis of Intermediate 1-4: Intermediate 1-3 (2.70 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, phosphorus oxychloride (4.46 mL, 48.0 mmol) was added, and the mixture was stirred under reflux for 1.5 hours under argon gas protection. After monitoring the completion of the reaction by TLC, it was evaporated to dryness under reduced pressure, adjusted to weak basicity with saturated sodium bicarbonate added with ice, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using dichloromethane / methanol = 20:1 to obtain 2.03 g of yellow solid product 1-4 with a yield of 80%. ESI-MS m / z 319.1 [M+H] + 。

[0056] 1.3 Synthesis of Compound A1: Intermediate 1-4 (2.04 g, 6.4 mmol) was dissolved in a mixed solvent of 50 mL of methanol / dichloromethane (v / v = 2:1), sodium borohydride (1.46 g, 38.4 mmol) was added in one batch under an ice bath, and the mixture was stirred at room temperature for 4 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride solution, the organic solvent was evaporated to dryness under reduced pressure, dichloromethane was added for extraction, washed successively with saturated sodium bicarbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using dichloromethane / methanol = 15:1 to obtain 1.82 g of white solid product A1 with a yield of 89%. 1 H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 15.0, 7.4 Hz, 2H), 7.11 (t, J = 7.5 Hz, 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, 4.7 Hz, 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). 1313C NMR (150 MHz, CDCl3) δ 146.3, 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] + 。

[0057] Example 2: (S)-5-(2-(1H-Indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((S)-A1)

Chem.

[0058] Example 3: (R)-5-(2-(1H-Indol-3-yl)ethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline ((R)-A1) [Chemical formula] For the synthesis of Intermediate 1-4, refer to Example 1. 1-4 (0.95 g, 3.0 mmol) was dissolved in 10 mL of anhydrous DMF, and the catalyst RuCl[(R,R)-TsDPEN(p-cymene)] (57 mg, 0.09 mmol) was added under room temperature and argon gas protection. Subsequently, a mixed solution of formic acid / triethylamine (v / v = 5 / 2, 1.1 mL) was added, and the mixture was stirred overnight at room temperature. After monitoring the completion of the reaction by TLC, the reaction solution was neutralized to a weakly basic pH with saturated NaHCO3 solution. Subsequently, 5 volumes of ice water were added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed once with NaHCO3 solution and once with NaCl solution, and dried over Na2SO4. After evaporation of the organic solvent to dryness, purification was performed by column chromatography using dichloromethane / methanol = 15:1 to obtain 1.78 g of a white solid product (R)-A1 with a yield of 87%. The optical purity was 95:5 er (chromatographic conditions: Chiral IA (4.6 mm × 250 mmL), n-hexane / isopropanol / triethylamine = 80 / 20 / 0.1, 0.8 mL / min, 254 nm UV, room temperature). 1 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 15.0, 7.4 Hz, 2H), 7.11 (t, J = 7.5 Hz, 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, 4.7 Hz, 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). 13 13C NMR (150 MHz, CDCl3) δ 146.3, 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] + 。

[0059] Example 4: 1-(2-(1H-Indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (A2) Referring to the synthetic route of A1, replace the raw material 1-1 in Example 1 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) to obtain compound A2. The yield is 89%. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 4.36 (t, J = 6.1 Hz, 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, 7.1 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 148.4, 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] + .

[0060] Example 5: (S)-1-(2-(1H-Indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((S)-A2) Referring to the synthetic route of (S)-A1, replace the raw material 1-1 in Example 2 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) to obtain compound (S)-A2. 11H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 4.36 (t, J = 6.1 Hz, 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, 7.1 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6) δ 148.4, 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] + .

[0061] Example 6: (R)-1-(2-(1H-Indol-3-yl)ethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((R)-A2) Referring to the synthetic route of (R)-A1, replace the starting material 1-1 in Example 3 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) to obtain the compound (R)-A2. 1 1H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 4.36 (t, J = 6.1 Hz, 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, 7.1 Hz, 2H). 1313C NMR (100 MHz, DMSO-d6) δ 148.4, 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] + .

[0062] Example 7: 1-(2-(1H-Indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A3) [Chemical formula] 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 sequentially added. The mixture was heated and stirred at 80 °C for 2 hours. After monitoring the completion of the reaction by TLC, the organic solvent was evaporated to dryness, and then saturated sodium bicarbonate was slowly added. The mixture was stirred at room temperature to adjust the pH to neutral. The precipitated solid was collected by suction filtration, washed once with saturated sodium bicarbonate and then with water, and dried to obtain 4.62 g of bright yellow intermediate 2-2 with a yield of 81%, which was used directly in the next step. 2-2 (4.56 g, 16.0 mmol) was dissolved in an ultra-dry tetrahydrofuran solution and reserved. Under an ice bath at -5 °C, 50 mL of ultra-dry tetrahydrofuran was added to a 250 mL two-necked round-bottom flask, and lithium aluminum tetrahydride (1.82 g, 48.0 mmol) was added in three portions. Under the protection of the ice bath and argon gas, 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 tube was attached, and the reaction was protected with argon gas. The reaction was transferred to an oil bath and heated to reflux for 2 hours. After monitoring the completion of the reaction by TLC, the reaction flask was transferred to an ice bath at -5 °C and stirred. Ice water was added dropwise to quench the reaction until the bubbles disappeared. Then, the insoluble solid was collected by suction filtration and washed with ethyl acetate. The filtrate was collected, the organic solvent was spin-dried, extracted with water and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using dichloromethane / methanol / ammonia water = 10:1:0.1 to obtain 2.88 g of a brown liquid product 2-3 with a yield of 70%. 1 H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.33 (m, 5H), 6.89 (br.d, J = 8.8 Hz, 1H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 5.04 (s, 2H), 3.72 (s, 3H), 2.73 t, J = 6.8 Hz, 2H), 2.53 t, J = 6.8 Hz, 2H). ESI-MS m / z 258.1 [M + H] + 。

[0063] Synthesis of Intermediate 3-3: The raw materials 3-1 (5-methoxyindole-3-carbaldehyde, 3.50 g, 20 mmol) and malonic acid (4.08 g, 40 mmol) were dissolved in 50 mL of pyridine, and piperidine (340 mg, 4 mmol) was added under argon gas protection, followed by reacting at 100 °C for 3 hours. After evaporating and removing the solvent, the reaction product was transferred to an ice bath at 0 °C, 20 mL of 6N hydrochloric acid was added dropwise, stirred for 30 minutes, then suction filtered and washed with water to obtain 3.12 g of white solid 3-2 with a yield of 72%, which was directly used in the next step. 3-2 (2.17 g, 10 mmol) was dissolved in 40 mL of methanol, 217 mg of palladium-carbon hydrogenation catalyst (containing 10% water) was added, heated to 55 °C under 1-2 bar of hydrogen gas protection and reacted overnight. After monitoring the completion of the reaction by TLC, suction filtration was carried out, 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 (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.62 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 8.5, 2.5 Hz, 1H), 3.76 (s, 3H), 2.89 (2H, t, J = 7.5 Hz), 2.58 (2H, t, J = 7.5 Hz). ESI-MS m / z 218.0 [M-H] - 。

