CN106187999A - Substituted piperidines and its production and use - Google Patents

Abstract

The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics. Specifically, it relates to a substituted piperidine compound represented by general formula I, its stereoisomer, its pharmaceutically acceptable salt or its solvate, its preparation method, its pharmaceutical composition and its use. The present invention proves through the experimental results of biological activity test that the compound has higher binding activity to acetylcholine-binding protein, and the substituted piperidine compound of the present invention can be used as a ligand small molecule of nicotinic acetylcholine receptor for the preparation of prophylaxis and and/or drugs to treat neurodegenerative diseases or dementia or depression.

Description

Substituted piperidine compounds and their preparation method and use

technical field

The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics. Specifically, it relates to a substituted piperidine compound represented by general formula I, its stereoisomer, its pharmaceutically acceptable salt or its solvate, its preparation method, its pharmaceutical composition and its use. The substituted piperidine compound of the present invention can be used as a ligand small molecule of nAChRs to prepare drugs for preventing and treating neurodegenerative diseases or depression.

Background technique

Alzheimer's disease (AD), also known as Alzheimer's disease, is a chronic neurodegenerative disease common in the elderly, and its clinical manifestations are progressively aggravated mental retardation, memory loss, and mental behavior. exception etc. It is a serious threat to the health of the elderly, especially in today's aging society, this situation is getting worse and has aroused widespread concern. Depression is a mental illness with emotional pathological changes as the main symptom, and there are 350 million people with depression worldwide. Depression has become the fourth leading disease in the world, and there is a huge clinical need for the treatment of this disease. Currently, the first-line drugs for the treatment of depression include selective serotonin (5-HT) reuptake inhibitor (SSRI) and 5-HT/NE dual reuptake inhibitor (5-HT/NE reuptake inhibitor, SNRI). . However, these drugs have problems such as slow onset time, ineffective treatment for some patients, inability to effectively improve anhedonia, slow improvement in cognitive ability of patients, and easy to cause sexual dysfunction.

At present, acetylcholinesterase inhibitors are still the main drugs for the clinical treatment of AD. Practice has shown that although they can reverse the learning and memory deficits caused by choline function damage and alleviate the symptoms of some patients, they cannot fundamentally change the disease state (Barril , X. et al Mini Rev. Med. Chem. 2001, 1, 255).

Studies have shown that there are two types of cholinergic receptors in the brain: muscarinic type (mAChRs) and nicotinic type (nAChRs). The former has no change in the AD brain, while the number of the latter is significantly reduced. Moreover, nicotine, an agonist of nAChRs, improves cognition and memory. So nAChRs began to become the focus of attention. Studies have shown that nAChRs have the function of regulating the excitability of neurons, which can make neurons in a suitable physiological state and maintain normal behavioral responses, especially cognitive processes. At present, many nAChRs ligand small molecules have entered clinical phase II in the treatment of AD, such as Abbott's ABT-089, Sanofi's SSR-180711, and AstraZeneca's AZD-1446.

As early as 1972, Janowsky et al. found that choline-adrenaline imbalance can lead to depressive-like effects. In 2006, Gotti proposed that α ₄ β ₂ (a subtype of nAChRs) widely distributed in the basal ganglia, striatum, thalamus, hypothalamus, amygdala, ventral tegmental area, locus coeruleus and dorsal raphe nucleus is activated Manages the release of monoamines such as dopamine. Clinical data also show that depression symptoms will be reduced after taking the drug varenicline (α ₄ β ₂ partial agonist) in patients with depression. In the forced swimming test in mice, the antidepressant effects of citalopram and reboxetine were enhanced after administration of α ₄ β ₂ agonists. On the contrary, for mice with _β2 gene knockout, the motility decreased in the forced swimming test, and even taking tricyclic antidepressants had no effect at all. The nAChRs ligand small molecule BB-243 studied by the Autonomous University of Madrid in Spain is currently in the preclinical research stage in the field of depression treatment. In addition, Pfizer's nAChRs ligand small molecule CP601927 performed well in the mouse tail suspension test and forced swimming test, and entered the clinical phase II in 2010.

In 2003, Miyazawa published cryo-electron microscopy images of the nAChRs of the electric ray in Nature. This allows researchers to have a general understanding of the basic structure of nAChRs. However, since nAChRs is a transmembrane protein, its purification and isolation are very difficult, and a complete crystal structure has not been obtained so far. However, in the research of new drugs, relevant researchers need to understand the changes and similarities and differences of the domains of nAChRs when they bind to different ligands, which makes it more urgent to understand the crystal structure of nAChRs.

In summary, in view of the fact that AChBP has been proved to have similar ligand-binding domains and the same pharmacological properties as nAChRs in the prior art, it is currently common to use acetylcholine-binding protein (AChBP) to indirectly study nAChRs. This application The inventor intends to seek a protein with a complete crystal structure to replace nAChRs. Since the ligand binding domains of AChBP and nAChRs have homology, the basic characteristics, structural characteristics, and the position of the binding site of the two are similar. This application intends to pass Acetylcholine-binding protein (AChBP) studies nAChRs, providing a class of substituted piperidine compounds with acetylcholine-binding protein (AChBP) binding activity for the preparation of drugs for the prevention and/or treatment of neurodegenerative diseases or dementia or depression.

Contents of the invention

One object of the present invention is to provide substituted piperidine compounds of general formula I having acetylcholine-binding protein (AChBP) binding activity, which can be used as ligand small molecules of nAChRs for the preparation and prevention of neurodegenerative diseases or depression drug.

Another object of the present invention is to provide a substituted piperidine compound represented by general formula I below, its stereoisomers and pharmaceutically acceptable salts or solvates thereof.

Another object of the present invention is to provide a method for preparing substituted piperidine compounds represented by general formula I, their stereoisomers and pharmaceutically acceptable salts or solvates thereof.

Another object of the present invention is to provide a pharmaceutical composition containing the substituted piperidine compound represented by general formula I, its stereoisomers and pharmaceutically acceptable salts or solvates thereof.

Another object of the present invention is to provide the use of the substituted piperidine compounds represented by the general formula I, their stereoisomers, pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions containing the compounds.

