CN112552232B - A modified derivative of pyridone six-alkyne amine and its preparation method and application - Google Patents

Abstract

The invention is aThe modified derivatives of pyridone hexa-alkynylamine as shown in formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof and application of the modified derivatives of pyridone hexa-alkynylamine or pharmaceutically acceptable salts thereof in preparing medicaments for preventing or treating related diseases, particularly Alzheimer's disease and Parkinson's disease by inhibiting monoamine oxidase, chelating metallic iron ions, resisting A beta and resisting oxidation. The invention synthesizes a series of novel single-molecule multi-target anti-AD active compounds, innovatively combines a pyridone derivative with iron ion chelating activity and propargylamine with MAO-B inhibitory activity, has obvious advantages for Alzheimer's disease with complex pathogenesis, and the combined molecules are far superior to CP20 (deferiprone) in the aspect of iron ion chelating activity.

Description

A modified derivative of pyridone six-alkyne amine and its preparation method and application

technical field

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of multi-target anti-Aβ aggregation and anti-oxidation agents with azirynyl and pyridone derivatives that have the ability to chelate iron ions and inhibit monoamine oxidase B. Anti-Alzheimer's disease pyridone hexa-alkyne amine modified derivatives and its preparation method and its application in the preparation of drugs for the treatment of Alzheimer's disease and other diseases.

Background technique

Alzheimer's disease (AD) is a neurodegenerative disease that affects the physical and mental health of tens of millions of elderly people around the world, causing patients to show symptoms such as memory loss and cognitive decline. As global aging intensifies, the number of people living with AD is expected to increase to 131 million by 2050.

The cause of AD is a mystery. Case analysis shows that the etiology of AD is closely related to extracellular β-amyloid (Aβ), intracellular neurofibrillary tangles (NFT), glial cell activation, inflammation and mitochondrial disease. So far, the only four clinically available drugs, namely Donepezil, Galantamine, Rivastigmine and Memantine, are not effective in completely curing the disease. In recent years, the defects of drugs targeting N-methyl-D-aspartic acid (NMDA) or acetylcholinesterase (AChE) have gradually emerged, and research on AD treatment options has gradually shifted from single-target combination therapy to multi-target Development of Point Therapy. Targeted Drugs (MTDs).

With the deepening of research on the pathological mechanism of AD, researchers have found that the level of metal ions in the brain of patients is 3-7 times that of normal people. Accumulating evidence indicates that the disturbance of biometal homeostasis interferes with the normal degradation of amyloid precursor protein (APP), which leads to the production of interfering factors in the human body, thereby promoting the conversion of APP into insoluble monomeric amyloid-β (Aβ). These metals will further combine with monomeric Aβ to promote its aggregation into senile plaques. In addition, high iron content will promote the accumulation of NFT. Transition metal cations with variable valence states, especially iron ions, can also generate reactive oxygen species (ROS) through electron transfer catalysis when their valence state changes. ROS are also considered to be the culprits of oxidative damage in the AD brain. Therefore, modulating iron ion levels in the brain is a potential therapeutic strategy for the treatment of AD.

At the same time, studies have shown that the levels of monoamine oxidases (MAOs) in the brains of AD patients are also abnormal, especially MAO-B. Under physiological conditions, MAO catalyzes the oxidative deamination of monoamine neurotransmitters to aldehydes. Neurotoxic products catalyzed by MAO-B, such as hydrogen peroxide, promote the formation of ROS and cause neuronal damage. Therefore, the development of MAO-B inhibitors is considered as a potential option for the treatment of AD.

Therefore, the development of multi-target iron chelators with MAO-B inhibitory activity, anti-Aβ and anti-oxidation has great research prospects in the research and development of multi-target anti-AD active compounds.

Contents of the invention

In order to solve the above problems, the present invention designed a multi-drug drug with potential anti-AD activity, iron chelation and MAO-B inhibitory activity based on computer-aided drug design, drug-like 5 rules, and multi-platform prediction of blood-brain barrier penetration. Pyridone hexa-alkyne amine modified derivative with potential anti-Alzheimer's disease, and preparation method thereof Application of iron ion, anti-Aβ and anti-oxidation to prevent or treat related diseases, especially Alzheimer's disease and Parkinson's disease.

To achieve the above object, the present invention provides the following technical solutions:

The present invention provides a modified derivative of pyridone hexa-alkyne amine as shown in formula (I) and a pharmaceutically acceptable salt thereof:

In formula (I):

R ¹ is H or C ₁ -C ₆ straight or branched chain alkyl;

R ² is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH, COOCH ₃ or (CH ₂ ) _m1 OH, m ₁ =1-6 ;

R ³ is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH or COOCH ₃ ;

其中，X为C₃-C₁₀的环烷基；m₂＝0-6；R ⁴ is C ₁ -C ₁₆ straight or branched alkyl, C ₂ -C ₁₆ straight or branched alkynyl, C ₂ -C ₁₆ straight or branched alkenyl, (CH ₂ )m _2X ,

Wherein, X is a C ₃ -C ₁₀ cycloalkyl group; m ₂ =0-6;

Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Z ₁ , Z ₂ , Z ₃ , Z ₄ , and Z ₅ are each independently H, CH ₃ , Cl, Br, F, I, CF ₃ , CN, NH ₂ , NO ₂ , OH, OCH ₃ , CH(CH ₃ ) ₂ or C(CH ₃ ) ₃ ;

n ₁ or n ₂ is the number of CH ₂ , and n ₁ or n ₂ is 1-6.

其中，Y₁、Z₁各自独立为H、CH₃、Cl、F、CF₃、OCH₃，n₁或n₂为1-3。Preferably, each of R ¹ , R ² or R ³ is independently H or C ₁ -C ₄ straight or branched chain alkyl; R ⁴ is C ₁ -C ₄ straight or branched chain alkyl, C ₂ - C ₄ straight or branched chain alkynyl or

Wherein, Y ₁ and Z ₁ are each independently H, CH ₃ , Cl, F, CF ₃ , OCH ₃ , and n ₁ or n ₂ is 1-3.

n₁或n₂优选为1。Preferably, R ¹ is CH ₃ ; R ² and R ³ are H; R ⁴ is benzyl,

n ₁ or n ₂ is preferably 1.

Specifically, the modified derivative of pyridone six-alkyne amine shown in formula (I) is one of the following compounds:

Specifically, the pharmaceutically acceptable salt is the hydrochloride salt of the modified derivative of pyridone hexa-alkyne amine represented by formula (I).

The present invention also provides a preparation method of a modified derivative of pyridone hexa-alkyne amine represented by formula (I). The synthesis idea is as follows: first, the intermediate represented by formula 4 is obtained through a series of reactions using the compound of formula 1 as a raw material; The compound shown in formula 5 is synthesized by different substituted amine derivatives as raw materials, then the intermediate of formula 4 and the intermediate of formula 5 are put together by reaction to obtain the compound of formula 6, and finally the compound of formula (I) is obtained by deprotection the indicated target compounds.