[0064] Synthesis of Intermediate 3-4: Referring to the synthesis route of A1, raw material 1-1 in Example 1 was replaced with 2-3, and raw material 1-2 in Example 1 was replaced with 3-3 to obtain white solid product 3-4. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.45 - 7.33 (m, 5H), 7.37 (d, J = 8.1 Hz, 1H), 7.22 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.12 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 1.7 Hz, 1H), 6.38 (dd, J = 7.9, 1.7 Hz, 1H), 5.44 (s, 1H), 5.10 (s, 2H), 3.80 (s, 3H), 3.37 (q, J = 6.6 Hz, 2H), 3.09 (t, J = 7.1 Hz, 2H), 2.54 (dt, J = 17.5, 7.0 Hz, 4H). ESI-MS m / z 459.2 [M + H] + 。

[0065] Synthesis of Intermediate 3 - 5: Intermediate 3 - 4 (3.66 g, 8.0 mmol) was dissolved in 50 mL of anhydrous acetonitrile, phosphorus oxychloride (4.46 mL, 48.0 mmol) was added, and the mixture was stirred under argon gas protection for 1.5 h while refluxing. After monitoring the completion of the reaction by TLC, it was evaporated to dryness under reduced pressure, adjusted to weakly basic with saturated sodium bicarbonate added with ice, extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using dichloromethane / methanol = 20:1 to obtain 2.71 g of yellow solid product 3 - 5 with a yield of 77%. ESI-MS m / z 441.2 [M + H] + 。

[0066] Synthesis of Compound A3: Intermediate 3-5 (2.64 g, 6.0 mmol) was dissolved in a mixed solvent of 50 mL of methanol / dichloromethane (v / v = 2:1). Sodium borohydride (1.37 g, 36.0 mmol) was added in one batch under an ice bath, and the mixture was stirred at room temperature for 4 hours. After monitoring the completion of the reaction by TLC, the reaction was quenched with saturated ammonium chloride solution. The organic solvent was evaporated to dryness under reduced pressure, and then dichloromethane was added for extraction. The extract was washed successively with saturated sodium bicarbonate and saturated sodium chloride solutions, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using dichloromethane / methanol = 15:1 to obtain 2.22 g of white solid product A1 with a yield of 84%. 1 H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.48 - 7.36 (m, 5H), 7.32 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 15.0, 7.4 Hz, 2H), 7.11 (t, J = 7.5 Hz, 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 (150 MHz, CDCl3) δ 146.3, 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] + .

[0067] Example 8: 6-(Benzyloxy)-1-(2-(5-fluoro-1H-indol-3-yl)ethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A4) Referring to the synthetic route of A3, raw material 3-1 in Example 7 was replaced with 5-fluoroindole-3-carbaldehyde (CAS: 2338-71-8) to obtain Compound A4. 11H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.47 - 7.36 (m, 5H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 15.0, 7.4 Hz, 2H), 7.10 (t, J = 7.5 Hz, 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 13C NMR (150 MHz, CDCl3) δ 146.3, 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, 47.9, 35.7, 26.0, 21.1. ESI-MS m / z 431.2 [M+H] + .

[0068] Example 9: 1-(2-(1H-Indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (A5) Referring to the synthetic route of A3, intermediate 3-3 in Example 7 was replaced with 3-indolepropionic acid (CAS: 830-96-6) to obtain compound A5. 1 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.46 - 7.36 (m, 5H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 15.0, 7.4 Hz, 2H), 7.11 (t, J = 7.5 Hz, 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). 1313C NMR (150 MHz, CDCl3) δ 146.8, 145.3, 137.3, 130.9, 127.3, 126.8, 122.1, 121.3, 119.0, 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] + 。

[0069] Example 10: 5-(2-(1H-Indol-3-yl)ethyl)-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A12)

Chemical formula

[0070] 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) Referring to the synthetic route of A12, replace the raw material A1 in Example 1 with (S)-A1 to obtain the yellow solid product (S)-A12. 1 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25 - 7.11 (m, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 9.3 Hz, 2H), 5.88 (s, 2H), 3.96 - 3.90 (m, 2H), 3.61 (dd, J = 8.0, 4.4 Hz, 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 13C NMR (125 MHz, CDCl3) δ 145.6, 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] + 。

[0071] 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) Referring to the synthetic route of A12, replace the raw material A1 in Example 1 with (R)-A1 to obtain the yellow solid product (R)-A12. 1 H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.25 - 7.11 (m, 2H), 6.95 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 9.3 Hz, 2H), 5.88 (s, 2H), 3.96 - 3.90 (m, 2H), 3.61 (dd, J = 8.0, 4.4 Hz, 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 (125 MHz, CDCl3) δ 145.6, 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] + .

[0072] 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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and carry out a substitution reaction with compound A1 to obtain A13. 11H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 - 7.09 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.54 (d, J = 9.4 Hz, 2H), 5.88 (s, 2H), 3.98 - 3.92 (m, 2H), 3.59 (dd, J = 8.3, 4.5 Hz, 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 13C NMR (125 MHz, CDCl3) δ 145.6, 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] + .

[0073] 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) Referring to the synthetic route of (S)-A12, replace bromomethylcyclohexane in Example 11 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and carry out a substitution reaction with compound (S)-A1 to obtain (S)-A13. 11H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 - 7.09 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.54 (d, J = 9.4 Hz, 2H), 5.88 (s, 2H), 3.98 - 3.92 (m, 2H), 3.59 (dd, J = 8.3, 4.5 Hz, 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 13C NMR (125 MHz, CDCl3) δ 145.6, 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] + .

[0074] 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) Referring to the synthetic route of (R)-A12, replace bromomethylcyclohexane in Example 12 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and carry out a substitution reaction with compound (R)-A1 to obtain (R)-A13. 11H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 - 7.09 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.54 (d, J = 9.4 Hz, 2H), 5.88 (s, 2H), 3.98 - 3.92 (m, 2H), 3.59 (dd, J = 8.3, 4.5 Hz, 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 13C NMR (125 MHz, CDCl3) δ 145.6, 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] + .

[0075] Example 16: t-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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6), and carry out a substitution reaction with compound A1 to obtain A14. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 161.5, 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] + .

[0076] Example 17: (S)-t-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) Referring to the synthetic route of (S)-A12, replace bromomethylcyclohexane in Example 11 with 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6), and carry out a substitution reaction with compound (S)-A1 to obtain (S)-A14. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 161.5, 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] + .

[0077] 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) Referring to the synthetic route of (R)-A12, replace bromomethylcyclohexane in Example 12 with 1-Boc-4-bromomethylpiperidine (CAS: 158407-04-6), and carry out a substitution reaction with compound (R)-A1 to obtain (R)-A14. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 161.5, 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] + .

