CN117946031A

CN117946031A - Substituted aromatic phenol derivatives of KNa1.1 channel inhibitors

Info

Publication number: CN117946031A
Application number: CN202211285716.1A
Authority: CN
Inventors: 张亮仁; 黄卓; 李忠堂; 刘振明; 王秋风; 郑汝秋; 李奕言
Original assignee: Peking University
Current assignee: Peking University
Priority date: 2022-10-20
Filing date: 2022-10-20
Publication date: 2024-04-30

Abstract

The application discloses a substituted aromatic phenol derivative of a KNa1.1 channel inhibitor, which is shown as (I), wherein the definition of each substituent is shown in the specification. In addition, the application also discloses a preparation method of the compound and a pharmaceutical composition containing the compound. The substituted aromatic phenol derivative has a selective inhibition effect on KNa1.1 channels, and can be used as an antiepileptic drug.

Description

Substituted aromatic phenol derivatives of KNa1.1 channel inhibitors

Technical Field

The present invention relates to pharmaceutical chemistry technology, in particular to substituted aromatic phenol derivatives of KNa1.1 channel inhibitors, and a preparation method, a pharmaceutical composition and application thereof.

Background

Epilepsy is one of the most common neurological disorders affecting more than seven million people worldwide. It is characterized by a sustained propensity to produce spontaneous epileptic seizures and produces a number of consequences including neurobiology, cognition, socioeconomic. Classification of epilepsy generally has three levels: convulsion type, epilepsy type, complications, and any hierarchically classified epileptic etiology includes six types, genetic, structural, metabolic, infectious, immunological and unknown.

The KCNT gene related missense mutation is found to be related to various epileptic diseases, and the latest research result shows that the pathogenic site of KCNT is more than 50 at present, and the pathogenic mutation is concentrated in three functional areas of a hole area, an RCK area and an NAD+ binding area. The most common among KCNT 1-related epileptic phenotypes include infant malignant metastatic local seizures (MALIGNANT MIGRATING PARTIAL seizures of infancy, MMPSI) and autosomal dominant hereditary night frontal lobe seizures (Autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE). MMPSI is an early-stage epileptic encephalopathy in infants, characterized by the random occurrence of drug-resistant convulsive episodes in the first 6 months after birth of the infant, accompanied by the transfer of epileptic foci from one brain region to another. Exon sequencing showed that at least 50% of MMPSI patients had mutations at the intracellular C-terminus of the kna1.1 channel. Functional studies indicate that this mutation may mimic the C-terminal phosphorylation of Protein Kinase C (PKC), which in turn leads to constitutive activation of the channel. Another common KCNT 1-related epilepsy ADNFLE is localized epilepsy that occurs in children of average age 6, characterized by the occurrence of group motor epilepsy during sleep, with varying degrees of mental disorder (Intellectual disability, ID), and mental problems. In addition, a small proportion of KCNT gene mutant patients suffer from leukoencephalopathy (leukoencephalopathies), garden Syndrome (Ohtahara Syndrome), west Syndrome (West Syndrome), and the like. And the same KCNT mutations may lead to different epilepsy, i.e. the genotype-phenotype relationship of the KCNT1 mutations is not a direct correspondence.

Most cases reported so far in which the KCNT gene mutation causes epilepsy are functionally enhanced mutations (GOFs), the mechanism of which mainly comprises changing the sensitivity of the K _Na 1.1 channel to sodium ions or increasing the maximum open probability (Po) of the single channel, enhancing the synergistic opening of the K _Na 1.1 channel, and changing the interaction of the K _Na 1.1 channel with binding proteins such as phosphatase and actin regulatory factor 1 (Phosphatase and actin regulator 1, phar1), resulting in a sustained phosphorylation state of the channel. Although pathogenic mutations result in a different mechanism of enhanced function of the K _Na 1.1.1 channel, all GOF mutations increase the magnitude of the outward current and shift half of the activation voltage toward the hyperpolarized voltage. There are also very few reduced-function mutations (LOFs), the LOF mutation reported in the first instance for epileptogenic KCNT1 was F932 (911) I, which was accompanied by severe leukoencephalopathy and myelination delay, and in vitro studies on CHO cells found that the mechanism of reduced function might be to reduce the expression of mutated channels on the membrane.

The study of the mechanism by which GOF mutations result in enhanced neuronal excitability and thus epileptic initiation is not clear, and it is currently a common hypothesis to suggest that such GOF mutations of the K _Na 1.1.1 channel are expressed in gabaergic inhibitory interneurons and enhance neuronal hyperpolarization, which reduces their release of inhibitory neurotransmitters and thus reduces inhibition of excitatory neurons, thereby enhancing the excitability of the neural network. Yet another hypothesis is that the GOF mutated kna1.1 channel is believed to activate rapidly after onset of action potential, accelerating repolarization and increasing fast AHP, thereby allowing for voltage-gated sodium channels.

A number of different types of potassium channels are expressed in the heart, such as delayed rectifier potassium channels, instantaneous outward potassium channels, inward rectifier potassium channels, etc. in voltage-gated potassium channels, which are most inhibited by a third class of antiarrhythmic agents, but the effect studies of the third class of antiarrhythmic agents on ligand-gated potassium channels have not been widely conducted. In 1996, several scientists from japan therefore tested the effect of the third class of antiarrhythmic agents amiodarone (Amiodarone), E-4031, MS-551 on sodium activated potassium channels in guinea pig ventricular cells. Single channel results show that E-4031 and MS-551 can inhibit channel current by reducing channel opening time at 300 mu M concentration, and amiodarone can exert inhibition effect by reducing channel opening probability at lower concentration, and IC ₅₀ is 1 mu M. Subsequent studies in 1998 evaluated the effect of the first class of antiarrhythmic quinidine (Quinidine), mexiletine (Mexiletine), flumazenil (FLECAINIDE), and the fourth class of antiarrhythmic Verapamil (VERAPAMIL), benpridil (Bepridil), SD-3212 on the K _Na 1.1 channel, where quinidine (100 μm), mexiletine (100 μm), flumazenil (10 μm) all inhibited the channel activity incompletely by reducing the single channel open time, whereas the fourth class of antiarrhythmic drug inhibited the channel current potently by reducing the channel open probability, IC ₅₀ was verapamil (3.36 μm), benpridil (0.51 μm), SD-3212 (0.53 μm), respectively. In 2006, a stable transformation system of K _Na 1.1.1 channels was constructed in HEK-293 cells, recorded with whole cells and single channel patch clamp, respectively, and both quinidine and benpurl were found to reduce single channel open time and open probability and suppress macroscopic currents, IC ₅₀ was quinidine (89.6. Mu.M) and benpurl (1. Mu.M), respectively. In xenopus oocytes, the antiarrhythmic drug, ammonium chloride (Clofilium), was effective in inhibiting the KNA channel and in slowing the activation rate of the channel, with ammonium chloride having an IC ₅₀ of 109. Mu.M for the K _Na 1.1 channel and slightly stronger than 331. Mu.M for the K _Na 1.2 channel.

However, these antiarrhythmic drugs are all lacking selectivity as channel inhibitors, they also act on many other types of channels, and thus in recent years, there has been a continued effort to develop novel, selective K _Na 1.1.1 channel inhibitors. However, the binding pattern of inhibitors to the K _Na 1.1.1 channel has not been studied in detail, but the mechanism by which quinidine, benfodil, and chlorphenamine inhibit the hERG channel has been explained more fully. These inhibitors pass through phospholipid bilayer membranes, bind from the intracellular side to the side chains of aromatic amino acid residues at the vestibule of the inner pore of the hERG channel, and exert a blocking effect. Therefore, researchers put forward the hypothesis that the inhibitors of quinidine and benfodil can be combined with the vestibule of the inner hole of the K _Na 1.1 channel, and the compounds are proved to be possibly combined with the F346 site of the channel to play a blocking role by using the chicken K _Na 1.1 channel structure analyzed by a cryo-electron microscope through computer modeling and molecular mutation experiments. They then determined a model inhibitor binding pocket and screened potent K _Na 1.1.1 channel inhibitors from the compound library using virtual screening and finally screened two micromolar compounds, BC12, BC14, which exhibited less cytotoxicity and hERG channel inhibition while blocking K _Na 1.1.1 channels strongly. Another study utilized high throughput thallium ion flow screening to obtain a potent inhibitor VU0606170 with an IC ₅₀ of 1.84. Mu.M for WT channels on HEK293 cell line, and selectivity evaluation experiments demonstrated that VU0606170 had no significant effect on K _Na1.2,K_Ca.1, GIRK1/2, kv2.1, TREK1, cav3.2, nav1.7 channels. At the same time, VU0606170 can reduce the discharge rate of the rat cortex neurons with high excitability, which proves that the neuron excitability can be reduced by selectively inhibiting the K _Na 1.1 channel. In addition, one study published in 2021 utilizes high-flux rubidium ion flow screening and full-automatic patch clamp technology, and combines structure-activity relationship analysis to reconstruct compound 31, which has strong inhibition on disease treatment mutation of human and murine WT channels and clinical common KNa1.1 channels. Compound 31 exhibits selectivity for hERG, nav1.5, cav1.2, IKs, K _Ca1.1,K_Na 1.2.2 and is capable of reducing the frequency of CA1 vertebral neuron discharge and reducing the number of convulsive episodes in treated mutant mice while not affecting spontaneous activity.

Of these several inhibitors, only quinidine was clinically tested in patients. One of 2014 documents indicates that quinidine has an inhibitory effect on the channels encoded by the seven KCNT gene mutations found clinically, i.e. quinidine may be used in the treatment of several refractory epilepsy associated with KCNT gene. In one clinical study with quinidine for treatment KCNT of 1-related epilepsy, only 20% of patients treated showed a 50% or more decrease in seizure frequency after clinical use of quinidine and sustained spontaneous convulsions were more or less severe, 20% of patients showed less than 50% of seizure frequency, 40% of patients showed complete failure to use quinidine, and 15% of patients showed exacerbation, but in another study quinidine treatment resulted in a 25% or more decrease in seizure frequency in 45% of patients. Quinidine can almost completely suppress convulsive episodes and enhance mental performance in clinical treatment of a 25 month old R428Q patient with MPSI. In the treatment of another 6 year old R428Q patient without MPSI, quinidine had little effect on the frequency of convulsions. Similarly, quinidine was able to reduce seizure by 80% in one patient aged 3 years EIMFS (K629N), whereas it was totally ineffective in another patient aged 11 with an unknown epileptic type (Y796H), part KCNT of the pathogenic mutation study results are shown in the following table. Studies indicate that quinidine clinical efficacy has a greater correlation with both patient age and epileptic type, and generally the less aged the patient is, the more pronounced the therapeutic effect of quinidine, which may be in combination with the higher permeability of quinidine across the blood brain barrier in older individuals, or the more severe drug resistance of individuals from prolonged seizures in older individuals.

Overall, the therapeutic effect of quinidine is not ideal, which may be related to its low blood brain barrier permeability, and quinidine concentrations in human cerebrospinal fluid may be only 4-37% of the unbound serum concentration. In the central nervous system with a large distribution of K _Na 1.1.1 channels, the effective concentration of quinidine is even lower, which is very unfavorable for quinidine to exert therapeutic effects. In the case of clinical use of quinidine in treating KCNT 1-related epileptic patients, serum quinidine concentrations are in the range of 1.23-14.8 μm and exert toxic effects beyond 18.5 μm. Since IC ₅₀ of the in vitro quinidine to K _Na 1.1.1 channel is 89.6 mu M, the quinidine has a narrower safety window and poor curative effect in clinical use. The clinical application of quinidine is also replete with adverse effects while having poor therapeutic effects, which can be associated with cardiotoxicity as an antiarrhythmic agent, such as causing arrhythmia, conduction block, quinine Ding Yunjue, etc., as well as extra-cardiac toxicity, such as gastrointestinal reaction, cinchona reaction, etc. In a study using quinidine as a therapeutic agent for KCNT-related epilepsy, a total of 43 patients had a prolonged QT interval in the clinical trial of 47% of the patients, 11% of the patients had sedated, 5% had arrhythmia, 5% had elevated liver function, and 5% had rash. These side effects also limit the use of quinidine to some extent.

Disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

In one aspect, the present application provides a substituted aromatic phenol derivative as a kna1.1 channel inhibitor, the substituted aromatic phenol derivative being represented by formula (I), or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof:

In formula (I), R ₁ is hydrogen, unsubstituted C ₁-C₆ alkyl or substituted C ₁-C₆ alkyl, where the substituted C ₁-C₆ alkyl is substituted with one or more of the following groups: optionally substituted aromatic hydrocarbon groups, optionally substituted C ₃-C₈ cycloalkyl groups, optionally substituted C ₃-C₈ heterocycloalkyl groups, and optionally substituted heteroaryl groups;

r ₂ is R ₃ is hydrogen, R ₄ is selected from hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy, or R ₃ and R ₄ together with the carbon to which they are attached form an optionally substituted benzene ring; or R ₂ is hydrogen and R ₃ is/>R ₄ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached form/>Substituted benzene ring, or/>Substituted five-or six-membered nitrogen heterocycles;

L ₁ is a single bond, C ₁-C₆ alkylene, aza C ₁-C₆ alkylene, or C ₂-C₆ alkenylene;

L ₂ is-CH ₂ -or-C (O) -, Is not present,/>Is a single bond;

L ₂ is-ch=, Singly (v)Is absent;

Or alternatively Is a five-membered or six-membered nitrogen heterocycle and/>Absence of;

R ₅ and R ₆ are each independently absent, hydrogen, unsubstituted C ₁-C₆ alkyl, group A substituted C ₁-C₆ alkyl, unsubstituted C ₃-C₈ cycloalkyl, group A substituted C ₃-C₈ cycloalkyl, unsubstituted C ₁-C₆ alkanoylamino, group A substituted C ₁-C₆ alkanoylamino, unsubstituted five-or six-membered nitrogen heterocycle, group A substituted five-or six-membered nitrogen heterocycle; or R ₅ and R ₆ together with the N to which they are attached form an unsubstituted five-or six-membered nitrogen heterocycle, or a five-or six-membered nitrogen heterocycle substituted with group a;

The group A is selected from one or more of the following groups: optionally substituted phenyl, unsubstituted C ₁-C₄ alkyl, phenyl substituted C ₁-C₄ alkyl, amino substituted C ₁-C₄ alkanoyl, hydroxy, unsubstituted C ₁-C₄ alkoxy, amino, optionally substituted phenoxy, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl.

In some embodiments, in formula (I), R ₁ is hydrogen, unsubstituted C ₁-C₆ alkyl, or substituted C ₁-C₆ alkyl, where the substituted C ₁-C₆ alkyl refers to being substituted with one or more of the following groups: optionally substituted aromatic hydrocarbon groups, optionally substituted C ₃-C₈ cycloalkyl groups, and optionally substituted heteroaryl groups; the optionally substituted aryl, optionally substituted C ₃-C₈ cycloalkyl or optionally substituted heteroaryl refers to an unsubstituted aryl (e.g. phenyl or naphthyl), an unsubstituted C ₃-C₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyclohexyl) or an unsubstituted heteroaryl (e.g. pyrrolyl, thienyl, pyridyl, pyrimidinyl or quinolinyl), respectively, or an aryl, C ₃-C₈ cycloalkyl or heteroaryl substituted by one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

In some embodiments, R ₁ is hydrogen, unsubstituted C ₁-C₄ alkyl, or C ₁-C₄ alkyl substituted with a group selected from the group consisting of: optionally substituted phenyl, optionally heteroaryl, and optionally substituted C ₃-C₈ cycloalkyl; here, the optionally substituted phenyl, optionally heteroaryl, or optionally substituted C ₃-C₈ cycloalkyl refers to an unsubstituted phenyl, an unsubstituted heteroaryl, or an unsubstituted C ₃-C₈ cycloalkyl, respectively, or a phenyl, C ₃-C₈ cycloalkyl, or heteroaryl substituted with one or more selected from the following groups: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

In some embodiments, R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, or methyl substituted with a group selected from the group consisting of: optionally substituted phenyl, optionally substituted pyrrolyl, optionally substituted thiophene, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl; here, the optionally substituted phenyl group, optionally substituted pyrrolyl group, optionally substituted thiophene, optionally substituted pyridinyl group, optionally substituted pyrimidinyl group, optionally substituted quinolinyl group, optionally substituted cyclopentyl group or optionally substituted cyclohexyl group means an unsubstituted phenyl group, an unsubstituted pyrrolyl group, an unsubstituted thiophene group, an unsubstituted pyridinyl group, an unsubstituted pyrimidinyl group, an unsubstituted quinolinyl group, an unsubstituted cyclopentyl group or an unsubstituted cyclohexyl group, or is substituted with one or more selected from the following groups: halogen, cyano, nitro, hydroxy, phenyl substituted with a group B selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and trifluoromethyl.

In some embodiments, R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, or methyl substituted with a group selected from the group consisting of: phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl, substituted quinolinyl, cyclohexyl, substituted cyclohexyl; here, the substituted phenyl group, substituted pyridyl group, substituted pyrimidinyl group, substituted quinolinyl group or substituted cyclohexyl group means being substituted with one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, phenyl substituted with a group B selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and trifluoromethyl.

In some embodiments, R ₁ is hydrogen, methyl or isopropyl, or methyl substituted with a group selected from the group consisting of: phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl, substituted quinolinyl, cyclohexyl, substituted cyclohexyl; here, the substituted phenyl group, substituted pyridyl group, substituted pyrimidinyl group, substituted quinolinyl group or substituted cyclohexyl group means being substituted with one or more selected from the group consisting of: chlorine, fluorine, bromine, cyano, nitro, hydroxy, phenyl substituted with a group B selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and trifluoromethyl.

In some embodiments, R ₁ is hydrogen, methyl, isopropyl, cyclohexylmethyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, benzyl, 3-nitrobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 4- (2-cyanophenyl) benzyl, 3-quinolinylmethyl, or (2-chloro-pyridin-5-yl) methyl.

In some embodiments, R ₂ is:

R ₃ is hydrogen; r ₄ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy;

preferably, R ₄ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy.

In some embodiments, R ₂ is hydrogen and R ₃ is:

R ₄ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy;

In some embodiments, R ₂ is:

R ₃ and R ₄ together with the carbon to which they are attached form an optionally substituted benzene ring, or an optionally substituted five-or six-membered nitrogen heterocycle;

Preferably, R ₃ and R ₄ together with the carbon to which they are attached form an unsubstituted benzene ring, or an unsubstituted five-or six-membered nitrogen heterocycle;

Preferably, R ₃ and R ₄ together with the carbon to which they are attached form a benzene ring or five-or six-membered nitrogen heterocycle substituted with one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy;

Preferably, the five-or six-membered nitrogen heterocycle is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine;

Preferably, R ₃ and R ₄ together with the carbon to which they are attached form a benzene ring or five-or six-membered nitrogen heterocycle substituted with one or more selected from the group consisting of: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethoxy, phenyl and phenyl substituted with a group B, wherein the group B is selected from one or more of the following groups: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy;

More preferably, R ₃ and R ₄ together with the carbon to which they are attached form a benzene ring, pyridine, pyrrole, or a benzene ring, pyridine or pyrrole substituted with one or more selected from the group consisting of: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy.

In some embodiments, formula (I) is a compound of formula (I-1):

Optionally, the pyridine ring in formula (I-1) is substituted with one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

In some embodiments, formula (I) is a compound of formula (I-4):

Optionally, the pyrrole ring in formula (I-4) is substituted with one or more groups selected from: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

In some embodiments, R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached formA substituted phenyl ring, optionally further substituted with one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy;

preferably, the benzene ring may be further substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy.

In some embodiments, R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached formSubstituted five-or six-membered nitrogen heterocycles;

Preferably, the five-or six-membered nitrogen heterocycle may be further substituted with one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy;

preferably, the five-or six-membered nitrogen heterocycle may be further substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy.

In some embodiments, formula (I) is a compound of formula (I-2) or (I-3) or (I-5) or (I-6):

Optionally, the pyridine or pyrrole ring in formula (I-2) or (I-3) or (I-5) or (I-6) is substituted with one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

In some embodiments, L ₁ is a single bond 、-CH₂-、-(CH₂)₂-、-(CH₂)₃-、-(CH₂)₄-、-(CH₂)₅-、-CH₂-NH-、-CH₂-CH₂-NH-、-CH₂-NH-CH₂-、-CH₂-NH-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-CH₂-、 or-ch=ch-.

In some embodiments, L ₁ is a single bond 、-CH₂-、-(CH₂)₂-、-CH₂-NH-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-、 or-ch=ch-.

In some embodiments, L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ are each independently hydrogen, unsubstituted C ₁-C₆ alkyl, group A substituted C ₁-C₆ alkyl, unsubstituted C ₃-C₈ cycloalkyl, group A substituted C ₃-C₈ cycloalkyl, unsubstituted C ₁-C₆ alkanoylamino, group A substituted C ₁-C₆ alkanoylamino, unsubstituted five-or six-membered nitrogen heterocycle, group A substituted five-or six-membered nitrogen heterocycle; or R ₅ and R ₆ together with the N to which they are attached form an unsubstituted five-or six-membered nitrogen heterocycle, or a five-or six-membered nitrogen heterocycle substituted with group a; the group A is selected from one or more of the following groups: optionally substituted phenyl, unsubstituted C ₁-C₄ alkyl, phenyl substituted C ₁-C₄ alkyl, amino substituted C ₁-C₄ alkanoyl, hydroxy, unsubstituted C ₁-C₄ alkoxy, amino, optionally substituted phenoxy, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl.

In some embodiments, L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, group A-substituted methyl, group A-substituted ethyl, group A-substituted n-propyl, group A-substituted isopropyl, group A-substituted n-butyl, group A-substituted isobutyl, group A-substituted tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, group A-substituted cyclopropyl, group A-substituted cyclobutyl, group A-substituted cyclopentyl, group A-substituted cyclohexyl, group A-substituted cycloheptyl, group A-substituted cyclooctyl, carboxamide, acetamido, propionylamino, butyrylamino, group A-substituted carboxamido, group A-substituted acetamido, group A-substituted propionylamino, group A-substituted butyrylamino, pyrrolidine, group A-substituted cycloheptyl, group A-substituted cyclooctyl, group A-substituted butyrylamino, group A-substituted acetamido dihydropyrrole, pyrrole, indoline, indole, isoindole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole benzothiazole, benzotriazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine, triazine, indolopyridine, phenothiazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine, triazine, pteridine, pyridine, or combinations thereof indolo tetrahydropyridines, group A-substituted pyrrolidines, group A-substituted pyrroles, group A-substituted indolines, group A-substituted indoles, group A-substituted isoindoles, group A-substituted pyrazolidines, group A-substituted pyrazoles, group A-substituted dihydroimidazoles, group A-substituted imidazolines, group A-substituted imidazoles, group A-substituted thiazoles, group a-substituted triazoles, group a-substituted oxazoles, group a-substituted benzimidazoles, group a-substituted indazoles, group a-substituted benzoxadiazoles, group a-substituted benzothiazoles, group a-substituted benzotriazoles, group a-substituted purines, group a-substituted piperidines, group a-substituted pyridines, quinolines, group a-substituted isoquinolines, group a-substituted acridines, group a-substituted phenothiazines, group a-substituted phenazines, group a-substituted pyridazines, group a-substituted pyrimidines, group a-substituted piperazines, group a-substituted pyrazines, group a-substituted morpholines, group a-substituted pteridines, group a-substituted triazines, group a-substituted indolopyridines, and group a-substituted indoloetetrahydropyridines;

The group A is selected from one or more of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, benzyl, phenyl, substituted phenyl, aminoacetyl, carbamoyl, hydroxy, amino, phenoxy, substituted phenoxy, pyrrolidinyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, pyrrole, indole, isoindole, pyrazolidine, pyrazole, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, benzotriazole, purine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, pyrazine, morpholine, pteridine, triazine, and indolopyridine; here, the substituted phenyl or substituted phenoxy refers to a benzene ring substituted with one or more of the following groups: halogen, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, halogenated C ₁-C₄ alkoxy, nitro, cyano, hydroxy and amino.

In some embodiments, L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ are each independently hydrogen, methyl, ethyl, N-propyl, N-butyl, 2-hydroxyethyl, 2-aminoethyl, cyclohexyl, 4-methylcyclohexyl, phenoxyacetamido, phenylpropionamido, oxazolyl, pyrazolyl, 1-methylpyrazol-5-yl, 4-methylpiperidinyl, 1-methylpiperidin-4-yl, morpholinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, 4-phenylpiperidinyl, 4-carbamoyl-piperidinyl, pyridinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2) piperazinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo-tetrahydropyridine and 7-cyanotetrahydroisoquinolinyl.

In some embodiments, L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ together with the N to which they are attached form an unsubstituted five-or six-membered nitrogen heterocycle, or a five-or six-membered nitrogen heterocycle substituted with group A; here, the five-or six-membered nitrogen heterocycle is selected from the following nitrogen heterocycles: pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, isoindole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, benzotriazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine, triazine, indolopyridine, indolo tetrahydropyridine;

In some embodiments, L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ together with the N to which they are attached form the following group: pyrazolyl, oxazolyl, piperidinyl, 4-methylpiperidinyl, 1-methylpiperidin-4-yl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-phenylpiperidinyl, 4-carbamoylpiperidinyl, pyridinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2 yl) piperazinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo tetrahydropyridinyl, and 7-cyanotetrahydroisoquinolinyl.

In some embodiments, L ₂ is-ch=,At the same time is a single bond, and/>And R ₆ is absent; r ₅ is unsubstituted C ₁-C₆ alkyl, C ₁-C₆ alkyl substituted with group A, unsubstituted C ₃-C₈ cycloalkyl, C ₃-C₈ cycloalkyl substituted with group A, unsubstituted C ₁-C₆ alkanoylamino, C ₁-C₆ alkanoylamino substituted with group A, unsubstituted five-or six-membered nitrogen heterocycle, five-or six-membered nitrogen heterocycle substituted with group A.

In some embodiments, L ₂ is-ch=,At the same time is a single bond, and/>And R ₆ is absent; r ₅ is unsubstituted five-membered or six-membered nitrogen heterocycle, or five-membered or six-membered nitrogen heterocycle substituted by group A; the five-membered or six-membered nitrogen heterocyclic ring is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine.

In some embodiments, L ₂ is-ch=,At the same time is a single bond, and/>And R ₆ is absent; r ₅ is unsubstituted five-membered or six-membered nitrogen heterocycle, or five-membered or six-membered nitrogen heterocycle substituted by group A; the five-membered or six-membered nitrogen heterocycle is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine; the group A is selected from one or more of the following groups: phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or benzyl.

In some embodiments, L ₂ is-ch=,At the same time is a single bond, and/>And R ₆ is absent; r ₅ is pyridinyl, pyrazolyl, 4-methyl-pyrazol-5-yl, oxazolyl, piperidinyl, 4-methylpiperidin-4-yl, morpholinyl, piperazinyl, 4-methylpiperazinyl, or 4-phenylpiperidinyl.

In some embodiments, L ₂ is-ch=,At the same time is a single bond, and/>And R ₆ is absent; r ₅ is 4-methylpiperazinyl.

In some embodiments of the present invention, in some embodiments,Is a five-membered or six-membered nitrogen heterocycle and/>And R ₆ is absent; r ₅ is absent, hydrogen, unsubstituted C ₁-C₆ alkyl, group A substituted C ₁-C₆ alkyl, unsubstituted C ₃-C₈ cycloalkyl, group A substituted C ₃-C₈ cycloalkyl, unsubstituted C ₁-C₆ alkanoylamino, group A substituted C ₁-C₆ alkanoylamino, unsubstituted five-or six-membered nitrogen heterocycle, group A substituted five-or six-membered nitrogen heterocycle.

In some embodiments of the present invention, in some embodiments,Is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine, and/>And R ₆ is absent; r ₅ is absent or hydrogen.

In some embodiments of the present invention, in some embodiments,Is pyrazole, oxazole, piperidine or pyridine, and/>And R ₆ is absent; r ₅ is absent, hydrogen or methyl.

In some embodiments, L ₁ is-CH ₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ are each ethyl.

In some embodiments, L ₁ is-CH ₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form pyrazolyl, oxazolyl, pyridinyl, 4-methylpiperazinyl, 4-methylpiperidinyl, 4-phenylpiperidinyl, piperidinyl, 4-carbamoylpiperidinyl, or morpholinyl. /(I)

In some embodiments, L ₁ is a single bond; l ₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ is hydrogen and R ₅ is pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl, 4-methylpiperidinyl, cyclohexyl, 4-methylcyclohexyl, 2-hydroxyethyl, n-butyl, phenoxyacetamido, 1-methylpiperidin-4-yl or phenylpropionamido;

in some embodiments, L ₁ is a single bond; l ₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl or 4-methylpiperazinyl.

In some embodiments, L ₁ is a single bond; l ₂ is-ch=,Singly (v)Is absent; r ₆ is absent and R ₅ is pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl or 4-methylpiperazinyl.

In some embodiments, L ₁ is-CH ₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ is hydrogen and R ₅ is cyclohexyl or 2-aminoethyl.

In some embodiments, L ₁ is-CH ₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl or 4-methylpiperazinyl.

In some embodiments, L ₁ is-ch=ch-or-CH ₂-CH₂ -; Is pyrazolyl, oxazolyl, piperazinyl or pyridine; both R ₅ and R ₆ are absent, or one is hydrogen and the other is absent or methyl.

In some embodiments, L ₁ is-CH ₂-NH-CH₂-CH₂ -or-CH ₂-NH-CH₂-CH₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ are each methyl.

In some embodiments, L ₁ is-CH ₂-NH-CH₂-CH₂ -or-CH ₂-NH-CH₂-CH₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ constitute 4-methylpiperazinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2 yl) piperazinyl, 4- (4-chlorophenyl) piperazinyl, 4-methylpiperidinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo tetrahydropyridinyl, or 7-cyanotetrahydroisoquinolinyl.