Specifically, the method includes the following steps:

(1) Dissolve the compound shown in formula 4 in organic solvent A, add the compound of formula 5, basic substance B, and react at 30-80°C for 24-48h. After the reaction, the obtained reaction solution C is post-treated A to obtain the formula 6 compounds; the ratio of the amount of the compound of the formula 4, the compound of the formula 5 and the basic substance B is 1:0.5～5:1～5 (preferably 1:0.5～2:1～3); the described The alkaline substance B is one or any mixture of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably triethylamine;

(2) Dissolve the compound of formula 6 obtained in step (1) in anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of 0.01 to 0.04 mmol/mL compound of formula 6, under nitrogen protection, at -78°C-0°C Add anhydrous dichloromethane solution of boron trichloride (BCl ₃ ) dropwise slowly to the anhydrous dichloromethane solution of the compound of formula 6. After the dropwise addition, continue stirring for 1-3 h, add methanol X to quench, and then transfer Continue to stir and react at room temperature for 12-24h, and the obtained reaction solution D is subjected to post-treatment B to obtain the compound shown in formula (I); the compound shown in formula 6 and boron trichloride have a substance ratio of 1:1 ～5 (preferably 1:2～3); the volume of the methanol X is 15～40mL/mmol (preferably 20～35mL/mmol) based on the amount of the intermediate of formula 6; the methanol X is also methanol , which is defined here as Methanol X for convenience of description, and has no special meaning;

In formulas 4-6 or formula (I), n ₁ and n ₂ are the number of CH ₂ , and n ₁ or n ₂ are 1-6 respectively;

R ¹ is H, C ₁ -C ₆ straight or branched chain alkyl;

R ² is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH, COOCH ₃ or (CH ₂ ) _m1 OH, m ₁ =1-6 ;

R ³ is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH or COOCH ₃ ;

其中，X为C₃-C₁₀的环烷基；m₂＝0-6；R ⁴ is C ₁ -C ₁₆ straight chain or branched chain alkyl, C ₂ -C ₁₆ straight chain or branched chain alkynyl, C ₂ -C ₁₆ straight chain or branched chain alkenyl, (CH ₂ ) _m2 X,

Wherein, X is a C ₃ -C ₁₀ cycloalkyl group; m ₂ =0-6;

Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Z ₁ , Z ₂ , Z ₃ , Z ₄ , and Z ₅ are each independently H, CH ₃ , Cl, Br, F, I, CF ₃ , CN, _NH2 , _NO2 , OH, _OCH3 , CH( _CH3 ) ₂ or C( _CH3 ) ₃ .

其中，Y₁、Z₁各自独立为H、CH₃、Cl、F、CF₃、OCH₃，n₁或n₂为1-3。Preferably, each of R ¹ , R ² or R ³ is independently H or C ₁ -C ₄ straight or branched chain alkyl; R ⁴ is C ₁ -C ₄ straight or branched chain alkyl, C ₂ - C ₄ straight or branched chain alkynyl or

Wherein, Y ₁ and Z ₁ are each independently H, CH ₃ , Cl, F, CF ₃ , OCH ₃ , and n ₁ or n ₂ is 1-3.

n₁或n₂优选为1。Preferably, R ¹ is CH ₃ ; R ² and R ³ are H; R ⁴ is benzyl,

n ₁ or n ₂ is preferably 1.

Preferably, the hexa-alkyne amine-modified derivative of pyridone represented by formula (I) is one of the following compounds:

Preferably, the organic solvent A described in step (1) is acetone, ethanol, methanol, methylene chloride, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N,N -one or a mixture of any of dimethylformamide and N,N-dimethylacetamide, preferably acetonitrile.

Further, in step (1), the amount of the organic solvent A added is 10-20 mL/mmol based on the amount of the compound of formula 4.

Further, in step (1), the reaction conditions are preferably 50-70°C for 30-40 hours.

Further, post-treatment A in step (1) is: concentrating the reaction solution C under reduced pressure, performing gradient elution with a mixed solution of dichloromethane:methanol=30:1～15:1, and collecting The eluate containing the target product (detected by TLC spot plate) was concentrated under reduced pressure to remove the solvent to obtain the compound represented by formula 6.

Further, the concentration of boron trichloride in the anhydrous dichloromethane solution of boron trichloride described in step (2) is 0.05～0.15mmol/mL (preferably 0.08mmol/mL～0.13mmol/mL)

Further, the post-treatment B in step (2) is: the obtained reaction solution D is distilled off under reduced pressure to remove the solvent, and recrystallized with a mixed solvent of methanol and ether to obtain the compound shown in formula (I). In the mixed solvent of methanol and ether, The volume ratio of methanol to ether is 1:5.

Further, in step (2), the reaction temperature is preferably -20 to -40°C.

In addition, the compound represented by formula 4 of the present invention is specifically prepared according to the following method:

S1: Dissolve the hydroxypyrone, benzyl bromide and basic substance E shown in Formula 1 in the organic solvent M, and react at 25-90°C for 2-12 hours. After the reaction is completed, the obtained reaction solution G is concentrated under reduced pressure Obtain solid, wash with water, and dry to obtain the compound shown in formula 2; The molar ratio of the feeding material of hydroxypyrone shown in formula 1, benzyl bromide and basic substance E is 1:1～5:1～ 4 (preferably 1:1～3:2～4); the alkaline substance E is one or any of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine A mixture of several, preferably potassium carbonate or sodium hydroxide, more preferably potassium carbonate.

S2: Dissolve the intermediate shown in Formula 2 in the organic solvent H, add the compound of Formula 7 and the basic substance A, and react at 30-80°C for 1-5h. After the reaction, the obtained reaction solution J is post-treated C obtains the compound shown in formula 3; The substance ratio of described formula 2, formula 7 compound and basic substance A is 1:1～4:1～4 (preferably 1:2～4:2～4 ); the compound of formula 7 is one of the following compounds: C ₁ -C ₆ linear or branched fatty amine, ammonia; the basic substance A is potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, carbonic acid One or any mixture of sodium hydrogen or triethylamine, preferably potassium carbonate or sodium hydroxide, more preferably sodium hydroxide; when the compound of formula 7 is ammonia, its mass fraction is 25-28% The form of ammonia water participates in the reaction;

S3: Thionyl chloride (AR, purity ≥ 99.0%) is added dropwise to the intermediate shown in formula 3, and reacted at 20-50°C for 1-5h. After the reaction is completed, the obtained reaction solution K is post-treated. D The intermediate shown in formula 4 is obtained; the substance ratio of the intermediate shown in formula 3 and thionyl chloride is 1:1-5 (preferably 1:1-3).

In formulas 1-4, _n2 is the number of _CH2 , and _n2 is 1-6;

R ¹ is H, C ₁ -C ₆ straight or branched chain alkyl;

R ² is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH, COOCH ₃ or (CH ₂ ) _m1 OH, m ₁ =1-6 ;

R ³ , is H, C ₁ -C ₆ linear or branched alkyl, F, CF ₃ , OH, OCH ₃ , CHOHCH ₃ , COOH or COOCH ₃ ;

Further, the organic solvent M described in S1 is acetone, ethanol, methanol, methylene chloride, chloroform, carbon tetrachloride, acetonitrile, toluene, dimethyl sulfoxide, dioxane, N,N-dimethyl One or a mixture of formamide and N,N-dimethylacetamide, preferably acetone or ethanol, more preferably ethanol.

Still further, the amount of the organic solvent M added is 1-3 mL/mmol based on the amount of the hydroxypyrone represented by the formula 1.

Furthermore, in S1, the reaction temperature is preferably 25-70°C, and the reaction time is preferably 3-8h.

Further, in S2, the organic solvent H is acetone, ethanol, methanol, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, toluene, dimethyl sulfoxide, dioxane, N,N-di One or a mixture of any of methylformamide and N,N-dimethylacetamide, preferably ethanol.

Still further, the amount of the organic solvent H added is 1-3 mL/mmol based on the amount of the intermediate represented by the formula 2.

Furthermore, in S2, the reaction temperature is preferably 40-70°C, and the reaction time is preferably 2-4h.

