CN115974839A

CN115974839A - AChE/SERT double-target-point inhibitor and preparation method and application thereof

Info

Publication number: CN115974839A
Application number: CN202211669100.4A
Authority: CN
Inventors: 杨新春; 李剑; 成佳兴; 赵金龙; 李晓康; 许祥诚; 梅丹; 陈亮
Original assignee: Zhuhai Teng Pai Pharmaceutical Co ltd
Current assignee: Zhuhai Teng Pai Pharmaceutical Co ltd
Priority date: 2021-12-24
Filing date: 2022-12-23
Publication date: 2023-04-18
Anticipated expiration: 2042-12-23
Also published as: CN115974839B; WO2023116915A1

Abstract

The invention discloses an AChE/SERT double-target inhibitor, a preparation method and application thereof, and particularly discloses a compound shown as a formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of the above, or a solvate of any one of the above. The compound of the invention has both acetylcholinesterase inhibitory activity and serotonin transporter inhibitionThe composition has good in-vitro and in-vivo blood brain barrier permeability, is used for treating Alzheimer disease, depression, and co-morbidity of Alzheimer disease and depression, avoids harmful drug interaction generated by combined medication, and reduces the medication difficulty and body burden of patients.

Description

AChE/SERT double-target-point inhibitor and preparation method and application thereof

Technical Field

The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a novel AChE/SERT double-target inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as an acetylcholinesterase inhibitor and a serotonin transporter inhibitor, especially application of the compound in preparing a medicament for preventing and/or treating Alzheimer disease, depression, alzheimer disease and depression co-morbidity.

Background

Alzheimer's Disease (AD), commonly known as senile dementia and dementia, is a progressively developing lethal neurodegenerative disease with clinical manifestations of global dementia, such as memory dysfunction, aphasia, disuse, agnosia, impaired visuospatial skills, executive dysfunction and personality and behavioral changes, accompanied by psychiatric symptoms such as depression, irritability and anxiety. Clinical data show that 90% of AD patients are associated with neuropsychiatric symptoms, wherein depression is one of the most common comorbidities, accounts for about 50% of AD patients, is 10 times higher than the morbidity of the general population, and is different from common depression, and the AD-depression comorbidities are more difficult to cure and have higher mortality rate. At the same time, depressed patients are also often associated with cognitive memory impairment, about two thirds of depressed patients are associated with cognitive impairment, and cognitive impairment remains after 94% of depressed patients recover, depression being considered a prodromal symptom or risk factor for AD. At present, 3500 million AD patients and 2 hundred million 6400 million depression patients exist in the world, so that the potential number of patients suffering from AD-depression is huge, and related treatment medicines are developed and have wide market prospects and important social values.

At present, the pathogenesis of the AD-depression co-morbidity is not clear, and no targeted treatment method exists. The existing method is to use anti-AD drugs and antidepressant drugs for combined administration. However, it is noted that the efficacy of such combination is often not good, and the efficacy of treating a single disease with a single drug cannot be achieved, and since patients are mainly elderly, there is a higher risk of drug-drug interaction. At present, no medicine for improving/treating AD-depression is available clinically. Acetylcholinesterase inhibitors (achei) are the most prominent anti-AD drugs, including Tacrine (which is subsequently removed from the market due to hepatotoxicity) developed by Warner-Lambert, donepezil (Donepezil) developed by japanese drugs of defense (Eisai), rivastigmine (Rivastigmine) developed by norwa, galantamine (galanthine) developed by qiangsheng, and huperzine developed by shanghai academy of sciences in china. Wherein donepezil is a reversible acetylcholinesterase inhibitor that increases the concentration of acetylcholine in the synaptic cleft by inhibiting the hydrolysis of acetylcholine by acetylcholinesterase. Meanwhile, donepezil is a selective acetylcholinesterase inhibitor, has small toxic and side effects, and is the first choice of the existing drugs for treating mild to moderate Alzheimer's disease. Anti-depression treatmentThe therapeutic drugs are mainly Selective Serotonin Reuptake Inhibitors (SSRIs), selectively inhibit the reuptake of serotonin (serotonin, 5-HT) by inhibiting the serotonin transporter (SERT), and improve the concentration of the 5-HT in the neurosynaptic gap in the brain of a depressed patient. Such as the anti-major depressive drug Vilazodone (Vilazodone), which has both selective 5-HT reuptake inhibitory activity and 5-HT _1A Agonistic activity. Therefore, aiming at the existing mature targets of AD and depression, the development of the medicine for simultaneously improving the levels of acetylcholine and serotonin in the brain can be expected to treat AD-depression co-morbidity.

A class of AChE/SERT/5-HT was previously disclosed in the graduation paper of Lixiaokang doctor, university of eastern China _1A Three-target active small molecules are used for treating AD-depression co-morbidity, but 5-HT in the AD-depression co-morbidity is discovered through extensive literature research _1A Agonistic activity may exacerbate memory impairment in AD patients. 5-HT _1A Receptors affect memory by affecting the activity of glutamatergic, cholinergic and GABAergic neurons of the cerebral cortex and hippocampal projections. Studies have shown that human subjects take 5-HT _1A Receptor agonists Ipsapirone or 5-HT _1A After the receptor partial agonist Tandospirone, its language memory capacity is impaired. In addition, many studies have shown that 5-HT _1A Receptor antagonists, such as NAD-299, WAY-100635 and Lecozotan (SRA-333) SR, have the effects of enhancing cholinergic transmission and improving cognitive functions, and have been shown to improve memory in animal models of cognitive dysfunction. Lecozotan, as developed by Hewlett-packard, can significantly improve the task completion efficiency of aged rhesus monkeys, reverse the memory deficiency of marmosets caused by glutamate antagonists, and enter clinical stage II in 2005 for the treatment of patients with mild to moderate AD. Thus, the previously reported AChE/SERT/5-HT _1A Three target active small molecule, 5-HT _1A The agonistic activity may play a role that is detrimental to disease treatment, and there is a great need to develop a AChE/SERT dual-target inhibitor that is more beneficial for treating AD-depression co-morbidities.

The pathological mechanism of the AD-depression comorbid disease is complex, the market demand is huge, the therapeutic drugs face the blank, the research and development of the effective therapeutic drugs have important social value and medical value, the huge market demand can be met, the drug-drug interaction generated after the comorbid patients take the drugs in a combined mode can be avoided, and the medicine taking difficulty and the body burden of the patients are reduced.

Disclosure of Invention

The invention aims to provide an acetylcholinesterase (AChE)/5-hydroxytryptamine transporter (SERT) double-target inhibitor with a novel structure.

The invention solves the technical problems through the following technical scheme:

the invention provides a compound shown as a formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of the compounds (referring to the compound shown as the formula I, the tautomer thereof or the stereoisomer thereof), or a solvate of any one of the compounds (referring to the compound shown as the formula I, the tautomer thereof, the stereoisomer thereof or the pharmaceutically acceptable salt of any one of the compounds);

each one of

Independently a double or single bond;

each R ¹ Independently CN, halogen, C substituted by 1,2 or 3 halogen ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkoxy group;

m1 is 0, 1,2,3 or 4;

R ² is H, C ₁ -C ₆ Alkyl or C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkyl group;

each R ³ Independently halogen, C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy radicalOr C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkoxy group;

m2 is 0, 1,2,3 or 4;

R ⁴ is C ₆ -C ₁₀ Aryl, C substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl, benzyl substituted with 1,2 or 3 halogens, cyclopentane substituted with 1,2 or 3 halogens, cyclohexane substituted with 1,2 or 3 halogens, "heteroatom selected from 1,2 or 3 of N, O and S, 5-to 12-membered heterocycloalkyl group having 1,2 or 3 heteroatoms substituted with 1,2 or 3 halogens," heteroatom selected from 1,2 or 3 of N, O and S, 5-to 12-membered heterocycloalkyl group having 1,2 or 3 heteroatoms substituted with 1,2 or 3 halogens "," heteroatom selected from 1,2 or 3 of N, O and S, 5-to 12-membered heteroaryl group having 1,2 or 3 heteroatoms or "heteroatom substituted with 1,2 or 3 halogens" selected from 1,2 or 3 of N, O and S, 5-to 12-membered heteroaryl group having 1,2 or 3 heteroatoms;

R ⁵ is H, halogen, C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkoxy group; or, R5 is linked to a marked carbon to form- (CH) ₂ ) _n2 -; n2 is 0 or 1;

n is 1,2,3, 4, 5 or 6;

n1 is 0, 1,2 or 3.

In certain preferred embodiments of the present invention, certain groups of the compound of formula I, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula I, its tautomer, or its stereoisomer), or a solvate of any of the foregoing (referring to the compound of formula I, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing) are defined as follows, and the groups that are not mentioned are the same as those described in any of the embodiments of the present invention (abbreviated as "in one of the embodiments of the present invention"),

R ¹ in (1), the halogenElement, said C substituted by 1,2 or 3 halogen ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I, e.g., F.

In one embodiment of the invention, R ¹ Wherein C is substituted by 1,2 or 3 halogen ₁ -C ₆ Alkyl and said C ₁ -C ₆ In the alkyl radical, the said C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

In one embodiment of the invention, R ¹ Wherein said C is substituted by 1,2 or 3 halogens ₁ -C ₆ The alkyl group is trifluoromethyl.

In one embodiment of the invention, R ¹ In (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

In one embodiment of the invention, R ² In (1), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

In one embodiment of the invention, R ² Wherein said C is substituted by 1,2 or 3 halogens ₁ -C ₆ In alkyl, the halogen is independently F, cl, br or I, e.g., F.

In one embodiment of the invention, R ³ Wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I, e.g., F.

In the present inventionIn a certain embodiment, R ³ In (A), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

In one embodiment of the invention, R ³ In (1), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

In one embodiment of the present invention, R ⁴ In (1), the C ₆ -C ₁₀ Aryl and said C substituted by 1,2 or 3 halogens ₆ -C ₁₀ In aryl radical, the C ₆ -C ₁₀ Aryl is phenyl or naphthyl, for example phenyl.

In one embodiment of the present invention, R ⁴ Wherein said C is substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl, said benzyl substituted with 1,2 or 3 halogens, said cyclopentane substituted with 1,2 or 3 halogens, said cyclohexane substituted with 1,2 or 3 halogens, said "heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heterocycloalkyl having 1,2 or 3 heteroatoms, and said" heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heteroaryl having 1,2 or 3 heteroatoms, said halogens are independently F, cl, br or I, e.g. F.

In one embodiment of the invention, R ⁴ Wherein said C is substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl is phenyl substituted by 1,2 or 3F, e.g.

In one embodiment of the invention, R ⁴ In (A), the"the hetero atom is selected from 1,2 or 3 of N, O and S, the 5-to 12-membered heterocycloalkyl group having 1,2 or 3 hetero atoms" and said 5-to 12-membered heterocycloalkyl group substituted with 1,2 or 3 halogens "are selected from 1,2 or 3 of N, O and S, the 5-to 12-membered heterocycloalkyl group having 1,2 or 3 hetero atoms" and said "the hetero atom is selected from 1,2 or 3 of N, O and S, the 5-to 12-membered heterocycloalkyl group having 1,2 or 3 hetero atoms" are independently "the hetero atom is selected from 1 or 2 of N, O and S, the 5-to 6-membered heterocycloalkyl group having 1 or 2 hetero atoms".

In one embodiment of the invention, R ⁴ In (1), the "heteroatom is selected from 1,2 or 3 of N, O and S, and 5-12 membered heteroaryl having 1,2 or 3 of heteroatom number" and the "heteroatom substituted by 1,2 or 3 of halogen is selected from 1,2 or 3 of N, O and S, and 5-12 membered heteroaryl having 1,2 or 3 of heteroatom number", and the "heteroatom is selected from 1,2 or 3 of N, O and S, and 5-12 membered heteroaryl having 1,2 or 3 of heteroatom number" is independently "5-6 membered heteroaryl having 1 or 2 of

heteroatom number

1 or 2, and 1 or 2 of heteroatom number".

In one embodiment of the invention, R ⁵ Wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I, e.g., F.

In one embodiment of the invention, R ⁵ In (1), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

In one embodiment of the invention, R ⁵ In (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxyA radical or a tert-butoxy radical, for example a methoxy radical.

In one embodiment of the present invention, R ¹ Independently CN, halogen or C substituted by 1,2 or 3 halogen ₁ -C ₆ An alkyl group; preferably F, CF ₃ Or CN, more preferably F or CN.

In one embodiment of the invention, m1 is 1.

In one embodiment of the present invention, R ² Is H or C ₁ -C ₆ The alkyl group is preferably H or methyl, and more preferably H.

In one aspect of the present invention, the first and second electrodes are,

is->

Preferably in a manner which is +>

/>

In one embodiment of the present invention, R ³ Is halogen, such as F.

In one embodiment of the present invention, m2 is 0 or 1.

In one embodiment of the invention, R ⁴ Is C ₆ -C ₁₀ Aryl or C substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl, preferably phenyl,

Further preferably phenyl or->

In one embodiment of the invention, R ⁵ Is H; or, R ⁵ Linked to the carbon marked-CH ₂ -。

In one embodiment of the present invention, n1 is 0.

In one embodiment of the invention, n is 1,2,3 or 4.

In one embodiment of the present invention, the compound represented by formula I has a structure represented by formula I-A or formula I-B:

wherein, n, m1, m2 and R ¹ 、R ² 、R ³ And R ⁴ Is as defined in any one of the present invention.

In a certain embodiment of the present invention, the compound represented by formula I is any one of the following compounds:

/>

/>

the invention also provides a preparation method of the compound shown in the formula I, which is a first method or a second method as follows:

the first method comprises the following steps:

in a solvent, under the action of an acid binding agent, carrying out substitution reaction on a compound shown as a formula II and a compound shown as a formula III to obtain a compound shown as a formula I;

x is halogen;

the second method comprises the following steps:

under the action of sodium cyanoborohydride, carrying out reductive amination reaction on a compound shown as a formula II and a compound shown as a formula IV to obtain a compound shown as a formula I;

n3= n-1 (i.e., 0, 1,2,3, 4, or 5);

*、

n、n1、m1、m2、R ¹ 、R ² 、R ³ 、R ⁴ and R ⁵ Is as defined in any one of the present invention.

The invention also provides a compound shown as the formula II:

wherein, the,

n1、m2、R ³ 、R ⁴ And R ⁵ Is as defined in any one of the present invention.

In a certain embodiment of the present invention, the compound represented by formula II is any one of the following compounds:

/>

the present invention also provides a pharmaceutical composition comprising:

(1) A compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula I, the tautomer thereof, or the stereoisomer thereof), or a solvate of any of the foregoing (referring to the compound of formula I, the tautomer thereof, the stereoisomer thereof, or the pharmaceutically acceptable salt of any of the foregoing), according to any of the present inventions; and

(2) A pharmaceutically acceptable carrier.

In the pharmaceutical composition, the compound shown in formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing (referring to the compound shown in formula I, the tautomer thereof, or the stereoisomer thereof), or a solvate of any one of the foregoing (referring to the compound shown in formula I, the tautomer thereof, the stereoisomer thereof, or the pharmaceutically acceptable salt of any one of the foregoing) is used as an active ingredient, and the content is safe and effective. "safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous), and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents.

In the case of pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1 to 2000mg, preferably 20 to 500mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

The invention also provides a compound shown in the formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing (referring to the compound shown in the formula I, the tautomer thereof or the stereoisomer thereof), or a solvate of any one of the foregoing (referring to the compound shown in the formula I, the tautomer thereof, the stereoisomer thereof or the pharmaceutically acceptable salt of any one of the foregoing), or a use of the pharmaceutical composition, wherein the use is selected from the following group:

(i) For the preparation of acetylcholinesterase inhibitors;

(ii) For the preparation of serotonin transporter inhibitors;

(iii) The preparation method is used for preparing the acetylcholinesterase and serotonin transporter dual inhibitor;

(iv) For the preparation of a medicament for the treatment of alzheimer's disease;

(v) For the preparation of a medicament for the treatment of depression;

(vi) Can be used for preparing medicine for treating Alzheimer disease and depression.

The present invention also provides a method for preventing and/or treating a disease, which comprises: administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (referring to the compound of formula I, the tautomer thereof, or the stereoisomer thereof), or a solvate of any of the foregoing (referring to the compound of formula I, the tautomer thereof, the stereoisomer thereof, or the pharmaceutically acceptable salt of any of the foregoing), or the pharmaceutical composition, as described in any of the present inventions, selected from the group consisting of:

(i) Alzheimer's disease;

(ii) Depression;

(iii) Co-morbidities of alzheimer's disease and depression.

Unless otherwise defined, the terms used in the present invention have the following meanings:

it will be appreciated by those skilled in the art that, in accordance with common practice used in the art, the present invention describes the structural formulae used in the structural formulae of the radicals

Means that the corresponding group is linked to other fragments, groups in the compound through this site.

As used herein, a substituent may be preceded by a single dash "-" indicating that the named substituent is attached to the parent moiety by a single bond.

