5-htt / hdac dual inhibitors, methods of making and uses thereof

Abstract

The application discloses a 5-HTT / HDAC dual inhibitor and a preparation method and application thereof. Based on the principle of rational drug design, a novel small-molecule compound with multi-target points and potential antidepressant activity is designed and synthesized, which has 5-HTT and HDAC inhibitory activity. The compound has advantages over previous 5-HTT compounds in the design strategy, and the isoxazoles structure is introduced to improve the antidepressant activity, and the compound has good improvement on the long treatment time and large side effects of the currently used antidepressant compounds. The 5-HTT / HDAC dual inhibitor has 5-HTT inhibitor effect and HDAC inhibitory effect, and is a multi-target isoxazole derivative for realizing the antidepressant effect of aromatic groups and isoxazoles.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a class of 5-HTT / HDAC dual inhibitors and the preparation method and application thereof. BACKGROUND

[0002] Depression is a state characterized by low mood or loss of interest, and is a common form of psychological distress. The morbidity and mortality associated with major depression make it the leading cause of disability worldwide. There is also evidence that medical illness increases the risk of depression, especially high-morbidity diseases associated with metabolism (such as cardiovascular disease) and autoimmunity.

[0003] Antidepressants are the first choice for the treatment of depression, and the currently clinically used antidepressants are selective 5-hydroxytryptamine (5-HT) reuptake inhibitors. For example, the patent specification with publication number CN103316019A discloses a pharmaceutical combination for treating depression, which comprises a selective 5-hydroxytryptamine reuptake inhibitor and a glucocorticoid receptor antagonist. Also, for example, the patent specification with publication number CN1173330A discloses a pharmaceutical composition containing mirtazapine and one or more selective 5-hydroxytryptamine reuptake inhibitors. The main mechanism of action of selective 5-hydroxytryptamine reuptake inhibitors is to inhibit the reuptake of 5-HT transporter (5-HTT) in the presynaptic membrane, thereby inhibiting the reuptake of 5-HT, resulting in an increase in the level of 5-HT in the synaptic cleft. Most patients with depression have a significant effect after treatment with this class of classic antidepressants, but clinical trials have shown that this class of drugs still has the defects of slow onset, low remission rate and many side effects.

[0004] A large number of studies have shown that histone modification plays an important role in mental diseases including depression, anxiety, phobia and schizophrenia. Among them, acetylation is one of the most widespread modifications of histones, and its modification degree is finely regulated by the metabolic state of the body. Histone deacetylase (HDAC) is a class of regulatory enzymes for histone deacetylation, which controls the level of histone acetylation, and its activity and expression can be inhibited by histone deacetylase inhibitors. HDAC inhibitors have great potential in the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and mental diseases such as epilepsy and schizophrenia. Studies have shown that the classic HDAC inhibitor vorinostat (SAHA) can significantly reduce the level of HDAC in depressed mice. In addition, current antidepressants also improve synaptic plasticity to some extent by affecting the acetylation state of the brain, thereby exerting an antidepressant effect. For example, the patent specification with publication number CN114540460A discloses the application of an HDCA inhibitor in the preparation of a drug for treating depression. Therefore, it is very promising to develop antidepressants targeting HDAC. SUMMARY

[0005] The present application introduces HDAC inhibitor pharmacophore into the compounds which only inhibit 5-HTT target by structural modification and modification of the compounds, and obtains a series of novel 5-HTT / HDAC dual-target inhibitors. The compounds are expected to improve the deficiencies of single-target antidepressants and improve the antidepressant activity. In addition, the preparation method and pharmacological activity thereof are also studied.

[0006] 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, the structural formula of the 5-HTT / HDAC dual inhibitor is shown as formula (I) or (II):

[0007]

[0008] Among them:

[0009] R 1 is a substituted or unsubstituted aromatic group;

[0010] R 2 , R 3 are independently C1-C10 alkyl;

[0011] R 4 is and forms an amide bond with -NH-OH.

[0012] Further, the 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof, R 1 is a substituted or unsubstituted aromatic ring or heteroaromatic ring;

[0013] R 2 , R 3 are independently C1-C5 alkyl;

[0014] R 4 is forms an amide bond with -NH-OH.

[0015] Still further, the 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof,

[0016] R 1 is selected from the following structures:

[0017] R 2 , R 3are each independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-;

[0018] R 4 is para or meta forms an amide bond with -NH-OH.