In some embodiments, the substituted aromatic phenol derivatives provided herein, or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, are selected from one of the following compounds:

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 01);

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperidine (LZ 02);

N, N-diethyl-2- (4-methylbenzyloxy) -1-naphthylethylamine (LZ 03);

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-phenylpiperidine (LZ 04);

n- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -piperidine (LZ 05);

1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 06);

1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -piperidine-4-carboxamide (LZ 07);

2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 08);

2- (2- (4-bromobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 09);

2- (2- (3-nitrobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 10);

1- (2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) -4-methylpiperazine (LZ 11);

1- (2- (4-methylpiperazin-1-yl) ethyl) -2-naphthol (LZ 12);

n- (2- (2- (4-fluorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 13);

n- (2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 14);

n- (2- (2- (quinolin-3-methoxy) naphthalen-1-yl) ethyl) morpholine (LZ 15);

n- (2- (2- (6-chloropyridin-3-methoxy) naphthalen-1-yl) ethyl) morpholine (LZ 16);

4'- ((1- (2-morpholinoethyl) naphthalen-2-yl) oxymethyl) - [1,1' -biphenyl ] -2-carbonitrile (LZ 17);

n- (2- (2-isopropoxy-naphthalen-1-yl) ethyl) morpholine (LZ 18);

(E) -1- (2- (4-fluorobenzyloxy) naphthalen-1-yl) -N- (4-methylpiperazin-1-yl) -azomethine (LZ 19);

n- ((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperazin-1-amine (LZ 20);

1- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperazine (LZ 21);

1- ((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperidine (LZ 22);

n- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 23);

n- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -cyclohexylamine (LZ 24);

(1 r,4 r) -N- ((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methyl-1-cyclohexylamine (LZ 25);

2- (((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) amino) -1-ethanol (LZ 26);

N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 27);

n- ((2- ((4-methylbenzyl) oxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 28);

N- ((2- (benzyloxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 29);

N- ((2- (cyclohexylmethoxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 30);

n- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 31);

n' - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -3-phenylpropionyl hydrazide (LZ 33);

N' - ((2- (benzyloxy) naphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 34);

N' - ((2-isopropoxy naphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 35);

N' - ((2-methoxynaphthalen-1-yl) methyl) -3-phenylpropionyl hydrazide (LZ 36);

1- (3- (2- (4-fluorobenzyloxy) naphthalen-1-yl) -propyl) -4-methylpiperazine (LZ 37);

N- (3- (2- (4-bromobenzyloxy) naphthalen-1-yl) -propyl) ethylenediamine (LZ 38);

N- (3- (2- ((4-bromobenzyl) oxy) naphthalen-1-yl) propyl) cyclohexylamine (LZ 39);

(E) -4- (2- (2- (4-bromobenzyloxy) naphthalen-1-yl) vinyl) pyridine (LZ 40);

4- (2- (2-benzyloxy-naphthalen-1-yl) ethyl) piperidine (LZ 41);

4- (2- (2- (benzyloxy) naphthalen-1-yl) ethyl) pyridine (LZ 42);

n- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -3- (4-methylpiperazin-1-yl) propan-1-amine (LZ 43);

N ¹ - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -N ³,N³ -dimethylpropane-1, 3-diamine (LZ 44);

4- (5-ethyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) -N- ((2- ((4-fluorobenzyloxy) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 45);

4- (9-ethyl-1, 3,4, 9-tetrahydro-2H-pyridin [3,4-b ] indol-2-yl) -N- (2- (4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 46);

4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 47);

N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butan-1-amine (LZ 48);

N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (o-tolyl) piperazin-1-yl) butan-1-amine (LZ 49);

n- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (3-methoxyphenyl) piperazin-1-yl) butan-1-amine (LZ 50);

N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) butan-1-amine (LZ 51);

4- (4- (4-chlorophenyl) piperazin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 52);

2- (4- (((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) amino) butyl) -1,2,3, 4-tetrahydroisoquinoline-7-carbonitrile (LZ 53);

4- (4-benzylpiperidin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 54);

4- (4-chlorophenyl) -1- (4- (((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) amino) butyl) piperidin-4-ol (LZ 55);

n- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4-methylpiperazin-1-yl) butan-1-amine (LZ 56);

N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4-methylpiperidin-1-yl) butan-1-amine (LZ 57);

N ¹ - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -N ⁴,N⁴ -dimethylbutane-1, 4-diamine (LZ 58);

n- (2- ((4-fluorobenzyl) oxy) benzyl) -4- (4-methylpiperazin-1-yl) butan-1-amine (LZ 60);

N ¹ - (2- ((4-fluorobenzyl) oxy) benzyl) -N ⁴,N⁴ -dimethylbutane-1, 4-diamine (LZ 61);

n- (5-chloro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 62);

N- (5-methoxy-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 63);

N- (5-methyl-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 64);

n- (5-nitro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 65);

N- (5-fluoro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 66);

N- (2- ((4-bromobenzyl) oxy) -5-chlorobenzyl) -1-methylpiperidin-4-amine (LZ 67);

N- (2- ((4-bromobenzyl) oxy) -5-methoxybenzyl) -1-methylpiperidin-4-amine (LZ 68);

N- (2- ((4-bromobenzyl) oxy) -5-fluorobenzyl) -1-methylpiperidin-4-amine (LZ 69);

n- (2- ((4-bromobenzyl) oxy) -5-methylbenzyl) -1-methylpiperidin-4-amine (LZ 70);

N- (2- ((4-bromobenzyl) oxy) -5-nitrobenzyl) -1-methylpiperidin-4-amine (LZ 71);

N- (5-methoxy-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 72);

1-methyl-N- (5-methyl-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) piperidin-4-amine (LZ 73);

n- (5-fluoro-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 74);

1-methyl-N- (5-nitro-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) piperidin-4-amine (LZ 75); and

N- (3- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 76).

In another aspect, the present application provides a method for preparing the above substituted aromatic phenol derivative, comprising the steps of:

in the case where R ₂ is not hydrogen in the compound of formula (I),

Coupling reaction is carried out on the compound of the formula (II) and the compound of the formula (III) to obtain the compound of the formula (I);

Or alternatively

Coupling the compound of formula (IV) with a compound of formula (V) to give a compound of formula (I)

In the compound of the formula (II), n is 0, 1 or 2, Z is-C (O) H or-Br; in the compound of formula (III), X ₁ is hydrogen and R ₉ is a nitrogen-containing group; in the compound of formula (V), X ₂ is a leaving group such as-Br; the definition of other groups is the same as that of the compound of the formula (I);

in the case where R ₂ is hydrogen in the compound of formula (I), the compound of formula (I) is prepared in a similar manner.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme one:

Scheme one:

reagents and conditions:

(i) Glyoxal (40% aqueous solution), potassium hydroxide, water, room temperature overnight;

(ii) Hydrochloric acid, dichloromethane/water, 50 ℃,3 hours;

(iii) Lithium aluminum hydride, tetrahydrofuran, at 0 ℃ to room temperature for 3 hours;

(iv) 4-substituted benzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetonitrile, room temperature to 50 ℃ for 12 hours;

(v) Dess-martin oxidant, dichloromethane, overnight at room temperature;

(vi) Substituted amine, sodium triacetoxyborohydride, dichloromethane, room temperature overnight.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme two:

Scheme II:

reagents and conditions:

(i) Alicyclic amine (N-methylpiperazine or morpholine), at room temperature for 3 hours;

(iia) 4-substituted benzyl bromide, potassium tert-butoxide, anhydrous tetrahydrofuran, 0 ℃ to room temperature overnight;

(iiia) ① borane-tetrahydrofuran complex, tetrahydrofuran, reflux, overnight; ② Hydrochloric acid, methanol, reflux for 12 hours; ③ Sodium hydroxide, water, ph=8.

(Iib) lithium aluminum hydride, tetrahydrofuran, 0 ℃ to room temperature for 3 hours;

(iiib) substituted benzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetonitrile, room temperature or 50 ℃ overnight.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme three:

Scheme III:

reagents and conditions:

(i) 4-fluorobenzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetone at 20-56 ℃ overnight;

(iia) 1-amino-4-methylpiperazine, dichloromethane, overnight at room temperature;

(iiia) sodium borohydride, glacial acetic acid, anhydrous methanol, room temperature, overnight;

(iib) substituted amine, sodium triacetoxyborohydride, dichloromethane, overnight at room temperature;

(iic) hydrazide compound, absolute ethanol, reflux, 48h;

(iiib) sodium cyanoborohydride, anhydrous methanol, glacial acetic acid, and overnight at room temperature.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme four:

scheme IV:

reagents and conditions:

(i) Acrylic acid, amberlyst15 ion exchange resin, toluene, reflux, 48h;

(ii) Lithium aluminum hydride, tetrahydrofuran, at 0 ℃ to room temperature for 3 hours;

(iii) 4-substituted benzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetonitrile, 50 ℃ overnight;

(iv) Carbon tetrabromide, triphenylphosphine, dichloromethane, room temperature, 5h;

(v) Substituted amine, potassium carbonate, tetrabutylammonium iodide, acetonitrile, reflux, overnight.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme five:

Scheme five:

reagents and conditions:

(i) 2-methylpyridine/4-methylpyridine, acetic anhydride, reflux, 48 hours;

(ii) 4-fluorobenzyl bromide/4-bromobenzyl bromide, sodium methoxide, N, N-dimethylformamide, at room temperature for 8 hours;

(iiia) hydrogen, platinum dioxide, glacial acetic acid, ethanol, room temperature, 36 hours;

(iiib) hydrogen, palladium on charcoal, methanol, room temperature, overnight;

in some embodiments, the present application provides a process for preparing the above substituted aromatic phenol derivatives, as shown in scheme six:

scheme six:

Reagents and conditions:

(i) 4-amino-1-butanol or 3-amino-1-propanol, sodium triacetoxyborohydride, anhydrous methanol, glacial acetic acid, overnight at room temperature;

(ii) Di-tert-butyl dicarbonate, triethylamine, dichloromethane, overnight at room temperature;

(iii) Carbon tetrabromide, triphenylphosphine, dichloromethane, room temperature and 3h; ;

(iv) ① organic amine compound, potassium carbonate, tetrabutylammonium iodide, acetonitrile, 25-60 ℃ overnight; ② Saturated dioxane solution of hydrochloric acid at room temperature overnight.

In some embodiments, the present application provides a process for preparing the above substituted aromatic phenol derivatives, as shown in scheme seven:

Scheme seven:

Reagents and conditions:

(i) 4-fluorobenzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetone, refluxing and passing liquid;

(ii) ① 4-amino-1-butanol, sodium triacetoxyborohydride, dichloromethane, overnight at room temperature; ② Di-tert-butyl dicarbonate, triethylamine, dichloromethane, overnight at room temperature;

(iii) Carbon tetrabromide, triphenylphosphine, room temperature, 3h;

(iv) ① primary amine compound, potassium carbonate, tetrabutylammonium iodide, acetonitrile, 60 ℃; ② Saturated dioxane solution of hydrochloric acid at room temperature overnight.

In some embodiments, the present application provides a process for the preparation of the above substituted aromatic phenol derivatives, as shown in scheme eight:

Scheme eight:

Reagents and conditions:

(i) 4-substituted benzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetone, 20-56 ℃ and 3-8 h;

(ii) 1-methyl-4-aminopiperidine, sodium triacetoxyborohydride, dichloromethane, overnight at room temperature.

In some embodiments, the present application provides a process for preparing the above substituted aromatic phenol derivatives, as shown in scheme nine:

Scheme nine:

Reagents and conditions:

(i) 4-fluorobenzyl bromide, potassium carbonate, tetrabutylammonium iodide, acetone, and refluxing overnight;

In a fourth aspect, the present application provides a pharmaceutical composition comprising a pharmacologically effective amount of a substituted aromatic phenol derivative as described above, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier. The derivative is mixed with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition of the application. The pharmaceutical composition may be administered orally in the form of tablets, capsules, pills, powders, granules, powders, or syrups, or parenterally in the form of injections. The pharmaceutical composition has a unit dose of 0.1mg to 1g.

The above pharmaceutical composition can be prepared by conventional pharmaceutical methods. Suitable pharmaceutically acceptable carriers include diluents or fillers, as well as binders, excipients, disintegrants, lubricants, stabilizers, sweeteners or flavoring agents, pigments, dyes, and the like. Common excipients include: saccharide derivatives, starch derivatives, cellulose derivatives, acacia, etc.; binders such as gelatin, polyvinylpyrrolidone, polyethylene glycol; disintegrants such as sodium carboxymethyl cellulose, polyvinylpyrrolidone; lubricants such as talc, calcium stearate, magnesium stearate, spermaceti and the like; stabilizers such as methyl parahydroxybenzoate; there are also various sweeteners or flavors, colors or dyes, and diluents such as water and various organic solvents such as ethanol, propylene glycol, glycerin, and the like.

In a fifth aspect, the present application provides a substituted aromatic phenol derivative as described above, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition thereof, for use as a medicament.

In a sixth aspect, the present application provides the use of the substituted aromatic phenol derivative, as shown in formula (I), or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition thereof, for treating or preventing a disease for which a kna1.1 channel inhibitor is indicated.

In a seventh aspect, the application provides an application of the substituted aromatic phenol derivative shown in the formula (I), or pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition thereof in preparing medicines for treating or preventing KNa1.1 channel inhibitor applicable diseases.

In an eighth aspect, the present application provides a method of treating or preventing a disease for which a KNa1.1 channel inhibitor is indicated, the method comprising administering to a patient in need thereof a therapeutically effective amount of a substituted aromatic phenol derivative as described above, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition thereof.

In some embodiments, the kno1.1 pathway inhibitor is a selective kno1.1 pathway inhibitor. The KNa1.1 channel inhibitor is suitable for use in diseases including, but not limited to, central nervous system diseases such as epilepsy, convulsions, cardiac arrhythmias, neuropathic pain, epileptic encephalopathy, myocardial infarction, pain, psychosis or muscle disorders.

Definition of the definition

In the present application, the halogen is chlorine, fluorine, bromine or iodine.

C ₁-C₆ alkyl is a straight-chain or branched alkane having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl.

Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application. Other advantages of the application may be realized and attained by the structure particularly pointed out in the written description and drawings.

Drawings

The accompanying drawings are included to provide an understanding of the principles of the application, and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain, without limitation, the principles of the application.

FIG. 1 is a graph of the magnitude-response of quinidine, benzydil, LZ23, LZ38, LZ53, LZ41, LZ46, LZ58, and K _Na 1.1.1 in concentration gradients, from which the current inhibition IC ₅₀ can be calculated;

In fig. 2, a: the inhibition of hERG channel by compounds quinidine, LZ23, LZ41 is illustrated; b: the compounds LZ23 and LZ41 are shown to have a strong inhibition effect on K _Na1.1^Y796H.

In fig. 3, a: the inhibition of hERG channel by compound LZ41 at 100. Mu.M is illustrated; b: illustrating the inhibition of BK channel by Compound LZ41 at 10. Mu.M; c: illustrating the inhibition of the Na _V 1.5 channel by Compound LZ41 at 10. Mu.M; d: illustrating the inhibition of the Na _V 1.2 channel by Compound LZ41 at 10. Mu.M; e: illustrating the selectivity of compound LZ41 for the K _Na1.1、hERG、BK、Na_V1.5、Na_V 1.2 channel;

FIG. 4 illustrates the selectivity of quinidine, compounds LZ23, LZ38, LZ53, LZ46, LZ58 for the K _Na1.1、hERG、BK、Na_V1.5、Na_V 1.2.2 channel;

In fig. 5, a: three doses of 30mg/kg, 60mg/kg, 120mg/kg of compound LZ23, and three doses of 30mg/kg, 60mg/kg, 120mg/kg of LZ41 have a delayed effect on seizure time; b: three doses of 30mg/kg, 60mg/kg and 120mg/kg of the compound ZL23 and three doses of 30mg/kg, 60mg/kg and 120mg/kg of ZL41 have a seizure frequency reducing effect.

Detailed Description

In order to make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application will be described in detail hereinafter. It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be arbitrarily combined with each other.

In the present invention, abbreviations are:

Me methyl group

Et ethyl group

Ac acetyl group

MeCN acetonitrile

Boc

DCM dichloromethane

PE Petroleum ether

DMF dicarboxamide

THF tetrahydrofuran

TBAI tetrabutylammonium iodide

DMAP 4-dimethylaminopyridine

EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

R.t. room temperature

Half-maximal inhibitory amount of IC ₅₀

DIPEA diisopropylethylamine

HATU 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

MeOH methanol

FBS fetal bovine serum

PBS phosphate buffer

Adenosine ATP triphosphate

Tris tromethamine

GTP guanosine triphosphate

EGTA ethylene glycol bis (2-aminoethylether) tetraacetic acid

HEPES 4-hydroxyethylpiperazine ethanesulfonic acid

Nuclear magnetic data were determined by a Bruker AVANCE III model 400 nmr, internal standard TMS (tertramethyl silance); nuclear magnetic data were processed by mestReNova (ver.6.1.0, mesrelab Research s.l.) software; high resolution mass spectrometry data (ESI-TOF) were determined by Bruker Apex IV FTMS fourier ion cyclotron transform mass spectrometry; thin layer chromatography silica gel plate (Shanghai bang Co., ltd.); column chromatography silica gel (200-300 mesh, shanghai Pont industries, inc.).

All solvents, starting materials and reagents were, unless otherwise indicated, commercially available as analytical products.

Example 1, 2-dihydro-naphtho [2,1-b ] furan-1, 2-diol (2)

The synthesis method comprises the following steps: potassium hydroxide (225 mmol) was weighed and dissolved in water (360 mL), 2-naphthol (27 g,187 mmol) was added, and the mixture was stirred in a conical flask for 3 hours to allow complete dissolution. The now prepared potassium 2-naphthol solution was transferred to a dropping funnel and slowly added dropwise to a round bottom flask containing 40% glyoxal in water (135 g,1.12 mol) and the clear solution in the flask appeared as a white precipitate. After the completion of the dropwise addition, the reaction solution was stirred and reacted overnight at room temperature, a large amount of pale yellow precipitate was observed to be precipitated, and the liquid phase was dark yellowish brown. When the precipitate is not increased any more, the reaction is stopped, the reaction system is reduced in pressure and filtered to obtain a pale yellow precipitate, and the pale yellow precipitate is washed with a small amount of chloroform (20 mL multiplied by 2) to obtain a crude product (35.8 g, 94%) of a target product, and the subsequent reaction can be directly carried out without purification. The mother liquor after suction filtration was left at 4℃overnight to precipitate pale yellow needle-like crystals, which were then filtered and washed twice with a small amount of chloroform (2 mL. Times.2), to give a pure target product (560 mg).

¹H NMR(400MHz,DMSO-d₆)δ7.96–7.84(m,4H),7.51(ddd,J＝8.4,6.8,1.4Hz,1H),7.40(d,J＝6.4Hz,1H),7.34(ddd,J＝8.0,6.8,1.1Hz,1H),7.16(d,J＝8.8Hz,1H),5.82(d,J＝6.9Hz,1H),5.69(dd,J＝6.4,1.6Hz,1H),5.22(d,J＝6.8Hz,1H).MS(ESI) Theoretical value C ₁₂H₁₀O₃[M+H]⁺ m/z 202.1, found 202.1.

EXAMPLE 2 naphtho [2,1-b ] furan-2 (1H) -one (3)

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The synthesis method comprises the following steps: crude 1, 2-dihydro-naphtho [2,1-b ] furan-1, 2-diol (2, 25 g) was dissolved in dichloromethane (200 mL) and the solution was placed in a round bottom flask containing 3mol/L aqueous hydrochloric acid (250 mL). The reaction was stirred at 50℃for three hours, then the aqueous phase was removed by pipetting, and the dichloromethane-organic phase was washed with saturated brine (200 mL. Times.2) and dried over anhydrous sodium sulfate. The reaction solution is separated by silica gel column chromatography (petroleum ether: ethyl acetate=7:1-5:1) to obtain white to light pink crystals of the target product (10.5g).¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝8.3Hz,1H),7.81(d,J＝8.8Hz,1H),7.59(dd,J＝8.2,1.4Hz,1H),7.54(ddd,J＝8.2,6.5,1.2Hz,1H),7.44(ddd,J＝8.1,6.5,1.5Hz,1H),7.30(d,J＝8.8Hz,1H),3.91(s,2H).¹³C NMR(101MHz,CDCl₃)δ174.49,152.30,130.54,129.78,129.33,129.18,127.69,124.93,122.94,116.64,111.50,32.21.

Example 3 1- (2-hydroxyethyl) -2-naphthol (4)

The synthesis method comprises the following steps: naphtho [2,1-b ] furan-2 (1H) -one (3, 33.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and ice-cooled to a system temperature of 0 ℃. Lithium aluminum hydride (100.0 mmol) was taken and added slowly to the system in three portions to avoid excessive bubbles. The reaction was continued to room temperature for about 3 hours, and saturated ammonium chloride was added to the reaction system to quench the reaction until no significant bubbles were generated. The reaction solution is subjected to rotary evaporation to remove tetrahydrofuran and part of water, and a proper amount of dichloromethane is added to fully dissolve solids in the system, and diatomite is subjected to suction filtration. The filter residue was redissolved in dichloromethane, stirred overnight, filtered through celite, and the filtrate obtained was combined with the filtrate from the first suction. Extracting the total filtrate with saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate by rotary evaporation, separating by silica gel column chromatography (petroleum ether: ethyl acetate=5:1-4:1), and obtaining the target product as white crystals (yield) ：84％).¹H NMR(400MHz,DMSO-d₆)δ9.53(s,1H),7.93(d,J＝8.5Hz,1H),7.75(d,J＝8.1Hz,1H),7.63(d,J＝8.7Hz,1H),7.51–7.37(m,1H),7.26(t,J＝7.4Hz,1H),7.15(d,J＝8.7Hz,1H),4.76(t,J＝5.4Hz,1H),3.71–3.48(m,2H),3.16(t,J＝7.7Hz,2H).

General synthesis method one:

2- ((4-substituted benzyl) oxy) -1-naphthanoethanol (5 a-5 b):

The synthesis method comprises the following steps: 1- (2-hydroxyethyl) -2-naphthol (4, 3.00g,16.0 mmol) was dissolved in acetonitrile (100 ml), and substituted benzyl bromide (19.0 mmol), potassium carbonate (48 mmol) and tetrabutylammonium iodide (8.0 mmol) were added respectively, stirred at room temperature and reacted overnight, and the reaction was monitored by silica gel thin layer chromatography, still a clear starting material was seen. And heating the reaction system to 50 ℃ for continuous reaction, and after heating the reaction for 3 hours, almost completely reacting the raw materials, and ending the reaction. The reaction solution is taken to remove acetonitrile by rotary evaporation, and is dissolved in dichloromethane again, insoluble inorganic salts are removed by suction filtration, and the filtrate is taken to be extracted by anhydrous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation of the filtrate, followed by separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate=5:1 to 4:1) to give the objective product (yield: 48% to 86%).

Example 4 2- ((4-fluorobenzyl) oxy) -1-naphthanoethanol (5 a)

The synthesis method comprises the following steps: the same general synthetic method I adopts the compound 1- (2-hydroxyethyl) -2-naphthol (4) and 4-fluorobenzyl bromide as raw materials to obtain white powder with yield ：64％.¹H NMR(400MHz,CDCl₃)δ8.01(dd,J＝8.7,1.1Hz,1H),7.79(dd,J＝8.2,1.5Hz,1H),7.74(d,J＝9.0Hz,1H),7.49(ddd,J＝8.4,6.8,1.4Hz,1H),7.46–7.39(m,2H),7.36(ddd,J＝8.0,6.8,1.1Hz,1H),7.29(d,J＝9.0Hz,1H),7.13–7.02(m,2H),5.18(s,2H),3.91(t,J＝6.8Hz,2H),3.43(t,J＝6.8Hz,2H).¹³C NMR(101MHz,CDCl₃)δ162.53(d,J＝246.6Hz,1C),153.94,133.43,132.96(d,J＝3.3Hz,1C),129.53,129.20(d,J＝8.3Hz,2C),128.60,128.36,126.64,123.67,123.22,120.40,115.61(d,J＝21.5Hz,2C),114.50,70.67,62.86,28.68.

Example 5 2- ((4-bromobenzyl) oxy) -1-naphthaleneethanol (5 b)

The synthesis method comprises the following steps: the white solid is obtained by using the compound 1- (2-hydroxyethyl) -2-naphthol (4) and 4-bromobenzyl bromide as raw materials according to the same general synthetic method I, and the yield is: 68%.

General synthesis method II:

2- ((4-substituted benzyl) oxy) -1-naphtaleneacaldehyde (6 a-6 b):

The synthesis method comprises the following steps: 2- ((4-substituted benzyl) oxy) -1-naphthanol (5 a-5 b,5.3 mmol) was dissolved in dichloromethane (120 ml), dess-martin oxidant (6.6 mmol) was added, stirred at room temperature, reacted overnight, and the reaction was monitored by silica gel thin layer chromatography. After the reaction, insoluble matters were removed from the reaction solution by suction filtration, the filtrate was extracted once with a saturated sodium bicarbonate solution, and the organic phase was collected by extraction with a saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, the solvent of the filtrate was removed by rotary evaporation, and the residue was chromatographed on a silica gel column (petroleum ether: ethyl acetate=7:1) to give the desired product 2- ((4-substituted benzyl) oxy) -1-naphtaleneacaldehyde (6 a-6 b).

Example 6 2- ((4-fluorobenzyl) oxy) -1-naphtalenal (8 a)

The synthesis method comprises the following steps: the same general synthetic method II uses 2- ((4-fluorobenzyl) oxy) -1-naphthalene ethanol (5 a) as raw material to obtain white solid with yield ：70％.¹H NMR(400MHz,CDCl₃)δ9.66(t,J＝2.2Hz,1H),7.99–7.71(m,3H),7.50(ddd,J＝8.4,6.8,1.4Hz,1H),7.45–7.29(m,3H),7.16–6.97(m,2H),5.19(s,2H),4.16(d,J＝2.2Hz,2H).¹³C NMR(101MHz,CDCl₃)δ199.91,162.58(d,J＝246.5Hz),154.22,133.43,132.60(d,J＝3.3Hz),129.60,129.42,129.30(d,J＝8.1Hz),128.72,127.23,123.96,122.80,115.65(d,J＝21.5Hz),114.38,114.35,70.72,40.65.

Example 7 2- ((4-bromobenzyl) oxy) -1-naphtalenal (8 a)

The synthesis method comprises the following steps: in the same way as in the general synthesis method II, 2- ((4-bromobenzyl) oxy) -1-naphthalene ethanol (5 b) is used to obtain white solid with yield ：65％.¹H NMR(400MHz,CDCl₃)δ9.68(t,J＝2.2Hz,1H),7.87–7.75(m,3H),7.57–7.45(m,3H),7.39(ddd,J＝8.0,6.8,1.1Hz,1H),7.34–7.26(m,4H),5.19(s,2H),4.18(d,J＝2.2Hz,2H).¹³C NMR(101MHz,CDCl₃)δ199.83,154.11,135.85,133.41,131.86(2C),129.63,129.42,129.03(2C),128.72,127.26,124.00,122.79,122.09,114.32,114.19,70.57,40.65.

And a general synthesis method III:

2- ((4-substituted benzyl) oxy) -1-naphthylethylamine analogues (LZ 01 to LZ 07)

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The synthesis method comprises the following steps: 2- ((4-substituted benzyl) oxy) -1-naphthanal (6 a-6 b,2.65 mmol) was dissolved in dichloromethane (100 ml), secondary amine compound (3.18 mmol) was added, the reaction was stirred at room temperature for 1h, then sodium triacetoxyborohydride (1.3 mmol) was added every 30min, the reaction was carried out overnight at room temperature, and the reaction was monitored by silica gel thin layer chromatography. After the reaction is finished, ammonia water is slowly added into the reaction system to adjust the pH of the system to be alkaline, a proper amount of dichloromethane is added, the mixture is extracted once by saturated sodium bicarbonate, the organic phase is extracted again by saturated sodium chloride solution, and the organic phase is collected. The final organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate solvent removed by rotary evaporation, and the residue was purified by silica gel column chromatography (di-zero methane: anhydrous methanol=50:1-30:1) to give the desired product 2- ((4-substituted benzyl) oxy) -1-naphthylethylamine analog.

Example 8 1- (2- (4-Fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 01)

The synthesis method comprises the following steps: the synthesis method is the same as the general synthesis method III, and 2- ((4-fluorobenzyl) oxy) -1-naphthalene acetaldehyde (6 a) and 1-methylpiperazine are used as raw materials to obtain white powder, and the yield ：84％.¹H NMR(400MHz,CDCl3)δ7.99(dd,J＝8.6,1.1Hz,1H),7.78(dd,J＝8.2,1.4Hz,1H),7.71(d,J＝9.0Hz,1H),7.49(ddd,J＝8.4,6.8,1.4Hz,1H),7.46–7.40(m,2H),7.34(ddd,J＝8.0,6.8,1.1Hz,1H),7.27(d,J＝9.1Hz,1H),7.11–7.03(m,2H),5.16(s,2H),3.45–3.20(m,2H),2.63–2.57(m,2H),2.79–2.40(m,8H),2.32(s,3H).¹³C NMR(101MHz,CDCl3)δ162.48(d,J＝246.2Hz,1C),153.44,133.18,133.14,129.44,129.21(d,J＝8.2Hz,2C),128.58,127.90,126.51,123.50,123.11,121.92,115.47(d,J＝21.6Hz,2C),114.48,70.51,58.08,55.10(2C),53.05(2C),46.05,22.66.HRMS(ESI) is calculated to be C ₂₄H₂₈FN₂O,[M+H]⁺ m/z 379.2186 and the measured value is 379.2184.

Example 9 1- (2- (4-Fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperidine (LZ 02)

The synthesis method comprises the following steps: in the same way as in the third general synthesis method, 2- ((4-fluorobenzyl) oxy) -1-naphthaldehyde (6 a) and 1-methylpiperidine are used as raw materials to obtain white powder, and the calculated value C ₂₅H₂₉FNO,[M+H]⁺ m/z 378.2233 of the yield ：89％.¹H NMR(400MHz,CDCl₃)δ7.98(d,J＝8.2Hz,1H),7.77(dd,J＝8.2,1.3Hz,1H),7.73(d,J＝9.0Hz,1H),7.51(ddd,J＝8.4,6.8,1.4Hz,1H),7.47–7.39(m,2H),7.35(ddd,J＝8.0,6.8,1.1Hz,1H),7.27(d,J＝8.8Hz,1H),7.12–7.04(m,2H),5.16(s,2H),3.61–3.35(m,2H),3.27(d,J＝11.3Hz,2H),2.92–2.69(m,2H),2.39–2.20(m,2H),1.84–1.60(m,2H),1.55–1.40(m,3H),0.97(d,J＝5.5Hz,3H).¹³C NMR(101MHz,CDCl₃)δ162.56(d,J＝246.6Hz,1C),153.49,133.00(d,J＝3.3Hz,1C),132.95,129.46(d,J＝8.3Hz,2C),129.41,128.60,128.53,127.05,123.76,122.85,119.87,115.55(d,J＝21.5Hz,2C),114.24,70.58,57.34,53.39(2C),32.60,29.96,21.50,21.39(2C).HRMS(ESI) is found, and the measured value is 378.2228.