The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See, in particular, berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977), or, handbook of Pharmaceutical Salts: properties, selection, and Use (P.Heinrich Stahl and Camile G.Wermeth, ed., wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.

The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the invention with respect to all stereoisomers of the compound is not less than 95%.

When any variable (e.g., halogen) occurs multiple times within the definition of a compound, the definition of the occurrence of that variable at each position is independent of the definition of the occurrence of the remaining positions, and their meanings are independent of one another and do not affect one another. Thus, if a group is substituted with 1,2 or 3 halogens, that is, the group may be substituted with up to 3 halogens, the definition of halogen at that position is independent of the definition of halogen at the remaining positions. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

The term "alkoxy" refers to the group-O-R ^X Wherein R is ^X Is an alkyl group as defined above.

The term "heterocycloalkyl" refers to a cyclic group of a specified heteroatom species (1, 2, or 3 of N, O, and S) having a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1,2, or 3), that is monocyclic, bridged, or spiro, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

The term "aryl" means C ₆ -C ₁₀ Aryl, such as phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably 1,2 or 3 aromatic cyclic groups independently selected from nitrogen, oxygen and sulfur, which is monocyclic or bicyclic, when bicyclic, at least one ring has aromaticity, e.g., furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, and the like.

The term "pharmaceutically acceptable carrier" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all materials, except the active ingredient, in pharmaceutical formulations. See pharmacopoeia of the people's republic of China (2015), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).

The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: alleviating one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade leading to or causing the disorder or (b) one or more biological manifestations of the disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of the disorder or disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of skill in the art.

The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

In the use, the acetylcholinesterase inhibitor, the serotonin transporter inhibitor or the dual acetylcholinesterase and serotonin transporter inhibitor may be used in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: the kit can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to the conventional method in the field, so as to provide rapid detection for the inhibitory effect of acetylcholinesterase and/or serotonin transporters.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the inventor of the invention researches extensively and deeply and develops a compound shown as a formula I, has acetylcholinesterase inhibition activity and serotonin transporter inhibition activity, has good in-vitro and in-vivo blood brain barrier permeability, is used for treating the co-diseases of Alzheimer disease, depression, alzheimer disease and depression, avoids the harmful drug interaction generated by drug combination, and reduces the drug taking difficulty and the body burden of a patient.

Drawings

FIG. 1 shows Compound I _b -7 effect on acetylcholinesterase AChE activity in mouse brain.

FIG. 2 shows Compound I _b -7 results of antidepressant efficacy experiments on tail-suspended depression model mice.

FIG. 3 shows Compound I _b -7 results of antidepressant effect experiments on forced swimming model mice.

FIG. 4 shows Compound I _b -4 antidepressants for model mice with caudal suspension depressionAnd (5) effect experiment results.

FIG. 5 shows Compound I _b -7 results of pharmacodynamic experiments on cognitive impairment model mice.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) butyl) -1H-indole-5-carbonitrile (I) _a Preparation of (1)

Step a Synthesis of (E) -3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) prop-2-en-1-one

At-78 ℃ under N ₂ Anhydrous THF (250 mL) was added to the protected two-necked flask, LDA (2M THF solution) (60 mmol) was added thereto, the mixture was stirred for a while, an anhydrous THF solution (100 mL) of 4-bromoacetophenone (10 g, 50mmol) was added dropwise via a constant pressure funnel, after the addition was completed, the mixture was stirred for 0.5h, an anhydrous THF solution (100 mL) of 1-benzyl-4-piperidinecarboxaldehyde (10.2g, 50mmol) was slowly added dropwise via a constant pressure funnel, the mixture was stirred for 1 to 2h, and the mixture was returned to room temperature. Adding NH to the reaction solution ₄ The reaction was quenched with a saturated solution of Cl, THF was evaporated under reduced pressure, the residue was extracted with dichloromethane (200 mL. Times.3), the combined organic phases were washed with a saturated NaCl solution, and then anhydrous Na ₂ SO ₄ The crude product after drying and evaporation to dryness was purified by column chromatography eluting with ethyl acetate: petroleum ether =1 to give 10g of a white solid as (E) -3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) prop-2-en-1-one in 51.8% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.78(d,J＝9.7,2.9Hz,2H),7.60(d,J＝8.6Hz,2H),7.42–7.31(m,J＝7.1,4.6Hz,5H),7.03(dd,J＝15.5,6.7Hz,1H),6.81(dd,J＝15.5,1.1Hz,1H),3.57(s,2H),2.97(d,J＝10.1Hz,2H),2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H).

Step b Synthesis of tert-butyl- (E) -4- (4- (3- (1-benzylpiperidin-4-yl) acryloyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate

(E) -3- (1-Benzylpiperidin-4-yl) -1- (4-bromobenzene) prop-2-en-1-one (10g, 25mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (9.4g, 30mmol) were dissolved in anhydrous tetrahydrofuran (250 mL), and Pd (dppf) Cl was added ₂ Catalyst (1g, 0.025mmol), K ₂ CO ₃ (10g, 1.5mmol), degassed by a water pump for 2 minutes, and heated to 80 ℃ under nitrogen protection for overnight reaction. Filtering to remove inorganic substances when the reaction is finished, evaporating to remove the solvent under reduced pressure, pulping the residue with ethyl acetate (80 mL) for 1 hour, filtering, washing the filter cake with water (80 mL) once, extracting the organic phase with dichloromethane (80 mL) for three times, combining the organic phases, washing with saturated NaCl solution, and removing anhydrous Na ₂ SO ₄ Drying, filtering to remove Na ₂ SO ₄ The solvent was removed by rotary evaporation to give 10g of a white solid as tert-butyl- (E) -4- (4- (3- (1-benzylpiperidin-4-yl) acryloyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate in 79.5% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.78(d,J＝9.7,2.9Hz,2H),7.60(d,J＝8.6Hz,2H),7.42–7.31(m,J＝7.1,4.6Hz,5H),7.03(dd,J＝15.5,6.7Hz,1H),6.81(dd,J＝15.5,1.1Hz,1H),3.57(s,2H),2.97(d,J＝10.1Hz,2H),2.27(s,1H),2.18–2.03(m,2H),1.86–1.75(m,2H),1.70–1.57(m,2H).

Step c Synthesis of tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidine-1-carboxylate

700mg of t-butyl- (E) -4- (4- (3- (1-benzylpiperidin-4-yl) acryloyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate was dissolved in 10mL of methanol, and 70mg of 10 wt% 10% Pd/C (water content 55%) was added thereto, and hydrogen was replaced with stirring 3 to 4 times, followed by vigorous stirring and reaction at room temperature overnight. After the reaction was completed, the Pd/C was filtered through celite, and the filtrate was spin-dried. The crude product was directly fed to the next step without purification to give 330mg of a clear oil, which was tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidine-1-carboxylate in 66% yield.

Step d Synthesis of 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one

500mg of tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidine-1-carboxylate was dissolved in 10mL of methylene chloride, and 3mL of trifluoroacetic acid was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a spinning mode, 10mL of dichloromethane is added into the crude product for redissolving, 20mL of saturated sodium bicarbonate solution is added for washing an organic phase, the organic phase is separated, an aqueous phase is extracted for 3-4 times (20 mL) by dichloromethane, the organic phase is combined, the crude product is washed by saturated saline, dried by anhydrous sodium sulfate, filtered, dried in a spinning mode, the crude product is purified by column chromatography, the eluent is methanol and dichloromethane =1 10, 200mg of colorless oily matter is obtained, the oily matter is 3- (1-benzyl piperidine-4-yl) -1- (4- (piperidine-4-yl) phenyl) propan-1-one, and the yield is 50%. ¹ H NMR(400MHz,CD ₃ OD)δ7.97(d,J＝8.4Hz,1H),7.46(d,J＝7.6Hz,2H),7.41(d,J＝8.3Hz,1H),4.13(s,1H),3.51(d,J＝12.7Hz,1H),3.36(s,1H),3.33(s,1H),3.15(td,J＝12.8,2.8Hz,1H),3.07(t,J＝7.3Hz,1H),3.00(tt,J＝12.1,3.6Hz,1H),2.79(t,J＝11.7Hz,1H),2.08(d,J＝13.9Hz,1H),2.00–1.86(m,J＝23.4,12.8Hz,2H),1.69(dd,J＝14.1,7.1Hz,1H),1.60(s,1H),1.43(dd,J＝23.3,11.6Hz,1H).

Step e 3- (4- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) butyl) -1H-indole-5-carbonitrile (I) _a Synthesis of (1)

3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one (100mg, 0.248mmol) and 3- (4-chlorobutyl) -1H-indole-5-carbonitrile (69mg, 0.298mmol) were placed in a flask, acetonitrile (10 mL) as a solvent, triethylamine (103. Mu.L, 0.745 mmol) as an acid-binding agent, and potassium iodide as a catalyst, and reacted at 80 ℃ under reflux overnight. After the reaction is finished, the solvent is evaporated to dryness, and the crude product is purified by column chromatography (methanol: dichloromethane =1 = 20) to obtain I _a -1 77mg, yellow solid, 3- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) butyl) -1H-indole-5-carbonitrile in 53% yield. ¹ H NMR(600MHz,CD ₃ OD)δ8.02–7.99(s,1H),7.94(s,1H),7.93(s,1H),7.49–7.46(m,1H),7.40–7.33(m,8H),7.26(s,1H),3.79(s,2H),3.38–3.33(m,2H),3.09(d,J＝11.9Hz,2H),3.03(t,J＝7.5Hz,2H),2.89–2.78(m,5H),2.64(t,J＝11.7Hz,2H),2.36(t,J＝11.5Hz,2H),1.97(m,2H),1.90(m,2H),1.86–1.71(m,7H),1.65(q,J＝7.2Hz,2H),1.46(m,1H),1.39–1.34(m,1H).HRMS(ESI)m/z calcd for C ₃₉ H ₄₇ N ₄ O[M+H] ⁺ 587.3750,found 587.3752.

Example 2- (3- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) propyl) -1H-indole-5-carbonitrile (I) _a Preparation of (2)

The 3- (4-chlorobutyl) -1H-indole-5-carbonitrile from step e in example 1 was replaced with 3- (3-bromopropyl) -1H-indole-5-carbonitrile, and the remaining required starting materials, reagents and preparation methods were the same as those of example 1 to give product I _a -2, yellow solid, yield 55%. ¹ H NMR(600MHz,CD ₃ OD)δ8.05(d,J＝0.8Hz,1H),7.95(s,1H),7.93(s,1H),7.48(d,J＝8.4Hz,1H),7.43–7.36(m,8H),7.30(s,1H),3.89(s,2H),3.41(d,J＝11.6Hz,2H),3.18(d,J＝15.1Hz,2H),3.04(t,J＝7.4Hz,2H),2.93–2.86(m,J＝13.7,6.4Hz,4H),2.86–2.80(m,1H),2.69(t,J＝11.3Hz,2H),2.49(s,2H),2.13–2.06(m,2H),1.99(d,J＝13.0Hz,2H),1.95–1.84(m,J＝27.2,18.8,8.9Hz,4H),1.66(dd,J＝14.5,7.2Hz,2H),1.51(s,1H),1.44–1.34(m,J＝24.2,7.9Hz,2H).HRMS(ESI)m/z calcd for C ₃₈ H ₄₅ N ₄ O[M+H] ⁺ 573.3593,found573.3592.

Example 3- (2- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) ethyl) -1H-indole-5-carbonitrile (I) _a Preparation of (3)

The 3- (4-chlorobutyl) -1H-indole-5-carbonitrile obtained in step e in example 1 was replaced with 3- (2-bromoethyl) -1H-indole-5-carbonitrile, and the remaining required raw materials, reagents and preparation methods were the same as in example 1 to give product I _a -3, yellow solid, yield 58%. ¹ H NMR(400MHz,DMSO-d ₆ )δ11.56(s,1H),8.22(s,1H),7.96(d,J＝8.0Hz,2H),7.56(d,J＝8.4Hz,1H),7.53–7.46(m,2H),7.45–7.34(m,7H),4.05(s,2H),3.64(s,2H),3.23–3.10(m,4H),3.08–2.83(m,6H),2.11–1.70(m,8H),1.57(q,J＝7.2,6.7Hz,2H),1.45(s,1H),1.36–1.21(m,3H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₃ N ₄ O[M+H] ⁺ 559.3437,found 559.3436.

Example 4- (4- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) butyl) -1H-indole-5-carbonitrile (I) _a Preparation of (4)

Replacing 4-bromoacetophenone in the step a in the example 1 with 5-bromoindanone, and obtaining a product I by using the other needed raw materials, reagents and preparation methods which are the same as the example 1 _a -4, yellow solid, yield 52%. ¹ H NMR(400MHz,CD ₃ OD)δ8.02(d,J＝0.8Hz,1H),7.68–7.63(m,1H),7.52–7.43(m,J＝9.6,6.3,3.4Hz,7H),7.38(dd,J＝8.5,1.5Hz,1H),7.33(d,J＝8.1Hz,1H),7.28(s,J＝7.1Hz,1H),4.14(s,2H),3.57(d,J＝12.2Hz,2H),3.44–3.34(m,3H),3.16–3.06(m,2H),3.06–2.94(m,J＝12.2Hz,3H),2.92–2.75(m,6H),2.13–1.91(m,6H),1.89–1.78(m,6H),1.56–1.36(m,3H).HRMS(ESI)m/z calcd for C ₄₀ H ₄₇ N ₄ O[M+H] ⁺ 599.3750,found 599.3751.

Example 5- (3- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) propyl) -1H-indole-5-carbonitrile (I) _a Preparation of (5)

Replacing 4-bromoacetophenone in the step a in the example 1 with 5-bromoindanone, replacing 3- (4-chlorobutyl) -1H-indole-5-carbonitrile in the step e with 3- (3-bromopropyl) -1H-indole-5-carbonitrile, and obtaining a product I by the same steps as the example 1 as the raw materials, the reagents and the preparation method for the rest _a -5, yellow solid, yield 50%. ¹ H NMR(400MHz,CD ₃ OD)δ8.05(d,J＝2.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.52–7.47(m,1H),7.46–7.37(m,7H),7.32(d,J＝7.7Hz,2H),3.97(s,2H),3.45(d,J＝12.2Hz,2H),3.42–3.36(m,1H),3.35(s,1H),3.23(s,1H),2.99–2.85(m,5H),2.85–2.69(m,4H),2.61(t,J＝11.6Hz,2H),2.17–2.06(m,2H),2.06–1.91(m,5H),1.90–1.72(m,3H),1.51–1.35(m,3H).HRMS(ESI)m/z calcd for C ₃₉ H ₄₅ N ₄ O[M+H] ⁺ 585.3593,found 585.3594.

Example 6- (2- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) ethyl) -1H-indole-5-carbonitrile (I) _a Preparation of (6)

The 4-bromoacetophenone in step a in example 1 was replaced with 5-bromoindanone, the 3- (4-chlorobutyl) -1H-indole-5-carbonitrile in step e was replaced with 3- (2-bromoethyl) -1H-indole-5-carbonitrile, and the remaining required starting materials, reagents and preparation methods were the same as in example 1 to give product I _a -6, yellow solid, yield 52%. ¹ H NMR(400MHz,CD ₃ OD)δ8.13(s,1H),7.69(d,J＝7.9Hz,1H),7.57–7.47(m,7H),7.45(dd,J＝8.5,1.4Hz,1H),7.42(d,J＝2.6Hz,1H),7.38(d,J＝8.0Hz,1H),4.18(s,2H),3.66(s,2H),3.53–3.39(m,3H),3.26(s,4H),3.07–2.76(m,7H),2.19–1.78(m,9H),1.55–1.44(m,J＝9.1Hz,2H).HRMS(ESI)m/z calcd for C ₃₈ H ₄₃ N ₄ O[M+H] ⁺ 571.3437,found 571.3438.

Example 7- ((4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (1)

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Intermediate 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one (4-1) was prepared according to the procedure of example 1, steps a-d.

5-cyanoindole-3-carbaldehyde (51mg, 0.298mmol) and 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one (100mg, 0.248mmol) were placed in a flask, and dissolved with anhydrous methanol: anhydrous dichloromethane =1 (v: v), followed by addition of sodium cyanoborohydride (31mg, 0.497mmol) and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried by spinning, and the crude product was purified by column chromatography (methanol: dichloromethane = 1) _b -1, white solid, 3- ((4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile. ¹ H NMR(400MHz,CD ₃ OD)δ8.21(s,1H),7.94(s,1H),7.92(s,1H),7.59(s,1H),7.56(d,J＝8.6Hz,1H),7.50–7.33(m,9H),4.17(s,2H),3.89(s,2H),3.16(s,2H),3.04(t,J＝7.4Hz,2H),2.73(d,J＝39.5Hz,3H),2.50(s,2H),1.95(s,2H),1.86(d,J＝13.3Hz,4H),1.73–1.61(m,2H),1.49(s,1H),1.43–1.30(m,3H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₁ N ₄ O[M+H] ⁺ 545.3280,found545.3281.

