CN113956182A - HDAC/MAO-B dual inhibitor and preparation and application thereof - Google Patents
HDAC/MAO-B dual inhibitor and preparation and application thereof Download PDFInfo
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- CN113956182A CN113956182A CN202111180441.0A CN202111180441A CN113956182A CN 113956182 A CN113956182 A CN 113956182A CN 202111180441 A CN202111180441 A CN 202111180441A CN 113956182 A CN113956182 A CN 113956182A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses an HDAC/MAO-B dual inhibitor, a preparation method thereof and application thereof in preparing drugs for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase and neuroprotective antioxidants. HDAC/MAO-B dual inhibitors have the following general formulaFormula (I) or (II):
in the formulae (I), (II): r is each independently an aromatic group or a substituted aromatic group. HDAC/MAO-B dual inhibitors, which have both HDAC and MAO-B inhibitory effects, are multi-target hydroxamic acid/anthranilamide propylamine-type derivatives that synergistically achieve neuroprotection and antioxidant with propynylamine groups in conjunction with hydroxamic acid or anthranilamide groups.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to an HDAC/MAO-B dual inhibitor, and preparation and application thereof.
Background
Alzheimer's Disease (AD) is a progressive neurodegenerative Disease characterized by the abnormal deposition of amyloid β peptide and microtubule-associated protein tau, the most common form of dementia among the elderly, accounting for about 60% -70% of dementia. The pathogenesis of AD is quite complex and is not fully elucidated at present. Among them, the cholinergic hypothesis, the amyloid-beta hypothesis, the Tau protein abnormal phosphorylation hypothesis, the metal ion hypothesis, the oxidative stress hypothesis, and the inflammation hypothesis are the main pathogenesis hypothesis.
Monoamine oxidase (MAO) is A metabolic enzyme containing flavin adenine dinucleotide and is present in the outer mitochondrial membrane, including two subtypes, MAO-A and MAO-B. The biological activity of MAO-B in cerebral cortex and hippocampus of AD patients is obviously enhanced, and high level of MAO-B is generated by H generated by oxidative deamination2O2Can react with iron through Fenton to generate hydroxyl free radicals, so as to stimulate the generation of Reactive Oxygen Species (ROS), and finally lead to neuron damage and inflammatory reaction. Studies have shown that redox damage is a significant feature of AD, and evidence of ROS-mediated neuronal damage is observed in the brains of AD patients. Therefore, MAO-B has recently been regarded as a valuable potential target for the treatment of AD and has received extensive attention and research.
With the development of genomics and bioinformatics, there is increasing evidence that inflammation and immune responses in the brain are key factors in the onset and progression of AD. During the progression of AD, chronic inflammation mediated by a β deposition leads to dysfunction of microglia and astrocytes, which in turn leads to neuronal dysregulation and damage, ultimately leading to deterioration of cognitive function.
Previous studies have demonstrated that Histone Deacetylase (HDAC) plays a key role in innate immunity and IFN signaling pathways, as well as in lymphocyte development and function, and that HDAC can regulate TLR and IFN signaling pathways that affect the innate immune processes of the body. In addition, HDACs can also regulate the antigen presentation process, as well as the growth and differentiation of lymphocytes, thereby affecting the adaptive immune process of the body. These effects are quite complex and diverse, with multiple effects of promotion/inhibition. Of the 18 HDAC isoforms, HDAC1 activity plays an important role in neuroinflammatory modulation, and inhibition of HDAC1 activity has a potential anti-inflammatory effect. Therefore, HDAC1 is also a valuable potential target for the treatment of AD.
In conclusion, the development of multi-target small molecule compounds with dual MAO-B and HDAC inhibitory effects, neuroprotection and anti-oxidation by using multi-target design strategy is a potentially effective method for treating AD.
Disclosure of Invention
In view of the above technical problems, the present invention provides a class of HDAC/MAO-B dual inhibitors, which have both HDAC inhibition and MAO-B inhibition, and is multi-target hydroxamic acid/anthranilamide propylamine type derivatives that synergistically achieve neuroprotection and antioxidant with propylamine groups and hydroxamic acid or anthranilamide groups.
The invention designs and synthesizes a novel small molecular compound which has multiple target points of HDAC and MAO-B inhibitory activity and potential anti-AD activity based on a reasonable drug design principle.
HDAC/MAO-B dual inhibitors are compounds having the following general formula (I) or (II) and/or pharmaceutically acceptable salts thereof:
in the formulae (I), (II):
r is each independently an aromatic group or a substituted aromatic group.
Further, R is phenyl, benzyl and aromatic heterocycle independently, or substituted phenyl, benzyl and aromatic heterocycle.
In a preferred embodiment, in the formulae (I), (II):
each R is independently selected from the following structures:
R1is H, the following group which is mono-or disubstituted on the ring: -F, -Cl, -NH2、-NHCOCH3、-OH、-Ph、-OPh、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CF3、-OCF3、-SCF3。
Further preferably, in the formulae (I), (II):
each R is independently selected from the following structures:
R1is H, the following group which is mono-or disubstituted on the ring: -F, -Cl, -CH3、-CH2CH3、-OCH3、-OCH2CH3、-CF3、-SCF3、-NH2。
In a preferred embodiment, 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 the formulae (I-1), (II-1):
R1independently of each other H, the following radicals mono-or disubstituted on the ring: -F, -Cl, -NH2、-NHCOCH3、-OH、-Ph、-OPh、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CF3、-OCF3、-SCF3。
In a preferred embodiment, the HDAC/MAO-B dual inhibitor is a compound I having the following structure1～I16、II1～II16And/or pharmaceutically acceptable salts thereof:
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 a general formula (I), and the synthesis route thereof is as follows:
the method specifically comprises the following steps:
carrying out nucleophilic substitution reaction on bromopropyne 1 and aromatic group or substituted aromatic group amine compound to generate an intermediate 2, then carrying out nucleophilic substitution reaction on bromomethyl benzoate to obtain an intermediate 3, and hydrolyzing and NH reacting the intermediate 32Condensing and deprotecting OTHP amide to obtain the hydroxamic acid propynylamine derivative shown in the formula (I).