[0019] Still further, the 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof,

[0020] R 1 is selected from the following structures:

[0021] R 2 is -CH2CH2-; R 3 is -CH2-;

[0022] R 4 forms a para or meta position on the benzene ring

[0023] In particular, the 5-HTT / HDAC dual inhibitor can be selected from the following compounds I1-I 20 or II1-II 20 :

[0024]

[0025] The present application also provides a preparation method of the 5-HTT / HDAC dual inhibitor, and a synthesis route comprises:

[0026]

[0027] The preparation method comprises the steps of:

[0028] The acid 1 with aromatic group is reduced by lithium aluminum hydride to obtain an intermediate alcohol 2;

[0029] The intermediate alcohol 2 is subjected to a nucleophilic substitution reaction with p-toluenesulfonyl chloride to obtain an intermediate 3;

[0030] The intermediate 5 or 6 is obtained by subjecting the chloromethyl benzoic acid methyl ester or the chloromethyl cinnamic acid methyl ester 4 to a nucleophilic substitution reaction with 1-Boc-piperazine or 2-Boc-octahydro-pyrrolo[3,4-C]pyrrole;

[0031] The intermediate 5 or 6 is subjected to a deprotection to obtain an intermediate 7 or 8;

[0032] The intermediate 7 or 8 is subjected to a nucleophilic substitution reaction with the intermediate 3 to obtain an intermediate 9 or 10;

[0033] The intermediate 9 or 10 is subjected to an amine-ester exchange reaction to obtain the 5-HTT / HDAC dual inhibitor as shown in formula (I) or (II).

[0034] The present application also provides the use of the 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof in the preparation of an antidepressant drug. The target of the antidepressant drug is 5-HTT.

[0035] As a general inventive concept, the present application also provides an antidepressant drug containing a safe and effective amount of the 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof. The antidepressant drug can also include at least one of a pharmacologically acceptable salt, an excipient, a carrier.

[0036] Compared with the prior art, the present application has the following beneficial effects:

[0037] The present application is based on the principle of rational drug design, and a new small-molecule compound with 5-HTT and HDAC inhibitory activity and potential antidepressant activity is designed and synthesized.

[0038] The compound of the present application is superior to the previous 5-HTT compound in design strategy, and the hydroxamic acid structure which can improve the antidepressant activity is introduced, thereby improving the antidepressant activity, and the long treatment time and large side effects of the currently used antidepressant compounds are well improved.

[0039] The 5-HTT / HDAC dual inhibitor of the present application has both 5-HTT inhibitor effect and HDAC inhibitory effect, and is a kind of multi-target hydroxamic acid derivative which realizes antidepressant effect in cooperation with aromatic group and hydroxamic acid. DETAILED DESCRIPTION

[0040] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The operation methods not specified in the following examples are usually carried out according to the conventional conditions or the conditions suggested by the manufacturers.

[0041] (I) Preparation of intermediate 2

[0042]

[0043] Reaction formula 1: synthesis route of intermediates 2 and 3. Reaction reagents and conditions: (a) LiAlH4, THF, 0-70℃, 2h; (b) TsCl, NEt3, DMAP, DCM, r.t., 5h.

[0044] To a 100 mL round bottom flask equipped with magnetic stirring, lithium aluminum hydride (1.53 mmol) was added, followed by anhydrous tetrahydrofuran (3 mL) and stirred at 0 °C for 10 min, then a solution of phenylacetic acid 1 (0.51 mmol) in tetrahydrofuran (5 mL) was added dropwise slowly using a constant pressure dropping funnel. After the addition was completed, the solution was allowed to warm to room temperature and the reaction was continued at 70 °C under nitrogen protection. The reaction progress was monitored by TLC, using dichloromethane:methanol (10:1 by volume) as the developing solvent. After the reaction was completed, the solution was stirred at 0 °C and water (0.058 mL), 15% NaOH (0.058 mL) and water (0.17 mL) were added dropwise slowly. The solution was allowed to continue to react at 0 °C until it changed from gray to white solid. The filtrate was collected by suction filtration, the filter cake was washed with dichloromethane, and the organic layers were combined. The solvent was removed by concentration under reduced pressure, and the residue was purified by column chromatography using dichloromethane:methanol (50:1 by volume) as the eluent. A yellow solid was obtained, which was intermediate 2a (91%).

[0045] Following the same procedure as described above in Reaction Scheme 1, intermediates 2b, 2c, and 2d were prepared by changing the reactants.

[0046] To a 50 mL round bottom flask equipped with magnetic stirring, 3,4-dihydroxyphenylacetic acid (100 mg, 0.60 mmol), 1,2-dibromoethane (1.2 mmol), potassium carbonate (1.8 mmol), and ethylene glycol (2 mL) were added sequentially and heated to 120 °C. The reaction progress was monitored by TLC, using dichloromethane:methanol (30:1 by volume) as the developing solvent. After the reaction was completed, the solution was allowed to cool to room temperature, diluted with water, and acidified to pH <1 with 20% HCl. The organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using dichloromethane:methanol (30:1 by volume) as the eluent. A light yellow liquid was obtained, which was intermediate 1 (60%). Following the same procedure as described above in Reaction Scheme 1, intermediate 2e was prepared by changing the reactants.