Example 8- ((4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-indene-5-Yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (2)

And (c) replacing 4-bromoacetophenone in the step a with 5-bromoindanone, and obtaining 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one through the steps a-d.

3- (1-Benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one was replaced with 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one, and the remaining required raw materials, reagents and preparation methods were the same as in example 7 to give product I _b -2, white solid, yield 60%. ¹ H NMR(400MHz,CD ₃ OD)δ8.06(d,J＝0.8Hz,1H),7.50(d,J＝7.9Hz,1H),7.42(d,J＝8.5Hz,1H),7.36(s,1H),7.34–7.29(m,2H),7.24(d,J＝4.4Hz,4H),7.22–7.17(m,J＝6.3Hz,2H),3.77(s,2H),3.50(s,2H),3.07(d,J＝10.8Hz,2H),2.87(t,2H),2.72–2.52(m,4H),2.20(t,2H),2.03(t,2H),1.83–1.67(m,7H),1.63(d,J＝13.6Hz,1H),1.48(s,1H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₁ N ₄ O[M+H] ⁺ 557.3280,found 557.3279.

Example 9- ((4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) piperidin-1-yl) methyl) -1-methyl-1H-indole-5-carbonitrile (I) _b Preparation of (3)

E, the 5-cyano-indole-3-carbaldehyde in step e is replaced with 3-formyl-1-methyl-1H-indole-5-carbonitrile, and the remaining required raw materials, reagents and preparation methods are the same as in example 7, to give product I _b -3, clear oil, yield 59%. ¹ H NMR(400MHz,CDCl ₃ )δ8.13(s,1H),7.88(d,J＝8.0Hz,2H),7.44(d,J＝8.6Hz,1H),7.40–7.27(m,7H),7.25–7.19(m,1H),7.15(s,1H),3.80(s,3H),3.73(s,2H),3.50(s,2H),3.08(d,J＝10.4Hz,2H),3.00–2.81(m,4H),2.63–2.47(m,1H),2.20–2.07(m,2H),2.02–1.90(m,2H),1.88–1.76(m,4H),1.74–1.66(m,3H),1.39–1.30(m,4H).HRMS(ESI)m/zcalcd for C ₃₇ H ₄₃ N ₄ O[M+H] ⁺ 559.3437,found 559.3438.

Example 10- ((4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1-methyl-1H-indole-5-carbonitrile (I) _b Preparation of (4)

The procedure is as in example 7 except for replacing 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one with 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one and 5-cyano-indole-3-carbaldehyde with 3-formyl-1-methyl-1H-indole-5-carbonitrile to give product I _b -4, clear oil, yield 63%. ¹ H NMR(400MHz,CDCl ₃ )δ8.15(d,J＝1.6Hz,1H),7.66(d,J＝7.9Hz,1H),7.49–7.43(m,1H),7.39–7.28(m,7H),7.24–7.16(m,2H),3.81(s,3H),3.75(s,2H),3.56(s,2H),3.28(s,1H),3.10(d,J＝11.1Hz,2H),2.98–2.90(m,2H),2.78–2.64(m,2H),2.63–2.52(m,1H),2.19–2.10(m,2H),2.08–1.98(m,2H),1.91–1.79(m,5H),1.76–1.66(m,2H),1.58–1.48(m,1H),1.42–1.32(m,3H).HRMS(ESI)m/z calcd for C ₃₈ H ₄₃ N ₄ O[M+H] ⁺ 571.3437,found 571.3438.

Example 11- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) butyl) -1H-indole-5-carbonitrile (I) _a Preparation of (7)

The specific operation is the same as the step a in the above example 1, and the compound is prepared by Aldol condensation reaction of 4-bromoacetophenone and 1-benzyl-4-piperidine formaldehyde.

Synthesis of 3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) propan-1-one

Under ice bath, trichlorosilane is prepared into 25 percent (volume ratio) of anhydrous dichloromethane solution, and the bottle mouth is sealed for standby.

(E) -3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) prop-2-en-1-one (800mg, 2.08mmol) was dissolved in anhydrous dichloromethane (16 mL) under ice bath, HMPA (73. Mu.L, 0.416 mmol) and a solution of trichlorosilane in anhydrous dichloromethane (420. Mu.L, 4.16 mmol) were added sequentially with stirring, and after stirring for 1 hour in ice bath, stirring was continued at room temperature until TLC indicated that the starting material was completely reacted. Transferring the reaction solution to a large beaker, slowly adding 100mL of saturated sodium bicarbonate solution and 100mL of ethyl acetate, stirring for 1h, filtering off white insoluble substances with diatomite to obtain a filtrate liquid separation, extracting the aqueous phase with ethyl acetate (30 mL) for three times, combining organic phases, washing with saturated NaCl solution, and washing with anhydrous Na ₂ SO ₄ After drying, the solvent was removed by rotary evaporation and the crude product obtained was purified by column chromatography (ethyl acetate: petroleum ether =1 6) to give 3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) propan-1-one as a white solid in 69% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.81(d,J＝8.6Hz,2H),7.60(d,J＝8.6Hz,2H),7.44–7.30(m,J＝14.5,7.7Hz,5H),3.68(s,2H),3.16–2.88(m,J＝23.9,16.5Hz,4H),2.09(d,J＝29.7Hz,2H),1.87–1.66(m,J＝13.9,6.7Hz,5H),1.38(d,J＝36.9Hz,2H).

Step b: synthesis of tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate

(E) -3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) propan-2-en-1-one in step b of example 1 was replaced with 3- (1-benzylpiperidin-4-yl) -1- (4-bromophenyl) propan-1-one, and the remaining required starting materials, reagents and preparation were the same as in example 1 to give tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate as a white solid in 54% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.91(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.43–7.29(m,5H),6.28–6.07(m,1H),4.11(s,2H),3.94–3.57(m,4H),3.29–2.92(m,J＝44.0Hz,4H),2.54(s,2H),2.12(s,2H),1.92–1.59(m,7H),1.50(s,9H).

Step d: synthesis of 3- (1-benzylpiperidin-4-yl) -1- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) propan-1-one

Tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionylphenyl) piperidine-1-carboxylate in step d of example 1 was replaced with tert-butyl-4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate, and the remaining required starting materials, reagents and preparation were the same as in example 1 to give 3- (1-benzylpiperidin-4-yl) -1- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) propan-1-one as a clear oil in 73% yield. ¹ H NMR(400MHz,CD ₃ OD)δ7.98(d,J＝8.2Hz,2H),7.60(d,J＝8.4Hz,2H),7.46–7.34(m,5H),6.32(s,1H),3.88(s,2H),3.83(d,J＝3.0Hz,2H),3.43(t,J＝6.1Hz,2H),3.17(d,J＝12.2Hz,2H),3.06(t,J＝7.4Hz,2H),2.79(d,J＝1.9Hz,2H),2.48(t,J＝11.7Hz,2H),1.87(d,J＝13.6Hz,2H),1.68(dd,J＝14.3,7.1Hz,2H),1.52(t,J＝16.4Hz,1H),1.45–1.31(m,2H).

Step e:3- (4- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) butyl) -1H-indole-5-carbonitrile (I) _a Synthesis of (E) -7)

Examples of the invention1 step e replacement of 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propyl-1-one with 3- (1-benzylpiperidin-4-yl) -1- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) propan-1-one, the remaining required starting materials, reagents and preparation method were the same as in example 1 to give I _a -7 as 3- (4- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) butyl) -1H-indole-5-carbonitrile as a yellow solid in 56% yield. ¹ H NMR(600MHz,CD ₃ OD)δ7.99(d,J＝0.8Hz,1H),7.94(d,J＝8.5Hz,2H),7.55(d,J＝8.5Hz,2H),7.46(d,J＝8.4Hz,1H),7.38–7.35(m,J＝5.4,2.9Hz,5H),7.34–7.30(m,1H),7.23(s,1H),6.30–6.27(m,1H),3.71(s,2H),3.27(s,2H),3.04(t,J＝7.5Hz,4H),2.86–2.81(m,J＝7.1Hz,4H),2.67–2.59(m,4H),2.26(s,2H),1.84–1.75(m,J＝14.7,9.4Hz,4H),1.73–1.63(m,4H),1.42(s,1H),1.37–1.32(m,2H).HRMS(ESI)m/z calcd for C ₃₉ H ₄₅ N ₄ O[M+H] ⁺ 585.3593,found 585.3592.

Example 12- (3- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) propyl) -1H-indole-5-carbonitrile (I) _a Preparation of (8)

Example 11 was repeated except for the required starting materials, reagents and preparation method similar to example 11 except for replacing 3- (4-chlorobutyl) -1H-indole-5-carbonitrile with 3- (3-bromopropyl) -1H-indole-5-carbonitrile obtained in step e of example 11 to give product I _a -8, yellow solid, yield 54%. ¹ H NMR(400MHz,CD ₃ OD)δ8.01(d,J＝1.6Hz,1H),7.96–7.89(m,2H),7.56–7.51(m,2H),7.46(d,J＝8.4Hz,1H),7.36(dd,J＝8.5,1.6Hz,1H),7.31(d,J＝4.3Hz,4H),7.29–7.24(m,2H),6.31–6.26(m,1H),3.51(d,J＝2.1Hz,2H),3.20(q,J＝3.0Hz,2H),3.06–2.97(m,1H),2.90(dd,J＝12.1,3.4Hz,2H),2.82(t,J＝7.4Hz,2H),2.75(t,J＝5.7Hz,2H),2.64–2.53(m,4H),2.06–1.93(m,5H),1.79–1.68(m,3H),1.62(q,J＝7.0Hz,3H),1.38–1.33(m,1H).HRMS(ESI)m/z calcd for C ₃₈ H ₄₃ N ₄ O[M+H] ⁺ 571.3437,found 571.3436.

Example 13- (2- (4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) ethyl) -1H-indole-5-carbonitrile (I) _a Preparation of (2) to (9)

The 3- (4-chlorobutyl) -1H-indole-5-carbonitrile obtained in step e of example 11 was replaced with 3- (2-bromoethyl) -1H-indole-5-carbonitrile, and the remaining desired starting materials, reagents and preparation methods were the same as in example 11 to give product I _a -9 as yellow solid, yield 57%. ¹ H NMR(400MHz,CD ₃ OD)δ8.09(d,J＝1.5Hz,1H),8.03–7.96(m,2H),7.62(d,J＝8.5Hz,2H),7.51(dd,J＝8.4,0.7Hz,1H),7.48–7.39(m,6H),7.34(s,1H),6.41–6.35(m,1H),3.99(s,2H),3.49(d,J＝3.5Hz,2H),3.37(s,2H),3.25(d,J＝13.5Hz,2H),3.11(dt,J＝14.7,7.3Hz,4H),3.03(t,J＝5.8Hz,2H),3.00–2.91(m,2H),2.74(s,2H),2.62(s,2H),1.93(d,J＝13.7Hz,2H),1.71(q,J＝7.2Hz,2H),1.64–1.52(m,1H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₁ N ₄ O[M+H] ⁺ 557.3280,found 557.3281.

Example 14- (4- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) butyl) -1H-indole-5-carbonitrile (I) _a Preparation of (10)

The 4-bromoacetophenone in the step a of the example 11 is replaced by 5-bromoindanone, the 3- (4-chlorobutyl) -1H-indole-5-carbonitrile in the step e is replaced by 3- (2-bromoethyl) -1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as the example 11, so that a product I is obtained _a -10, yellow solid, yield 57%. ¹ H NMR(400MHz,CD ₃ OD)δ8.01(s,1H),7.66(d,J＝8.2Hz,1H),7.62(s,1H),7.52(d,J＝8.5Hz,1H),7.50–7.43(m,J＝7.6Hz,6H),7.36(d,J＝8.5Hz,1H),7.27(s,1H),6.31(s,1H),4.21(s,2H),3.70(s,2H),3.50–3.35(m,J＝16.7,7.2Hz,3H),3.10–3.00(m,2H),2.99–2.76(m,J＝39.3,18.6Hz,8H),2.01(dd,J＝34.7,14.4Hz,2H),1.84(d,J＝19.6Hz,6H),1.59–1.38(m,3H),1.37–1.20(m,2H).HRMS(ESI)m/z calcd for C ₄₀ H ₄₅ N ₄ O[M+H] ⁺ 597.3593,found 597.3592.

Example 15- (3- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydropyridin-1H-inden-5-yl) -3, 6-dihydro-1 (2H) -yl) propyl) -1H-indole-5-carbonitrile (I) _a Preparation of (11)

The 4-bromoacetophenone in the step a of the example 11 is replaced by 5-bromoindanone, the 3- (4-chlorobutyl) -1H-indole-5-carbonitrile in the step e is replaced by 3- (3-bromopropyl) -1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as the example 11, so that a product I is obtained _a -11, yellow solid, yield 57%. ¹ H NMR(400MHz,CD ₃ OD)δ8.03(d,J＝1.5Hz,1H),7.63(d,J＝8.1Hz,1H),7.57(s,1H),7.52–7.45(m,2H),7.43–7.35(m,6H),7.27(s,1H),6.35–6.29(m,1H),3.89(s,2H),3.40–3.36(m,1H),3.23–3.12(m,3H),2.95–2.76(m,6H),2.74–2.64(m,4H),2.57–2.46(m,2H),2.03(p,J＝7.6Hz,2H),1.93(d,J＝13.8Hz,1H),1.89–1.77(m,2H),1.73(d,J＝4.0Hz,1H),1.48–1.32(m,4H).HRMS(ESI)m/z calcd for C ₃₉ H ₄₃ N ₄ O[M+H] ⁺ 583.3437,found 583.3436.

Example 16- (2- (4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethyl) -1H-indole-5-carbonitrile (I) _a Preparation of (12)

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The 4-bromoacetophenone in step a of example 11 was replaced with 5-bromoindanone, the 3- (4-chlorobutyl) -1H-indole-5-carbonitrile in step e was replaced with 3- (2-bromoethyl) -1H-indole-5-carbonitrile, and the rest was desiredThe starting materials, reagents and preparation methods were the same as in example 11 to give product I _a -12 as yellow solid, yield 53%. ¹ H NMR(600MHz,CD ₃ OD)δ8.10(d,J＝0.6Hz,1H),7.67(d,J＝8.1Hz,1H),7.63(s,1H),7.55(d,J＝8.1Hz,1H),7.53–7.49(m,3H),7.49–7.46(m,3H),7.40(dd,J＝8.5,1.4Hz,1H),7.38(s,1H),6.37(s,1H),4.23(s,2H),3.73(s,2H),3.47–3.38(m,J＝17.1,8.1Hz,3H),3.29–3.25(m,2H),3.20(s,3H),2.96(t,J＝12.0Hz,2H),2.88–2.81(m,3H),2.11–1.79(m,5H),1.58–1.40(m,4H).HRMS(ESI)m/z calcd for C ₃₈ H ₄₁ N ₄ O[M+H] ⁺ 569.3280,found 569.3282.

Example 17- ((4- (4- (3- (1-benzylpiperidin-4-yl) propionyl) phenyl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (5)

The 3- (1-benzylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one from example 7 was replaced with 3- (1-benzylpiperidin-4-yl) -1- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) propan-1-one, and the remaining required starting materials, reagents and preparation were the same as in example 7 to give product I _b -5, white solid, yield 57%. ¹ H NMR(400MHz,CD ₃ OD)δ8.17(d,J＝1.6Hz,1H),7.93(d,2H),7.57–7.50(m,3H),7.48(s,1H),7.43–7.39(m,1H),7.39–7.30(m,5H),6.34–6.25(m,1H),3.95(s,2H),3.75(s,2H),3.12–2.98(m,4H),2.88(t,2H),2.63(s,2H),2.31(t,J＝11.8Hz,2H),1.91(s,1H),1.85–1.77(m,2H),1.70–1.61(m,2H),1.45(s,1H),1.38–1.30(m,3H).HRMS(ESI)m/z calcd for C ₃₆ H ₃₉ N ₄ O[M+H] ⁺ 543.3124,found543.3123.

Example 18- ((4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (6)

3- (1-Phenylpiperidin-4-yl) -1- (4- (piperidin-4-yl) phenyl) propan-1-one was replaced with 2- ((1-phenylpiperidin-4-yl) methyl) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-indol-1-one, and the remaining required raw materials, reagents and preparation methods were the same as in example 7 to give product I _b -6, yellow solid, yield 52%. ¹ H NMR(400MHz,CD ₃ OD)δ8.24(s,1H),7.64(d,J＝9.5Hz,2H),7.60(s,1H),7.58(d,J＝8.6Hz,1H),7.49(q,J＝8.1Hz,7H),6.32(s,1H),4.35(s,2H),4.23(s,2H),3.68(s,2H),3.41(dd,J＝16.9,7.4Hz,3H),3.28(d,J＝5.6Hz,2H),2.95(t,J＝11.5Hz,2H),2.87–2.74(m,4H),2.07(d,J＝14.1Hz,1H),1.97(d,J＝14.1Hz,1H),1.93–1.79(m,2H),1.57–1.38(m,3H).HRMS(ESI)m/z calcd for C ₃₇ H ₃₉ N ₄ O[M+H] ⁺ 555.3124,found 555.3123.

