CN115636787A

CN115636787A - Compound with Tau protein inhibitory activity and preparation method thereof

Info

Publication number: CN115636787A
Application number: CN202211387131.0A
Authority: CN
Inventors: 徐志斌
Original assignee: Beijing Institute of Technology BIT
Current assignee: Beijing Institute of Technology BIT
Priority date: 2022-11-07
Filing date: 2022-11-07
Publication date: 2023-01-24
Anticipated expiration: 2042-11-07
Also published as: CN115636787B

Abstract

The invention relates to the technical field of medicines, and provides a compound with Tau protein inhibitory activity and a preparation method thereof. The compound has a structure shown in formula I

Wherein R is selected from the following structures:

R ₁ represents

Or

Y represents carbon or nitrogen; r ₂ Represents one or more of methyl, ethyl, methoxy, phenoxy or methylenedioxy, and n =1 to 3. The compound provided by the invention has higher Tau protein inhibition activity, can be used for preparing medicines for treating and/or preventing aging and neurodegenerative diseases, and has important significance for researching and developing the medicines.

Description

Compound with Tau protein inhibitory activity and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a compound with Tau protein inhibitory activity and a preparation method thereof.

Background

Tau protein is a microtubule-associated protein that is widely found in the central and peripheral nervous systems. Tau protein in the central nervous system is mainly involved in the assembly of microtubules and maintains microtubule stability. Many aging and neurodegenerative diseases (e.g., alzheimer, parkinson, etc.) have been associated with abnormalities in Tau protein, e.g., abnormal accumulation and increase in Tau protein potentiates memory impairment. Relevant studies have shown that neuroprotection can be achieved by reducing the accumulation and precipitation of Tau protein. Therefore, tau protein is considered as an important target for the research and development of drugs that can be used for the treatment of aging and neurodegenerative diseases.

However, tau protein is an endogenous unordered structure non-enzyme protein, and the surface of Tau protein lacks an active binding pocket, which brings difficulty to the research of related inhibitors. Therefore, research and development of a compound with Tau protein inhibitory activity are of great significance for treating, relieving or preventing aging and neurodegenerative diseases.

Disclosure of Invention

In order to find a novel compound with high Tau protein inhibitory activity, the embodiment of the invention designs and synthesizes a series of compounds with novel structures and high Tau protein inhibitory activity through extensive and intensive research, can effectively treat, relieve and/or prevent aging and neurodegenerative diseases by inhibiting the activity of Tau protein, and has important significance for researching the development of drugs for aging and neurodegenerative diseases.

In a first aspect of embodiments of the present invention, there is provided a compound having the structure of formula i:

wherein R is selected from the following structures:

R ₁ represents

Y represents carbon or nitrogen;

R ₂ represents one or more of methyl, ethyl, methoxy, phenoxy or methylenedioxy, and n =1 to 3.

The compound provided by the invention has a novel structure and higher Tau protein inhibition activity, can effectively treat, relieve and/or prevent aging and neurodegenerative diseases by inhibiting the activity of Tau protein, and has important significance for researching the development of drugs for aging and neurodegenerative diseases.

In a second aspect of the embodiments of the present invention, there is provided a process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as described in the first aspect, when R is

When the compound is

The preparation method of the compound comprises the following steps:

s1, synthesis of a compound III:

reacting a compound II with a structure shown in a formula II with piperazine in a first solvent in the presence of a first base to obtain a compound III with a structure shown in a formula III;

s2, synthesis of a compound I-a:

reacting a compound III with a structure shown in a formula III with a compound IV with a structure shown in a formula IV or a compound V with a structure shown in a formula V in a second solvent in the presence of a carbodiimide condensation agent and 1-hydroxybenzotriazole to obtain a compound I-a with a structure shown in a formula I-a.

In a third aspect, the invention provides a process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as described in the first aspect, when R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-b:

and (3) reacting the compound VI with the structure of the formula VII with a third solvent in the presence of a second base and the first catalyst to obtain the compound I-b with the structure of the formula I-b.

In a fourth aspect, the invention provides a process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as described in the first aspect, when R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-c:

and (3) reacting the compound VIII with the structure of the formula VII with the compound VII with the formula VII in a fourth solvent in the presence of a third base and a second catalyst to obtain the compound I-c with the formula I-c.

The method provided by the invention has the advantages of simple operation of the whole preparation process, easy control and low requirements on production equipment, and is suitable for industrial large-scale production.

In a fifth aspect of the present invention, there is provided a pharmaceutical composition having Tau protein inhibitory activity, comprising a compound having the structure of formula i as described in the first aspect or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the invention, a compound having the structure of formula i, or a pharmaceutically acceptable salt thereof, is used as an active ingredient in a pharmaceutical composition.

In a sixth aspect of the present invention, there is provided a use of the compound having the structure of formula i in the first aspect or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating aging and neurodegenerative diseases.

For the application of the compound and the pharmaceutical composition provided by the invention in preparing the medicine for treating the aging and the neurodegenerative diseases, a mode of applying a therapeutically effective amount of the compound or the pharmaceutical composition provided by the invention to a patient needing to treat the aging and the neurodegenerative diseases is adopted to realize the treatment effect. The compound or the pharmaceutical composition provided by the invention can be used alone as a treatment means for treating aging and neurodegenerative diseases, and can also be used in combination with other conventional treatment means for treating aging and neurodegenerative diseases, such as surgery, radiotherapy, chemotherapy and the like.

The therapeutically effective amount of the compound or pharmaceutical composition provided by the present invention for the treatment of aging and neurodegenerative diseases depends on many factors. May vary depending on the particular species of aging and neurodegenerative disease that is to be treated, as can be determined by one skilled in the art without undue experimentation. The actual treatment will also take into account factors such as the age and weight of the patient, the severity of the condition, the particular mode of administration, etc., and will ultimately depend on the discretion of the attendant physician or clinician.

