WO2023061101A1 - Hdac/mao-b dual inhibitor, preparation thereof, and application thereof - Google Patents

Abstract

Disclosed are an HDAC/MAO-B dual inhibitor, the preparation thereof, and an application in the preparation of a drug and neuroprotective antioxidant for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase. The HDAC/MAO-B dual inhibitor has the following general formula (I) or (II): in the formulas (I) and (II): each R is independently an aromatic group or a substituted aromatic group. The HDAC/MAO-B dual inhibitor has both an HDAC inhibitory effect and an MAO-B inhibitory effect, being a multi-target hydroxamic acid/anthranilamide propargyl amine-type derivative that achieves neuroprotection and anti-oxidation by means of the synergy of a propynylamine group and hydroxamic acid or an anthranilamide group.

Description

HDAC/MAO-B dual inhibitor and its preparation and application

This application claims the priority of the Chinese patent application with the application number 202111180441.0 and the title of the invention "HDAC/MAO-B dual inhibitor and its preparation and application" submitted to the China Patent Office on October 11, 2021, the entire content of which is passed References are incorporated in this application.

technical field

The invention relates to the field of medicinal chemistry, in particular to HDAC/MAO-B dual inhibitors and their preparation and application.

Background technique

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by abnormal deposition of amyloid β peptide and microtubule-associated protein Tau. It is the most common form of dementia in the elderly. It accounts for 60% to 70% of the number of people with dementia. The pathogenesis of AD is very complex, and the pathogenesis of this disease has not been fully elucidated yet. Among them, the cholinergic hypothesis, the β-amyloid protein theory, the abnormal phosphorylation theory of Tau protein, the metal ion hypothesis, the oxidative stress hypothesis, and the inflammation hypothesis are the main pathogenesis hypotheses.

Monoamine oxidase (monoamine oxidase, MAO) is a metabolic enzyme containing flavin adenine dinucleotide, present in the mitochondrial outer membrane, including two subtypes, namely MAO-A and MAO-B. The biological activity of MAO-B in the cerebral cortex and hippocampus of AD patients is significantly enhanced, and the H ₂ O ₂ produced by high levels of MAO-B through oxidative deamination can react with iron to generate hydroxyl free radicals through Fenton, thereby stimulating reactive oxygen species. clusters (ROS), ultimately leading to neuronal damage and inflammatory responses. Studies have shown that redox damage is a prominent feature of AD, and evidence of ROS-mediated neuronal damage has been observed in the brains of AD patients. Therefore, in recent years, MAO-B has been considered as a valuable potential target for the treatment of AD and has received extensive attention and research.

With the development of genomics and bioinformatics, more and more evidences have shown that inflammation and immune response in the brain are key factors in the pathogenesis and progression of AD. During AD progression, chronic inflammation mediated by Aβ deposition leads to microglia and astrocyte dysfunction, which in turn leads to neuronal dysregulation and damage, ultimately leading to cognitive deterioration.

Existing studies have confirmed that histone deacetylase (histone deacetylase, HDAC) plays a key role in innate immunity and IFN signaling pathways, as well as lymphocyte development and function, HDAC can regulate TLR and IFN signaling pathways to affect the body's innate immunity process. In addition, HDAC can also regulate the antigen presentation process, as well as the growth and differentiation of lymphocytes, thereby affecting the body's adaptive immune process. And these effects are very complex and diverse, with multiple functions of promotion/inhibition. Among the 18 HDAC subtypes, HDAC1 activity plays an important role in the regulation of neuroinflammation, and inhibition of HDAC1 activity has potential anti-inflammatory effects. Therefore, HDAC1 is also a valuable potential target for the treatment of AD.

In summary, the development of multi-target small molecule compounds with dual inhibitory effects on MAO-B and HDAC, neuroprotection and anti-oxidation by using multi-target design strategy is a potentially effective method for the treatment of AD.

Contents of the invention

Aiming at the above-mentioned technical problems, the present invention provides a class of HDAC/MAO-B dual inhibitors, which not only have HDAC inhibitory effect but also have MAO-B inhibitory effect. Multi-target hydroxamic acid/anthranilamide propargylamine derivatives with formamide groups synergistically achieving neuroprotection and antioxidation.

Based on the principle of rational drug design, the present invention designs and synthesizes a novel small molecular compound with HDAC and MAO-B inhibitory activity, multi-target and potential anti-AD activity.

HDAC/MAO-B dual inhibitors are compounds of the following general formula (I) or (II) and/or pharmaceutically acceptable salts thereof:

In formula (I), (II):

R are each independently an aromatic group or a substituted aromatic group.

Further, R are independently phenyl, benzyl, aromatic heterocycle, or substituted phenyl, benzyl, aromatic heterocycle.

In a preferred example, in formula (I), (II):

R is independently selected from the following structures:

R ¹ is H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -NH ₂ , -NHCOCH ₃ , -OH, -Ph, -OPh, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CF ₃ , -OCF ₃ , -SCF ₃ .

Further preferably, in formula (I), (II):

R is independently selected from the following structures:

R ¹ is H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CF ₃ , -SCF _3. -NH ₂ .

In a preferred example, the HDAC/MAO-B dual inhibitor is a compound having the following general formula (I-1) or (II-1) and/or a pharmaceutically acceptable salt thereof:

In formula (I-1), (II-1):

R ¹ is independently H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -NH ₂ , -NHCOCH ₃ , -OH, -Ph, -OPh, -CH ₃ , -CH _{2 CH3} , _-OCH3 , _-OCH2CH3 , _-CF3 , _-OCF3 , _{-SCF3 .}

In a preferred example, the HDAC/MAO-B dual inhibitors are compounds I ₁ to I ₁₆ , II ₁ to II ₁₆ and/or pharmaceutically acceptable salts thereof with the following structures:

The invention also provides a preparation method of the HDAC/MAO-B dual inhibitor.

1. The HDAC/MAO-B dual inhibitor is a compound with general formula (I-1), and its synthetic route:

Specifically include:

Bromopropyne 1 undergoes a nucleophilic substitution reaction with an aromatic group or a substituted aromatic group amine compound to generate an intermediate 2, and then reacts with methyl bromomethylbenzoate to obtain an intermediate 3 through a nucleophilic substitution reaction, and then intermediate 3 After hydrolysis, NH ₂ OTHP amide condensation and deprotection, the hydroxamic acid propargyl amine derivative represented by formula (I-1) is obtained.

2. The HDAC/MAO-B dual inhibitor is a compound with general formula (II-1), and its synthetic route:

Specifically include:

One amino group of o-phenylenediamine 4 is protected by di-tert-butyl dicarbonate mono-Boc to obtain intermediate 5, which is then reacted with 4-chloromethyl benzoyl chloride to generate intermediate 6, which is combined with bromopropyne 1 and aromatic group The intermediate 2 generated by the nucleophilic substitution reaction of the aryl group or substituted amine compound is subjected to the nucleophilic substitution reaction to obtain the intermediate 7, and finally deprotected to obtain the anthranilamide propargyl amine derivative of formula (II-1) thing.

In the above two synthetic routes, the substituents of R ¹ preferably range from: -H, -Cl, -F, -CH ₃ , -OCH ₃ , -3,4-Cl, -2,6-Cl, -3- Cl-4-F.

The present invention also provides the application of the HDAC/MAO-B dual inhibitor in the preparation of medicines and neuroprotective antioxidants for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase.

Such diseases include Alzheimer's disease, Parkinson's disease, inflammatory diseases, and the like.

Compared with the prior art, the main advantages of the present invention include: the HDAC/MAO-B dual inhibitor of the present invention has both HDAC inhibitory effect and MAO-B inhibitory effect. Anthranilamide groups synergistically achieve neuroprotection and anti-oxidation multi-target hydroxamic acid/anthranilamide propargylamine derivatives.

Description of drawings

Fig. 1 is that CCK-8 method and DCFH-DA method measure cell viability and antioxidant activity result;

Figure 2 is the inhibitory effect of Example 6 (I ₆ ) on intracellular ROS generation;

Fig. 3 is the effect of Example 6 (I ₆ ) on the cognitive impairment of ICR mice induced by scopolamine.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods not indicated in the following examples are generally in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer.