[0078] 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) 1.0 A14 was dissolved in a mixed solvent of 20 mL of dichloromethane / trifluoroacetic acid (v / v = 5:1), stirred at room temperature for 1 hour, and after monitoring the completion of the reaction of the raw material by TLC, a saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 8 - 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and purified by column chromatography using dichloromethane / methanol = 10:1 to obtain yellow solid A15. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 146.0, 145.5, 136.1, 132.3, 127.5, 127.1, 121.5, 121.1, 119.2, 118.7, 116.5, 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] + .

[0079] 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) 1.0 (S)-A14 was dissolved in a mixed solvent of 20 mL of dichloromethane / trifluoroacetic acid (v / v = 5:1), stirred at room temperature for 1 hour, and after monitoring the completion of the reaction of the raw materials by TLC, a saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 8 - 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and purified by column chromatography using dichloromethane / methanol = 10:1 to obtain the yellow solid (S)-A15. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 146.0, 145.5, 136.1, 132.3, 127.5, 127.1, 121.5, 121.1, 119.2, 118.7, 116.5, 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] + 。

[0080] 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) 1.0 (R)-A14 was dissolved in a mixed solvent of 20 mL of dichloromethane / trifluoroacetic acid (v / v = 5:1), stirred at room temperature for 1 hour, and after monitoring the completion of the reaction of the raw material by TLC, saturated sodium carbonate solution was added to the reaction solution to adjust the pH to 8 - 9, extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and purified by column chromatography using dichloromethane / methanol = 10:1 to obtain the yellow solid (R)-A15. 11H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 2H), 5.46 (s, 2H), 4.09 (s, 2H), 3.52 (dd, J = 8.9, 4.1 Hz, 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 13C NMR (125 MHz, CDCl3) δ 146.0, 145.5, 136.1, 132.3, 127.5, 127.1, 121.5, 121.1, 119.2, 118.7, 116.5, 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] + .

[0081] 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) 1.0 A15 was dissolved in 20 mL of acetonitrile, 510 mg of iodomethane and 1.65 g of potassium carbonate were added successively, and the mixture was refluxed for 24 hours. After monitoring the completion of the reaction of the raw materials by TLC, the organic solvent was spin-dried, 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, the solvent was evaporated to dryness, and purified by column chromatography using dichloromethane / methanol = 15:1 to obtain yellow solid A16. ESI-MS m / z 432.2 [M + H] + .

[0082] 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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 3-bromomethyltetrahydrofuran (CAS: 165253-29-2), and carry out a substitution reaction with compound A1 to obtain A17. ESI-MS m / z 405.1 [M+H] + 。

[0083] 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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromoethyltetrahydropyran (CAS: 4677-20-7), and carry out a substitution reaction with compound A1 to obtain A18. 1 H NMR(400MHz,CDCl3)δ 8.08(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,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,2H),2.04-2.17(m,2H),1.76-1.85(m,2H),1.36-1.26(m,2H). 1313C NMR (125 MHz, CDCl3): δ 147.4, 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] + 。

[0084] Example 25: 5-(2-(1H-Indol-3-yl)ethyl)-6-benzyl-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A23) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with benzyl bromide, and carry out a substitution reaction with Compound A1 to obtain A23. ESI / MS m / z 411.2 [M+H] + 。

[0085] 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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethylpyridine (CAS: 54751-01-8), and carry out a substitution reaction with Compound A1 to obtain A24. ESI / MS m / z 412.2 [M+H] + 。

[0086] 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) Referring to the synthetic route of A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 5-(bromomethyl)pyrimidine (CAS: 25198-96-3), and carry out a substitution reaction with Compound A1 to obtain A25. ESI / MS m / z 413.2 [M+H] + 。

[0087] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-3 in Example 7 with 3,4-dimethoxyphenylethylamine and 3-indolepropionic acid respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydro pyran (CAS: 125552-89-8) to obtain A26. ESI / MS m / z 413.2 [M+H] + . Pale yellow solid 1 H NMR (400 MHz, CDCl3) δ 8.06 (brs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 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, 4.4 Hz, 2H), 3.32 (dd, J = 19.4, 10.0 Hz, 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 (125 MHz, CDCl3): δ 147.2, 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

[0088] 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) Referring to the synthetic routes of A3 and A12, replace 2-1 and 3-3 in Example 7 with 1,4-benzodioxane-6-carboxaldehyde (CAS: 29668-44-8) and 3-indolepropionic acid respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A27. White solid. 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.35 (d, J = 8.3 Hz, 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 = 13.7 Hz, 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 (125 MHz, CDCl3) δ 160.9, 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.

[0089] 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) Referring to the synthetic routes of A3 and A12, replace 2-1 and 3-3 in Example 7 with 4-benzyloxy-3-methoxybenzaldehyde (CAS: 2426-87-1) and 3-indolepropionic acid respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A28. ESI-MS m / z 511.3.

[0090] 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) Referring to the synthetic routes of A3 and A12, replace 2-1 and 3-3 in Example 7 with 3-benzyloxy-4-methoxybenzaldehyde (CAS: 6346-05-0) and 3-indolepropionic acid respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A29. ESI-MS m / z 511.3.

[0091] 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)

Chemical formula

[0092] 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)

Chemical Structure

[0093] 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) Referring to the synthetic route of A31, the reaction reagent n-butylaldehyde 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] + 。

[0094] 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) Referring to the synthetic route of A31, the reaction reagent n-butylaldehyde in Example 33 was replaced with benzaldehyde to obtain A33. ESI / MS m / z 495.0 [M+H] + 。

[0095] 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) Referring to the synthesis route of A31, replace the reaction reagent n-butyl aldehyde in Example 43 with phenylacetaldehyde to obtain A34. ESI / MS m / z 509.2 [M+H] + 。

[0096] 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]dioxepta[2,3-g]isoquinoline (A35)

Chemical Structure

[0097] 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) Referring to the synthesis route of A35, replace the reaction reagent 1,3-dibromopropane in Example 37 with 2-bromoethyl methyl ether (CAS: 6482-24-2) to obtain A36. ESI / MS m / z 523.3 [M+H] + 。

[0098] 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]tetraoxacyclododeca[2,3-g]isoquinoline (A37) With reference to the synthetic route of A35, replace the reaction reagent 1,3-dibromopropane in Example 37 with 1,14-dibromo-3,6,9,12-tetraoxatetradecane (CAS: 57602-02-5) to obtain A37. ESI / MS m / z 521.2 [M+H] + .

[0099] 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) [Chemical formula] Dissolve compound A28 (1.0 g, 2.0 mmol) in 20 mL of methanol, then add 100 mg of Pd / C catalyst (containing 10% moisture) and ammonium formate (1.26 g, 20 mmol), and heat and stir at 55 °C for 12 hours. After monitoring the completion of the reaction by TLC, perform suction filtration, collect the filtrate, evaporate the solvent to dryness, and purify by column chromatography using dichloromethane / methanol = 20:1 to obtain 0.70 g of A38 with a yield of 83% and the property of being a yellow solid. ESI / MS m / z 420.2 [M+H] + .