Example 19- ((4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (7)

Step i Synthesis of 6-tert-Butoxycarbonyl-1-oxa-6-azaspiro [2.5] octane

Under stirring in ice bath, 2.4g of 60% sodium hydrogen was slowly added to 40mL of anhydrous DMSO, and after the addition was completed, the temperature was raised to 65 ℃ and stirred for 1 hour to sufficiently dissolve the sodium hydrogen. After the reaction solution was returned to room temperature, 13.3g of trimethylsulfoxidide was slowly added thereto and stirred at room temperature for 0.5 hour to produce a sulfoxylium salt having high reactivity. Then 5.0g N-tert-butoxycarbonyl-4-piperidone was dissolved in 50mL anhydrous DMSO, and slowly added dropwise to the reaction mixture with stirring, and reacted at room temperature for 1 hour to produce a cyclopropane compound after the sulfoxide sulfonium salt reacted with a carbonyl group. After the reaction was completed, 100mL of water and 100mL of ethyl acetate were added to the reaction mixture, and the reaction mixture was allowed to reactExtracting the product into ethyl acetate, separating to obtain an organic phase, extracting the water phase with ethyl acetate for three times (100 mL multiplied by 3), combining the organic phases, washing with water for three times (200 mL multiplied by 3), combining the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, and directly feeding the product into the next step without purification after spin-drying to obtain an intermediate 6-tert-butyloxycarbonyl-1-oxa-6-azaspiro [2.5]]Octane, 5.35g brown oil, 99% yield. ¹ H NMR(400MHz,CDCl ₃ )δ3.73(d,J＝13.1Hz,2H),3.43(ddd,J＝13.3,9.5,3.7Hz,2H),2.69(s,2H),1.80(ddd,J＝13.8,9.4,4.5Hz,2H),1.48(s,9H),1.43(s,2H).

Step j Synthesis of 1-tert-Butoxycarbonyl-4-fluoro-4- (hydroxymethyl) piperidine

1.0g of intermediate 6-tert-butoxycarbonyl-1-oxa-6-azaspiro [2.5] was added as a brown oil]Octane was placed in a 50mL plastic tube, and dissolved in 20mL of methylene chloride at-10 ℃ maintained in an ice salt bath, and 0.6mL of a 70% pyridine hydrofluoric acid solution (olah's reagent) was added dropwise with stirring, followed by reaction at-10 ℃ for 1 hour. After the reaction is finished, the reaction solution is transferred to a plastic beaker, potassium carbonate particles are added to neutralize the reaction solution to be neutral under stirring, dichloromethane is used for extraction for three times (100 mL multiplied by 3), organic phases are combined, the mixture is washed by saturated saline solution, anhydrous sodium sulfate is used for drying, products are purified by column chromatography after spin drying, eluent is ethyl acetate: petroleum ether =1, 550mg of intermediate 1-tert-butoxycarbonyl-4-fluoro-4- (hydroxymethyl) piperidine is obtained, and the yield is 50%. ¹ H NMR(400MHz,DMSO-d ₆ )δ5.76(s,1H),4.98(t,J＝6.0Hz,1H),3.76(d,J＝13.4Hz,2H),3.41(dd,J＝20.1,6.0Hz,2H),2.98(s,2H),1.70(dd,J＝13.9,10.4Hz,2H),1.54(dtd,J＝35.8,13.8,13.0,5.1Hz,2H),1.40(s,9H).

Step k Synthesis of 1-tert-Butoxycarbonyl-4-fluoro-4-piperidinecarboxaldehyde

1.5g of intermediate 1-tert-butoxycarbonyl-4-fluoro-4- (hydroxymethyl) piperidine was dissolved in 15mL of anhydrous dichloromethane, 4.1g of dessimidine reagent was dissolved in 30mL of anhydrous dichloromethane, and the dessimidine solution was slowly added dropwise to the solution of (4-fluoro-1-tert-butoxycarbonyl-substituted piperidin-4-yl) methanol with stirring in an ice bath at 0 ℃ and reacted at room temperature for 1 to 2 hours after completion of the dropwise addition. After the reaction of the raw materials is finished, 40mL of saturated sodium bicarbonate solution and 40mL of 10% sodium thiosulfate solution are added into the reaction, stirring is carried out for half an hour, dichloromethane is added for extraction for three times (50 mL multiplied by 3), organic phases are combined, the obtained product is washed by saturated saline solution, dried by anhydrous sodium sulfate, and after rotary drying, the product is purified by column chromatography, and an eluent is ethyl acetate: petroleum ether =1:2.5, so that 750mg of intermediate 1-tert-butoxycarbonyl-4-fluoro-4-piperidinecarboxaldehyde is obtained, and the yield is 48%. ¹ H NMR(400MHz,CDCl ₃ )δ9.74(d,J＝4.9Hz,1H),4.03(d,J＝13.3Hz,2H),3.20–3.05(m,2H),1.89–1.69(m,4H),1.47(s,9H).

Step l Synthesis of tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-inden-2-ylidene) methyl) -4-fluoropiperidine-1-carboxylate

Weighing 550mg of viscous sugar-shaped intermediate 1-tert-butoxycarbonyl-4-fluoro-4-piperidinecarboxaldehyde into a 100mL round-bottom flask, adding 30mL of tetrahydrofuran to dissolve the viscous sugar-shaped intermediate, adding 500mg of 5-bromoindanone and 660mg of sodium hydroxide under stirring, stirring vigorously for 8-10 minutes, transferring the reaction solution into a beaker when the reaction solution turns black from yellow, adding 40mL of water to dilute the reaction solution, dropwise adding 1N hydrochloric acid aqueous solution to neutralize the reaction solution until the reaction solution is neutral, and turning the solution from black to red. The reaction solution was extracted three times with ethyl acetate (50 mL), and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ Drying, suction filtration, rotary evaporation to remove the solvent, and column chromatography to purify the residual organic substances, wherein ethyl acetate and petroleum ether =1 11 are eluted to obtain 668mg of the target compound tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-indene-2-ylidene) methyl) -4-fluoropiperidine-1-carboxylate, which is a white solid with a yield of 76%. ¹ H NMR(400MHz,CDCl ₃ )δ7.72(d,J＝8.2Hz,1H),7.68(s,1H),7.55(dd,J＝8.2,1.7Hz,1H),6.69(dt,J＝26.6,2.2Hz,1H),4.01(d,J＝13.6Hz,2H),3.90(s,2H),3.16(t,J＝12.7Hz,2H),1.98–1.85(m,3H),1.83–1.73(m,1H),1.48(s,9H).

Step m: (E) Synthesis of (E) -5-bromo-2- ((4-fluoropiperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one

Tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-inden-2-ylidene) methyl) -4-fluoropiperidine-1-carboxylate (500mg, 1.18mmol) is dissolved in 10mL of dichloromethane, and 3mL of trifluoroacetic acid is added dropwise with stirring, and the mixture is stirred at room temperature for 1 hour. After the reaction, the reaction solution and part of trifluoroacetic acid were spin-dried, 10mL of dichloromethane was added to the crude product to redissolve it, and 20mL of saturated sodium bicarbonate solution was added to wash the organic phase, and a large amount of white solid was precipitated as 380mg of (E) -5-bromo-2- ((4-fluoropiperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one with a yield of 99%. ¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(s,1H),8.64(s,1H),7.93(s,1H),7.74–7.65(m,2H),6.73(d,J＝25.5,2.3Hz,1H),3.93(s,2H),3.32(s,2H),3.11(s,2H),2.24–2.07(m,3H).

Step n: (E) Synthesis of (E) -2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -5-bromo-2, 3-dihydro-1H-inden-1-one

2.0g of (E) -5-bromo-2- ((4-fluoropiperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one are dissolved in 20mL of DMF, and 806. Mu.L of benzyl bromide are added dropwise with stirring, and solid potassium carbonate (1.28 g) is added and the reaction is carried out at room temperature for 1 hour. After the reaction, 80mL of ethyl acetate and 80mL of water were added to the reaction system for extraction, the organic phase was washed with water three times (100 mL. Times.3), the organic phases were combined, washed with saturated brine, and anhydrous Na ₂ SO ₄ Drying, suction filtering, rotary evaporating to remove solvent, and directly feeding the obtained product to the next step without purification. 2.0g of (E) -2- ((1-benzyl-4-fluoro)Piperidin-4-yl) methylene) -5-bromo-2, 3-dihydro-1H-inden-1-one as a white solid in 75% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.72(d,J＝8.1Hz,1H),7.67(s,1H),7.54(d,J＝8.2,1.7Hz,1H),7.42–7.28(m,5H),6.75(dt,J＝26.4,2.2Hz,1H),3.89(s,2H),3.61(s,2H),2.80(s,2H),2.45(s,2H),2.16–1.87(m,4H).

Step b: synthesis of tert-butyl- (E) -4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

(E) -2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -5-bromo-2, 3-dihydro-1H-inden-1-one (500mg, 1.2mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (448mg, 1.5mmol) were dissolved in anhydrous 1, 4-dioxane (15 mL), and Pd (PPh) was added ₃ ) ₄ (70mg, 0.060mmol) and K ₂ CO ₃ (500mg, 3.6 mmol), degassed by a water pump for 2 minutes, and reacted at 100 ℃ overnight under nitrogen. Spin-drying the reaction solution, adding 100mL ethyl acetate and 100mL water into the reaction system for extraction, washing the organic phase with saturated saline solution, and removing anhydrous Na ₂ SO ₄ Drying, suction filtration, rotary evaporation to remove solvent, adding 20mL ethyl acetate for pulping, filtering to obtain 300mg of tert-butyl- (E) -4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate as white solid with a yield of 48%. ¹ H NMR(400MHz,CDCl3)δ7.81(d,J＝8.1Hz,1H),7.46(d,J＝1.5Hz,1H),7.42(dd,J＝8.1,1.6Hz,1H),7.38–7.27(m,5H),6.71(d,J＝26.5Hz,1H),3.89(s,2H),3.66(t,J＝5.6Hz,2H),3.56(s,2H),2.75(d,J＝11.8,3.9Hz,2H),2.56(s,2H),2.40(t,J＝11.8,11.2,3.7Hz,2H),2.03–1.89(m,4H),1.50(s,9H).

Step c: synthesis of tert-butyl-4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylic acid ester

1.0g of tert-butyl- (E) -4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was dissolved in a mixed solvent of 10mL of methanol and 10mL of methylene chloride, and 100mg of 10% Pd/C (aqueous 55%) was added to replace hydrogen with stirring 3 to 4 times, and the reaction was carried out overnight at room temperature. After the reaction, pd/C was filtered off with celite, the filter cake was washed with 30mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product is purified by column chromatography eluting with ethyl acetate: dichloromethane = 1. 262mg of tert-butyl-4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylic acid ester are obtained as a white solid in a yield of 26%. ¹ H NMR(400MHz,CDCl ₃ )δ7.72(d,J＝8.0Hz,1H),7.44–7.30(m,5H),7.29(s,1H),7.24(d,J＝8.0Hz,1H),4.29(s,2H),3.62(s,2H),3.43(dd,J＝17.3,7.9Hz,1H),2.95(dd,J＝17.4,4.5Hz,1H),2.89–2.70(m,6H),2.44(dd,J＝28.5,14.7Hz,2H),2.04–1.96(m,1H),1.94–1.80(m,4H),1.77–1.62(m,5H),1.51(s,9H)

Step d: synthesis of 2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

500mg of tert-butyl-4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate are dissolved in 10mL of dichloromethane, and 3mL of trifluoroacetic acid are added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a rotary mode, 10mL of dichloromethane is added into the crude product for redissolving, 20mL of saturated sodium bicarbonate solution is added for washing an organic phase, the organic phase is separated, an aqueous phase is extracted by dichloromethane for 3-4 times (20 mL), the organic phase is combined, saturated salt water is used for washing, anhydrous sodium sulfate is used for drying, and after filtration, the filtrate is dried in a rotary mode and can be directly used for the next step without purification, 200mg of target intermediate 2- ((1-benzyl-4-fluoropiperidine-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-indene-1-one and white solid are obtained, and the yield is 95%.

Step e: synthesis of 3- ((4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

5-cyano-indole-3-carbaldehyde (53mg, 0.314mmol) and 2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (120mg, 0.285mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added with sodium cyanoborohydride (36mg, 0.571mmol), and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 80mg of 3- ((4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile as a white solid in 49% yield. ¹ H NMR(600MHz,CDCl ₃ )δ8.83(s,1H),8.10(s,1H),7.59(d,J＝7.9Hz,1H),7.34(s,2H),7.26–7.22(m,5H),7.21–7.17(m,2H),7.15(d,J＝8.1Hz,1H),3.67(s,2H),3.46(s,2H),3.32(dd,J＝17.4,7.9Hz,1H),3.01(dd,J＝11.3,3.5Hz,2H),2.85(dd,J＝17.4,4.4Hz,1H),2.76–2.70(m,1H),2.69–2.60(m,2H),2.54–2.47(m,1H),2.36–2.24(m,3H),2.08–2.01(m,2H),1.91–1.83(m,1H),1.80–1.71(m,5H),1.70–1.63(m,1H),1.60–1.52(m,1H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₀ N ₄ O[M+H] ⁺ 575.3186,found 575.3188.

Example 20- ((4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (1) to (8)

(E) Synthesis of (E) -5-bromo-2- ((4-fluoropiperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one proceeds as in example 19.

Step a: (E) Synthesis of (E) -5-bromo-2- ((4-fluoro-1-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one

The benzyl bromide from step n of example 19 was replaced with 2-fluorobenzyl bromide, and the remaining required starting materials, reagents and preparation were the same as in step n of example 19 to give 350mg of (E) -5-bromo-2- ((4-fluoro-1-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one as a white solid in 52% yield. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.91(s,1H),7.71–7.63(m,2H),7.44(t,J＝7.7Hz,1H),7.33(q,J＝7.0Hz,1H),7.18(q,J＝8.6,7.9Hz,2H),6.70(d,1H),3.90(s,2H),3.58(s,2H),2.76–2.66(m,2H),2.37–2.25(m,2H),2.08–1.95(m,2H),1.95–1.83(m,4H).

Step b: synthesis of tert-butyl- (E) -4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

The procedure was followed for the replacement of (E) -2- ((1-phenyl-4-fluorobenzyl-4-yl) methylene) -5-bromo-2, 3-dihydro-1H-inden-1-one with (E) -5-bromo-2- ((4-fluoro-1-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one and the remaining required starting materials, reagents and preparation were the same as in example 19, step b, to give tert-butyl- (E) -4- (2- ((4-fluoro-1- (2-fluorophenyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate as a white solid in 43% yield. ¹ H NMR(400MHz,CDCl ₃ )δ7.81(d,J＝8.1Hz,1H),7.46(s,1H),7.42(d,J＝8.2Hz,1H),7.15(t,J＝7.5Hz,1H),7.06(t,J＝9.2Hz,1H),6.70(d,J＝26.4Hz,1H),6.20(s,1H),4.12(d,J＝3.9Hz,2H),3.89(d,J＝2.9Hz,2H),3.66(t,J＝5.7Hz,4H),2.81(s,2H),2.62–2.37(m,4H),2.13–1.85(m,4H),1.50(s,9H).

Step c: synthesis of tert-butyl-4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate

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1.0g of tert-butyl- (E) -4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was dissolved in a mixed solvent of 10mL of methanol and 10mL of methylene chloride, and 100mg of 10% Pd/C (aqueous 55%) was added to displace hydrogen 3 to 4 times with stirring, and the reaction was allowed to proceed overnight at room temperature. After the reaction, pd/C was filtered off with celite, the filter cake was washed with 30mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product is purified by column chromatography eluting with ethyl acetate: dichloromethane = 1. 230mg of intermediate tert-butyl-4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate are obtained in the form of a white solid with a yield of 23%. ¹ H NMR(400MHz,Acetone-d ₆ )δ7.59(t,J＝8.1Hz,1H),7.52–7.46(m,1H),7.43(d,J＝6.1Hz,1H),7.35–7.25(m,2H),7.20–7.13(m,1H),7.13–7.04(m,1H),4.22(d,J＝13.2Hz,2H),3.57(d,J＝22.9Hz,2H),3.50–3.31(m,1H),2.98–2.83(m,4H),2.78–2.66(m,2H),2.44–2.34(m,1H),2.01–1.91(m,1H),1.89–1.75(m,4H),1.74–1.53(m,4H),1.46(s,9H),1.38–1.23(m,3H).