Specifically, the present invention provides a substituted piperidine compound represented by the following general formula I, its stereoisomer, its pharmaceutically acceptable salt or its solvate, and a pharmaceutical composition comprising the compound; X , Y, R ₁ , R ₂ , m, n are defined as follows;

in:

X and Y are each independently nitrogen or carbon, and one of X and Y is nitrogen and the other is carbon;

R ₁ is H, an alkyl group or an aromatic group. Alkyl is C1~C10 straight chain or branched chain alkyl, C3~C6 cycloalkyl or heterocycloalkyl; aromatic group is phenyl, naphthyl (1-naphthyl or 2-naphthyl) and other benzene Aryl, or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), pyrrolyl, imidazolyl, condensed Heteroaryl such as heterocyclyl, the aromatic group may be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, Cycloalkoxy, Alkoxyalkyl, Cycloalkoxyalkyl, Alkyl, Cycloalkyl, Cycloalkylalkyl, Alkenyl, Alkynyl, Phenyl, -NR'R", -(C=O) NR'R'' or -NR'(C=O)R";

R ₂ is an aromatic group, and the aromatic group is a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridine base), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrrolyl, imidazolyl, fused heteroaryl and other heteroaryl groups, the aromatic group can optionally consist of one or more of the following substituent substitution: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkane Base, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R" or -NR'(C=O)R";

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, when X is carbon and Y is nitrogen:

R ₁ is H, an alkyl group or an aromatic group. Alkyl is C1~C10 straight chain or branched chain alkyl, C3~C6 cycloalkyl or heterocycloalkyl; aromatic group is phenyl, naphthyl (1-naphthyl or 2-naphthyl) and other benzene Aryl, or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), pyrrolyl, imidazolyl, condensed Heteroaryl such as heterocyclyl, the aromatic group may be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, Cycloalkoxy, Alkoxyalkyl, Cycloalkoxyalkyl, Alkyl, Cycloalkyl, Cycloalkylalkyl, Alkenyl, Alkynyl, Phenyl, -NR'R", -(C=O) NR'R'' or -NR'(C=O)R";

R ₂ is an aromatic group, and the aromatic group is a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridine base), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrrolyl, imidazolyl, fused heteroaryl and other heteroaryl groups, the aromatic group can optionally consist of one or more of the following substituent substitution: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkane Base, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R" or -NR'(C=O)R";

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, when X is nitrogen and Y is carbon:

R ₁ is heteroaryl, heteroaryl is pyridine ring (2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), pyrrole group, imidazolyl group, fused heterocyclic group, etc., the heteroaryl group can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkane Oxygen, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C =O)NR'R'' or -NR'(C=O)R";

R ₂ is an aromatic group, and the aromatic group is a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridine base), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrrolyl, imidazolyl, fused heteroaryl and other heteroaryl groups, the aromatic group can optionally consist of one or more of the following substituent substitution: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkane Base, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R" or -NR'(C=O)R";

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, when X is nitrogen and Y is carbon:

R ₁ is H, alkyl or phenyl aryl. Alkyl is C1～C10 straight chain or branched chain alkyl, C3～C6 cycloalkyl or heterocycloalkyl; benzene aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), etc. , the phenyl aryl can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkane Oxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R'' or is -NR'(C=O)R";

R ₂ is a heteroaromatic ring, and the heteroaryl ring is a pyridine ring (2-pyridyl, 3-pyridyl or 4-pyridyl), a pyrimidine ring (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), pyrrole ring, imidazole ring, fused heterocycle, etc. The heteroaryl ring can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkoxane radical, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R", or -NR '(C=O)R";

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, when X is nitrogen and Y is carbon:

R ₁ is H, alkyl or phenyl aryl. Alkyl is C1～C10 straight chain or branched chain alkyl, C3～C6 cycloalkyl or heterocycloalkyl; benzene aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), etc. , the phenyl aryl can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkane Oxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R'' or is -NR'(C=O)R";

R ₂ is a benzene-based aryl group, and the benzene-based aryl group is phenyl, naphthyl (1-naphthyl or 2-naphthyl), etc., and the benzene-based aryl group can be optionally substituted by one or more of the following substituents: Halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkyl Alkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R" or -NR'(C=O)R";

m is an integer of 1-4, and n is an integer of 1-4, but m and n are not 1 at the same time.

In a preferred embodiment of the present invention, X and Y are each independently nitrogen or carbon, and one of X and Y is nitrogen and the other is carbon;

R ₁ is an aromatic group, and the aromatic group is a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridine base), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrrolyl, imidazolyl, fused heteroaryl and other heteroaryl groups, the aromatic group can be optionally composed of one or more of the following Substituent Substitution: Halogen, Trifluoromethyl, Trifluoromethoxy, Cyano, Hydroxy, Amino, Alkoxy, Cycloalkoxy, Alkoxyalkyl, Cycloalkoxyalkyl, Alkyl, Cycloalkyl , cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R'' or -NR'(C=O)R";

R ₂ is heteroaryl, heteroaryl is pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), pyrrole group, imidazolyl group, condensed heterocyclic group, etc. The heteroaryl can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, amino, alkoxy, cycloalkoxy, alkoxane radical, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl, -NR'R", -(C=O)NR'R", or -NR '(C=O)R";

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, X and Y are each independently nitrogen or carbon, and one of X and Y is nitrogen and the other is carbon;

R ₁ is an aromatic group, and the aromatic group is a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), or pyridyl (2-pyridyl, 3-pyridyl or 4-pyridine base), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl), pyrrolyl, imidazolyl, fused heteroaryl and other heteroaryl groups, the aromatic group can optionally consist of one or more of the following Substituent substitution: halogen, trifluoromethyl, trifluoromethoxy, cyano, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkane Alkyl, alkenyl, alkynyl, phenyl;

R is heteroaryl, heteroaryl is pyridyl ( ₂ -pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl), condensed Heterocyclyl etc. The heteroaryl can be optionally substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkane Oxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl;

m is an integer of 1-4; n is an integer of 1-4.

In a preferred embodiment of the present invention, when X is carbon and Y is nitrogen:

R ₁ and R ₂ are each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2- pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl) and other aryl groups, R ₁ and R ₂ can be independently substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano radical, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl;

m and n are 1, 2 or 3 each independently.

In a preferred embodiment of the present invention, when X is nitrogen and Y is carbon:

R ₁ is aryl such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridyl (2-pyridyl, 3-pyridyl or 4-pyridyl), R ₂ is pyridyl (2- pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl (2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl) and other heteroaryl groups. R ₁ and R ₂ may be independently substituted by one or more of the following substituents: halogen, trifluoromethyl, trifluoromethoxy, cyano, alkoxy, cycloalkoxy, alkoxyalkyl, cyclo Alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, phenyl;

m and n are 1, 2 or 3 each independently.

In a preferred embodiment of the present invention, when X is nitrogen and Y is carbon:

R ₁ and R ₂ are each independently a benzene-based aryl group such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), and R ₁ and R ₂ may be independently substituted by one or more of the following substituents: Halogen, trifluoromethyl, trifluoromethoxy, cyano, alkoxy, cycloalkoxy, alkoxyalkyl, cycloalkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkene base, alkynyl, phenyl;

m and n are each independently 1 or 2 or 3, but m and n are not 1 at the same time.