Example 1: Preparation of 4-((Benzyl(propargyl)amine)methyl)-N-hydroxybenzamide (Compound I ₁ )

Benzylamine (964mg, 9mmol), potassium carbonate (622mg, 4.5mmol) and N,N-dimethylformamide DMF (10mL) were sequentially added to a 50mL round bottom flask equipped with a magnetic stirrer, and stirred at room temperature. Subsequently, a solution of propyne bromide (1,536 mg, 4.5 mmol) in N,N-dimethylformamide (10 mL) was slowly added dropwise using a constant pressure dropping funnel, and the reaction was continued at room temperature after the addition was complete. The progress of the reaction was monitored by TLC, and the developing solvent was n-hexane:ethyl acetate (volume ratio 3:2). After the reaction, add water (20mL) to the reaction solution, extract with ethyl acetate (20mL×3), then wash the organic phase with water (20mL×2), saturated brine (20mL×2), anhydrous sodium sulfate After drying, the solvent was distilled off under reduced pressure, and the column was purified on silica gel. The eluent was n-hexane:ethyl acetate (volume ratio 5:1), and finally a light yellow liquid, Intermediate 2 (434 mg, 67%) was obtained.

¹ H-NMR (400MHz,DMSO-d ₆ )δ7.36-7.30(m,2H),7.15-7.09(m,2H),3.71(s,2H),3.25(d,J＝2.5Hz,2H) ,3.08(t,J=2.4Hz,1H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ140.1,128.1,128.0,126.6,82.8,73.8,51.2,36.6.

Into a 50 mL round bottom flask equipped with a magnetic stirrer bar, Intermediate 2 (392 mg, 2.7 mmol), methyl bromomethylbenzoate (806 mg, 3.5 mmol), triethylamine (273 mg, 2.7 mmol) and acetonitrile ( 15mL), heated to 60°C to react. The progress of the reaction was monitored by TLC, and the developing solvent was n-hexane:ethyl acetate (volume ratio 5:1 to 20:1). After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent, dichloromethane (15mL) and water (15mL) were added to dissolve the mixture by shaking, and the liquid was separated. The aqueous layer was washed with dichloromethane (15mL×2) Extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, purified on column silica gel, and the eluent was n-hexane:ethyl acetate (volume ratio 5:1), and finally obtained a light yellow liquid, namely intermediate 3(459,58 %).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ7.95(d, J=8.3Hz, 2H), 7.52(d, J=8.3Hz, 2H), 7.39-7.25(m, 5H), 3.85(s , 3H), 3.71(s, 2H), 3.64(s, 2H), 3.26(t, J=2.3Hz, 1H), 3.20(d, J=2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO -d ₆ )δ166.6,144.8,138.7,129.7,129.2,129.1,129.0,128.8,127.7,78.6,77.0,57.2,56.8,52.5,41.3.

Intermediate 3 (880 mg, 3 mmol) was dissolved in 15 mL of methanol, and 10% aqueous sodium hydroxide solution (4.5 mL, 11.25 mmol) was added to reflux for 40 min. After the reaction was completed, the solvent was evaporated under vacuum, the residue was dissolved in water (10mL), then acidified with concentrated hydrochloric acid or acetic acid under ice-bath conditions, filtered and washed with water to obtain a white solid, the obtained white solid (2mmol) was dissolved in 15mL 1-Hydroxybenzotriazole HOBt (324 mg, 2.4 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide salt were stirred at 0°C for 15 min in dichloromethane DCM Salt EDCI (230 mg, 2.4 mmol) was then added and stirring was continued for 15 min in the ice bath. Subsequently, O-(2H-tetrahydropyran-2-yl)hydroxylamine (234 mg, 2 mmol) was added, and the mixture was reacted at room temperature overnight. After complete conversion of the starting material, 15 mL of water was added and extracted three times with dichloromethane (15 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified on a silica gel column (n-hexane:ethyl acetate volume ratio: 5:1) to obtain a pale yellow liquid. A solution of trifluoroacetic acid TFA (2719 mg, 23.85 mmol) in 10 mL of dichloromethane was slowly added dropwise to the obtained pale yellow liquid in 10 mL of dichloromethane, and the resulting mixture was stirred at room temperature for 10 h. After the reaction, saturated sodium bicarbonate was added until the bubbles disappeared, and extracted three times with dichloromethane (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the crude product was purified on column silica gel (dichloromethane:methanol volume ratio 60:1 to 20:1), and the crude product was recrystallized from n-hexane/dichloromethane to obtain compound I ₁ (37 %), a brownish-yellow solid with a melting point of 117.1-118.4°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.17(s, 1H), 9.00(s, 1H), 7.73(d, J=8.0Hz, 2H), 7.43(d, J=8.0Hz, 2H ),7.36-7.32(m,4H),7.29-7.24(m,1H),3.66(s,2H),3.62(s,2H),3.25(t,J=2.3Hz,1H),3.18(d, J＝1.6Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.1, 141.9, 138.4, 131.7, 128.6, 128.5, 128.4, 127.2, 127.0, 78.2, 76.5, 56.7, 56.3, 40.8. HRMS ( ESI) calcd for C ₁₈ H ₁₉ N ₂ O ₂ 295.1441[M+H] ⁺ ,found 295.1441.

Embodiment 2: the preparation of N-hydroxyl-4-(((2-methylbenzyl) (propargyl) amine) methyl) benzamide (compound I2)

Benzylamine was replaced by 2-methylbenzylamine, and compound I ₂ (29%) was obtained by referring to the synthesis method of Example 1, a white solid with a melting point of 112.1-112.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.17(s, 1H), 9.00(s, 1H), 7.71(d, J=8.0Hz, 2H), 7.38(d, J=8.0Hz, 2H ),7.31-7.29(m,1H),7.17-7.13(m,3H),3.67(s,2H),3.62(s,2H),3.27(t,J=2.2Hz,1H),3.12(d, J＝2.0Hz, 2H), 2.31(s, 3H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.2, 141.8, 137.2, 136.1, 131.7, 130.2, 129.6, 128.6, 127.3, 126.9, 125.6, 78.2 ,76.5,56.5,55.1,40.5,18.8.HRMS(ESI)calcd for C ₁₉ H ₂₁ N ₂ O ₂ 309.1598[M+H] ⁺ ,found 309.1583.

Example 3: Preparation of 4-(((4-fluorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (compound I ₃ )

Benzylamine was replaced by 4-fluorobenzylamine, and compound I ₃ (42%) was obtained according to the synthesis method of Example 1, a light brown solid with a melting point of 135.9-137.0°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.19(s, 1H), 9.02(s, 1H), 7.72(d, J=8Hz, 2H), 7.43-7.37(m, 4H), 7.19- 7.14(m,2H),3.65(s,2H),3.60(s,2H),3.26(d,J=2.0Hz,1H),3.17(d,J=2.0Hz,2H).13C NMR(100MHz, ₍ ^{_ _ _} d, ² J＝21Hz), 78.2, 76.6, 56.3, 55.9, 40.8. HRMS (ESI) calcd for C ₁₈ H ₁₈ FN ₂ O ₂ 313.1347[M+H]+, found 313.1340.

Example 4: Preparation of N-hydroxy-4-(((4-methylbenzyl)(propargyl)amine)methyl)benzamide (compound I ₄ )

Benzylamine was replaced by 4-methylbenzylamine, and compound I4 (49%) was obtained by referring to the synthetic method of Example 1, an off-white solid with a melting point of 138.9-140.2°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.16(s, 1H), 8.99(s, 1H), 7.72(d, J=7.8Hz, 2H), 7.41(d, J=7.8Hz, 2H ),7.23(d,J=7.6Hz,2H),7.15(d,J=7.7Hz,2H),3.64(s,2H),3.57(s,2H),3.22(t,J=2.3Hz,1H ), 3.16(d, J＝2.3Hz, 2H), 2.28(s, 3H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.1, 141.9, 136.2, 135.2, 131.7, 128.9, 128.6, 128.4, 126.9 ,78.3,76.3,56.4,56.2,40.7,20.7.HRMS(ESI)calcd for C ₁₉ H ₂₁ N ₂ O ₂ 309.1598[M+H] ⁺ ,found 309.1598.

Example 5: Preparation of 4-(((2-chlorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (compound I ₅ )

Benzylamine was replaced by 2-chlorobenzylamine, and compound I ₅ (36%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 127.6-130.0°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.19(s, 1H), 9.03(s, 1H), 7.71(d, J=7.7Hz, 2H), 7.56(d, J=7.4Hz, 1H ),7.43(t,J=8.4Hz,3H),7.33(dt,J=22.8,7.5Hz,2H),3.76(s,2H),3.72(s,2H),3.30(s,1H),3.22 (s,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ164.5,142.1,136.2,133.9,132.3,131.2,129.9,129.4,129.1,127.7,127.4,78.6,77.2,56.9,54.4,41.5. HRMS(ESI) calcd for C ₁₈ H ₁₈ ClN ₂ O ₂ 329.1051[M+H] ⁺ ,found 329.1047.