Step d: synthesis of 2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

Tert-butyl-4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate was replaced with tert-butyl-4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate, and the remaining required starting materials, reagents and preparation were the same as in step d of example 19 to give tert-butyl-4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate200mg of the title intermediate 2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 95% yield. ¹ H NMR(600MHz,CD ₃ OD)δ7.64(d,J＝7.9Hz,1H),7.45–7.40(m,1H),7.34–7.29(m,1H),7.16(td,J＝7.5,1.2Hz,1H),7.09(t,J＝9.7,8.2,1.1Hz,1H),3.64(s,1H),3.43(d,J＝17.4Hz,1H),3.35–3.32(m,1H),2.97–2.86(m,2H),2.81–2.73(m,1H),2.42(t,J＝13.7,11.4,2.9Hz,1H),2.30(dd,J＝27.2,14.7Hz,1H),2.01–1.92(m,2H),1.90–1.71(m,3H),1.65(t,J＝17.3,14.7Hz,1H).

Step f: synthesis of 3- ((4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

The procedure was followed for substituting 2- ((1-benzyl-4-fluoropiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one with 2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one and the remaining required starting materials, reagents and preparation were the same as in example 19, step f, to give 3- ((4- (2- ((4-fluoro-1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile in a white solid yield of 58%. ¹ H NMR(600MHz,CD ₃ OD)δ8.05(s,1H),7.51(d,J＝8.0Hz,1H),7.41(d,J＝8.5Hz,1H),7.35–7.28(m,4H),7.23–7.17(m,2H),7.06(td,J＝7.4,1.2Hz,1H),7.01–6.96(m,1H),3.73(s,2H),3.53(s,2H),3.36–3.28(m,1H),3.04(d,J＝11.3Hz,2H),2.81(dd,J＝17.3,4.7Hz,1H),2.73(s,1H),2.70–2.63(m,2H),2.59–2.52(m,1H),2.35–2.28(m,2H),2.24–2.13(m,3H),1.90–1.83(m,1H),1.78–1.60(m,7H),1.59–1.49(m,1H).HRMS(ESI)m/z calcd for C ₃₇ H ₃₉ N ₄ O[M+H] ⁺ 593.3092,found593.3092.

Example 21- ((4- (2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (2) to (9)

Scheme 4:

step a Synthesis of tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-inden-2-ylidene) methyl) piperidine-1-carboxylate

At-78 ℃ under N ₂ Anhydrous THF (250 mL) was added to the protected two-necked flask, LDA (2M THF solution) (60 mmol) was added thereto, the mixture was stirred for a while, an anhydrous THF solution (100 mL) of 5-bromoindanone (10 g, 50mmol) was added dropwise via a constant pressure funnel, after the addition was completed, the mixture was stirred for 0.5h, an anhydrous THF solution (100 mL) of N-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (10.2 g, 50mmol) was slowly added dropwise via a constant pressure funnel, the mixture was stirred for 1 to 2h, and the mixture was returned to room temperature. Adding NH to the reaction solution ₄ The reaction was quenched with a saturated solution of Cl, THF was evaporated under reduced pressure, the residue was extracted with dichloromethane (200 mL. Times.3), the combined organic phases were washed with a saturated NaCl solution, and then anhydrous Na ₂ SO ₄ The crude product after drying to dryness was purified by column chromatography, ethyl acetate: petroleum ether =1, eluting to give 11.6g of a white solid as tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-inden-2-ylidene) methyl) piperidine-1-carboxylate in 55% yield. ¹ H NMR(400MHz,Acetone-d ₆ )δ7.84(s,1H),7.71–7.62(m,2H),6.62(dt,J＝9.7,2.2Hz,1H),4.12(d,J＝13.5Hz,2H),3.87–3.82(m,2H),2.96–2.93(m,4H),2.73–2.60(m,1H),1.78–1.69(m,2H),1.45(s,9H).

Step m: (E) Synthesis of (E) -5-bromo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-1-one

Tert-butyl- (E) -4- ((5-bromo-1-oxo-1, 3-dihydro-2H-inden-2-ylidene) methyl) piperidine-1-carboxylic acid ester (1g, 2.46mmol) was dissolved in 250mL of dichloromethane, and 80mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour. After the reaction, the reaction solution and part of trifluoroacetic acid were spin-dried, 100mL of dichloromethane was added to the crude product to redissolve it, 50mL of saturated sodium bicarbonate solution was added to wash the organic phase, and a large amount of white solid was precipitated to obtain 675mg of (E) -5-bromo-2- ((4-fluoropiperidin-4-yl) methylene) -2, 3-dihydro-1H-inden-1-one with a yield of 90%. The crude product can be directly used in the next step without purification.

Step b: synthesis of tert-butyl- (E) -4- (1-oxo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

(E) -5-bromo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-1-one (900mg, 2.94mmol) and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 g, 3.53mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), and Pd (dppf) Cl was added ₂ (108mg, 0.147mmol) and K ₂ CO ₃ (1.22g, 8.82mmol), degassed by a water pump for 2 minutes, and reacted at 100 ℃ overnight under nitrogen. Spin-drying the reaction solution, adding 100mL ethyl acetate and 100mL water into the reaction system for extraction, washing the organic phase with saturated saline solution, and removing anhydrous Na ₂ SO ₄ Drying, suction filtration, rotary evaporation to remove the solvent, addition of 20mL ethyl acetate for slurry, filtration to obtain 451mg tert-butyl- (E) -4- (1-oxo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate as a brown solid in 38% yield. ¹ H NMR(400MHz,CD ₃ OD)δ7.78(d,J＝8.1Hz,1H),7.66(s,1H),7.57(d,J＝8.1Hz,1H),6.65(d,J＝9.8Hz,1H),6.35(s,1H),4.14(s,2H),3.80(s,2H),3.69(s,2H),3.63(q,J＝7.0Hz,1H),3.28(d,J＝12.6Hz,2H),2.97–2.88(m,2H),2.62(s,2H),1.89(d,J＝13.6Hz,2H),1.69–1.56(m,2H),1.52(s,9H).

Step c: synthesis of tert-butyl-4- (1-oxo-2- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylic acid ester

1.0g of tert-butyl- (E) -4- (1-oxo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was dissolved in a mixed solvent of 10mL of methanol and 10mL of methylene chloride, 100mg of 10% Pd/C was added, and hydrogen was replaced with stirring 3 to 4 times, and the reaction was carried out overnight at room temperature. After the reaction, pd/C was filtered off with celite, the filter cake was washed with 30mL of a mixed solution of methanol and dichloromethane, and the filtrate was spin-dried. The crude product is purified by column chromatography eluting with ethyl acetate: dichloromethane = 1. 285mg of tert-butyl-4- (2- ((1-phenyl-4-fluoropiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate are obtained as a white solid in 45% yield. ¹ H NMR(400MHz,CD3OD)δ7.63(d,J＝8.0Hz,1H),7.42(s,1H),7.32(d,J＝8.0Hz,1H),4.22(d,2H),3.46–3.34(m,3H),3.01(td,J＝12.9,3.1Hz,2H),2.92–2.73(m,4H),2.12–2.03(m,1H),1.98(s,2H),1.84(d,J＝11.8,3.6Hz,2H),1.63(qd,J＝12.7,4.3Hz,2H),1.48(s,9H),1.46–1.41(m,2H).

Step n: synthesis of tert-butyl-4- (2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate

361mg of tert-butyl-4- (1-oxo-2- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate was dissolved in 10mL of acetonitrile and 5mL of DMF, and 160. Mu.L of 2-fluorobenzyl bromide was added dropwise with stirring, followed by addition of 363mg of solid potassium carbonate and reaction at room temperature for 1 hour. Filtering to remove salts, adding 1N HCl solution to neutralize to neutrality, adding ethyl acetate to extract for three times (30 mL multiplied by 3), combining organic phases, washing once (30 mL) with water, washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering to obtain a filtrate, carrying out column chromatography purification on a crude product after spin-drying, and obtaining 174mg of an intermediate tert-butyl-4- (2- ((1- (2-fluorobenzyl) piperazine, wherein the eluent is methanolPyridin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylic acid ester as a colorless oily liquid in 38% yield. ¹ H NMR(400MHz,Acetone-d ₆ )δ7.58(d,J＝7.9Hz,1H),7.50(s,1H),7.43(s,1H),7.36–7.27(m,2H),7.17(t,J＝7.4Hz,1H),7.09(t,J＝9.3Hz,1H),4.22(d,J＝13.2Hz,2H),3.58(s,2H),3.37(dd,J＝17.0,7.8Hz,1H),3.00–2.67(m,9H),1.82(dq,J＝12.8,4.6Hz,4H),1.71(d,J＝12.5Hz,1H),1.62(qd,J＝12.6,4.3Hz,3H),1.46(s,9H),1.39–1.25(m,3H).

Step d: synthesis of 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

453mg of tert-butyl-4- (2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate were dissolved in 25mL of dichloromethane, and 8mL of trifluoroacetic acid was added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a rotary mode, 10mL of dichloromethane is added into the crude product for redissolution, 5mL of saturated sodium bicarbonate solution is added for washing an organic phase, dichloromethane is used for extracting an aqueous phase for three times (20 mL multiplied by 3), the organic phase is combined and washed by saturated common salt water, anhydrous sodium sulfate is used for drying, a filtrate is obtained by filtration, and 329mg of 2- ((1- (2-fluorobenzyl) piperidine-4-yl) methyl) -5- (piperidine-4-yl) -2, 3-dihydro-1H-indene-1-ketone can be obtained after rotary drying, and the next step can be directly carried out without purification. White solid, yield 90%.

Step f: synthesis of 3- ((4- (2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (100mg, 0.174mmol) were placed in a flask, and anhydrous methanol: anhydrous dichlorohydrin was addedMethane =1 (v: v) was dissolved, and sodium cyanoborohydride (30mg, 0.476 mmol) was added thereto, followed by reaction at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times, the organic phase was washed once with saturated solution, the solvent was dried over anhydrous sodium sulfate and the crude product was purified by column chromatography (methanol: dichloromethane =1: 20) to give 80mg of 3- ((4- (2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile as a white solid in 60% yield. ¹ H NMR(600MHz,CD ₃ OD)δ8.27–8.25(m,1H),7.63–7.60(m,2H),7.58(dd,J＝8.5,0.8Hz,1H),7.49(dd,J＝8.5,1.6Hz,1H),7.46–7.41(m,2H),7.37–7.31(m,2H),7.19(td,J＝7.6,1.2Hz,1H),7.14–7.09(m,1H),3.68(s,2H),3.40–3.34(m,2H),3.31–3.29(m,1H),3.00(t,J＝13.8Hz,2H),2.87–2.80(m,2H),2.79–2.65(m,4H),2.29(td,J＝11.5,2.6Hz,1H),2.24–2.14(m,2H),2.08–1.99(m,2H),1.88–1.79(m,3H),1.74(d,J＝13.2Hz,1H),1.66(qd,J＝12.3,4.0Hz,1H),1.57(s,1H),1.43–1.34(m,3H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₀ N ₄ O[M-H] ⁺ 573.3030,found 573.3031.

Example 22- ((4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (1) to (10)

Synthesis of tert-butyl-4- (1-oxo-2- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate was carried out in the same manner as in example 21.

Step a: synthesis of tert-butyl-4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate

500mg of tert-butyl-4- (1-oxo-2- (piperidine)-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylic acid ester was dissolved in 10mL acetonitrile and 5mL DMF, 220. Mu.L of 3-fluorobenzyl bromide was added dropwise with stirring, 502mg of potassium carbonate solid was added, and the reaction was carried out at room temperature for 1 hour. Filtering to remove salts, adding 1N HCl solution to neutralize to neutrality, adding ethyl acetate to extract for three times (30 mL multiplied by 3), combining organic phases, washing once with water (30 mL), washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering to obtain a filtrate, carrying out column chromatography purification on a crude product after spin-drying, wherein an eluent is methanol: dichloromethane =1 = 60, 254mg of intermediate tert-butyl-4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate is obtained, and the yield is 40%. ¹ H NMR(400MHz,CDCl ₃ )δ7.67(d,J＝7.9Hz,1H),7.35–7.28(m,1H),7.27(d,J＝2.9Hz,1H),7.21(d,J＝7.9Hz,2H),7.15(d,J＝9.8Hz,1H),6.99(td,J＝8.5,2.6Hz,1H),4.27(s,2H),3.67(s,2H),3.31(dd,J＝16.9,7.6Hz,1H),3.03(d,J＝10.8Hz,2H),2.73(m,5H),2.19(s,2H),1.96–1.88(m,1H),1.86–1.74(m,4H),1.54(s,5H),1.49(s,9H),1.43–1.36(m,1H).

Step b: synthesis of 2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

615mg of tert-butyl-4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate are dissolved in 25mL of dichloromethane, and 8mL of trifluoroacetic acid are added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a rotary mode, 10mL of dichloromethane is added into the crude product for redissolving, 5mL of saturated sodium bicarbonate solution is added for washing an organic phase, dichloromethane is used for extracting an aqueous phase for three times (20 mL multiplied by 3), the organic phase is combined and washed by saturated saline, anhydrous sodium sulfate is used for drying, a filtrate is obtained through filtration, 392mg of 2- ((1- (3-fluorobenzyl) piperidine-4-yl) methyl) -5- (piperidine-4-yl) -2, 3-dihydro-1H-indene-1-one is obtained after rotary drying, and the crude product can be put into the next step without purification. White solid, yield 78%. ¹ H NMR(400MHz,CD ₃ OD)δ7.65(d,J＝7.9Hz,1H),7.46(s,1H),7.42–7.31(m,2H),7.24–7.14(m,2H),7.07(td,J＝8.5,2.6Hz,1H),3.76(s,2H),3.51(d,J＝13.4,2.8Hz,2H),3.38(dd,J＝17.2,7.5Hz,1H),3.15(td,J＝13.0,3.1Hz,2H),3.10–2.99(m,3H),2.86–2.72(m,2H),2.33(t,J＝11.9Hz,2H),2.09(d,J＝14.7,4.0Hz,2H),2.03–1.75(m,5H),1.66(s,1H),1.49–1.30(m,3H).

Step c: synthesis of 3- ((4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (100mg, 0.238mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added with sodium cyanoborohydride (30mg, 0.476mmol) and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 73mg of 3- ((4- (2- ((1- (3-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile as a white solid in 55% yield. ¹ H NMR(600MHz,CDCl ₃ )δ8.81(s,1H),8.19(s,1H),7.66(d,J＝8.0Hz,1H),7.43(s,2H),7.33–7.28(m,2H),7.28–7.21(m,2H),7.11–7.03(m,2H),6.93(td,J＝8.5,2.7Hz,1H),3.77(s,2H),3.50(s,2H),3.30(dd,J＝17.1,7.8Hz,1H),3.11(dt,J＝11.7,3.5Hz,2H),2.89(t,J＝11.3Hz,2H),2.76(dd,J＝17.1,3.9Hz,1H),2.73–2.67(m,1H),2.64–2.55(m,1H),2.20–2.12(m,2H),2.04–1.96(m,2H),1.94–1.88(m,1H),1.87–1.81(m,4H),1.73(d,J＝12.6,3.1Hz,1H),1.67(d,J＝12.8,3.1Hz,1H),1.58–1.48(m,1H),1.42–1.30(m,2H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₀ FN ₄ O[M+H] ⁺ 575.3186,found 575.3187.

Example 23- ((4- (2-) ((1- (3-Fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (11)

A, step a: synthesis of tert-butyl-4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate

500mg of tert-butyl-4- (1-oxo-2- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate was dissolved in 10mL of acetonitrile and 5mL of DMF, and 227. Mu.L of 4-fluorobenzyl bromide was added dropwise with stirring, and 502mg of solid potassium carbonate was added to the solution, followed by reaction at room temperature for 1 hour. Filtering to remove salts, adding 1N HCl solution to neutralize to neutrality, adding ethyl acetate to extract for three times (30 mL multiplied by 3), combining organic phases, washing once with water (30 mL), washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering to obtain a filtrate, carrying out column chromatography purification on a crude product after spin-drying, wherein an eluent is methanol: dichloromethane =1 = 60, and 200mg of intermediate tert-butyl-4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate is obtained in a colorless oily liquid with a yield of 32%. ¹ H NMR(400MHz,CDCl ₃ )δ7.67(d,J＝7.9Hz,1H),7.40(s,2H),7.24–7.18(m,2H),7.04(t,J＝8.4Hz,2H),4.27(s,2H),3.69(s,2H),3.31(dd,J＝17.0,7.7Hz,1H),3.04(s,2H),2.88–2.62(m,5H),2.35–2.05(m,2H),1.94–1.73(m,6H),1.70–1.60(m,5H),1.49(s,9H).

Step d: synthesis of 2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

619mg of tert-butyl-4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate were dissolved in 25mL of dichloromethane, and 8mL of trifluoroacetic acid was added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a spinning mode, 10mL of dichloromethane is added into the crude product for redissolving, 5mL of saturated sodium bicarbonate solution is added for washing an organic phase, dichloromethane is used for extracting an aqueous phase for three times (20 mL multiplied by 3), the organic phase is combined and washed by saturated sodium chloride, anhydrous sodium sulfate is used for drying, a filtrate is obtained through filtration, and 400mg of 2- ((1- (4-fluorobenzyl) piperidine-4-yl) methyl) -5- (piperidine-4-yl) -2, 3-dihydro-1H-indene-1-ketone can be obtained after drying in a spinning mode, and the crude product can be put into the next step without purification. White solid, yield 80%.