Example 10N, N-diethyl-2- (4-methylbenzyloxy) -1-naphthylethylamine (LZ 03)

The synthesis method comprises the following steps: in the same way as in the third general synthesis method, 2- ((4-fluorobenzyl) oxy) -1-naphthalene acetaldehyde (6 a) and diethylamine are used as raw materials to obtain white powder, and the calculated value C ₂₃H₂₇FNO,[M+H]⁺ m/z 352.2077 of the yield ：83％.¹H NMR(400MHz,CDCl₃)δ8.02(d,J＝8.6Hz,1H),7.80(dd,J＝8.2,1.3Hz,1H),7.72(d,J＝8.9Hz,1H),7.51(ddd,J＝8.5,6.8,1.5Hz,1H),7.48–7.41(m,2H),7.36(ddd,J＝8.0,6.7,1.1Hz,1H),7.29(d,J＝9.0Hz,1H),7.13–7.00(m,2H),5.16(s,2H),3.37–3.23(m,2H),2.77–2.71(m,2H),2.69(q,J＝7.2Hz,4H),1.08(t,J＝7.2Hz,6H).¹³C NMR(101MHz,CDCl₃)δ162.53(d,J＝246.1Hz),153.50,133.21,133.11(d,J＝3.2Hz),129.47,129.43(d,J＝8.2Hz),128.59,127.83,126.55,123.50,123.07,122.09,115.45(d,J＝21.5Hz)114.38,70.58,51.83,46.92,22.18,11.78.HRMS(ESI) is found to be 352.2070.

Example 11 1- (2- (4-Fluorobenzyloxy) -1-naphthylethyl) -4-phenylpiperidine (LZ 04)

The synthesis method comprises the following steps: in the same way as in the third general synthesis method, 2- ((4-fluorobenzyl) oxy) -1-naphthaldehyde (6 a) and 4-phenylpiperidine are used as raw materials to obtain a white powder, yield ：76％.¹H NMR(400MHz,CDCl₃)δ8.07(d,J＝8.6Hz,1H),7.80(dd,J＝8.2,1.3Hz,1H),7.76(d,J＝9.0Hz,1H),7.55(ddd,J＝8.4,6.7,1.3Hz,1H),7.48–7.42(m,2H),7.41–7.21(m,7H),7.13–7.05(m,2H),5.20(s,2H),3.68–3.35(m,4H),2.97–2.78(m,2H),2.68–2.55(m,1H),2.54–2.37(m,2H),2.30–2.04(m,2H),1.93(d,J＝13.3Hz,2H).¹³C NMR(101MHz,CDCl₃)δ162.59(d,J＝247.0Hz,1C),153.52,132.95,132.91,129.52(d,J＝8.1Hz,2C),129.43,128.80,128.69(2C),128.60(2C),127.29,126.86(2C),126.78(2C),123.91,122.99,115.63(d,J＝21.6Hz,2C)114.17,70.65,57.11,53.44(2C),41.39,31.31,29.72,21.13.HRMS(ESI) calculated as C ₃₀H₃₁NOF,[M+H]⁺ m/z 440.2390, found value 440.2383.

EXAMPLE 12N- (2- (4-Fluorobenzyloxy) -1-naphthylethyl) -piperidine (LZ 05)

The synthesis method comprises the following steps: in the same way as in the third general synthesis method, 2- ((4-fluorobenzyl) oxy) -1-naphthalene acetaldehyde (6 a) and piperidine are used as raw materials to obtain white powder, and the yield ：80％.¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝8.6Hz,1H),7.78(dd,J＝8.3,1.4Hz,1H),7.70(d,J＝9.0Hz,1H),7.58–7.41(m,3H),7.34(ddd,J＝8.0,6.7,1.1Hz,1H),7.27(d,J＝9.1Hz,1H),7.13–7.01(m,2H),5.17(s,2H),3.50–3.18(m,2H),2.79–2.33(m,6H),1.65(p,J＝5.6Hz,4H),1.46(p,J＝7.4,6.8Hz,2H).¹³C NMR(101MHz,CDCl₃)δ162.46(d,J＝246.0Hz,1C),153.42,133.25(d,J＝3.2Hz,1C),133.20,129.45,129.17(d,J＝8.1Hz,2C),128.53,127.79,126.45,123.48,123.23,122.29,115.43(d,J＝21.4Hz,2C),114.58,70.54,58.85,54.44(2C),25.97(2C),24.44,22.52.HRMS(ESI) is calculated to be C ₂₄H₂₇FNO,[M+H]⁺ m/z 364.2077 and the actual measurement value is 364.2068.

Example 13 1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 06)

The synthesis method comprises the following steps: the same general synthetic method III uses 2- ((4-bromobenzyl) oxy) -1-naphthaldehyde (6 b) and 1-methylpiperazine as raw materials to obtain white solid with yield ：84％.¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.6Hz,1H),7.77(dd,J＝8.2,1.3Hz,1H),7.73(d,J＝9.0Hz,1H),7.59–7.44(m,3H),7.43–7.29(m,3H),7.23(d,J＝9.0Hz,1H),5.14(s,2H),3.53–3.40(m,2H),3.37–3.26(m,2H),2.91–2.78(m,2H),2.49–2.27(m,2H),1.77–1.66(m,2H),1.61–1.43(m,3H),0.97(d,J＝5.8Hz,3H).¹³C NMR(101MHz,CDCl₃)δ153.46,136.25,132.94,131.88(2C),129.48,129.36(2C),128.81,128.67,127.29,123.93,122.86,122.16,119.44,114.14,70.58,57.06,53.28(2C),32.20,29.79,25.69,21.31,21.24.

HRMS (ESI) calculated C ₂₅H₂₉BrNO,[M+H]⁺ m/z 438.1433, found 438.1429.

Example 14 1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -piperidine-4-carboxamide (LZ 07)

The synthesis method comprises the following steps: in the same way as the third synthesis method, 2- ((4-bromobenzyl) oxy) -1-naphthaldehyde (6 b) and 4-piperidinecarboxamide are taken as raw materials to obtain white powder, and the calculated value C ₂₅H₂₈BrN₂O₂,[M+H]⁺ m/z 467.1334 of the yield ：90％.¹H NMR(400MHz,DMSO-d₆)δ7.96(d,J＝8.6Hz,1H),7.85(d,J＝8.2Hz,1H),7.81(d,J＝9.0Hz,1H),7.68–7.58(m,2H),7.52(ddd,J＝8.2Hz,6.7Hz,1.4Hz,1H),7.50–7.45(m,3H),7.36(t,J＝7.5Hz,1H),7.24(s,1H),6.76(s,1H),5.27(s,2H),3.60–3.12(m,3H),3.04–2.81(m,2H),2.47–2.37(m,1H),2.18–1.90(m,3H),1.86–1.38(m,4H).¹³C NMR(101MHz,CDCl₃)δ176.24,152.30,135.46,132.09,130.67(2C),128.43,127.95(2C),127.56,126.91,125.53,122.54,122.07,120.94,120.79,113.40,69.41,57.21,52.04(2C),41.72,27.94(2C),21.73.HRMS(ESI) is found to be 467.1331.

The general synthesis method is four:

2- (2-hydroxynaphthalen-1-yl) -N-substituted acetamide analogues (7 a-7 b):

The synthesis method comprises the following steps: naphtho [2,1-b ] furan-2 (1H) -one (3, 120 mmol) was taken and dissolved in alicyclic amine (e.g. 1-methylpiperazine or morpholine, 50 ml) and stirred at room temperature for 0.5H to 2H, and the reaction was monitored by silica gel thin layer chromatography. After the reaction is finished, the reaction solution is subjected to rotary evaporation to remove most of the solvent, so that thick brown yellow liquid or a small amount of solid precipitation is obtained, 50ml of ethyl acetate is added, ultrasonic oscillation is carried out for 1min, standing is carried out, a large amount of white solid precipitation is visible, and ethyl acetate is removed by suction filtration, so that a white flaky crystal is obtained. Taking the filtrate, rotationally evaporating to remove the filtrate, adding a small amount of ethyl acetate, standing overnight at 0 ℃, precipitating again to obtain white flaky crystals, and carrying out suction filtration to obtain white flaky crystals, namely target products, and concentrating, cooling at low temperature, standing, and carrying out suction filtration until no solid is precipitated. And combining the obtained crystals to obtain the total product 2- (2-hydroxynaphthalene-1-yl) -N-substituted acetamide analogue.

Example 15 2- (2-hydroxynaphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (7 a)

The synthesis method comprises the following steps: the same general synthetic method IV uses naphtho [2,1-b ] furan-2 (1H) -ketone (3) and 1-methylpiperazine as raw materials to obtain white crystals with yield ：87％.¹H NMR(400MHz,CDCl₃)δ10.22(brs,1H),7.81(d,J＝8.6Hz,1H),7.77(dd,J＝8.1,1.3Hz,1H),7.65(d,J＝8.8Hz,1H),7.47(ddd,J＝8.5,6.8,1.4Hz,1H),7.30(ddd,J＝8.0,6.8,1.0Hz,1H),7.15(d,J＝8.8Hz,1H),4.14(s,2H),3.83(t,J＝5.0Hz,2H),3.67(t,J＝5.0Hz,2H),2.36(p,J＝5.0Hz,4H),2.25(s,3H).¹³C NMR(101MHz,CDCl₃)δ171.99,155.07,132.79,129.27,129.21,129.09,126.64,122.69,121.46,120.01,112.92,55.08,54.41,46.75,45.82,42.32,29.85.

Example 16 2- (2-hydroxynaphthalen-1-yl) -1-morpholinoethanone (7 b)

The synthesis method comprises the following steps: the same general synthetic method is adopted, and naphtho [2,1-b ] furan-2 (1H) -ketone (3) and morpholine are used as raw materials to obtain white crystals with yield ：96％.¹H NMR(400MHz,DMSO-d₆)δ9.71(brs,1H),7.80(d,J＝8.5Hz,1H),7.77(dd,J＝8.3,1.3Hz,1H),7.68(d,J＝8.8Hz,1H),7.40(ddd,J＝8.5,6.8,1.4Hz,1H),7.26(ddd,J＝8.0,6.7,1.1Hz,1H),7.17(d,J＝8.8Hz,1H),4.03(s,2H),3.70(t,J＝4.7Hz,2H),3.60(t,J＝4.7Hz,2H),3.54(t,J＝4.7Hz,2H),3.43(t,J＝4.7Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ169.72,152.93,134.53,128.54,128.37,126.44,123.77,122.67,118.33,114.45,66.69,46.09,42.32,29.96.

General synthesis method five:

2- (2-substituted benzyloxy-naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone analogues (LZ 08-LZ 10)

The synthesis method comprises the following steps: crystals (1.76 mmol) of 2- (2-hydroxynaphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (7 a) were dissolved in anhydrous tetrahydrofuran (40 ml), and the reaction system was cooled to 0℃by being placed in an ice bath. 2ml of potassium tert-butoxide (3.6 mmol) in anhydrous tetrahydrofuran (1.8 mmol/L) was slowly poured into the reaction mixture, stirred for 15min, 4-substituted benzyl bromide was added, stirred overnight, and the reaction was monitored by silica gel thin layer chromatography. After the reaction, the solvent was removed by rotary evaporation, the residue was redissolved in methylene chloride, insoluble matter was removed by suction filtration through celite, and the filtrate was extracted with saturated sodium chloride solution. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate by rotary evaporation, and the residue was purified and enriched by column chromatography on silica gel (dichloromethane: anhydrous methanol=70:1-40:1) to give the desired product, 2- (2-substituted benzyloxy-naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone analogue, as a white solid.

Example 17 2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 08)

The synthesis method comprises the following steps: the same general synthetic method five uses 2- (2-hydroxynaphthalene-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (7 a) and 4-chlorobenzyl bromide as raw materials to obtain white powder, yield ：54％.¹H NMR(400MHz,CDCl₃)δ7.96(dd,J＝8.7,1.1Hz,1H),7.78(dd,J＝8.3,1.4Hz,1H),7.77(d,J＝9.0Hz,1H),7.49(ddd,J＝8.4,6.8,1.4Hz,1H),7.39–7.32(m,5H),7.27(d,J＝8.7Hz,1H),5.16(s,2H),4.14(s,2H),3.71–3.48(m,4H),2.31(t,J＝5.1Hz,2H),2.26(s,3H),2.24(t,J＝4.9Hz,2H).¹³C NMR(101MHz,CDCl₃)δ169.48,153.40,135.76,133.86,133.81,129.57,128.97,128.89(2C),128.81(2C),128.44,126.85,123.78,123.62,118.16,114.53,70.86,55.12,54.80,46.03,45.59,41.99,30.52.HRMS(ESI) calculated value C ₂₄H₂₆ClN₂O₂,[M+H]⁺ m/z 409.1683, measured value 409.1677.

Example 18 2- (2- (4-bromobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 09)

The synthesis method comprises the following steps: the same general synthetic method five uses 2- (2-hydroxynaphthalene-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (7 a) and 4-bromobenzyl bromide as raw materials to obtain white powder, yield ：68％.¹H NMR(400MHz,CDCl₃)δ7.96(dd,J＝8.6,1.1Hz,1H),7.78(dd,J＝8.3,1.3Hz,1H),7.76(d,J＝9.0Hz,1H),7.54–7.49(m,2H),7.48(ddd,J＝8.4,6.8,1.4Hz,1H),7.35(ddd,J＝8.0,6.8,1.1Hz,1H),7.32–7.28(m,2H),7.25(d,J＝9.0Hz,1H),5.13(s,2H),4.13(s,2H),3.61(q,J＝5.5Hz,4H),2.30(t,J＝5.1Hz,2H),2.26(s,3H),2.23(t,J＝5.0Hz,2H).¹³C NMR(101MHz,CDCl₃)δ169.45,153.40,136.29,133.81,131.75(2C),129.57,129.19(2C),128.97,128.45,126.85,123.78,123.61,121.95,118.17,114.51,70.86,55.13,54.80,46.05,45.59,42.00,30.50.HRMS(ESI) calculated value C ₂₄H₂₆BrN₂O₂,[M+H]⁺ m/z 453.1178, measured value 453.1176.

Example 19 2- (2- (3-nitrobenzyloxy) naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 10)

The synthesis method comprises the following steps: the same general synthetic method five uses 2- (2-hydroxynaphthalene-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (7 a) and 3-nitrobenzyl bromide as raw materials to obtain yellow powder, yield ：50％.¹H NMR(400MHz,CDCl₃)δ8.36(t,J＝2.0Hz,1H),8.20(ddd,J＝8.3,2.4,1.1Hz,1H),7.92(dd,J＝8.6,1.0Hz,1H),7.83–7.72(m,3H),7.57(t,J＝7.9Hz,1H),7.51(ddd,J＝8.4,6.8,1.3Hz,1H),7.37(ddd,J＝8.0,6.8,1.1Hz,1H),7.28(d,J＝8.9Hz,1H),5.30(s,2H),4.20(s,2H),3.66(dt,J＝11.9,4.9Hz,4H),2.33(t,J＝5.1Hz,4H),2.27(s,3H).¹³C NMR(101MHz,CDCl₃)δ169.22,153.18,139.53,133.73,133.20,129.72,129.64(2C),129.13,128.53,126.99,123.98,123.45,122.98,122.09,118.40,114.43,70.33,55.18,54.80,46.05,45.59,42.00,30.46.HRMS(ESI) calculated value C ₂₄H₂₆N₃O₄,[M+H]⁺ m/z 420.1923, measured value 420.1921.

Example 20 1- (2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) -4-methylpiperazine (LZ 11)

The synthesis method comprises the following steps: the compound 2- (2- (4-chlorobenzyloxy) -naphthalen-1-yl) -1- (4-methylpiperazin-1-yl) ethanone (LZ 08,0.83 mmol) was dissolved in dry tetrahydrofuran (40 ml), borane-tetrahydrofuran complex (1 mmol/L tetrahydrofuran solution, 3.33ml,3.33 mmol) was added, stirred and refluxed at 65℃for overnight reaction, and the reaction was detected by silica gel thin layer chromatography until the starting material was substantially completely reacted. After the completion of the reaction, anhydrous methanol (5 ml) was added to quench the reaction, and the reaction system was cooled to room temperature. The reaction mixture was taken and subjected to rotary evaporation to remove the solvent, 6mol/L hydrochloric acid was added to obtain a methanol solution (40 ml), and the mixture was heated to reflux for overnight reaction. After the completion of the reaction, the reaction mixture was cooled to room temperature, and an aqueous sodium hydroxide solution was slowly added dropwise to adjust the pH of the reaction system to 10. The reaction mixture was taken and the solvent was removed by rotary evaporation, and the residue was redissolved in dichloromethane and extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation of the filtrate, and the residue was purified and enriched by column chromatography on silica gel (petroleum ether: ethyl acetate=7:1 to 3:1) to give the desired product 1- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) -4-methylpiperazine as a white solid in yield 61％.¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.6Hz,1H),7.78(dd,J＝8.2,1.3Hz,1H),7.71(d,J＝9.0Hz,1H),7.49(ddd,J＝8.5,6.8,1.4Hz,1H),7.45–7.30(m,5H),7.25(d,J＝9.0Hz,1H),5.17(s,2H),3.41–3.27(m,2H),2.69–2.57(m,2H),3.02–2.38(m,10H),2.35(s,3H).¹³C NMR(101MHz,CDCl₃)δ153.45,135.99,133.84,133.21,129.54,128.86(2C),128.80(2C),128.69,128.09,126.69,123.66,123.17,121.81,114.45,70.47,58.07,55.04(2C),52.98(2C),46.02,22.70.HRMS(ESI) calculated as C ₂₄H₂₈ClN₂O,[M+H]⁺ m/z 395.1890, found 395.1889.

General synthesis method six:

2- (2-hydroxynaphthalen-1-yl) -N-substituted ethylamine analogues (8, LZ 12)

The synthesis method comprises the following steps: crystals (18.4 mmol) of 2- (2-hydroxynaphthalen-1-yl) -1-fatty amino ethanone (7 a to 7 b) were dissolved in anhydrous tetrahydrofuran (100 ml), and the temperature of the reaction system was lowered to 0℃by ice bath. Taking lithium aluminum hydride (92.2 mmol) and slowly adding the lithium aluminum hydride into a reaction system for multiple times, adding the lithium aluminum hydride again after no bubbles are generated, stirring the lithium aluminum hydride in an ice bath after the lithium aluminum hydride is completely added for reaction for 3 hours, and adding a saturated ammonium chloride aqueous solution to quench the reaction until no obvious bubbles are generated. The solvent in the reaction solution was removed by rotary evaporation, and the residue was added with dichloromethane and sufficiently dissolved by ultrasonic vibration, and insoluble matter was removed by suction filtration with celite, leaving filtrate and filter residue. The filter residue is dissolved in dichloromethane again, stirred overnight, filtered off with suction, and the filtrate obtained is combined with the first filtrate and extracted with saturated sodium chloride solution. Yield the organic phase, dried over anhydrous sodium sulfate, filtered, the filtrate solvent removed by rotary evaporation, and the residue purified and enriched by silica gel column chromatography (dichloromethane: anhydrous methanol=100:1-75:1) to give the desired product, 2- (2-hydroxynaphthalen-1-yl) -N-substituted ethylamine analogue, as a white to pale orange solid.

Example 21- (2-morpholinoethyl) -2-naphthol (8)

The synthesis method comprises the following steps: in the same way as the general synthesis method six, using 2- (2-hydroxynaphthalene-1-yl) -1-morpholinoethanone (7 b) as raw material, white to light orange-red solid is obtained, yield ：71％.1H NMR(400MHz,DMSO-d₆)δ11.43(s,1H),8.09(d,J＝8.5Hz,1H),7.81(dd,J＝8.2,1.3Hz,1H),7.72(d,J＝8.8Hz,1H),7.49(ddd,J＝8.4,6.8,1.4Hz,1H),7.31(ddd,J＝8.1,6.8,1.1Hz,1H),7.26(d,J＝8.9Hz,1H),4.08–3.96(m,2H),3.93–3.78(m,2H),3.67–3.54(m,2H),3.53–3.38(m,2H),3.30–2.97(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ153.41,133.37,128.95,128.89,128.65,127.08,122.96,122.87,118.36,114.00,63.80(2C),55.01,51.29(2C),19.55.HRMS(ESI) calculated as C ₁₆H₂₀NO₂, [ M+H ] +m/z 258.1494, found 258.1496.

Example 22 1- (2- (4-methylpiperazin-1-yl) ethyl) -2-naphthol (LZ 12)

The synthesis method comprises the following steps: the same general synthetic method six uses 2- (2-hydroxynaphthalene-1-yl) -1- (4-methylpiperazine-1-yl) ethanone (7 a) as raw material to obtain white to pale yellow solid with yield ：60％.¹H NMR(400MHz,CDCl₃)δ12.67(s,1H),7.84(d,J＝8.8Hz,1H),7.76(dd,J＝8.1,1.4Hz,1H),7.65(d,J＝8.8Hz,1H),7.43(ddd,J＝8.4,6.8,1.4Hz,1H),7.28(ddd,J＝8.0,6.8,1.1Hz,1H),7.19(d,J＝8.8Hz,1H),3.28–3.14(m,2H),2.88–2.73(m,2H),3.12–2.36(m,8H),2.34(s,3H).¹³C NMR(101MHz,CDCl₃)δ154.98,133.17,128.89,128.78,128.35,126.13,122.27,121.78,120.45,118.95,59.10,54.67(2C),53.29(2C),45.81,23.87.

HRMS (ESI) calculated C ₁₇H₂₃N₂ O, [ m+h ] +m/z 271.1811, found 271.1810.

Seven general synthesis methods:

N- (2- (2- (O-substituted) oxy-naphthalen-1-yl) ethyl) morpholine analogues (LZ 13 to LZ 18)

The synthesis method comprises the following steps: 1- (2-morpholinoethyl) -2-naphthol (8) solid (1.36 mmol) was taken in acetonitrile (40 ml), bromide (e.g. 2-cyano-4' -bromomethylbiphenyl) (1.63 mmol), potassium carbonate (408 mmol), tetrabutylammonium iodide (0.68 mmol) were added, stirred at room temperature, the reaction was monitored by thin layer chromatography on silica gel overnight until complete reaction of starting material 8, and if incomplete, heated to 50 ℃ until complete reaction. After the reaction, the reaction solution is removed by rotary evaporation to obtain a solvent, methylene dichloride is added into the concentrate, the concentrate is fully dissolved by ultrasonic oscillation, insoluble substances are removed by suction filtration, and the filtrate is extracted by saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent was removed by rotary evaporation, and the residue was purified and enriched by column chromatography on silica gel (dichloromethane: anhydrous methanol=100:1-50:1) to give the solid, i.e., the desired product N- (2- (2- (O-substituted) oxy-naphthalen-1-yl) ethyl) morpholine analogue

Example 23N- (2- (4-fluorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 13)

The synthesis method comprises the following steps: in the same way as in the general synthesis method seven, 1- (2-morpholinoethyl) -2-naphthol (8) and 4-fluorobenzyl bromide are used as raw materials to obtain a pale yellow solid, and the yield 75％.¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.6Hz,1H),7.79(d,J＝8.2Hz,1H),7.73(d,J＝9.0Hz,1H),7.50(ddd,J＝8.4,6.7,1.4Hz,1H),7.47–7.41(m,2H),7.36(ddd,J＝8.1,6.8,1.1Hz,1H),7.28(d,J＝9.0Hz,1H),7.11–7.04(m,2H),5.18(s,2H),3.76(t,J＝4.7Hz,4H),3.42–3.12(m,2H),2.65–2.48(m,6H).¹³C NMR(101MHz,CDCl₃)δ162.49(d,J＝246.4Hz,1C),153.45,133.16(d,J＝3.1Hz,1C),133.12,129.44,129.21(d,J＝8.1Hz,2C),128.61,127.97,126.54,123.53,123.05,121.80,115.49(d,J＝21.5Hz,2C),114.49,70.53,67.03(2C),58.56,53.68(2C),22.48.HRMS(ESI) is calculated to be C ₂₃H₂₅FNO₂,[M+H]⁺ m/z 366.1869 and the actual measurement value is 366.1864.

Example 24N- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 14)

The synthesis method comprises the following steps: the same general synthesis method seven uses 1- (2-morpholinoethyl) -2-naphthol (8) and 4-chlorobenzyl bromide as raw materials to obtain white solid with yield ：72％.¹H NMR(400MHz,CDCl₃)δ7.98(d,J＝8.6Hz,1H),7.79(dd,J＝8.3,1.3Hz,1H),7.71(d,J＝9.0Hz,1H),7.50(ddd,J＝8.4,6.8,1.4Hz,1H),7.44–7.32(m,5H),7.25(d,J＝4.3Hz,1H),5.18(s,2H),3.91–3.62(m,4H),3.38–3.28(m,2H),2.63–2.52(m,6H).¹³C NMR(101MHz,CDCl₃)δ153.37,135.92,133.77,133.13,129.47,128.76(2C),128.67(2C),128.61,127.98,126.56,123.56,123.06,121.83,114.42,70.41,67.05(2C),58.57,53.70(2C),22.53.

HRMS (ESI) calculated C ₂₃H₂₅ClNO₂,[M+H]⁺ m/z 382.1574, found 382.1569.

Example 25N- (2- (2- (quinolin-3-methoxy) naphthalen-1-yl) ethyl) morpholine (LZ 15)

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The synthesis method comprises the following steps: in the same manner as in the seventh general synthesis method, 1- (2-morpholinoethyl) -2-naphthol (8) and 3-bromomethylquinoline are used as raw materials to obtain pale yellow solid, yield ：58％.¹H NMR(400MHz,CDCl₃)δ8.19(d,J＝8.5Hz,1H),8.10(d,J＝8.5Hz,1H),8.01(d,J＝8.6Hz,1H),7.83(dd,J＝8.2,1.4Hz,1H),7.81–7.73(m,2H),7.72(d,J＝8.5Hz,1H),7.69(d,J＝9.0Hz,1H),7.56(ddd,J＝8.2,6.8,1.2Hz,1H),7.50(ddd,J＝8.4,6.7,1.4Hz,1H),7.35(ddd,J＝8.4,6.7,1.0Hz,1H),7.31(d,J＝9.0Hz,1H),5.53(s,2H),3.77(t,J＝4.6Hz,4H),3.50–3.36(m,2H),2.71–2.63(m,2H),2.62(t,J＝4.7Hz,4H).¹³C NMR(101MHz,CDCl₃)δ158.16,153.35,147.63,137.01,133.12,129.91,129.45,128.97,128.65,128.12,127.76,127.61,126.61,126.57,123.52,123.00,121.46,119.10,114.19,72.30,67.05(2C),58.58,53.75(2C),22.67.HRMS(ESI) calculated as C ₂₆H₂₇N₂O₂,[M+H]⁺ m/z 399.2073, found value 399.2072.

EXAMPLE 26N- (2- (2- (6-chloropyridin-3-methoxy) naphthalen-1-yl) ethyl) morpholine (LZ 16)

The synthesis method comprises the following steps: in the same way as in the general synthesis method seven, 1- (2-morpholinoethyl) -2-naphthol (8) and 3-bromomethyl-6-chloropyridine are used as raw materials to obtain a white solid, and the yield is ：62％.¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝2.5Hz,1H),7.99(d,J＝8.6Hz,1H),7.84–7.77(m,2H),7.74(d,J＝9.0Hz,1H),7.52(ddd,J＝8.4,6.8,1.4Hz,1H),7.44–7.33(m,2H),7.26(d,J＝9.0Hz,1H),5.22(s,2H),3.78–3.75(m,4H),3.39–3.15(m,2H),2.73–2.39(m,6H).¹³C NMR(101MHz,CDCl₃)δ152.92,151.24,148.69,137.93,133.10,131.89,129.66,128.64,128.18,126.73,124.28,123.83,123.11,122.09,114.16,68.03,67.01(2C),58.58,53.71(2C),22.60.HRMS(ESI), calculated value C ₂₂H₂₄ClN₂O₂,[M+H]⁺ m/z 383.1526, measured value 383.1524.

Example 27 4'- ((1- (2-morpholinoethyl) naphthalen-2-yl) oxymethyl) - [1,1' -biphenyl ] -2-carbonitrile (LZ 17)

The synthesis method comprises the following steps: the same general synthesis method seven uses 1- (2-morpholinoethyl) -2-naphthol (8) and 4- ((2-cyano) phenyl) bromobenzyl as raw materials to obtain pale yellow solid with yield 57％.¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝8.6Hz,1H),7.79(ddd,J＝9.5,8.1,1.3Hz,2H),7.74(d,J＝9.0Hz,1H),7.65(td,J＝7.7,1.4Hz,1H),7.63–7.57(m,4H),7.55–7.48(m,2H),7.45(td,J＝7.6,1.3Hz,1H),7.36(ddd,J＝8.4,6.7,1.0Hz,1H),7.32(d,J＝9.0Hz,1H),5.29(s,2H),3.76(t,J＝4.6Hz,4H),3.45–3.29(m,2H),2.66–2.61(m,2H),2.61–2.53(m,4H).¹³C NMR(101MHz,CDCl₃)δ153.56,145.03,138.10,137.79,133.81,133.16,132.89,130.04,129.46,129.01(2C),128.63,128.02,127.69,127.56(2C),126.53,123.50,123.08,121.78,118.68,114.45,111.33,70.69,67.08(2C),58.61,53.73(2C),22.58.

HRMS (ESI) calculated C ₃₀H₂₉N₂O₂,[M+H]⁺ m/z 449.2229, found 449.2229.