[0100] 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) [Chemical formula] Compound A29 (1.0 g, 2.0 mmol) was dissolved in 20 mL of methanol, then 100 mg of Pd / C catalyst (containing 10% moisture) and ammonium formate (1.26 g, 20 mmol) were added, and the mixture was heated with stirring at 55 °C for 12 hours. After monitoring the completion of the reaction by TLC, it was filtered by suction, the filtrate was collected, the solvent was evaporated to dryness, and then purified by column chromatography using dichloromethane / methanol = 20:1 to obtain 0.71 g of A39, with a yield of 85%, and the property was a yellow solid. ESI / MS m / z 420.2 [M+H] + 。

[0101] 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)

Chemical Structure

[0102] 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) Refer to the synthetic route of A40, replace the reaction reagent iodoethane in Example 52 with 2-iodo-1,1,1-trifluoroethane (CAS: 353-83-3) to obtain A41. ESI / MS m / z 503.2 [M+H] + 。

[0103] 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) Refer to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with (iodomethyl)cyclopropane (CAS: 33574-02-6) to obtain A42. ESI / MS m / z 475.3 [M+H] + 。

[0104] 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) Refer to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with (iodomethyl)cyclopropane (CAS: 27935-87-1) to obtain A43. ESI / MS m / z 503.2 [M+H] + 。

[0105] 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) Refer to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with ethyl bromoacetate to obtain A44. ESI / MS m / z 507.2 [M+H] + 。

[0106] 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) Referring to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with 1-(2-bromoethyl)-4-methylpiperazine (CAS: 801152-34-1) to obtain A45. ESI / MS m / z 547.4 [M+H] + 。

[0107] 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) Referring to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with 4-methylbenzyl bromide (CAS: 104-81-4) to obtain A46. ESI / MS m / z 525.4 [M+H] + 。

[0108] 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) Referring to the synthetic route of A40, replace the reaction reagent iodoethane in Example 42 with 4-methylbenzyl bromide (CAS: 104-81-4) to obtain A47. ESI / MS m / z 525.4 [M+H] + 。

[0109] 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) Referring to the synthesis route of A40, replace the reaction reagent iodoethane in Example 42 with 4-bromomethylpyrimidine (CAS: 25198-96-3) to obtain A48. ESI / MS m / z 513.3 [M+H] + 。

[0110] 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)

Chemical formula

[0111] 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 trifluoromethanesulfonate (A50) Referring to the synthesis route of A49, replace the trifluoroacetic anhydride in Example 51 with trifluoromethanesulfonic anhydride to obtain A50. ESI / MS m / z 553.2 [M+H] + 。

[0112] Example 53: 1-(2-(1H-Indol-3-yl)ethyl)-7-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl benzenesulfonate (A51) Referring to the synthetic route of A49, replace trifluoroacetic anhydride in Example 51 with benzenesulfonyl chloride to obtain A51. ESI / MS m / z 561.2 [M+H] + .

[0113] 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) Referring to the synthetic route of A49, replace trifluoroacetic anhydride in Example 51 with 4-trifluoromethylbenzenesulfonyl chloride (CAS: 2991-42-6) to obtain A52. ESI / MS m / z 629.2 [M+H] + .

[0114] 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) [Chemical formula] 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 and reacted at 120 °C for 24 hours under argon gas protection. After monitoring the completion of the reaction by TLC, suction filtration was carried out, and the residue was washed with ethyl acetate. The filtrate was collected, the same amount of water as the organic phase was added, and the mixture was washed three times. The organic phase was concentrated and purified by column chromatography using dichloromethane / methanol = 40:1 to obtain 0.32 g of A53, with a yield of 43%. The product was a yellow solid. ESI / MS m / z 497.3 [M+H] + .

[0115] 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)ethane-1-amine (A54) [Chemical formula] 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, and diisopropyl azodicarboxylate (DIAD, 1.04 g, 7.5 mmol) was added dropwise while stirring at 0 °C. After the addition was complete, the mixture was transferred to room temperature and stirred for 6 hours. After monitoring the completion of the reaction by TLC, water and ethyl acetate were added for extraction. The organic phase was collected, concentrated, and then dissolved in 10 mL of dichloromethane / trifluoroacetic acid (v / v = 5:1) and reacted for 2 hours while stirring at room temperature. A saturated sodium bicarbonate solution was added to the reaction solution to neutralize trifluoroacetic acid, adjust the pH to 8, extract with dichloromethane, collect the organic phase, concentrate, and purify by column chromatography using dichloromethane / methanol = 10:1 to obtain 0.32 g of A54. The two-step yield was 47%, and the property was a yellow oily substance. ESI / MS m / z 464.3 [M+H] + 。

[0116] 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) Referring to the synthetic routes of A3 and A12, steps 2-3 and 3-1 in Example 7 were respectively replaced with pepper ethylamine and 5-methoxyindole-3-carbaldehyde, and the reaction reagent bromomethylcyclohexane in Example 10 was replaced with 4-bromomethyltetrahydro-pyran to obtain A55. ESI / MS m / z 449.3 [M+H] + 。

[0117] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-methoxyindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A56. 1 H NMR(500MHz,CDCl3)δ 7.94(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),2.96-2.75(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)δ 153.8,146.7,131.7,127.9,122.0,111.9,111.8,111.4,110.6,101.1,68.1,61.3,56.0,55.9,55.8,43.9,31.9,31.7,22.2.ESI / MS m / z 465.2[M+H] + .

[0118] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine and 5-fluoroindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A57. 11H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.26 (d, J = 3.9 Hz, 1H), 7.20 (dd, J = 9.7, 2.5 Hz, 1H), 7.03 (s, 1H), 6.93 (td, J = 9.0, 2.5 Hz, 1H), 6.53 (d, J = 21.4 Hz, 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 = 25.7 Hz, 3H), 2.13 - 1.93 (m, 2H), 1.81 - 1.63 (m, 5H). ESI / MS m / z 437.1 [M+H] + 。

[0119] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-fluoroindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A58. ESI / MS m / z 437.1 [M+H] + 。

[0120] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine and 5-chloroindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A59. ESI / MS m / z 453.2 [M+H] + 。

[0121] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-chloroindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A60. ESI / MS m / z 469.1 [M+H] + 。

[0122] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-bromoindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A61. ESI / MS m / z 513.1 [M+H] + 。

[0123] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine and 5-methylindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A62. ESI / MS m / z 449.1 [M+H] + 。

[0124] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-methylindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A63. ESI / MS m / z 449.1 [M+H] + 。

[0125] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 7-methylindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A64. ESI / MS m / z 449.1 [M+H] + 。

[0126] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine and 5-benzyloxyindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A65. ESI / MS m / z 525.2 [M+H] + 。

[0127] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine and 5-benzyloxyindole-3-carbaldehyde respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran to obtain A66. ESI / MS m / z 541.3 [M+H] + .

[0128] 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-indol-5-ol (A67)

Chemical Structure

[0129] Example 70: 3-(2-(6,7-Dimethoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-1H-indol-5-ol (A68) Referring to the synthetic route of A67, replace the starting material A65 in Example 69 with A66 to obtain A68. ESI / MS m / z 450.1 [M+H] + . ESI / MS m / z 451.1 [M+H] + .