2. The HDAC/MAO-B dual inhibitor is a compound with a general formula (II), and the synthesis route thereof is as follows:
the method specifically comprises the following steps:
o-phenylenediamine 4 is protected by di-tert-butyl dicarbonate and mono-Boc to obtain an intermediate 5, then the intermediate 5 reacts with 4-chloroformyl chloride to generate an intermediate 6, the intermediate 6 and bromopropyne 1 and an aromatic group or substituted aromatic group amine compound are subjected to nucleophilic substitution reaction to generate an intermediate 2, and then an intermediate 7 is obtained through nucleophilic substitution reaction, and finally deprotection is carried out to obtain the anthranilamide propyne amine type derivative shown in the formula (II).
In both of the above synthetic routes, R1The preferred ranges of substituents are: -H, -Cl, -F, -CH3、-OCH3、-3,4-Cl、-2,6-Cl、-3-Cl-4-F。
The invention also provides application of the HDAC/MAO-B dual inhibitor in preparing drugs for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase and neuroprotective antioxidants.
The diseases include Alzheimer's disease, Parkinson's disease, inflammatory diseases, and the like.
Compared with the prior art, the invention has the main advantages that: the HDAC/MAO-B dual inhibitor has HDAC inhibition effect and MAO-B inhibition effect, and is a multi-target hydroxamic acid/anthranilamide propylamine derivative which realizes neuroprotection and antioxidation by the synergism of propylamine groups and hydroxamic acid or anthranilamide groups.
Drawings
FIG. 1 shows the results of the measurement of cell viability and antioxidant activity by CCK-8 method and DCFH-DA method;
FIG. 2 shows example 6 (I)6) Inhibition of intracellular ROS production;
FIG. 3 shows example 6 (I)6) Effect on scopolamine induced ICR mouse cognitive impairment.
Detailed Description
The invention is further described with reference to the following drawings and specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples are conducted under conditions not specified, usually according to conventional conditions, or according to conditions recommended by the manufacturer.
Example 1: preparation of 4- ((benzyl (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)1) Preparation of
To a 50mL round-bottom flask equipped with a magnetic stir bar were added benzylamine (964mg, 9mmol), potassium carbonate (622mg, 4.5mmol), and N, N-dimethylformamide DMF (10mL) in that order, and the mixture was stirred at room temperature. Then, bromopropyne (1, 536mg, 4.5mmol) in N, N-dimethylformamide (10mL) was slowly added dropwise using a constant pressure dropping funnel, and the reaction was continued at room temperature after the addition was completed. The reaction progress was monitored by TLC using n-hexane as a developing solvent: ethyl acetate (volume ratio 3: 2). After completion of the reaction, water (20mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL × 3), and then the organic phase was washed with water (20mL × 2) and a saturated saline solution (20mL × 2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and purified on silica gel column, eluent was n-hexane: ethyl acetate (5: 1 by volume) to finally obtain a pale yellow liquid, intermediate 2(434mg, 67%).1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ140.1,128.1,128.0,126.6,82.8,73.8,51.2,36.6.
To a 50mL round bottom flask equipped with a magnetic stir bar were added in order intermediate 2(392mg, 2.7mmol), methyl bromomethylbenzoate (806mg, 3.5mmol), triethylamine (273mg, 2.7mmol), and acetonitrile (15mL), and heated to 60 deg.C for reaction. The reaction progress was monitored by TLC using n-hexane as a developing solvent: ethyl acetate (5: 1 to 20:1 by volume). 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 shake and dissolve the mixture, liquid was separated, the aqueous layer was extracted with dichloromethane (15mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, purified on silica gel column, eluent was n-hexane: ethyl acetate (volume ratio 5:1) to obtain a light yellow liquidIntermediate 3(459, 58%).1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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(880mg, 3mmol) was dissolved in 15mL of methanol, and 10% aqueous sodium hydroxide (4.5mL, 11.25mmol) was added and reacted under reflux for 40 min. After completion of the reaction, the solvent was evaporated under vacuum and the residue was dissolved in water (10mL) and then acidified with concentrated hydrochloric acid or acetic acid under ice bath conditions, filtered and washed with water to give a white solid, the resulting white solid (2mmol) was dissolved in 15mL of dichloromethane DCM and stirred at 0 ℃ for 15min, 1-hydroxybenzotriazole HOBt (324mg, 2.4mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride EDCI (230mg, 2.4mmol) were then added and stirring continued in ice bath for 15 min. Subsequently, O- (2H-tetrahydropyran-2-yl) hydroxylamine (234mg, 2mmol) was added, and the mixture was reacted at room temperature overnight. After complete conversion of the starting material, 15mL of water were 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 by silica gel column (n-hexane: ethyl acetate volume ratio 5:1) to obtain a pale yellow liquid. To a 10mL solution of the resulting pale yellow liquid in dichloromethane was slowly added dropwise a 10mL solution of trifluoroacetic acid TFA (2719mg, 23.85mmol) in dichloromethane, and the resulting mixture was stirred at room temperature for 10 h. After completion of the reaction, saturated sodium bicarbonate was added until bubbles disappeared, and extracted three times with dichloromethane (10 mL). Drying the organic layer with anhydrous sodium sulfate, concentrating the solvent under reduced pressure, purifying the crude product with silica gel column (dichloromethane: methanol volume ratio 60:1 to 20:1), and recrystallizing with n-hexane/dichloromethane to obtain compound I1(37%) a tan solid with a melting point of 117.1-118.4 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H19N2O2 295.1441[M+H]+,found 295.1441.