Further, the post-treatment C in S2 is: after the reaction stops, the reaction solution J is concentrated under reduced pressure, and subjected to silica gel column chromatography (dichloromethane:methanol=50:1～20:1 gradient elution), to collect the reaction solution containing the target The eluate of the product (detected by TLC spot plate) was concentrated under reduced pressure to remove the solvent to obtain the compound represented by formula 3.

Furthermore, in S3, the reaction temperature is preferably 25-40°C, and the reaction time is preferably 2-4h.

Further, in S3, the amount of thionyl chloride (AR, purity ≥ 99.0%) is 1-5 mL/mmol based on the amount of the intermediate represented by the formula 3.

Further, the method of post-processing D in S3 is: the reaction solution K is concentrated under reduced pressure to remove the solvent, and recrystallized with a mixed solvent of methanol and ether to obtain the compound shown in formula 4. The volume ratio of methanol and ether in the mixed solvent of methanol and ether is 1:8.

Further, the compound represented by formula 5 of the present invention is prepared according to the following method:

Add different substituted amine derivatives and basic substances M into the organic solvent L, and the compound of formula 8 is also dissolved in the organic solvent D and placed in a constant pressure dropping funnel, and reacted dropwise at 10-50°C for 5-24h, and the reaction After the end, the obtained reaction solution P is subjected to post-treatment E to obtain the compound shown in formula 5; the substance ratio of the different substituted amine derivatives, the compound of formula 8 and the basic substance M is 1:0.5～2:1 ~5 (preferably 1:0.5~1:1~3);

The different substituted amine derivatives are one of the following compounds: C ₁ -C ₁₆ straight chain or branched saturated fatty amine, C ₂ -C ₁₆ straight chain or branched alkyne amine, C ₂ -C ₁₆ straight chain or branched enamine, H ₂ N(CH ₂ ) _m2 X,

The alkaline substance M is one or any mixture of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine, preferably potassium carbonate or triethylamine, more Potassium carbonate is preferred;

In H ₂ N(CH ₂ ) _m2 X, X is a C ₃ -C ₁₀ cycloalkyl group; m ₂ =0-6;

In formula 5 and formula 8,

R ⁴ is C ₁ -C ₁₆ straight chain or branched chain alkyl, C ₂ -C ₁₆ straight chain or branched chain alkynyl, C ₂ -C ₁₆ straight chain or branched chain alkenyl, (CH ₂ ) _m2 X,

Wherein, X is a C ₃ -C ₁₀ cycloalkyl group; m ₂ =0-6;

Y ₁ , Y ₂ , Y ₃ , Y ₄ , Y ₅ , Z ₁ , Z ₂ , Z ₃ , Z ₄ , and Z ₅ are each independently H, CH ₃ , Cl, Br, F, I, CF ₃ , CN, NH ₂ , NO ₂ , OH, OCH ₃ , CH(CH ₃ ) ₂ or C(CH ₃ ) ₃ ; n ₁ is 1-6;

Further, the organic solvent L or organic solvent D described in the preparation method of the compound of formula 5 is acetone, ethanol, methanol, methylene chloride, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane Cyclo, N,N-dimethylformamide, N,N-dimethylacetamide or any mixture of several, preferably N,N-dimethylformamide.

Further, the volume of the organic solvent L is 1-5 mL/mmol based on the amount of the different substituted amine derivatives; the volume of the organic solvent D is based on the amount of the compound of formula 8 Calculated as 1 ~ 5mL/mmol.

Further, the reaction conditions are preferably 25-40°C, and the reaction time is preferably 10-20h.

Further, the post-treatment E is: add ethyl acetate to the reaction solution P, extract 3 times with saturated brine, combine the organic layers, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and finally use n-hexane:acetic acid Ethyl ester=5:1 was used as the eluent for silica gel column chromatography, and the eluate containing the target compound (detected by TLC spot plate) was combined and concentrated under reduced pressure to obtain the intermediate shown in formula 5.

The present invention also provides a modified derivative of the above-mentioned pyridone hexa-alkyne amine or a pharmaceutically acceptable salt thereof in the preparation of drugs for preventing or treating related diseases by inhibiting monoamine oxidase, chelating metal iron ions, anti-Aβ and anti-oxidation Applications.

Preferably, the disease is Alzheimer's disease or Parkinson's disease.

Compared with the prior art, the beneficial effect of the present invention is that: the present invention synthesizes a series of novel single-molecule multi-target anti-AD active compounds, innovatively combining pyridone derivatives with iron ion chelating activity with MAO -B inhibitory activity of propargyl amine organically combined has a significant advantage for Alzheimer's disease with complex pathogenesis, and the combined molecule is far superior to CP20 (deferiprone) in terms of iron ion chelation activity.

Detailed ways

The present invention will be further elaborated below in conjunction with specific examples, but the present invention is not limited to these examples.

Example 1

The preparation method of 1-methyl-2-((benzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a1)

Kojic acid (12.78g, 90mmol), benzyl bromide (23.08g, 135mmol), and potassium carbonate (24.84g, 180mmol) were added to a 500mL single-necked bottle, and reacted at 60°C for 5h under the condition of ethanol as the solvent (250mL). After the reaction, the reaction system was concentrated under reduced pressure to obtain the crude product as a light yellow solid, which was washed with water and dried to obtain a white solid (18.75 g), with a yield of 89.8%.

Take the above white solid (13.92g, 60mmol), dissolve it in ethanol (150mL), then add sodium hydroxide (4.80g, 120mmol), 9.30g methylamine aqueous solution (mass fraction: 40%; methylamine 120mmol), at 50 The reaction was carried out at ℃ for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=50:1～20:1 gradient elution, the gradient ratio used was: 50:1,35 :1,20:1), the eluate containing the target compound (obtained by TLC plate) was combined and concentrated under reduced pressure to obtain a brownish yellow solid (10.25g), with a yield of 69.7%.

Take the above tan solid (9.80g, 40mmol), put it in a 150mL single-necked bottle, slowly add thionyl chloride (AR, purity ≥ 99.0%, 80mL) dropwise, and stir the reaction at 30°C for 2h. After completion, the reaction solution was concentrated under reduced pressure, recrystallized from a methanol/ether mixed solution (v:v=1:8) to obtain an intermediate of formula 4 (9.21g), 1-methyl-2-(chloromethyl)-5 -Hydroxypyridin-4-one, yield 87.5%.

Benzylamine (0.21g, 2mmol), potassium carbonate (0.41g, 3mmol) and N,N-dimethylformamide (10mL) were added to a 50mL single-necked bottle, and 3-bromopropane Alkyne (0.12g, 1mmol) in N,N-dimethylformamide solution (3mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL) was added and washed with 20mL ×3 extracted with saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1 elution), and collected the target compound (through The eluate (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.10 g), with a yield of 69.0%.

Take the above-mentioned bright yellow transparent liquid (0.10g, 0.69mmol) into a 50mL single-necked bottle, add 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.27g, 1.04mmol) in sequence, Triethylamine (0.11g, 1.04mmol), using acetonitrile (12mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated under reduced pressure, purified by silica gel column chromatography (dichloromethane:methanol= 30:1～15:1 gradient ratio used for gradient elution: 30:1, 20:1, 15:1), collect the eluate containing the target product (obtained by TLC plate), concentrate under reduced pressure to obtain a yellow oil Liquid (0.18g), yield 70.1%.