Step f: synthesis of 3- ((4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

5-cyano-indole-3-carbaldehyde (49mg, 0.285mmol) and 2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (100mg, 0.238mmol) were placed in a flask, and anhydrous methanol: anhydrous dichloromethane =1 (v: v) was added to dissolve, and sodium cyanoborohydride (30mg, 0.6 mmol) was added thereto, and reacted overnight at 30 ℃. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 80mg of 3- ((4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile as a white solid in 67% yield. ¹ H NMR(400MHz,CD ₃ OD)δ8.17(s,1H),7.61(d,1H),7.53(d,J＝8.4Hz,1H),7.46(s,1H),7.42(d,J＝8.7,1.7Hz,2H),7.39–7.33(m,2H),7.30(d,J＝8.0Hz,1H),7.07(td,J＝8.7,1.4Hz,2H),3.85(d,J＝3.1Hz,2H),3.53(s,2H),3.39–3.34(m,1H),3.16(d,J＝11.2Hz,2H),2.92(t,J＝11.5Hz,2H),2.78(dd,J＝17.3,2.2Hz,1H),2.66(s,1H),2.33–2.20(m,2H),2.06(t,J＝12.0Hz,2H),1.93–1.76(m,6H),1.72(d,J＝13.3Hz,1H),1.56(s,1H),1.42–1.22(m,4H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₀ FN ₄ O[M+H] ⁺ 575.3186,found 575.3185.

Example 24- ((1-Benzylpiperidin-4-yl) methyl) -5- (1- ((5-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of (12)

Step a: synthesis of tert-butyl-4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate

540mg of tert-butyl-4- (1-oxo-2- (piperidin-4-ylmethyl) -2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate was dissolved in 10mL of acetonitrile and 5mL of DMF, and 171. Mu.L of benzyl bromide was added dropwise with stirring, and 542mg of solid potassium carbonate was added thereto to react at room temperature for 1 hour. Filtering to remove salts, adding 1N HCl solution to neutralize to neutrality, adding ethyl acetate to extract for three times (30 mL multiplied by 3), combining organic phases, washing once (30 mL), washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering to obtain filtrate, and performing rotary drying to obtain a crude product which does not need purification and can be directly put into the next step to obtain 658mg of an intermediate, namely tert-butyl-4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate which is colorless oily liquid and has the yield of 32%. ¹ H NMR(400MHz,CDCl ₃ )δ7.68(d,J＝7.9Hz,1H),7.41–7.27(m,5H),7.21(d,J＝8.0Hz,1H),4.27(s,1H),3.57(s,1H),3.30(dd,J＝16.9,7.6Hz,1H),2.94(s,1H),2.85–2.66(m,2H),2.05(s,1H),1.96–1.87(m,1H),1.83(d,J＝12.6Hz,2H),1.78–1.57(m,2H),1.49(s,4H),1.43–1.30(m,1H).

Step d: synthesis of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

392mg of tert-butyl-4- (2- ((1-benzylpiperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidine-1-carboxylate are dissolved in 25mL of dichloromethane and 8mL of trifluoroacetic acid are added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a rotary mode, 10mL of dichloromethane is added into the crude product for redissolving, 5mL of saturated sodium bicarbonate solution is added for washing an organic phase, dichloromethane is used for extracting an aqueous phase for three times (20 mL multiplied by 3), the organic phase is combined and washed by saturated sodium chloride, anhydrous sodium sulfate is used for drying, a filtrate is obtained by filtration, and 204mg of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-indene-1-one can be directly put into the next step without purification after the rotary drying. White solid, yield 65%. ¹ H NMR(400MHz,CD ₃ OD)δ7.64(d,J＝7.9Hz,1H),7.45(s,1H),7.42–7.29(m,J＝15.2,6.8Hz,6H),3.73(s,2H),3.57–3.45(m,2H),3.42–3.26(m,3H),3.23–2.96(m,5H),2.79(d,J＝17.2Hz,2H),2.31(t,J＝11.6Hz,2H),2.07(d,J＝13.9Hz,2H),2.01–1.73(m,5H),1.65(s,1H),1.43–1.31(m,3H).

Step f: synthesis of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (1- ((5-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one

5-fluoro-indole-3-carbaldehyde (99mg, 0.608mmol) and 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (204mg, 0.507mmol) were placed in a flask, and dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), followed by addition of sodium cyanoborohydride (64mg, 1.01mmol) and reaction at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 89mg of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (1- ((5-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 33% yield. ¹ H NMR(600MHz,CD ₃ OD)δ7.59(d,J＝8.0Hz,1H),7.39(s,1H),7.37(s,1H),7.36–7.30(m,6H),7.30–7.25(m,2H),6.90(td,J＝9.1,2.5Hz,1H),3.92(s,2H),3.58(s,2H),3.34(d,J＝7.9Hz,1H),3.24(d,J＝11.6Hz,2H),2.99–2.92(m,2H),2.79–2.67(m,3H),2.43(t,J＝11.9Hz,2H),2.11(t,J＝12.2,3.4Hz,2H),1.93–1.77(m,7H),1.71(d,J＝13.3,3.1Hz,1H),1.62–1.53(m,2H),1.35(d,J＝4.9Hz,1H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₁ FN ₃ O[M+H] ⁺ 550.3234,found 550.3231.

Example 25- ((1-Benzylpiperidin-4-yl) methyl) -5- (1- ((4-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of (E) -13)

The procedure for the synthesis of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one is as in example 24.

Step f: 4-fluoro-indole-3-carbaldehyde (92mg, 0.5631 mmol) and 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (189mg, 0.469mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added with sodium cyanoborohydride (59mg, 0.940mmol), and reacted at 30 ℃ overnight. After quenching the reaction with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with a saturated solution, dried over anhydrous sodium sulfate and the solvent was dried by spinning, and the crude product was purified by column chromatography (methanol: dichloromethane =1 20) to give 97mg of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (1- ((4-fluoro-1H-indol-3-yl)Yl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 38% yield. ¹ H NMR(400MHz,CD ₃ OD)δ7.58(d,J＝8.0Hz,1H),7.38(s,1H),7.34–7.30(m,4H),7.29–7.22(m,3H),7.17(d,J＝8.1Hz,1H),7.03(td,J＝8.0,5.0Hz,1H),6.69(dd,J＝11.6,7.7Hz,1H),3.93(s,2H),3.52(s,2H),3.24–3.14(m,2H),2.91(t,J＝11.4Hz,2H),2.80–2.68(m,2H),2.67–2.56(m,1H),2.37–2.25(m,2H),2.08–1.99(m,2H),1.89–1.75(m,6H),1.69(dt,J＝13.0,3.1Hz,1H),1.59–1.47(m,1H),1.39–1.29(m,4H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₁ FN ₃ O[M+H] ⁺ 550.3234,found 550.3231.

Example 26- ((1-Benzylpiperidin-4-yl) methyl) -5- (1- ((6-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of (1) to (14)

Step f: 6-fluoro-indole-3-carbaldehyde (85mg, 0.519mmol) and 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (174mg, 0.432mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added with sodium cyanoborohydride (54mg, 0.864mmol), and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 84mg of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (1- ((6-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 36% yield. ¹ H NMR(600MHz,CD ₃ OD)δ7.63(dd,J＝8.7,5.2Hz,1H),7.59(d,J＝8.0Hz,1H),7.38(s,1H),7.35–7.31(m,4H),7.30–7.21(m,3H),7.08(dd,J＝9.8,2.3Hz,1H),6.85(ddd,J＝9.7,8.7,2.3Hz,1H),3.92(s,2H),3.58(s,2H),3.23(d,J＝11.6Hz,2H),3.01–2.91(m,2H),2.79–2.72(m,1H),2.71–2.63(m,1H),2.45–2.38(m,2H),2.11(tt,J＝12.0,2.9Hz,2H),1.92–1.76(m,6H),1.70(dt,J＝13.2,3.1Hz,1H),1.60–1.51(m,1H),1.37–1.28(m,5H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₁ FN ₃ O[M+H] ⁺ 550.3234,found 550.3233.

Example 27- ((1-Benzylpiperidin-4-yl) methyl) -5- (1- ((5- (trifluoromethyl) -1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of (15)

Step f: 5-trifluoromethyl-indole-3-carbaldehyde (107mg, 0.501mmol) and 2- ((1-benzylpiperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (168mg, 0.417 mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added sodium cyanoborohydride (52mg, 0.835mmol) and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 90mg of 2- ((1-benzylpiperidin-4-yl) methyl) -5- (1- ((5- (trifluoromethyl) -1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 37% yield. ¹ H NMR(600MHz,CD ₃ OD)δ8.03(s,1H),7.59(d,J＝8.0Hz,1H),7.51(d,J＝8.5Hz,1H),7.42(s,1H),7.40–7.36(m,2H),7.34–7.30(m,4H),7.29–7.24(m,2H),3.86(s,2H),3.55(s,2H),3.17(d,J＝12.2Hz,2H),2.93(dd,J＝15.1,11.4Hz,2H),2.80–2.62(m,3H),2.28(td,J＝11.7,3.1Hz,2H),2.07(tt,J＝12.2,3.2Hz,2H),1.90–1.77(m,6H),1.70(dt,J＝13.3,3.1Hz,1H),1.61–1.50(m,1H),1.37–1.29(m,4H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₁ F ₃ N ₃ O[M+H] ⁺ 600.3202,found 600.3203.

Example 28- (1- ((5-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of-16)

The procedure for the synthesis of 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one is as in example 21.

Step f: 5-fluoro-indole-3-carbaldehyde (62mg, 0.382mmol) and 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (134mg, 0.319mmol) were placed in a flask, dissolved with anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then sodium cyanoborohydride (40mg, 0.637mmol) was added and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1: 20) to give 70mg of 5- (1- ((5-fluoro-1H-indol-3-yl) methyl) piperidin-4-yl) -2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -2, 3-dihydro-1H-inden-1-one as a white solid in 40% yield. ¹ H NMR(600MHz,CD ₃ OD)δ7.59(d,J＝8.0Hz,1H),7.43–7.37(m,2H),7.36–7.24(m,5H),7.15(td,J＝7.5,1.2Hz,1H),7.07(ddd,J＝9.6,8.3,1.2Hz,1H),6.88(td,J＝9.1,2.5Hz,1H),3.83(s,2H),3.61(s,2H),3.21–3.15(m,2H),3.00–2.90(m,2H),2.78–2.62(m,3H),2.36–2.29(m,2H),2.10(tt,J＝11.9,3.4Hz,2H),1.90–1.76(m,6H),1.69(dt,J＝13.1,3.1Hz,1H),1.52(s,1H),1.37–1.28(m,4H).HRMS(ESI)m/z calcd for C ₃₆ H ₄₀ F ₂ N ₃ O[M+H] ⁺ 568.3139,found 568.3138.

Example 29- ((1- (2-Fluorobenzyl) piperidin-4-yl) methyl) -5- (1- ((5- (trifluoromethyl) -1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (I) _b Preparation of (E) -17)

Step f: 5-trifluoromethyl-indole-3-carbaldehyde (91mg, 0.428mmol) and 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one (150mg, 0.357mmol) were placed in a flask, dissolved by adding anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then added with sodium cyanoborohydride (45mg, 0.713mmol) and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1: 20) to give 74mg of 2- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -5- (1- ((5- (trifluoromethyl) -1H-indol-3-yl) methyl) piperidin-4-yl) -2, 3-dihydro-1H-inden-1-one as a white solid in 34% yield. ¹ H NMR(600MHz,CD ₃ OD)δ8.06(s,1H),7.61(d,J＝8.0Hz,1H),7.54(d,J＝8.5Hz,1H),7.47–7.39(m,4H),7.36–7.28(m,2H),7.17(td,J＝7.5,1.2Hz,1H),7.10(ddd,J＝9.7,8.3,1.2Hz,1H),3.92(s,2H),3.64(s,2H),3.25–3.19(m,2H),2.96(dt,J＝12.7,8.4Hz,2H),2.81–2.66(m,3H),2.40–2.31(m,2H),2.13(tt,J＝11.9,3.3Hz,2H),1.92–1.78(m,6H),1.73(d,J＝3.2Hz,1H),1.58–1.50(m,1H),1.39–1.31(m,4H).HRMS(ESI)m/z calcd for C ₃₇ H ₄₀ F ₄ N ₃ O[M+H] ⁺ 618.3108,found 618.3107.

Example 30 (E) -3- ((4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (18)

Synthesis of tert-butyl- (E) -4- (1-oxo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was carried out as in example 24.

A, step a: synthesis of tert-butyl- (E) -4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate

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1.3g of tert-butyl- (E) -4- (1-oxo-2- (piperidin-4-ylmethylene) -2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate were dissolved in 20mL of acetonitrile and 5mL of DMF, and 516. Mu.L of 4-fluorobenzyl bromide was added dropwise with stirring, followed by addition of 1.3g of potassium carbonate and stirring at room temperature for 1 hour. After the reaction, acetonitrile was spin-dried, the remaining reaction solution was extracted with 50mL of ethyl acetate and 50mL of water, the organic phase was separated and washed with water three times (50 mL. Times.3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried. The crude product was purified by column chromatography eluting with methanol: dichloromethane = 1. 750mg of white solid are obtained, yield 47%. ¹ H NMR(400MHz,CDCl ₃ )δ7.84(d,J＝8.0Hz,1H),7.50–7.40(m,2H),7.35–7.29(m,1H),7.20–7.07(m,2H),6.98(t,J＝8.0Hz,1H),6.76(d,J＝9.6Hz,1H),6.21(s,1H),4.14(s,2H),3.74–3.65(m,4H),3.56(s,2H),2.95(s,2H),2.58(s,2H),2.39(s,1H),2.24–2.02(m,2H),1.73(s,2H),1.52(s,9H).

Step b: (E) Synthesis of (E) -2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-inden-1-one

439mg of tert-butyl- (E) -4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate were dissolved in 25mL of dichloromethane, and 8mL of trifluoroacetic acid was added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a spinning mode, 10mL of dichloromethane is added into the crude product for redissolving, 5mL of saturated sodium bicarbonate solution is added for washing an organic phase, dichloromethane is used for extracting an aqueous phase for three times (20 mL multiplied by 3), the organic phase is combined and washed by saturated sodium chloride, anhydrous sodium sulfate is used for drying, a filtrate is obtained through filtration, 246mg of (E) -2- ((1- (4-fluorobenzyl) piperidine-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-indene-1-one is obtained after drying in a spinning mode, and the crude product can be put into the next step without purification. White solid, yield 70%.

Step c: synthesis of 3- ((4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile

5-cyanoindole-3-carbaldehyde (99mg, 0.608mmol) and (E) -2- ((1- (4-fluorobenzyl) piperidin-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-inden-1-one (204mg, 0.507mmol) were placed in a flask, and dissolved with anhydrous methanol: anhydrous dichloromethane =1 (v: v), followed by addition of sodium cyanoborohydride (64mg, 1.01mmol), and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 89mg of 3- ((4- (2- ((1- (4-fluorobenzyl) piperidin-4-yl) methyl) -1-oxo-2, 3-dihydro-1H-inden-5-yl) piperidin-1-yl) methyl) -1H-indole-5-carbonitrile as a white solid in 33% yield. ¹ HNMR(400MHz,CD ₃ OD)δ8.20(s,1H),7.73(d,J＝8.2Hz,1H),7.63(s,1H),7.54(d,J＝8.8Hz,2H),7.49(s,1H),7.43(d,J＝8.6,1.5Hz,1H),7.38(dd,J＝8.3,5.4Hz,2H),7.08(t,J＝8.6Hz,2H),6.66(d,J＝9.6Hz,1H),6.37(s,1H),3.94(s,2H),3.74(s,2H),3.57(s,2H),3.36(s,2H),2.96(d,J＝11.6Hz,2H),2.87(t,J＝5.8Hz,2H),2.67(s,2H),2.56–2.42(m,1H),2.18(t,J＝11.5Hz,2H),1.78(d,J＝13.1Hz,2H),1.69–1.55(m,2H).HRMS(ESI)m/z calcd for C ₃₇ H ₃₆ FN ₄ O[M+H] ⁺ 571.2873,found 571.2874.

Example 31 (E) -3- ((4- (2- ((1-benzyl-4-fluoro)Piperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile (I) _b Preparation of (E) -19)

The procedure for the synthesis of tert-butyl- (E) -4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate was as in example 19.

Step d: (E) Synthesis of (E) -2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-inden-1-one

530mg of tert-butyl- (E) -4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate are dissolved in 10mL of dichloromethane, and 3mL of trifluoroacetic acid are added dropwise with stirring and stirred at room temperature for 1 hour. After the reaction is finished, the reaction solution and part of trifluoroacetic acid are dried in a rotary mode, 10mL of dichloromethane is added into the crude product for redissolving, 20mL of saturated sodium bicarbonate solution is added for washing an organic phase, the organic phase is separated, an aqueous phase is extracted for 3-4 times (20 mL) by dichloromethane, the organic phase is combined, the crude product is washed by saturated brine, anhydrous sodium sulfate is dried, and after filtration, the filtrate is dried in a rotary mode and can be directly used for the next step without purification, 440mg of target intermediate (E) -2- ((1-benzyl-4-fluoropiperidine-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridine-4-yl) -2, 3-dihydro-1H-indene-1-one is obtained, wherein the white solid is obtained, and the yield is 98%.