Example 2: n-hydroxy-4- (((2-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I)2) Preparation of
Substitution of benzylamine with 2-methylbenzylamine and Synthesis method according to example 1 to obtain Compound I2(29%) white solid, melting point 112.1-112.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O2309.1598[M+H]+,found 309.1583.
Example 3: 4- (((4-fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)3) Preparation of
Substitution of benzylamine with 4-fluorobenzylamine, Compound I was obtained according to the synthesis method of example 13(42%) light brown solid, melting point 135.9-137.0 ℃.1H-NMR(400MHz,DMSO-d6)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,DMSO-d6)δ164.2,161.4(d,1J＝241.2Hz),141.9,134.5(d,4J＝2.9Hz),131.7,130.5(d,3J＝8.0Hz),128.5,127.0,115.1(d,2J＝21Hz),78.2,76.6,56.3,55.9,40.8.HRMS(ESI)calcd for C18H18FN2O2 313.1347[M+H]+,found 313.1340.
Example 4: n-hydroxy-4- (((4-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I)4) Preparation of
Substitution of benzylamine with 4-methylbenzylamine and Synthesis of Compound I with reference to example 14(49%) off-white solid, melting point 138.9-140.2 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O2309.1598[M+H]+,found 309.1598.
Example 5: 4- (((2-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)5) Preparation of
Substitution of benzylamine with 2-chlorobenzylamine, according to the synthetic method of example 1, Compound I was obtained5(36%) off-white solid, melting point 127.6-130.0 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H18ClN2O2 329.1051[M+H]+,found329.1047.
Example 6: 4- (((2-fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)6) Preparation of
Substitution of benzylamine with 2-fluorobenzylamine, Synthesis of Compound I with reference to example 16(49%) light brown solid, melting point 115.4-116.8 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ164.6,161.3(d,1J＝243.8Hz),142.2,132.2,131.5(d,4J＝4.4Hz),129.7(d,3J＝8.2Hz),128.9,127.4,125.4(d,2J＝14Hz),124.8(d,4J＝3.3Hz),115.8(d,2J＝21.5Hz),78.66,76.93,56.90,50.19,41.53.HRMS(ESI)calcd for C18H18FN2O2 313.1347[M+H]+,found 313.1341.
Example 7: 4- (((3-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)7) Preparation of
Substitution of benzylamine with 3-chlorobenzylamine, according to the synthetic method of example 1 Compound I was obtained7(52%) off-white solid, melting point 123.1-125.2 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H18ClN2O2 329.1051[M+H]+,found329.1052.
Example 8: n-hydroxy-4- (((2-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I)8) Preparation of
Substitution of benzylamine with 2-methoxybenzylamine, according to the synthesis method of example 1, Compound I was obtained8(49%) off-white solid, melting point 127.8-130.5 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O3325.1547[M+H]+,found 325.1537.
Example 9: n-hydroxy-4- (((4-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I)9) Preparation of
Substitution of benzylamine with 4-methoxybenzylamine, according to the synthesis method of example 1, Compound I was obtained9(48%) off-white solid, melting point 123.5-124.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O3 325.1547[M+H]+,found 325.1533.
Example 10: n-hydroxy-4- (((3-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound I)10) Preparation of
Compound I was obtained by substituting benzylamine with 3-methylbenzylamine according to the synthesis method of example 110(49%) off-white solid, melting point 109.8-111.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O2 309.1598[M+H]+,found 309.1589.
Example 11: 4- (((2, 6-dichlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)11) Preparation of
Compound I was obtained by substituting benzylamine with 2, 6-dichlorobenzylamine according to the synthesis method of example 111(34%) the melting point of the red-brown solid is 103.5-105.1 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H17Cl2N2O2 363.0662[M+H]+,found 363.0660.
Example 12: 4- (((3, 4-dichlorobenzyl)(propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)12) Preparation of
Compound I was obtained by substituting benzylamine with 3, 4-dichlorobenzylamine according to the synthesis method of example 112(46%) off-white solid, melting point 152.6-154.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H17Cl2N2O2363.0662[M+H]+,found 363.0656.
Example 13: 4- (((3-fluorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)13) Preparation of
Substitution of benzylamine with 3-fluorobenzylamine and Synthesis method according to example 1 to obtain Compound I13(41%) off-white solid, melting point 114.9-116.6 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ164.1,162.3(d,1J＝242.0Hz),141.7,141.6(d,3J＝7.1Hz),131.8,130.3(d,3J＝8.3Hz),128.5,127.0,124.5(d,4J＝2.4Hz),115.0(d,2J＝21.0Hz),114.0(d,2J＝20.8Hz),78.1,76.6,56.3,56.1,40.9.HRMS(ESI)calcd for C18H18FN2O2 313.1347[M+H]+,found 313.1332.