Add the above-mentioned oily liquid (0.18g, 0.48mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (0.96mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane solution (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted trichloro Boron solution, after dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, and finally concentrate the reaction solution under reduced pressure, and use methanol/diethyl ether (v:v= 1:5) mixed solution was recrystallized to obtain a white solid a1 (0.13g) with a yield of 96.0%.

mp173-175℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₈ N ₂ O ₂ [M+H]+: 283.1441; found: 283.1438; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12 ( s,1H),8.28(s,1H),7.42(s,1H),7.33(d,J＝4.4Hz,3H),7.31–7.24(m,1H),4.04(s,3H),3.86(s ,2H),3.70(s,2H),3.38(t,J=2.4Hz,1H),3.27(d,J=2.4Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ160.26,146.27, 144.67, 137.54, 133.98, 129.53, 128.89, 128.03, 114.74, 77.94, 65.39, 57.48, 53.90, 43.53, 41.75.

Example 2

The preparation method of 1-methyl-2-((3-chlorobenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a2)

3-Chlorobenzylamine (0.28g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (10mL) were added to a 50mL single-necked bottle, and then 3 -Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (2mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (20mL) was added , extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1), collected the The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.14 g), with a yield of 77.8%.

Take the above-mentioned bright yellow transparent liquid (0.12g, 0.67mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.10g, 1mmol), with acetonitrile (16mL) as the reaction solvent, at 60 ° C for 36h, after the reaction, the concentrated reaction solution was purified by silica gel column chromatography (dichloromethane: Methanol=30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC plate), and concentrate under reduced pressure A yellow oily liquid (0.17 g) was obtained with a yield of 62.3%.

Add the above-mentioned oily liquid (0.12g, 0.29mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (0.87mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane solution (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride at -30°C Solution, after dropping, continue to keep stirring at this temperature for 2h, add 10mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12h, finally concentrate the reaction solution, and use methanol/ether (v:v=1:5) The mixed solvent was recrystallized to obtain a white solid a2 (0.80 g) with a yield of 87.0%.

mp177-179℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ ClN ₂ O ₂ [M+H]+: 317.1051; found: 317.1050; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.16( s,1H),8.29(s,1H),7.40(s,1H),7.38–7.28(m,3H),4.05(s,3H),3.86(s,2H),3.71(s,2H),3.41 (t, J=2.4Hz, 1H), 3.29 (d, J=2.4Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ ) δ160.24, 146.24, 144.65, 140.41, 133.98, 133.51, 130.76, 129.05, 128.12, 127.97, 114.71, 80.23, 77.95, 56.86, 54.04, 43.52, 41.93.

Example 3

The preparation method of 1-methyl-2-((3-fluorobenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a3)

3-Fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.34g, 2.5mmol) and N,N-dimethylformamide (9mL) were added to a 50mL single-necked bottle respectively, and the 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (3mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL ), extracted with 20mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1 elution), the collection containing The eluate of the target compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.11 g), with a yield of 67.5%.

Take the above-mentioned bright yellow transparent liquid (0.10g, 0.61mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.15g, 1.5mmol), using acetonitrile (16mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was finished, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.15 g), yield 63.1%.

Add the above-mentioned oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.14mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane solution (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride at -30°C Solution, after dropping, continue to keep stirring at this temperature for 2h, add 10mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12h, finally concentrate the reaction solution, and use methanol/ether (v:v=1:5) The mixed solvent was recrystallized to obtain a white solid a3 (0.09 g) with a yield of 78.9%.

mp185-187℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ FN ₂ O ₂ [M+H]+: 301.1347; found: 301.1349; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.15( s,1H),8.28(s,1H),7.43–7.34(m,2H),7.21–7.06(m,3H),4.04(s,3H),3.86(s,2H),3.71(s,2H) ,3.40(t, J＝2.4Hz, 1H), 3.28(d, J＝2.6Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ162.67(d, ¹ J _CF ＝263.4Hz), 160.25, 146.38, 144.62, 140.84(d, ³ J _CF ＝7.3Hz), 133.98, 130.82(d, ³ J _CF ＝8.3Hz), 125.42(d, ⁴ J _CH ＝2.4Hz), 115.89(d, ² J _CF ＝21.1), 114.80(d, ² J _CF ＝20.9), 114.62, 80.23, 77.89, 56.91, 54.02, 43.51, 41.93.

Example 4

The preparation method of 1-methyl-2-((4-methylbenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a4)

4-Methylbenzylamine (0.24g, 2mmol), potassium carbonate (0.28g, 2mmol) and N,N-dimethylformamide (8mL) were added to a 50mL single-necked bottle respectively, and then the 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (4mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (20mL ), extracted with 20mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1 elution), the collection containing The eluate of the target compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g), with a yield of 75.5%.

Take the above-mentioned bright yellow transparent liquid (0.08g, 0.5mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.15g, 1.5mmol), using acetonitrile (20mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was finished, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.13 g), yield 67.3%.

Add the above-mentioned oily liquid (0.13g, 0.34mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.02mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave white solid a4 (0.08g) with a yield of 79.5%.

mp190-192℃; ESI-HRMS: m/z calcd for C ₁₈ H ₂₀ ClN ₂ O ₂ [M+H]+: 297.1598; found: 297.1581; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08( s,1H),8.26(s,1H),7.38(s,1H),7.21(d,J=8.0Hz,2H),7.13(d,J=7.8Hz,2H),4.03(s,3H), 3.83(s, 2H), 3.64(s, 2H), 3.36(t, J=2.4Hz, 1H), 3.25(d, J=2.4Hz, 2H), 2.28(s, 3H). ¹³ C NMR (100MHz ,DMSO-d ₆ )δ160.23, 146.41, 144.64, 137.20, 134.46, 133.97, 129.51, 129.45, 114.68, 77.99, 77.88, 57.22, 53.81, 43.51, 41.63, 21.20.

Example 5

The preparation method of 1-methyl-2-((4-fluorobenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a5)

4-fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (9mL) were added to a 50mL single-necked bottle, and then 3 -Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (4mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL) was added , extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1), collected the The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.13 g), with a yield of 79.7%.

Take the above-mentioned bright yellow transparent liquid (0.10g, 0.61mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.20g, 2mmol), with acetonitrile (18mL) as the reaction solvent, at 60 ° C for 36h, after the reaction, the concentrated reaction solution was purified by silica gel column chromatography (dichloromethane: Methanol=30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC plate), and concentrate under reduced pressure A yellow oily liquid (0.15 g) was obtained with a yield of 63.1%.

Add the above-mentioned oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane solution (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride at -30°C Solution, after dropping, continue to keep stirring at this temperature for 2h, add 10mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12h, finally concentrate the reaction solution, and use methanol/ether (v:v=1:5) The mixed solvent was recrystallized to obtain a white solid a5 (0.10 g) with a yield of 87.7%.

mp188-190℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ FN ₂ O ₂ [M+H]+: 301.1347; found: 301.1345; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.16( s,1H),8.29(s,1H),7.42(s,1H),7.41–7.35(m,2H),7.18–7.12(m,2H),4.03(s,3H),3.85(s,2H) ,3.68(s,2H),3.39(t,J=2.4Hz,1H),3.26(d,J=2.4Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ162.02(d, ¹ J _CF ＝242Hz),160.28,146.32,144.66,133.99,133.03,131.50(d, ³ J _CF ＝8.2Hz),115.63(d, ² J _CF ＝21.1Hz)114.70,80.14,77.92,56.64,53.85,43.52 ,41.75.

Example 6

The preparation method of 1-methyl-2-((4-chlorobenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a6)

4-Chlorobenzylamine (0.28g, 2mmol), potassium carbonate (0.41g, 3mmol) and N,N-dimethylformamide (10mL) were added to a 50mL single-necked bottle, and 3 -Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (3mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL) was added , extracted with 20 mL×3 saturated brine, combined the organic layers, added anhydrous sodium sulfate to dry, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), collected the target The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g), with a yield of 66.7%.