Drawings

FIG. 1 shows a NMR spectrum of a compound III having a structure of the formula III obtained in example 1 of the present invention.

FIG. 2 is a NMR chart of a compound III having a structure of formula III obtained in example 1 of the present invention.

FIG. 3 shows a NMR spectrum of Compound 1 obtained in example 1 of the present invention.

FIG. 4 shows a NMR C spectrum of Compound 1 obtained in example 1 of the present invention.

FIG. 5 is a high resolution mass spectrum of Compound 1 obtained in example 1 of the present invention.

FIG. 6 is a NMR spectrum of Compound 2 obtained in example 2 of the present invention.

FIG. 7 is a NMR spectrum of Compound 2 obtained in example 2 of the present invention.

FIG. 8 is a high resolution mass spectrum of Compound 2 obtained in example 2 of the present invention.

FIG. 9 shows a NMR spectrum of Compound 3 obtained in example 3 of the present invention.

FIG. 10 is a NMR spectrum of Compound 3 obtained in example 3 of the present invention.

FIG. 11 is a high resolution mass spectrum of Compound 3 obtained in example 3 of the present invention.

FIG. 12 is a NMR spectrum of Compound 4 obtained in example 4 of the present invention.

FIG. 13 is a NMR spectrum of Compound 4 obtained in example 4 of the present invention.

FIG. 14 is a high resolution mass spectrum of Compound 4 obtained in example 4 of the present invention.

FIG. 15 is a NMR spectrum of Compound 5 obtained in example 5 of the present invention.

FIG. 16 is a NMR spectrum of Compound 5 obtained in example 5 of the present invention.

FIG. 17 is a high resolution mass spectrum of Compound 5 obtained in example 5 of the present invention.

FIG. 18 is a NMR spectrum of Compound 6 obtained in example 6 of the present invention.

FIG. 19 is a NMR spectrum of Compound 6 obtained in example 6 of the present invention.

FIG. 20 is a high resolution mass spectrum of Compound 6 obtained in example 6 of the present invention.

FIG. 21 is a NMR spectrum of Compound 7 obtained in example 7 of the present invention.

FIG. 22 is a NMR spectrum of Compound 7 obtained in example 7 of the present invention.

FIG. 23 is a high resolution mass spectrum of Compound 7 obtained in example 7 of the present invention.

FIG. 24 is a NMR spectrum of Compound 8 obtained in example 8 of the present invention.

FIG. 25 is a NMR spectrum of Compound 8 obtained in example 8 of the present invention.

FIG. 26 is a high resolution mass spectrum of Compound 8 obtained in example 8 of the present invention.

FIG. 27 is a NMR spectrum of Compound 9 obtained in example 9 of the present invention.

FIG. 28 is a NMR spectrum of Compound 9 obtained in example 9 of the present invention.

FIG. 29 is a high resolution mass spectrum of Compound 9 obtained in example 9 of the present invention.

FIG. 30 is a NMR spectrum of Compound 10 obtained in example 10 of the present invention.

FIG. 31 is a NMR spectrum of Compound 10 obtained in example 10 of the present invention.

FIG. 32 is a high resolution mass spectrum of Compound 10, obtained in example 10 of the present invention.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific examples described herein are merely illustrative of the invention and that the embodiments of the invention are not limited thereto.

Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.

Some of the terms involved in the expression of the present invention are defined as follows:

the term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid and the like; the organic acid includes acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, malonic acid, or the like. Or, a salt formed when an acid proton present in the parent compound is replaced with a metal ion or coordinated with an organic base; the metal ions include alkali metal ions, alkaline earth ions, aluminum ions and the like; the organic base includes ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

The term "pharmaceutically acceptable carrier" refers to a pharmaceutical carrier that is conventional in the pharmaceutical art, a carrier that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound, such as: diluents such as water and the like; fillers, such as starch, sucrose, and the like; binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone; humectants, such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate and magnesium stearate, and polyethylene glycol, and the like. In addition, other adjuvants such as flavoring agent and sweetener can also be added into the above medicinal composition.

Pleuromutilin is a diterpenoid compound which is separated from Pleurotus mutilus and Pleurotus passecerianus of Pleurotus of higher fungi Basidiomycetes in 50 th century and consists of 5-membered, 6-membered and 8-membered ring fused tricyclic frameworks and glycolate side chains. The tricyclic nucleus of pleuromutilin is positioned in the peptidyl transferase center of 50S subunit, and the 14-position side chain covers the combination site of transferase and tRNA, so as to inhibit the formation of peptide bond directly and prevent the synthesis of bacterial protein. Pleuromutilins have therefore been used as lead compounds for the development of novel antibiotic drugs. Up to now, a number of semi-synthetic pleuromutilin derivatives have been prepared for use as antibacterial agents. Representative of these are the veterinary antibiotics tiamulin, valnemulin, and the human antibiotics restamulin (retapamulin) and lefamoulin (lefamulin).

With the progress of research, the clinical application range of pleuromutilins is continuously expanded. The study shows that tiamulin (0.1-10 mu mol. L) with certain concentration ^-1 ) When the composition is used together with anticancer drugs, the composition can inhibit the activity of ATP enzyme of tumor cells and drug transporters on cell membranes, thereby increasing the sensitivity of the tumor cells to the anticancer drugs.

Due to the complexity of the structure of the parallel tricyclic framework of pleuromutilin and the importance of antibacterial activity thereof, researchers focus on structural modification of pleuromutilin and mostly focus on 14 side chains, the parallel tricyclic framework is rarely involved, and the parallel tricyclic framework itself is not improved so as to obtain the pleuromutilin compound which has the inhibitory activity on Tau protein and can be used for treating aging and neurodegenerative diseases.