EXAMPLE 28N- (2- (2-Isopropoxy naphthalen-1-yl) ethyl) morpholine (LZ 18)

The synthesis method comprises the following steps: the same general synthesis method seven uses 1- (2-morpholinoethyl) -2-naphthol (8) and isopropyl bromide as raw materials to obtain a tan solid with yield 56％.¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝8.6Hz,1H),7.77(dd,J＝8.3,1.2Hz,1H),7.77(d,J＝9.1Hz,1H),7.57(ddd,J＝8.4,6.8,1.4Hz,1H),7.37(ddd,J＝8.0,6.8,1.0Hz,1H),7.22(d,J＝9.1Hz,1H),4.75(hept,J＝6.1Hz,1H),4.59–4.36(m,2H),4.25–3.91(m,2H),3.84–3.72(m,2H),3.87–3.49(m,2H),3.27–3.10(m,2H),3.10–2.94(m,2H),1.41(d,J＝6.0Hz,6H).¹³C NMR(101MHz,CDCl₃)δ152.80,132.74,129.42,129.13,128.59,127.70,123.98,123.01,117.17,114.84,71.13,63.26(2C),56.61,51.58(2C),22.66(2C),19.48.

HRMS (ESI) calculated C ₁₉H₂₆NO₂, [ m+h ] +m/z 300.1564, found 300.1959.

General synthesis method eight:

2-substituted oxy-1-naphthaldehyde (10 a-10 g):

The synthesis method comprises the following steps: 2-hydroxy-1-naphthanaldehyde (9, 11.6 mmol) was dissolved in acetone (100 ml), bromide (13.9 mmol), potassium carbonate (34.8 mmol) and tetrabutylammonium iodide (5.8 mmol) were added, stirred at room temperature, reacted overnight, and the reaction was detected by silica gel thin layer chromatography, if the reaction of the starting material 9 was apparently not completely reacted after overnight, the reaction system was heated to 56℃and refluxed until the reaction of the starting material was complete. At the end of the reaction, the solvent of the reaction solution was removed by rotary evaporation, the residue was added with dichloromethane and sufficiently dissolved by ultrasonic vibration, insoluble matters were removed by suction filtration, and the filtrate was extracted by dissolution with saturated sodium chloride. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=50:1) to give the solid, i.e. the target product 2-substituted oxy-1-naphthaldehyde.

Example 29- ((4-bromobenzyl) oxy) -1-naphthaldehyde (10 a)

The synthesis method comprises the following steps: the same general synthetic method eight uses 2-hydroxy-1-naphthaldehyde (9) and 4-bromobenzyl bromide as raw materials to obtain pale yellow solid with yield ：82％.¹H NMR(400MHz,DMSO-d₆)δ10.83(s,1H),9.10(d,J＝8.7Hz,1H),8.28(d,J＝9.2Hz,1H),7.95(d,J＝8.1Hz,1H),7.85–7.57(m,4H),7.57–7.29(m,4H),5.45(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ191.73,163.37,138.30,136.26,132.01(2C),131.13,130.45(2C),130.27,129.08,128.77,125.30,124.36,121.81,116.63,115.54,70.52.

Example 30- ((4-fluorobenzyl) oxy) -1-naphthaldehyde (10 b)

The synthesis method comprises the following steps: the same general synthetic method eight uses 2-hydroxy-1-naphthaldehyde (9) and 4-fluorobenzyl bromide as raw materials to obtain pale yellow solid with yield ：85％.¹H NMR(400MHz,CDCl₃)δ10.95(s,1H),9.28(d,J＝8.7Hz,1H),8.05(d,J＝9.1Hz,1H),7.78(d,J＝8.1Hz,1H),7.63(ddd,J＝8.5,7.0,1.4Hz,1H),7.48–7.40(m,3H),7.33(d,J＝9.1Hz,1H),7.15–7.06(m,2H),5.30(s,2H).¹³C NMR(101MHz,CDCl₃)δ192.05,164.10,163.08,137.64,131.86,131.70,130.11,129.53,129.45,128.92,128.38,125.18,125.16,117.54,116.05,115.83,114.04,71.08.

Example 31 2-benzyloxy-1-naphthaldehyde (10 c)

The synthesis method comprises the following steps: the same general synthetic method eight uses 2-hydroxy-1-naphthaldehyde (9) and bromobenzyl as raw materials to obtain white solid with yield ：85％.¹H NMR(400MHz,DMSO-d₆)δ10.83(s,1H),9.11(d,J＝8.6Hz,1H),8.27(d,J＝9.2Hz,1H),7.93(d,J＝8.1Hz,1H),7.69(d,J＝9.2Hz,1H),7.64(t,J＝7.8Hz,1H),7.54(d,J＝7.5Hz,2H),7.47(d,J＝7.5Hz,1H),7.42(t,J＝7.3Hz,2H),7.35(t,J＝7.3Hz,1H),5.46(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ191.26,163.13,137.79,136.30,131.88,130.66,129.74,128.59,128.27,128.24,128.15,127.80,124.76,123.86,116.13,116.11,115.16,70.88.

Example 32- ((4-methylbenzyl) oxy) -1-naphthaldehyde (10 d)

The synthesis method comprises the following steps: the same general synthetic method eight uses 2-hydroxy-1-naphthaldehyde (9) and 4-methylbenzyl bromide as raw materials to obtain white solid with yield ：80％.¹H NMR(400MHz,CDCl₃)δ10.96(s,1H),9.29(d,J＝8.7Hz,1H),8.03(d,J＝9.1Hz,1H),7.77(d,J＝8.1Hz,1H),7.62(ddd,J＝8.5,6.9,1.3Hz,1H),7.47–7.38(m,1H),7.34(d,J＝8.7Hz,3H),7.21(d,J＝7.9Hz,2H),5.30(s,2H),2.37(s,3H).

Example 33 2- (cyclohexylmethoxy) -1-naphthaldehyde (10 e)

The synthesis method comprises the following steps: the same general synthesis method eight uses 2-hydroxy-1-naphthaldehyde (9) and cyclohexyl bromomethane as raw materials to obtain light yellow brown blocky solid with yield ：76％.¹H NMR(400MHz,CDCl₃)δ10.94(s,1H),9.29(d,J＝8.7Hz,1H),8.00(d,J＝9.2Hz,1H),7.74(d,J＝8.1Hz,1H),7.60(ddd,J＝8.5,6.8,1.5Hz,1H),7.40(ddd,J＝8.0,6.8,1.2Hz,1H),7.23(d,J＝9.2Hz,1H),3.98(d,J＝5.8Hz,2H),1.94–1.83(m,2H),1.84–1.68(m,3H),1.32(dt,J＝12.2,2.8Hz,2H),1.29–1.19(m,2H),1.13(qd,J＝12.8,12.4,2.8Hz,2H).¹³C NMR(101MHz,CDCl₃)δ192.16,164.00,139.25,137.60,131.68,129.89,129.57,128.30,124.99,124.72,119.24,116.74,113.64,77.48,77.16,76.84,74.95,38.00,29.93,26.48,25.85.

Example 34 (E) -1- (2- (4-Fluorobenzyloxy) naphthalen-1-yl) -N- (4-methylpiperazin-1-yl) -azomethine (LZ 19)

The synthesis method comprises the following steps: 2- (4-Fluorobenzyloxy) -1-naphthaldehyde (10 b,1.78 mmol) was dissolved in dichloromethane (50 ml), 1-amino-4-methylpiperazine (2.14 mmol) was added, stirred at room temperature, and reacted for 3h, and the reaction was detected by silica gel thin layer chromatography until the reaction of the starting material 10b was complete. After the reaction, ammonia water is slowly added into the reaction system, and the pH of the reaction system is regulated to be alkaline. Proper amount of dichloromethane was added, and the mixture was extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent was removed by rotary evaporation, and the concentrate was purified by column chromatography over silica gel (dichloromethane: anhydrous methanol=100:1-50:1) to give the desired product (E) -1- (2- (4-fluorobenzyloxy) naphthalen-1-yl) -N- (4-methylpiperazin-1-yl) -azomethine (LZ 19) as a white to pale yellow powder in yield ：72％.¹H NMR(400MHz,CDCl₃)δ9.06(dd,J＝8.6,1.1Hz,1H),8.26(s,1H),7.81–7.68(m,2H),7.49(ddd,J＝8.5,6.8,1.4Hz,1H),7.43–7.39(m,2H),7.36(ddd,J＝8.0,6.7,1.2Hz,1H),7.25(d,J＝9.3Hz,2H),7.13–6.97(m,2H),5.18(s,2H),3.29(t,J＝5.1Hz,4H),2.67(t,J＝5.1Hz,4H),2.39(s,3H).¹³C NMR(101MHz,CDCl₃)δ162.50(d,J＝246.5Hz,1C),155.08,134.40,132.93(d,J＝3.5Hz,1C),131.65,130.22,129.87,129.16(d,J＝8.1Hz,2C),128.09,127.30,126.11,124.15,118.67,115.53(d,J＝21.6Hz,2C),114.92,71.28,54.56(2C),51.17(2C),46.01.HRMS(ESI) calculated as C ₂₃H₂₅FN₃O,[M+H]⁺ m/z378.1982, found 378.1975.

Example 35N- ((2- (4-Fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperazin-1-amine (LZ 20)

The synthesis method comprises the following steps: (E) -1- (2- (4-Fluorobenzyloxy) naphthalen-1-yl) -N- (4-methylpiperazin-1-yl) -azomethine (LZ 19,0.794 mmol) was dissolved in anhydrous methanol (40 ml), sodium borohydride (2.4 mmol) and glacial acetic acid (2 ml) were added, stirred at room temperature and reacted overnight, and the reaction was detected by silica gel thin layer chromatography until the reaction was not decreasing. At the end of the reaction, insoluble matter was removed by suction filtration, the filtrate solvent was removed by rotary evaporation, the residue was redissolved with dichloromethane, the pH of the system was adjusted to alkaline with ammonia, extracted with saturated sodium bicarbonate solution, and the filtrate was collected and re-extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate solvent removed by rotary evaporation, and the concentrate was chromatographed on a column of silica gel (dichloromethane: anhydrous methanol=70:1-30:1) to give the desired product N- ((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperazin-1-amine (LZ 20), yield ：69％.¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝8.6Hz,1H),7.82–7.67(m,2H),7.51(t,J＝7.7Hz,1H),7.48–7.40(m,2H),7.35(t,J＝7.5Hz,1H),7.28(d,J＝9.2Hz,1H),7.13–7.00(m,2H),5.17(s,2H),4.45(s,2H),3.34–2.38(m,8H),2.32(s,3H).¹³C NMR(101MHz,CDCl₃)δ162.57(d,J＝246.4Hz,1C),154.23,133.64,132.87(d,J＝3.3Hz,1C),129.54(d,J＝8.1Hz,2C),129.48,129.11,128.35,126.92,123.78,123.58,119.83,115.53(d,J＝21.6Hz,2C).114.43,70.81,55.63,55.07,54.54,51.15,45.60,42.93.HRMS(ESI) calculated as C ₂₃H₂₇FN₃O,[M+H]⁺ m/z 380.2138, found 380.2134.

General synthesis method nine:

2-substituted oxynaphthylmethylamine analogues (LZ 21 to LZ 31):

The synthesis method comprises the following steps: 2-substituted-naphthylaldehyde (10 a-10 g,2.5 mmol) was dissolved in dichloromethane (50 ml), primary or secondary amine compound (3.0 mmol) was added, stirred at room temperature for 1h, followed by addition of sodium triacetoxyborohydride (1.2 mmol) every half an hour, and the reaction was detected by silica gel thin layer chromatography until the reactant 2-substituted-naphthylaldehyde (10 a-10 g) was no longer reduced. After the reaction, ammonia water is slowly added into the reaction system, the pH of the solution is regulated to be alkaline, a proper amount of dichloromethane is added, and the solution is extracted for 2 times by using saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent removed by rotary evaporation, and the concentrate was purified by column chromatography over silica gel (dichloromethane: anhydrous methanol=30:1-10:1) to give a colorless to pale yellow oily liquid or white solid as the target product, 2-substituted oxynaphthylmethylamine analogues (LZ 21 to LZ 31).

Example 36- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperazine (LZ 21)

The synthesis method comprises the following steps: in the same way as in the general synthesis method nine, 2- (4-bromobenzyloxy) -naphthaldehyde (10 a) and 1-methylpiperazine are used as raw materials to obtain colorless oily liquid, and the theoretical value C ₂₃H₂₆BrN₂O[M+H]⁺ m/z 425.1229 of yield ：72％.¹H NMR(400MHz,CDCl₃)δ8.20(d,J＝8.6Hz,1H),7.77(d,J＝8.7Hz,2H),7.57–7.42(m,3H),7.42–7.30(m,3H),7.26(d,J＝9.1Hz,1H),5.15(s,2H),4.01(s,2H),2.72–2.39(m,J＝63.5Hz,8H),2.31(s,3H).¹³C NMR(101MHz,CDCl₃)δ154.60,136.33,134.23,131.74(2C),129.45,129.41,128.97(2C),128.12,126.40,124.75,123.77,121.82,119.84,114.65,70.81,55.13(2C),52.66(2C),51.79,45.75.HRMS(ESI) and the measured value 425.1228 are obtained.

Example 37- ((2- (4-Fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methylpiperidine (LZ 22)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, using 2- (4-fluorobenzyloxy) -naphthaldehyde (10 a) and 4-methylpiperidine as raw materials, a colorless oily liquid was obtained, and the calculated value C ₂₄H₂₇FNO,[M+H]⁺ m/z 364.2077 was found to be ：65％.¹H NMR(400MHz,CDCl₃)δ8.25(dd,J＝8.6,1.1Hz,1H),7.75(dd,J＝8.2,1.4Hz,1H),7.74(d,J＝8.9Hz,1H),7.50–7.43(m,3H),7.34(ddd,J＝8.0,6.7,1.2Hz,1H),7.26(d,J＝9.0Hz,1H),7.11–7.03(m,2H),5.15(s,2H),3.94(s,2H),2.89(dt,J＝11.7,3.3Hz,2H),2.09(td,J＝11.6,2.5Hz,2H),1.57–1.48(m,2H),1.34(tdt,J＝10.3,7.0,3.8Hz,1H),1.23–1.07(m,2H),0.87(d,J＝6.4Hz,3H).¹³C NMR(101MHz,CDCl₃)δ162.43(d,J＝245.8Hz,1C),154.58,134.43,133.34(d,J＝3.2Hz,1C),129.49,129.16(d,J＝8.1Hz,2C),129.01,128.02,126.21,125.08,123.67,121.21,115.42(d,J＝21.6Hz,2C),115.06,71.06,54.10(2C),52.40,34.56(2C),30.96,21.98.HRMS(ESI) in yield, and 364.2072 was found to be an actual value.

Example 38N- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 23)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, 2- (4-bromobenzyloxy) -naphthaldehyde (10 a) and 1-methyl-4-aminopiperidine are used as raw materials to obtain a colorless oily liquid, yield ：63％.¹H NMR(400MHz,Methanol-d₄)δ8.14(dd,J＝8.7,1.0Hz,1H),8.06(d,J＝9.1Hz,1H),7.91(d,J＝8.1Hz,1H),7.69–7.61(m,3H),7.58(d,J＝9.1Hz,1H),7.57–7.51(m,2H),7.46(ddd,J＝8.0,6.8,1.0Hz,1H),5.36(s,2H),4.77(s,2H),3.70–3.44(m,3H),3.21–2.98(m,2H),2.88(s,3H),2.49–2.20(m,2H),2.10–1.91(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ155.71,136.63,132.83,132.10,131.94(2C),130.93(2C),128.98,128.90,127.74,124.39,123.80,121.76,114.67,113.01,70.11,53.08,51.83(2C),42.75,38.77,25.98(2C).HRMS(ESI) was calculated as C ₂₄H₂₈BrN₂O,[M+H]⁺ m/z 439.1385, found value 439.1385.

Example 39N- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -cyclohexylamine (LZ 24)

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The synthesis method comprises the following steps: in the same manner as in the general synthesis method nine, using 2- (4-bromobenzyloxy) -naphthaldehyde (10 a) and cyclohexylamine as raw materials, a white solid was obtained, and the yield ：86％.¹H NMR(400MHz,CDCl₃)δ8.04(dd,J＝8.6,1.1Hz,1H),7.87–7.69(m,2H),7.51(ddd,J＝8.4,6.8,1.3Hz,1H),7.48–7.39(m,2H),7.35(ddd,J＝8.0,6.8,1.1Hz,1H),7.29(d,J＝9.0Hz,1H),7.14–6.98(m,2H),5.19(s,2H),4.27(s,2H),2.54(tt,J＝10.0,3.6Hz,1H),1.93(d,J＝11.8Hz,2H),1.71(dt,J＝12.0,3.3Hz,2H),1.32–0.96(m,6H).¹³C NMR(101MHz,CDCl₃)δ162.51(d,J＝246.2Hz,1C),153.96,133.35,133.10(d,J＝3.2Hz,1C),129.59,129.25(d,J＝8.1Hz,2C),128.97,128.51,126.85,123.67,123.21,122.59,115.49(d,J＝21.5Hz,2C),114.78,70.80,56.95,40.82,33.64(2C),26.23,25.08(2C).HRMS(ESI) was calculated as C ₂₄H₂₈BrN₂O,[M+H]⁺ m/z 364.1998, found to be 364.1997.

Example 40 (1R, 4R) -N- ((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) -4-methyl-1-cyclohexylamine (LZ 25)

The synthesis method comprises the following steps: in the same manner as in the general synthesis method nine, using 2- (4-bromobenzyloxy) -naphthaldehyde (10 a) and trans-4-methyl-1-cyclohexylamine as raw materials, a white solid was obtained, and the calculated value C ₂₅H₂₉FNO,[M+H]⁺ m/z 378.2233 was ：70％.¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝8.6Hz,1H),7.81–7.73(m,2H),7.51(ddd,J＝8.4,6.8,1.4Hz,1H),7.47–7.40(m,2H),7.35(ddd,J＝8.0,6.8,1.1Hz,1H),7.28(d,J＝17.5Hz,1H),7.12–7.04(m,2H),5.19(s,2H),4.27(s,2H),2.48(tt,J＝11.0,3.8Hz,1H),2.00–1.90(m,2H),1.73–1.61(m,2H),1.33(tdt,J＝12.8,6.4,3.2Hz,1H),1.21–1.07(m,2H),0.94(ddd,J＝14.9,11.8,3.2Hz,2H),0.87(d,J＝6.5Hz,3H).¹³C NMR(101MHz,CDCl₃)δ162.50(d,J＝246.2Hz,1C),153.94,133.32,133.08(d,J＝3.2Hz,1C),129.57,129.22(d,J＝8.2Hz,2C),128.96,128.51,126.84,123.66,123.17,122.58,115.48(d,J＝21.4Hz,2C),114.76,70.79,57.01,40.90,34.00(2C),33.57(2C),32.52,22.36.HRMS(ESI), found to be 378.2225.

Example 41 2- (((2- (4-fluorobenzyloxy) naphthalen-1-yl) methyl) amino) -1-ethanol (LZ 26):

The synthesis method comprises the following steps: the same general synthesis method nine, using 2- (4-fluorobenzyloxy) -naphthaldehyde (10 b) and 2-hydroxyethylamine as raw materials, gave a pale yellow powder, yield ：81％.¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝8.6Hz,1H),7.82(d,J＝9.1Hz,1H),7.75(d,J＝8.2Hz,1H),7.53(ddd,J＝8.4,6.8,1.3Hz,1H),7.49–7.42(m,2H),7.34(t,J＝7.5Hz,1H),7.26(d,J＝9.1Hz,1H),7.11–6.97(m,2H),5.28(s,2H),4.48(s,2H),3.62–3.44(m,2H),2.92–2.76(m,2H).¹³C NMR(101MHz,CDCl₃)δ162.63(d,J＝246.7Hz,1C),155.28,132.74,132.26(d,J＝3.0Hz,1C),131.56,129.68(d,J＝8.4Hz,2C),129.02,128.68,127.90,124.16,122.38,115.70(d,J＝21.5Hz,2C),113.51,113.18,70.45,57.74,49.90,42.03.HRMS(ESI) calculated as C ₂₀H₂₁FNO₂,[M+H]⁺ m/z326.1556, found 326.1550.

Example 42N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 27)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, 2- (4-fluorobenzyloxy) -1-naphthaldehyde (10 b) and 4-amino-1-methylpiperidine were used as raw materials to obtain a colorless oily liquid, yield ：72％.¹H NMR(400MHz,CDCl₃)δ8.05(s,1H),7.83(t,J＝9.8Hz,2H),7.56(t,J＝7.4Hz,1H),7.47(s,2H),7.40(t,J＝7.5Hz,1H),7.35(d,J＝9.1Hz,1H),7.16–7.06(m,2H),5.22(s,2H),4.26(s,2H),3.17–2.96(m,4H),2.51(s,3H),2.39–1.96(m,3H),1.89–1.75(m,3H).¹³C NMR(101MHz,DMSO-d₆)δ163.18,160.76,155.40,132.95,132.92,132.41,131.61,130.78,130.70,128.50,128.42,127.21,123.88,123.43,115.47,115.26,114.24,112.56,69.73,52.61,51.32,42.24,38.28,25.53.HRMS(ESI) was calculated as C ₂₄H₂₈N₂OF,[M+H]⁺ m/z 379.2180, found value 379.2186.

Example 43N- ((2- ((4-methylbenzyl) oxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 28)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, 2- (4-methylbenzyloxy) -1-naphthaldehyde (10 d) and 4-amino-1-methylpiperidine were used as raw materials to obtain a colorless oily liquid, yield ：75％.¹H NMR(400MHz,DMSO-d₆)δ8.21(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.94(d,J＝8.0Hz,1H),7.61(dd,J＝16.0,8.3Hz,2H),7.48(d,J＝7.7Hz,2H),7.44(t,J＝7.4Hz,1H),7.25(d,J＝7.8Hz,2H),5.32(s,2H),4.58(s,2H),3.40(d,J＝13.2Hz,2H),3.34(s,6H),2.90(t,J＝12.7Hz,1H),2.68(s,3H),2.33(s,3H),2.11–1.99(m,1H).¹³C NMR(101MHz,DMSO-d₆)δ137.44,133.68,133.61,132.37,132.29,131.57,129.07,128.46,128.33,127.22,123.86,123.21,114.38,110.66,91.25,85.98,70.44,70.43,54.91,51.41,51.40,42.29,38.51,25.66,20.83.HRMS(ESI) was calculated as C ₂₅H₃₁N₂O,[M+H]⁺ m/z 375.2429, found value 375.2436.

Example 44N- ((2- (benzyloxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 29)

The synthesis method comprises the following steps: the same general synthesis method nine uses 2-benzyloxy-1-naphthaldehyde (10 c) and 4-amino-1-methylpiperidine as raw materials to obtain colorless oily liquid with yield ：82％.¹H NMR(400MHz,CDCl₃)δ8.01(d,J＝8.6Hz,1H),7.79(dd,J＝8.3,3.5Hz,2H),7.51(ddd,J＝8.4,6.8,1.4Hz,1H),7.45(d,J＝7.0Hz,2H),7.40(t,J＝7.1Hz,2H),7.34(t,J＝7.9Hz,3H),5.23(s,2H),4.25(s,2H),2.94(d,J＝6.6Hz,2H),2.75(s,1H),2.40(s,3H),2.06(d,J＝11.6Hz,3H),2.00(s,1H),1.64(d,J＝9.4Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ139.21,136.65,132.39,131.62,128.54,128.48,128.43,128.29,128.17,128.16,127.22,123.89,123.88,123.30,114.29,112.54,70.53,52.64,51.35,42.24,40.28,38.43,29.15,25.55.

HRMS (ESI) calculated C ₂₄H₂₉N₂O,[M+H]^c m/z 361.2276, found 361.2280.

Example 45N- ((2- (cyclohexylmethoxy) naphthalen-1-yl) methyl) -1-methylpiperidin-4-amine (LZ 30)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, 2- (cyclohexylmethoxy) -1-naphthaldehyde (10 e) and 4-amino-1-methylpiperidine were used as raw materials to obtain a colorless oily liquid, yield ：70％.¹H NMR(400MHz,DMSO-d₆)δ8.21(d,J＝8.5Hz,1H),8.06(d,J＝9.1Hz,1H),7.93(d,J＝7.9Hz,1H),7.64–7.55(m,1H),7.53(d,J＝9.2Hz,1H),7.43(t,J＝7.4Hz,1H),4.59(s,2H),4.04(d,J＝6.1Hz,2H),3.51(d,J＝12.6Hz,2H),3.42(d,J＝13.5Hz,1H),3.04(s,2H),2.70(d,J＝20.5Hz,3H),2.42(d,J＝12.6Hz,2H),2.12(d,J＝13.6Hz,2H),1.89(d,J＝11.8Hz,3H),1.72(dd,J＝27.9,12.2Hz,3H),1.38–1.16(m,4H),1.10(q,J＝13.2,12.5Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ155.74,132.39,131.67,128.43,128.27,127.17,123.68,123.19,113.92,111.98,111.81,80.23,73.94,53.01,52.71,51.40,42.22,38.43,37.21,29.38,26.10,25.58,25.24.HRMS(ESI) was calculated as C ₂₄H₃₅N₂O,[M+H]⁺ m/z 367.2745, found to be 363.2749.

Example 46N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 31)

The synthesis method comprises the following steps: in the same manner as in the conventional synthesis method nine, 2- (4-fluorobenzyloxy) -1-naphthalene aldehyde (10 b) and n-butylamine are used as raw materials to obtain a colorless oily liquid, yield ：78％.¹H NMR(400MHz,DMSO-d₆)δ8.19(d,J＝8.6Hz,1H),8.08(d,J＝9.1Hz,1H),7.94(d,J＝7.8Hz,1H),7.70–7.64(m,2H),7.63–7.57(m,2H),7.44(t,J＝7.3Hz,1H),7.31–7.20(m,2H),5.34(s,2H),4.54(s,2H),3.34(s,1H),2.90(s,2H),1.59(ddd,J＝12.7,10.4,6.8Hz,2H),1.25(h,J＝7.4Hz,2H),0.81(t,J＝7.4Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ163.15,160.72,155.48,133.03,132.47,131.50,130.52,130.44,128.50,128.43,127.27,123.84,123.18,115.34,115.12,114.24,112.70,69.66,47.01,27.10,19.39,13.43.HRMS(ESI) calculated as C ₂₂H₂₅NOF,[M+H]⁺ m/z 388.1919, found value 388.1920.

General synthesis method ten:

N' - ((2-substituted oxynaphthalen-1-yl) methylene) hydrazide analogs (11 a-11 d):

The synthesis method comprises the following steps: 2-substituted oxynaphthalene formaldehyde (10 b,10c,10f,10g,1.78 mmol) was taken and dissolved in absolute ethanol (50 ml), hydrazide compound (3.58 mmol) was added, stirred, heated to 90℃for reflux, reacted overnight, and the reaction was monitored by silica gel thin layer chromatography until the starting 2-substituted oxybenzaldehyde was no longer reduced. After the reaction, the reaction solution was cooled to room temperature to see precipitation of a white solid, the filtrate solvent was removed by suction filtration and rotary evaporation, the solid obtained by suction filtration was dissolved in methylene chloride and combined with the filtrate concentrate, and the white solid was obtained by purification and enrichment by silica gel column chromatography (petroleum ether: ethyl acetate=4:1), namely the target product N' - ((2-substituted oxynaphthalen-1-yl) methylene) -3-phenylpropionyl hydrazide (11 a to 11 d).

Example 47N' - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methylene) -3-phenylpropionyl hydrazide (11 a)

The synthesis method comprises the following steps: the general synthesis method is ten, and the 2- (4-fluorobenzyloxy) -naphthaldehyde (10 b) and 3-phenylpropionyl hydrazide are used as raw materials to obtain white powder, and the yield is: 90%. MS (ESI) theory C ₂₇H₂₃FN₂O₂,[M+H]⁺ m/z 427.49, found 427.18.

Example 48N' - ((2- (benzyloxy) naphthalen-1-yl) methylene) -2-phenoxyacethydrazide (11 b)

The synthesis method comprises the following steps: the general synthesis method is ten, and the white powder is obtained by taking 2-benzyloxy-naphthaldehyde (10 c) and 2-phenoxy acethydrazide as raw materials, and the yield is: 87%. MS (ESI) theory C ₂₇H₂₄N₂O₂,[M+H]⁺ m/z409.50, found 409.19.

Example 49N' - ((2-isopropoxynaphthalen-1-yl) methylene) -2-phenoxyacethydrazide (11 c)

The synthesis method comprises the following steps: the general synthesis method is ten, and the white solid is obtained by taking 2-isopropoxy-naphthaldehyde (10 f) and 2-phenoxyacetyl hydrazine as raw materials, and the yield is: 56%. MS (ESI) theory C ₂₃H₂₄N₂O₂,[M+H]⁺ m/z361.46, found 361.19.

Example 50N' - ((2-methoxynaphthalen-1-yl) methylene) -3-phenylpropionyl hydrazide (11 d)

The synthesis method comprises the following steps: the general synthesis method is ten, and the white solid is obtained by taking 2-methoxy-naphthaldehyde (10 g) and 3-phenylpropionyl hydrazide as raw materials, and the yield is: 70%. MS (ESI) theory C ₂₁H₂₀N₂O₂,[M+H]⁺ m/z333.40, found 333.16.

The general synthesis method is eleven:

n' - ((2-substituted oxy-1-naphthyl) methyl) hydrazide analogs (LZ 33-LZ 36)

The synthesis method comprises the following steps: n' - ((2-substituted oxy-1-naphthalene) methylene) -3-phenylpropionyl hydrazide (11 a to 11d,0.91 mmol) was dissolved in anhydrous methanol (50 ml), stirred at room temperature, sodium cyanoborohydride (4.52 mmol) was added and reacted overnight, and the reaction was monitored by silica gel thin layer chromatography until the starting material was no longer reduced. The solvent of the reaction solution was removed by rotary evaporation, and the residue was redissolved in dichloromethane and extracted with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give the desired product N' - ((2-substituted oxy-1-naphthyl) methyl) -3-phenylpropionyl hydrazide (LZ 33 to LZ 36) as a white solid.

Example 51N' - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -3-phenylpropionyl hydrazide (LZ 33)

The synthesis method comprises the following steps: in the same manner as in the general synthesis method eleven, using N' - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methylene) -3-phenylpropionate (11 a) as a raw material, a white powder was obtained, yield ：90％.¹H NMR(400MHz,DMSO-d₆)δ9.49(s,1H),8.31(d,J＝8.6Hz,1H),7.91–7.82(m,2H),7.60(dd,J＝8.2,5.8Hz,2H),7.51(dd,J＝18.9,8.3Hz,2H),7.38(t,J＝7.4Hz,1H),7.23(dt,J＝15.6,8.3Hz,3H),7.20–7.13(m,3H),5.27(s,2H),4.34(s,2H),2.77(t,J＝7.8Hz,2H),2.33–2.25(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ170.57,162.90,160.48,154.30,141.13,135.16,133.64,133.61,133.40,129.68,129.60,129.33,128.87,128.24,128.17,126.53,125.88,123.74,123.53,119.02,115.41,115.30,115.09,69.88,44.96,35.19,30.90.HRMS(ESI) calculated as C ₂₇H₂₆N₂O₂F,[M+H]⁺ m/z 429.1976, found 429.1978.