In the present invention, unless otherwise stated or pointed out, the term "halogen" refers to fluorine, chlorine, bromine or iodine;

Unless otherwise stated or indicated, the term "alkyl" refers to a monovalent saturated straight or branched hydrocarbon chain. The hydrocarbon chain generally contains 1-6 carbons, including pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and isohexyl. A preferred type of alkyl group represents a hydrocarbon chain containing 1 to 4 carbons and includes butyl, isobutyl, sec-butyl and tert-butyl. Another preferred type of alkyl group represents a hydrocarbon chain containing 1-3 carbons, especially methyl, ethyl, propyl, isopropyl;

Unless otherwise stated or indicated, the term "alkenyl" refers to a carbon chain containing only one or more double bonds, including dienes, trienes, and polyolefins. A preferred type of alkenyl represents a hydrocarbon chain containing from 2 to 6 carbons, containing at least one double bond. A preferred type of alkenyl is vinyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl; 1,3-butadienyl; 1-,2-,3-, 4- or 5-hexenyl; 1,3-hexadienyl or 1,3,5-hexatrienyl;

Unless otherwise specified or indicated, the term "alkynyl" refers to carbon chains containing only one or more triple bonds and includes diynes, triynes and polyalkynes. A preferred type of alkynyl group represents a hydrocarbon chain containing from 2 to 6 carbons, containing at least one triple bond. The best types of alkynyl among these are ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl; 1,3-butadiynyl; 1-,2-,3 - or 4-pentynyl; 1,3-pentadiynyl; 1-, 2-, 3-, 4- or 5-hexynyl; 1,3-hexadiynyl or 1,3,5- Hexatriynyl;

The epoxyalkyl groups all refer to cyclized alkyl groups, preferably containing 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Unless otherwise stated or indicated, the term "alkoxy" refers to O-alkyl, alkyl is as defined above;

Unless otherwise stated or indicated, the term "epoxyalkyl" refers to O-cycloalkyl, cycloalkyl as defined above;

Unless otherwise specified or pointed out, the term "aromatic group" refers to an aromatic carbon chain such as phenyl, naphthyl (1-naphthyl or 2-naphthyl) or fluorenyl;

Unless otherwise stated or pointed out, among the one or more substituents, the halogen substitution is 2-chloro, 3-chloro, 4-chloro, 2,3-dichloro, 2,4-dichloro; The trifluoromethyl is substituted by 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl; the alkyl is substituted by 2-methyl, 3-methyl, 4-methyl replace;

Unless otherwise stated or pointed out, the substituted piperidine compounds described in general formula I, their stereoisomers and pharmaceutically acceptable salts or solvates thereof, are characterized in that the stereoisomers can be The left-handed, right-handed, and racemic forms of chiral compounds, and their mixtures in any proportion;

Unless otherwise stated or pointed out, the substituted piperidine compounds described in general formula I, their stereoisomers and pharmaceutically acceptable salts or solvates thereof are characterized in that the salts are composed of the Substituted piperidine compounds form pharmaceutically acceptable acid addition salts with inorganic acids or organic acids;

Unless otherwise stated or pointed out, the substituted piperidine compounds described in general formula I, their stereoisomers and pharmaceutically acceptable salts or solvates thereof, are characterized in that the inorganic acid is hydrochloric acid, hydrogen Bromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or any combination of two or more; the organic acid is tartaric acid, acetic acid, mandelic acid, maleic acid, fumaric acid, benzoic acid, succinic acid One or a combination of any two or more of acid, lactic acid, citric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid;

The invention provides a preparation method of substituted piperidine compounds, their stereoisomers and pharmaceutically acceptable salts or solvates thereof, the method uses the following synthetic route:

The reaction steps are as follows:

a) using compound A as a raw material, reacting with Boc anhydride under the action of triethylamine to obtain compound B;

b) Compound B undergoes a nucleophilic substitution reaction with an alkyl halide under the action of LDA to obtain Compound C;

c) compound B reacts with cycloisopropyl malonate and triisopropyl borate to generate compound E;

d) Compound E undergoes a nucleophilic substitution reaction with one or more aralkyl Grignard reagents of different carbon chain lengths under the catalysis of cuprous iodide to obtain compound F;

e) Compound F was heated to 135°C in a mixed solution of DMSO-H ₂ O and reacted for two days to obtain Compound G;

f) compound G uses borane as a reducing agent, and refluxes in THF for 24-48h to obtain compound H;

g) compound C is reduced by THF solution of tetrahydrolithium aluminum to obtain compound D;

h) Nucleophilic substitution reaction of compound D and compound H with fluorinated compound under the action of sodium hydride to obtain compound J;

i) Compound J is deprotected under the action of trifluoroacetic acid to obtain the target compound.

The substituted piperidine compounds, their stereoisomers and pharmaceutically acceptable salts or solvates thereof provided by the present invention are preferably one of the following compounds:

The present invention provides piperidine compounds with acetylcholine-binding protein binding activity, which can be further used to prevent, delay or treat neurodegenerative diseases, Alzheimer's disease, Parkinson's disease and dementia in the preparation of nAChRs ligand small molecules disease, depression applications.

The substituted piperidine compounds of the present invention have obvious acetylcholine-binding protein binding activity, and are used for further research on possible high-activity nAChRs ligand small molecules, which may improve cognitive function and alleviate diseases such as AD and depression at the same time Advances in innovative medicines provide valuable information.

detailed description

The present invention will be further elaborated below in conjunction with the examples, and the following embodiments can only describe the present invention by way of example. It is obvious that those skilled in the art can make various changes and modifications to the present invention within the scope and spirit of the present invention. It is to be understood that the present invention is intended to cover variations and modifications included in the appended claims.

Instruments used in experiments and sample analysis:

Both ¹ HNMR and ¹³ CNMR were measured on a Varian Mercury plus 400 NMR instrument.

LS-MS was determined by Agilent 1100Series LC/MSD1946D mass spectrometer.

Special chemical reagents were purchased from reagent companies such as sigma, Alfa, Acros, and Anaiji. General chemical reagents were purchased from Sinopharm Shanghai Chemical Reagent Company, all of which were of domestic analytical grade.

The main solvents include petroleum ether, ethyl acetate, dichloromethane, methanol, etc., which were purchased from Sinopharm Group and were of synthetic grade.

The column chromatography silica gel is chemically pure silica gel from Qingdao Ocean Chemical Factory, generally 300-400 mesh.

The TLC silica gel plate is a HSF-254 thin-layer chromatography prefabricated plate produced by Yantai Chemical Industry.

The ultraviolet lamp is the ZF-1 type three-purpose ultraviolet analyzer of Shanghai Gucun Electro-optical Instrument Factory.