Step f: (E) Synthesis of (E) -3- ((4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-indol-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile

5-cyano-indole-3-carbaldehyde (64mg, 0.374mmol) and (E) -2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -5- (1, 2,3, 6-tetrahydropyridin-4-yl) -2, 3-dihydro-1H-inden-1-one (130mg, 0.312mmol) were placed in a flask, dissolved with anhydrous methanol: anhydrous dichloromethane =1 (v: v), and then sodium cyanoborohydride (39mg, 0.624mmol) was added and reacted at 30 ℃ overnight. The reaction was quenched with water, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, washed three times with water, the organic phase was washed once with saturated solution, dried over anhydrous sodium sulfate and the solvent was dried, and the crude product was purified by column chromatography (methanol: dichloromethane =1 = 20) to give 78mg of (E) -3- ((4- (2- ((1-benzyl-4-fluoropiperidin-4-yl) methylene) -1-oxo-2, 3-dihydro-1H-indol-5-yl) -3, 6-dihydropyridin-1 (2H) -yl) methyl) -1H-indole-5-carbonitrile as a white solid in 44% yield. ¹ H NMR(400MHz,CD ₃ OD)δ8.21(s,1H),7.76(d,J＝8.1Hz,1H),7.65(d,J＝4.8Hz,1H),7.58–7.53(m,2H),7.52(s,1H),7.44(dd,J＝8.5,1.5Hz,1H),7.39–7.33(m,5H),6.72(d,J＝25.7Hz,1H),6.39(s,1H),4.01(s,2H),3.93(s,2H),3.62(s,2H),2.94(s,2H),2.82(d,J＝11.6Hz,3H),2.70(s,2H),2.47(s,2H),2.15–1.94(m,5H).HRMS(ESI)m/z calcd for C ₃₇ H ₃₆ FN ₄ O[M+H] ⁺ 571.2873,found 571.2874.

Effect example 1

The effect example shows the inhibition experiment and the activity result of the compound of the present invention on acetylcholinesterase (AChE). The compound with acetylcholinesterase inhibiting activity can inhibit the hydrolysis of acetylcholine in brain, so as to increase the concentration of acetylcholine in brain, promote memory and cognition, and can be used for symptom improvement and treatment of AD. This section measures acetylcholinesterase activity using the modified Ellman method. Taking the cerebral cortex of an SD mouse as an AChE enzyme source, adding thioacetyl choline into a reaction template under the condition of optimal enzyme reaction, adding an object to be detected, and detecting the activity of the AChE enzyme by a colorimetric method. In the experiment, the cerebral cortex of SD rat is used as the source of acetylcholinesterase, and the sampling method comprises the steps of dying the rat, quickly taking out the brain, separating the cortex on ice, preparing brain homogenate by using 75mM phosphate buffer solution (pH 7.4), and storing the brain homogenate in a centrifuge tube at-20 ℃ for later use. Before the experiment, the enzyme is activatedThe source is in the optimum enzyme activity state, the solution is diluted by precooled PBS until the absorbance is 0.3-0.35, and then 10 percent volume fraction of butyrylcholinesterase inhibitor OMPA of the solution is added. The experimental procedure was as follows: (1) A96-well plate was taken and added to each well 10. Mu.L of the cortex homogenate, 50. Mu.L of phosphate buffer (0.1M), 50. Mu.L of the color reagent 5,5' -dithiobis (2-nitrobenzoic acid) (DTNB) at a concentration of 0.2%, 109. Mu.L of deionized water, 30. Mu.L of the choline substrate thioacetyl choline (S-Ach) at a concentration of 2mM, and 1. Mu.L of the compound to be tested (concentration gradient of 1nM to 10 mM). (2) After 20 minutes at room temperature, the reaction was terminated by adding 50. Mu.L of 3% SDS. At this time, the thioacetyl choline is decomposed into Thiocholine (Thiocholine) under the action of AChE in the cortex, and then the Thiocholine rapidly reacts with a color-developing agent DTNB to generate a yellow substance 5-mercapto-2-nitrobenzoate with the maximum absorption wavelength of 412 nm. (3) The inhibition rate of the compound on AChE was calculated by comparing the degree of decrease in absorbance per well after addition of the test substance, using a multifunctional microplate reader (DTX 880, beckman Coulter) to read the absorbance at a wavelength of 450nm, taking the reading of the wells without the inhibitor as 100%. Performing nonlinear fitting on the calculated inhibition rate and corresponding concentration, and calculating half Inhibition Concentration (IC) of the compound by using Graphpad software ₅₀ Value). The enzyme activity without inhibitor is taken as 100 percent in the experiment, the AChE inhibitor donepezil in the anti-Alzheimer Disease (AD) medicaments in the markets is taken as a positive control, and the activity result is taken as the median Inhibitory Concentration (IC) ₅₀ Values), the activity results are shown in table 1.

Table 1: data on inhibitory Activity of the Compounds of the invention on Acetylcholinesterase

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As can be seen from Table 1, the compounds of the present invention have potent acetylcholinesterase inhibitory activity, wherein the inhibitory activity of some preferred compounds is even better than that of donepezil which is a marketed anti-AD drug, indicating that the compounds of the present invention have the potential to treat AD.

Effect example 2

The effect example shows the inhibition test and the activity result of the compound of the present invention on the activity of serotonin transporter (SERT). The compound with the activity can increase the concentration of serotonin in the brain by inhibiting the reuptake of the serotonin in the brain, and can be used for treating depression or improving AD. Human embryonic kidney cell HEK293 was used to express human 5-HT Transporter in this experiment and tested using the commercially available Kit Neurotransmitting Transporter Uptake Assay Kit (Molecular Devices, cat. R8173). The kit uses a fluorescent substrate to simulate monoamine neurotransmitters such as 5-HT and the like, and enters cells through a specific transporter such as a serotonin transporter, so that the fluorescence intensity of the cells is increased. The specific experimental method is as follows: (1) cell plating: thawing the cells and culturing for 3-4 days. After passage, the cells were cultured in a cell culture incubator for 3 more days. After digesting the cells with trypsin-EDTA, the cells were collected by centrifugation at 1000rpm for five minutes. Resuspend cells in 10mL of medium. The cells are blown to prevent adhesion. And (4) counting the cells. Cells were diluted with medium to 1 million/mL, 20,000 cells per well, 37 ℃/5% CO ₂ Incubating for 16-20 hours under the condition. (2) transport experiments: HBSS solution of 20mM HEPES was prepared, containing 0.1% BSA as a diluent and working solution. Positive compounds were diluted in a 4-fold gradient of 10 concentrations, with a maximum concentration of 2. Mu.M. Test compounds were diluted 10 concentrations with a 3-fold gradient. The medium in the wells was discarded and 25. Mu.L of compound solution was added. The compounds were centrifuged at 300rpm for 15s, followed by incubation at 37 ℃ for 30min, followed by addition of 25. Mu.L of the dye solution per well, incubation at 37 ℃ for 30min, reading with Flexstation, and assayed at Ex/Em =440nm/520nm to calculate the inhibitory activity of the compounds on 5-HT reuptake. The experiment used vilazodone and Citalopram hydrobromide (Citalopram hydrobromide) as positive controls. IC for Activity results ₅₀ The results are shown in Table 2, in the form of. + -. SD (nM).

Table 2: inhibitory Activity data of Compounds of the present invention on serotonin transporters

As can be seen from Table 2, most of the compounds of the present invention have potent serotonin transporter inhibiting activity, wherein the inhibiting activity of some preferred compounds is lower than 10nM (better than that of citalopram hydrobromide positive control), which indicates that the compounds of the present invention can be developed into serotonin transporter inhibitor antidepressant drugs or anti-AD drugs. The compound of the invention has the inhibitory activity of both acetylcholinesterase and serotonin transporters, so the compound is a multi-target drug which is expected to treat AD-depression co-morbidity.

Effect example 3

This Effect example shows that the compounds of the present invention are directed to 5-HT _1A Agonist activity test and activity results of the receptor. Generation of human 5-HT using HEK293 cell overexpression _1A A receptor. The medium is DMEM medium containing 50mg/mL of G418 and 10% FBS, 5% CO ₂ Culture at 37 ℃. When the cells grew to 70%, the cells were digested, centrifuged, resuspended in buffer, and incubated in 384-well plates for 16-20 hours. The medium in the wells was discarded, a dilution of the test compound and the positive drug was added, incubation was carried out at room temperature for 60 minutes, 5. Mu.L of 4 × Eu-cAMP trap solution and 5. Mu.L of 4 × ULight-anti-cAMP solution were added, and then incubation at room temperature for 60 minutes was continued, followed by detection under Ex/Em =615nm/665nm conditions. The compound pair 5-HT was calculated using the blank as the minimum signal and the positive 8-OH-DAPT as the maximum signal _1A Receptor agonistic EC ₅₀ . Activity results are given in EC ₅₀ Expressed in + -SD (nM), the results are shown in Table 3.

Table 3: compound of the present invention para 5-HT _1A Agonistic activity data of

Wherein, the comparative compound A is from research on design, synthesis and activity of multi-target anti-AD active compounds and research on synthesis methodology of 3-aryl-3-hydroxyindolone, li Xiaokang, university of east China, 2018.

As can be seen from Table 3, most of the compounds of the present invention are directed to 5-HT _1A EC of receptor ₅₀ At more than a few hundred nanomolar, more than a hundred-fold difference from the positive control, and also much different from the AChE/SERT activity of the compound itself, indicating that the compound of the invention substantially removes 5-HT _1A Avoiding 5-HT _1A Memory impairment that may be triggered following receptor agonism.

Effect example 4 this effect example shows the inhibition experiment and the activity result of the compound of the present invention on the acetylcholinesterase activity in the mouse brain. The compound with acetylcholinesterase inhibiting activity can inhibit the hydrolysis of acetylcholine in brain, so as to increase the concentration of acetylcholine in brain, promote memory and cognition, and can be used for symptom improvement and treatment of AD.

The mouse intracerebral AChE inhibition experiment is a quick and efficient experiment, is used for evaluating the inhibition activity of a tested compound on the activity of the AChE in the brain of an animal, and can reflect the brain penetrating capability of the compound.

The experimental animals used ICR mice, male, with a body weight of about 17-21g. Weighing a certain amount of compound, dissolving the compound in PEG400, performing vortex oscillation to dissolve the compound, adding HS-15, and uniformly mixing to prepare a transparent and clear solution. The medicine is orally taken according to the dosage of 0.3 mg/kg-30 mg/kg, and the corresponding solvent control is taken by the solvent control group. After administration, the appearance and state of the mice are observed, and whether the mice have peripheral cholinergic side effects such as salivation, sweating, convulsion and the like is judged. After administration, the mice were decapitated at the sampling point (0.5-24 hours), brains were rapidly removed, the brains were diluted with precooled phosphate buffer to a homogenate, butyrylcholinesterase inhibitor OMPA was added, and thioacetyl choline (S-Ach), 5' -dithiobis (2-nitrobenzoic acid) and the like were added) (DTBN), reaction at room temperature for 20 minutes. No brain homogenate was added to the blank wells. After the experiment is finished, SDS is added into each hole to stop the reaction, and a proper amount of enzyme is added into the blank hole. The inhibition of AChE by the compound was calculated by measuring the absorbance value of each well using a multifunctional microplate reader (DTX 880, beckman Coulter) to read the absorbance at a wavelength of 450nm with the reading of the blank well as 100%. Performing nonlinear fitting on the calculated inhibition rate and the corresponding concentration, and calculating the IC of the compound on AChE in the mouse brain ₅₀ The value is obtained.

The experiment selects the compound I with stronger AChE and serotonin transporter double-target inhibition activity _b 7-the results are shown in tables 4-5 and FIG. 1.

Table 4: compound I _b Effect of-7 on Acetylcholinesterase Activity in ICR mice brain

The values in Table 4 are the acetylcholinesterase activity in the mouse brain 1 hour and 6 hours after administration. Solvent control (control) was 20% peg400 solution without compound, set as 100%, the remaining groups were in percentage values (Mean ± SD) compared to solvent control, P <0.05 (compared to solvent control), P <0.01 (compared to solvent control).

Table 5:1mg/kg of preferred Compound I _b -7 Effect on Acetylcholinesterase Activity in ICR mice brain

The values in Table 5 are the acetylcholinesterase activity in the mouse brain 0.5-24 hours after administration. The solvent control group was deionized water and set at 100%, and the other groups were calculated by percentage (Mean ± SD) compared to the solvent control group<0.05 (compared to solvent control group). About.. P<0.01 (compared to the solvent control). The values of AChE activity higher than 100% in the data in Table 4 are due to the fact that one mouse in the control group has low hippocampal AChE activity, which is an individual differenceThus after calibration I _b The hippocampal AChE activity of the-7 administration group has a value higher than 100%, but does not influence the experimental conclusion.

As can be seen from Table 4 and FIG. 1, compound I _b 7 the activity of AChE at the cerebral cortex and the hippocampus of the mice can be obviously inhibited under the condition of oral administration of 5mg/kg, and the inhibition activity has dose dependence and time dependence. Oral 5mg/kg dose of I _b 7 after 6 hours of intervention, the inhibition effect is obviously improved compared with the inhibition activity after 1 hour, and the inhibition activity is equivalent to the inhibition activity after 1 hour under the oral administration of 30mg/kg dose, and the AChE activity at the hippocampus and the cortex in the brain of the mouse is inhibited to 23.0 percent and 27.8 percent respectively.

As can be seen from Table 5, I _b 7 the AChE activity at the mouse brain endothelial layer was reduced to 49.49% at the oral dose of 1mg/kg without peripheral cholinergic side effects.

The above results demonstrate that Compound I _b 7 has stronger inhibition activity on AChE in the brain of a mouse after oral administration, and has better treatment potential on the Alzheimer disease.

The experiment selects another compound I with stronger AChE and serotonin transporter double-target inhibition activity _b -4, the results are shown in Table 6.

Table 6: compound I _b -4 Effect on Acetylcholinesterase Activity in ICR mice brain

The values in Table 6 are the acetylcholinesterase activity in the mouse brain 24 hours after administration. The solvent control group (control group) was a 20% peg400 solution without compound, set at 100%, and the remaining groups were percent values (Mean ± SD) compared to the solvent control group, # P <0.05 (compared to the solvent control group), # P <0.01 (compared to the solvent control group), and # P <0.005 (compared to the solvent control group).

As can be seen from Table 6, compound I _b -4 can obviously inhibit the activity of AChE at the cerebral cortex and the hippocampus of the mice under the dosage of oral administration of 1mg/kgAnd the inhibitory activity is dose-dependent. Oral 10mg/kg dose of I _b -4 after 24 hours of intervention, it inhibited AChE activity in mouse brain at hippocampus and cortex to 36.87% and 34.00%, respectively.

The above results demonstrate that Compound I _b -4 has stronger inhibitory activity to AChE in mouse brain after oral administration, and has better potential for treating Alzheimer disease.

Effect example 5

Effects of the compounds of the invention on behavioral experiments in mice in the tailed depression model and forced swimming model.

The tail suspension experiment is a classic, rapid and convenient antidepressant effect evaluation experiment, and belongs to a behavior despair model. The experimental principle is that the mouse is subjected to short-term and non-evasive acute stress in a tail suspension mode, so that the mouse enters a static state of giving up resistance, and a mouse depression model is established. Forced swimming is also a classic behavior despair model, and the mouse tries to escape but cannot escape, so that struggle is abandoned, a special depression immobility state is entered, and the animal immobility time is recorded in the experimental process to reflect the depression state. The antidepressant drug has the effects of reversing the static state and promoting the escape of the mouse and other related behaviors, so the immobility time of the mouse can be reduced, and the antidepressant effect of the drug can be effectively evaluated by measuring the immobility time of the mouse. In this example, compound I with strong AChE and serotonin transporter double-target inhibitory activity was selected _b -7 and I _b -4 carrying out the experiment. The antidepressant effect of the compound is evaluated by adopting a tail suspension experiment method reported by Steru et al or a forced swimming method in the experiment and by investigating whether the immobility time of a tail suspension mouse can be obviously shortened by giving a tested compound.