Example 52N' - ((2- (benzyloxy) naphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 34)

The synthesis method comprises the following steps: in the same way as the general synthesis method eleven, N' - ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methylene) -2-phenoxyacethydrazide (11 a) is taken as a raw material to obtain white powder, and the yield ：83％.¹H NMR(400MHz,CDCl₃)δ8.27(d,J＝8.6Hz,1H),7.81(d,J＝4.3Hz,1H),7.79(d,J＝3.3Hz,1H),7.54(ddd,J＝8.5,6.8,1.4Hz,1H),7.45(d,J＝6.9Hz,2H),7.41–7.34(m,3H),7.32(t,J＝3.5Hz,2H),7.31–7.27(m,2H),7.01(t,J＝7.4Hz,1H),6.78(d,J＝7.9Hz,2H),5.24(s,2H),4.63(s,2H),4.43(s,2H).¹³C NMR(101MHz,CDCl₃)δ167.50,157.25,155.11,137.21,133.76,130.15,129.83,129.43,128.91,128.74,128.60,128.08,127.36,127.31,123.95,123.35,123.32,122.20,118.46,118.44,114.81,114.73,67.20,67.17,48.06,45.74.HRMS(ESI) is calculated to be C ₂₆H₂₄N₂O₃,[M+Na]⁺ m/z 435.1678 and the actual measurement value is 435.1685.

Example 53N' - ((2-isopropoxynaphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 35)

The synthesis method comprises the following steps: in the same way as the general synthesis method eleven, N' - ((2-isopropoxynaphthalen-1-yl) methylene) -2-phenoxyacetyl hydrazine (11C) is taken as a raw material to obtain white powder, and the calculated value C ₂₂H₂₄N₂O₃,[M+Na]⁺ m/z 387.16776 of the yield ：70％.¹H NMR(400MHz,CDCl₃)δ8.24(d,J＝8.6Hz,1H),7.87–7.75(m,2H),7.52(ddd,J＝8.5,6.8,1.4Hz,1H),7.38–7.33(m,1H),7.34–7.23(m,3H),7.01(t,J＝7.4Hz,1H),6.84(d,J＝7.9Hz,2H),4.71(hept,J＝6.3Hz,1H),4.58(s,2H),4.53(s,2H),1.40(d,J＝6.1Hz,6H).¹³C NMR(101MHz,CDCl₃)δ167.45,157.33,154.51,140.38,133.83,129.95,129.88,129.33,128.57,127.17,123.83,123.29,122.25,119.22,116.23,114.79,97.38,72.01,67.31,59.34,45.98,22.58.HRMS(ESI) is calculated, and the measured value is 387.1685.

Example 54N' - ((2-methoxynaphthalen-1-yl) methyl) -3-phenylpropionyl hydrazide (LZ 36)

The synthesis method comprises the following steps: in the same way as the general synthesis method eleven, N' - ((2-methoxynaphthalene-1-yl) methylene) -3-phenylpropionyl hydrazide (11 d) is taken as a raw material to obtain white powder, and the calculated value C ₂₁H₂₃N₂O₂,[M+Na]⁺ m/z 357.1571 of the yield ：85％.¹H NMR(400MHz,CDCl₃)δ8.25(d,J＝8.6Hz,1H),7.79(t,J＝7.7Hz,2H),7.54(t,J＝7.6Hz,1H),7.40–7.32(m,1H),7.31–7.21(m,3H),7.23–7.14(m,2H),4.46(s,2H),3.95(s,3H),2.99–2.91(m,2H),2.45–2.36(m,2H),1.26(s,1H).¹³C NMR(101MHz,CDCl₃)δ172.00,155.82,140.69,133.78,130.11,129.15,128.78,128.69,128.57,128.44,127.33,126.45,123.77,123.73,123.23,113.12,56.74,45.51,45.50,36.63,31.59.HRMS(ESI) is calculated, and the measured value is 357.1579.

Example 55 1, 2-dihydro-3H-naphtho [2,1-b ] -3-pyranone (12)

The synthesis method comprises the following steps: beta-naphthol (30.7 mmol) was dissolved in toluene (70 ml), amberlyst 15 cation exchange resin (3.00 g) was added, acrylic acid (61.4 mmol) was added dropwise to the system, the system was heated to 110 ℃ to reflux, the reaction was continued for 48 hours, the reaction was monitored by silica gel thin layer chromatography, the color of the reaction system was gradually blackened, and after 48 hours no obvious unreacted raw material beta-naphthol was seen. After the reaction, the reaction system is cooled to room temperature, the solvent in the reaction liquid is removed by rotary evaporation, the residual black solid is added with ethyl acetate and is fully dissolved by ultrasonic oscillation, insoluble substances are removed by suction filtration through diatomite, and the filtrate is extracted for 2 times by saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate solvent was removed by rotary evaporation to give a brown oily liquid, i.e., crude 1, 2-dihydro-3H-naphtho [2,1-b ] -3-furanone (12), yield: 91%, which can be directly used in the next reaction.

EXAMPLE 56 1- (3-hydroxypropyl) -2-naphthol (13)

The synthesis method comprises the following steps: 1, 2-dihydro-3H-naphtho [2,1-b ] -3-furanone (12, 27.9 mmol) was taken as an oily liquid and dissolved in anhydrous tetrahydrofuran (100 ml), and the temperature of the reaction system was lowered to 0℃by an ice bath. Lithium aluminum hydride (184 mmol) is weighed and added into the reaction system slowly for three times, and after the generated bubbles gradually disappear, the system temperature is kept at 0 ℃ for continuous reaction for 3 hours. And after the reaction is finished, slowly adding a saturated ammonium chloride solution to quench the reaction until no obvious bubbles are generated. The solvent of the reaction solution was removed by rotary evaporation, ethyl acetate (200 ml) was added to the residue and sufficiently dissolved by ultrasonic vibration, insoluble matter was removed by suction filtration through celite, and the filtrate was extracted with saturated sodium chloride solution 2 times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate solvent was removed by rotary evaporation to give 1- (3-hydroxypropyl) -2-naphthol (13) as a pale yellow solid in yield: 85% of the catalyst can be directly used for the next reaction .¹H NMR(400MHz,CDCl₃)δ7.89(dd,J＝8.5,1.1Hz,1H),7.77(d,J＝8.1Hz,1H),7.64(d,J＝8.8Hz,1H),7.47(ddd,J＝8.4,6.8,1.4Hz,1H),7.32(ddd,J＝8.0,6.8,1.1Hz,1H),7.15(d,J＝8.8Hz,1H),3.68–3.50(m,2H),3.32–3.10(m,2H),2.22–1.88(m,2H).

Twelve general synthesis methods:

3- (2- (substituted benzyloxy) -naphthalen-1-yl) -1-propanol (14 a-14 b)

The synthesis method comprises the following steps: 1- (3-hydroxypropyl) -2-naphthol (13, 9.9 mmol) was dissolved in acetonitrile (100 ml), 4-substituted benzyl bromide (11.9 mmol), potassium carbonate (29.7 mmol) and tetrabutylammonium iodide (5.0 mmol) were added, stirred at room temperature, and the reaction was monitored by silica gel thin layer chromatography and left to react overnight without apparent starting material 1- (2-hydroxypropyl) -2-naphthol. At the end of the reaction, the solvent of the reaction solution is removed by rotary evaporation, methylene dichloride is added into the residue and is fully dissolved by ultrasonic oscillation, insoluble substances are removed by suction filtration, and the filtrate is extracted for 2 times by saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent removed by rotary evaporation, and the concentrate was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=7:1-4:1) to give the desired product 3- (2- (substituted benzyloxy) -naphthalen-1-yl) -1-propanol (14 a-14 b) as a white powder by purification and enrichment

Example 57 3- (2- (4-Fluorobenzyloxy) -naphthalen-1-yl) -1-propanol (14 a)

The synthesis method comprises the following steps: the white powder and the yield are obtained by using 1- (2-hydroxypropyl) -2-naphthol (13) and 4-fluorobenzyl bromide as raw materials in the same general synthesis method as twelve ：82％.1H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.6Hz,1H),7.80(d,J＝8.2Hz,1H),7.73(d,J＝9.0Hz,1H),7.50(ddd,J＝8.5,6.8,1.4Hz,1H),7.48–7.42(m,2H),7.37(ddd,J＝8.0,6.8,1.1Hz,1H),7.31(d,J＝9.0Hz,1H),7.14–7.05(m,2H),5.18(s,2H),3.54(t,J＝5.9Hz,2H),3.23(t,J＝7.1Hz,2H),1.93(p,J＝6.6Hz,2H).

Example 58 3- (2- (4-bromobenzyloxy) -naphthalen-1-yl) -1-propanol (14 b)

The synthesis method comprises the following steps: the same general synthetic method twelve, 1- (3-hydroxypropyl) -2-naphthol (13) and 4-bromobenzyl bromide are used as raw materials to obtain white powder with yield ：82％.¹H NMR(400MHz,CDCl₃)δ7.99(d,J＝8.6Hz,1H),7.80(dd,J＝8.1,1.5Hz,1H),7.73(d,J＝9.0Hz,1H),7.58–7.51(m,2H),7.50(ddd,J＝8.7,6.8,1.4Hz,1H),7.43–7.32(m,3H),7.29(s,1H),5.17(s,2H),3.56(t,J＝6.0Hz,2H),3.24(t,J＝7.1Hz,2H),1.99–1.88(m,2H).

Thirteen general synthesis methods:

2- (substituted benzyloxy) -1- (3-bromopropyl) naphthalene (15 a-15 b)

The synthesis method comprises the following steps: 3- (2- (substituted benzyloxy) -naphthalen-1-yl) -1-propanol (14 a or 14b,8.11 mmol) was dissolved in dichloromethane (100 ml), triphenylphosphine (12.2 mmol) was added and stirred at room temperature. Carbon tetrabromide (12.2 mmol) was additionally weighed and dissolved in methylene chloride (50 ml) to be sufficiently dissolved, and slowly added to the reaction system through a dropping funnel. After the completion of the dropwise addition, the reaction was carried out at room temperature, and the reaction was detected by silica gel thin layer chromatography, and after 4 hours, the raw material 14a or 14b was seen to be almost completely reacted. After the reaction, the reaction solution was extracted 2 times with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent of the filtrate was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=12:1-7:1) to give the desired product 2- (substituted benzyloxy) -1- (3-bromopropyl) naphthalene (15 a-15 b) as white crystals.

EXAMPLE 59 2- (4-Fluorobenzyloxy) -1- (3-bromopropyl) naphthalene (15 a)

The synthesis method comprises the following steps: the same general synthesis procedure was used as thirteen starting from 3- (2- (4-fluorobenzyloxy) -naphthalen-1-yl) -1-propanol (14 a) and the resulting colorless oily concentrate was used directly in the next reaction without silica gel column chromatography.

Example 60 2- (4-Bromobenzyloxy) -1- (3-bromopropyl) naphthalene (15 a)

The synthesis method comprises the following steps: the same general synthetic method thirteen uses 3- (2- (4-bromobenzyloxy) -naphthalene-1-yl) -1-propanol (14 b) as raw material to obtain white crystal with yield ：81％.¹H NMR(400MHz,CDCl₃)δ8.00(dd,J＝8.7,1.1Hz,1H),7.81(dd,J＝8.2,1.4Hz,1H),7.73(d,J＝9.0Hz,1H),7.59–7.49(m,3H),7.42–7.32(m,3H),7.27(d,J＝9.1Hz,1H),5.17(s,2H),3.50(t,J＝6.7Hz,2H),3.31–3.25(m,2H),2.26–2.16(m,2H).¹³C NMR(101MHz,CDCl₃)δ153.32,136.40,132.98,131.77(2C),129.47,128.91(2C),128.63,128.07,126.64,123.64,123.13,122.77,121.85,114.37,70.39,34.11,33.07,23.96.

Fourteen general synthesis methods:

3- (2- (4-bromobenzyloxy) -naphthalen-1-yl) -1-propylamine analogs (LZ 37-LZ 39)

The synthesis method comprises the following steps: 2- (4-substituted benzyloxy) -1- (3-bromopropyl) naphthalene (15 a or 15b,1.57 mmol) was dissolved in acetonitrile (50 ml), and potassium carbonate (4.71 mmol), tetrabutylammonium iodide (0.79 mmol), and a primary or secondary amine compound (1.73 mmol) were sequentially added, heated to 85℃and refluxed, and the reaction was detected by silica gel thin layer chromatography and after the reaction was continued for 24 hours, the starting material 15a or 15b was seen to be almost completely reacted. At the end of the reaction, the solvent was removed from the reaction mixture by rotary evaporation, the residue was redissolved in dichloromethane and the insoluble material was removed by suction filtration. The filtrate was extracted 2 times with saturated sodium chloride solution, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, the solvent of the filtrate was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (dichloromethane: anhydrous methanol=30:1-10:1) to give an oily liquid, i.e., the objective 3- (2- (4-bromobenzyloxy) -naphthalen-1-yl) -1-propylamine analog (LZ 37, LZ 39).

Example 61 1- (3- (2- (4-Fluorobenzyloxy) naphthalen-1-yl) -propyl) -4-methylpiperazine (LZ 37)

The synthesis method comprises the following steps: the same general synthesis method fourteen uses 2- (4-fluorobenzyloxy) -1- (3-bromopropyl) naphthalene (15 a) and 1-methylpiperazine as raw materials to obtain colorless oily liquid, yield ：48％.¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.6Hz,1H),7.77(dd,J＝8.2,1.3Hz,1H),7.69(d,J＝9.0Hz,1H),7.47(ddd,J＝8.5,6.8,1.4Hz,1H),7.45–7.39(m,2H),7.34(ddd,J＝8.0,6.8,1.1Hz,1H),7.27(d,J＝8.8Hz,1H),7.11–7.03(m,2H),3.18–3.03(m,2H),2.50–2.43(m,2H),2.89-2.06(m,8H),2.27(s,3H),1.88–1.73(m,2H).¹³C NMR(101MHz,CDCl₃)δ162.44(d,J＝246.1Hz,1C),153.24,133.33(d,J＝3.2Hz,1C),133.11,129.48,129.09(d,J＝8.2Hz,2C),128.49,127.53,126.25,124.53,123.48,123.43,115.48(d,J＝21.5Hz,2C),114.64,70.56,58.55,55.23(2C),53.25(2C),46.12,27.34,23.06.HRMS(ESI) calculated value C ₂₅H₃₀FN₂O,[M+H]⁺ m/z 393.2342, measured value 393.2336.

Example 62N- (3- (2- ((4-bromobenzyl) oxy) naphthalen-1-yl) propyl) cyclohexylamine (LZ 39)

The synthesis method comprises the following steps: the same general synthesis method fourteen uses 2- (4-bromobenzyloxy) -1- (3-bromopropyl) naphthalene (15 b) and cyclohexylamine as raw materials to obtain colorless oily liquid, yield ：46％.¹H NMR(400MHz,DMSO-d₆)δ8.03(d,J＝8.6Hz,1H),7.86(dd,J＝12.9,8.5Hz,2H),7.66–7.58(m,2H),7.58–7.51(m,1H),7.50(t,J＝8.9Hz,3H),7.43–7.34(m,1H),5.28(s,2H),3.13(t,J＝7.6Hz,2H),3.03–2.88(m,4H),1.87(dt,J＝15.5,7.5Hz,5H),1.72(s,2H),1.59(d,J＝12.3Hz,1H),1.30–1.02(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ152.96,141.84,139.87,136.89,132.30,131.42,129.61,128.97,128.54,128.02,126.56,123.48,122.92,121.69,120.92,118.95,114.82,98.22,69.40,55.79,43.71,28.67,26.39,24.67,23.81,21.59.HRMS(ESI) calculated value C ₂₆H₃₁NOBr,[M+H]⁺ m/z 452.1582, measured value 452.1589.

EXAMPLE 63N- (3- (2- (4-bromobenzyloxy) naphthalen-1-yl) -propyl) ethylenediamine (LZ 38)

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The synthesis method comprises the following steps: 2- (4-Bromobenzyloxy) -1- (3-bromopropyl) naphthalene (15 b,1.57 mmol) was dissolved in acetonitrile (50 ml), followed by addition of potassium carbonate (4.71 mmol), tetrabutylammonium iodide (0.79 mmol) and N-Boc-ethylenediamine (1.73 mmol), and heating to 85℃to reflux and reaction overnight. At the end of the reaction, the solvent was removed from the reaction mixture by rotary evaporation, the residue was redissolved in dichloromethane and the insoluble material was removed by suction filtration. The filtrate was extracted 2 times with saturated sodium chloride solution, the organic phase was collected and dried over anhydrous sodium sulfate, filtered, the solvent of the filtrate was removed by rotary evaporation, and the concentrate was purified by silica gel column chromatography (dichloromethane: anhydrous methanol=30:1 to 10:1) to give an oily liquid. The resulting oily liquid was dissolved in saturated dioxane hydrochloric acid solution (20 ml), stirred overnight at normal temperature to remove Boc protecting group, pH of the solution was adjusted to alkaline, the solvent was removed by rotary evaporation, and extracted twice with saturated sodium bicarbonate solution, the organic phase was taken out and dried over anhydrous sodium sulfate, filtered, and the filtrate was chromatographed over silica gel column (dichloromethane: anhydrous methanol=8:1) to give colorless oily liquid, calculated yield ：25％.¹H NMR(400MHz,DMSO-d₆)δ9.53(s,2H),8.41(s,3H),8.05(d,J＝8.6Hz,1H),7.87(dd,J＝8.4,1.3Hz,1H),7.83(d,J＝9.0Hz,1H),7.66–7.59(m,2H),7.56–7.45(m,4H),7.38(ddd,J＝7.9,6.7,1.0Hz,1H),5.29(s,2H),3.24–3.17(m,4H),3.14(t,J＝7.8Hz,2H),3.10–2.96(m,2H),1.95(p,J＝8.9Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ153.35,137.34,132.80,131.96(2C),130.26(2C),129.41,128.96,128.43,127.05,123.91,123.49,122.25,121.37,115.30,69.81,47.44,44.66,35.86,26.60,22.20.HRMS(ESI) C ₂₂H₂₆BrN₂O,[M+H]⁺ m/z 413.1229, found 413.1222.

Example 64 (E) -4- (2- (2-acetoxynaphthalen-1-yl) vinyl) pyridine (16)

The synthesis method comprises the following steps: 2-hydroxy-1-naphthaldehyde (9, 81.3 mmol) was dissolved in acetic anhydride (40 ml), stirred at room temperature, 4-methylpyridine (81.3 mmol) was added, the reaction system temperature was raised to 125℃and refluxed, and the reaction was continued for 48 hours. After the reaction, the projection system was cooled to room temperature to obtain a brownish red pasty thick liquid, which was diluted with ethyl acetate (120 ml), and the solvent was removed from the reaction mixture by rotary evaporation, dichloromethane was added and sufficiently dissolved by ultrasonic vibration, and extracted with a saturated sodium chloride solution 2 times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed by rotary evaporation to give a solvent, and the concentrate was purified and enriched by column chromatography on silica gel (petroleum ether: ethyl acetate=4:1) to give (E) -4- (2- (2-acetoxynaphthalen-1-yl) vinyl) pyridine (16), a yellow powdery solid, in the yield ：33％.¹H NMR(400MHz,DMSO-d₆)δ8.63–8.55(m,2H),8.24(d,J＝8.2Hz,1H),8.01(d,J＝7.2Hz,1H),7.97(d,J＝8.8Hz,1H),7.85(d,J＝16.7Hz,1H),7.75–7.67(m,2H),7.67–7.54(m,2H),7.38(d,J＝8.8Hz,1H),7.03(d,J＝16.7Hz,1H),2.30(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ169.74,150.60(2C),146.39,144.42,133.59,132.12,131.89,129.79,128.93,127.61,126.38,126.06,125.35,125.22,122.75,121.57(2C),21.31.

Fifteen general synthetic methods:

(E) -4- (2- (2- (4-substituted benzyloxy) naphthalen-1-yl) vinyl) pyridine (17, LZ 40)

The synthesis method comprises the following steps: (E) -4- (2- (2-Acetyloxynaphthalen-1-yl) vinyl) pyridine (16, 0.45 mmol) was dissolved in N, N-dimethylformamide (30 ml), 4-substituted benzyl bromide (0.54 mmol) and anhydrous sodium methoxide powder (0.61 mmol) were added in this order, and the reaction was monitored by silica gel thin layer chromatography with stirring at normal temperature and continued for 8 hours, whereby the reaction of the raw material 16 was seen to be almost complete. At the end of the reaction, the solvent in the reaction system was removed by rotary evaporation, methylene chloride (60 ml) was added to dissolve it sufficiently, insoluble matter was removed by suction filtration, and the filtrate was extracted with saturated sodium chloride solution 2 times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give the desired product (E) -4- (2- (4-substituted benzyloxy) naphthalen-1-yl) vinyl) pyridine (17, lz 40) as a white to pale yellow solid.

Example 65 4- (2- (2- (benzyloxy) naphthalen-1-yl) vinyl) pyridine (17)

The synthesis method comprises the following steps: fifteen common synthetic methods are adopted, and (E) -4- (2- (2-acetoxyl naphthalene-1-yl) vinyl) pyridine (16) and bromobenzyl are taken as raw materials to obtain white solid with yield ：77％.¹H NMR(400MHz,DMSO-d₆)δ8.56(d,J＝5.5Hz,2H),8.26(d,J＝8.6Hz,1H),8.01–7.86(m,3H),7.59(d,J＝6.2Hz,3H),7.54(dd,J＝13.2,7.5Hz,3H),7.46–7.36(m,3H),7.31(dd,J＝15.7,9.3Hz,2H),5.37(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ154.29,150.01,149.44,144.90,137.09,132.06,131.84,129.90,128.85,128.45,128.27,127.88,127.56,127.23,127.02,126.26,123.84,123.78,123.62,122.38,120.75,118.68,115.21,70.55,40.15,39.94,39.73,39.52,39.31,39.10,38.89.

Example 66 (E) -4- (2- (2- (4-bromobenzyloxy) naphthalen-1-yl) vinyl) pyridine (LZ 40)

The synthesis method comprises the following steps: fifteen common synthetic methods are adopted, wherein (E) -4- (2- (2-acetoxyl naphthalene-1-yl) vinyl) pyridine (16) and 4-bromobenzyl bromide are taken as raw materials, light yellow needle-shaped crystals are obtained, the yield is ：84％.¹H NMR(400MHz,CDCl₃)δ8.67–8.52(m,2H),8.19(dd,J＝8.5,1.1Hz,1H),7.86–7.71(m,3H),7.52(ddd,J＝8.3,6.8,1.3Hz,1H),7.50–7.45(m,2H),7.41(ddd,J＝8.2,6.8,1.1Hz,1H),7.40–7.35(m,2H),7.33–7.27(m,3H),7.15(d,J＝16.6Hz,1H),5.21(s,1H).¹³C NMR(101MHz,CDCl₃)δ154.06,150.26(2C),145.34,135.97,132.55,132.44,131.77(2C),129.93,129.60,128.97(2C),128.57,127.05,126.59,124.16,123.95,122.00,120.77(2C),120.33,114.92,70.94.HRMS(ESI), calculated value C ₂₄H₁₉BrNO,[M+H]⁺ m/z 416.0650, and measured value is 416.0647.

Example 67 4- (2- (2-Benzyloxyn-1-yl) ethyl) piperidine (LZ 41)

The synthesis method comprises the following steps: (E) -4- (2- (2- (benzyloxy) naphthalene-1-yl) vinyl) pyridine (17, 2.96 mmol) was dissolved in absolute ethanol (20 ml), glacial acetic acid (5 ml) was added, and the mixture was stirred at room temperature in a medium-pressure hydrogenator. Platinum dioxide (25 mg) was added to the reaction system, and stirred at room temperature under 3 atm for 24 hours. The almost complete reaction of starting material 17 was observed by thin layer chromatography on silica gel, the reaction was stopped, the platinum dioxide was removed by suction filtration using celite, the reaction solution was transferred to a round bottom flask (100 ml) and the pH was adjusted to 10 by slowly dropwise addition of aqueous sodium hydroxide (1 mmol/L). The solvent was removed from the reaction by rotary evaporation, and the concentrate was completely dissolved by adding methylene chloride and extracted 2 times with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate by rotary evaporation, and the concentrate was purified and enriched by column chromatography on silica gel (dichloromethane: anhydrous methanol: ammonia=400:10:1) to give the desired product 4- (2- (2-benzyloxynaphthalen-1-yl) ethyl) piperidine (LZ 41) as a white solid, yield: 47%.

¹H NMR(400MHz,CDCl₃)δ7.88(d,J＝8.6Hz,1H),7.79(d,J＝8.0Hz,1H),7.72(d,J＝8.9Hz,1H),7.53–7.44(m,1H),7.47–7.37(m,4H),7.39–7.28(m,3H),5.18(s,2H),3.50–3.32(m,2H),3.16–3.03(m,2H),2.84–2.64(m,2H),1.99–1.90(m,2H),1.83–1.69(m,1H),1.66–1.57(m,4H).¹³C NMR(101MHz,CDCl₃)δ153.48,137.21,132.78,129.48,128.73(2C),128.68,128.20,127.85,127.60(2C),126.50,123.55,123.49,122.97,114.59,71.42,44.05(2C),35.78,33.88,28.72(2C),21.90.HRMS(ESI) Calculated C ₂₄H₂₈NO,[M+H]⁺ m/z346.2171, found 346.2565.

Example 68 4- (2- (2- (benzyloxy) naphthalen-1-yl) ethyl) pyridine (LZ 42)

The synthesis method comprises the following steps: (E) -4- (2- (2- (benzyloxy) naphthalene-1-yl) vinyl) pyridine (17, 2.96 mmol) was dissolved in absolute ethanol (20 ml), platinum dioxide (25 mg) was added, the mixture was placed in a medium-pressure hydrogenometer, stirred at normal temperature, the reaction was continued at a hydrogen gas pressure of 4 atm for 24 hours, the reaction was detected by silica gel thin layer chromatography, the reaction was stopped, platinum dioxide was removed by suction filtration using celite, the reaction solution was transferred to a round-bottomed flask (100 ml), and the solvent in the reaction solution was removed by rotary evaporation. The concentrate was redissolved with dichloromethane (50 ml) and extracted 2 times with saturated sodium bicarbonate solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed by rotary evaporation to give a solvent, and the concentrate was purified by column chromatography over silica gel (dichloromethane: anhydrous methanol=100:1) to give a white solid enriched in the desired product 4- (2- (2- (benzyloxy) naphthalen-1-yl) ethyl) pyridine (LZ 42), calculated yield ：50％.¹H NMR(400MHz,CDCl₃)δ8.36(d,J＝6.1Hz,2H),7.91(d,J＝8.5Hz,1H),7.86(d,J＝8.1Hz,1H),7.81(d,J＝9.0Hz,1H),7.54(ddd,J＝8.5,6.7,1.4Hz,1H),7.44(h,J＝7.7,7.0Hz,6H),7.34–7.27(m,3H),5.08(s,2H),3.50(t,J＝7.6Hz,2H),3.11(t,J＝7.6Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ157.77,153.24,153.22,144.03,143.98,137.35,132.23,128.82,128.76,128.49,128.15,127.85,127.48,126.62,126.59,125.79,123.37,123.35,122.88,121.27,114.80,70.17,35.11,25.30.HRMS(ESI) C ₂₄H₂₂NO,[M+H]⁺ m/z 3601700, found 340.1701.

Sixteen general synthesis methods:

((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -hydroxyalkyl-carbamic acid tert-butyl ester analogue (18 a-18 b):

The synthesis method comprises the following steps:

2- (4-Fluorobenzyloxy) -1-naphthaldehyde (10 b,14.28 mmol) was dissolved in anhydrous methanol (100 ml), glacial acetic acid (5 ml) was added, stirred at room temperature, and then 4-amino-1-butanol (19.2 mmol) or 3-amino-1-propanol (19.2 mmol) was added to react at room temperature for 0.5h. Then, sodium triacetoxyborohydride (6.37 mmol) was added every half an hour, and the reaction was monitored by silica gel thin layer chromatography, and after 4 hours of reaction, it was observed that the reaction of the starting material 10b was almost complete, and the reaction was terminated. Ammonia water is slowly added into the reaction liquid to adjust the pH value to be alkaline, and most of the solvent in the reaction liquid is removed by rotary evaporation. Dichloromethane was added and shaken well, extracted 1 time with saturated sodium bicarbonate solution, and the organic phase was extracted 1 time with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate solvent was removed by rotary evaporation to give a colorless oily viscous liquid, which was the crude product of compound 18a or 18 b.

The colorless oily viscous liquid was dissolved in methylene chloride (50 ml), and triethylamine (1 ml) and di-tert-butyl dicarbonate (19.2 mmol) were added in this order, followed by stirring at room temperature and overnight reaction, and the reaction was monitored by silica gel thin layer chromatography, and the reaction was stopped when the starting material 18a or 18b was almost completely reacted. The organic phase was collected by extraction 2 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the filtrate solvent was removed by rotary evaporation, and the concentrate was subjected to silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give the objective product 19a or 19b as a colorless oily viscous liquid.

Example 68 tert-butyl ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) (3-hydroxypropyl) carbamate (19 a)

The synthesis method comprises the following steps: sixteen common synthetic methods are adopted, 2- (4-fluorobenzyloxy) -1-naphthaldehyde (10 b) and 3-amino-1-propanol are taken as raw materials, colorless oily viscous liquid is obtained, and the yield is high ：75％.¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝8.7Hz,1H),7.80(t,J＝8.3Hz,2H),7.50(ddd,J＝8.5,6.8,1.4Hz,1H),7.45–7.34(m,4H),7.30(d,J＝9.1Hz,1H),7.14–7.02(m,2H),5.17(s,2H),4.12(q,J＝7.1Hz,2H),3.29(t,J＝32.8Hz,3H),1.56(d,J＝39.7Hz,9H),1.26(t,J＝7.1Hz,3H).