Take the above-mentioned bright yellow transparent liquid (0.09g, 0.5mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.10g, 1mmol), with acetonitrile (15mL) as the reaction solvent, at 60 ° C for 36h, after the reaction, the concentrated reaction solution was purified by silica gel column chromatography (dichloromethane: Methanol=30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC plate), and concentrate under reduced pressure A yellow oily liquid (0.17 g) was obtained with a yield of 83.5%.

Add the above-mentioned oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave a white solid a6 (0.11 g) with a yield of 93.8%.

mp187-189℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ ClN ₂ O ₂ [M+H]+: 317.1051; found: 317.1054; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10( s,1H),8.30–8.23(m,1H),7.45–7.33(m,6H),4.03(s,3H),3.84(s,2H),3.68(s,2H),3.38(t,J＝ 2.4Hz,1H),3.26(d,J＝2.4Hz,2H). ¹³ CNMR(100MHz,DMSO-d ₆ )δ160.28,146.19,144.68,136.62,133.94,132.55,131.38,128.84,114.66,78.01,77.86, 56.64, 53.88, 43.57, 41.80.

Example 7

The preparation method of 1-methyl-2-((2-chlorobenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a7)

2-Chlorobenzylamine (0.56g, 4mmol), potassium carbonate (1.10g, 8mmol) and N,N-dimethylformamide (20mL) were added to a 50mL single-necked bottle respectively, and then 3 -Bromopropyne (0.24g, 2mmol) in N,N-dimethylformamide solution (8mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (30mL) was added , extracted with 30 mL×4 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), collected the The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.26 g), with a yield of 72.2%.

Take the above-mentioned bright yellow transparent liquid (0.18g, 1mmol) in a 50mL one-mouth bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.39g , 1.5mmol), triethylamine (0.20g, 2mmol), with acetonitrile (25mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated, purified by silica gel column chromatography (dichloromethane: Methanol=30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC plate), and concentrate under reduced pressure A yellow oily liquid (0.26 g) was obtained with a yield of 63.9%.

Add the above-mentioned oily liquid (0.16g, 0.39mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.18mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave white solid a7 (0.09g) with a yield of 72.8%.

mp190-192℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ ClN ₂ O ₂ [M+H]+: 317.1051; found: 317.1056; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.17( s,1H),8.29(s,1H),7.49–7.40(m,2H),7.36–7.28(m,2H),4.02(s,3H),3.89(s,2H),3.77(s,2H) ,3.42(t,J=2.4Hz,1H),3.31(d,J=2.4Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ160.23,146.18,144.73,135.08,133.99,133.97,131.90, 130.03, 129.87, 127.74, 115.04, 78.04, 77.99, 54.34, 54.14, 43.38, 41.98.

Example 8

The preparation method of 1-methyl-2-((2-methoxybenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a8)

Add 2-methoxybenzylamine (0.82g, 6mmol), potassium carbonate (1.66g, 12mmol) and N,N-dimethylformamide (30mL) into a 50mL single-necked bottle respectively, and then pass through a constant pressure dropping funnel 3-Bromopropyne (0.36g, 3mmol) in N,N-dimethylformamide solution (12mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate ( 40 mL), extracted with 40 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), collected The eluate containing the target compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.42 g), with a yield of 80.0%.

Take the above-mentioned bright yellow transparent liquid (0.17g, 1mmol) in a 50mL one-mouth bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.39g , 1.5mmol), triethylamine (0.15g, 1.5mmol), using acetonitrile (20mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.25 g), yield 62.2%.

Add the above-mentioned oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave a white solid a8 (0.09 g) with a yield of 78.0%.

mp136-138℃; ESI-HRMS: m/z calcd for C ₁₈ H ₂₀ N ₂ O ₃ [M+H]+: 313.1547; found: 313.1550; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.20( s,1H),8.31(s,1H),7.40(s,1H),7.26(t,J＝7.3Hz,2H),7.02–6.85(m,2H),4.03(s,3H),3.87(s ,2H),3.73(s,3H),3.65(s,2H),3.39(s,1H),3.30(d,J=2.4Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ160. 21,158.03,146.07,144.75,134.00,131.03,129.62,124.85,120.64,115.13,111.44,78.13,77.84,55.81,54.09,51.56,43.37,42.00.

Example 9

The preparation method of 1-methyl-2-((4-trifluoromethylbenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4(1H)-one (a9)

Add 4-trifluoromethylbenzylamine (0.35g, 2mmol), potassium carbonate (0.48g, 3.5mmol) and N,N-dimethylformamide (9mL) into a 50mL single-necked bottle respectively, and then drop Slowly add 3-bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (4mL) dropwise into the reaction solution through a liquid funnel, and stir at 30°C for 12h. After the reaction, add ethyl acetate Esters (15 mL), extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1), collected The eluate containing the target compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.15 g), with a yield of 70.4%.

Take the above-mentioned bright yellow transparent liquid (0.14g, 0.66mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.27 g, 1.02mmol), triethylamine (0.21g, 2.04mmol), using acetonitrile (20mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloro Methane:methanol=30:1～15:1 gradient elution, used gradient ratio is: 30:1, 20:1, 15:1), collect the eluate containing target compound (obtained by TLC plate), subtract Concentrated under reduced pressure to obtain a yellow oily liquid (0.24 g), yield 82.6%.

Add the above-mentioned oily liquid (0.17g, 0.39mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.17mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave a white solid a9 (0.11 g) with a yield of 80.6%.

mp194-196℃; ESI-HRMS: m/z calcd for C ₁₈ H ₁₇ F ₃ N ₂ O ₂ [M+H]+: 351.1315; found: 351.1318; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11. 13(s,1H),8.27(s,1H),7.69(d,J=8.1Hz,2H),7.57(d,J=8.0Hz,2H),7.41(s,1H),4.05(s,3H ), 3.89(s, 2H), 3.80(s, 2H), 3.42(t, J=2.4Hz, 2H), 3.30(d, J=2.4Hz, 2H). ¹³ C NMR (100MHz, DMSO-d _{6 )} ^{, _} _{_} ^_ _{_} 77.90, 56.94, 54.10, 43.52, 42.08.

Example 10

The preparation method of 1-methyl-2-((3,5-difluorobenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a10)

Add 3,5-difluorobenzylamine (0.29g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (10mL) into a 50mL single-necked bottle respectively, and then drop the A solution of 3-bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide (5mL) was slowly added dropwise into the reaction solution through a funnel, and stirred at 30°C for 12h. After the reaction was completed, ethyl acetate was added (15 mL), extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), The eluate containing the target compound (obtained by TLC plate) was collected and concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.14 g), with a yield of 77.3%.

Take the above-mentioned bright yellow transparent liquid (0.12g, 0.66mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 0.99mmol), triethylamine (0.10g, 0.99mmol), using acetonitrile (18mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloro Methane:methanol=30:1～15:1 gradient elution, used gradient ratio is: 30:1, 20:1, 15:1), collect the eluate containing target compound (obtained by TLC plate), subtract Concentration under reduced pressure gave a yellow oily liquid (0.19 g), yield 70.6%.