Preparation Example

Embodiment 1: Compound I-1 3-((4-benzylpiperidin-4-yl)methoxy)pyridine

synthetic route:

Reaction steps:

a) Dissolve raw material A (ethyl 4-piperidinecarboxylate) (67.5g, 0.43mol) in 500ml of anhydrous dichloromethane, add triethylamine (72.4ml, 0.52mol) under stirring, and add Boc ₂ O (104.2g, 0.47mmol) in dichloromethane solution, after the addition, the system was gradually warmed to room temperature and reacted overnight. After the reaction was completed, 200ml of water was added to the system, the organic phase was washed with dilute hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 90 g of a colloidal yellow solid. The product was directly carried on to the next reaction without further treatment. Yield: 95%

MS(m/z):280[M+Na] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ4.11-4.05 (q, J=7.2Hz, 2H), 4.02-3.88 (m, 2H), 2.84-2.70 (m, 2H), 1.84-1.77 (m, 2H ),1.62-1.51(m,2H),1.39(s,9H),1.19(t,J＝6.8Hz,3H).

b) During the preparation of Compound C, first prepare LDA, dissolve diisopropylamine (3.1ml, 21.7mmol) in 20ml of anhydrous THF, add 11ml of n-butyllithium (2.4N , 26.4mmol), after the addition, react at this temperature for 5min and place it in an ice bath for 30min. After the preparation of LDA, it was re-cooled to -78°C, and 10ml of THF solution of product B (3.1g, 12.1mmol) was slowly added dropwise. After the addition, the system was reacted at -30°C for 30min. Continue cooling to -78°C, slowly add benzyl bromide (4.1g, 24.2mmol) dropwise, react at this temperature for 2h after the addition, and then gradually warm the system to room temperature overnight. After the reaction was completed, the reaction was quenched by adding 10 ml of saturated ammonium chloride solution under an ice bath, extracted with 100 ml of ethyl acetate, washed the organic phase with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and spin-drying, the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain 1.9 g of a colorless oil. Yield: 45%

MS(m/z):370[M+Na] ⁺

¹ H NMR (600MHz, CDCl ₃ )δ7.25-7.19(m,3H),7.05-7.02(m,2H),4.11-4.06(m,2H),3.95-3.90(m,2H),2.84-2.78 (m,4H),2.10-2.06(m,2H),1.46-1.42(m,11H),1.16(t,J=7.2Hz,3H).

g) During the preparation of compound D, the product C (482mg, 1.39mmol) from the previous step was dissolved in 50ml of anhydrous THF, and 1.39ml (1N, 1.39mmol) of a THF solution of lithium aluminum hydride was added under ice cooling, and After completion, react at this temperature for 1 h. After the reaction was completed, 10ml of 20% NaOH solution was added under ice bath to quench the mixture. After stirring for 1min, 200ml of ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Filter and spin-dry to obtain a colorless oil, which is called a white gel-packed solid 420 mg after long-term storage. The product was directly carried on to the next reaction without further treatment. Yield: 95%

MS(m/z):328[M+Na] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.22-7.16(m,2H),7.15-7.10(m,3H),3.70-3.58(brs,1H),3.49-3.41(m,2H),3.36-3.28 (m,4H),2.67(s,2H),1.44-1.32(m,13H).

h) During the preparation of compound I, the product D (396mg, 1.63mmol) from the previous step was dissolved in 10ml of anhydrous DMSO, and sodium hydride (72mg, 1.79mmol), 3-fluoropyridine (155μl, 1.79mmol) were added under stirring ), and the reaction was warmed to 60 °C overnight. After the reaction was complete, ice water was carefully added to quench the reaction. Extracted with 60ml of ethyl acetate, washed the organic phase with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was chromatographed on a silica gel column (PE:EA=3:1) to obtain 280 mg of a colorless oil . Yield: 45%

MS(m/z):383[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.35-8.19(m,2H),7.25-7.14(m,5H),7.05-7.01(m,2H),3.62(s,2H),3.59-3.51(m ,2H),3.46-3.35(m,2H),2.84(s,2H),1.59-1.54(m,4H),1.45-1.43(m,9H).

i) During the preparation of compound I-1, the product I (100 mg, 0.26 mmol) from the previous step was dissolved in 10 ml of a mixed solution of dichloromethane:TFA=3:1, and reacted at room temperature for 1 h. After the reaction was completed, the solvent was blown dry with nitrogen, the residue was dissolved in 50ml of dichloromethane, 2ml of 20% NaOH solution was added to adjust the system to strong alkalinity, and the organic phase was dried over anhydrous sodium sulfate. After filtration and spin-drying, the residue was separated on a silica gel plate (dichloromethane:methanol=15:1) to obtain 72 mg of a light yellow oil. Yield: 99%

MS(m/z):283[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ9.80-9.00 (brs, 1H), 8.33-8.30 (brs, 1H), 8.22-8.19 (brs, 1H), 7.24-7.14 (m, 5H), 7.02-6.98 (m,2H),3.67(s,2H),3.40-3.20(m,4H),2.86(s,2H),1.94-1.88(m,4H).

Example 2: Compound I-2 3-((4-(2-chlorobenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced by 2-chlorobenzyl bromide, and the total yield is 18.1%.

MS(m/z):317[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.23-8.21(m,1H),8.20-8.16(m,1H),7.28-7.17(m,1H),7.16-7.06(m,5H),3.80(s ,2H),3.00-2.90(m,2H),2.84-2.80(m,2H),2.35-2.25(brs,1H),1.78-1.59(m,4H).

Example 3: Compound I-3 3-((4-(2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with 2-trifluoromethylbenzyl bromide, and the total yield is 18.3%.

MS(m/z):351[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.30-8.19(s,2H),7.68-7.62(m,1H),7.48-7.41(m,1H),7.40-7.35(m,1H),7.35-7.25 (m,1H),7.18-7.10(m,1H),3.98-3.92(m,2H),3.38-3.34(m,2H),3.12-3.09(m,2H),2.01-2.00(m,4H) ..

Embodiment 4: Compound I-4 3-((4-(2-methylbenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with 2-methylbenzyl bromide, and the total yield is 18.8%.

MS(m/z):297[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.29-8.28(m,1H),8.19-8.17(m,1H),7.50-7.46(m,1H),7.43-7.39(m,1H),7.18- 7.08(m,4H),3.98(s,2H),3.28-3.14(m,4H),2.97(s,2H),2.32(s,3H),2.01-1.94(m,2H),1.92-1.82( m,2H)..

Example 5: Compound I-5 3-((4-(3-chlorobenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, wherein 3-chlorobenzyl bromide is used to replace benzyl bromide, and the total yield is 19.1%.

Example 6: Compound I-6 3-((4-(3-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, wherein benzyl bromide is replaced with 3-trifluoromethyl benzyl bromide, and the total yield is 19.2%.