Example 6: Preparation of 4-(((2-fluorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (compound I ₆ )

Benzylamine was replaced by 2-fluorobenzylamine, and compound I ₆ (49%) was obtained by referring to the synthesis method of Example 1, as a light brown solid with a melting point of 115.4-116.8°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.16(s, 1H), 8.99(s, 1H), 7.71(d, J=8.1Hz, 2H), 7.48(td, J=7.5, 1.8Hz ,1H),7.41(d,J=8.0Hz,2H),7.36-7.30(m,1H),7.22-7.14(m,2H),3.69(s,4H),3.26(t,J=2.3Hz, 2H), 3.21(d, J＝2.3Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.6, 161.3(d, ¹ J＝243.8Hz), 142.2, 132.2, 131.5(d, ⁴ J =4.4Hz), 129.7(d, ³ J=8.2Hz), 128.9, 127.4, 125.4(d, ² J=14Hz), 124.8(d, ⁴ J=3.3Hz), 115.8(d, ² J=21.5Hz ),78.66,76.93,56.90,50.19,41.53.HRMS(ESI)calcd for C ₁₈ H ₁₈ FN ₂ O ₂ 313.1347[M+H] ⁺ ,found 313.1341.

Example 7: Preparation of 4-(((3-chlorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (compound I ₇ )

Benzylamine was replaced by 3-chlorobenzylamine, and compound I 7 (52%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 123.1-125.2°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.20(s, 1H), 9.03(s, 1H), 7.74(d, J=8.0Hz, 2H), 7.43(d, J=8.0Hz, 2H ),7.42-7.37(m,1H),7.35-7.33(m,3H),3.68(s,2H),3.65(s,2H),3.35(s,1H),3.20(d,J＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.1, 141.7, 141.1, 133.1, 131.8, 130.3, 128.5, 128.3, 127.2, 127.2, 127.0, 78.1, 76.7, 56.4, 56.1, 40.9. HRMS (ESI )calcd for C ₁₈ H ₁₈ ClN ₂ O ₂ 329.1051[M+H] ⁺ ,found 329.1052.

Example 8: Preparation of N-hydroxy-4-(((2-methoxybenzyl)(propargyl)amine)methyl)benzamide (compound I ₈ )

Benzylamine was replaced by 2-methoxybenzylamine, and compound I 8 (49%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 127.8-130.5°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.16(s, 1H), 8.98(s, 1H), 7.72(d, J=7.8Hz, 2H), 7.42(d, J=7.9Hz, 2H ),7.39(dd,J＝7.5,1.7Hz,1H),7.26-7.22(m,1H),6.98-6.92(m,2H),3.77(s,3H),3.68(s,2H),3.62( s, 2H), 3.32 (s, 1H), 3.24 (d, J=2.3Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.2, 157.4, 142.1, 131.6, 129.3, 128.4, 128.2, 126.9, 126.0, 120.2, 110.87, 78.8, 76.1, 56.6, 55.3, 50.5, 41.4. HRMS (ESI) calcd for C ₁₉ H ₂₁ N ₂ O ₃ 325.1547[M+H]+, found 325.1537.

Example 9: Preparation of N-hydroxy-4-(((4-methoxybenzyl)(propargyl)amine)methyl)benzamide (compound I ₉ )

Benzylamine was replaced by 4-methoxybenzylamine, and compound I 9 (48%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 123.5-124.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.17(s, 1H), 9.00(s, 1H), 7.72(d, J=8.2Hz, 2H), 7.41(d, J=8.0Hz, 2H ),7.26(d,J=8.6Hz,2H),6.90(d,J=8.6Hz,2H),3.73(s,3H),3.64(s,2H),3.55(s,2H),3.23(t ,1H),3.16(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ164.2,158.4,142.0,131.7,130.1,129.8,128.4,126.9,113.7,78.3,76.3, 56.2, 56.1, 55.0, 40.6. HRMS (ESI) calcd for C ₁₉ H ₂₁ N ₂ O ₃ 325.1547[M+H]+, found 325.1533.

Example 10: Preparation of N-hydroxy-4-(((3-methylbenzyl)(propargyl)amine)methyl)benzamide (Compound I ₁₀ )

Benzylamine was replaced by 3-methylbenzylamine, and compound I 10 (49%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 109.8-111.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.16(s, 1H), 8.99(s, 1H), 7.72(d, J=8.4Hz, 2H), 7.42(d, J=8.4Hz, 2H ),7.25-7.21(m,1H),7.15-7.14(m,2H),7.07(d,J=7.6Hz,1H),3.66(s,2H),3.58(s,2H),3.24(t, J＝2.4Hz, 1H), 3.17(d, J＝2.4Hz, 2H), 2.30(s, 3H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.1, 141.9, 138.2, 137.4, 131.7, 129.2 ,128.4,128.2,127.8,126.9,125.7,78.2,76.3,56.7,56.4,40.8,21.0.HRMS(ESI)calcd for C ₁₉ H ₂₁ N ₂ O ₂ 309.1598[M+H] ⁺ ,found 309.1589.

Example 11: Preparation of 4-(((2,6-dichlorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (Compound I ₁₁ )

Benzylamine was replaced by 2,6-dichlorobenzylamine, and compound I ₁₁ (34%) was obtained by referring to the synthesis method of Example 1. The melting point of the brownish-red solid was 103.5-105.1°C.

¹ H-NMR(400MHz,DMSO-d ₆ )δ11.17(s,1H),9.01(s,1H),7.67(d,J=7.7Hz,2H), 7.47(d,J=7.5Hz,2H ),7.35(d,J=7.6Hz,1H),7.30(d,J=7.9Hz,2H),3.96(s,2H),3.71(s,2H),3.29(s,1H),3.14(s ,2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ161.1, 141.5, 136.2, 133.8, 131.7, 130.1, 128.7, 128.4, 126.8, 78.3, 76.5, 55.5, 52.6, 40.8. HRMS (ESI) calcd for C ₁₈ H ₁₇ Cl ₂ N ₂ O ₂ 363.0662[M+H]+, found 363.0660.

Example 12: Preparation of 4-(((3,4-dichlorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (compound I ₁₂ )

Benzylamine was replaced by 3,4-dichlorobenzylamine, and compound I ₁₂ (46%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 152.6-154.9°C.

¹ H-NMR (400MHz,DMSO-d ₆ )δ11.19(s,1H),9.03(s,1H),7.73(d,J=7.8Hz,2H),7.62-7.58(m,2H),7.41 (d, J=7.9Hz, 2H), 7.36(dd, J=8.2, 1.9Hz, 1H), 3.66(s, 2H), 3.63(s, 2H), 3.29(t, J=2.3Hz, 1H) ,3.19(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ164.0,141.5,139.8,131.7,130.9,130.5,130.3,129.6,128.7,128.4,126.9,78.0,76.5 ,56.3,55.5,40.9.HRMS(ESI)calcd for C ₁₈ H ₁₇ Cl ₂ N ₂ O ₂ 363.0662[M+H] ⁺ ,found 363.0656.

Example 13: Preparation of 4-(((3-fluorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (Compound I ₁₃ )

Benzylamine was replaced by 3-fluorobenzylamine, and compound I 13 (41%) was obtained with reference to the synthetic method of Example 1, an off-white solid with a melting point of 114.9-116.6°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.17(s, 1H), 9.00(s, 1H), 7.73(d, J=8.4Hz, 2H), 7.43(d, J=8.2Hz, 2H ),7.38(dd,J=8.0,6.1Hz,1H),7.21-7.07(m,3H),3.67(s,2H),3.65(s,2H),3.27(t,J=2.4Hz,1H) ,3.20(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ164.1,162.3(d, ¹ J=242.0Hz),141.7,141.6(d, ³ J=7.1Hz) ,131.8,130.3(d, ³ J＝8.3Hz),128.5,127.0,124.5(d, ⁴ J＝2.4Hz),115.0(d, ² J＝21.0Hz),114.0(d, ² J＝20.8Hz) ,78.1,76.6,56.3,56.1,40.9.HRMS(ESI)calcd for C ₁₈ H ₁₈ FN ₂ O ₂ 313.1347[M+H]+,found 313.1332.