In order to fully develop and utilize the medicinal value of the pleuromutilin compounds and expand the clinical application range of the pleuromutilin compounds, a series of compounds which have novel structures and higher Tau protein inhibition activity are designed and synthesized by improving the parallel tricyclic framework, and the compounds can effectively treat, relieve and/or prevent aging and neurodegenerative diseases by inhibiting the Tau protein activity and have important significance for the development of medicaments for researching the aging and the neurodegenerative diseases.

In a first aspect, this embodiment provides a compound having the structure of formula i:

wherein R is selected from the following structures:

R ₁ represents

Y represents carbon or nitrogen;

In some preferred embodiments, the compound having the structure of formula i may be selected from the following compounds:

in a second aspect, the embodiments of the present invention also provide a method for preparing a compound having the structure of formula I or a pharmaceutically acceptable salt thereof, wherein R is

When the compound is

The preparation method of the compound comprises the following steps:

s1, synthesis of a compound III:

s2, synthesis of a compound I-a:

Further, in step S1, the first base is at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide or potassium tert-butoxide, triethylamine, pyridine, piperidine, and pyrrole; the first solvent is at least one of acetonitrile, acetone, dimethyl sulfoxide, dimethylformamide or dimethylacetamide. In step S2, the second solvent is at least one of dimethylformamide, dimethylacetamide, dichloromethane, chloroform, or dimethylsulfoxide.

In a third aspect, the embodiments of the present invention also provide a method for preparing a compound having the structure of formula I or a pharmaceutically acceptable salt thereof, wherein R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-b:

and (3) reacting the compound VI with the structure of the formula VII with the compound VII with the structure of the formula VII in a third solvent in the presence of a second base and the first catalyst to obtain the compound I-b with the formula I-b.

Further, in the step of synthesizing the compound i-b, the second base is potassium carbonate; the first catalyst is potassium iodide; the third solvent is acetonitrile.

In a fourth aspect, the embodiments of the present invention also provide a method for preparing a compound having the structure of formula I or a pharmaceutically acceptable salt thereof, wherein R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-c:

Further, in the step of synthesizing the compound i-c, the third base is potassium carbonate; the second catalyst is potassium iodide; the fourth solvent is acetonitrile.

In a fifth aspect, the embodiments of the present invention further provide a pharmaceutical composition with Tau protein inhibitory activity, comprising the compound with the structure of formula i in the first aspect or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a sixth aspect, the present invention further provides a use of the compound having the structure of formula i in the first aspect or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating aging and neurodegenerative diseases.

Further, the above-mentioned aging and neurodegenerative diseases include alzheimer's disease, parkinson's disease, and the like.

The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.

In the examples below, NMR spectra were recorded using a

Varian Mercury

400 and 600 NMR spectrometer with chemical shifts expressed in δ (ppm); mass spectra were recorded on a Bruker ESQUIRE-3000 mass spectrometer, electrospray ionization (ESI); the silica gel for separation is not specified, but 200-300 mesh.

Example 1

The synthetic route for compound I-a is as follows:

the first step is as follows: synthesis of Compound III

Compound II (2- (4-methylphenylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester) (5.47g, 10mmol), anhydrous piperazine (1.72g, 20mmol), anhydrous potassium carbonate (2.78g, 20mmol) was dissolved in 30mL of acetonitrile, monitored by TLC, refluxed for 20h, and alkaline potassium permanganate was used as a color-developing agent. After the reaction, the reaction mixture was concentrated, washed with 10mL of water, the aqueous phase was extracted with ethyl acetate four times, 20mL of ethyl acetate was used for each extraction, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (dichloromethane: methanol (volume ratio) = 5:1) to give 0.79g of a pale yellow solid (i.e., compound iii) with a yield of 17.1% and a melting point of 107 ℃ to 110 ℃.

The pale yellow solid obtained (i.e. compound iii) was identified:

the nuclear magnetic resonance hydrogen spectrum of the light yellow solid is shown in figure 1, ¹ H NMR(600MHz,CDCl ₃ )δ:6.46(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.88(d,J＝9Hz,1H),5.71(s,1H),5.32(d,J＝10.8Hz,1H),5.17(d,J＝17.4Hz,1H),3.36(m,2H),3.14(d,1H),3.00(d,1H),2.90(t,4H),2.53(m,2H),2.44(m,2H),2.31(m,3H),2.02(m,2H),1.63(m,3H),1.52(m,2H),1.46(m,1H),1.36(d,1H),1.13(d,6H),0.80(d,3H),0.71(d,3H).

the nuclear magnetic resonance carbon spectrum of the light yellow solid is shown in figure 2, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.82,168.85,138.09,117.58,73.42,68.48,60.41,59.67,54.04,45.66,44.58,43.53,37.83,35.38,35.26,27.14,26.07,25.83,24.44,16.88,16.25,10.65.

the second step: synthesis of Compound 1

Compound III (2- (piperazinyl) acetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 111R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester) (0.115g, 0.25mmol), 4-fluorobenzoic acid (0.042g, 0.3mmol), EDCI (carbodiimide-based condensing agent) (0.048g, 0.25mmol), HOBT (1-hydroxybenzotriazole) (0.034g, 0.25mmol) was dissolved in 5mL of anhydrous DMF (dimethylformamide) and stirred at room temperature for 4 hours. After the reaction was complete, 20mL of saturated ammonium bicarbonate solution was added and stirring was continued for 0.5h. Then, the mixture was extracted four times with ethyl acetate, 20mL of ethyl acetate was used for each extraction, the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (chloroform: methanol (volume ratio) = 15) to obtain 0.138g of a white solid (i.e., compound 1) in 94.5% yield and a melting point of 118 ℃ to 120 ℃.