MS(m/z):351[M+H]

¹ H NMR (600MHz, CDCl ₃ )δ8.35-8.33(m,1H),8.26-8.24(m,1H),7.47-7.43(m,1H),7.35-7.31(m,2H),7.27-7.22 (m,2H),7.20-7.16(m,1H),4.91-4.88(brs,1H),3.68(s,2H),3.18-3.12(m,2H),3.05-3.00(m,2H),2.96 (s,2H),1.78-1.73(m,4H)..

Example 7: Compound I-7 3-((4-(3-methylbenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, wherein 3-methylbenzyl bromide is used to replace benzyl bromide, and the total yield is 19.3%.

MS(m/z):297[M+H]

¹ H NMR (600MHz, CDCl ₃ )δ8.36-8.35(m,1H),8.24-8.22(m,1H),7.25-7.19(m,2H),7.12-7.09(m,1H),7.01-6.99 (m,1H),6.87-6.85(m,2H),4.46-4.45(brs,1H),3.70(s,2H),3.16-3.11(m,2H),3.06-3.01(m,2H),2.85 (s,2H),2.21(s,3H),1.76-1.72(m,4H)..

Example 8: Compound I-8 3-((4-(4-chlorobenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, wherein 4-chlorobenzyl bromide is used to replace benzyl bromide, and the total yield is 18.3%.

MS(m/z):317[M+H]

¹ H NMR (600MHz, CDCl ₃ )δ8.78-8.26(m,1H),8.18-8.16(m,1H),7.18-7.15(m,1H),7.14-7.09(m,3H),6.94-6.91 (m,2H),3.58(s,2H),3.54-3.49(m,2H),3.38-3.33(m,2H),2.79(s,2H),1.54-1.49(m,4H),1.41(s ,9H)..

Example 9: Compound I-9 3-((4-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, wherein benzyl bromide is replaced with 4-trifluoromethylbenzyl bromide, and the total yield is 18.8%.

MS(m/z):351[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.32-8.31(m,1H),8.20-8.18(m,1H),7.56-7.53(m,2H),7.51-7.47(m,1H),7.43- 7.39(m,1H),7.37-7.34(m,2H),3.86(s,2H),3.33-3.28(m,2H),3.24-3.16(m,2H),3.05(s,2H),1.94- 1.80(m,4H)..

Example 10: Compound I-10 3-((4-(4-methylbenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with 4-methylbenzyl bromide, and the total yield is 19.8%.

MS(m/z):297[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.32-8.31(m,1H),8.20-8.17(m,1H),7.51-7.47(m,1H),7.43-7.39(m,1H),7.06- 7.00(m,4H),3.83(s,2H),3.42-3.36(m,2H),3.34-3.26(m,2H),2.91(s,2H),2.26(s,3H),1.96-1.84( m,4H)..

Example 11: Compound I-11 3-((4-([1,1'-biphenyl]-4-ylmethyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with 4-bromomethylbiphenyl, and the total yield is 18.1%.

MS(m/z):359[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.33-8.31 (m, 1H), 8.19-8.17 (m, 1H), 7.56-7.53 (m, 2H), 7.49-7.45 (m, 3H), 7.42- 7.36(m,3H),7.32-7.27(m,1H),7.20-7.18(m,2H),3.85(s,2H),3.40-3.34(m,2H),3.29-3.22(m,2H), 2.96(s,2H),1.96-1.84(m,4H)..

Example 12: Compound I-12 3-((4-(2,3-dichlorobenzoyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced by 2,3-dichlorobenzyl bromide, and the total yield is 18.1%.

MS(m/z):351[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.20-8.15(m,2H),7.43-7.37(m,3H),7.24-7.15(m,2H),4.00(s,2H),3.15(s, 2H), 3.11-3.04(m, 2H), 3.02-2.95(m, 2H), 1.88-1.75(m, 4H).

Example 13: Compound I-13 3-((4-(3,4-dichlorobenzyl)piperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced by 3,4-dichlorobenzyl bromide, and the total yield is 18.6%.

MS(m/z):351[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.31-8.29(m,1H),8.19-8.17(m,1H),7.42-7.37(m,3H),7.26-7.25(m,1H),7.07- 7.03(m,1H),3.81(s,2H),3.22-3.15(m,2H),3.12-3.04(m,2H),2.89(s,2H),1.84-1.70(m,4H).

Example 14: Compound I-14 3-((3-(3,4-dichlorobenzyl)piperidin-3-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with 3,4-dichlorobenzyl bromide, ethyl 3-piperidinecarboxylate is replaced with ethyl 4-piperidinecarboxylate; total yield: 20.1%; It is separated by chiral column to obtain I-14A and I-14B, and their NMR spectra are completely consistent;

MS(m/z):351[M+H]

¹ H NMR (400MHz, CDCl ₃ )δ8.36-8.34(m,1H),8.25-8.22(m,1H),7.28-7.19(m,4H),6.94-6.90(m,1H),3.82-3.78 (m,1H),3.72-3.68(m,1H),2.90-2.82(m,3H),2.78-2.69(m,3H),2.36-2.22(brs,1H),1.70-1.54(m,3H) ,1.50-1.42(m,1H)..

Example 15: Compound I-15 3-((4-phenethylpiperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that benzyl bromide is replaced with phenethyl bromide, and the total yield is 13.2%.

MS(m/z):297[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.32-8.30(m,1H),8.19-8.16(m,1H),7.55-7.51(m,1H),7.43-7.39(m,1H),7.26- 7.18(m,4H),7.16-7.11(m,1H),4.07(s,2H),3.32-3.27(m,4H),2.66-2.60(m,2H),2.06-1.98(m,2H), 1.94-1.86(m,4H)..

Example 16: Compound I-18 2-((4-benzylpiperidin-4-yl)methoxy)pyridine

The synthetic technical route refers to that described in Example 1, except that 2-fluoropyridine is used instead of 3-fluoropyridine, and the total yield is 15.2%.

MS(m/z):283[M+H]

¹ H NMR (400MHz, CDCl3) δ8.13-8.09 (m, 1H), 7.63-7.57 (m, 1H), 7.24-7.16 (m, 3H), 7.12-7.07 (m, 2H), 6.91-6.86 ( m,1H),6.82-6.80(m,1H),4.09(s,2H),3.34-3.26(m,2H),3.21-3.14(m,2H),2.86(s,2H),1.94-1.82( m,4H)..