Example 14: Preparation of 4-(((4-chlorobenzyl)(propargyl)amine)methyl)-N-hydroxybenzamide (Compound I ₁₄ )

Benzylamine was replaced by 4-chlorobenzylamine, and compound I ₁₄ (48%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 146.8-147.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.20(s, 1H), 9.03(s, 1H), 7.73(d, J=8.0Hz, 2H), 7.44-7.37(m, 6H), 3.66 (s,2H),3.62(s,2H),3.36(s,1H),3.19(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ164.1,141.8,137.5, 131.8,131.7,130.4,128.5,128.4,127.0,78.1,76.6,56.3,55.9,40.8.HRMS(ESI)calcd for C ₁₈ H ₁₈ ClN ₂ O ₂ 329.1051[M+H] ⁺ ,found 329.1042.

Example 15: Preparation of 4-(((3-chloro-4fluoro)(propargyl)amine)methyl)-N-hydroxybenzamide (Compound I ₁₅ )

Benzylamine was replaced by 3-chloro-4-fluorobenzylamine, and compound I ₁₅ (49%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 140.1-141.9°C.

¹ H-NMR (400MHz,DMSO-d ₆ )δ11.19(s,1H),9.03(s,1H),7.72(d,J=8.0Hz,2H),7.54-7.51(m,1H),7.41 (d, J=8.0Hz, 2H), 7.39-7.37(m, 2H), 3.66(s, 2H), 3.62(s, 2H), 3.28(t, J=2.3Hz, 1H), 3.19(d, J＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ164.1, 156.3(d, ¹ J＝244.2Hz), 141.6, 136.4(d, ⁴ J＝3.6Hz), 131.7, 130.3, 129.0(d, ³ J＝7.3Hz), 128.4, 127.0, 119.2(d, ² J＝17.5Hz), 116.7(d, ² J＝20.6Hz), 78.1, 76.5, 56.3, 55.5, 40.8.HRMS(ESI ) calcd for C ₁₈ H ₁₇ ClFN ₂ O ₂ 347.0957[M+H]+, found 347.0952.

Example 16: Preparation of N-hydroxy-4-(((3-methoxybenzyl)(propargyl)amine)methyl)benzamide (Compound I ₁₆ )

Benzylamine was replaced by 3-methoxybenzylamine, and compound I 16 (48%) was obtained by referring to the synthesis method of Example 1, an off-white solid with a melting point of 114.5-115.6°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ11.16(s, 1H), 8.99(s, 1H), 7.73(d, J=8.3Hz, 2H), 7.42(d, J=8.1Hz, 2H ),7.26(t,J=7.8Hz,1H),6.92(ddd,J=7.8,5.1,1.5Hz,2H),6.85-6.82(m,1H),3.75(s,3H),3.66(s, 2H), 3.60(s, 2H), 3.24(t, J=2.2Hz, 1H), 3.20(d, J=2.4Hz, 2H). ¹³ C-NMR(100MHz, DMSO-d ₆ )δ164.1, 159.3, 141.8,140.0,131.7,129.4,128.4,127.0,120.7,114.1,112.5,78.3,76.3,56.7,56.2,54.92,40.9. HRMS(ESI) calcd for C ₁₉ H ₂₁ N ₂ O ₃ 325.1547[M+H] +, found 325.1543.

Example 17: Preparation of N-(2-aminophenyl)-4-(((2-methylbenzyl)(propargyl)amine)methyl)benzamide (compound II ₁ )

To a 100 mL round bottom flask equipped with a magnetic stir bar was added o-phenylenediamine (4, 1.0 g, 9 mmol) and chloroform (30 mL), and the reaction mixture was cooled to 0°C. Sodium bicarbonate (0.78g, 5.4mmol) and sodium chloride (0.54g, 5.4mmol) were sequentially added to the reaction system and stirred at 0°C for 30min. Subsequently, a chloroform solution (20 mL) of di-tert-butyl dicarbonate (2.02 g, 9.2 mmol) was slowly added dropwise using a constant pressure dropping funnel. After the addition was complete, the reaction mixture was stirred at 0° C. for 10 min and then heated to reflux for reaction . The progress of the reaction was monitored by TLC, and the developing solvent was n-hexane:ethyl acetate (volume ratio 3:1). After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, added dichloromethane (30mL × 3) and water (20mL) for extraction, then added saturated sodium bicarbonate (50mL) and saturated sodium chloride ( 50mL) to wash the organic layer, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, purified on column silica gel, and the eluent was n-hexane:ethyl acetate (volume ratio 3:1 to 2:1), and finally obtained off-white Solid, intermediate 5 (1.14 g, 61%).

¹ H-NMR (400MHz, DMSO-d ₆ ) δ8.28(s, 1H), 7.18(d, J=8.0Hz, 1H), 6.84(td, J=7.6, 1.6Hz, 1H), 6.68(dd , J=8.0, 1.5Hz, 1H), 6.53(td, J=7.5, 1.5Hz, 1H), 4.82(s, 2H), 1.46(s, 9H). ¹³ C-NMR (100MHz, DMSO-d ₆ )δ153.6, 141.2, 124.9, 124.5, 123.7, 116.3, 115.7, 78.6, 28.2.

Intermediate 5 (1.14 g, 5.5 mmol), triethylamine (557 g, 5.5 mmol) and dichloromethane (30 mL) were added to a 100 mL round bottom flask equipped with a magnetic stir bar, and the reaction mixture was cooled to 0 °C. A solution of chloromethylbenzoyl chloride (1.56 g, 8.25 mmol) in dichloromethane (20 mL) was slowly added dropwise using a constant pressure dropping funnel, and the reaction mixture continued to react at 0°C after the dropwise addition was complete. The progress of the reaction was monitored by TLC, and the developing solvent was dichloromethane. After the reaction, add water (20mL×3) to wash the organic layer, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the reaction solvent, and purify on column silica gel, the eluent is n-hexane:ethyl acetate (volume ratio 3:1), Finally, a white solid, intermediate 6 (1.51 g, 76%) was obtained.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.87(s, 1H), 8.70(s, 1H), 7.98(d, J=8.2Hz, 2H), 7.61(d, J=8.1Hz, 2H ), 7.56(ddd, J=7.9, 3.3, 1.7Hz, 2H), 7.19(dtd, J=22.0, 7.5, 1.6Hz, 2H), 4.86(s, 2H), 1.46(s, 9H). ¹³ C -NMR (100MHz, DMSO-d ₆ )δ 164.9, 153.5, 141.4, 134.2, 131.8, 129.6, 128.9, 128.0, 126.1, 125.7, 124.1, 123.8, 79.6, 45.4, 28.0.

Intermediate 6 (433mg, 1.20mmol), Intermediate 2 (188mg, 1.18mmol), potassium carbonate (163mg, 1.18mmol), potassium iodide (20mg, 0.12mmol) were sequentially added to a 25mL round bottom flask equipped with a magnetic stir bar and acetonitrile (15 mL), the reaction mixture was heated to 60° C. to react. The progress of the reaction was monitored by TLC, and the developing solvent was n-hexane:ethyl acetate (volume ratio 5:1 to 20:1). After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent, water (15mL) and dichloromethane (15mL) were added to dissolve the mixture by shaking, and the liquid was separated. The aqueous layer was washed with dichloromethane (15mL×2) Extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified on column silica gel, eluting with n-hexane:ethyl acetate (volume ratio 5:1), and finally obtained a light yellow liquid, Intermediate 7 (519mg, 91%) .

Intermediate 7 (1 mmol) and dichloromethane (6 mL) were added to a 25 mL round bottom flask equipped with a magnetic stir bar, and the reaction mixture was stirred at room temperature. A solution of trifluoroacetic acid (228 g, 2 mmol) in dichloromethane (6 mL) was slowly added dropwise using a constant pressure dropping funnel, and the reaction mixture was continued to react at room temperature after the addition was complete. The progress of the reaction was monitored by TLC, and the developing solvent was n-hexane:ethyl acetate (volume ratio 3:2). After the reaction, add saturated sodium bicarbonate solution to the reaction mixture to remove excess trifluoroacetic acid, extract with water (15mL) and dichloromethane (6×3mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to remove the organic solvent to obtain The crude product was subsequently recrystallized from n-hexane and ethyl acetate to obtain compound II ₁ (76%), a white solid with a melting point of 137.5-139.1°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.61(s, 1H), 7.95(d, J=7.9Hz, 2H), 7.44(d, J=8.0Hz, 2H), 7.34-7.31(m ,1H),7.19-7.16(m,4H),6.97(td,J=7.6,1.6Hz,1H),6.78(dd,J=8.0,1.5Hz,1H),6.60(td,J=7.5,1.5 Hz,1H),4.88(s,2H),3.72(s,2H),3.65(s,2H),3.27(t,J＝2.3Hz,1H),3.15(d,J＝2.4Hz,2H), 2.34(s,3H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ165.1,143.0,142.1,137.2,136.1,133.5,130.2,129.6,128.5,127.8,127.2,126.6,126.4,125.5,126.2,11 ,116.1,78.2,76.5,56.5,55.0,40.5,18.8.HRMS(ESI)calcd for C ₂₅ H ₂₆ N ₃ O 384.2070[M+H] ⁺ ,found 384.2071.