The white solid obtained (i.e. compound 1) was identified:

the NMR spectrum of the white solid is shown in FIG. 3, ¹ H NMR(600MHz,CDCl ₃ )δ:7.39(m,2H),7.08(t,J＝8.4Hz,2H),6.46(dd,J ₁ ＝10.8Hz,J ₂ ＝16.8Hz,1H),5.91(d,J＝9Hz,1H),5.69(s,1H),5.35(d,J＝11.4Hz,1H),5.20(d,J＝17.4Hz,1H),3.78(s,2H),3.47(s,2H),3.37(s,2H),3.23(d,1H),3.09(d,1H),2.33(m,3H),2.05(q,1H),1.63(m,3H),1.52(m,4H),1.38(m,2H),1.29(d,2H),1.14(d,7H),0.82(d,3H),0.71(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 4, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.80,169.34,168.61,164.20,162.55,138.00,131.55,129.35,117.74,115.61,115.47,73.45,68.78,59.68,59.55,52.83,44.61,44.26,43.57,37.86,35.37,35.32,27.14,26.09,25.82,24.47,16.88,16.29,10.68.

the high resolution mass spectrum of the white solid is shown in FIG. 5, HR MS (ESI): m/z Calcd for C ₃₃ H ₄₇ FN ₃ O ₅ :584.34943.Found:584.34891(M+H ⁺ ).

Example 2

The synthetic route of the compound of example 2 is the same as that of the compound of example 1.

The first step is as follows: synthesis of Compound III

Compound iii was synthesized according to the first step of example 1.

The second step is that: synthesis of Compound 2

Compound III (2- (piperazinyl) acetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester) (0.115g, 0.25mmol), 3,4,5-trimethoxybenzoic acid (0.064g, 0.3mmol), EDCI (carbodiimide-based condensing agent) (0.048g, 0.25mmol), HOBT (1-hydroxybenzotriazole) (0.03g, 0.25mmol) was dissolved in 5mL of anhydrous DMF (dimethylformamide) and stirred at room temperature for 4h. After the reaction was complete, 20mL of saturated ammonium bicarbonate solution was added and stirring was continued for 0.5h. Then, the mixture was extracted four times with ethyl acetate, 20mL of ethyl acetate was used for each extraction, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (chloroform: methanol (volume ratio) = 12) to obtain 0.143g of a white solid, the yield was 87.0%, and the melting point was 128 ℃ to 130 ℃.

The white solid obtained (i.e. compound 2) was identified:

the NMR spectrum of the white solid is shown in FIG. 6, ¹ H NMR(600MHz,CDCl ₃ )δ:6.62(s,2H),6.46(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.94(d,J＝9Hz,1H),5.81(s,1H),5.37(d,J＝11.4Hz,1H),5.22(d,J＝12.6Hz,1H),3.86(d,9H),3.38(m,2H),3.19(d,1H),2.68(s,4H),2.35(m,3H),2.07(m,1H),1.56(m,8H),1.32(d,1H),1.25(m,2H),1.16(d,6H),0.84(d,4H),0.73(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 7, ¹³ C NMR(150MHz,CDCl ₃ )δ:173.31,170.14,167.31,153.38,139.53,137.80,130.32,117.96,104.48,73.51,69.54,60.91,59.81,58.57,56.30,44.50,44.30,43.63,37.94,35.39,29.69,27.10,26.10,25.89,25.80,24.44,16.86,10.73,1.01.

the high-resolution mass spectrum of the white solid is shown in FIG. 8, HR MS (ESI): m/z Calcd for C ₃₆ H ₅₄ N ₃ O ₈ :656.39054.Found:656.39014(M+H ⁺ ).

Example 3

The synthetic route of the compound of example 3 is the same as that of the compound of example 1.

The first step is as follows: synthesis of Compound III

Compound iii was synthesized according to the first step of example 1.

The second step is that: synthesis of Compound 3

Compound III (2- (piperazinyl) acetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 111R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester) (0.115g, 0.25mmol), 3- (4-methoxyphenyl) acrylic acid (0.0534g, 0.3mmol), EDCI (carbodiimide condensation agent) (0.048g, 0.25mmol), HOBT (1-hydroxybenzotriazole) (0.403g, 0.25mmol) was dissolved in 5mL of anhydrous DMF (dimethylformamide) and stirred at room temperature for 4h. After the reaction was complete, 20mL of saturated ammonium bicarbonate solution was added and stirring was continued for 0.5h. Then, the mixture was extracted four times with ethyl acetate, 20mL of ethyl acetate was used for each extraction, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (chloroform: methanol (volume ratio) = 25) to obtain 0.083g of a white solid, the yield was 53.0%, and the melting point was 131 ℃ to 134 ℃.

The white solid obtained (i.e. compound 3) was identified:

the NMR spectrum of the white solid is shown in FIG. 9, ¹ H NMR(600MHz,CDCl ₃ )δ:7.63(d,J＝15.0Hz,1H),7.46(d,J＝9.0Hz,2H),6.88(d,J＝9.0Hz,2H),6.72(d,J＝15.6Hz,1H),6.48(dd,J ₁ ＝11.4Hz,J ₂ ＝17.4Hz,1H),5.93(d,J＝9Hz,1H),5.75(s,1H),5.37(d,J＝10.8Hz,1H),5.21(d,J＝17.4Hz,1H),3.83(m,7H),3.39(s,2H),2.60(m,4H),2.34(m,3H),2.06(m,1H),1.65(m,3H),1.54(m,5H),1.31(d,1H),1.25(s,1H),1.16(d,6H),0,83(d,3H),0.73(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 10, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.94,168.64,165.69,160.89,142.72,138.01,129.32,127.90,117.84,114.28,114.22,73.52,68.83,59.74,55.35,53.09,52.61,45.54,44.63,44.30,43.61,41.87,37.92,35.43,35.36,29.68,27.19,26.14,25.88,25.82,24.51,16.92,10.72.

the high resolution mass spectrum of the white solid is shown in FIG. 11, HR MS (ESI): m/z Calcd for C ₃₆ H ₅₂ N ₃ O ₆ :622.38506.Found:622.38419(M+H ⁺ ).