[0130] 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)

Chemical Structure

[0131] After monitoring the completion of the reaction by TLC, add excess water to quench the reaction, extract with ethyl acetate, wash the organic phase once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, concentrate, and purify by column chromatography using dichloromethane / methanol = 20:1 to obtain 1.13 g of A69, with a yield of 85% and the property of being a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.1 Hz, 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, 1H), 3.41 (td, J = 11.4, 4.4 Hz, 2H), 3.32 (dd, J = 19.4, 10.0 Hz, 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). 1313C NMR (125 MHz, CDCl3): δ 145.2, 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, 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] + 。

[0132] 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)

Chemical Structure

[0133] 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) Referring to the synthetic route of A69, replace iodomethane in Example 71 with ethyl 2-bromoacetate to obtain A71. ESI / MS m / z 521.1 [M+H] + 。

[0134] 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) Dissolve 100 mg of compound A71 in a mixed solution of 10 mL of EtOH / 2N NaOH (v / v = 1:1), stir at room temperature for 1 hour, monitor the completion of the reaction of the raw material by TLC, then spin-dry the organic solvent, adjust the pH to 4 - 5 with 1N HCl, extract with dichloromethane, and recrystallize with ethyl acetate and n-hexane after concentration to obtain A72.

[0135] 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)ethanamide (A73) 100 mg of compound A72 was dissolved in 10 mL of 1,4-dioxane, 1 mL of pyridine (5 equiv.), 1.2 mL of t-butyl dicarbonate (2 equiv.) and 2.1 g of ammonium bicarbonate (10 equiv.), heated at 50 °C for 12 h, after monitoring the completion of the reaction of the starting materials by TLC, 50 mL of water was added to the reaction solution, extracted three times with ethyl acetate, the organic phases were combined, washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated to dryness, and purified by column chromatography using dichloromethane / methanol = 20:1 to obtain A73.

[0136] 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) Referring to the synthetic route of A69, replacing iodomethane in Example 71 with 2-iodoethanol (CAS: 624-76-0) gave A74. ESI / MS m / z 521.1 [M+H] + 。

[0137] Replacing iodomethane in the synthetic example of A65 with 2-iodoethanol (CAS: 624-76-0) and referring to the synthetic route of A65 gave A74. Purified by column chromatography using dichloromethane / methanol = 20:1, the property was a white solid. ESI / MS m / z 479.3 [M+H] + 。

[0138] 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) Refer to the synthetic route of A69, replace iodomethane in Example 71 with 1-bromo-2-(methylsulfonyl)ethane (CAS: 16523-02-7) to obtain A75. ESI / MS m / z 541.3 [M+H] + 。

[0139] 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) Refer to the synthetic route of A69, replace iodomethane in Example 71 with (2-bromomethyl)dimethylamine (CAS: 5459-68-7) to obtain A76. ESI / MS m / z 506.1 [M+H] + 。

[0140] 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) Refer to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 2-methylindole-3-carbaldehyde (CAS: 5416-80-8) respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydro pyran (CAS: 125552-89-8) to obtain A77. ESI / MS m / z 449.1 [M+H] + 。

[0141] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 7-azaindole-3-carboxaldehyde (CAS: 4649-09-6) respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A78. ESI / MS m / z 436.2 [M+H] + 。

[0142] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 4-azaindole-3-carboxaldehyde (CAS: 276862-85-2) respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A79. ESI / MS m / z 436.2 [M+H] + 。

[0143] Example 82: 5-(2-(Benzo[b]thien-3-yl)ethyl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydro-[1,3]dioxazolo[4,5-g]isoquinoline (A80) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine (CAS: 1484-85-1) and 2-thiophenecarboxaldehyde (CAS: 98-03-3) respectively, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) to obtain A80. ESI / MS m / z 436.1 [M+H] + 。

[0144] 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) Referring to the synthetic routes of A3 and A12, replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and carry out a substitution reaction with A3 to obtain A81. ESI / MS m / z 541.1 [M+H] + .

[0145] 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) Referring to the synthetic routes of A3 and A12, replace 3-1 in Example 7 with 5-fluoroindole-3-carbaldehyde, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) and let it participate in the last stage of the substitution reaction to obtain A82. ESI / MS m / z 529.2 [M+H] + .

[0146] 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) Referring to the synthetic routes of A3 and A12, replace 3-1 in Example 7 with 5-chloroindole-3-carbaldehyde, and replace the reaction reagent bromomethylcyclohexane in Example 10 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8) and let it participate in the last stage of the substitution reaction to obtain A83. ESI / MS m / z 545.3 [M+H] + .

[0147] 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) Referring to the synthetic routes of A3 and A12, replace 3-1 in Example 7 with 5-methoxyindole-3-carbaldehyde, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and through the final hydrolysis reaction, A84 is obtained. ESI / MS m / z 540.3 [M+H] + 。

[0148] 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) Referring to the synthetic routes of A3 and A12, replace 3-1 in Example 7 with 5-fluoroindole-3-carbaldehyde, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and through the final hydrolysis reaction, A85 is obtained. ESI / MS m / z 528.1 [M+H] + 。

[0149] Example 88: 1-(2-(1H-indol-3-yl)ethyl)-6-(benzyloxy)-7-methoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A86) Referring to the synthetic routes of A3 and A12, replace 3-3 in Example 7 with 3-indolepropionic acid, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and through the final hydrolysis reaction, A86 is obtained. ESI / MS m / z 510.0 [M+H] + 。

[0150] Example 89: 1-(2-(1H-Indol-3-yl)ethyl)-6,7-dimethoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (A87) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-3 in Example 7 with 3,4-dimethoxyphenylethylamine (CAS: 120-20-7) and 3-indolepropionic acid respectively, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and obtain A87 through the final hydrolysis reaction. ESI / MS m / z 434.4 [M+H] + .

[0151] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine (CAS: 120-20-7) and 5-fluoroindole-3-carbaldehyde respectively, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and obtain A88 through the final hydrolysis reaction. ESI / MS m / z 436.1 [M+H] + .