Example 18: Preparation of N-(2-aminophenyl)-4-((benzyl(propargyl)amine)methyl)benzamide (compound II ₂ )

Replace N-(2-methylbenzyl)propargylamine with N-benzylpropargylamine, and refer to the synthesis method of Example 17 to obtain compound II 2 (78%), a white solid with a melting point of 143.6-145.0°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.62(s, 1H), 7.97(d, J=8.0Hz, 2H), 7.49(d, J=8.0Hz, 2H), 7.39-7.34(m ,4H),7.27(ddd,J=8.6,5.2,2.2Hz,1H),7.17(dd,J=7.9,1.5Hz,1H),6.97(td,J=7.6,1.5Hz,1H),6.78( dd,J=8.0,1.4Hz,1H),6.60(td,J=7.5,1.5Hz,1H),4.88(s,2H),3.71(s,2H),3.65(s,2H),3.25(t ,J=2.2Hz,1H),3.22(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ165.1,143.0,142.1,138.3,133.5,128.6,128.3,128.3,127.8 ,127.1,126.6,126.4,123.4,116.2,116.1,78.2,76.3,56.6,56.4,40.8.HRMS(ESI)calcd for C ₂₄ H ₂₄ N ₃ O 370.1914[M+H]+,found 370.1909.

Example 19: Preparation of N-(2-aminophenyl)-4-(((2-chlorobenzyl)(propargyl)amine)methyl)benzamide (compound II ₃ )

Replace N-(2-methylbenzyl)propynylamine with N-(2-chlorobenzyl)propynylamine, and refer to the synthesis method of Example 17 to obtain compound II3 (68%), a white solid with a melting point of 124.1 -126.7°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.62(s, 1H), 7.91(d, J=7.8Hz, 2H), 7.50(d, J=8.0Hz, 2H), 7.38-7.33(m ,3H),7.15(d,J=7.8Hz,1H),6.96(td,J=7.6,1.6Hz,1H),6.77(dd,J=8.1,1.4Hz,1H),6.58(td,J= 7.5,1.4Hz,1H),4.89(s,2H),3.99(s,2H),3.75(s,2H),3.31(t,J＝2.3Hz,1H),3.16(d,J＝2.3Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 143.1, 141.9, 135.7, 133.6, 133.4, 130.6, 129.5, 128.9, 128.5, 127.9, 127.2, 126.7, 126.5, 123.3, 116.3, 116.2 ,76.7,56.5,53.9,41.0.HRMS(ESI)calcd for C ₂₄ H ₂₃ ClN ₃ O 404.1524[M+H]+,found 404.1523.

Example 20: Preparation of N-(2-aminophenyl)-4-(((3-methylbenzyl)(propargyl)amine)methyl)benzamide (Compound II ₄ )

N-(2-methylbenzyl)propynylamine was replaced by N-(3-methylbenzyl)propynylamine, and the synthetic method of Example 17 was used to obtain compound II ₄ (76%), white solid, melting point It is 137.2-139.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.63(s, 1H), 7.97(d, J=7.9Hz, 2H), 7.49(d, J=8.0Hz, 2H), 7.26-7.22(m ,1H),7.16(d,J=7.8Hz,3H),7.08(d,J=7.5Hz,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8.0, 1.4Hz,1H),6.59(td,J＝7.5,1.4Hz,1H),4.89(s,2H),3.70(s,2H),3.60(s,2H),3.25(t,1H),3.21( d, J＝2.4Hz, 2H), 2.31(s, 3H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 143.0, 142.1, 138.2, 137.4, 133.5, 129.2, 128.4, 128.2, 127.8 (127.83 ),127.8(127.79),126.6,126.4,125.7,123.4,116.2,116.1,78.3,76.3,56.6,56.4,40.8,21.0.HRMS(ESI)calcd for C25H26N3O 384.2070[M+H]+,found 384.2

Example 21: Preparation of N-(2-aminophenyl)-4-(((4-fluorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₅ )

N-(2-methylbenzyl) propargyl amine is replaced by N-(4-fluorobenzyl) propargyl amine, and compound II ₅ (80%) is obtained with reference to the synthetic method of Example 17, a white solid with a melting point of 135.7-138.1°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.63(s, 1H), 7.96(d, J=7.9Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.42-7.38(m ,2H),7.17(td,J=8.7,2.1Hz,3H),6.99-6.95(m,1H),6.78(dd,J=8.1,1.4Hz,1H),6.59(td,J=7.5,1.5 Hz,1H),4.88(s,2H),3.70(s,2H),3.63(s,2H),3.26(t,J=2.3Hz,1H),3.20(d,J=2.4Hz,2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 161.4(d, ¹ J＝241.1Hz), 143.1, 142.1, 134.5(d, ⁴ J＝2.9Hz), 133.6, 130.5(d, ³ J＝8.1 Hz), 128.4, 127.9, 126.7, 126.5, 123.4, 116.3, 116.1, 115.1 (d, ² J=21.1Hz), 78.2, 76.5, 56.3, 55.80, 40.7. HRMS (ESI) calcd for C ₂₄ H ₂₃ FN ₃ O 388.1820[M+H]+, found 388.1814.

Example 22: Preparation of N-(2-aminophenyl)-4-(((3-fluorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₆ )

N-(2-methylbenzyl)propynylamine was replaced by N-(3-fluorobenzyl)propynylamine, and compound II6 (53%) was obtained by referring to the synthesis method of Example 17, a white solid with a melting point of 137.9 -139.6°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.63(s, 1H), 7.97(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz, 2H), 7.40(td, J =7.9,6.1Hz,1H),7.24-7.15(m,3H),7.13-7.08(m,1H),6.97(ddd,J=8.8,7.4,1.6Hz,1H),6.78(dd,J=8.0 ,1.4Hz,1H),6.59(td,J=7.5,1.5Hz,1H),4.89(s,2H),3.72(s,2H),3.67(s,2H),3.28(t,J=2.3Hz ,1H),3.23(d,J=2.4Hz,2H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ165.1,162.3(d, ¹ J=242.1Hz),143.1,142.0,141.5(d, ³ J＝7.0Hz), 133.6, 130.3(d, ³ J＝8.2Hz), 128.4, 127.9, 126.6, 126.4, 124.5(d, ⁴ J＝2.4Hz), 123.4, 116.3, 116.1, 115.0(d, ² J =21.1Hz),114.0(d, ² J=20.8Hz),78.2,76.5,56.4,56.1,40.9.HRMS(ESI)calcd for C ₂₄ H ₂₃ FN ₃ O 388.1820[M+H]+,found 388.1819.

Example 23: Preparation of N-(2-aminophenyl)-4-(((3-methoxybenzyl)(propargyl)amine)methyl)benzamide (Compound II ₇ )

N-(2-methylbenzyl)propynylamine was replaced by N-(3-methoxybenzyl)propynylamine, and compound II ₇ (76%) was obtained with reference to the synthetic method of Example 17, a white solid, The melting point is 140.6-143.0°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.65(s, 1H), 7.96(d, J=7.9Hz, 2H), 7.49(d, J=7.5Hz, 2H), 7.29-7.24(m ,1H),7.15(d,J=7.8Hz,1H),6.99-6.93(m,3H),6.84(dd,J=8.2,3.0Hz,1H),6.78-6.75(m,1H),6.59( dd,J=9.1,5.9Hz,1H),4.90(s,2H),3.75(s,3H),3.69(s,2H),3.62(s,2H),3.28(t,J=2.4Hz,1H ), 3.23 (d, J=2.7Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 159.3, 143.0, 142.1, 140.0, 133.5, 129.3, 128.3, 127.8, 126.6, 126.4, 123.4, 120.7,116.2,116.1,114.1,112.5,78.3,76.3,56.6,56.3,54.9,40.9.HRMS(ESI)calcd for C ₂₅ H ₂₆ N ₃ O ₂ 400.2020[M+H]+,found 400.2016.