Example 4

The first step is as follows: synthesis of 2-piperazinyl benzonitrile

In a dry 15mL sealed tube, 1.0mmol of o-chlorobenzonitrile, 2.0mmol of piperazine, 1.0mmol of magnesium hydroxide, 2.0mL of NMP (N-methylpyrrolidone), and heating at 120 ℃ for 6 hours were carried out to stop the reaction. Filtering to remove solid, washing the filtrate with 10mL of water, extracting the aqueous phase with ethyl acetate for four times, wherein the usage amount of ethyl acetate used in each extraction is 20mL, drying the organic phase with anhydrous magnesium sulfate, filtering, concentrating, and separating by silica gel column chromatography to obtain 2-piperazinyl benzonitrile.

The second step is that: synthesis of Compound 4

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester (0.471g, 1.0mmol), 2-piperazinylbenzonitrile (0.225g, 1.2mmol), anhydrous potassium carbonate (0.278g, 2.0mmol) were taken, 1 to 2mg of potassium iodide was added and dissolved in 10mL of acetonitrile, monitored by TLC, and heated to reflux for 20 hours. After the reaction was completed, the solid was filtered off, concentrated, washed with 10mL of water, and the aqueous phase was extracted four times with ethyl acetate, the amount of ethyl acetate used for each extraction was 20mL, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (pure acetone) to obtain 0.149g of a white solid (i.e., compound 4) with a yield of 26.5%.

The white solid obtained (i.e. compound 4) was identified:

the NMR spectrum of the white solid is shown in FIG. 12, ¹ H NMR(600MHz,CDCl ₃ )δ:7.56(m,1H),7.48(m,1H),7.01(t,J＝7.2Hz,2H),6.50(dd,J ₁ ＝11.4Hz,J ₂ ＝17.4Hz,1H),5.95(d,J＝9.6Hz,1H),5.69(s,1H),5.37(d,J＝10.8Hz,1H),5.22(d,J＝18Hz,1H),3.39(m,2H),3.26(m,6H),3.13(d,1H),2.81(m,2H),2.73(m,2H),2.35(m,4H),2.07(m,1H),1.66(m,4H),1.56(m,2H),1.46(d,2H),1.33(d,1H),1.17(m,4H),0.83(d,3H),0.75(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 13, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.82,168.84,155.55,138.03,134.31,133.81,121.91,118.69,118.33,106.13,73.52,68.68,59.81,59.71,53.04,51.29,44.62,44.29,43.61,37.90,35.46,35.33,27.18,26.13,25.86,25.79,24.51,16.96,16.38,10.70.

the spectrum of the white solid in high resolution mass spectrum is shown in FIG. 14, HR MS (ESI): m/z Calcd for C ₃₃ H ₄₇ N ₄ O ₄ :563.35918.Found:563.36051(M+H ⁺ ).

Example 5

The synthetic route of the compound of example 5 is the same as that of the compound of example 4.

The first step is as follows: synthesis of 2-piperazine nicotinonitrile

2-piperazine nicotinonitrile was synthesized according to the first step of example 4.

The second step: synthesis of Compound 5

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-n-propyl-piperazino-cyclooctan-9-yl ester (0.471g, 1.0mmol), 2-piperazino-nicotinonitrile (0.226g, 1.2mmol), anhydrous potassium carbonate (0.278g, 2.0mmol) were taken, 1 to 2mg of potassium iodide was added and dissolved in 10mL of acetonitrile, monitored by TLC, and heated to reflux for 20 hours. After the reaction was completed, the solid was filtered off, concentrated, washed with 10mL of water, and the aqueous phase was extracted four times with ethyl acetate, the amount of ethyl acetate used for each extraction was 20mL, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (pure acetone) to obtain 0.385g of a white solid (i.e., compound 5) with a yield of 68.3%.

The white solid obtained (i.e. compound 5) was identified:

the NMR spectrum of the white solid is shown in FIG. 15, ¹ H NMR(600MHz,CDCl ₃ )δ:8.34(q,J＝4.8Hz,1H),7.76(q,J＝7.8Hz,1H),6.76(q,J＝7.2Hz,1H),6.50(q,J＝17.4Hz,1H),5.95(d,J＝9.6Hz,1H),5.69(s,1H),5.38(d,J＝10.2Hz,1H),5.22(d,J＝16.2Hz,1H),3.78(s,4H),3.40(m,2H),3.27(dd,1H),3.12(dd,1H),2.75(m,2H),2.67(m,2H),2.36(m,4H),2.07(q,1H),1.59(m,7H),1.33-1.51(m,5H),0.87(d,3H),0.76(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 16, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.83,168.80,160.52,151.86,143.85,137.99,118.05,117.89,114.13,94.95,73.55,68.71,59.83,59.73,52.75,47.83,44.67,44.31,43.63,37.92,35.48,35.34,29.69,27.19,26.15,25.87,24.53,16.97,16.39,10.72.

the high resolution mass spectrum of the white solid is shown in FIG. 17, HR MS (ESI): m/z Calcd for C ₃₂ H ₄₆ N ₅ O ₄ :564.35443.Found:564.35458(M+H ⁺ ).