[0152] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine (CAS: 120-20-7) and 5-methoxyindole-3-carbaldehyde respectively, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and obtain A89 through the final hydrolysis reaction. ESI / MS m / z 448.2 [M+H] + 。

[0153] 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) Referring to the synthetic routes of A3 and A12, replace 2-3 and 3-1 in Example 7 with pepper ethylamine (CAS: 120-20-7) and 5-chloroindole-3-carbaldehyde respectively, replace the reaction reagent bromomethylcyclohexane in Example 10 with 1-Boc-4-bromomethylpiperidine (CAS: 125552-89-8) to participate in the substitution reaction, and obtain A90 through the final hydrolysis reaction. ESI / MS m / z 452.2 [M+H] + 。

[0154] 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) Referring to the synthetic route of A12, use (S)-A2 as the raw material, replace bromomethylcyclohexane in Example 11 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and carry out a substitution reaction with compound (S)-A2 to obtain (S)-A26. Pale yellow solid 11H NMR (400 MHz, CDCl3) δ 8.06 (brs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 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, 4.4 Hz, 2H), 3.32 (dd, J = 19.4, 10.0 Hz, 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 13C NMR (125 MHz, CDCl3): δ 147.2, 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] + 。

[0155] 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) Referring to the synthetic route of A12, using (R)-A2 as the raw material, replacing bromomethylcyclohexane in Example 12 with 4-bromomethyltetrahydropyran (CAS: 125552-89-8), and subjecting compound (R)-A2 to a substitution reaction to obtain (R)-A26. Pale yellow solid 11H NMR (400 MHz, CDCl3) δ 8.06 (brs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 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, 4.4 Hz, 2H), 3.32 (dd, J = 19.4, 10.0 Hz, 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 13C NMR (125 MHz, CDCl3): δ 147.2, 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] + .

[0156] 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)

Chem.

[0157] 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) Referring to the synthetic route of A93, using 3-azaspiro[5.5]-9-undecanone (CAS: 1056629-32-3) and A2 as starting materials, A94 is obtained. ESI / MS m / z 502.4 [M+H] + .

[0158] 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) Referring to the synthetic route of A93, using 8-oxabicyclo[3.2.1]octan-3-one (CAS: 77745-32-5) and A2 as starting materials, A95 is obtained. ESI / MS m / z 461.3 [M+H] + .

[0159] 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) Referring to the synthetic route of A93, using nortropinone (CAS: 5632-84-8) and A2 as starting materials, A96 is obtained. ESI / MS m / z 460.4 [M+H] + .

[0160] 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) Using compound A26 as a synthetic intermediate, referring to the synthetic route of A69, replace iodomethane with benzyl bromide, and cause a substitution reaction at the 1-position of indole to obtain A97. ESI / MS m / z 525.3 [M+H] + 。

[0161] 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) Using compound A26 as a synthetic intermediate, referring to the synthetic route of A69, replace iodomethane with 4-fluorobenzyl bromide, and cause a substitution reaction at the 1-position of indole to obtain A98. ESI / MS m / z 543.3 [M+H] + 。

[0162] 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)

Chemical formula

[0163] Dissolve 5-2 (348 mg, 0.8 mmol) in 40 mL of DMF, add 4-fluorobenzyl bromide (181 mg, 0.96 mmol) and potassium carbonate (552 mg, 4.0 mmol), heat and react at 60 °C for 2 hours. After monitoring the completion of the reaction by TLC, add water and ethyl acetate and extract twice, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate, and recrystallize with ethyl acetate / petroleum ether (1 / 2, v / v) to obtain a yellow compound 5-3 (381 mg, yield 88%).

[0164] Dissolve 5-3 (381 mg, 0.7 mmol) in 40 mL of ultra-dry dichloromethane, slowly add dropwise a 1.0 M BBr3 solution (4.2 mL, 4.2 mmol) at -20 °C, then react for 2 hours while stirring at that temperature. After monitoring the completion of the reaction by TLC, slowly add water to quench, add water and dichloromethane and extract twice, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography using ethyl acetate / petroleum ether (1 / 3, v / v) to obtain a yellow compound 5-4 (267 mg, yield 72%).

[0165] Dissolve 5-4 (267 mg, 0.5 mmol) in 30 mL of DMF, add 2-iodo-1,1,1-trifluoroethane (158 mg, 0.75 mmol) and potassium carbonate (345 mg, 2.5 mmol), heat and react at 60 °C for 2 hours. After monitoring the completion of the reaction by TLC, add water and ethyl acetate and extract twice, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate, and recrystallize with ethyl acetate / petroleum ether (1 / 2, v / v) to obtain a yellow compound 5-5 (257 mg, yield 84%).

[0166] Dissolve 5-5 (257 mg, 0.42 mmol) in 15 mL of MeOH and 15 mL of H2O, add potassium carbonate (290 mg, 2.1 mmol), heat and react at 80 °C for 2 hours. After monitoring the completion of the reaction by TLC, add water and ethyl acetate and extract twice, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate, and subject to column chromatography using methanol / dichloromethane (1 / 30, v / v) to obtain a yellow compound A99 (206 mg, yield 95%). 1 H NMR (600 MHz, CDCl3) δ 8.75 (s, 1H), 7.44 (dd, J = 8.3, 5.4 Hz, 2H), 7.28 (dd, J = 9.6, 2.5 Hz, 1H), 7.22 (dd, J = 8.8, 4.3 Hz, 1H), 7.10 (t, J = 8.6 Hz, 2H), 7.04 (s, 1H), 6.96 (s, 1H), 6.73 (d, J = 6.2 Hz, 2H), 5.05 (s, 2H), 4.02 (dd, J = 8.9, 3.5 Hz, 1H), 3.09 - 2.78 (m, 6H), 2.72 (dt, J = 16.2, 5.7 Hz, 1H), 2.27 - 2.09 (m, 2H). ESI / MS m / z 517.2 [M+H] + 。

[0167] 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)

Chemical Structure

[0168] 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)

Chemical Structure

[0169] 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) [ka] Compound A82 is used as a synthetic intermediate. A82 (106mg, 0.2mmoL) is dissolved in 10mL of methanol, 11mg of palladium carbon (containing 10% water) and ammonium formate (126mg, 2mmoL) are added, and the mixture is heated at 60℃ under argon gas protection for 4 hours. After the reaction is completed by TLC, the palladium carbon is suction filtered, and then extracted twice with water and ethyl acetate, washed once with saturated saline, dried with anhydrous sodium sulfate, and concentrated to obtain intermediate 6-1, which is used directly in the next step of the reaction without column. 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 mixture was heated at 60° C. for 2 hours. After completion of the reaction was monitored by TLC, the mixture was extracted twice with water and ethyl acetate, washed once with saturated saline, dried over anhydrous sodium sulfate, concentrated, and recrystallized from ethyl acetate / petroleum ether (1 / 2, v / v) to obtain pale yellow compound A102 (67 mg, 61% yield). ESI / MS m / z 547.2 [M+H] +。

[0170] Examples of Pharmacological Activity and Pharmacokinetics Tests Example 1: TFEB Nuclear Invasion Activity Promotion Test Experiment The experimental procedure is as follows. 1. Cultivation of HeLa cells. In this experiment, first, a HeLa cell line that can stably express the TFEB-EGFP fluorescent protein needs to be incubated, and then the activity of the compound needs to be screened. 2. Screening of small molecule compounds that can induce TFEB-EGFP to invade the nucleus and generate lysosomes. When the density of the TFEB-EGFP stable transfection cell line cells in the 96-well plate reaches about 85%, the stable transfection cell line cells are treated with compound concentrations of 30 μM and 50 μM or Torin 1 (1 μM). After 3 hours, 6 hours, and 9 hours of treatment, the nuclear invasion status of TFEB is observed with a fluorescence microscope (Nikon) and the nuclear invasion rate is statistically analyzed. During this process, the experimenter conducts the screening using the double-blind method.