Example 14: 4- (((4-chlorobenzyl) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)14) Preparation of
Substitution of benzylamine with 4-chlorobenzylamine, according to the synthetic method of example 1, Compound I was obtained14(48%) off-white solid, melting point 146.8-147.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C18H18ClN2O2 329.1051[M+H]+,found 329.1042.
Example 15: 4- (((3-chloro-4-fluoro) (propargyl) amine) methyl) -N-hydroxybenzamide (Compound I)15) Preparation of
Compound I was obtained by substituting benzylamine with 3-chloro-4-fluorobenzylamine according to the synthesis method of example 115(49%) off-white solid, melting point 140.1-141.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ164.1,156.3(d,1J＝244.2Hz),141.6,136.4(d,4J＝3.6Hz),131.7,130.3,129.0(d,3J＝7.3Hz),128.4,127.0,119.2(d,2J＝17.5Hz),116.7(d,2J＝20.6Hz),78.1,76.5,56.3,55.5,40.8.HRMS(ESI)calcd for C18H17ClFN2O2 347.0957[M+H]+,found 347.0952.
Example 16: n-hydroxy-4- (((3-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound I)16) Preparation of
Substitution of benzylamine with 3-methoxybenzylamine, according to the synthesis method of example 1, Compound I was obtained16(48%) off-white solid, melting point 114.5-115.6 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C19H21N2O3 325.1547[M+H]+,found 325.1543.
Example 17: n- (2-aminophenyl) -4- (((2-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II)1) Preparation of
To a 100mL round bottom flask equipped with a magnetic stir bar was added o-phenylenediamine (4, 1.0g, 9mmol) and chloroform (30mL) and the reaction mixture was cooled to 0 ℃. Sodium bicarbonate (0.78g, 5.4mmol) and sodium chloride (0.54g, 5.4mmol) were added to the reaction in this order and stirred at 0 ℃ for 30 min. A chloroform solution (20mL) of di-tert-butyl dicarbonate (2.02g, 9.2mmol) was then slowly added dropwise using an isopiestic dropping funnel, and after completion of the addition, the reaction mixture was stirred at 0 ℃ for 10min and then heated to reflux for reaction. The reaction progress was monitored by TLC using n-hexane as a developing solvent: ethyl acetate (volume ratio 3: 1). After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the reaction solvent, and then extracted with dichloromethane (30 mL. times.3) and water (20mL), followed byThe organic layer was washed with saturated sodium bicarbonate (50mL) and saturated sodium chloride (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and purified on silica gel column, eluent n-hexane: ethyl acetate (3: 1 to 2: 1 by volume) finally yielded intermediate 5 as an off-white solid (1.14g, 61%).1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ153.6,141.2,124.9,124.5,123.7,116.3,115.7,78.6,28.2.
To a 100mL round bottom flask equipped with a magnetic stir bar were added intermediate 5(1.14g, 5.5mmol), triethylamine (557g, 5.5mmol) and dichloromethane (30mL) and the reaction mixture was cooled to 0 ℃. A solution of chloromethylbenzoyl chloride (1.56g, 8.25mmol) in dichloromethane (20mL) was slowly added dropwise using a constant pressure dropping funnel, and after completion of the addition, the reaction mixture was allowed to continue to react at 0 ℃. The reaction progress was monitored by TLC and the developing solvent was dichloromethane. After the reaction was completed, the organic layer was washed with water (20 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the reaction solvent, and purified on silica gel column, eluent was n-hexane: ethyl acetate (3: 1 by volume) finally yielded a white solid, intermediate 6(1.51g, 76%).1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ164.9,153.5,141.4,134.2,131.8,129.6,128.9,128.0,126.1,125.7,124.1,123.8,79.6,45.4,28.0.
To a 25mL round bottom flask equipped with a magnetic stir bar were added in order intermediate 6(433mg, 1.20mmol), intermediate 2(188mg, 1.18mmol), potassium carbonate (163mg, 1.18mmol), potassium iodide (20mg, 0.12mmol) and acetonitrile (15mL), and the reaction mixture was heated to 60 ℃ for reaction. The reaction progress was monitored by TLC using n-hexane as a developing solvent: ethyl acetate (5: 1 to 20:1 by volume). 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, liquid separation was performed, the aqueous layer was extracted with dichloromethane (15mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified on column silica gel, and the eluent was n-hexane: ethyl acetate (5: 1 by volume) to finally obtain intermediate 7(519mg, 91%) as a pale yellow liquid.
To a 25mL round bottom flask equipped with a magnetic stir bar were added intermediate 7(1mmol) and dichloromethane (6mL) and the reaction mixture was stirred at room temperature. A solution of trifluoroacetic acid (228g, 2mmol) in dichloromethane (6mL) was slowly added dropwise using an isopiestic dropping funnel, and after completion of the addition, the reaction mixture was allowed to continue at room temperature. The reaction progress was monitored by TLC using n-hexane as a developing solvent: ethyl acetate (volume ratio 3: 2). After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction mixture to remove excess trifluoroacetic acid, and extracted with water (15mL) and dichloromethane (6X 3mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was then recrystallized from n-hexane and ethyl acetate to obtain Compound II1(76%) white solid, melting point 137.5-139.1 ℃.1H-NMR(400MHz,DMSO-d6)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＝7.5,1.5Hz,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).13C-NMR(100MHz,DMSO-d6)δ165.1,143.0,142.1,137.2,136.1,133.5,130.2,129.6,128.5,127.8,127.2,126.6,126.4,125.5,123.4,116.2,116.1,78.2,76.5,56.5,55.0,40.5,18.8.HRMS(ESI)calcd for C25H26N3O384.2070[M+H]+,found 384.2071.