Example 6

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-N-propyl-piperazino-cyclooctan-9-yl ester (0.236g, 0.5mmol), N-ethyl- (4-phenoxyphenyl) methylamine (0.227g, 1.0mmol), anhydrous potassium carbonate (0.139g, 1.0mmol) were taken, 1 to 2mg of potassium iodide was added and dissolved in 10mL of acetonitrile, monitored by TLC, and heated under reflux for 20h. After the reaction was completed, the solid was filtered off, concentrated, and subjected to silica gel column chromatography (ethyl acetate: methanol (volume ratio) = 20) to obtain 0.191g of a white solid (i.e., compound 6) in a yield of 63.3% and a melting point of 73 ℃ to 78 ℃.

The white solid obtained (i.e. compound 6) was identified:

the NMR spectrum of the white solid is shown in FIG. 18, ¹ H NMR(600MHz,CDCl ₃ )δ:7.32(t,J＝7.8Hz,2H),7.28(s,2H),7.08(t,J＝7.2Hz,1H),6.98(d,J＝9.6Hz,2H),6.93(d,J＝8.4Hz,2H),6.51(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.92(d,J＝9.6Hz,1H),5.71(s,1H),5.38(d,J＝10.8Hz,1H),5.21(d,J＝17.4Hz,1H),3.73(q,2H),3.38(s,2H),3.20(q,2H),2.69(m,2H),2.33(m,2H),2.16(s,1H),2.04(q,1H),1.61(m,6H),1.45(d,1H),1.38(m,1H),1.26(m,1H),1.13(m,6H),1.07(t,3H),0.83(d,3H),0.69(d,3H).

the nuclear magnetic resonance carbon spectrum of the white solid is shown in figure 19, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.83,170.11,157.27,156.20,138.24,130.18,129.64,123.09,118.69,118.64,117.53,73.54,68.08,59.73,57.04,54.12,47.75,44.82,44.23,43.53,37.87,35.42,35.29,27.16,26.11,25.87,25.85,24.48,16.90,16.20,12.51,10.69.

the spectrum of the white solid with high resolution mass spectrum is shown in FIG. 20, HR MS (ESI): m/z Calcd for C ₃₇ H ₅₁ N ₂ O ₅ :603.37925.Found:603.37941(M+H ⁺ ).

Example 7

The synthetic route of the compound of example 7 is the same as that of the compound of example 6.

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-N-propyl-piperazino-cyclooctan-9-yl ester (0.236g, 0.5mmol), N-ethyl- (3-methylphenyl) methylamine (0.149g, 1.0mmol), anhydrous potassium carbonate (0.139g, 1.0mmol) were taken, 1 to 2mg of potassium iodide was added to dissolve in 10mL of acetonitrile, monitored by TLC, and heated to reflux for 20h. After the reaction was completed, the solid was filtered off, concentrated, and subjected to silica gel column chromatography (ethyl acetate: methanol (vol) = 20).

The yellow oil obtained (i.e. compound 7) was characterized:

the nuclear magnetic resonance hydrogen spectrum of the yellow oily matter is shown in figure 21, ¹ H NMR(600MHz,CDCl ₃ )δ:7.16(t,J＝7.2Hz,1H),7.13(s,1H),7.08(d,J＝7.8Hz,1H),7.04(d,J＝7.8Hz,1H),6.50(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.91(d,J＝9Hz,1H),5.74(s,1H),5.38(d,J＝11.4Hz,1H),5.21(d,J＝16.8Hz,1H),3.75(d,1H),3.66(d,1H),3.41(s,2H),3.18(dd,1H),2.68(m,1H),2.31(m,6H),2.03(m,1H),1.68-1.52(m,6H),1.45(d,1H),1.37(m,1H),1.14(m,6H),1.06(t,2H),0.83(t,3H),0.68(t,3H).

the nuclear magnetic resonance carbon spectrum of the yellow oily matter is shown in figure 22, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.89,138.25,137.81,129.57,128.08,127.99,127.82,125.97,117.52,73.54,68.04,59.74,57.59,54.18,47.87,44.79,44.32,44.23,43.53,37.87,35.43,35.28,27.15,26.11,25.87,24.47,21.33,16.91,16.83,16.18,12.47,10.68.

the yellow oil has a high resolution mass spectrum as shown in FIG. 23, HR MS (ESI): m/z Calcd for C ₃₂ H ₄₉ N ₂ O ₄ :525.36868.Found:525.36914(M+H ⁺ ).

Example 8

The synthetic route of the compound of example 8 is the same as that of the compound of example 6.

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-N-propyl-piperazino-cyclooctan-9-yl ester (0.236g, 0.5mmol), N-ethyl- (3,4,5-trimethoxyphenyl) methylamine (0.225g, 1.0mmol), anhydrous potassium carbonate (0.139g, 1.0mmol) were taken, 1 to 2mg of potassium iodide was added and dissolved in 10mL of acetonitrile, monitored by TLC, and heated under reflux for 20h. After the reaction was completed, the solid was filtered off, concentrated, and subjected to silica gel column chromatography (ethyl acetate: methanol (volume) = 20).