Example 17: Compound I-16 3-(2-(4-phenethylpiperidin-4-yl)ethoxy)pyridine

synthetic route:

Reaction steps:

c) The raw material 4-tert-butoxycarbonyl piperidone (compound B) (31.2g, 0.16mol), cycloisopropyl malonate (25g, 0.17mmol), triisopropyl borate (72.5ml, 0.32mol ) was dissolved in 300ml of ethyl acetate, acetic acid (1.8ml, 0.03mol) and ammonia water (1.1ml, 0.03mol) were added under stirring, and the system was reacted overnight at room temperature after the addition was complete. More solids gradually formed in the system. After the reaction was completed, it was filtered, and the filter cake was washed with a little ethyl acetate and dried to obtain 28 g of white powdery solid. Yield: 55%

MS(m/z):348[M+Na] ⁺

¹ H NMR (400MHz, d-DMSO) δ3.49(t, J=6.4Hz, 4H), 3.07(t, J=5.4Hz, 4H), 1.71(s, 6H), 1.42(s, 9H).

d) During the synthesis of compound F, the raw material cuprous iodide (300mg, 1.58mmol) was suspended in 200ml of anhydrous THF, and 77ml of phenethylmagnesium chloride (1N, 77mmol) was added at -10°C. React at this temperature for 30 min. The product E (10 g, 30.8 mmol) from the previous step was added in 10 times within 1 h. After the addition, the system was naturally warmed from -10°C to 0°C for 3 hours. After the reaction is completed, add concentrated ammonia water to the system: saturated ammonium chloride: water = 100ml of a mixed solution of 1:2:3 to quench the reaction, extract with ethyl acetate (60ml*3), combine the organic phases, wash with saturated brine, and anhydrous Dry over sodium sulfate to give a white solid. The solid was washed with a little ether and dried. 3.8 g of white powdery solid were obtained. Yield: 30%

MS(m/z):454[M+Na] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.24-7.20(m,2H),7.12-7.06(m,3H),3.70-3.60(m,2H),3.10-3.04(m,2H),2.85-2.65 (m,2H),1.99(s,2H),1.72-1.62(m,2H),1.48(s,6H),1.38(s,9H),1.18(t,J=7.6Hz,2H).

e) During the synthesis of compound G, the product F (10.3 g, 24.0 mmol) from the previous step was dissolved in 400 ml of DMF/H ₂ O (1/1) solution, and the system was heated to 135° C. for 2 days. After the reaction was completed, 100 ml of 1N NaOH solution and 500 ml of water were added to the system. Extract with 500ml ether, adjust the organic phase to pH<2 with 6N hydrochloric acid solution, extract the aqueous phase with ether (200ml*2), combine the organic phases, wash the organic phase with water, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and spin dry to obtain 6.4 g of a white powdery solid. The product was directly carried on to the next reaction without further treatment. Yield: 80%

MS(m/z):370[M+Na] ⁺

¹ H NMR (400MHz, d-DMSO) δ7.26-7.22 (m, 2H), 7.18-7.10 (m, 3H), 3.41-3.35 (m, 2H), 3.30-3.20 (m, 2H), 2.58- 2.50(m,2H),2.33(s,2H),1.65-1.58(m,2H),1.55-1.48(m,2H),1.43-1.35(m,11H).

f) During the synthesis of compound H, dissolve the product G (500mg, 1.44mmol) from the previous step in 50ml of anhydrous THF, add 2.16ml of borane dimethyl sulfide solution (2N, 4.32mmol) under stirring, and reflux the system overnight. After the reaction was completed, 50 ml of water was added, extracted with 200 ml of ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filter and spin dry. Obtained a colorless transparent oil 450mg. The product was directly carried on to the next reaction without further treatment. Yield: 99%

MS(m/z):356[M+Na] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.26-7.20(m,2H),7.16-7.10(m,3H),3.72-3.66(m,2H),3.42-3.35(m,4H),2.55-2.48 (m,2H),1.74-1.66(m,2H),1.61-1.55(m,2H),1.48-1.38(m,13H).

h) During the synthesis of compound J, the product H (543mg, 1.63mmol) from the previous step was dissolved in 10ml of anhydrous DMSO, and sodium hydride (72mg, 1.79mmol) and 3-fluoropyridine (155μl, 1.79mmol) were added under stirring. ), and the reaction was warmed to 60 °C overnight. After the reaction was complete, ice water was carefully added to quench the reaction. 60ml of ethyl acetate was extracted, the organic phase was washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the residue was subjected to silica gel column chromatography (PE:EA=3:1) to obtain 300 mg of a colorless oil . Yield: 45%

MS(m/z):411[M+H]

¹ H NMR (400MHz, CDCl ₃ )δ8.33-8.26(brs,1H),8.22-8.18(m,1H),7.29-7.24(m,2H),7.19-7.15(m,5H),4.06(t , J＝8Hz, 2H), 3.48-3.41(m, 4H), 2.61-2.55(m, 2H), 1.94(t, J＝6.8Hz, 2H), 1.72-1.66(m, 2H), 1.53(t ,J＝5.2Hz,4H),1.45(s,9H).

i) During the preparation of compound I-16, the product J (100 mg, 0.26 mmol) from the previous step was dissolved in 10 ml of a mixed solution of dichloromethane:TFA=3:1, and reacted at room temperature for 1 h. After the reaction was completed, the solvent was blown dry with nitrogen, the residue was dissolved in 50ml of dichloromethane, 2ml of 20% NaOH solution was added to adjust the system to strong alkalinity, and the organic phase was dried over anhydrous sodium sulfate. After filtration and spin-drying, the residue was separated on a silica gel plate (dichloromethane:methanol=15:1) to obtain 80 mg of a light yellow oil. Yield: 99%

MS(m/z):311[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.25-8.24(m,1H),8.16-8.14(m,1H),7.49-7.46(m,1H),7.42-7.37(m,1H),7.30- 7.22(m,4H),7.19-7.13(m,1H),4.21(t,J＝6Hz,2H),3.29-3.23(m,4H),2.67-2.62(m,2H),2.07(t,J =5.6Hz, 2H), 1.87-1.76(m, 6H).

Example 18: Compound I-17 3-(2-(4-benzylpiperidin-4-yl)ethoxy)pyridine

The synthetic technical route refers to that described in Example 17, except that phenethylmagnesium chloride is replaced with benzylmagnesium chloride, and the total yield is 14.2%.

MS(m/z):297[M+H]

¹ H NMR (400MHz, CD ₃ OD) δ8.28-8.26(m,1H),8.17-8.15(m,1H),7.52-7.48(m,1H),7.43-7.39(m,1H),7.35- 7.30(m,2H),7.28-7.22(m,3H),4.26(t,J=8Hz,2H),3.34-3.28(m,4H),2.86(s,2H),1.96(t,J=6.4 Hz, 2H), 1.82-1.77(m, 4H)..

Example 19 Compound I-19 4-((naphthalene-2-yloxy)methyl)-4-phenethylpiperidine

The synthetic technical route refers to that described in Example 17, except that 2-fluoronaphthalene is used to replace 3-fluoropyridine, and the total yield is 12.2%.