Example 18: n- (2-aminophenyl) -4- ((benzyl (propargyl) amine) methyl) benzamide (compound II)2) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N-benzylpropynylamine according to the synthetic method of example 172(78%) white solid, melting point 143.6-145.0 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C24H24N3O 370.1914[M+H]+,found 370.1909.
Example 19: n- (2-aminophenyl) -4- (((2-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II3) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (2-chlorobenzyl) propynylamine according to the synthetic method of example 173(68%) white solid, melting point 124.1-126.7 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.1,143.1,141.9,135.7,133.6,133.4,130.6,129.5,128.9,128.5,127.9,127.2,126.7,126.5,123.3,116.3,116.1,78.2,76.7,56.5,53.9,41.0.HRMS(ESI)calcd for C24H23ClN3O 404.1524[M+H]+,found 404.1523.
Example 20: n- (2-aminophenyl) -4- (((3-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II4) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3-methylbenzyl) propynylamine according to the synthetic method of example 174(76%) white solid, melting point 137.2-139.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 384.2069.
Example 21: n- (2-aminophenyl) -4- (((4-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II5) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (4-fluorobenzyl) propynylamine according to the synthetic method of example 175(80%) white solid, melting point 135.7-138.1 ℃.1H-NMR(400MHz,DMSO-d6)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＝7.5,1.5Hz,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).13C-NMR(100MHz,DMSO-d6)δ165.1,161.4(d,1J＝241.1Hz),143.1,142.1,134.5(d,4J＝2.9Hz),133.6,130.5(d,3J＝8.1Hz),128.4,127.9,126.7,126.5,123.4,116.3,116.1,115.1(d,2J＝21.1Hz),78.2,76.5,56.3,55.80,40.7.HRMS(ESI)calcd for C24H23FN3O 388.1820[M+H]+,found 388.1814.
Example 22: n- (2-aminophenyl) -4- (((3-fluorobenzyl) (propargyl) amine) methyl) Benzamide (Compound II)6) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3-fluorobenzyl) propynylamine according to the synthetic method of example 176(53%) white solid, melting point 137.9-139.6 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.1,162.3(d,1J＝242.1Hz),143.1,142.0,141.5(d,3J＝7.0Hz),133.6,130.3(d,3J＝8.2Hz),128.4,127.9,126.6,126.4,124.5(d,4J＝2.4Hz),123.4,116.3,116.1,115.0(d,2J＝21.1Hz),114.0(d,2J＝20.8Hz),78.2,76.5,56.4,56.1,40.9.HRMS(ESI)calcd for C24H23FN3O 388.1820[M+H]+,found 388.1819.
Example 23: n- (2-aminophenyl) -4- (((3-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II7) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3-methoxybenzyl) propynylamine according to the synthetic method of example 177(76%) white solid, melting point 140.6-143.0 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C25H26N3O2400.2020[M+H]+,found 400.2016.
Example 24: n- (2-aminophenyl) -4- (((3, 4-dichlorobenzyl) (propargyl) amine) methyl) benzamide (compound II8) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3, 4-dichlorobenzyl) propynylamine according to the synthetic method of example 178(68%) white solid, melting point 139.1-140.3 ℃.1H-NMR(400MHz,DMSO-d6)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＝2.2Hz,1H),3.22(d,J＝2.4Hz,2H).13C-NMR(100MHz,DMSO-d6)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 C24H22Cl2N3O 438.1134[M+H]+,found 438.1136.
Example 25: n- (2-aminophenyl) -4- (((4-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II9) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (4-chlorobenzyl) propynylamine according to the synthetic method of example 179(74%) white solid, melting point 126.2-127.7 ℃.1H-NMR(400MHz,DMSO-d6)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＝2.4Hz,2H).13C-NMR(100MHz,DMSO-d6)δ165.1,143.0,142.0,137.4,133.6,131.7,130.4,128.4,128.3,127.9,126.6,126.4,123.4,116.2,116.1,78.1,76.4,56.4,55.8,40.8.HRMS(ESI)calcd for C24H23ClN3O 404.1524[M+H]+,found 404.1527.
Example 26: n- (2-aminophenyl) -4- (((2, 6-dichlorobenzyl) (propargyl) amine) methyl) benzamide (compound II10) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (2, 6-dichlorobenzyl) propynylamine according to the synthetic method of example 1710(19%) white solid, melting point 174.5-176.3 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.0,143.0,141.7,136.2,133.8,133.5,130.0,128.6,128.3,127.7,126.5,126.4,123.3,116.2,116.1,78.3,76.3,55.5,52.6,40.7.HRMS(ESI)calcd for C24H22Cl2N3O 438.1134[M+H]+,found 438.1113.
Example 27: n- (2-aminophenyl) -4- (((4-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II11) Preparation of
The N- (2-methylbenzyl) propyneReplacement of the amine with N- (4-methoxybenzyl) propynylamine, according to the synthetic method of example 17, Compound II was obtained11(75%) white solid, melting point 126.7-128.6 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C25H26N3O2 400.2020[M+H]+,found 400.2013.
Example 28: n- (2-aminophenyl) -4- (((2-methoxybenzyl) (propargyl) amine) methyl) benzamide (Compound II12) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (2-methoxybenzyl) propynylamine according to the synthetic method of example 1712(77%) white solid, melting point 139.8-142.2 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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.HRMS(ESI)calcd for C25H26N3O2 400.2020[M+H]+,found 400.2022.