The yellow oil obtained (i.e. compound 8) was characterized:

the NMR spectrum of the yellow oil is shown in FIG. 24, ¹ H NMR(600MHz,CDCl ₃ )δ:6.57(s,1H),6.52(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.92(d,J＝9Hz,1H),5.68(s,1H),5.38(d,J＝12Hz,1H),5.21(d,J＝17.4Hz,1H),3.99-3.83(m,9H),3.75(d,1H),3.65(d,1H),3.38(s,2H),3.26(d,1H),3.18(d,1H),2.69(m,2H),2.40-2.33(m,3H),2.04(m,1H),1.65(m,4H),1.55(m,2H),1.45(d,2H),1.38(m,1H),1.28(d,1H),1.14(m,6H),1.07(t,2H),0.83(d,3H),0.69(d,3H).

the nuclear magnetic resonance carbon spectrum of the yellow oily matter is shown in figure 25, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.82,170.24,153.15,138.30,136.90,134.81,117.52,105.39,73.57,68.14,60.83,59.75,58.08,56.08,54.20,47.85,44.83,44.30,43.58,37.91,35.45,35.33,27.18,26.16,25.87,25.84,24.51,16.97,16.25,12.50,10.70.

the high resolution mass spectrum of the yellow oil is shown in FIG. 26, HR MS (ESI): m/z Calcd for C ₃₄ H ₅₃ N ₂ O ₇ :601.38473.Found:601.38526(M+H ⁺ ).

Example 9

The synthetic route for the compound of example 9 is the same as that for the compound of example 6.

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-N-propyl-piperazino-cyclooctan-9-yl ester (0.236g, 0.5mmol), N-ethyl- (3,4-dioxymethylenephenyl) methylamine (0.151g, 1.0mmol), anhydrous potassium carbonate (0.139g, 1.0mmol), 1-2 mg of potassium iodide dissolved in 10mL of acetonitrile, TLC monitoring, and heating and refluxing for 20h. After the reaction was completed, the solid was filtered off, concentrated, and subjected to silica gel column chromatography (ethyl acetate: methanol (volume) = 12).

The resulting yellow oil (i.e., compound 9) was characterized:

the NMR spectrum of the yellow oil is shown in FIG. 27, ¹ H NMR(600MHz,CDCl ₃ )δ:6.84(s,1H),6.70(q,J＝8.4Hz,2H),6.48(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.90(s,3H),5.72(s,1H),5.37(d,J＝11.4Hz,1H),5.20(d,J＝17.4Hz,1H),3.68(d,1H),3.61(d,1H),3.37(m,3H),3.17(q,2H),2.66(m,2H),2.31(m,3H),2.03(m,2H),1.53(m,3H),1.25(d,1H),1.14(d,8H),1.04(t,3H),0.83(d,3H),0.67(d,3H).

the nuclear magnetic resonance carbon spectrum of the yellow oily matter is shown in figure 28, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.85,170.08,165.71,147.65,146.58,138.24,121.85,117.51,109.23,107.76,100.81,73.54,68.05,59.73,57.39,53.97,47.69,44.80,44.22,43.52,37.86,35.41,35.27,27.15,26.10,25.86,25.79,24.47,16.89,16.16,12.52,10.67.

the yellow oil has a high resolution mass spectrum as shown in FIG. 29, HR MS (ESI): m/z Calcd for C ₃₂ H ₄₇ N ₂ O ₆ :555.34286.Found:555.34331(M+H ⁺ ).

Example 10

The synthetic route of the compound of example 10 is the same as that of the compound of example 6.

2- (methylsulfonyl) -hydroxyacetic acid-2-oxo- (4aS, 5R,6S,7S,9R,10R,10aR, 11R) -6-hydroxy-5,7,10,11-tetramethyl-7-vinyl-4a, 10-N-propyl-piperazino-cyclooctan-9-yl ester (0.236g, 0.5mmol), N-ethyl-3- (4' -methoxyphenyl) propylamine (0.193g, 1.0mmol), anhydrous potassium carbonate (0.139g, 1.0mmol) were taken, 1 to 2mg of potassium iodide was added to dissolve in 10mL of acetonitrile, monitored by TLC, and heated to reflux for 20h. After the reaction was completed, a solid was filtered off, concentrated, and subjected to silica gel column chromatography (dichloromethane: methanol (volume ratio) = 40).

The resulting yellow oil (i.e., compound 10) was characterized:

the NMR spectrum of the yellow oil is shown in FIG. 30, ¹ H NMR(600MHz,CDCl ₃ )δ:7.06(d,J＝8.4Hz,2H),6.80(d,J＝8.4Hz,2H),6.48(dd,J ₁ ＝10.8Hz,J ₂ ＝17.4Hz,1H),5.90(d,J＝9Hz,1H),5.70(s,1H),5.34(d,J＝10.8Hz,1H),5.18(d,J＝17.4Hz,1H),3.77(s,3H),3.37(m,2H),3.21(q,2H),2.60(m,5H),2.39(m,1H),2.33(m,2H),2.04(m,1H),1.84(m,1H),1.67(m,5H),1.54(m,3H),1.45(d,1H),1.37(m,1H),1.28(d,1H),1.23(m,1H),1.15(s,3H),1.12(s,3H),1.00(t,2H),0,83(d,3H),0.72(d,3H).

the nuclear magnetic resonance carbon spectrum of the yellow oily matter is shown in figure 31, ¹³ C NMR(150MHz,CDCl ₃ )δ:172.84,170.22,157.68,138.17,134.15,129.16,117.56,113.68,73.54,68.17,59.74,55.20,53.37,48.07,44.80,44.24,43.55,37.88,35.46,35.29,32.56,29.39,27.17,26.12,25.85,24.49,16.95,16.24,12.31,10.70.

the yellow oil has a high resolution mass spectrum as shown in FIG. 32, HR MS (ESI): m/z Calcd for C ₃₄ H ₅₃ N ₂ O ₅ :569.34490.Found:569.39566(M+H ⁺ ).

Test examples

1. Tau protein activity inhibition assay

1.1 cell Resuscitation

Huh7 cells highly expressing human Tau protein were transferred into a centrifuge tube, and centrifuged after adding fresh cell culture medium (DMEM +10% FBS). Discarding the supernatant, adding fresh culture medium into the cell precipitate, mixing, placing in a cell incubator, culturing at 37 deg.C, maintaining constant temperature and humidity, and continuously introducing 5% carbon dioxide gas.