Add the above-mentioned oily liquid (0.17g, 0.42mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.26mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave a white solid a10 (0.11 g) with a yield of 82.3%.

mp183-185℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₆ F ₂ N ₂ O ₂ [M+H]+: 319.1253; found: 319.1256; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11. 16(s,1H),8.30(s,1H),7.42(s,1H),7.17–7.09(m,1H),7.09–7.02(m,2H),4.04(s,3H),3.87(s, 3H), 3.73(s, 2H), 3.39(t, J=2.4Hz, 1H), 3.31(d, J=2.4Hz, 2H). ¹³ C NMR(100MHz, DMSO-d ₆ ) δ162.83(dd , ¹ J _CF ＝244.8, ³ J _CF ＝13.2),160.27,146.28,144.64,142.78(t, ³ J _CF ＝9Hz),133.99,114.57,112.18(dd, ² J _CF ＝24.8Hz, ⁴ J _CF ＝ 11.9Hz), 103.39(t, ² J _CF ＝51.2), 80.27, 77.93, 56.65, 54.03, 43.53, 42.11.

Example 11

The preparation method of 1-methyl-2-((4-methoxybenzyl (propargyl) amino) methyl)-5-hydroxypyridin-4 (1H)-one (a11)

Add 4-methoxybenzylamine (0.27g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (9mL) into a 50mL single-necked bottle respectively, and then pass through a constant pressure dropping funnel 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (5mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate ( 15mL), extracted with 20mL×3 saturated brine, combined organic layers, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), collected the target The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g), with a yield of 68.6%.

Take the above-mentioned bright yellow transparent liquid (0.11g, 0.63mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.25 g, 0.94mmol), triethylamine (0.14g, 1.41mmol), using acetonitrile (15mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography (dichloro Methane:methanol=30:1～15:1 gradient elution, used gradient ratio is: 30:1, 20:1, 15:1), collect the eluate containing target compound (obtained by TLC plate), subtract Concentration under reduced pressure gave a yellow oily liquid (0.18 g), yield 71.1%.

Add the above-mentioned oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C , after dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h. The mixed solvent was recrystallized to obtain a white solid a11 (0.10 g) with a yield of 86.6%.

mp158-160℃; ESI-HRMS: m/z calcd for C ₁₈ H ₂₀ N ₂ O ₃ [M+H]+: 313.1547; found: 313.1526; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.22 ( s,1H),8.29(s,1H),7.42(s,1H),7.29–7.23(m,2H),6.92–6.85(m,2H),4.03(s,3H),3.85(s,2H) ,3.73(s,3H),3.65(s,2H),3.39(t,J=2.4Hz,1H),3.27(d,J=2Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ160 .20, 159.28, 145.71, 144.74, 133.98, 131.08, 128.63, 114.98, 114.29, 78.32, 77.59, 56.92, 55.55, 53.46, 43.66, 41.63.

Example 12

Preparation method of 1-methyl-2-((2-methylbenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a12)

2-Methylbenzylamine (0.24g, 2mmol), potassium carbonate (0.41g, 3mmol) and N,N-dimethylformamide (8mL) were added to a 50mL single-necked bottle respectively, and then the 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (4mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL ), extracted with 20mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), and the target compound containing The eluate (obtained by TLC plate) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.11 g), with a yield of 69.2%.

Take the above-mentioned bright yellow transparent liquid (0.08g, 0.5mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.15g, 1.5mmol), using acetonitrile (20mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was finished, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.12 g), yield 62.2%.

Add the above-mentioned oily liquid (0.12g, 0.31mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (0.93mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave white solid a12 (0.07g) yield 76.3%

mp177-179℃; ESI-HRMS: m/z calcd for C ₁₈ H ₂₀ N ₂ O ₂ [M+H]+: 297.1598; found: 297.1599; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.17 ( s,1H),8.27(s,1H),7.37(s,1H),7.27(dd,J=7.8,1.8Hz,1H),7.21–7.11(m,3H),3.97(s,3H),3.84 (s, 2H), 3.68 (s, 2H), 3.41 (t, J = 2.4Hz, 1H), 3.26 (d, J = 2.4Hz, 2H), 2.25 (s, 3H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ160.24, 146.29, 144.71, 137.65, 135.48, 133.87, 130.78, 130.49, 128.12, 126.20, 114.93, 78.10, 78.03, 55.38, 53.76, 43.28, 41.864.19.

Example 13

Preparation method of 1-methyl-2-((3-methoxybenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a13)

Add 3-methoxybenzylamine (0.27g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (10mL) respectively into a 50mL single-necked bottle, and then pass through a constant pressure dropping funnel 3-Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (5mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate ( 15mL), extracted with 20mL×3 saturated brine, combined organic layers, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 elution), collected the target The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.12 g), with a yield of 68.6%.

Take the above-mentioned bright yellow transparent liquid (0.11g, 0.63mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.25 g, 0.94mmol), triethylamine (0.20g, 2mmol), using acetonitrile (18mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was finished, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.17g), yield 67.1%.

Add the above-mentioned oily liquid (0.15g, 0.37mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave white solid a13 (0.09g) with a yield of 78.0%.

mp159-161℃; ESI-HRMS: m/z calcd for C ₁₈ H ₂₀ N ₂ O ₃ [M+H]+: 313.1547; found: 313.1544; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.13 ( s,1H),8.27(s,1H),7.39(s,1H),7.24(t,J=7.8Hz,1H),6.90(dt,J=7.5,1.2Hz,1H),6.88–6.80(m ,2H),4.04(s,3H),3.84(s,2H),3.74(s,3H),3.67(s,2H),3.8(t,J=2.4Hz,1H),3.29(d,J= 2.4Hz,2H). ¹³ C NMR(100MHz,DMSO-d ₆ )δ160.21,159.75,146.29,144.65,139.16,133.94,129.96,121.62,114.89,114.73,113.44,78.01,758.94,537.596,5 ,41.96.

Example 14

Preparation method of 1-methyl-2-((2-fluorobenzyl(propargyl)amino)methyl)-5-hydroxypyridin-4(1H)-one (a14)

Add 4-fluorobenzylamine (0.25g, 2mmol), potassium carbonate (0.55g, 4mmol) and N,N-dimethylformamide (10mL) respectively in a 50mL single-necked bottle, and then 3 -Bromopropyne (0.12g, 1mmol) in N,N-dimethylformamide solution (5mL) was slowly added dropwise to the reaction solution, stirred at 30°C for 12h, after the reaction was completed, ethyl acetate (15mL) was added , extracted with 20 mL×3 saturated brine, combined the organic layers, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluted with n-hexane:ethyl acetate=5:1), collected the The eluate of the compound (obtained by TLC spotting) was concentrated under reduced pressure to obtain a bright yellow transparent liquid (0.11 g), with a yield of 67.5%.

Take the above-mentioned bright yellow transparent liquid (0.10g, 0.61mmol) in a 50mL single-necked bottle, add the 1-methyl-2-(chloromethyl)-5-hydroxypyridin-4-one (0.26 g, 1mmol), triethylamine (0.15g, 1.5mmol), using acetonitrile (20mL) as the reaction solvent, reacted at 60°C for 36h, after the reaction was finished, the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane : Methanol = 30:1～15:1 gradient elution, the gradient ratio used is: 30:1, 20:1, 15:1), collect the eluate containing the target compound (obtained by TLC spot plate), reduce pressure Concentration gave a yellow oily liquid (0.15 g), yield 63.1%.