Example 29: n- (2-aminophenyl) -4- (((3-chloro-4-fluorobenzyl) (propargyl) amine) methyl) benzamide (compoundSubstance II13) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3-chloro-4-fluorobenzyl) propynylamine according to the synthetic method of example 1713(73%) white solid, melting point 133.4-134.8 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.1,156.3(d,1J＝244.2Hz),143.0,141.8,136.4(d,4J＝3.6Hz),133.6,130.3,129.0(d,3J＝7.3Hz)128.4,127.9,126.6,126.4,123.3,119.3(d,2J＝17.5Hz),116.7(d,2J＝20.7Hz),116.2,116.1,78.1,76.5,56.3,55.4,40.8.HRMS(ESI)calcd for C24H22ClFN3O 422.1430[M+H]+,found 422.1433.
Example 30: n- (2-aminophenyl) -4- (((2-fluorobenzyl) (propargyl) amine) methyl) benzamide (Compound II14) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (2-fluorobenzyl) propynylamine according to the synthetic method of example 1713(43%) white solid, melting point 123.6-125.0 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.1,160.8(d,1J＝243.7Hz),143.0,141.9,133.5,130.5(d,4J＝4.3Hz),129.2(d,3J＝8.2Hz),128.3,127.8,126.6,126.4,125.0,124.8,124.3(d,4J＝3.2Hz),123.4,116.2(d,2J＝13.5Hz),115.3(d,2J＝21.5Hz),78.1,76.4,56.4,49.6,41.0.HRMS(ESI)calcd for C24H23FN3O 388.1820[M+H]+,found 388.1818.
Example 31: n- (2-aminophenyl) -4- (((3-chlorobenzyl) (propargyl) amine) methyl) benzamide (Compound II15) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (3-chlorobenzyl) propynylamine according to the synthetic method of example 1715(75%) white solid, melting point 135.2-136.9 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)δ165.1,143.0,141.9,141.1,133.6,133.0,130.2,128.4,128.2,127.9,127.2,127.1,126.6,126.4,123.4,116.2,116.1,78.1,76.5,56.4,56.0,40.9.HRMS(ESI)calcd for C24H23ClN3O 404.1524[M+H]+,found 404.1525.
Example 32: n- (2-aminophenyl) -4- (((4-methylbenzyl) (propargyl) amine) methyl) benzamide (Compound II16) Preparation of
Compound II obtained by substituting N- (2-methylbenzyl) propynylamine with N- (4-methylbenzyl) propynylamine according to the synthetic method of example 1716(68%) white solid, melting point 133.8-135.6 ℃.1H-NMR(400MHz,DMSO-d6)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).13C-NMR(100MHz,DMSO-d6)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 C25H26N3O 384.2070[M+H]+,found 384.2073.
Data of pharmacological experiments
1. Determination of the inhibitory Activity of Compounds on MAO-B
The experimental method comprises the following steps: monoamine oxidase B inhibitor screening kit (fluorescence method) from Sigma-Aldrich was stored at-80 ℃ until use. Test enzyme solutions, test substrate solutions, compound working solutions (100nM) were prepared as required by the instructions. Firstly, adding 10 mu L of working solution into a black 96-well plate by using a pipette gun, then adding 50 mu L of test enzyme solution, placing the plate into an enzyme-linked immunosorbent assay (ELISA) instrument preheated to 37 ℃ after the addition is finished, incubating for 10min, adding test substrate solution after the incubation is finished, placing the plate into the ELISA instrument again, measuring the fluorescence value of the plate at 37 ℃, testing for 30min, scanning once every 1min, and scanning for 30 times in total. The experiment is mainly divided into 2 groups, namely a sample group (S) and a blank control group (EC), wherein the sample group comprises a positive control group and a compound test group, and each group is tested twice in parallel. After the test was completed, the slope of each compound (including the positive control and the blank) was obtained by fitting, and the inhibition ratio was calculated according to the formula (%) inhibition ratio (%) (blank slope-sample group slope)/blank slope × 100%. Calculating the inhibition rates obtained by calculation under different concentrations according to Graphpad Prism software to obtain corresponding IC50The value is obtained.
TABLE 1 inhibition of MAO-B by examples 1-32
TABLE 2 IC for MAO-B inhibitory Activity of the preferred embodiments50Value of
Through IC50As a result of the measurement of the value, example 6 (I)6，IC5099.0 ± 1.3nM) performed the most excellent of the 32 compounds in the present case.
2. Determination of MAO-A inhibitory Activity of preferred Compounds
The experimental method comprises the following steps: monoamine oxidase a inhibitor screening kit (fluorescence method) from Sigma-Aldrich was stored at-80 ℃ until use. Test enzyme solutions, test substrate solutions, compound working solutions (10, 100, 500, 800, 1000, 4000, 6000, 8000, 10000nM) were formulated as required by the instructions. The MAO-B inhibitory activity assay was referenced except that the incubation temperature was adjusted to 25 ℃.
TABLE 3 inhibition Activity and selectivity of the preferred embodiments for MAO-B/MAO-A
From the results in Table 3, it is clear that example 6 (I)6) Shows potent MAO-B inhibitory activity and selectivity (SI ═ 100.2). Example 6 (I)6) Identified as a potent and selective MAO-B inhibitor.
3. Determination of the inhibitory Activity of Compounds on HDAC1
The experimental method comprises the following steps: screening for HDAC1 inhibitory activity HDAC1 kit based on fluorescence method (λ ex-360 nm/λ em-465 nm) was used. The test procedure was divided into two steps and was performed on the same microplate. A first step of incubating an acetylated lysine substrate with HDAC 1; in the second step, the fluorescent product is released by treatment with HDAC developer, and the excitation wave is at 360nmDetection was performed at long and 465nm emission wavelengths. Finally, the inhibition of the compound was calculated by the formula of (%) inhibition (initial activity-sample activity)/initial activity × 100%, and IC was calculated from the inhibition results as a function of concentration50The value is obtained.