[0171] The experimental results are as shown in Table 1. Table 1. Activity Data Table of Some Compounds a,b

Table 1-1

[0172]

Table 1-2

[0173] Experimental conclusion: As can be seen from the above experimental results, multiple compounds have a significant effect of inducing nuclear entry on TFEB in cells. Compounds A16, A24, A26, A55, A59, A62, A64, A66, A82, A83, A88, and A89 promoted the nuclear entry rate of TFEB to reach 80% - 90% at a concentration of 30 μM and at 3 hours. Compounds A3, A4, A5, A15, A29, A56, A57, A58, A60, A61, A63, A84, A85, A86, A90, A98, A99, A100, and A101 promoted the nuclear entry rate of TFEB to reach 90% - 100% at a concentration of 30 μM and at 3 hours. These compounds may induce the biosynthesis of lysosomes, activate the autophagy-lysosome pathway to degrade pathological protein deposits in the brain, and provide good options for development as therapeutic drugs for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0174] Example 2: Tissue distribution data of compound A26 in mice In three administration routes of oral administration (20 mg / kg), intraperitoneal injection (10 mg / kg), and intravenous injection (5 mg / kg) of the compound, the drug concentrations in plasma or cerebrospinal fluid were measured at two time points of 15 minutes and 30 minutes, and the experimental results are as shown in Table 2. Table 2. Tissue distribution data of compound A26 in mice a

Table 2

[0175] Experimental conclusion: At the 15-minute time point, preferably, the drug concentration ratios of compound A26 in the brain and plasma reached 3.4 times, 2.12 times, and 3.3 times respectively by the three administration methods of oral administration, intraperitoneal injection, and intravenous injection, indicating that compound A26 has good blood-brain barrier permeability and brain targeting ability, suggesting that there are advantages for the compound to be developed as a therapeutic drug for brain diseases.

[0176] All documents cited in the present invention are hereby incorporated by reference in this application as if each document was individually cited as a reference. Further, after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms are also included within the scope defined by the appended claims of this application.

Claims

1. A compound having the structure represented by the general formula (I), and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 where X is selected from the group consisting of O, S or NR ６ and is selected from the group consisting of m, n, and p are each independently selected from the group consisting of 0, 1, 2, 3, or 4, C ＊ The configuration of may independently be S-form, R-form, or racemic form, R １ and R ２ each independently represents hydrogen, deuterium, tritium, a halogen, a cyano group, a nitro group, a hydroxy group, a sulfhydryl group, a carboxy group, -S(O) ２ OH, a substituted or unsubstituted C １ to C １０ linear or branched alkyl group, a substituted or unsubstituted C １ to C １０ alkoxy group, a C ２ to C ６ linear or branched alkenyl group, a substituted or unsubstituted C ２ to C ６ alkynyl group, a substituted or unsubstituted saturated or partially unsaturated C ３ to C １０ membered carbocyclic group, a substituted or unsubstituted C ６ to C １０ aryl group, a substituted or unsubstituted saturated or partially unsaturated 5- to 12-membered heterocyclic group, a substituted or unsubstituted 5- to 12-membered heteroaryl group, a substituted or unsubstituted C ２ to C ６ acyl group, a substituted or unsubstituted C ２ to C ６ ester group, a substituted or unsubstituted C ０ to C ６ amino group, a substituted or unsubstituted C １ to C ６ amide group, a substituted or unsubstituted C １ to C ６ alkyl-sulfonyl group or a substituted or unsubstituted C １ to C ６ alkyl-sulfinyl group, or is selected from the group consisting of Alternatively, R １ and R ２ together with the atoms to which they are attached form a substituted or unsubstituted 5- to 12-membered heterocyclic or aromatic heterocyclic ring, R ３ is selected from the group consisting of hydrogen, a substituted or unsubstituted (—C １ —C ６ alkyl—C ６ —C １０ aryl group), a substituted or unsubstituted (—C １ ~C ６ alkyl—5- to 12-membered heteroaryl group), a substituted or unsubstituted (—C １ ~C ６ alkyl—C ３ ~C ８ carbocyclic group), a substituted or unsubstituted (—C １ ~C ６ alkyl—3- to 12-membered heterocyclic group), a substituted or unsubstituted (—C １ ~C ６ alkyl—7- to 20-membered hetero polycyclic group), a substituted or unsubstituted C ３ ~C ８ saturated or partially unsaturated carbocyclic group, a substituted or unsubstituted C ６ ~C １０ aryl group, a substituted or unsubstituted 3- to 12-membered heterocyclic group, a substituted or unsubstituted 7- to 20-membered hetero polycyclic group, wherein the hetero polycyclic group includes a fused ring, a bridged ring and a spiro ring structure, [Chemical 2] The ring is selected from the group consisting of a substituted or unsubstituted 3- to 12-membered heterocyclic group, a substituted or unsubstituted C ６ -C １０ aryl group, and a substituted or unsubstituted 5- to 12-membered heteroaryl group. R ４ and R ５ are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, nitro group, amino group, C １ to C ６ amine group, hydroxy group, hydroxymethyl group, carboxy group, C １ to C ６ amide, sulfhydryl group, -S(O) ２ OH, C １ to C ６ alkylsulfonyl group, substituted or unsubstituted C １ to C ６ alkyl group, substituted or unsubstituted C １ to C ６ alkoxy group, substituted or unsubstituted C ３ to C ８ cycloalkyl group, substituted or unsubstituted C ６ to C １０ aryl group, and substituted or unsubstituted 3- to 12-membered saturated or partially unsaturated heterocyclic group R ６ is selected from the group consisting of hydrogen, C １ ~C ６ alkylsulfonyl group, C １ ~C ６ alkyl group, C １ ~C ６ halogenated alkyl group, aryl group or heteroaryl-substituted C １ ~C ６ alkyl group, cycloalkane or heterocyclic hydrocarbon-substituted C １ ~C ６ alkyl group, C ３ ~C ８ saturated or partially unsaturated carbocyclic group, C ３ ~C ８ halogenated saturated or partially unsaturated carbocyclic group, C ６ ~C １０ aryl group, 3- to 12-membered heterocyclic group, -(CH ２ )qYR ７ and is selected from the group consisting of where q is selected from the group consisting of 0, 1, 2, 3, or 4, Y is O, S, NR ８ , CO or SO ２ selected from the group consisting of R ７ and R ８ are each independently selected from the group consisting of hydrogen, a hydroxy group, an amino group, a C １ -C ６ amine group, a substituted or unsubstituted C １ -C ６ alkoxy group, a C １ -C ６ alkyl group, a C １ -C ６ halogenated alkyl group, -C １ -C ６ alkyl-C ６ -C １ -C ６ alkyl-5- to 12-membered heteroaryl group, -C １ -C ６ alkyl-C ３ -C １ -C ６ alkyl-3- to 12-membered heterocyclic group, a C ３ -C ８ saturated or partially unsaturated carbocyclic group, a C ３ -C ８ halogenated saturated or partially unsaturated carbocyclic group, a C ６ -C １０ aryl group, a 5- to 12-membered heteroaryl group, a 3- to 12-membered saturated or partially unsaturated heterocyclic group where the heteroaryl group or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, In the above substitution or non-substitution, "substitution" means that the group is halogen, cyano group, nitro group, amino group, hydroxy group, hydroxymethyl group, carboxy group, sulfhydryl group, C １ to C ６ alkyl group, C １ to C ６ halogenated alkyl group, C １ to C ６ alkoxy group, C １ to C ６ alkoxycarbonyl group, C １ to C ６ halogenated alkoxy group, C ２ to C ６ alkenyl group, C ２ to C ６ alkynyl group, C １ to C ６ alkylsulfonyl group, C ３ to C ８ a saturated or partially unsaturated carbocyclic group, C ６ to C １０ aryl group, a 3- to 12-membered saturated or partially unsaturated heterocyclic group, and a 5- to 12-membered heteroaryl group, and is substituted by 1 to 3 substituents selected from the group consisting of the halogen is F, Cl, Br, or I, In another preferred example, the R ４ and R ５ are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano group, nitro group, amino group, NH ２ , C １ to C ６ amine group, hydroxy group, hydroxymethyl group, carboxy group, C ２ to C ６ amide, sulfhydryl group, -S(O) ２ OH, C １ to C ６ alkylsulfonyl group, C １ to C ６ alkyl group, halogen-substituted C １ to C ６ alkyl group, aryl group or heteroaryl-substituted C １ to C ６ alkyl group, cycloalkane or heterocyclic hydrocarbon-substituted C １ to C ６ alkyl group, C １ to C ６ alkoxy group, aryl group or heteroaryl-substituted C １ to C ６ alkoxy group, C １ to C ６ halogenated alkoxy group, C ３ to C ８ cycloalkyl group, C ３ to C ８ halogenated cycloalkyl group, C ６ to C １０ aryl group, and a 3- to 12-membered saturated or partially unsaturated heterocyclic group, and a compound having the structure represented by the general formula (I), and a racemic compound, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ are independently selected from the group consisting of a substituted or unsubstituted C １ -C １０ linear or branched alkyl group, a substituted or unsubstituted saturated or partially unsaturated C ３ -C １０ membered carbocyclic group, a substituted or unsubstituted C ５ -C １０ aryl group In another preferred example, the R １ and R ２ are independently selected from the group consisting of a substituted or unsubstituted C １ -C ６ linear or branched alkyl group, a substituted or unsubstituted saturated or partially unsaturated C ３ -C ６ membered carbocyclic group, and a substituted or unsubstituted phenyl group. The compound according to Claim 1, and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof.