1.2 cell passages

Cell culture medium was discarded at the clean bench. And (4) adding sterilized PBS for washing, removing the PBS, adding pancreatin, and placing in a cell culture box for digestion. When cells were observed to round under the microscope and some of the cells were detached from the bottom of the dish, cell culture medium was added to stop digestion. And (4) lightly blowing and beating by using a cell pipette, blowing up the cells attached to the bottom of the dish, and blowing away. After the cells were transferred to a centrifuge tube and centrifuged, the supernatant was discarded and removed. Adding a proper amount of culture medium, blowing, beating, uniformly mixing, taking the cell suspension, inoculating into a culture bottle, and culturing in a constant temperature and humidity box.

1.3 treatment with drug

On a 96-well plate, a 40 μ M DMSO solution of the test sample was added to the culture solution containing the cells, and the control group was given the same volume of DMSO blank solution. All cells were cultured in an incubator.

1.4 extraction of Total protein from cell samples

The cell samples were first placed on ice, the original medium was aspirated away, and washed twice with pre-chilled PBS. Add the appropriate amount of home-made homogenate (50 mM Tris-HCl pH 7.4-7.5,100mM NaCl,1% Trion X-100,5mM EDTA,1 100 PMSF,1 1000 cocktail containing 4- (2-aminoethyl) -benzenesulfonyl fluoride hydrochloride, aprotinin, betadine, leupeptin, n- [ n- (l-3-trans-carboxymethyl-2-carbonyl) -l-leucyl ] -agmatine, pepstatin A). And repeatedly scraping cells on the bottom surface of the pore plate by using a cell scraper, finally concentrating all homogenate, and collecting the homogenate into a dry centrifugal tube by using a gun head. Shaking, mixing, standing, cracking on ice for 20-30min, and centrifuging in precooled centrifuge. The supernatant is divided into three parts: all samples were sampled at equal volumes and then approximately 10 μ L each was sampled for protein concentration determination, and the remaining liquid and the precipitate obtained after separation were stored in a freezer at-80 ℃ for further use.

1.5 sample preparation

To the sample was added a sample buffer (200 mM Tris-HCl, pH6.8,8% SDS,40% glycerol) in a volume ratio of 3:1, and a dye (bromophenol blue: β -mercaptoethanol volume ratio = 1:3) in a volume ratio of 10.

1.6 sample determination

Protein samples of each group of cells in 1.5 were isolated and assayed by western blotting, and the inhibition ratios were calculated, the results of which are shown in table 1 below.

Wherein the inhibition ratio (%) = (total concentration of Tau protein expressed by blank control cells-concentration of Tau protein sample in cells after separation and purification)/total concentration of Tau protein expressed by blank control cells × 100%.

Inhibition of Tau protein at cellular level by the series of compounds in Table 1

Compound numbering	1	2	3	4	5
						Inhibition (%) 40. Mu.M	-6.015	12.89	64.9	53.54	12.94
Compound numbering	6	7	8	9	10
						Inhibition (%) of 40. Mu.M	100.3	83.82	23.11	83.94	21.55

As can be seen from table 1, compounds 2 to 10 provided in the examples of the present invention have inhibitory activity against Tau protein at a cellular level, and particularly, compounds 6, 7 and 9 have strong inhibitory activity against Tau protein. Therefore, the serial expanded lactam derivatives provided by the embodiment of the invention have better inhibitory activity on Tau protein at a cellular level, and can be used for preparing medicaments for treating neurodegenerative diseases such as senile dementia, parkinson and the like.

In addition, through a plurality of experimental researches, the inventor finds that the parent nucleus structure in the series of compounds is

Is replaced by

Thereafter, the inhibitory activity of the series of compounds on Tau protein disappeared.

The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; such modifications and substitutions do not substantially depart from the spirit and scope of the embodiments of the present invention, and are intended to be included within the scope of the present invention.

Claims

1. A compound having the structure of formula I:

wherein R is selected from the following structures:

R ₁ represents

Y represents carbon or nitrogen;

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound having the structure of formula i is selected from the group consisting of:

3. a process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-2,

when R is

When the compound is

The preparation method of the compound comprises the following steps:

R ₃ represents fluorine or methoxy;

s1, synthesis of a compound III:

s2, synthesis of a compound I-a:

4. The method according to claim 3, wherein in step S1, the first base is at least one of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium or potassium tert-butoxide, triethylamine, pyridine, piperidine; the first solvent is at least one of acetonitrile, acetone, dimethyl sulfoxide or dimethylformamide and dimethylacetamide;

in step S2, the second solvent is at least one of dimethylformamide, dimethylacetamide, dichloromethane, chloroform, or dimethylsulfoxide.

5. A process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-2,

when R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-b:

6. The method of claim 5, wherein the second base is potassium carbonate; the first catalyst is potassium iodide; the third solvent is acetonitrile.

7. A process for the preparation of a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-2,

when R is

When the compound is

The preparation method of the compound comprises the following steps:

synthesis of Compounds I-c:

and reacting the compound VIII with the structure shown in the formula VIII with the compound II with the formula II in a fourth solvent in the presence of a third base and a second catalyst to obtain the compound I-c with the formula I-c.

8. The method of claim 7, wherein the third base is potassium carbonate; the second catalyst is potassium iodide; the fourth solvent is acetonitrile.

9. A pharmaceutical composition having Tau protein inhibitory activity comprising a compound having the structure of formula i as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound having the structure of formula i according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention and/or treatment of aging and neurodegenerative diseases.