Add the above-mentioned oily liquid (0.15g, 0.38mmol) and anhydrous dichloromethane (15mL) into a 100mL single-necked bottle, and 1.0mol/L boron trichloride (1.11mL, purchased from Sarn Chemical Technology Co., Ltd., batch No.: GK130009, the solvent is dichloromethane) diluted with anhydrous dichloromethane (10mL) and placed in a constant pressure dropping funnel, under _N2 protection, slowly drop the diluted boron trichloride solution at -30°C After dropping, continue to keep stirring at this temperature for 2 h, add 10 mL of methanol to quench at low temperature, then transfer to room temperature and continue to stir for 12 h, finally concentrate the reaction solution, and mix with methanol/ether (v:v=1:5) Solvent recrystallization gave white solid a14 (0.10 g) with a yield of 87.7%.

mp176-178℃; ESI-HRMS: m/z calcd for C ₁₇ H ₁₇ FN ₂ O ₂ [M+H]+: 301.1347; found: 301.1346; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.17( s,1H),8.29(s,1H),7.45–7.30(m,3H),7.21–7.12(m,2H),4.02(s,3H),3.88(s,2H),3.73(s,2H) ,3.40(t, J＝2.4Hz, 1H), 3.29(d, J＝2.4Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ161.29(d, ¹ J _CF ＝244.1Hz), 160.24, 146.21, 144.70, 133.98, 131.96(d, ³ J _CF ＝4.1Hz), 130.21(d, ³ J _CF ＝8.2Hz), 124.91(d, ⁴ J _CF ＝3.2Hz), 124.51(d, ² J _CF ＝14Hz), 115.86(d, ² J _CF ＝21.4Hz), 114.83, 77.96, 77.89, 54.03, 50.42, 43.33, 41.79.

Comparative example 1

The preparation process of compound formula 6 is the same as that of Example 1, except that potassium carbonate (0.14g, 1.04mmol) is used to replace triethylamine (0.11g, 1.04mmol) in the preparation process of formula 6 to obtain the intermediate of formula 6, Yield 0.12g, yield 46.7%

Comparative example 2

The preparation process of compound a1 is the same as that of Example 1, the difference is that in this example, after the addition of boron trichloride is completed, the stirring is continued at room temperature for 12 hours, and then quenched by adding 10 mL of methanol, and the stirring reaction is continued for 2 hours, and the resulting reaction solution is post-treated In the end, compound a1 could not be obtained.

The reason why the b1 compound could not be obtained may be that after the boron trichloride was added dropwise, another reaction occurred in the system during the 12h stirring at room temperature, because we did not remove the excess boron trichloride in the reaction system. Quenching is carried out, and we can also get verification from the reaction phenomenon: the system changes from a solid suspension to a clear solution with a large amount of oil adhering to the bottom of the bottle, indicating that the originally generated a1 compound may have undergone other reactions, and then transformed into other compounds or mixtures.

Example 15

Below are the pharmacological experiment data of some compounds of the present invention:

1. Determination of the inhibitory activity of the compound on MAO-B

experimental method:

Purchase the MAO-B kit from BioVision and store it at -20°C for later use, and prepare the enzyme solution and substrate solution in advance according to the operation of the kit. Take 5 μL of different concentrations of the compound to be tested (100 nM, 250 nM, 500 nM, 1 μM, 2 μM, 4 μM, 20 μM) and 25 μL of the enzyme solution, mix them into a Corning bottom-reading 96-well microtest plate, shake and incubate at 37 ° C for 10 minutes, and then 20 [mu]L of substrate solution was added and the results were quantified based on the fluorescence generated (excitation, 535 nm; emission, 587 nm) in a multi-detection microplate fluorescence reader.

The results show that the compounds prepared in Examples 1 to 16 of the present invention have a better inhibitory effect on MAO-B. When the drug concentration is 100 nM, it can reach up to 46.69 ± 0.71%, which is close to 49.91 ± 2.73% of the positive control drug Pargyline, the most effective The IC ₅₀ value of the compound reached 105.2±3.4nM, which was close to the IC ₅₀ value of the positive control drug Pargyline 97.0±4.2nM. It is a relatively promising lead compound.

Table 1. Examples 1-14 inhibit the rate of MAO-B

Table 2. IC ₅₀ values of inhibitory activity of some examples

From the determination of IC ₅₀ values, we can know that Example a1 (IC ₅₀ =105.2±3.4) and Example a8 (IC ₅₀ =119.1±4.8) performed the best among the 14 compounds in this case.

2. Determination of compound b1-14's ability to chelate iron ions

According to the principle of spectrophotometry, a set of automatic titration system (Automatic Titration system) was used to measure pK _a . The system consists of: automatic titrator (Metrohm Dosimat 765liter mL syringe), pH meter [Mettler Toledo MP230 with Metrohm pH electrode (6.0133.100) and a reference electrode (6.0733.100)], UV-Vis spectrophotometer (HP 8453) And the computer with the VB program set.

Titration of pK _a : add 45mL (0.1M) potassium chloride solution to a cuvette with an optical path length of 50mm, correct the baseline, add 40μL saturated Na ₂ EDTA solution, add 1.5M hydrochloric acid, acidify to pH about 2. Add 20 μL of 50 mM DMSO solution of the compound to be tested, and stir at a constant speed. Automatic titration starts after the absorption spectrum is stable. That is, the automatic buret is added dropwise with 0.1M KOH solution, and the amount of addition is controlled to just increase the pH of the solution by 0.1 units. After the addition is completed, the system will automatically collect a full-wavelength spectrum after 30 seconds after the pH of the system is balanced. (The judging standard for the pH balance of the solution to be tested is: the change of the pH value within 3 seconds does not exceed 0.001, and the reading can be considered to be stable). The system automatically repeats the operation of automatic titration until the pH reaches the specified end point pH value. All the data measured during the whole process are recorded and backed up by the internal Visual Basic program. The collected spectral results were analyzed using the HypSpec2014 program and pK _a was calculated.

Determination of Logβ1: Add 45 mL of 0.1 M potassium chloride solution to a quartz cuvette with an optical path of 50 mm, correct the baseline, and acidify it with 1.5 M hydrochloric acid to a pH of about 2.1. Add 60 μL of working solution with a concentration of 50 mM and stabilize for 2 min. According to the ligand/iron ion = 1.1/1, add the acidic solution of FeCl ₃ and stir at a constant speed.

After the OD value is stable, a certain amount of (4M) HCl solution is added to the automatic burette, so that the pH of the solution drops by 0.1 units. After the pH is stable, start to monitor the spectrum. If the maximum value of the spectral absorption curve is also stable, collect and save all the spectral signals once. (The judging standard for pH stability is: when the pH value does not change more than 0.001 within 3 seconds; the spectral absorption stability standard is: the change rate does not exceed 1% within 2 minutes). The cycle is repeated until the specified pH is reached. All data measured during the whole process are recorded and backed up by the internal Visual Basic program.

Determination of Logβ2 and Logβ3: Add 25mL of KCl solution with a concentration of 0.1M and 20mL of DMSO to a quartz cuvette with an optical path length of 50mm. Wait for the spectrum to stabilize before calibrating the baseline. Acidify to pH about 2.5 with 1.5M hydrochloric acid. A solution of the compound to be tested at a concentration of 50 mM was added and stabilized for 2 min. Add the acidic solution of _FeCl3 according to the ratio of ligand/iron ion=5/1, and stir at a constant speed. After the OD value is stable, add a certain amount of 0.1M HCl solution to the automatic buret to increase the pH of the solution by 0.1 units. After the pH value is stable for 1 min, start to collect and save a full-spectrum signal. (The criterion for pH stability is: when the pH value does not change by more than 0.001 within 3 seconds, the pH reading can be considered stable. Repeat this cycle until the specified pH value is reached. All data measured during the entire process are passed through the internal Visual Basic program record and backup.