Example 24: Preparation of N-(2-aminophenyl)-4-(((3,4-dichlorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₈ )

Replace N-(2-methylbenzyl)propynylamine with N-(3,4-dichlorobenzyl)propynylamine, and obtain compound II ₈ (68%) according to the synthetic method of Example 17, white solid , with a melting point of 139.1-140.3°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.66(s, 1H), 7.97(d, J=7.8Hz, 2H), 7.63-7.60(m, 2H), 7.48(d, J=8.0Hz ,2H),7.38(dd,J=8.3,2.0Hz,1H),7.15(d,J=7.8Hz,1H),6.97(td,J=7.6,1.6Hz,1H),6.77(dd,J= 8.1,1.4Hz,1H),6.59(td,J=7.6,1.4Hz,1H),4.91(s,2H),3.71(s,2H),3.65(s,2H),3.31(t,J=2.2 Hz, 1H), 3.22 (d, J=2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.0, 143.0, 141.8, 139.8, 133.6, 131.0, 130.5, 130.3, 129.6, 128.8, 128.4 ,127.9,126.6,126.4,123.3,116.2,116.1,78.1,76.5,56.4,55.4,40.9.HRMS(ESI)calcd for C ₂₄ H ₂₂ Cl ₂ N ₃ O 438.1134[M+H]+,found 438.1136.

Example 25: Preparation of N-(2-aminophenyl)-4-(((4-chlorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₉ )

Replace N-(2-methylbenzyl)propynylamine with N-(4-chlorobenzyl)propynylamine, and obtain compound II9 (74%) according to the synthesis method of Example 17, a white solid with a melting point of 126.2 -127.7°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.62(s, 1H), 7.97(d, J=7.9Hz, 2H), 7.48(d, J=7.9Hz, 2H), 7.43-7.38(m ,4H),7.17(dd,J=7.9,1.5Hz,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8.1,1.4Hz,1H),6.60(td, J=7.5,1.5Hz,1H),4.88(s,2H),3.71(s,2H),3.64(s,2H),3.26(t,J=2.3Hz,1H),3.21(d,J=2.4 Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 143.0, 142.0, 137.4, 133.6, 131.7, 130.4, 128.4, 128.3, 127.9, 126.6, 126.4, 123.4, 116.2, 116.1, 74.1, 76. ,56.4,55.8,40.8.HRMS(ESI)calcd for C ₂₄ H ₂₃ ClN ₃ O 404.1524[M+H]+,found 404.1527.

Example 26: Preparation of N-(2-aminophenyl)-4-(((2,6-dichlorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₀ )

Replace N-(2-methylbenzyl)propynylamine with N-(2,6-dichlorobenzyl)propynylamine, and obtain compound II ₁₀ (19%) according to the synthetic method of Example 17, white solid , with a melting point of 174.5-176.3°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.60(s, 1H), 7.91(d, J=7.9Hz, 2H), 7.49(d, J=8.0Hz, 2H), 7.38-7.33(m , 3H), 7.15(d, J=7.8Hz, 1H), 6.96(td, J=7.6, 1.6Hz, 1H), 6.77(dd, J=8.0, 1.4Hz, 1H), 6.59(td, J= 7.5,1.5Hz,1H),4.88(s,2H),3.99(s,2H),3.75(s,2H),3.29(t,J=2.3Hz,1H),3.17(d,J=2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.0, 143.0, 141.7, 136.2, 133.8, 133.5, 130.0, 128.6, 128.3, 127.7, 126.5, 126.4, 123.3, 116.2, 116.1, 78.3, 756.3, ,52.6,40.7.HRMS(ESI)calcd for C ₂₄ H ₂₂ Cl ₂ N ₃ O 438.1134[M+H]+,found 438.1113.

Example 27: Preparation of N-(2-aminophenyl)-4-(((4-methoxybenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₁ )

N-(2-methylbenzyl)propynylamine was replaced by N-(4-methoxybenzyl)propynylamine, and compound II ₁₁ (75%) was obtained with reference to the synthetic method of Example 17, a white solid, The melting point is 126.7-128.6°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.65(s, 1H), 7.96(d, J=7.9Hz, 2H), 7.48(d, J=7.9Hz, 2H), 7.28(d, J =8.7Hz, 2H), 7.16(dd, J=7.9, 1.5Hz, 1H), 6.99-6.90(m, 3H), 6.78(dd, J=8.0, 1.5Hz, 1H), 6.59(td, J= 7.5,1.5Hz,1H),4.91(s,2H),3.74(s,3H),3.68(s,2H),3.56(s,2H),3.27(t,J＝2.3Hz,1H),3.18( d, J＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 158.4, 143.0, 142.2, 133.5, 130.1, 129.8, 128.3, 127.8, 126.6, 126.4, 123.4, 116.2, 116.1, 113.7,78.3,76.2,56.2,56.0,55.0,40.6.HRMS(ESI)calcd for C ₂₅ H ₂₆ N ₃ O ₂ 400.2020[M+H]+,found 400.2013.

Example 28: Preparation of N-(2-aminophenyl)-4-(((2-methoxybenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₂ )

N-(2-methylbenzyl)propynylamine was replaced by N-(2-methoxybenzyl)propynylamine, and compound II ₁₂ (77%) was obtained with reference to the synthetic method of Example 17, a white solid, The melting point is 139.8-142.2°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.61(s, 1H), 7.95(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz, 2H), 7.42(dd, J =7.5,1.8Hz,1H),7.25(ddd,J=8.7,7.4,1.8Hz,1H),7.17(dd,J=7.9,1.6Hz,1H),7.00-6.94(m,3H),6.78( dd,J=8.0,1.5Hz,1H),6.60(td,J=7.5,1.5Hz,1H),4.88(s,2H),3.79(s,3H),3.73(s,2H),3.65(s ,2H),3.27(d,J=2.4Hz,2H),3.23(t,J=2.3Hz,1H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ165.1,157.4,143.1,142.4,133.4, 129.3, 128.3, 128.2 _, 127.7, 126.6, 126.4 _, 126.1, 123.4, 120.2, 116.2, 116.1, 110.9, 78.8, 76.1 _{, 56.6} , 55.3, 50.4 _{, 41.4.} 400.2020[M+H]+, found 400.2022.

Example 29: Preparation of N-(2-aminophenyl)-4-(((3-chloro-4-fluorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₃ )

N-(2-methylbenzyl)propynylamine was replaced by N-(3-chloro-4-fluorobenzyl)propynylamine, and compound II ₁₃ (73%) was obtained with reference to the synthetic method of Example 17, white Solid with a melting point of 133.4-134.8°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.66(s, 1H), 7.97(d, J=7.8Hz, 2H), 7.55-7.54(m, 1H), 7.48(d, J=7.9Hz ,2H),7.41-7.38(m,2H),7.15(d,J=7.8Hz,1H),6.97(td,J=7.6,1.6Hz,1H),6.77(dd,J=8.0,1.5Hz, 1H),6.61-6.57(m,1H),4.91(s,2H),3.70(s,2H),3.64(s,2H),3.31(t,J＝2.3Hz,1H),3.22(d,J ＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 156.3 (d, ¹ J＝244.2Hz), 143.0, 141.8, 136.4 (d, ⁴ J＝3.6Hz), 133.6, 130.3 ,129.0(d, ³ J＝7.3Hz)128.4,127.9,126.6,126.4,123.3,119.3(d, ² J＝17.5Hz),116.7(d, ² J＝20.7Hz),116.2,116.1,78.1,76.5 ,56.3,55.4,40.8.HRMS(ESI)calcd for C ₂₄ H ₂₂ ClFN ₃ O 422.1430[M+H] ⁺ ,found 422.1433.

Example 30: Preparation of N-(2-aminophenyl)-4-(((2-fluorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₄ )

N-(2-methylbenzyl) propargyl amine is replaced by N-(2-fluorobenzyl) propargyl amine, the synthetic method of referring to embodiment 17 obtains compound II 13 (43%), white solid, melting point is 123.6-125.0°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.62(s, 1H), 7.96(d, J=7.9Hz, 2H), 7.49(td, J=7.8, 5.7Hz, 3H), 7.34(tdd ,J=7.5,5.3,1.9Hz,1H),7.24-7.16(m,3H),6.97(td,J=7.6,1.6Hz,1H),6.78(d,J=7.9Hz,1H),6.60( td,J=7.6,1.4Hz,1H),4.88(s,2H),3.74(s,2H),3.72(s,2H),3.26(t,J=2.1Hz,1H),3.24(d,J ＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 160.8(d, ¹ J＝243.7Hz), 143.0, 141.9, 133.5, 130.5(d, ⁴ J＝4.3Hz), 129.2 (d, ³ J＝8.2Hz), 128.3, 127.8, 126.6, 126.4, 125.0, 124.8, 124.3(d, ⁴ J＝3.2Hz), 123.4, 116.2(d, ² J＝13.5Hz), 115.3(d, ² J＝21.5Hz), 78.1, 76.4, 56.4, 49.6, 41.0. HRMS (ESI) calcd for C ₂₄ H ₂₃ FN ₃ O 388.1820[M+H] ⁺ ,found 388.1818.