MS(m/z):346[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ8.01-7.94(m,1H),7.82-7.76(m,3H),7.52-7.47(m,1H),7.41-7.36(m,1H),7.32-7.27 (m,2H),7.23-7.16(m,5H),4.02(s,2H),3.40-3.24(m,4H),2.64-2.58(m,2H),2.11-1.93(m,6H).

Example 20 Compound I-20 4-(2-(naphthalene-2-yloxy)ethyl)-4-phenethylpiperidine

The synthetic technical route refers to that described in Example 17, except that 2-fluoronaphthalene is used to replace 3-fluoropyridine, and the total yield is 12.6%.

MS(m/z):360[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.80-7.74(m,3H),7.66-7.58(brs,1H),7.50-7.45(m,1H),7.38-7.30(m,3H),7.25-7.20 (m,3H),7.16-7.11(m,2H),4.16(t,J＝6.8Hz,2H),3.32-3.24(m,4H),2.66-2.60(m,2H),2.07-2.02(m ,2H),1.94-1.88(m,4H),1.83-1.77(m,2H).

Example 21 Compound I-21 4-(2-(naphthalene-2-yloxy)ethyl)-4-phenethylpiperidine

The synthetic technical route refers to that described in Example 17, except that 2-fluoronaphthalene is used to replace 3-fluoropyridine, and the total yield is 12.6%.

MS(m/z):346[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ7.79-7.73(m,3H),7.50-7.44(m,1H),7.39-7.28(m,4H),7.20-7.11(m,4H),4.21(t , J=6Hz, 2H), 3.43-3.36(m, 2H), 3.33-3.24(m, 2H), 2.81(s, 2H), 1.98-1.82(m, 2H).

Example 22 Determination of acetylcholine-binding protein binding activity of substituted piperidine compounds:

This part of the biological activity test was completed in the radioisotope laboratory of Fudan University.

①Experimental materials:

1 AChBP protein: obtained by plasmid transfection and expression.

2 [ ³ H] Epibatidine (54.1 Cimmol): purchased from Perkin-Elmer Life Science Company

3 Nicotine (nicotine receptor agonist): purchased from Anaiji Company

4 Epibatidine (nicotine receptor agonist): purchased from Sigma Adrich

5 Scintillation reagent: purchased from Perkin-Elmer

6 DMSO: purchased from Shanghai Sangon Biological Company

7 Water: The pure water meter is produced by ELGA Company, No. CLXXUVFM2

8 Ultrafiltration centrifuge tube: purchased from Merk Company, model 10kd

9 PBS-TRIs buffer: the concentration is 1.4mM KH ₂ PO ₄ , 4.3mM Na ₂ HPO ₄ , 137mM NaCl, 2.7mM KCl, 20mM Trizma base, 4% DMSO, 0.05% Tween 20, pH 7.4, inorganic salts used etc. are analytically pure reagents of Sinopharm Group.

②Main instruments:

1 Scintillation instrument: purchased from Perkin-Elmer Company Model: Tri-Carb 2910TR

2 Centrifuge: Model: sigma 3k15

③Experimental method

The principle of this experiment is [ ³ H]Epibatidine competitive binding experiment. The specific experimental method is as follows: use PBS-TRIs buffer to make AChBP protein into PBS-TRIs solution, and [ ³ H]Epibatidine is also made into PBS-TRIs solution, add 10 μL protein solution and 20 μL [ ³ H ] Epibatidine solution. After incubating for 3 minutes, 2 μL of DMSO solution of different concentrations of ligand small molecules to be tested was added, and the same volume of buffer was added to the blank group. Then make up to 200 μL with buffer. Mix and incubate for 3 minutes. Then the solution was transferred to an ultrafiltration centrifuge tube and centrifuged at 10,000 rpm for 10 min. During the centrifugation, glass vials for scintillation readings of the test liquid were prepared, and 2 mL of lipophilic scintillation liquid was added to each bottle. After centrifugation, take 50 μL ^of the centrifuged solution and place it in a glass vial, mix well, and measure the radioactive intensity by a liquid scintillation counter. Group experiments with two pairs of tubes.

Binding rate = (sample tube dpm – blank dpm) / (total radioactivity dpm) * 100%

The activity of the compound obtained is as shown in Table 1:

Table 1: Acetylcholine-binding protein binding activity of some compounds

Through screening at the molecular level, the results show that some compounds exhibit certain acetylcholine-binding protein-binding activity. For further research on possible high-activity nAChRs ligand small molecules, the research may improve cognitive function and relieve AD and depression at the same time. Innovative drugs for disease progression such as

Claims (18)

1. the substituted piperidines shown in formula I, its stereoisomer and pharmaceutically acceptable salt thereof or it is molten Agent compound,

Wherein: X, Y, R₁、R₂, m, n be defined as follows:

Be each independently in nitrogen or carbon, and X, Y one of X, Y be nitrogen another be carbon；

R₁For H, alkyl or aromatic group；Described alkyl is the straight or branched alkyl of C1～C10, the ring of C3～C6 Alkyl or Heterocyclylalkyl；Described aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine Base (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole Cough up base, imidazole radicals, the heteroaryl of condensed hetero ring base, optionally by following one or more replacements on described aromatic group Base replaces: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R ", -(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For aromatic group, described aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyrrole Piperidinyl (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), Pyrrole radicals, imidazole radicals, the heteroaryl of condensed hetero ring base, optionally by following one or more on described aromatic group Substituent group replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, Alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R ", -(C=O) NR ' R " or-NR ' (C=O) R ".

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

When X is carbon, and Y is nitrogen:

R₁For H, alkyl or aromatic group.Alkyl is the straight or branched alkyl of C1～C10, the cycloalkyl of C3～C6 Or Heterocyclylalkyl；Aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyrrole Piperidinyl, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, miaow Oxazolyl, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: halogen, Trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen alkane Base, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or -NR ' (C=O) R "；

R₂For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " Or-NR ' (C=O) R ".

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁For heteroaryl, heteroaryl is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base, optionally by following on heteroaryl One or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " Or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁For H, alkyl or benzene series aryl, described alkyl is the straight or branched alkyl of C1～C10, the cycloalkanes of C3～C6 Base or Heterocyclylalkyl；Benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), on benzene series aryl optionally by Following one or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alcoxyl Base, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, benzene Base ,-NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For hetero-aromatic ring, hetero-aromatic ring is pyridine ring (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine ring (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole ring, imidazole ring, condensed hetero ring；On described hetero-aromatic ring optionally by under Arrange one or more substituent group replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁For H, alkyl or benzene series aryl, described alkyl is the straight or branched alkyl of C1～C10, the cycloalkanes of C3～C6 Base or Heterocyclylalkyl；Benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), alternative on described benzene series aryl Ground is replaced by following one or more substituent groups: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, Alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, Phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or-NR ' (C=O) R "；

R₂For benzene series aryl, described benzene series aryl is phenyl, naphthyl (1-naphthyl or 2-naphthyl), optional on benzene series aryl Replaced by following one or more substituent groups to selecting property: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, ammonia Base, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, Alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4, and n is the integer of 1-4, but is 1 during m, n difference.