Example 69 tert-butyl ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) (4-hydroxybutyl) carbamate (19 b)

The synthesis method comprises the following steps: sixteen common synthetic methods are adopted, 2- (4-fluorobenzyloxy) -1-naphthaldehyde (10 b) and 4-amino-1-butanol are taken as raw materials, colorless oily viscous liquid is obtained, and the yield is high ：78％.¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),7.80(t,J＝8.9Hz,2H),7.54–7.46(m,1H),7.47–7.34(m,3H),7.31(d,J＝9.0Hz,1H),7.14–7.04(m,3H),5.16(s,2H),3.36(s,2H),2.94(s,3H),1.54(d,J＝39.0Hz,9H),1.39–1.21(m,5H).¹³C NMR(101MHz,CDCl₃)δ171.29,163.94,161.49,155.08,133.80,132.83,132.80,130.15,129.57,129.49,128.39,127.24,124.19,115.84,115.62,114.56,71.27,62.52,60.52,44.42,39.06,30.02,28.74,28.64,24.27,21.17,14.32.

Seventeenth general synthesis method:

(bromoalkyl) ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) carbamic acid tert-butyl ester analogues (20 a-20 b)

The synthesis method comprises the following steps: tert-butyl ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -hydroxyalkyl-carbamate analogue (18 a to 18b,9.0 mmol) was taken in dichloromethane (100 ml) and triphenylphosphine (18.2 mmol) was added and stirred at ambient temperature. Carbon tetrabromide (18.2 mmol) was dissolved in dichloromethane (50 ml) and was completely dissolved, transferred to a dropping funnel and was slowly added dropwise to the reaction system, after 1h of dropwise addition, all of the carbon tetrabromide was added to the reaction system, the reaction was continued at room temperature, and after 3h, it was observed that the raw material 18a or 18b was almost completely reacted by monitoring the reaction by silica gel thin layer chromatography, and the reaction was ended. The reaction solution is extracted for 2 times by saturated sodium chloride solution, an organic phase is collected, dried by anhydrous sodium sulfate, suction filtration and rotary evaporation are carried out to remove filtrate solvent, the concentrate is purified and enriched by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to obtain colorless oily liquid, and white blocky crystals are obtained after standing for 2 hours at normal temperature, namely the target product (bromoalkyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester analogues (20 a-20 b).

Example 70 (3-bromopropyl) ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) carbamic acid tert-butyl ester (20 a)

The synthesis method comprises the following steps: seventeen common synthetic methods are adopted, and ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) (3-hydroxypropyl) carbamic acid tert-butyl ester (19 a) is taken as a raw material to obtain white blocky crystals with yield ：80％.¹H NMR(400MHz,CDCl₃)δ7.86–7.76(m,2H),7.54–7.48(m,1H),7.47–7.41(m,2H),7.38(t,J＝7.4Hz,1H),7.31(d,J＝9.0Hz,1H),7.15–7.05(m,3H),5.18(s,2H),5.05(s,2H),3.22(t,J＝5.9Hz,1H),3.07(s,3H),1.77(p,J＝6.8Hz,2H),1.72–1.64(m,1H),1.59(s,3H),1.50(s,5H).

Example 71 (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) carbamic acid tert-butyl ester (20 b)

The synthesis method comprises the following steps: seventeen common synthetic methods are adopted, and ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) (4-hydroxybutyl) carbamic acid tert-butyl ester (19 b) is taken as a raw material to obtain white blocky crystals with yield 85％.¹H NMR(400MHz,CDCl₃)δ8.22(d,J＝8.1Hz,1H),7.81(t,J＝9.5Hz,2H),7.51(t,J＝7.5Hz,1H),7.44(dd,J＝8.4,5.5Hz,2H),7.38(t,J＝7.4Hz,1H),7.32(d,J＝9.0Hz,1H),7.11(t,J＝8.6Hz,2H),5.17(s,2H),5.05(d,J＝11.4Hz,2H),3.11(d,J＝6.8Hz,1H),3.04–2.89(m,3H),1.58(dd,J＝14.5,7.1Hz,6H),1.50(s,5H),1.46–1.36(m,2H).

Eighteen general synthetic methods:

((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methylamino) alkylamine analogs (LZ 43-LZ 58)

The synthesis method comprises the following steps:

A tert-butyl (bromoalkyl) ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) carbamate analog (20 a-20 b,0.96 mmol) was dissolved in acetonitrile (50 ml), potassium carbonate (2.8 mmol), tetrabutylammonium iodide (1.2 mmol) and secondary amine compound (1.4 mmol) were added in sequence, stirred at room temperature and reacted overnight, the reaction was monitored by silica gel thin layer chromatography, the reaction was ended if the raw material 20a or 20b was almost completely reacted, and if it was observed that the raw material was obviously unreacted, the reaction system was heated to 60℃until the raw material was no longer reacted. After the reaction is finished, when the temperature of the reaction system is room temperature, insoluble substances are removed by suction filtration, and the filtrate is removed by rotary evaporation to obtain a solvent. The concentrate was taken and dissolved in dichloromethane and extracted twice with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate solvent was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (dichloromethane: absolute methanol=100:1 to 50:1) to give a colorless to pale yellow oily thick liquid.

The oily thick liquid obtained by the purification is added into a self-made saturated dioxane hydrochloride solution (20 ml), and the mixture is stirred at normal temperature for overnight reaction. After the reaction, the pH of the solution is regulated to be alkaline, the reaction solution is removed by rotary evaporation, the solution is redissolved in dichloromethane, the solution is extracted twice by saturated sodium bicarbonate solution, the organic phase is dried by anhydrous sodium sulfate and filtered, the filtrate is purified and enriched by silica gel column chromatography (dichloromethane: absolute methanol=15:1-10:1) to obtain colorless to pale yellow oily thick liquid, the colorless to pale yellow oily thick liquid is dissolved in methanol aqueous solution (absolute methanol: ultrapure water=1:4, total 20 ml), and the hydrochloride of the target product N-substituted- ((2- (4-fluorobenzyloxy) naphthalene-1-yl) methylamino) alkylamine analogue is obtained by vacuum freeze drying.

Example 72N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -3- (4-methylpiperazin-1-yl) propan-1-amine (LZ 43)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and tert-butyl (3-bromopropyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 a) and 1-methylpiperazine are used as raw materials to obtain pale yellow powder, the calculated value C ₂₆H₃₃N₃OF,[M+H]⁺ m/z 422.2606 of the yield ：40％.¹H NMR(400MHz,DMSO-d₆)δ8.20(d,J＝8.6Hz,1H),8.08(d,J＝9.1Hz,1H),7.94(d,J＝8.1Hz,1H),7.71–7.63(m,2H),7.63(d,J＝3.5Hz,1H),7.60(d,J＝9.4Hz,1H),7.45(t,J＝7.5Hz,1H),7.32–7.22(m,2H),5.38(s,2H),4.59(d,J＝5.3Hz,3H),3.53(d,J＝26.0Hz,10H),3.20–3.04(m,2H),2.81(s,3H),2.17(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ155.38,133.12,133.09,132.45,131.64,131.63,130.25,130.17,128.51,127.39,123.93,123.06,115.47,115.26,114.42,114.39,112.47,106.31,69.62,69.59,48.04,40.71,40.69.HRMS(ESI), and the measured value is 422.2608.

Example 73N ¹ - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -N ³,N³ -dimethylpropane-1, 3-diamine (LZ 44)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and tert-butyl (3-bromopropyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 a) and dimethylamine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₂₃H₂₈N₂OF,[M+H]⁺ m/z 367.2180 of the yield ：35％.¹H NMR(400MHz,DMSO-d₆)δ8.20(d,J＝8.6Hz,1H),8.08(d,J＝9.1Hz,1H),7.94(d,J＝8.1Hz,1H),7.71–7.64(m,2H),7.63(d,J＝3.5Hz,1H),7.60(d,J＝9.2Hz,1H),7.45(t,J＝7.5Hz,1H),7.33–7.22(m,2H),5.38(s,2H),4.59(t,J＝4.1Hz,3H),3.49(s,6H),2.95(d,J＝116.1Hz,4H),2.16(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ155.38,133.12,133.09,132.45,131.69,131.64,130.25,130.17,128.53,128.51,127.40,123.94,123.06,115.47,115.26,114.42,112.48,69.63,48.00,47.25,44.66,40.70,7.19.HRMS(ESI) and the measured value 367.2186 are obtained.

Example 74 4- (5-Ethyl-1, 3,4, 5-tetrahydro-2H-pyrido [4,3-b ] indol-2-yl) -N- ((2- ((4-fluorobenzyloxy) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 45)

The synthesis method comprises the following steps: the same general synthesis method is eighteen, and adopts (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and 5-ethyl-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indole as raw materials to obtain white powder, wherein the yield is ：55％.¹H NMR(400MHz,CDCl₃)δ7.90(d,J＝8.5Hz,1H),7.66(d,J＝8.1Hz,1H),7.62(d,J＝9.1Hz,1H),7.47–7.40(m,1H),7.41(s,1H),7.41–7.35(m,1H),7.36(d,J＝3.2Hz,1H),7.35(d,J＝1.9Hz,1H),7.30(t,J＝7.4Hz,1H),7.23(s,1H),7.23–7.15(m,1H),7.10(d,J＝7.1Hz,1H),7.06(d,J＝8.6Hz,1H),7.02(d,J＝9.1Hz,1H),5.10(s,2H),4.39(s,2H),3.80(q,J＝7.2Hz,2H),3.49(d,J＝5.1Hz,2H),2.93(t,J＝5.5Hz,2H),2.69(q,J＝5.8Hz,4H),2.58(t,J＝5.5Hz,2H),1.93(s,2H),1.73(q,J＝9.3,7.7Hz,3H),1.16(t,J＝7.2Hz,3H).¹³C NMR(101MHz,CDCl₃)δ154.96,146.46,135.87,132.66,132.21,131.44,129.91,129.83,128.74,128.43,128.17,125.35,124.23,122.58,121.12,118.97,117.48,115.80,115.58,113.12,109.12,104.85,70.37,55.91,53.43,50.22,48.36,48.08,40.72,37.68,25.80,25.70,25.33,20.76,15.42.HRMS(ESI) calculated value C ₃₅H₃₉N₃OF,[M+H]⁺ m/z 536.3076, and the measured value is 536.3077.

Example 75 4- (9-Ethyl-1, 3,4, 9-tetrahydro-2H-pyridin [3,4-b ] indol-2-yl) -N- (2- (4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 46)

The synthesis method comprises the following steps: the same general synthesis method is eighteen, and (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and 9-ethyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole are taken as raw materials to obtain light yellow powder, the calculated value C ₃₅H₃₉N₃OF,[M+H]⁺ m/z 536.3080 of yield ：65％.¹H NMR(400MHz,DMSO-d₆)δ8.06(dd,J＝8.8,5.8Hz,2H),7.93(d,J＝8.1Hz,1H),7.60(q,J＝9.5,7.6Hz,3H),7.54(d,J＝7.9Hz,1H),7.47–7.34(m,3H),7.25(t,J＝8.8Hz,2H),7.08(t,J＝7.6Hz,1H),6.98(t,J＝7.4Hz,1H),5.31(s,2H),4.52(s,2H),4.06(q,J＝6.9Hz,2H),3.64(s,2H),3.37(d,J＝20.5Hz,2H),3.00(t,J＝7.0Hz,2H),2.77–2.61(m,3H),2.54(t,J＝6.3Hz,3H),1.64(dq,J＝25.3,7.3Hz,3H),1.20(t,J＝7.0Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ160.68,155.16,135.59,133.04,133.01,132.43,131.40,130.23,130.15,128.56,127.31,126.30,123.91,123.89,122.83,122.81,120.42,118.41,117.60,115.42,115.21,114.44,109.10,106.35,69.74,56.35,50.21,48.65,47.47,40.61,37.08,23.92,23.88,20.87,15.35.HRMS(ESI) and the measured value 536.3077.

Example 76 4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 47)

The synthesis method comprises the following steps: the same general synthesis method is eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1- (2, 3-dichlorophenyl) piperazine hydrochloride are used as raw materials to obtain light yellow powder, wherein the calculated value C ₃₂H₃₅N₃OFCl₂,[M+H]⁺ m/z 566.2150 and the measured value 566.2141 of yield ：35％.¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝8.6Hz,1H),7.84–7.75(m,2H),7.57(ddd,J＝8.4,6.8,1.4Hz,1H),7.49–7.41(m,2H),7.42–7.33(m,1H),7.31(d,J＝9.0Hz,1H),7.17–7.03(m,4H),6.74(d,J＝6.9Hz,1H),5.22(s,2H),4.39(s,2H),2.81(t,J＝6.4Hz,7H),2.51(s,4H),2.35(t,J＝6.9Hz,2H),1.63(q,J＝6.7Hz,2H),1.54(p,J＝7.0Hz,2H).¹³C NMR(101MHz,CDCl₃)δ161.41,154.49,150.99,133.94,133.22,132.95,132.62,130.28,130.27,129.60,129.52,129.37,128.61,127.59,127.43,125.99,124.65,124.12,123.15,118.68,115.80,115.59,114.30,112.46,70.90,58.05,53.07,50.79,48.98,42.42,26.87,24.64.HRMS(ESI) are calculated.

Example 77N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (2-methoxyphenyl) piperazin-1-yl) butan-1-amine (LZ 48)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1- (2-methoxyphenyl) piperazine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₃₃H₃₉N₃O₂F,[M+H]⁺ m/z528.3035 and the measured value 528.3026 of yield ：60％.¹H NMR(400MHz,DMSO-d₆)δ8.21(d,J＝8.6Hz,1H),8.08(d,J＝9.1Hz,1H),7.95(d,J＝8.2Hz,1H),7.72–7.63(m,2H),7.62(dd,J＝13.2,8.5Hz,2H),7.45(t,J＝7.5Hz,1H),7.35–7.25(m,2H),7.07–6.95(m,2H),6.98–6.87(m,2H),5.37(s,2H),4.58(s,2H),3.80(s,3H),3.56(s,4H),3.49(s,4H),3.13(d,J＝8.7Hz,2H),3.08(s,1H),3.00(s,2H),1.88–1.66(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ161.81,161.78,160.06,143.05,140.38,135.14,131.66,131.49,130.44,130.38,127.63,126.85,126.80,126.80,121.55,121.38,112.78,70.01,64.82,55.48,51.96,51.87,51.29,51.25,48.21,45.94,43.50,42.25,41.42,36.06,25.47,13.00,12.29.HRMS(ESI) are calculated.

Example 78N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (o-tolyl) piperazin-1-yl) butan-1-amine (LZ 49)

The synthesis method comprises the following steps: the general synthetic method is similar to eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1- (o-tolyl) piperazine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₃₃H₃₉N₃OF,[M+H]⁺ m/z 512.3080 and the measured value 512.3077 are calculated by yield ：65％.¹H NMR(400MHz,DMSO-d₆)δ8.22(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.94(dd,J＝8.2,1.3Hz,1H),7.68(dd,J＝8.6,5.7Hz,2H),7.65–7.56(m,2H),7.44(t,J＝7.5Hz,1H),7.34–7.23(m,2H),7.16(t,J＝8.2Hz,1H),6.59(dd,J＝8.2,2.3Hz,1H),6.55(t,J＝2.3Hz,1H),6.45(dd,J＝8.2,2.3Hz,1H),5.36(s,2H),4.55(t,J＝5.4Hz,2H),3.81(d,J＝12.9Hz,2H),3.73(s,3H),3.49(d,J＝11.6Hz,2H),3.24(t,J＝12.3Hz,2H),3.09(q,J＝9.2,8.3Hz,5H),2.98(d,J＝8.1Hz,2H),1.87–1.69(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ163.12,160.70,160.29,155.45,150.78,133.14,133.10,132.49,131.58,130.41,130.33,129.92,128.53,128.48,127.37,123.91,123.18,115.50,115.28,114.34,112.62,108.46,105.45,102.24,69.64,66.36,55.02,54.52,50.30,46.61,45.28,22.60,20.37.HRMS(ESI).

Example 79N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (3-methoxyphenyl) piperazin-1-yl) butan-1-amine (LZ 50)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1- (3-methoxyphenyl) piperazine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₃₃H₃₉N₃O₂F,[M+H]⁺ m/z528.3023 and the measured value 528.3026 of yield ：78％.¹H NMR(400MHz,DMSO-d₆)δ8.22(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.94(d,J＝8.0Hz,1H),7.72–7.65(m,2H),7.62(d,J＝9.2Hz,1H),7.60–7.56(m,1H),7.44(t,J＝7.5Hz,1H),7.33–7.26(m,2H),7.16(t,J＝8.2Hz,1H),6.59(dd,J＝8.2,2.3Hz,1H),6.55(t,J＝2.3Hz,1H),6.45(dd,J＝8.2,2.3Hz,1H),5.36(s,2H),4.55(t,J＝5.4Hz,2H),3.81(d,J＝12.9Hz,2H),3.73(s,3H),3.49(d,J＝11.7Hz,2H),3.24(t,J＝12.3Hz,2H),3.09(q,J＝9.2,8.3Hz,5H),2.98(d,J＝8.1Hz,2H),1.85–1.68(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ163.12,160.70,160.29,155.45,150.78,133.14,133.10,132.49,131.58,130.41,130.33,129.92,128.53,128.48,127.37,123.91,123.18,115.50,115.28,114.34,112.62,108.46,105.45,102.24,69.64,66.36,55.02,54.52,50.30,46.61,45.28,22.60,20.37.HRMS(ESI) are obtained.

Example 80N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4- (pyrimidin-2-yl) piperazin-1-yl) butan-1-amine (LZ 51)

The synthesis method comprises the following steps: the same general synthesis method is eighteen, and the (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and 2- (piperazine-1-yl) pyrimidine are taken as raw materials to obtain white powder with the yield ：72％.¹H NMR(400MHz,DMSO-d₆)δ8.46(d,J＝4.7Hz,2H),8.21(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.93(d,J＝8.1Hz,1H),7.68(dd,J＝8.3,5.6Hz,2H),7.62(d,J＝9.3Hz,1H),7.58(d,J＝8.0Hz,1H),7.43(t,J＝7.5Hz,1H),7.29(t,J＝8.7Hz,2H),6.77(t,J＝4.7Hz,1H),5.36(s,2H),4.68(d,J＝13.7Hz,2H),4.55(t,J＝5.4Hz,2H),3.51(t,J＝9.7Hz,4H),3.09–2.90(m,6H),1.88–1.66(m,5H).¹³C NMR(101MHz,DMSO-d₆)δ163.12,160.69,160.38,158.14,156.51,155.44,133.13,133.10,132.49,131.57,130.40,130.32,128.52,128.47,127.36,123.90,123.17,115.49,115.27,114.34,112.61,111.27,69.63,54.65,50.19,46.59,40.39,40.26,22.59,20.36.

HRMS (ESI) calculated C ₃₀H₃₅N₅OF,[M+H]⁺ m/z 500.2825, found 500.2826.

Example 81 4- (4- (4-chlorophenyl) piperazin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 52)

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The synthesis method comprises the following steps: the same general synthetic method is eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1- (4-chlorophenyl) piperazine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₃₂H₃₆N₃OFCl,[M+H]⁺ m/z 532.2531 and the measured value 532.2531 of yield ：85％.¹H NMR(400MHz,DMSO-d₆)δ8.21(d,J＝8.6Hz,1H),8.08(d,J＝9.1Hz,1H),7.94(d,J＝7.9Hz,1H),7.72–7.64(m,2H),7.66–7.55(m,2H),7.44(t,J＝7.4Hz,1H),7.34–7.25(m,4H),7.07–6.98(m,2H),5.36(s,2H),4.56(t,J＝5.5Hz,2H),3.80(d,J＝12.8Hz,2H),3.50(d,J＝11.8Hz,2H),3.23(t,J＝12.3Hz,2H),3.08(dq,J＝12.6,7.6,5.5Hz,5H),2.97(s,2H),1.88–1.67(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ160.69,155.42,148.43,133.11,133.08,132.47,131.58,130.38,130.29,128.81,128.52,128.48,127.36,123.90,123.54,123.14,117.48,115.48,115.27,114.34,112.60,69.63,66.34,54.49,50.21,46.60,45.07,40.41,22.59,20.34.HRMS(ESI) are calculated.

Example 82 2- (4- (((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) amino) butyl) -1,2,3, 4-tetrahydroisoquinoline-7-carbonitrile (LZ 53)

The synthesis method comprises the following steps: in the same manner as in the eighteen general synthetic methods, tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 1,2,3, 4-tetrahydroisoquinoline-7-nitrile are used as raw materials to obtain white powder, the calculated value C ₃₂H₃₂FN₃O,[M+H]⁺ m/z494.2610 of yield ：52％.¹H NMR(400MHz,CD₃OD)δ8.16(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.93(d,J＝8.1Hz,1H),7.71–7.57(m,6H),7.47(t,J＝8.0Hz,2H),7.27–7.16(m,2H),5.40(s,2H),4.77(s,3H),4.53–4.33(m,1H),3.94–3.78(m,1H),3.79–3.54(m,1H),3.54–3.26(m,2H),3.26–3.17(m,3H),1.95(td,J＝13.1,10.8,7.8Hz,3H),1.84(dq,J＝15.2,7.4Hz,3H).¹³C NMR(101MHz,CD₃OD)δ165.34,162.90,157.09,138.19,134.24,134.20,133.95,133.52,132.64,131.93,131.47,131.38,131.12,130.77,130.67,130.01,129.14,125.36,123.11,119.12,116.69,116.47,115.05,113.14,112.13,71.59,56.66,53.31,50.63,48.24,42.74,26.68,24.15,22.52.HRMS(ESI) and the measured value 494.2608.

Example 83 4- (4-Benzylpiperidin-1-yl) -N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 54)

The synthesis method comprises the following steps: the general synthesis method is similar to eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 4-benzyl piperidine are used as raw materials to obtain pale yellow oily viscous liquid, the calculated value C ₃₄H₄₀N₂OF,[M+H]⁺ m/z 511.3130 of the yield ：35％.¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝8.6Hz,1H),7.80(t,J＝9.3Hz,2H),7.57(ddd,J＝8.4,6.8,1.3Hz,1H),7.48–7.41(m,2H),7.40–7.34(m,1H),7.31(d,J＝9.0Hz,1H),7.24(d,J＝7.6Hz,2H),7.19–7.13(m,1H),7.11–7.07(m,2H),7.06–7.03(m,2H),5.21(s,2H),4.34(s,2H),3.41(s,2H),2.86(d,J＝11.7Hz,3H),2.74(t,J＝6.2Hz,2H),2.42–2.28(m,4H),1.84(td,J＝12.0,2.5Hz,2H),1.64–1.45(m,5H),1.25(s,1H),1.08(qd,J＝12.3,11.6,3.8Hz,2H).¹³C NMR(101MHz,CDCl₃)δ154.15,146.67,139.58,133.26,132.84,132.82,132.74,129.57,129.46,129.40,129.32,128.93,128.62,128.57,128.38,127.17,126.07,123.91,123.13,120.86,115.72,115.50,114.55,77.23,70.88,62.14,58.34,50.83,49.28,49.22,42.86,38.03,27.61,24.81.HRMS(ESI) and the measured value 511.3125.

Example 84 4- (4-chlorophenyl) -1- (4- (((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) amino) butyl) piperidin-4-ol (LZ 55)

The synthesis method comprises the following steps: the same general synthesis method is eighteen, and tert-butyl (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamate (20 b) and 4- (4-chlorophenyl) piperidin-4-ol are used as raw materials to obtain pale yellow powder, the calculated value C ₃₃H₃₇N₂O₂FCl,[M+H]⁺ m/z 547.2534 of the yield ：45％.¹H NMR(400MHz,CDCl₃)δ8.14(d,J＝8.6Hz,1H),7.82–7.74(m,2H),7.55(ddd,J＝8.5,6.8,1.4Hz,1H),7.48–7.39(m,2H),7.37(ddd,J＝8.0,6.8,1.0Hz,1H),7.31(s,1H),7.29(s,2H),7.25(d,J＝8.8Hz,2H),7.14–7.03(m,2H),5.20(s,2H),4.32(s,2H),3.47(s,4H),2.79–2.70(m,3H),2.69(s,1H),2.43–2.32(m,3H),1.90(t,J＝11.9Hz,1H),1.57(d,J＝3.4Hz,4H).¹³C NMR(101MHz,DMSO-d₆)δ154.12,148.93,132.86,130.75,129.98,129.96,129.90,128.85,128.29,127.68,126.79,126.77,126.74,126.66,123.62,123.53,115.37,115.36,115.16,115.12,94.12,69.93,69.35,69.34,57.66,57.64,48.83,48.54,48.53,41.98,37.55,24.16,24.15.HRMS(ESI), and the measured value is 547.2528.

Example 85N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4-methylpiperazin-1-yl) butan-1-amine (LZ 56)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and 1-methylpiperazine are used as raw materials to obtain white powder, wherein the calculated value C ₂₇H₃₅N₃OF,[M+H]⁺ m/z 436.2765 and the measured value 436.2764 are calculated by yield ：42％.¹H NMR(400MHz,DMSO-d₆)δ8.20(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.94(d,J＝7.8Hz,1H),7.72–7.62(m,2H),7.66–7.56(m,2H),7.44(ddd,J＝7.9,6.8,1.0Hz,1H),7.34–7.24(m,2H),5.36(s,2H),4.56(t,J＝5.4Hz,2H),3.70(s,4H),3.61(s,4H),3.56–3.39(m,1H),3.09(s,1H),2.97(s,3H),2.81(s,3H),1.76(s,4H).¹³C NMR(101MHz,DMSO-d₆)δ163.10,160.67,155.23,133.12,133.09,132.50,131.34,130.32,130.23,128.57,128.49,127.29,123.88,123.08,115.44,115.23,114.43,113.44,69.70,51.67,46.93,40.57,31.16,28.63,23.31,21.54,21.04.HRMS(ESI).

Example 86N- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -4- (4-methylpiperidin-1-yl) butan-1-amine (LZ 57)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and 4-methylpiperidine are taken as raw materials to obtain white powder, the calculated value C ₂₈H₃₆N₂OF,[M+H]⁺ m/z435.2804 of the yield ：40％.¹H NMR(400MHz,CDCl₃)δ8.15(d,J＝8.6Hz,1H),7.84(d,J＝9.1Hz,1H),7.76(d,J＝8.1Hz,1H),7.55(ddd,J＝8.4,6.8,1.3Hz,1H),7.52–7.47(m,2H),7.34(t,J＝7.5Hz,1H),7.29(d,J＝9.1Hz,1H),7.09(t,J＝8.6Hz,2H),5.27(s,2H),4.49(s,2H),3.20(d,J＝11.8Hz,2H),2.80(d,J＝6.4Hz,2H),2.74–2.61(m,2H),2.43(d,J＝12.1Hz,2H),1.70(s,5H),1.63(d,J＝10.8Hz,2H),1.46(s,2H),0.88(d,J＝4.3Hz,4H).¹³C NMR(101MHz,DMSO-d₆)δ163.10,160.67,155.23,133.12,133.09,132.50,131.34,130.32,130.23,128.57,128.49,127.29,123.88,123.08,115.47,115.44,115.23,114.43,113.44,69.70,51.67,46.93,40.57,31.16,28.63,23.31,21.54,21.04.HRMS(ESI) and the measured value 435.2812.

Example 87N ¹ - ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) -N ⁴,N⁴ -dimethylbutane-1, 4-diamine (LZ 58)

The synthesis method comprises the following steps: the same general synthetic method is eighteen, and (4-bromobutyl) ((2- ((4-fluorobenzyl) oxy) naphthalene-1-yl) methyl) carbamic acid tert-butyl ester (20 b) and dimethylamine hydrochloride are used as raw materials to obtain white powder, wherein the calculated value C ₂₄H₂₉N₂OF,[M+H]⁺ m/z 381.2336 of the yield ：32％.¹H NMR(400MHz,DMSO-d₆)δ11.10–11.03(m,1H),9.39–9.26(m,2H),8.22(d,J＝8.6Hz,1H),8.07(d,J＝9.1Hz,1H),7.93(d,J＝8.1Hz,1H),7.69(dd,J＝8.2,5.7Hz,2H),7.62(d,J＝9.2Hz,1H),7.57(d,J＝8.0Hz,1H),7.43(t,J＝7.4Hz,1H),7.29(t,J＝8.8Hz,2H),5.36(s,2H),4.54(t,J＝5.3Hz,2H),3.45(s,3H),2.96(p,J＝6.2Hz,4H),2.69(d,J＝4.5Hz,5H),1.71(q,J＝3.9Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ163.11,160.69,155.45,133.12,132.48,131.55,130.45,130.37,128.51,128.46,127.34,123.88,123.18,115.47,115.26,114.32,112.59,69.62,55.53,46.59,41.73,40.36,40.15,39.94,39.73,39.52,39.31,39.10,38.89,22.43,20.98.HRMS(ESI) and the measured value 381.2342.

Example 88 2- ((4-fluorobenzyl) oxy) benzaldehyde (22)

The synthesis method comprises the following steps: salicylaldehyde (21, 40.1 mmol) was dissolved in acetone (100 ml), potassium carbonate (122 mmol), tetrabutylammonium iodide (20.3 mmol), 4-fluorobenzyl bromide (48.1 mmol) were added sequentially, the reaction system was heated to 56 ℃ to reflux, and the reaction was carried out overnight, and the reaction was detected by silica gel thin layer chromatography, and the almost complete reaction of the starting material 21 was observed. After the reaction is finished, after the reaction system is cooled to room temperature, insoluble inorganic salts are removed by suction filtration, the solvent is removed by rotary evaporation, yellow viscous liquid is obtained, dichloromethane is added for full dissolution, and saturated sodium chloride solution is used for extraction twice. The organic phase was collected, dried over anhydrous sodium sulfate, filtered with suction, the filtrate solvent was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=100:1), and enriched to give a colorless oily thick liquid, yield ：95％.¹H NMR(400MHz,CDCl₃)δ10.53(s,1H),7.86(dd,J＝7.6,1.8Hz,1H),7.59–7.50(m,1H),7.47–7.37(m,2H),7.13–7.07(m,2H),7.04(dd,J＝8.0,2.9Hz,2H),5.15(s,2H).