The experimental animal is C57 mouse with average weight of 20-25g and age of 5-6 weeks, and is purchased from Shanghai Jiesi Experimental animals Co. Feeding with free water feeding diet, and pre-adapting to environment for one week. Before the experiment, the mouse tails are numbered and grouped, 10 mice are in one group, and the weight is weighed. The experiment is divided into a solvent control group, a positive drug vilazodone group and a tested compound group. The test solution is prepared on the same day as the experiment, the tested compound is dissolved in PEG400, and then 20% HS-15 normal saline solution is added to prepare a clear and uniform solution. The final liquid medicine composition is 25% PEG400+15% of HS +60% line. The solvent control group was administered with 0.9% physiological saline, and the positive drug and test compound groups were administered orally as a liquid medicine prepared by the above method. Two mice were dosed at intervals of 8 minutes according to the mouse numbering sequence, and after completion, they were returned to the original cage position, and after 1 hour, the tail suspension experiment was performed. When hanging the tail, fixing the tail 2cm away from the top of the tail of the mouse to the top of the tail hanging box by using a medical adhesive tape, wherein the distance between the mouse and the nearest object is required to be more than or equal to 15cm. And recording the experiment for 6 minutes, taking down the mouse after the experiment is finished, returning the mouse to the original cage position, and wiping the tail suspension box with alcohol to remove the odor of the animal. In the forced swimming experiment, the experimental animal is placed in a glass cylinder filled with water, the water temperature is controlled to be about 25 ℃ (the temperature is not more than 1 ℃ from top to bottom), the liquid level is adjusted according to the size of the experimental animal and is generally about 18cm, the experiment video is recorded for 6 minutes, the next group of animals is started after one group of animals is completed every time, and the influence of the smell of the mice on the experiment is avoided. The experiment adopts a double-blind system, namely, an operator who administers the medicine and performs the tail suspension experiment and a statistic person who does not move the time need to be different persons and do not know each other. The statistical personnel counts the immobility time of the mouse within 4 minutes after the recording for 6 minutes, and the movement behavior (behavior of subjective obvious escape) of the mouse can be mainly divided into (1) forward or backward movement; (2) twisting the body to try to catch the hanging part; and (3) shaking, swinging and twitching the body. The mean immobility time statistics for each group of mice after completion of the recording are plotted.

The experiment selects the compound I with stronger AChE and serotonin transporter double-target inhibition activity _b 7 performing antidepressant effect experiment. In a set of tail suspension experiments, a solvent control group (normal saline, 10 mL/kg), a vilazodone multi-administration group (15 mg/kg, once a day, continuous administration for 5 days), a vilazodone single-administration group (30 mg/kg, once administration), I and II are set in the experiments _b Mice tail suspension behavioural experiments were carried out in 7-dose groups (3 mg/kg, once daily for 5 days), and the effect of the anti-depressant compound was reflected by the decrease in the immobility time of the mice, and the experimental results are shown in the figure2。*P<0.05 (compared to solvent control group). About.. P<0.01 (compared to the solvent control).

As can be seen from FIG. 2, preferred compounds I _b 7 the immobility time of the tail-suspended mice can be obviously reduced under the condition of oral administration of 3mg/kg for 5 consecutive days, which indicates that the compound has antidepressant effect and is expected to be used for treating depression.

In another forced swimming experiment, solvent control group (normal saline), multiple administration group (10 mg/kg, once daily, continuous administration for 7 days), and I _b 7 multiple dose groups (0.1 mg/kg, once daily for 7 days), I _b 7 multiple dose groups (0.3 mg/kg, once daily for 7 consecutive days) and I _b The forced swimming test of mice was carried out in a group of 7 doses (1.0 mg/kg, once a day, for 7 days) and the anti-depressant effect of the compound was reflected by the reduction of the immobility time of the mice, and the test results are shown in FIG. 3.* P is<0.05 (compared to solvent control group). About.. P<0.01 (compared to the solvent control). As can be seen from FIG. 3, preference is given to compounds I _b 7 the immobility time of the forced swimming mice can be obviously reduced under the condition that the oral administration dosage of 0.1-1.0mg/kg is carried out for 7 consecutive days, which indicates that the compound has antidepressant effect and is expected to be used for treating depression.

In addition, another compound I with stronger activity is selected in the experiment _b -4 performing antidepressant effect experiments. In a set of tail suspension experiments, a solvent control group (normal saline), a single administration group (30 mg/kg, once administration) of vilazodone and I are set in the experiment _b -4 Single administration group (0.1 mg/kg, once administration), I _b -4 Single administration group (0.3 mg/kg, once administration), I _b 4 Single administration group (1.0 mg/kg, one administration) and I _b 4 Single dose group (3.0 mg/kg, single dose) mouse tail suspension behavioural tests were performed, and the test results are shown in FIG. 4, which reflect the antidepressant effect of the compound by the degree of reduction of the immobility time of the mice. * P is<0.05 (compared to solvent control group). About.. P<0.01 (compared to the solvent control). As can be seen from FIG. 4, preferred compounds I _b -4 can obviously reduce the immobility time of tail-suspended mice under the dosage of 3mg/kg orally taken once, which indicates that the compound has antidepressant effect and is expected to be usedCan be used for treating depression.

Effect example 6

The effect of the compounds of the invention on the behavioural behaviour of scopolamine-induced cognitive impairment C57 mice.

The scopolamine-induced cognitive impairment animal model is a common classical pharmacological model for evaluating candidate drugs for resisting Alzheimer disease. Scopolamine has similar affinity with various subtype M receptors as an M choline receptor blocking drug, can block the combination of acetylcholine and intracerebral M receptors, mainly acts on the acquisition stage of memory, thereby influencing the transmission of information and leading to the impairment of learning and memory functions, and can be used as one of the classic methods for modeling senile dementia. Research proves that single administration of scopolamine can be used as a learning and memory impairment model to cause functional changes, and the impairment of the model is reversible.

In this example, a model was made by administering 1mg/kg of scopolamine, and 22-25 g of C57 mice were used as the experimental subjects to receive the test compound at one time and to observe whether the animals could improve the memory impairment caused by scopolamine. The target compound is dissolved with 20% PEG400 to prepare a clear oral reagent, the administration dosage is 0.1-5 mg/kg, and donepezil hydrochloride 10mg/kg is used as a positive control group. The compound was administered 30min later and then 1mg/kg scopolamine was intraperitoneally injected, 30min later the behaviours of the mice were tested by Y maze/water maze experimental observations.

The experiment selects the compound I with stronger AChE and serotonin transporter double-target inhibition activity _b -7 performing cognitive impairment model experiments. The experiment was set with solvent control group (normal saline), modeling group (1 mg/kg scopolamine), I _b 7 multiple dose groups (0.1 mg/kg, once daily, 7 consecutive days), I _b 7 multiple dose groups (0.3 mg/kg, once daily, 7 consecutive days), I _b 7-multiple dose group (1.0 mg/kg, once daily for 7 days), and donepezil multiple dose group (10 mg/kg, once daily for 7 days), and the memory and cognitive ability of the experimental mice were evaluated by Y maze to investigate whether the test compound could improve memory cognitive impairment, and the experimental results are shown in fig. 5. ^## P<0.01 (compared to solvent control group). SP<0.05 (compared to the modeling group). SP<0.01 (compare to the build module). As can be seen from FIG. 5, preferred compounds I _b 7 can obviously improve the memory cognitive function of mice under the dosage of 0.3mg/kg and 1.0mg/kg by oral administration at one time, which indicates that the composition is expected to be used for treating the Alzheimer disease. Experimental results show that the compound can improve cognitive impairment induced by scopolamine.

Effect example 7

The pharmacokinetic properties and blood brain distribution ratio of the compounds of the invention. Any drug must reach the focal site for therapeutic action, and for central system drugs, it is important for good blood brain barrier permeability and good brain blood distribution ratio.

The experiment selects the compound I with stronger activity _b -4 carrying out pharmacokinetic properties and blood brain distribution ratio experiments. ICR mice were used for intragastric administration of compound I _b -4 (10 mg/kg) or intravenous administration of Compound I _b 4 (2 mg/kg), collecting plasma and brain tissues at different time points, detecting the concentration of the test substance in the plasma and brain tissues of ICR mice, and calculating related parameters. The results are shown in tables 7 and 8. As shown in Table 7, compound I _b The oral bioavailability of-4 was 35.83. As can be seen from Table 8, compound I _b The plasma drug concentration reached a peak rapidly after oral administration of-4 and continued to decline slowly after 0.5 hours. And the compound I _b 4 the concentration in the brain is first increased gradually, reaching a peak at 16-24 hours, and then gradually decreased and excreted by metabolism. Within 8-48 hours after administration, compound I _b The cerebral blood ratios of-4 are all greater than 1, indicating that Compound I _b -4 has good blood-brain barrier permeability. Furthermore, compounds I _b The oral plasma metabolic half-life of-4 is longer than 23.97 hours, and once-a-day administration is considered.

TABLE 7 Compound I _b Pharmacokinetic parameters of-4

TABLE 8 combination ofSubstance I _b Brain blood concentration distribution ratio of-4

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Claims

1. A compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing;

each one of

Independently a double or single bond;

m1 is 0, 1,2,3 or 4;

each R ³ Independently halogen, C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkoxy group;

m2 is 0, 1,2,3 or 4;

R ⁴ is C ₆ -C ₁₀ Aryl, C substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl, benzyl substituted by 1,2 or 3 halogens, cyclopentane substituted by 1,2 or 3 halogens, cyclohexane substituted by 1,2 or 3 halogens, a "5-to 12-membered heterocycloalkyl group whose heteroatom number is 1,2 or 3, which heteroatom number is 1,2 or 3, and" heteroatom substituted by 1,2 or 3 halogens "is selected from 1,2 or 3 of N, O and S, a 5-12 membered heterocycloalkyl group having 1,2 or 3 hetero atoms, a" 5-12 membered heteroaryl group having 1,2 or 3 hetero atoms selected from N, O and S, and 1,2 or 3 hetero atoms, or a "5-12 membered heteroaryl group having 1,2 or 3 hetero atoms substituted with 1,2 or 3 halogens", a "5-12 membered heteroaryl group having 1,2 or 3 hetero atoms selected from N, O and S;

R ⁵ is H, halogen, C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C substituted by 1,2 or 3 halogens ₁ -C ₆ An alkoxy group; or, R ⁵ To form- (CH) s by linkage to the carbon marked by ₂ ) _n2 -; n2 is 0 or 1;

n is 1,2,3, 4, 5 or 6;

n1 is 0, 1,2 or 3.

2. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I;

(2)R ¹ wherein said C is substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C ₁ -C ₆ In the alkyl radical, the said C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isoPropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(3)R ¹ in (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(4)R ² in (A), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

(5)R ² wherein C is substituted by 1,2 or 3 halogen ₁ -C ₆ In alkyl, the halogen is independently F, cl, br or I;

(6)R ³ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I;

(7)R ³ in (A), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the said C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

(8)R ³ in (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(9)R ⁴ in (A), the C ₆ -C ₁₀ Aryl and said C substituted by 1,2 or 3 halogens ₆ -C ₁₀ In aryl radical, the C ₆ -C ₁₀ Aryl being phenyl or naphthyl；

(10)R ⁴ Wherein C is substituted by 1,2 or 3 halogen ₆ -C ₁₀ Aryl, said benzyl substituted with 1,2 or 3 halogens, said cyclopentane substituted with 1,2 or 3 halogens, said cyclohexane substituted with 1,2 or 3 halogens, said "heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heterocycloalkyl group with 1,2 or 3 heteroatoms, and said" heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heteroaryl group with 1,2 or 3 heteroatoms, said halogens are independently F, cl, br or I;

(11)R ⁴ wherein C is substituted by 1,2 or 3 halogen ₆ -C ₁₀ Aryl is phenyl substituted with 1,2 or 3F;

(12)R ⁴ wherein the "hetero atom is selected from 1,2 or 3 of N, O and S, the 5-to 12-membered heterocycloalkyl group having 1,2 or 3 hetero atoms" and the "hetero atom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, and the 5-to 12-membered heterocycloalkyl group having 1,2 or 3 hetero atoms" is independently "the 5-to 6-membered heterocycloalkyl group having 1 or 2 hetero atoms selected from 1 or 2 of N, O and S, and 1 or 2 hetero atoms";

(13)R ⁴ wherein the "heteroatom is selected from 1,2 or 3 of N, O and S, the 5-to 12-membered heteroaryl group having 1,2 or 3 of heteroatoms, and the" heteroatom substituted with 1,2 or 3 of halogens "is selected from 1,2 or 3 of N, O and S, and the 5-to 12-membered heteroaryl group having 1,2 or 3 of heteroatoms, the" heteroatom is selected from 1,2 or 3 of N, O and S, and the 5-to 12-membered heteroaryl group having 1,2 or 3 of heteroatoms "is independently" a 5-to 6-membered heteroaryl group having 1 or 2 of heteroatoms selected from N, O and S, and 1 or 2 of heteroatoms ";

(14)R ⁵ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F, cl, br or I;

(15)R ⁵ in (A), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

(16)R ⁵ in (1), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

3. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F;

(2)R ¹ wherein said C is substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl;

(3)R ¹ in (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy;

(4)R ² in (A), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl;

(5)R ² wherein said C is substituted by 1,2 or 3 halogens ₁ -C ₆ In alkyl, the halogen is independently F;

(6)R ³ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F;

(7)R ³ in (1), the C ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the said C ₁ -C ₆ Alkyl is independently methyl;

(8)R ³ in (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy;

(9)R ⁴ in (A), the C ₆ -C ₁₀ Aryl and said C substituted by 1,2 or 3 halogens ₆ -C ₁₀ In aryl radical, the C ₆ -C ₁₀ Aryl is phenyl;

(10)R ⁴ wherein said C is substituted by 1,2 or 3 halogens ₆ -C ₁₀ Aryl, said benzyl substituted with 1,2 or 3 halogens, said cyclopentane substituted with 1,2 or 3 halogens, said cyclohexane substituted with 1,2 or 3 halogens, said heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heterocycloalkyl group having 1,2 or 3 heteroatoms, and said heteroatom substituted with 1,2 or 3 halogens is selected from 1,2 or 3 of N, O and S, a 5-12 membered heteroaryl group having 1,2 or 3 heteroatoms, said halogens are independently F;

(11)R ⁵ wherein said halogen, said C substituted by 1,2 or 3 halogens ₁ -C ₆ Alkyl and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy, the halogen is independently F;

(12)R ⁵ in (A), the C ₁ -C ₆ Alkyl radicals andsaid C substituted by 1,2 or 3 halogens ₁ -C ₆ In the alkyl radical, the C ₁ -C ₆ Alkyl is independently methyl;

(13)R ⁵ in (A), the C ₁ -C ₆ Alkoxy and said C substituted by 1,2 or 3 halogens ₁ -C ₆ In alkoxy radical, the C ₁ -C ₆ Alkoxy is independently methoxy.

4. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ wherein C is substituted by 1,2 or 3 halogen ₁ -C ₆ Alkyl is trifluoromethyl;

(2)R ⁴ wherein C is substituted by 1,2 or 3 halogen ₆ -C ₁₀ Aryl is

5. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ independently CN, halogen or C substituted by 1,2 or 3 halogen ₁ -C ₆ An alkyl group;

(2) m1 is 1;

(3)R ² is H or C ₁ -C ₆ An alkyl group;

(4)R ³ is halogen;

(5) m2 is 0 or 1;

(6)R ⁴ is C ₆ -C ₁₀ Aryl or C substituted by 1,2 or 3 halogens ₆ -C ₁₀ An aryl group;

(7)R ⁵ is H; or, R ⁵ To form-CH by linking to marked carbon ₂ -；

(8) n1 is 0;

(9) n is 1,2,3 or 4.

6. A compound of formula I, a tautomer, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ independently of one another is F, CF ₃ Or CN;

(2)R ² is H or methyl;

(3)R ³ is F;

(4)R ⁴ is a phenyl group,

7. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I satisfies one or more of the following conditions:

(1)R ¹ independently is F or CN;

(2)R ² is H;

(3)R ⁴ is phenyl or

8. A compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1,

is composed of

Preferably in a manner which is +>

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9. The compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I has a structure according to formula I-a or I-B:

wherein, n, m1, m2 and R ¹ 、R ² 、R ³ And R ⁴ As defined in any one of claims 1 to 8.

10. A compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to claim 1, wherein the compound of formula I is any one of:

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11. the preparation method of the compound shown in the formula I is a first method or a second method as follows:

the first method comprises the following steps:

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x is halogen;

the second method comprises the following steps:

n3＝n-1；

*、

n、n1、m1、m2、R ¹ 、R ² 、R ³ 、R ⁴ and R ⁵ As defined in any one of claims 1 to 10.

12. A pharmaceutical composition, comprising:

(1) A compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to any one of claims 1-10; and

(2) A pharmaceutically acceptable carrier.

13. Use of a compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a solvate of any of the foregoing, according to any one of claims 1-10, or a pharmaceutical composition according to claim 12, selected from:

(i) For the preparation of acetylcholinesterase inhibitors;

(ii) For the preparation of serotonin transporter inhibitors;

(v) For the preparation of a medicament for the treatment of depression;

14. A compound of formula II:

wherein, the,

n1、m2、R ³ 、R ⁴ And R ⁵ Is as defined in any one of claims 1 to 10.

15. The compound of formula II according to claim 14, wherein the compound of formula II is any one of the following compounds:

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