Substituted piperidines shown in formula I the most according to claim 1, its stereoisomer and medicine thereof Acceptable salt or its solvate on, it is characterised in that

Be each independently in nitrogen or carbon, and X, Y one of X, Y be nitrogen another be carbon；

R₁For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, cycloalkyloxy, alkoxyalkyl, ring Alkoxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl ,-NR ' R " ,-(C=O) NR ' R ' ' or It is-NR ' (C=O) R "；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrrole radicals, imidazole radicals, condensed hetero ring base；Optionally by following on heteroaryl One or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, alkoxyl, Cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl, -NR ' R " ,-(C=O) NR ' R " or-NR ' (C=O) R "；

M is the integer of 1-4；N is the integer of 1-4.

7. according to the substituted piperidines shown in the formula I described in claim 1 or 6, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

Be each independently in nitrogen or carbon, and X, Y one of X, Y be nitrogen another be carbon；

R₁For aromatic group, aromatic group is phenyl, the benzene series aryl of naphthyl (1-naphthyl or 2-naphthyl), or pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), pyrroles Base, imidazole radicals, the heteroaryl of condensed hetero ring base, aromatic group is optionally replaced by following one or more substituent groups: Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkane Base, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

R₂For heteroaryl, heteroaryl is pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine Base, 4-pyrimidine radicals or 5-pyrimidine radicals), condensed hetero ring base；Optionally by following one or more substituent groups on heteroaryl Replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxygen alkane Base, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M is the integer of 1-4；N is the integer of 1-4.

Substituted piperidines shown in formula I the most according to claim 1 and 2, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

When X is carbon, and Y is nitrogen:

R₁、R₂It is each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals Or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine radicals), R₁、R₂On can be independently by following one Individual or multiple substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

9. according to the substituted piperidines shown in the formula I described in claim 1 or 4 or 6 or 7, its solid Isomer and pharmaceutically acceptable salt thereof or its solvate, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁For phenyl, naphthyl (1-naphthyl or 2-naphthyl), pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), R₂For pyridine radicals (2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals), pyrimidine radicals (2-pyrimidine radicals, 4-pyrimidine radicals or 5-pyrimidine Base)；R₁、R₂On can independently by following one or more substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, Cyano group, alkoxyl, cycloalkyloxy, alkoxyalkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, Alkynyl, phenyl；

M, n are each independently 1 or 2 or 3.

The most according to claim 1 or 5 the substituted piperidines shown in formula I, its stereoisomer and Its pharmaceutically acceptable salt or its solvate, it is characterised in that

When X is nitrogen, and Y is carbon:

R₁、R₂It is each independently phenyl, naphthyl (1-naphthyl or 2-naphthyl), R₁、R₂On can be independently by following one Individual or multiple substituent groups replace: halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkoxyl, cycloalkyloxy, alcoxyl Alkyl, cycloalkanes oxyalkyl, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, phenyl；

M, n are each independently 1 or 2 or 3, but are 1 during m, n difference.

11. according to the substituted piperidines shown in the formula I described in claim 1-10, its stereoisomer and Pharmaceutically acceptable salt or its solvate, it is characterised in that

In described one or more substituent groups, halogen substiuted is 2-chlorine, 3-chlorine, 4-chlorine, 2,3-dichloros, and 2,4-dichloros take Generation；Described trifluoromethyl is substituted by 2-trifluoromethyl, 3-trifluoromethyl, and 4-trifluoromethyl replaces；Described alkyl takes On behalf of 2-methyl, 3-methyl, 4-methyl replaces.

12. substituted piperidines shown in formula I according to claim 1, its stereoisomer and Pharmaceutically acceptable salt or its solvate, it is characterised in that

Described stereoisomer is the mixed of the levo form of chipal compounds, d-isomer, racemic modification, and arbitrary proportion Compound.

Substituted piperidines, its stereoisomer and medicine thereof shown in 13. formula I according to claim 1 Acceptable salt or its solvate on, it is characterised in that

Described salt is formed pharmaceutically acceptable acid by described substituted piperidines with mineral acid or organic acid Addition salts.

Substituted piperidines, its stereoisomer and medicine thereof shown in 14. formula I according to claim 13 Acceptable salt or its solvate on, it is characterised in that

Described mineral acid be the one in hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid or any two kinds or Above compositions；Described organic acid is tartaric acid, acetic acid, mandelic acid, maleic acid, fumaric acid, benzoic acid, succinum One in acid, lactic acid, citric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid or any two kinds or more than Compositions.

The substituted piperidines shown in formula I, its stereoisomer and medicine thereof described in 15. 1 kinds of claim 1 Acceptable salt or the preparation method of its solvate on, it is characterised in that use following synthetic route:

Instead Answer step as follows:

A) with compound A as raw material, under triethylamine effect, compound B is obtained with Boc anhydride reaction；

B) compound B obtains compound C with alkyl halide generation nucleophilic substitution under LDA effect；

C) compound B and malonic acid ring isopropyl ester, triisopropyl borate ester reacting generating compound E；

D) compound E occurs with the aralkyl Grignard reagent of one or more different carbon chain lengths under Hydro-Giene (Water Science). is catalyzed Nucleophilic substitution obtains compound F；

E) compound F is at DMSO-H₂The mixed solution of O is heated to 135 DEG C of reactions and within two days, obtains compound G；

F) compound G is with borine as reducing agent, and the 24-48h that refluxes in THF obtains compound H；

G) compound C obtains compound D through the THF solution reduction of tetrahydrochysene lithium aluminum；

H) compound D and compound H obtains chemical combination with fluoric compound generation nucleophilic substitution under sodium hydride effect Thing J；

I) compound J deprotection base under trifluoroacetic acid effect obtains target compound.

16. 1 kinds of preventing and treating neurodegenerative diseases or antidepressant agents compositions, it is characterised in that shown in formula I Substituted piperidines, its stereoisomer and pharmaceutically acceptable salt thereof or its solvate are active component.

Arbitrary described substituted piperidines, its stereoisomer and pharmaceutically may be used in 17. claim 1～15 Accept salt or its solvate as nAChRs the little molecule of part preparation prevention and/or treatment nervus retrogression disease Purposes in sick or dementia or antidepressant agents.

18. purposes according to claim 17, it is characterised in that described neurodegenerative diseases is alzheimer ' Silent disease (AD) or Parkinson's disease (PD)；Described dementia is Alzheimer's disease (AD), Lewy body dementia Or vascular dementia (VaD) (DLB).