3. R １ and R ２ together with the atoms to which they are attached form a substituted or unsubstituted 5- to 12-membered heterocyclic ring, In another preferred example, the R １ and R ２ together with the atoms to which they are attached form a substituted or unsubstituted 5- to 7-membered heterocyclic ring. The compound according to Claim 1, and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof.

4. R ３ is selected from the group consisting of hydrogen, a substituted or unsubstituted C ６ to C １０ aryl group, a substituted or unsubstituted 3- to 12-membered heterocyclic group, or a substituted or unsubstituted 7- to 20-membered hetero polycyclic group, wherein the hetero polycyclic group includes a fused ring, a bridged ring, and a spiro ring structure The compound according to Claim 1, and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof.

5. 【Fig. 3】 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 group, characterized in that The compound according to Claim 1, and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof.

6. The compound is characterized in that it is selected from the following group The compound according to Claim 1, and a racemic compound, R-isomer, S-isomer, or pharmaceutically acceptable salt thereof. 【Chemical Formula 4-1】 【Chemical Formula 4-2】 【Chemical Formula 4-3】 【Chemical Formula 4-4】 【Chemical Formula 4-5】 [Chemical Formula 4-6] 【Chemical Formula 4-7】

7. A method for preparing a compound represented by the general formula (I), wherein (1) In a mixed solvent of nitromethane and an organic acid, a compound of Formula II ａ is subjected to a Henry reaction with nitromethane to obtain an α,β-unsaturated nitro group compound II ｂ , and the compound of Formula II ｂ is subjected to a reduction reaction to obtain a compound of Formula II ｃ , and 【Chemical Formula 5】 (2) In a basic solvent, in the presence of malonic acid and a base catalyst, reacting a compound of formula I ａ with malonic acid by a Knoevenagel reaction to obtain a compound of formula I ｂ , and reducing the compound of formula I ｂ with a reducing agent to obtain a compound of formula I ｃ ; and [Chemical Formula 6] (3) In an inert solvent, in the presence of a condensing agent, a compound of formula II ｃ is reacted with a compound of formula I ｃ to obtain a compound of formula I ｄ and 【Chemical Formula 7】 (4) In an inert solvent, a Bischler-Napieralski cyclization reaction is carried out using the compound of formula I ｄ to obtain a compound of formula I ｅ and 【Chemical 8】 (5) In an inert solvent, a reduction reaction is carried out using the compound of Formula I ｅ to obtain the compound of Formula I ｆ and 【Chemical Formula 9】 In an inert solvent, a compound of formula I ｆ is subjected to a substitution reaction with a halogenated hydrocarbon I ｇ to obtain a compound of formula (I), and 【Chemical Formula 10】 Here, R １ and R ２ and R ３ and R ４ and R ５ and R ６ wherein the definitions of X, m, n, and p are as described in claim 1, the preparation method.

8. The organic acid described in step (1) is acetic acid or formic acid, and the reducing agent is LiAlH ４ , sodium borohydride or zinc powder, and In another preferred example, the basic solvent described in step (2) is pyridine, the base catalyst is piperidine, the reducing agent is a combination of a palladium-carbon hydrogenation catalyst and hydrogen gas, or a combination of a palladium-carbon hydrogenation catalyst and ammonium formate, In another preferred example, the condensing agent described in step (3) is HATU or a combination of EDCI and HOBt, In another preferred example, the ring-closure reaction described in step (4) uses POCl ３ phosphorus oxychloride as a Lewis acid, In another preferred example, the reduction reaction described in step (5) uses a borohydride as a reducing agent, or uses a Noyori's catalyst as an asymmetric reduction catalyst, In another preferred example, the substitution reaction described in step (6) is characterized by using potassium carbonate, cesium carbonate, or sodium carbonate as the base for the catalytic reaction, The preparation method according to Claim 7.

9. A pharmaceutical composition, wherein The pharmaceutical composition, comprising: (1) the compound according to any one of claims 1 to 6, its racemic compound, 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 racemic compound, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, for preventing and / or treating diseases associated with lysosomal dysfunction and biosynthetic deficiency, In another preferred example, the disease is a neurodegenerative disease caused by the accumulation of pathological proteins, In another preferred example, the disease is selected from the group consisting of Alzheimer's disease and Parkinson's disease. Use of the compound according to any one of claims 1 to 6, its racemic compound, R-isomer, S-isomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9.

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