According to the values of pK _a1 , pK _a2 , Logβ1, Logβ2 and Logβ3 determined by the above method, then use HYSS software to fit and calculate pFe ³⁺

The results show that the pFe ³⁺ values of Examples a1-14 are basically greater than 19, indicating that the series of compounds are outstanding in iron ion chelating activity. Especially in Example a11, its pFe ³⁺ value is 21.03, which is nearly 1000 times stronger than the control drug CP20 used in this experiment. It shows that this series of compounds also have great potential for further research.

Table 3. pFe ³⁺ values of Examples 1 to 14

a: pK _a and Logβ1 measurement system: 0.1M KCl solution; Logβ2 and Logβ3 measurement system: DMSO:KCl(0.1M)=2:3(V/V)

b: Measured in 0.1M KCl solution

c: Literature Xie YY, Lu ZD, Kong XL, Zhou T, Bansal S, Hider R. Systematic comparison of the mono-,dimethyl-and trimethyl 3-hydroxy-4(1H)-pyridones-Attempted optimization of the orally active iron chelator , deferiprone.Eur JMed Chem 2016; 115:132-140) reported CP20 (deferiprone) reference value (0.1KCl)

We can know that embodiment a9 (pFe=21.03) and embodiment a11 (pFe=21.44) perform the best among the 14 compounds in this case through the determination of iron ion chelation constant.

3. Calculation of drug properties parameters of compounds a1~14 and prediction of blood-brain barrier penetration ^a

The blood-brain barrier is the separation of circulating blood and cerebrospinal fluid in the central nervous system. Blood-brain barrier penetration is an important indicator of central nervous system (CNS) drugs. For Examples a1-14, we calculated their drug-like constants and predicted whether they could penetrate the blood-brain barrier. All of our results are carried out on the SwissADME website (http://www.swissadme.ch/), the prediction results show that the implementation of a1~14 is in line with the five rules of drug-like, and the prediction results show that they can pass through the blood-brain barrier, and also Therefore, it is shown that this series of compounds has great development potential while being innovative. The specific results are shown in Table 4

The drug-like parameter value ^a of table 4 embodiment 1～14

a: MW: compound molecular mass; iLogP: calculated logarithm of octanol-water partition coefficient; tPSA: topological polar surface area; HBA: hydrogen bond acceptor; HBD: hydrogen bond donor; BBB permeant: blood-brain permeant Barrier: 1; Cannot cross the blood-brain barrier: 0.

Through the simulation calculation on the website, we can know that the 16 compounds in this case all show good drug-like properties and blood-brain barrier penetration.

Claims (9)

1. A modified derivative of pyridone six-alkyne amine as shown in formula (I) and a pharmaceutically acceptable salt thereof:

In formula (I): R ¹ is a C ₁ -C ₆ linear or branched alkyl group; ^R2 is H; ^R3 is H; ^R4 is

Y ₁ and Z ₁ are each independently H, CH ₃ , Cl, Br, F, I, CF ₃ , CN, NH ₂ , NO ₂ , OH, OCH ₃ , CH(CH ₃ ) ₂ or C(CH ₃ ) ₃ ; n ₁ or n ₂ is the number of CH ₂ , and n ₁ or n ₂ is 1-6. 2. The pyridone hexa-alkyne amine-modified derivative and the pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Y ₁ and Z ₁ are each independently H, CH ₃ , Cl, F, CF ₃ , OCH ₃ , n ₁ or n ₂ is 1-3. 3. The pyridone hexa-alkyne amine modified derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that: the pyridone hexa-alkyne amine modified derivative is one of the following:

4. A modified derivative of pyridone hexa-alkyne amine as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: said pharmaceutically acceptable salt is pyridine shown in formula (I) The hydrochloride salt of ketone six alkyne amine modified derivatives. 5. a preparation method of pyridone six alkyne amine modified derivatives and pharmaceutically acceptable salt thereof as shown in formula (I) as claimed in claim 1, it is characterized in that described method is specifically as follows Steps to proceed: (1) Dissolve the compound shown in formula 4 in organic solvent A, add the compound of formula 5, basic substance B, and react at 30-80°C for 24-48h. After the reaction, the obtained reaction solution C is post-treated A to obtain the formula 6 compounds; the ratio of the amount of the compound of formula 4, the compound of formula 5 and the basic substance B is 1:0.5～5:1～5; the basic substance B is potassium carbonate, potassium hydroxide, One or any mixture of sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine; (2) Dissolve the compound of formula 6 obtained in step (1) in anhydrous dichloromethane to obtain an anhydrous dichloromethane solution of 0.01 to 0.04 mmol/mL compound of formula 6, under nitrogen protection, at -78°C-0°C Slowly add boron trichloride in anhydrous dichloromethane solution dropwise into the anhydrous dichloromethane solution of the compound of formula 6. After the dropwise addition, continue stirring for 1-3h, add methanol X to quench, then transfer to room temperature and continue stirring After reacting for 12-24h, the obtained reaction solution D is subjected to post-treatment B to obtain the compound shown in formula (I); the compound shown in formula 6 and boron trichloride have a substance ratio of 1:1 to 5; The volume of methanol X is 15 to 40 mL/mmol based on the amount of the intermediate of formula 6;

In formulas 4-6 or formula (I), n ₁ and n ₂ are the number of CH ₂ , and n ₁ or n ₂ are 1-6 respectively; R ¹ is a C ₁ -C ₆ linear or branched alkyl group; ^R2 is H; ^R3 is H; ^R4 is

Y ₁ and Z ₁ are each independently H, CH ₃ , Cl, Br, F, I, CF ₃ , CN, NH ₂ , NO ₂ , OH, OCH ₃ , CH(CH ₃ ) ₂ or C(CH ₃ ) ₃ . 6. A preparation method of pyridone six alkyne amine modified derivatives and pharmaceutically acceptable salts thereof as shown in formula (I) as claimed in claim 5, characterized in that: the step (1) The organic solvent A mentioned is acetone, ethanol, methanol, methylene chloride, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N,N-dimethylformamide, N, One or a mixture of any of the N-dimethylacetamides; the amount of the organic solvent A added is 10-20 mL/mmol based on the amount of the intermediate represented by the formula 4. 7. a preparation method of pyridone six alkyne amine modified derivatives and pharmaceutically acceptable salts thereof as shown in formula (I) as claimed in claim 5, characterized in that: The post-treatment A described in step (1) is: the reaction solution C is concentrated under reduced pressure, and subjected to silica gel column chromatography, and gradient elution is carried out with a mixed solution of dichloromethane:methanol=30:1～15:1, Collect the eluate containing the target product, and concentrate under reduced pressure to remove the solvent to obtain the compound shown in formula 6; The way of post-processing B in step (2) is: the obtained reaction solution D is distilled off under reduced pressure to remove the solvent, and the mixed solvent of methanol and ether is used for recrystallization to obtain the compound shown in formula (I). In the mixed solvent of methanol and ether, The volume ratio of methanol to ether is 1:5. 8. A preparation method of pyridone hexa-alkyne amine modified derivatives and pharmaceutically acceptable salts thereof as shown in formula (I) as claimed in claim 5, characterized in that: in step (1), The reaction temperature is 50-70°C, and the reaction time is 30-40h; in step (2), the reaction temperature is -20-40°C. 9. A modified derivative of pyridone six alkyne amines shown in formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof is prepared by inhibiting monoamine oxidase, chelating metal iron ions, anti-Aβ and The application of anti-oxidation in drugs to prevent or treat related diseases; The disease is Alzheimer's disease or Parkinson's disease.