Example 31: Preparation of N-(2-aminophenyl)-4-(((3-chlorobenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₅ )

N-(2-methylbenzyl) propargyl amine is replaced by N-(3-chlorobenzyl) propargyl amine, and compound II ₁₅ (75%) is obtained with reference to the synthetic method of Example 17, a white solid with a melting point of 135.2-136.9°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.63(s, 1H), 7.97(d, J=7.9Hz, 2H), 7.49(d, J=8.0Hz, 2H), 7.41-7.33(m ,4H),7.16(d,J=7.8Hz,1H),6.97(td,J=7.6,1.5Hz,1H),6.78(dd,J=8.1,1.5Hz,1H),6.59(td,J= 7.5,1.4Hz,1H),4.89(s,2H),3.71(s,2H),3.66(s,2H),3.28(t,J＝2.4Hz,1H),3.22(d,J＝2.4Hz, 2H). ¹³ C-NMR (100MHz, DMSO-d ₆ ) δ165.1, 143.0, 141.9, 141.1, 133.6, 133.0, 130.2, 128.4, 128.2, 127.9, 127.2, 127.1, 126.6, 126.4, 123.4, 116.2, 116. ,76.5,56.4,56.0,40.9.HRMS(ESI)calcd for C ₂₄ H ₂₃ ClN ₃ O 404.1524[M+H] ⁺ ,found 404.1525.

Example 32: Preparation of N-(2-aminophenyl)-4-(((4-methylbenzyl)(propargyl)amine)methyl)benzamide (Compound II ₁₆ )

N-(2-methylbenzyl) propargyl amine is replaced by N-(4-methylbenzyl) propargyl amine, the synthetic method of referring to Example 17 obtains compound II ₁₆ (68%), white solid, melting point It is 133.8-135.6°C.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ9.62(s, 1H), 7.96(d, J=7.9Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.25(d, J =7.8Hz, 2H), 7.16(d, J=8.0Hz, 3H), 6.97(td, J=7.6, 1.5Hz, 1H), 6.78(dd, J=8.0, 1.4Hz, 1H), 6.59(td ,J=7.5,1.4Hz,1H),4.88(s,2H),3.69(s,2H),3.59(s,2H),3.25(t,1H),3.19(d,J=2.4Hz,2H) ,2.29(s,3H). ¹³ C-NMR(100MHz,DMSO-d ₆ )δ165.1,143.0,142.2,136.2,135.2,133.5,128.9,128.6,128.3,127.8,126.6,126.4,123.4,116.2,116.1, 78.3,76.3,56.3(56.32),56.3(56.31),40.7,20.7.HRMS(ESI)calcd for C ₂₅ H ₂₆ N ₃ O 384.2070[M+H]+,found 384.2073.

Pharmacological Experimental Data

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

Experimental method: The Monoamine Oxidase B Inhibitor Screening Kit (fluorescence method) purchased from Sigma-Aldrich was stored at -80°C for future use. Prepare test enzyme solution, test substrate solution, and compound working solution (100nM) according to the instructions. First, use a pipette gun to add 10 μL of working solution to the black 96-well plate, and then add 50 μL of test enzyme solution. Test the substrate solution, then place it in a microplate reader to measure its fluorescence value at 37°C, test for 30 minutes, scan once every 1 minute, and scan 30 times in total. The experiment is mainly divided into two groups, namely the sample group (S) and the blank control group (EC). The sample group includes the positive control group and the compound test group, and each group is tested twice in parallel. After the test, the slope of each compound (including positive control and blank group) was obtained by fitting, and the inhibition rate was calculated according to the formula inhibition rate (%)=(blank group slope-sample group slope)/blank group slope×100% . The inhibition rates calculated at different concentrations were then calculated according to the GraphpadPrism software to obtain the corresponding IC ₅₀ values.

Table 1. Examples 1-32 inhibit rate of MAO-B

Table 2. IC _values of preferred embodiments for MAO-B inhibitory activity

It can be seen from the determination of IC ₅₀ value that Example 6 (I ₆ , IC ₅₀ =99.0±1.3nM) performed the best among the 32 compounds in this case.

2. Determination of preferred compounds for MAO-A inhibitory activity

Experimental method: The monoamine oxidase A inhibitor screening kit (fluorescence method) purchased from Sigma-Aldrich was stored at -80°C for future use. Prepare test enzyme solution, test substrate solution, and compound working solution (10, 100, 500, 800, 1000, 4000, 6000, 8000, 10000 nM) according to the instructions. Except that the incubation temperature was adjusted to 25°C, other operations refer to the MAO-B inhibitory activity test experiment.

Table 3. The inhibitory activity and selectivity of preferred embodiment to MAO-B/MAO-A

It can be known from the results in Table 3 that Example 6 (I ₆ ) exhibited strong MAO-B inhibitory activity and selectivity (SI=100.2). Example 6 (I ₆ ) was identified as a potent and selective MAO-B inhibitor.

3. Determination of the inhibitory activity of compounds on HDAC1

Experimental method: The screening of HDAC1 inhibitory activity adopts the HDAC1 kit based on the fluorescence method (λex=360nm/λem=465nm). The test procedure is divided into two steps and performed on the same microplate. In the first step, the acetylated lysine substrate is incubated with HDAC1; in the second step, the fluorescent product is released by treatment with HDAC developer, which is detected at an excitation wavelength of 360nm and an emission wavelength of 465nm. Finally, the inhibition rate of the compound was calculated by the formula inhibition rate (%)=(initial activity-sample activity)/initial activity×100%, and then the _IC50 value was calculated according to the function graph of inhibition rate-concentration according to the results of different inhibition rates.

As shown in Table 4, the derivatives of the general formula (II) (II ₇ , II ₁₂ ) have significantly weaker HDAC1 inhibitory activity than the derivatives of the general formula (I) (I ₂ , I ₆ , I ₁₁ , I ₁₅ ). In these preferred embodiments, I ₆ has the strongest inhibitory activity on HDAC1 (IC ₅₀ =21.4nM), comparable to the positive control drug SAHA (IC ₅₀ =13.3nM).

Table 4. IC _values of preferred embodiments for HDAC1 inhibitory activity

4. Determination of embodiment 6 (I ₆ ) neuroprotective effect and antioxidant activity

4.1 Neuroprotective effect test

Experimental method: cells were digested and counted, and a cell suspension of 1.0× ¹⁰⁵ cells/mL was prepared, and 100 μl of cell suspension was added to each well of a 96-well cell culture plate; the 96-well cell culture plate was placed at 37°C, 5%, CO ₂ Culture in an incubator for 24 hours; dilute the drug with the medium to the required working solution concentration (50 μM), add 100 μl of the corresponding drug-containing medium to each well, and add Aβ1-42 (action concentration: 40 μM) to each well after acting for 2 hours. At the same time, a negative control group was set up; the 96-well cell culture plate was placed in a 37°C, 5%, _CO2 incubator for 24 hours; the 96-well plate was stained with CCK-8, λ = 450nm, and the OD value was determined; 10 μl of CCK-8, continue to cultivate in the incubator for 2-3 hours; shake gently for 10 minutes to remove air bubbles in the 96-well plate; under the condition of λ=450nm, read the OD value of each well with a microplate reader, and calculate the inhibition rate .

Inhibition rate (%)=(OD value of negative control group-OD value of experimental group)/OD value of negative control group×100%.

4.2 Antioxidant test (flow type)

Experimental method: wash the cells once with PBS (centrifuge at 1000rpm, 5min) to collect and adjust the cell concentration to 1×10 ⁶ /mL; dilute DCFH-DA with serum-free medium according to 1:1000, so that the final concentration is 10 μM, after the cells are collected Suspended in diluted DCFH-DA, incubated in a 37°C cell culture incubator for 20min. Inverted and mixed every 3 to 5 minutes to make the probe fully contact with the cells; wash the cells 3 times with serum-free cell culture medium to fully remove DCFH-DA that did not enter the cells; detect with a flow cytometer (Ex = 488nm; Em=530nm) the situation of intracellular active oxygen.

4.3 Antioxidant test (imaging)

Experimental method: cells in the logarithmic growth phase were digested and inoculated into 24-well plates. The next day, after the cells adhered to the wall, the corresponding drug-containing medium was added according to the group settings, and a negative control group was set up at the same time; after the compound was acted for 2 hours, Add Aβ1-42 to act for 24 hours; wash the cells twice with PBS; dilute DCFH-DA with serum-free culture medium according to 1:1000, so that the final concentration is 10 μM, add it to a 24-well plate; wash the cells with serum-free cell culture medium for 3 times to fully remove the DCFH-DA that did not enter the cells; observe the active oxygen in the cells with a microscope.