Example 89 (2- ((4-fluorobenzyl) oxy) benzyl) (4-hydroxybutyl) carbamic acid tert-butyl ester (23)

The synthesis method comprises the following steps:

2- ((4-fluorobenzyl) oxy) benzaldehyde (22, 18.43 mmol) was dissolved in dichloromethane (100 ml), 4-amino-1-butanol (27.93 mmol) was added and stirred at room temperature for 0.5h, then sodium triacetoxyborohydride (9.29 mmol) was added every half an hour, and after the reaction was detected by silica gel thin layer chromatography and continued for 4h, almost complete reaction of starting material 22 was observed. Ammonia water is slowly added into the reaction liquid to adjust the pH of the reaction liquid to be alkaline, and most of the solvent in the reaction system is removed by rotary evaporation. To the mixture was added an appropriate amount of methylene chloride (50 ml), and the mixture was extracted 2 times with a saturated sodium hydrogencarbonate solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered off with suction, and the solvent was removed from the filtrate by rotary evaporation to give a colorless thick oily liquid for further reaction.

The colorless thick oily liquid obtained above was dissolved in methylene chloride (50 ml), and di-tert-butyl dicarbonate (28.2 mmol) and triethylamine (3 ml) were added thereto, followed by stirring at room temperature and overnight reaction. The solvent was removed from the reaction mixture by rotary evaporation, redissolved in dichloromethane (60 ml) and extracted 2 times with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was removed from the filtrate by rotary evaporation, and the concentrate was purified and enriched by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give the desired product, tert-butyl (4-hydroxybutyl) carbamate (23), as a colorless oily thick liquid, yield: 78%. MS (ESI) theory C ₂₃H₃₀FNO₄,[M+H]⁺ m/z 404.49, found 404.22.

Example 90 (4-bromobutyl) (2- ((4-fluorobenzyl) oxy) benzyl) carbamic acid tert-butyl ester (24)

The synthesis method comprises the following steps: tert-butyl (2- ((4-fluorobenzyl) oxy) benzyl) (4-hydroxybutyl) carbamate (23, 2.45 mmol) was taken in dichloromethane (30 ml), triphenylphosphine (4.91 mmol) was added and stirred at ambient temperature. Carbon tetrabromide (4.91 mmol) was additionally taken and completely dissolved in methylene chloride (30 ml), transferred to a dropping funnel and slowly added dropwise into the reaction system, the colorless solution was gradually changed to red to finally be pale yellow, the dropwise addition was complete after about 0.5h, the reaction was continued at normal temperature, the reaction was monitored by silica gel thin layer chromatography, and after 5h of reaction, the almost complete reaction of the raw material 23 was observed. After the completion of the reaction, the reaction mixture was extracted with a saturated sodium chloride solution 2 times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent of the reaction solution was removed by rotary evaporation, and the concentrate was purified and enriched by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give a colorless oily viscous liquid, which was allowed to stand in a refrigerator at 4 ℃ for 4 hours as white lump crystals, namely tert-butyl (24) carbamate as the target product (4-bromobutyl) (2- ((4-fluorobenzyl) oxy) benzyl) and yield ：80％.¹H NMR(400MHz,CDCl₃)δ7.40(dd,J＝8.4,5.4Hz,2H),7.22(t,J＝7.4Hz,2H),7.08(t,J＝8.5Hz,2H),6.96(t,J＝7.4Hz,1H),6.91(d,J＝8.1Hz,1H),5.04(s,2H),4.48(d,J＝29.0Hz,2H),3.48(t,J＝7.2Hz,1H),3.37–3.31(m,2H),3.20(dd,J＝21.9,6.1Hz,2H),1.59(d,J＝17.2Hz,4H),1.48(s,4H),1.41(s,4H).¹³C NMR(101MHz,CDCl₃)δ163.96,161.51,155.10,133.80,132.83,130.20,129.61,129.53,128.41,127.26,124.60,124.18,115.88,115.66,114.41,79.73,71.17,43.79,39.07,33.40,30.36,28.64,26.90.

Nineteenth general synthetic method:

(2- ((4-fluorobenzyl) oxy) benzyl) -4-substituted butyl-1-amine (LZ 60-LZ 61)

The synthesis method comprises the following steps:

Tert-butyl (4-bromobutyl) (2- ((4-fluorobenzyl) oxy) benzyl) carbamate (24, 1.07 mmol) was dissolved in acetonitrile (50 ml), potassium carbonate (3.76 mmol), tetrabutylammonium iodide (0.99 mmol) and secondary amine compound (1.19 mol) were added in this order, the reaction system temperature was heated to 80℃to reflux the reaction, and after the reaction was detected by silica gel thin layer chromatography and continued overnight, the reaction was observed to be almost complete for starting material 24, and the reaction was completed. The reaction system was allowed to stand to room temperature, insoluble inorganic salts were removed by suction filtration, the solvent in the filtrate was removed by rotary evaporation, methylene chloride (60 ml) was added to the concentrate to be sufficiently dissolved, and extraction was performed 2 times with a saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate solvent was removed by rotary evaporation to give a thick liquid as a colorless oil.

The colorless oily thick liquid obtained above was taken and added with a self-made saturated dioxane hydrochloride solution (20 ml), and stirred at normal temperature for overnight reaction. After the reaction, the pH of the reaction solution was adjusted to be alkaline, the solvent of the reaction solution was removed by rotary evaporation, the reaction solution was redissolved in methylene chloride, extracted 2 times with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified and enriched by silica gel column chromatography (methylene chloride: absolute methanol=15:1 to 10:1) to give a colorless oily liquid, which was dissolved in an aqueous methanol solution (absolute methanol: ultrapure water=1:4, total 20 ml) and subjected to vacuum freeze-drying to give a white powder, namely the target product (2- ((4-fluorobenzyl) oxy) benzyl) -4-substituted butyl-1-amine (LZ 60 to LZ 61).

Example 91N- (2- ((4-fluorobenzyl) oxy) benzyl) -4- (4-methylpiperazin-1-yl) butan-1-amine (LZ 60)

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The synthesis method comprises the following steps: according to the same general synthesis method, nineteen (4-bromobutyl) (2- ((4-fluorobenzyl) oxy) benzyl) carbamic acid tert-butyl ester (24) and 1-methylpiperazine are used as raw materials, and colorless oily liquid is obtained, and a calculated value C ₂₃H₃₃N₃OF,[M+H]⁺ m/z 386.2604 and an actual measurement value 386.2608 are calculated by using a yield ：38％.¹H NMR(400MHz,DMSO-d₆)δ7.61(dd,J＝8.5,5.7Hz,2H),7.56(d,J＝7.2Hz,1H),7.44–7.35(m,1H),7.27(t,J＝8.8Hz,2H),7.17(d,J＝8.3Hz,1H),7.02(t,J＝7.5Hz,1H),5.18(s,2H),4.10(t,J＝5.5Hz,2H),3.67(s,2H),3.49(s,7H),3.13(d,J＝28.9Hz,2H),2.84(d,J＝26.9Hz,5H),1.73(q,J＝11.2,7.9Hz,4H).¹³C NMR(101MHz,DMSO-d₆)δ156.49,156.46,139.97,133.10,133.07,133.04,131.56,131.52,130.59,130.10,130.02,120.64,120.15,115.44,115.22,112.41,100.37,73.90,68.84,45.81,44.51,22.42,22.40.HRMS(ESI).

Example 92N ¹ - (2- ((4-fluorobenzyl) oxy) benzyl) -N ⁴,N⁴ -dimethylbutane-1, 4-diamine (LZ 61)

The synthesis method comprises the following steps: according to the same general synthesis method, nineteen (4-bromobutyl) (2- ((4-fluorobenzyl) oxy) benzyl) carbamic acid tert-butyl ester (24) and dimethylamine hydrochloride are used as raw materials, and colorless oily liquid is obtained, and the calculated value C ₂₀H₂₈N₂OF,[M+H]⁺ m/z 331.2184 of yield ：45％.¹H NMR(400MHz,DMSO-d₆)δ7.64–7.56(m,2H),7.55(d,J＝6.7Hz,1H),7.45–7.36(m,1H),7.32–7.22(m,2H),7.17(d,J＝8.2Hz,1H),7.02(t,J＝7.3Hz,1H),5.18(s,2H),4.10(t,J＝5.6Hz,2H),3.49(s,6H),3.13(d,J＝29.8Hz,1H),2.89(d,J＝8.3Hz,2H),2.81(s,2H),1.73(s,4H).¹³C NMR(101MHz,DMSO-d₆)δ163.04,160.61,156.45,149.11,133.06,133.02,131.49,130.61,130.08,130.00,122.64,120.64,120.14,115.43,115.22,112.41,68.84,45.84,44.58,22.45.HRMS(ESI) is found to be 331.2186.

Twenty general synthetic methods:

2- (4-substituted benzyloxy) -5-substituted benzaldehydes (26 a-26 n)

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The synthesis method comprises the following steps: 2-hydroxy-5-substituted benzaldehyde (25 a-25 e,3.28 mmol) is taken and dissolved in acetone (50 ml), potassium carbonate (3.28 mmol), tetrabutylammonium iodide (1.64 mmol) and 4-substituted benzyl bromide (3.94 mmol) are sequentially added, stirring is carried out for 3h at normal temperature, if the reaction is monitored by silica gel thin layer chromatography, if the raw material 2-hydroxy-5-substituted benzaldehyde is almost completely reacted, the reaction system is heated to 50 ℃ if obvious raw materials are remained until the raw materials are almost completely reacted, and the total reaction time is less than or equal to 8h. After the reaction is finished, the reaction system is cooled to room temperature, insoluble inorganic salts are removed by rotary evaporation, and the solvent of the filtrate is removed by rotary evaporation, so that colorless to yellow oily thick liquid is obtained. The oily liquid was redissolved in dichloromethane (60 ml) and extracted 2 times with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was removed by rotary evaporation to give a solvent, and the concentrate was purified and enriched by column chromatography on silica gel (petroleum ether: ethyl acetate=50:1) to give a white to pale yellow solid powder, i.e., the desired product, 2- (4-substituted benzyloxy) -5-substituted benzaldehydes (26 a to 26 n).

Example 93- ((4-fluorobenzyl) oxy) -5-chlorobenzaldehyde (26 a)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white powder is obtained by taking 2-hydroxy-5-chlorobenzaldehyde (25 a) and 4-fluorobenzyl bromide as raw materials, and the yield is high ：85％.¹H NMR(400MHz,CDCl₃)δ10.02(s,1H),7.71–7.64(m,3H),7.37(dd,J＝8.2,5.5Hz,2H),7.14–7.00(m,2H),5.10(s,2H).

Example 94- ((4-fluorobenzyl) oxy) -5-methoxybenzaldehyde (26 b)

The synthesis method comprises the following steps: the same general synthetic method twenty uses 2-hydroxy-5-methoxybenzaldehyde (25 b) and 4-fluorobenzyl bromide as raw materials to obtain white powder with yield ：83％.¹H NMR(400MHz,CDCl3)δ10.47(s,1H),7.39(dd,J＝8.2,5.5Hz,2H),7.34(d,J＝3.2Hz,1H),7.15–7.03(m,3H),6.99(d,J＝9.0Hz,1H),5.10(s,2H),3.80(d,J＝2.0Hz,3H).

Example 95 2- ((4-fluorobenzyl) oxy) -5-methylbenzaldehyde (26 c)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white powder is obtained by taking 2-hydroxy-5-methylbenzaldehyde (25 c) and 4-fluorobenzyl bromide as raw materials, and the yield is high ：90％.¹H NMR(400MHz,CDCl₃)δ10.52(s,1H),7.68(d,J＝2.1Hz,1H),7.43(dt,J＝8.1,4.1Hz,2H),7.36(dd,J＝8.5,2.3Hz,1H),7.16–7.06(m,2H),6.96(d,J＝8.5Hz,1H),5.15(s,2H),2.34(s,3H).

Example 96 2- ((4-fluorobenzyl) oxy) -5-nitrobenzaldehyde (26 d)

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The synthesis method comprises the following steps: the same general synthesis method is twenty, 2-hydroxy-5-nitrobenzaldehyde (25 d) and 4-fluorobenzyl bromide are used as raw materials, and light yellow powder is obtained, and the yield is high ：67％.¹H NMR(400MHz,CDCl₃)δ10.50(s,1H),8.73(d,J＝2.6Hz,1H),8.44(dd,J＝9.1,2.6Hz,1H),7.46(dd,J＝8.0,5.5Hz,3H),7.17(dt,J＝16.9,8.8Hz,2H),5.31(s,2H).

Example 97 2- ((4-fluorobenzyl) oxy) -5-fluorobenzaldehyde (26 e)

The synthesis method comprises the following steps: the same general synthetic method twenty uses 2-hydroxy-5-fluorobenzaldehyde (25 e) and 4-fluorobenzyl bromide as raw materials to obtain white powder with yield ：78％.¹H NMR(400MHz,Chloroform-d)δ10.45(d,J＝3.1Hz,1H),7.52(dd,J＝8.2,3.3Hz,1H),7.40(ddd,J＝8.1,5.1,2.3Hz,2H),7.24(ddd,J＝9.1,7.6,2.2Hz,1H),7.15–7.05(m,2H),7.01(dd,J＝9.1,3.9Hz,1H),5.13(s,2H).

Example 98- ((4-bromobenzyl) oxy) -5-chlorobenzaldehyde (26 f)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white powder is obtained by taking 2-hydroxy-5-chlorobenzaldehyde (25 a) and 4-bromobenzyl bromide as raw materials, and the yield is high ：75％.¹H NMR(400MHz,CDCl₃)δ10.45(s,1H),7.81(d,J＝2.8Hz,1H),7.58–7.51(m,2H),7.47(dd,J＝8.9,2.7Hz,1H),7.30(d,J＝8.4Hz,2H),6.97(d,J＝8.9Hz,1H),5.13(s,2H).

Example 99- ((4-bromobenzyl) oxy) -5-methoxybenzaldehyde (26 g)

The synthesis method comprises the following steps: the same general synthetic method twenty uses 2-hydroxy-5-methoxybenzaldehyde (25 b) and 4-bromobenzyl bromide as raw materials to obtain white powder with yield ：82％.¹H NMR(400MHz,DMSO-d₆)δ10.38(s,1H),7.59(d,J＝8.1Hz,2H),7.46(d,J＝8.2Hz,2H),7.26(s,3H),7.18(s,1H),5.22(s,2H),3.75(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ188.88,154.90,153.42,136.10,131.41,129.76,124.98,122.96,121.08,116.12,111.01,110.34,110.31,69.70,55.54.

Example 100- ((4-bromobenzyl) oxy) -5-fluorobenzaldehyde (26 h)

The synthesis method comprises the following steps: the same general synthetic method twenty uses 2-hydroxy-5-fluorobenzaldehyde (25 e) and 4-bromobenzyl bromide as raw materials to obtain white powder with yield ：76％.¹H NMR(400MHz,DMSO-d₆)δ7.62–7.55(m,2H),7.45–7.38(m,2H),7.20(d,J＝9.3Hz,1H),7.03(dd,J＝6.9,2.1Hz,2H),5.10(s,2H).

Example 101- ((4-bromobenzyl) oxy) -5-methylbenzaldehyde (26 i)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white flocculent solid is obtained by taking 2-hydroxy-5-methylbenzaldehyde (25 c) and 4-bromobenzyl bromide as raw materials, and the yield is ：82％.¹H NMR(400MHz,DMSO-d₆)δ10.39(s,1H),7.62–7.57(m,2H),7.51(d,J＝2.4Hz,1H),7.46(dd,J＝8.7,2.3Hz,3H),7.19(d,J＝8.5Hz,1H),5.23(s,2H),2.27(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ192.49,189.17,158.46,136.83,136.07,132.67,131.43,130.07,129.69,127.79,124.27,121.07,114.15,69.10,19.80.

Example 102- ((4-bromobenzyl) oxy) -5-nitrobenzaldehyde (26 j)

The synthesis method comprises the following steps: the same general synthesis method is twenty, 2-hydroxy-5-nitrobenzaldehyde (25 d) and 4-bromobenzyl bromide are used as raw materials, and light yellow solid is obtained, and the yield is high ：70％.¹H NMR(400MHz,CDCl₃)δ10.49(s,1H),8.71(d,J＝2.9Hz,1H),8.41(dd,J＝9.2,2.9Hz,1H),7.61–7.53(m,2H),7.33(d,J＝8.4Hz,2H),7.15(d,J＝9.2Hz,1H),5.27(s,2H).

Example 103 5-methoxy-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 k)

The synthesis method comprises the following steps: the same general synthesis method is twenty, and the white flocculent solid is obtained by taking 2-hydroxy-5-methoxybenzaldehyde (25 b) and 4- (trifluoromethyl) benzyl bromide as raw materials, and the yield is ：78％.¹H NMR(400MHz,CDCl₃)δ10.52(s,1H),7.66(d,J＝8.1Hz,2H),7.55(d,J＝8.0Hz,2H),7.36(d,J＝3.3Hz,1H),7.11(dd,J＝9.0,3.3Hz,1H),6.96(d,J＝9.0Hz,1H),5.21(s,2H),3.80(s,3H).

Example 104 5-methyl-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 l)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white solid is obtained by taking 2-hydroxy-5-methylbenzaldehyde (25 c) and 4- (trifluoromethyl) benzyl bromide as raw materials, and the yield is ：81％.¹H NMR(400MHz,CDCl₃)δ10.53(s,1H),7.71–7.62(m,3H),7.56(d,J＝8.1Hz,2H),7.34(dd,J＝8.5,2.4Hz,1H),6.91(d,J＝8.5Hz,1H),5.23(s,2H),2.32(s,3H).

Example 105 5-fluoro-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 m)

The synthesis method comprises the following steps: the same general synthetic method is twenty, and the white solid is obtained by taking 2-hydroxy-5-fluorobenzaldehyde (25 e) and 4- (trifluoromethyl) benzyl bromide as raw materials, and the yield is ：65％.¹H NMR(400MHz,CDCl₃)δ10.49(d,J＝3.1Hz,1H),7.67(d,J＝8.1Hz,2H),7.60–7.50(m,3H),7.28–7.20(m,1H),6.99(dd,J＝9.1,3.8Hz,1H),5.24(s,2H).

Example 106- ((4- (trifluoromethyl) benzyl) oxy) -5-nitrobenzaldehyde (26 n)

The synthesis method comprises the following steps: the same general synthesis method is twenty, 2-hydroxy-5-nitrobenzaldehyde (25 e) and 4- (trifluoromethyl) benzyl bromide are used as raw materials, and light yellow solid is obtained, and the yield is high ：70％.¹H NMR(400MHz,CDCl₃)δ10.51(s,1H),8.70(d,J＝2.9Hz,1H),8.41(dd,J＝9.2,2.9Hz,1H),7.70(d,J＝8.1Hz,2H),7.59(d,J＝8.1Hz,2H),7.17(d,J＝9.2Hz,1H),5.39(s,2H).

General synthesis method twenty-one:

n- (5-substituted-2- ((4-substituted benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 62 to LZ 75)

The synthesis method comprises the following steps: 2- (4-substituted benzyloxy) -5-substituted benzaldehyde (26 a-26 n,3.31 mmol) was dissolved in methylene chloride (50 ml), 4-amino-1-methylpiperidine (3.94 mmol) was added, stirred at room temperature and reacted overnight, the reaction was monitored by silica gel thin layer chromatography, it was observed that the starting materials 26 a-26 n were almost completely reacted, and aqueous ammonia was slowly added to the reaction solution to adjust the pH of the system to be alkaline. The reaction solution is extracted for 2 times by saturated sodium bicarbonate solution, an organic phase is collected, dried by anhydrous sodium sulfate, filtered, and filtered, the filtrate is removed by rotary evaporation to obtain a solvent, the concentrate is purified and enriched by silica gel column chromatography (dichloromethane: anhydrous methanol=15:1-8:1) to obtain colorless oily thick liquid, the colorless oily thick liquid is dissolved in methanol aqueous solution (anhydrous methanol: water=1:4, total 20 ml), and white to pale yellow solid is obtained by vacuum freeze drying, namely the target product N- (5-substituted-2- ((4-substituted benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 62-LZ 75).

Example 107N- (5-chloro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 62)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-fluorobenzyl) oxy) -5-chlorobenzaldehyde (26 a) and 4-amino-1-methylpiperidine are taken as raw materials, white powder is obtained, and the calculated value C ₂₀H₂₅N₂OFCl,[M+H]⁺ m/z 3.363.1636 and the measured value 363.1639 of the yield ：70％.¹H NMR(400MHz,CDCl₃)δ7.37(dd,J＝8.5,5.4Hz,2H),7.27(d,J＝2.7Hz,1H),7.17(dd,J＝8.7,2.6Hz,1H),7.07(t,J＝8.6Hz,2H),6.83(d,J＝8.7Hz,1H),5.02(s,2H),3.77(s,2H),2.87(d,J＝11.2Hz,2H),2.53(s,1H),2.34(s,3H),2.17(s,2H),1.92(d,J＝12.9Hz,2H),1.50(q,J＝11.4,10.0Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ163.13,160.70,155.44,132.61,132.58,131.41,130.42,130.34,130.13,124.11,122.12,115.42,115.21,114.12,69.37,51.60,51.24,42.23,41.35,25.41.HRMS(ESI) are calculated.

Example 108N- (5-methoxy-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 63)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-fluorobenzyl) oxy) -5-methoxybenzaldehyde (26 b) and 4-amino-1-methylpiperidine are used as raw materials, white powder is obtained, the calculated value C ₂₁H₂₈N₂O₂F,[M+H]⁺ m/z 359.2130 of the yield ：78％.¹H NMR(400MHz,DMSO-d₆)δ7.58(dd,J＝8.5,5.7Hz,2H),7.29(d,J＝3.1Hz,1H),7.25(t,J＝8.8Hz,2H),7.10(d,J＝9.0Hz,1H),6.96(dd,J＝9.0,3.1Hz,1H),5.09(s,2H),4.09(s,2H),3.73(s,3H),3.42(d,J＝12.6Hz,2H),3.19(s,1H),2.95(t,J＝11.7Hz,3H),2.67(s,3H),2.27(d,J＝12.6Hz,2H),2.02(q,J＝13.0,12.3Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ153.04,150.46,133.19,133.17,130.24,130.20,130.16,120.83,117.53,117.52,115.38,115.26,115.17,113.60,69.45,55.57,51.41,51.27,51.24,41.81,25.43.HRMS(ESI) is obtained, and the measured value is 359.2135.

Example 109N- (5-methyl-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 64)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-fluorobenzyl) oxy) -5-methylbenzaldehyde (26C) and 4-amino-1-methylpiperidine are taken as raw materials, white powder is obtained, the calculated value C ₂₁H₂₈N₂OF,[M+H]⁺ m/z 343.2182 of the yield ：75％.¹H NMR(400MHz,DMSO-d₆)δ7.60(dd,J＝8.5,5.7Hz,2H),7.39(d,J＝1.8Hz,1H),7.26(t,J＝8.8Hz,2H),7.21(dd,J＝8.4,1.9Hz,1H),7.07(d,J＝8.4Hz,1H),5.12(s,2H),4.08(s,2H),3.35(s,8H),3.19(s,1H),2.95(t,J＝11.3Hz,2H),2.68(s,2H),2.26(s,2H),2.12–1.95(m,1H).¹³C NMR(101MHz,DMSO-d₆)δ190.02,154.48,133.05,132.32,130.89,130.27,130.19,129.36,128.68,119.69,115.38,115.17,112.29,68.97,51.52,51.26,50.91,42.25,42.06,25.44,20.02.HRMS(ESI) is obtained, and the measured value is 343.2186.

Example 110N- (5-Nitro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 65)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-fluorobenzyl) oxy) -5-nitrobenzaldehyde (26 d) and 4-amino-1-methylpiperidine are taken as raw materials, light yellow powder is obtained, the calculated value C ₂₀H₂₅N₃O₃F,[M+H]⁺ m/z 374.1873 of the yield ：80％.¹H NMR(400MHz,DMSO-d₆)δ8.56(d,J＝2.8Hz,1H),8.33(dd,J＝9.2,2.8Hz,1H),7.67(ddd,J＝9.1,5.6,2.9Hz,2H),7.40(d,J＝9.3Hz,1H),7.34–7.22(m,2H),5.31(s,2H),4.23–4.16(m,2H),3.52(s,1H),3.41(d,J＝12.1Hz,2H),3.25(s,1H),3.08–2.91(m,2H),2.69(dd,J＝11.6,4.6Hz,3H),2.28(d,J＝12.6Hz,2H),2.04(qd,J＝13.9,3.9Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ163.29,161.94,160.86,140.31,131.95,131.92,130.76,130.68,127.72,126.81,121.32,115.51,115.30,112.75,70.12,51.78,51.24,42.23,41.35,25.45.HRMS(ESI) is obtained, and the measured value is 374.1880.

Example 111N- (5-fluoro-2- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 66)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-fluorobenzyl) oxy) -5-fluorobenzaldehyde (26 e) and 4-amino-1-methylpiperidine are taken as raw materials, white powder is obtained, the calculated value C ₂₀H₂₅N₂OF₂,[M+H]⁺ m/z 347.1932 of the yield ：73％.¹H NMR(400MHz,CDCl₃)δ7.41–7.31(m,2H),7.11–6.99(m,3H),6.89(ddd,J＝9.0,7.9,3.1Hz,1H),6.83(dd,J＝9.0,4.5Hz,1H),4.99(s,2H),3.79(s,2H),3.41(d,J＝0.9Hz,3H),3.02–2.92(m,2H),2.63(tt,J＝9.1,3.6Hz,1H),2.42(s,3H),1.97–1.86(m,2H),1.57(ddt,J＝14.7,9.7,4.7Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ163.10,160.68,156.96,154.61,152.93,132.80,130.37,121.67,118.56,118.32,116.70,115.41,115.20,113.68,69.55,51.25,42.24,41.42,39.10,25.40.HRMS(ESI) is obtained, and the measured value is 347.1935.

Example 112N- (2- ((4-bromobenzyl) oxy) -5-chlorobenzyl) -1-methylpiperidin-4-amine (LZ 67)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-bromobenzyl) oxy) -5-chlorobenzaldehyde (26 f) and 4-amino-1-methylpiperidine are taken as raw materials to obtain white powder, and the calculated value C ₂₀H₂₅N₂OClBr,[M+H]⁺ m/z 423.0831 and the measured value 423.0839 of yield ：81％.¹H NMR(400MHz,DMSO-d₆)δ7.72(d,J＝2.7Hz,1H),7.63(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.45(dd,J＝8.9,2.7Hz,1H),7.17(d,J＝8.9Hz,1H),5.16(s,2H),4.12(s,2H),3.42(d,J＝12.4Hz,2H),3.35(s,2H),2.99(d,J＝13.5Hz,2H),2.68(s,3H),2.28(d,J＝13.4Hz,2H),2.04(q,J＝12.2Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ156.48,155.31,135.84,131.41,130.15,130.10,124.18,122.16,121.24,114.12,69.30,69.27,66.33,51.65,51.25,51.21,42.24,41.33,25.43,25.40.HRMS(ESI) are obtained.

Example 113N- (2- ((4-bromobenzyl) oxy) -5-methoxybenzyl) -1-methylpiperidin-4-amine (LZ 68)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-bromobenzyl) oxy) -5-methoxybenzaldehyde (26 g) and 4-amino-1-methylpiperidine are used as raw materials to obtain white powder, and the calculated value C ₂₁H₂₈N₂O₂Br,[M+H]⁺ m/z 419.1330 and the measured value 419.1334 of yield ：73％.¹H NMR(400MHz,DMSO-d₆)δ7.63–7.56(m,2H),7.44(d,J＝8.4Hz,2H),7.16(d,J＝3.0Hz,1H),7.01(d,J＝9.0Hz,1H),6.84(dd,J＝8.9,3.1Hz,1H),5.05(s,2H),3.88(s,2H),3.71(s,3H),2.92(d,J＝11.5Hz,2H),2.71(ddt,J＝10.1,7.5,3.4Hz,1H),2.31(s,3H),2.20(s,2H),1.94(d,J＝14.0Hz,2H),1.89(s,1H),1.69–1.53(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ153.21,150.14,136.71,131.33,129.91,120.97,116.48,113.51,113.36,83.99,69.28,55.45,52.59,52.53,52.52,44.29,44.27,42.91,40.20,28.40,21.39.HRMS(ESI) are obtained.

Example 114N- (2- ((4-bromobenzyl) oxy) -5-fluorobenzyl) -1-methylpiperidin-4-amine (LZ 69)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-bromobenzyl) oxy) -5-fluorobenzaldehyde (26 h) and 4-amino-1-methylpiperidine are taken as raw materials to obtain white powder, and the calculated value C ₂₀H₂₅N₂OBrF,[M+H]⁺ m/z 407.1128 and the measured value 407.1134 of yield ：65％.¹H NMR(400MHz,DMSO-d₆)δ7.64–7.56(m,2H),7.44(d,J＝8.4Hz,2H),7.33(dd,J＝9.1,2.6Hz,1H),7.14–7.02(m,2H),5.10(s,2H),3.83(s,2H),3.04–2.95(m,4H),2.67(t,J＝9.7Hz,2H),2.39(s,3H),1.92(d,J＝13.2Hz,2H),1.68–1.49(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ157.46,155.11,152.27,152.26,136.39,131.37,129.86,121.05,116.61,116.37,114.48,113.40,113.32,69.24,52.19,43.79,43.79,43.03,28.67,21.19.HRMS(ESI) are obtained.

Example 115N- (2- ((4-bromobenzyl) oxy) -5-methylbenzyl) -1-methylpiperidin-4-amine (LZ 70)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4-bromobenzyl) oxy) -5-methylbenzaldehyde (26 i) and 4-amino-1-methylpiperidine are taken as raw materials, white powder is obtained, the calculated value C ₂₁H₂₈N₂OBr,[M+H]⁺ m/z 403.1378 of the yield ：70％.¹H NMR(400MHz,DMSO-d₆)δ7.61(d,J＝8.3Hz,2H),7.46(d,J＝8.1Hz,2H),7.27(s,1H),7.13(d,J＝8.2Hz,1H),7.00(d,J＝8.4Hz,1H),5.10(s,2H),3.92(s,2H),3.34(s,2H),2.91(d,J＝11.6Hz,3H),2.81–2.72(m,1H),2.28(d,J＝21.3Hz,6H),1.93(d,J＝15.8Hz,3H),1.66–1.49(m,1H).¹³C NMR(101MHz,DMSO-d₆)δ153.21,150.14,136.71,131.33,129.91,120.97,116.48,113.51,113.36,83.99,69.28,55.45,52.59,52.53,52.52,44.29,44.27,42.91,40.20,28.40,21.39.HRMS(ESI) is obtained, and the measured value is 403.1385.