As a result of Table 4, the derivatives (II) of the general formula (II) series7、II12) The inhibiting activity on HDAC1 is obviously weaker than that of the derivative (I) in the general formula (I) series2、I6、I11、I15). In these preferred embodiments I6The inhibitory activity against HDAC1 was strongest (IC)5021.4nM), comparable to the positive control SAHA (IC)50＝13.3nM)。
TABLE 4 IC of preferred embodiments for HDAC1 inhibitory Activity50Value of
4. Example 6 (I)6) Measurement of neuroprotective Effect and antioxidant Activity
4.1 neuroprotective Effect testing
The experimental method comprises the following steps: digesting and counting the cells to prepare a cell suspension of 1.0 × 105Each well of a 96-well cell culture plate is added with 100 mu l of cell suspension; the 96-well cell culture plate was placed at 37 ℃ and 5% CO2Culturing for 24h in an incubator; diluting the drug with culture medium to required working solution concentration (50 μ M), adding 100 μ l of corresponding drug-containing culture medium into each well, acting for 2h, adding Abeta 1-42 (action concentration 40 μ M) into each well, and establishing negative control group; the 96-well cell culture plate was placed at 37 ℃ and 5% CO2Culturing for 24h in an incubator; a 96-well plate is subjected to CCK-8 staining, and the OD value is measured when the lambda is 450 nm; adding 10 mul CCK-8 into each hole, and continuously culturing in an incubator for 2-3 h; mixing gently by shaking table for 10min to remove bubbles in 96-well plate; the OD value of each well was read by a microplate reader under a condition of λ 450nm, and the inhibition rate was calculated. The inhibition ratio (%) was (negative control OD value-experimental OD value)/negative control OD value × 100%.
4.2 Oxidation resistance test (STREAMING)
The experimental method comprises the following steps: cells were washed once with PBS (centrifugation 1000rpm, 5min) and collected and adjusted to a cell concentration of 1X 106Per mL; DCFH-DA was diluted with serum-free medium at a final concentration of 10. mu.M at a ratio of 1:1000, collected, suspended in the diluted DCFH-DA, and incubated in a cell incubator at 37 ℃ for 20 min. Mixing the above solutions in a reverse manner for 3-5min to make the probe and cells contact thoroughly; washing the cells 3 times with serum-free cell culture medium to sufficiently remove DCFH-DA that has not entered the cells; the intracellular reactive oxygen species were detected by flow cytometry (Ex 488 nm; Em 530 nm).
4.3 Oxidation resistance test (imaging)
The experimental method comprises the following steps: digesting and inoculating the cells in logarithmic growth phase into a 24-well plate, adding corresponding drug-containing culture media according to the group setting after the cells adhere to the wall the next day, and simultaneously setting up a negative control group; after the compound acts for 2 hours, adding Abeta 1-42 to act for 24 hours; cells were washed twice with PBS; according to 1:1000, diluting DCFH-DA with serum-free culture solution to a final concentration of 10 μ M, and adding into a 24-well plate; washing the cells 3 times with serum-free cell culture medium to sufficiently remove DCFH-DA that has not entered the cells; the condition of active oxygen in the cells is observed by a microscope.
The results of the above test are shown in FIGS. 1 and 2.
Compared to the blank group, the viability of cells treated with a β 1-42 was significantly reduced to 52.31% (reduced by 47.69%), while the viability of cells treated with the compound of example 6 was increased to 73.62%, indicating that the compound of example 6 had a reversal effect on nerve damage. As shown in FIG. 2, Compound I6Significantly reduced intracellular ROS production, consistent with a significantly reduced green fluorescence intensity (I)6+ Abeta 1-42vs Abeta 1-42: 21.76% vs 44.58%). In summary, the compounds I6Has neuroprotective and ROS production inhibiting activities, which are related to its antioxidant effects.
5. Example 6 (I)6) In vivo ethological test
The experimental method comprises the following steps: after the mice are purchased, the mice are raised for seven days before the animal center, and the environmental stress influence is eliminated. IP administration (positive drug, test drug) (15mg/kg, 3mg/ml) or blank solvent, 30min later, intraperitoneal injection of scopolamine (15mg/kg, 3mg/ml) respectively, and continuous administration for 15 days. The behavioral studies of each mouse included 11-14 days of learning and memory training (no exercise tracks recorded on the first two days) and a 15 day exploration trial (five days total). The water maze device is placed in a dark room, an escape platform with the diameter of 10cm is placed in the center of the fourth quadrant of the water maze device, in the experimental process, a mouse trains the escape platform once in each of the four quadrants of the pool, the time for the mouse to find the escape platform (successful escape) lasts for 120s each time is recorded. The mice were kept on the platform for 10s, regardless of whether they successfully reached the platform within 120 s. On the last day (day 5), the platform was evacuated, the mice received a 120s maintenance challenge from the second quadrant, and the time the mice reached the missing platform and the number of times they crossed the platform position were recorded. Data such as escape latency, running track, number of intersections at platform positions and the like are recorded by Panlab SMART 3.0 and processed by Graphpad Prism 8 software.