The measurement results according to the above-mentioned experimental method are shown in Fig. 1 and Fig. 2 .

Compared with the blank group, the viability of cells treated with Aβ1-42 decreased significantly to 52.31% (47.69%), while the viability of cells treated with the compound of Example 6 increased to 73.62%, indicating that the compound of Example 6 has the effect of reversing nerve damage. As shown in Figure 2, compound I ₆ significantly reduced the generation of intracellular ROS, which was consistent with the significantly reduced green fluorescence intensity (I ₆ +Aβ1-42 vs Aβ1-42: 21.76% vs 44.58%). In summary, compound I ₆ has neuroprotective and ROS-inhibiting activities, which are related to its antioxidant effect.

5. Example 6 (I ₆ ) in vivo behavioral test

Experimental method: After the mice were purchased, they were raised in the animal center for seven days to eliminate the influence of environmental stress. IP administration (positive drug, test drug) (15 mg/kg, 3 mg/ml) or blank solvent, 30 minutes later, scopolamine (15 mg/kg, 3 mg/ml) was injected intraperitoneally, and the medication was continued for 15 days. The behavioral study of each mouse included 11-14 days of learning and memory training (the first two days did not record the movement track) and the 15th day of the exploration test (a total of five days). The water maze device was placed in a dark room, and an escape platform with a diameter of 10 cm was placed in the center of the fourth quadrant. During the experiment, the mice were trained to find the platform once in each of the four quadrants of the pool, and each time lasted 120s, the time for the mouse to find the platform (successful escape) was recorded. Regardless of whether the mouse successfully reached the platform within 120s, it must remain on the platform for 10s. On the last day (day 5), the platform was evacuated, and the mice received a 120-s exploration experiment from the second quadrant, and then the time to reach the missing platform and the number of times the mice crossed the platform location were recorded. Data such as escape latency, running trajectory, and number of platform intersections are recorded by Panlab SMART3.0 and processed by Graphpad Prism 8 software.

The results are shown in Figure 3. The control group showed normal spatial learning and memory abilities, while the model group significantly prolonged the time to find the hidden platform after being treated with scoccholine (Figure 3A and Figure 3B, the distance of the first crossing platform: 7.7±1.2 vs2.4±0.5; time to cross the platform for the first time: 41.4±5.9vs 12.5±2.7), the number of times entering the hidden platform was significantly reduced (Fig. Memory skills are severely impaired, which is consistent with the disorganized trajectory of the mod group (D-2). Compared with the model group, the time to find the hidden platform was significantly shortened in the mice treated with Youjiangning (Figure 3A and Figure 3B, the first crossing platform distance: 2.9±0.7vs 7.7±1.2; the first crossing platform time: 14.0±2.9vs41. 4±5.9), the number of times of entering the hidden platform increased significantly (Figure 3C, the number of times of crossing the platform: 3.9±0.5vs 2.0±0.5), indicating that Ujiangning has a good effect on improving cognitive function. In addition, compared with the model group, the distance and time for the mice treated in Example 6 (I ₆ ) to cross the platform for the first time were significantly shortened (Fig. Plateau time: 18.4±2.5vs 41.4±5.9), showing that Example 6 (I ₆ ) has a good cognitive enhancement effect. Compared with Example 6 (I ₆ ), the Ucampling group showed stronger cognition and memory improvement ability (Fig. 3A and Fig. 3B, first crossing the platform distance: 2.9 ± 0.7vs 3.4 ± 0.4; first crossing the platform time : 14.0±2.9 vs 18.4±2.5). Interestingly, Example 6 (I ₆ ) entered the hidden platform more times than Urbutanin at the same time (Fig. 3C, number of crossing platforms: 4.5±0.4 vs 3.9±0.5).

Based on the above results, compound I ₆ significantly improved the learning and memory ability of ICR mice, showing potential therapeutic effects.

In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (14)

1. The HDAC/MAO-B dual inhibitor is characterized in that it is a compound having the following general formula (I) or (II) and/or a pharmaceutically acceptable salt thereof:

   

   In formula (I), (II):

   R are each independently an aromatic group or a substituted aromatic group.
2. HDAC/MAO-B dual inhibitor according to claim 1, is characterized in that, in described formula (I), (II):

   R are independently phenyl, benzyl, aromatic heterocycle, or substituted phenyl, benzyl, aromatic heterocycle.
3. HDAC/MAO-B dual inhibitor according to claim 1, is characterized in that, in described formula (I), (II):

   R is independently selected from the following structures:

   

   R ¹ is H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -NH ₂ , -NHCOCH ₃ , -OH, -Ph, -OPh, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CF ₃ , -OCF ₃ , -SCF ₃ .
4. HDAC/MAO-B dual inhibitor according to claim 3, is characterized in that, in formula (I), (II):

   R is independently selected from the following structures:

   

   R ¹ is H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -CF ₃ , -SCF _3. -NH ₂ .
5. The HDAC/MAO-B dual inhibitor according to claim 1 is characterized in that it is a compound of the following general formula (I-1) or (II-1) and/or a pharmaceutically acceptable salt thereof:

   

   In formula (I-1), (II-1):

   R ¹ is independently H, and the following groups are monosubstituted or disubstituted on the ring: -F, -Cl, -NH ₂ , -NHCOCH ₃ , -OH, -Ph, -OPh, -CH ₃ , -CH _{2 CH3} , _-OCH3 , _-OCH2CH3 , _-CF3 , _-OCF3 , _{-SCF3 .}
6. The HDAC/MAO-B dual inhibitor according to claim 1, characterized in that it is one of compounds I ₁ to I ₁₆ and II ₁ to II ₁₆ having the following structure and/or a pharmaceutically acceptable salt thereof :

   

   
7. The preparation method of the HDAC/MAO-B dual inhibitor according to claim 5, characterized in that, the HDAC/MAO-B dual inhibitor is a compound with general formula (I-1), and its synthetic route:

   

   Specifically include:

   Bromopropyne (1) carries out nucleophilic substitution reaction with aromatic group amine compound or substituted aromatic group amine compound R-NH ₂ to generate intermediate (2), followed by nucleophilic substitution reaction with methyl bromomethylbenzoate Substitution reaction to obtain intermediate (3), and then the intermediate (3) undergoes hydrolysis, NH ₂ OTHP amide condensation and deprotection to obtain hydroxamic acid propargylamine derivatives represented by formula (I-1).
8. The preparation method according to claim 7, characterized in that, the temperature of the nucleophilic substitution reaction between the intermediate (2) and methyl bromomethylbenzoate is 60°C.
9. The preparation method of the HDAC/MAO-B dual inhibitor according to claim 5, characterized in that, the HDAC/MAO-B dual inhibitor is a compound with general formula (II-1), and its synthetic route:

   

   Specifically include:

   Ortho-phenylenediamine (4) obtains intermediate (5) through mono-Boc protection of di-tert-butyl dicarbonate wherein one amino group obtains intermediate (5), and then reacts with 4-chloromethyl benzoyl chloride to generate intermediate (6), said intermediate ( 6) Carry out nucleophilic substitution reaction with propyne bromide (1) and aromatic group amine compound or substituted aromatic group amine compound to produce intermediate (7) through nucleophilic substitution reaction, and finally deprotect to obtain Formula (II-1) anthranilamide propargyl amine derivatives.
10. The preparation method according to claim 9, characterized in that the temperature of the reaction between the intermediate (5) and 4-chloromethylbenzoyl chloride is 0°C.
11. The preparation method according to claim 9, characterized in that, the intermediate (6) undergoes a nucleophilic substitution reaction with propyne bromide (1) and an aromatic group amine compound or a substituted aromatic group amine compound to generate The nucleophilic substitution reaction temperature of the intermediate is 60°C.
12. The application of the HDAC/MAO-B dual inhibitor according to any one of claims 1 to 6 in the preparation of drugs or neuroprotective antioxidants for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase.
13. The use according to claim 8, characterized in that the diseases include Alzheimer's disease, Parkinson's disease, and inflammatory diseases.
14. A method for treating Alzheimer's disease, Parkinson's disease or inflammatory disease, characterized in that the administration of the HDAC/MAO-B dual inhibitor according to any one of claims 1 to 6 as the inhibitor of monoamine oxidase, histone Drugs for sirtuins.

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