Example 116N- (2- ((4-bromobenzyl) oxy) -5-nitrobenzyl) -1-methylpiperidin-4-amine (LZ 71)

The synthesis method comprises the following steps: the general synthesis method twenty-one is carried out by taking 2- ((4-bromobenzyl) oxy) -5-nitrobenzaldehyde (26J) and 4-amino-1-methylpiperidine as raw materials to obtain pale yellow powder, obtaining yield ：82％.¹H NMR(400MHz,DMSO-d₆)δ8.57(d,J＝2.9Hz,1H),8.34(dd,J＝9.2,2.8Hz,1H),7.66(d,J＝8.3Hz,2H),7.58(d,J＝8.3Hz,2H),7.39(d,J＝9.3Hz,1H),5.32(s,2H),4.23(s,2H),3.44(d,J＝12.2Hz,2H),3.37(s,3H),2.99(s,2H),2.69(s,3H),2.29(s,1H),2.20–1.97(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ163.55,161.79,140.37,135.15,131.49,130.40,127.65,126.86,126.79,121.56,121.38,112.78,100.09,86.26,70.01,51.86,51.28,42.24,41.39,25.46.HRMS(ESI) calculated value C ₂₀H₂₅N₃O₃Br,[M+H]⁺ m/z 434.1075, measured value 434.1079.

Example 117N- (5-methoxy-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 72)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 5-methoxy-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 k) and 4-amino-1-methylpiperidine are used as raw materials, white powder is obtained, the calculated value C ₂₂H₂₈N₂O₂F₃,[M+H]⁺ m/z 409.2098 of yield ：65％.¹H NMR(400MHz,CDCl₃)δ7.67(d,J＝8.1Hz,2H),7.56(d,J＝8.0Hz,2H),7.01(s,1H),6.86(d,J＝8.9Hz,1H),6.79(dd,J＝8.9,3.0Hz,1H),5.13(s,2H),3.86(s,2H),3.78(s,3H),3.49(s,9H),3.11(s,2H),2.85(s,1H),2.53(s,3H),1.81(d,J＝9.3Hz,1H).¹³C NMR(101MHz,CDCl₃)δ181.35,154.13,154.10,150.78,141.31,141.13,141.12,130.70,130.37,127.96,127.90,125.86,125.82,125.79,125.75,125.71,125.50,122.79,117.51,116.84,113.08,77.36,70.17,55.92,44.35,28.12,27.69.HRMS(ESI) is obtained, and the measured value is 409.2103.

Example 118 1-methyl-N- (5-methyl-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) piperidin-4-amine (LZ 73)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 5-methyl-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 l) and 4-amino-1-methylpiperidine are used as raw materials, white powder is obtained, the calculated value C ₂₂H₂₈N₂OF₃,[M+H]⁺ m/z 393.2150 of yield ：75％.¹H NMR(400MHz,DMSO-d₆)δ7.78(d,J＝8.2Hz,2H),7.72(d,J＝8.1Hz,2H),7.26(d,J＝2.2Hz,1H),7.11(dd,J＝8.2,2.2Hz,1H),6.99(d,J＝8.3Hz,1H),5.23(s,2H),3.90(s,2H),2.84(d,J＝11.4Hz,2H),2.69(t,J＝10.1Hz,1H),2.25(s,5H),2.07(s,2H),1.90(d,J＝11.1Hz,3H),1.57–1.44(m,3H).¹³C NMR(101MHz,DMSO-d₆)δ154.02,142.04,132.95,131.13,129.34,129.28,128.49,128.15,125.59,125.32,125.28,125.24,125.21,122.89,112.02,68.65,52.94,52.86,44.69,43.32,29.00,20.11.HRMS(ESI) is obtained, and the measured value is 393.2154.

Example 119N- (5-fluoro-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 74)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 5-fluoro-2- ((4- (trifluoromethyl) benzyl) oxy) benzaldehyde (26 m) and 4-amino-1-methylpiperidine are used as raw materials, so that white powder is obtained, the calculated value C ₂₁H₂₅N₂OF₄,[M+H]⁺ m/z 397.1899 of the yield ：68％.¹H NMR(400MHz,CDCl₃)δ7.44–7.35(m,2H),7.16–7.02(m,3H),6.92(td,J＝8.4,3.1Hz,1H),6.86(dd,J＝8.9,4.5Hz,1H),5.03(s,2H),3.81(s,2H),2.91(dt,J＝10.3,4.3Hz,2H),2.56(s,1H),2.38(s,3H),2.22(s,2H),1.94(dd,J＝12.9,4.8Hz,2H),1.53(qd,J＝10.1,3.6Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ157.52,155.17,152.19,141.81,128.53,128.22,128.09,125.57,125.39,125.35,125.32,125.28,122.87,113.35,113.27,69.12,52.17,43.71,43.04,28.62,28.57.HRMS(ESI) is obtained, and the measured value is 397.1903.

Example 120 1-methyl-N- (5-nitro-2- ((4- (trifluoromethyl) benzyl) oxy) benzyl) piperidin-4-amine (LZ 75)

The synthesis method comprises the following steps: according to the general synthesis method twenty-one, 2- ((4- (trifluoromethyl) benzyl) oxy) -5-nitrobenzaldehyde (26 n) and 4-amino-1-methylpiperidine are taken as raw materials, white powder is obtained, the calculated value C ₂₁H₂₅N₃O₃F₃,[M+H]⁺ m/z 424.1841 of the yield ：82％.¹H NMR(400MHz,DMSO-d₆)δ8.59(d,J＝2.9Hz,1H),8.35(dd,J＝9.2,2.9Hz,1H),7.83(s,4H),7.39(d,J＝9.3Hz,1H),5.46(s,2H),4.28(s,2H),3.57(s,1H),3.44(d,J＝12.3Hz,2H),2.99(t,J＝12.0Hz,2H),2.69(s,3H),2.32(d,J＝12.4Hz,2H),2.14–1.97(m,3H).¹³C NMR(101MHz,DMSO-d₆)δ161.66,140.56,140.48,128.85,128.59,127.65,126.81,125.55,125.48,125.45,125.41,121.49,112.79,77.48,69.87,66.34,51.93,51.29,42.25,41.43,25.49.HRMS(ESI) is obtained, and the measured value is 424.1848.

Example 121- ((4-fluorobenzyl) oxy) benzaldehyde (28)

The synthesis method comprises the following steps: 3-hydroxybenzaldehyde (27, 40.94 mmol) was dissolved in acetone (100 ml), potassium carbonate (12.3 mmol), tetrabutylammonium iodide (20.3 mmol) and 4-fluorobenzyl bromide (48.3 mmol) were sequentially added, the reaction system was heated to 56℃to reflux, the reaction was carried out overnight, the reaction was monitored by silica gel thin layer chromatography, the reaction was stopped, the reaction was allowed to stand to cool the reaction system to room temperature, and insoluble inorganic salts were removed by suction filtration. The solvent of the filtrate was removed by rotary evaporation to give a thick liquid as a yellow oil, which was fully dissolved by adding methylene chloride (80 ml), and extracted 2 times with saturated sodium chloride solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered with suction, the filtrate solvent was removed by rotary evaporation, and the concentrate was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=50:1) to give a pale yellow powder, i.e. the target product 3- ((4-fluorobenzyl) oxy) benzaldehyde (28), in yield ：95％.¹H NMR(400MHz,CDCl₃)δ9.98(s,1H),7.47(d,J＝7.0Hz,3H),7.46–7.38(m,2H),7.29–7.21(m,1H),7.09(t,J＝8.6Hz,2H),5.09(s,2H).

Example 122N- (3- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 76)

The synthesis method comprises the following steps: 3- ((4-fluorobenzyl) oxy) benzaldehyde (28, 3.48 mmol) was dissolved in methylene chloride (50 ml), 4-amino-1-methylpiperidine (4.78 mmol) was added, stirred at room temperature for 0.5h, then sodium triacetoxyborohydride (1.65 mmol) was added every half an hour, the reaction was monitored by silica gel thin layer chromatography, after 6 hours it was observed that the starting material 28 was almost completely reacted, and aqueous ammonia was slowly added to the reaction solution to adjust the pH of the solution to alkaline. The reaction solution was extracted 2 times with saturated sodium bicarbonate, the organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, the filtrate solvent was removed by rotary evaporation, the concentrate was purified by column chromatography on silica gel (dichloromethane: anhydrous methanol=10:1), the enriched colorless oily viscous liquid was dissolved in aqueous methanol (methanol: ultrapure water=1:4, 20 ml) and dried by vacuum freeze to give a white powder, the target product N- (3- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 76), calculated as C ₂₀H₂₆N₂OF,[M+H]⁺ m/z 329.2029, yield ：65％.¹H NMR(400MHz,DMSO-d₆)δ7.56–7.48(m,2H),7.44(s,1H),7.34(t,J＝7.9Hz,1H),7.28–7.19(m,2H),7.20(d,J＝7.8Hz,1H),7.04(dd,J＝8.2,2.2Hz,1H),5.12(s,2H),4.14(s,2H),3.48(d,J＝11.9Hz,2H),3.21(d,J＝15.8Hz,1H),3.00(s,2H),2.68(s,3H),2.36(d,J＝12.6Hz,2H),2.07(q,J＝12.0Hz,3H).¹³C NMR(101MHz,DMSO-d₆)δ163.00,160.58,158.26,133.33,133.11,133.08,130.09,130.01,129.75,122.46,116.60,115.39,115.18,75.59,68.56,51.22,51.14,47.01,42.24,25.39.HRMS(ESI), found 329.2029.

Test example 1

The compound is discovered through evaluating the current inhibition effect of HEK293 cell line with high expression of K _Na 1.1.1; intensive studies on quinidine have found that inhibition of current is exhibited on HEK293 cells that express high levels of K _Na 1.1.1. The specific test method is as follows:

HEK293 cell culture with high expression of K _Na 1.1.1

Human embryonic kidney cells (Human embryonic kidney 293cells, HEK 293T) were cultured using DMEM basal medium (Gibco, carlsbad, calif., USA) with 10% Fetal Bovine Serum (FBS), and the cells were placed in a constant temperature incubator containing 5% CO ₂ at 37℃for stationary culture. Typically 2-3 days when cells grow to about 80-90%. HEK293T cells were seeded 18-20h prior to transfection in 35mm dishes with 8X 8 (mm) slides at a density of approximately 2X 10 ⁶, each containing 2mL of medium. One 1.5mL EP tube was used to dilute 0.8. Mu.g of plasmid into 100. Mu.L of Opti-MEM I Reduced Serum Medium, the other 1.5mL EP tube was used to dilute 0.8. Mu.L of Lipofectamine ^TM 2000 into 100. Mu.L of Opti-MEM I Reduced Serum Medium, and the mixture was allowed to stand at room temperature for 5min, and the two were mixed and allowed to stand at room temperature for 20min. The plated cell culture dish was removed by pipetting 10% FBS medium and replaced with 2ml Opti-MEM I ReducedSerum Medium. Mu.L of the mixture of liposomes and plasmid was added to the dish and mixed well by gentle shaking and placed in a constant temperature incubator containing 5% CO ₂ at 37 ℃. And (3) standing and culturing for 3-4h, and changing the culture medium into a normal culture medium for continuous culture. Transfection for 22-30h was used for subsequent experiments.

Electrophysiological recording

For current changes on highly expressed cell lines, whole cell patch clamp recording mode was used, where cells were placed in extracellular fluid. After the electrode is injected into the internal liquid, the electrode is moved until the electrode is immersed into the extracellular liquid, positive pressure is given to the electrode before the electrode approaches cells, positive pressure is released and gentle negative pressure is given when the electrode contacts the surface of a cell membrane to enable the electrode resistance to rise by 0.2-0.3MΩ, sealing operation is completed when the resistance rises to 1GΩ, fast capacitor (C-fast) is automatically compensated, membrane rupture operation is completed by manually giving short negative pressure stimulation with gradually accelerated frequency through a mouth or an injector, slow capacitor (C-slow) is automatically compensated, and series resistance is compensated to 70-80%. When the medicine is screened, extracellular fluid is firstly given to eliminate the interference of water flow on cells, and the current is recorded as a control when the current is stable, and gravity administration is adopted, wherein the administration time is 1-2min. All recordings were made at room temperature (23-25 ℃). The data was recorded by PATCHMASTER software.

In fig. 1, a concentration gradient of a test compound K _Na 1.1.1 was applied to the above system to obtain a dose-response curve, and the inhibition IC ₅₀ of the compounds quinidine, benidil, LZ23, LZ38, LZ53, LZ41, LZ46, LZ58 against current was calculated.

In fig. 2, a: the inhibition of hERG channel by compounds quinidine, LZ23, LZ41 was demonstrated, showing selectivity for K _Na 1.1.1 channel; b: the compounds LZ23 and LZ41 are shown to have a strong inhibition effect on K _Na1.1^Y796H.

In fig. 3, a: the inhibition of hERG channel by compound LZ41 at 100. Mu.M is illustrated; b: illustrating the inhibition of BK channel by Compound LZ41 at 10. Mu.M; c: illustrating the inhibition of the Na _V 1.5 channel by Compound LZ41 at 10. Mu.M; d: illustrating the inhibition of the Na _V 1.2 channel by Compound LZ41 at 10. Mu.M; e: the selectivity of compound LZ41 for the K _Na1.1、hERG、BK、Na_V1.5、Na_V 1.2.2 channel is illustrated.

In fig. 4, the selectivity of quinidine, compounds LZ23, LZ38, LZ53, LZ46, LZ58 for the K _Na1.1、hERG、BK、Na_V1.5、Na_V 1.2.2 channel is illustrated.

Test example 2

Evaluation of anti-epileptic Effect

C57BL/6N male mice (6-8 weeks, 18-22 g) were purchased from Vetong Lihua corporation (Beijing, china), license number SCXK (Beijing) 2019-0314. The breeding is maintained in an environment with artificial illumination for 12 hours, day and night alternation, the temperature is 18-25 ℃ and the relative humidity is 40-60%, food and water are sufficient and can be taken at will, and the mice are used for experiments after being adapted to the environment for one week. The positive control group is carbamazepine, the solvent is 0.3 percent sodium carboxymethyl cellulose, and the administration dosage is 120mg/kg. Quinine Ding Rong is added with drinking water after DMSO to prepare uniform solution, so that the DMSO concentration is less than 2%, and the administration dosage is 60mg/kg. The candidate compounds LZ23 and LZ41 are respectively prepared into three administration doses of 30mg/kg,60mg/kg and 120mg/kg dissolved in drinking water, and the negative control group is drinking water. All the compound solutions are prepared by adopting a gastric lavage administration mode, and the compound solutions are administered to animals by a gastric lavage needle in a volume of 10 mL/kg. Mice were injected post-cervical subcutaneously with 80mg/kg of a physiological saline solution of pentyltetrazole in a volume of 5 mL/kg. The time of the first muscle twitch, the time of the first tonic clonus, the total duration of tonic clonus, and the tonic clonus seizure rate within 30min were recorded for each group of mice, and the results are shown in fig. 5.

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Although the embodiments of the present application are described above, the embodiments are only used for facilitating understanding of the present application, and are not intended to limit the present application. Any person skilled in the art can make any modification and variation in form and detail without departing from the spirit and scope of the present disclosure, but the scope of the present disclosure is to be determined by the appended claims.

Claims

1. A substituted aromatic phenol derivative represented by formula (I), or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof:

r ₂ is R ₃ is hydrogen, R ₄ is selected from hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy, or R ₃ and R ₄ together with the carbon to which they are attached form an optionally substituted benzene ring, or an optionally substituted five-or six-membered nitrogen heterocycle; or R ₂ is hydrogen and R ₃ isR ₄ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached formSubstituted benzene ring, or/>Substituted five-or six-membered nitrogen heterocycles;

L ₂ is-CH ₂ -or-C (O) -, Is not present,/>Is a single bond;

L ₂ is-ch=, Singly (v)Is absent;

2. The substituted aromatic phenol derivative of claim 1, wherein R ₁ is hydrogen, unsubstituted C ₁-C₄ alkyl, or C ₁-C₄ alkyl substituted with a group selected from the group consisting of: optionally substituted phenyl, optionally heteroaryl, and optionally substituted C ₃-C₈ cycloalkyl; here, the optionally substituted phenyl, optionally heteroaryl, or optionally substituted C ₃-C₈ cycloalkyl refers to an unsubstituted phenyl, an unsubstituted heteroaryl, or an unsubstituted C ₃-C₈ cycloalkyl, respectively, or a phenyl, C ₃-C₈ cycloalkyl, or heteroaryl substituted with one or more selected from the following groups: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or alternatively

R ₁ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, or methyl substituted with a group selected from the group consisting of: optionally substituted phenyl, optionally substituted pyrrolyl, optionally substituted thiophene, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted quinolinyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl; here, the optionally substituted phenyl group, optionally substituted pyrrolyl group, optionally substituted thiophene, optionally substituted pyridinyl group, optionally substituted pyrimidinyl group, optionally substituted quinolinyl group, optionally substituted cyclopentyl group or optionally substituted cyclohexyl group means an unsubstituted phenyl group, an unsubstituted pyrrolyl group, an unsubstituted thiophene group, an unsubstituted pyridinyl group, an unsubstituted pyrimidinyl group, an unsubstituted quinolinyl group, an unsubstituted cyclopentyl group or an unsubstituted cyclohexyl group, or is substituted with one or more selected from the following groups: halogen, cyano, nitro, hydroxy, phenyl substituted with a group B selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and trifluoromethyl; or alternatively

R ₁ is hydrogen, methyl or isopropyl, or methyl substituted with a group selected from: phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, quinolinyl, substituted quinolinyl, cyclohexyl, substituted cyclohexyl; here, the substituted phenyl group, substituted pyridyl group, substituted pyrimidinyl group, substituted quinolinyl group or substituted cyclohexyl group means being substituted with one or more selected from the group consisting of: chlorine, fluorine, bromine, cyano, nitro, hydroxy, phenyl substituted with a group B selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and trifluoromethyl; or alternatively

R ₁ is hydrogen, methyl, isopropyl, cyclohexylmethyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, benzyl, 3-nitrobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 4- (2-cyanophenyl) benzyl, 3-quinolinylmethyl or (2-chloro-pyridin-5-yl) methyl.

3. The substituted aromatic phenol derivative according to claim 1, wherein L ₁ is a single bond 、-CH₂-、-(CH₂)₂-、-(CH₂)₃-、-(CH₂)₄-、-(CH₂)₅-、-CH₂-NH-、-CH₂-CH₂-NH-、-CH₂-NH-CH₂-、-CH₂-NH-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-CH₂-、 or-ch=ch-; or alternatively

L ₁ is a single bond 、-CH₂-、-(CH₂)₂-、-CH₂-NH-CH₂-CH₂-、-CH₂-NH-CH₂-CH₂-CH₂-、 or-ch=ch-.

4. The substituted aromatic phenol derivative according to claim 1, wherein L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ are each independently hydrogen, unsubstituted C ₁-C₆ alkyl, group A substituted C ₁-C₆ alkyl, unsubstituted C ₃-C₈ cycloalkyl, group A substituted C ₃-C₈ cycloalkyl, unsubstituted C ₁-C₆ alkanoylamino, group A substituted C ₁-C₆ alkanoylamino, unsubstituted five-or six-membered nitrogen heterocycle, group A substituted five-or six-membered nitrogen heterocycle; or R ₅ and R ₆ together with the N to which they are attached form an unsubstituted five-or six-membered nitrogen heterocycle, or a five-or six-membered nitrogen heterocycle substituted with group a; the group A is selected from one or more of the following groups: optionally substituted phenyl, unsubstituted C ₁-C₄ alkyl, phenyl-substituted C ₁-C₄ alkyl, amino-substituted C ₁-C₄ alkanoyl, hydroxy, unsubstituted C ₁-C₄ alkoxy, amino, optionally substituted phenoxy, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl; or alternatively

L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ are each independently hydrogen, methyl, ethyl, N-propyl, N-butyl, 2-hydroxyethyl, 2-aminoethyl, cyclohexyl, 4-methylcyclohexyl, phenoxyacetamido, phenylpropionamido, pyrazolyl, 1-methylpyrazol-5-yl, oxazolyl, pyridinyl, 4-methylpiperidinyl, 1-methylpiperidin-4-yl, morpholinyl, piperazinyl, 4-methylpiperazinyl, piperidinyl, 4-phenylpiperidinyl, 4-carbamoyl piperidinyl, pyridinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2 yl) piperazinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo tetrahydropyridine and 7-cyanotetrahydroisoquinolyl; or alternatively

L ₂ is-CH ₂ -or-C (O) -,Is not present,/>Is a single bond; r ₅ and R ₆ together with the N to which they are attached form the following group: pyrazolyl, 1-methylpyrazol-5-yl, oxazolyl, pyridinyl, piperidinyl, 4-methylpiperidinyl, 1-methylpiperidin-4-yl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-phenylpiperidinyl, 4-carbamoyl piperidinyl, pyridinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2-yl) piperazinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo tetrahydropyridinyl and 7-cyanotetrahydroisoquinolyl.

5. The substituted aromatic phenol derivative according to claim 1, wherein L ₂ is-ch=, At the same time is a single bond, and/>And R ₆ is absent; r ₅ is unsubstituted five-membered or six-membered nitrogen heterocycle, or five-membered or six-membered nitrogen heterocycle substituted by group A; the five-membered or six-membered nitrogen heterocycle is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine; the group A is selected from one or more of the following groups: phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or benzyl.

6. The substituted aromatic phenol derivative according to claim 1, wherein,Is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine or triazine, and/>And R ₆ is absent; r ₅ is absent, hydrogen or methyl.

7. The substituted aromatic phenol derivative according to any one of claims 1 to 6, wherein R ₂ isR ₃ is hydrogen; or R ₂ is hydrogen, R ₃ is/>

R ₄ is selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or alternatively

R ₄ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and trifluoromethoxy.

8. The substituted aromatic phenol derivative according to any one of claims 1 to 7, wherein R ₂ isR ₃ and R ₄ together with the carbon to which they are attached form an optionally substituted benzene ring; here, the optionally substituted benzene ring is an unsubstituted benzene ring, or a benzene ring substituted with one or more groups selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or alternatively

R ₄ together with R ₃ and the carbon to which it is attached form an optionally substituted benzene ring; here, the optionally substituted benzene ring is an unsubstituted benzene ring, or a benzene ring substituted with one or more groups selected from the group consisting of: fluorine, chlorine, bromine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy; or alternatively

R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached formA substituted benzene ring, wherein the benzene ring may be further substituted with one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy and halogenated C ₁-C₄ alkoxy.

9. The substituted aromatic phenol derivative according to any one of claims 1 to 8, wherein R ₂ is:

R ₃ and R ₄ together with the carbon to which they are attached form an optionally substituted five-or six-membered nitrogen heterocycle; here, the five-or six-membered nitrogen heterocycle is pyrrolidine, dihydropyrrole, pyrrole, indoline, indole, pyrazolidine, pyrazole, dihydroimidazole, imidazoline, imidazole, thiazole, triazole, oxazole, benzimidazole, indazole, benzoxadiazole, benzothiazole, purine, piperidine, pyridine, quinoline, isoquinoline, acridine, phenothiazine, phenazine, pyridazine, pyrimidine, piperazine, pyrazine, morpholine, pteridine, or triazine; or alternatively

R ₃ and R ₄ together with the carbon to which they are attached form pyridine, pyrrole, or pyridine or pyrrole substituted with one or more selected from the group consisting of: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy; or alternatively

The formula (I) is a compound of formula (I-1):

Optionally, the pyridine ring in formula (I-1) is substituted with one or more selected from the group consisting of: halogen, cyano, nitro, hydroxy, unsubstituted phenyl, phenyl substituted with a group B, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, C ₂-C₆ alkylene, C ₂-C₆ alkynyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy, wherein the group B is selected from one or more of the following groups: halogen, cyano, nitro, hydroxy, unsubstituted C ₁-C₄ alkyl, halogenated C ₁-C₄ alkyl, unsubstituted C ₁-C₄ alkoxy, and halogenated C ₁-C₄ alkoxy; or alternatively

The formula (I) is a compound of formula (I-4):

10. The substituted aromatic phenol derivative of any of claims 1-9 wherein R ₂ is hydrogen, R ₃ and R ₄ together with the carbon to which they are attached formSubstituted five-or six-membered nitrogen heterocycles;

Preferably, the five-or six-membered nitrogen heterocycle may be further substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy and trifluoromethoxy; or alternatively

The formula (I) is a compound of formula (I-2) or (I-3) or (I-5) or (I-6):

11. The substituted aromatic phenol derivative according to any one of claims 1 to 10, wherein L ₁ is-CH ₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ are each ethyl;

L ₁ is-CH ₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form pyrazolyl, oxazolyl, pyridinyl, 4-methylpiperazinyl, 4-methylpiperidinyl, 4-phenylpiperidinyl, piperidinyl, 4-carbamoylpiperidinyl, or morpholinyl; or alternatively

L ₁ is a single bond; l ₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ is hydrogen and R ₅ is pyrazolyl, oxazolyl, pyridinyl, 4-methylpiperidinyl, cyclohexyl, 4-methylcyclohexyl, 2-hydroxyethyl, n-butyl, phenoxyacetamido, 1-methylpiperidin-4-yl or phenylpropionamido; or alternatively

L ₁ is a single bond; l ₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl or 4-methylpiperazinyl; or alternatively

L ₁ is a single bond; l ₂ is-ch=,Singly (v)Is absent; r ₆ is absent, R ₅ is pyrazolyl, 1-methyl-pyrazol-5-yl, oxazolyl, pyridinyl or 4-methylpiperazinyl; or alternatively

L ₁ is-CH ₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ is hydrogen, R ₅ is cyclohexyl or 2-aminoethyl; or alternatively

L ₁ is-CH ₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ together with the N to which they are attached form 4-methylpiperazinyl; or alternatively

L ₁ is-ch=ch-or-CH ₂-CH₂ -; Is pyrazolyl, oxazolyl, piperazinyl or pyridine; r ₅ and R ₆ are both absent, or one is hydrogen and the other is absent or methyl; or alternatively

L ₁ is-CH ₂-NH-CH₂-CH₂ -or-CH ₂-NH-CH₂-CH₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ are each methyl; or alternatively

L ₁ is-CH ₂-NH-CH₂-CH₂ -or-CH ₂-NH-CH₂-CH₂-CH₂-;L₂ is-CH ₂ -; is not present,/> Is a single bond; r ₆ and R ₅ constitute 4-methylpiperazinyl, 4- (2, 3-dichlorophenyl) piperazinyl, 4- (2-methoxyphenyl) piperazinyl, 4- (2-methylphenyl) piperazinyl, 4- (3-methoxyphenyl) piperazinyl, 4- (pyrimidin-2 yl) piperazinyl, 4- (4-chlorophenyl) piperazinyl, 4-methylpiperidinyl, 4- (4-chlorophenyl) -4-hydroxypiperidinyl, 4-benzylpiperidinyl, N-ethylindolo tetrahydropyridinyl, or 7-cyanotetrahydroisoquinolinyl.

12. The substituted aromatic phenol derivative according to claim 1, which is selected from one of the following compounds:

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 01);

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-methylpiperidine (LZ 02);

N, N-diethyl-2- (4-methylbenzyloxy) -1-naphthylethylamine (LZ 03);

1- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -4-phenylpiperidine (LZ 04);

n- (2- (4-fluorobenzyloxy) -1-naphthylethyl) -piperidine (LZ 05);

1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -4-methylpiperazine (LZ 06);

1- (2- (4-bromobenzyloxy) -1-naphthylethyl) -piperidine-4-carboxamide (LZ 07);

1- (2- (4-methylpiperazin-1-yl) ethyl) -2-naphthol (LZ 12);

n- (2- (2- (4-fluorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 13);

n- (2- (2- (4-chlorobenzyloxy) naphthalen-1-yl) ethyl) morpholine (LZ 14);

n- (2- (2- (quinolin-3-methoxy) naphthalen-1-yl) ethyl) morpholine (LZ 15);

n- (2- (2-isopropoxy-naphthalen-1-yl) ethyl) morpholine (LZ 18);

n- ((2- (4-bromobenzyloxy) naphthalen-1-yl) methyl) -cyclohexylamine (LZ 24);

n- ((2- ((4-fluorobenzyl) oxy) naphthalen-1-yl) methyl) butan-1-amine (LZ 31);

N' - ((2- (benzyloxy) naphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 34);

N' - ((2-isopropoxy naphthalen-1-yl) methyl) -2-phenoxyacethydrazide (LZ 35);

N' - ((2-methoxynaphthalen-1-yl) methyl) -3-phenylpropionyl hydrazide (LZ 36);

(E) -4- (2- (2- (4-bromobenzyloxy) naphthalen-1-yl) vinyl) pyridine (LZ 40);

4- (2- (2-benzyloxy-naphthalen-1-yl) ethyl) piperidine (LZ 41);

4- (2- (2- (benzyloxy) naphthalen-1-yl) ethyl) pyridine (LZ 42);

N- (3- ((4-fluorobenzyl) oxy) benzyl) -1-methylpiperidin-4-amine (LZ 76);

or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof.

13. A pharmaceutical composition comprising a pharmacologically effective amount of the substituted aromatic phenol derivative of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.

14. A substituted aromatic phenol derivative according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition according to claim 13, for use as a medicament.

15. Use of a substituted aromatic phenol derivative according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition according to claim 13, for the treatment or prevention of a kna1.1 channel inhibitor-suitable disease.

16. Use of a substituted aromatic phenol derivative according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition according to claim 13, for the preparation of a medicament for the treatment or prophylaxis of a disease for which a kna1.1 channel inhibitor is indicated.

17. The use according to claim 16, wherein the kna1.1 channel inhibitor is a selective kna1.1 channel inhibitor.

18. A method of treating or preventing a kna1.1 channel inhibitor-suitable disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a substituted aromatic phenol derivative of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, prodrug or stereoisomer thereof, or a pharmaceutical composition of claim 13.

19. The method according to claim 18, wherein the kna1.1 channel inhibitor-suitable disease includes, but is not limited to, central nervous system diseases such as epilepsy, convulsions, arrhythmias, neuropathic pain, epileptic encephalopathy, myocardial infarction, pain, psychosis or muscle disorders.