As shown in FIG. 3, the control group showed normal spatial learning and memory abilities, while the model group was treated with scopoline to significantly prolong the time for finding the hidden platform (FIG. 3A and FIG. 3B, first platform crossing distance: 7.7. + -. 1.2vs 2.4. + -. 0.5; first platform crossing time: 41.4. + -. 5.9vs 12.5. + -. 2.7), the number of times of entering the hidden platform was significantly reduced (FIG. 3C, platform crossing number: 2.0. + -. 0.5vs 5.8. + -. 0.9), indicating that the spatial learning and memory abilities of the mouse were severely impaired, which is in a disordered track with the module group (D-2). Compared with the model group, the time for searching the hidden platform by the mice treated by the Yongning is obviously shortened (the distance of the first platform passing through is 2.9 +/-0.7 vs 7.7 +/-1.2 and the time of the first platform passing through is 14.0 +/-2.9 vs 41.4 +/-5.9 in fig. 3A and 3B), the frequency of entering the hidden platform is obviously increased (the frequency of the platform passing through is 3.9 +/-0.5 vs 2.0 +/-0.5 in fig. 3C), and the Yongning has a good improvement effect on the cognitive function. Furthermore, example 6 (I) compared to the model group6) The distance and time for the treated mice to first cross the platform was significantly shortened (fig. 3A and 3B, first cross platform distance: 3.4 plus or minus 0.4vs 7.7 plus or minus 1.2; first-pass platform time: 18.4. + -. 2.5vs 41.4. + -. 5.9) showing example 6 (I)6) Has good cognitive enhancement effect. And embodiments thereof6(I6) In contrast, the eugonin group exhibited greater cognitive and memory improvement (fig. 3A and 3B, first-pass platform distance: 2.9 plus or minus 0.7vs 3.4 plus or minus 0.4; first-pass platform time: 14.0 ± 2.9vs 18.4 ± 2.5). Interestingly, example 6 (I)6) More times than the prohibitions enter the hidden platform at the same time (fig. 3C, number of platform crossings: 4.5 + -0.4 vs 3.9 + -0.5).
Based on the above results, Compound I6Obviously improves the learning and memory ability of ICR mice and shows potential therapeutic action.
Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the above description of the present invention, and equivalents also fall within the scope of the invention as defined by the appended claims.
Claims (9)
- HDAC/MAO-B dual inhibitors characterized by being compounds having the following general formula (I) or (II) and/or pharmaceutically acceptable salts thereof:
in the formulae (I), (II):r is each independently an aromatic group or a substituted aromatic group. - 2. The HDAC/MAO-B dual inhibitor according to claim 1, wherein in formula (I), (II):r is phenyl, benzyl and aromatic heterocycle independently or substituted phenyl, benzyl and aromatic heterocycle respectively.
- 3. The HDAC/MAO-B dual inhibitor according to claim 1, wherein in formula (I), (II):each R is independently selected from the following structures:
R1is H, the following group which is mono-or disubstituted on the ring: -F, -Cl, -NH2、-NHCOCH3、-OH、-Ph、-OPh、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CF3、-OCF3、-SCF3。 - 4. The HDAC/MAO-B dual inhibitor according to claim 1, which is a compound having the following general formula (I-1) or (II-1) and/or a pharmaceutically acceptable salt thereof:
in the formulae (I-1), (II-1):R1independently of each other H, the following radicals mono-or disubstituted on the ring: -F, -Cl, -NH2、-NHCOCH3、-OH、-Ph、-OPh、-CH3、-CH2CH3、-OCH3、-OCH2CH3、-CF3、-OCF3、-SCF3。 - 5. The HDAC/MAO-B dual inhibitor according to claim 1, which is a compound I having the following structure1～I16、II1～II16And/or pharmaceutically acceptable salts thereof:
- 6. the method for preparing HDAC/MAO-B dual inhibitor according to any of claims 1-5, wherein the HDAC/MAO-B dual inhibitor is a compound of formula (I):
the method specifically comprises the following steps:carrying out nucleophilic substitution reaction on bromopropyne 1 and aromatic group or substituted aromatic group amine compound to generate an intermediate 2, then carrying out nucleophilic substitution reaction on bromomethyl benzoate to obtain an intermediate 3, and hydrolyzing and NH reacting the intermediate 32Condensing and deprotecting OTHP amide to obtain the hydroxamic acid propynylamine derivative shown in the formula (I). - 7. The method for preparing HDAC/MAO-B dual inhibitor according to any of claims 1-5, wherein the HDAC/MAO-B dual inhibitor is a compound of formula (II):
the method specifically comprises the following steps:o-phenylenediamine 4 is protected by di-tert-butyl dicarbonate and mono-Boc to obtain an intermediate 5, then the intermediate 5 reacts with 4-chloroformyl chloride to generate an intermediate 6, the intermediate 6 and bromopropyne 1 and an aromatic group or substituted aromatic group amine compound are subjected to nucleophilic substitution reaction to generate an intermediate 2, and then an intermediate 7 is obtained through nucleophilic substitution reaction, and finally deprotection is carried out to obtain the anthranilamide propyne amine type derivative shown in the formula (II). - 8. Use of the HDAC/MAO-B dual inhibitor according to any one of claims 1 to 5 for preparing a medicament for preventing and treating related diseases by inhibiting monoamine oxidase and histone deacetylase, and a neuroprotective antioxidant.
- 9. Use according to claim 8, wherein said diseases comprise alzheimer's disease, parkinson's disease, inflammatory diseases.
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| CN115521228A (en) * | 2022-09-26 | 2022-12-27 | 中国药科大学 | BChE and HDAC double-target inhibitor and preparation method and application thereof |
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