[0047] (B) Preparation of Intermediate 3

[0048] Into a 50 mL round bottom flask equipped with magnetic stirring, was added Intermediate 2 (2.33 mmol), triethylamine (3.50 mmol), 4-dimethylaminopyridine DMAP (0.47 mmol) and dichloromethane (7 mL) successively, stirred at 0 °C for 15 min, then a solution of p-toluenesulfonyl chloride (2.80 mmol) in dichloromethane (5 mL) was added dropwise slowly using a constant pressure dropping funnel, the reaction was shifted to room temperature. The reaction progress was monitored by TLC, eluent was dichloromethane. After completion of the reaction, water (20 mL) was added to the reaction mixture, extracted with dichloromethane (20 mL x 3), then the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, purified by column chromatography using silica gel, eluent was dichloromethane, finally obtained yellow-green oil, which was Intermediate 3a (83.8 %). Following the same procedure as described above, changing the reactants, Intermediate 3b, 3c, 3d, 3e were prepared according to Reaction Scheme 1.

[0049] (III) Preparation of Intermediates 5a-5d and 6a-6d

[0050]

[0051] Reaction Scheme 2: Synthetic route of Intermediates 5a-d and 6a-d. Reagents and conditions: (a) DIPEA, CH3CN, r.t., 12 h; (b) HC1·Dioxane, MeOH, 0 °C, 12 h.

[0052] Into a 50 mL round bottom flask equipped with magnetic stirring, was added methyl p-chloromethyl benzoate 4a (2.71 mmol), 1-Boc-piperazine (3.25 mmol), N,N- diisopropylethylamine DIPEA (5.42 mmol), acetonitrile (10 mL) successively, stirred at room temperature. The reaction progress was monitored by TLC, eluent was dichloromethane:methanol (50:1 by volume). After completion of the reaction, water (20 mL) was added to the reaction mixture, extracted with dichloromethane (20 mL x 3), then the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, purified by column chromatography using silica gel, eluent was dichloromethane:methanol (80:1 by volume), finally obtained yellowish liquid, which was Intermediate 5a (90 %). Following the same procedure as described above, changing the substrates, Intermediates 5b, 5c, 6a, 6b, 6c were prepared according to Reaction Scheme 2.

[0053] Into a 100 mL round bottom flask equipped with magnetic stirring, was added intermediate 5a (1.0 mmol) and methanol (12 mL) at 0 °C with stirring. Then hydrochloric acid dioxane solution (10 mL) was added slowly using a constant pressure dropping funnel. The reaction was carried out at room temperature after the addition was completed. TLC was used to monitor the reaction progress with dichloromethane:methanol (50:1, by volume) as the developing solvent. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. The mixture was shaken with ethyl acetate, filtered, washed with ethyl acetate and dried to give white solid, intermediate 7a (94.5%). Intermediates 7b, 7c, 7d, 8a, 8b, 8c, 8d were prepared according to the same procedure as described above in Reaction Scheme 2 by changing the substrates.

[0054] (Four) Preparation of intermediates 7a-d and 8a-d

[0055] Into a 100 mL round bottom flask equipped with magnetic stirring, was added intermediate 5a (1.0 mmol) and methanol (12 mL) at 0 °C with stirring. Then hydrochloric acid dioxane solution (10 mL) was added slowly using a constant pressure dropping funnel. The reaction was carried out at room temperature after the addition was completed. TLC was used to monitor the reaction progress with dichloromethane:methanol (50:1, by volume) as the developing solvent. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure. The mixture was shaken with ethyl acetate, filtered, washed with ethyl acetate and dried to give white solid, intermediate 7a (94.5%). Intermediates 7b, 7c, 7d, 8a, 8b, 8c, 8d were prepared according to the same procedure as described above in Reaction Scheme 2 by changing the substrates.

[0056] (Five) Preparation of intermediates 9a-t and 10a-t

[0057]

[0058] Reaction Scheme 3: Synthetic route of intermediates 9a-t and 10a-t. Reagents and conditions: (a) DIPEA, CH3CN, r.t., 12 h.

[0059] Intermediate 7a (0.85 mmol), intermediate 3a (1.28 mmol), N,N-diisopropylethylamine (DIPEA) (2.56 mmol), and acetonitrile (10 mL) were added sequentially to a 50 mL round-bottom flask equipped with a magnetic stirrer, and the mixture was heated to 70 °C. The reaction was monitored by TLC with dichloromethane:methanol (10:1 v / v). After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent. Dichloromethane (20 mL) and water (20 mL) were added, and the mixture was shaken to dissolve and separated. The aqueous layer was extracted with dichloromethane (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography with dichloromethane:methanol (30:1 v / v). A pale yellow liquid, intermediate 9a (33.1%), was finally obtained. Intermediates 9b-t and 10a-t were prepared by changing the substrate and following the same method as in reaction formula 3.

[0060] (vi) 5-HTT / HDAC dual inhibitor final product I 1～20 II 1～20 Preparation

[0061]

[0062] Reaction 4: 5-HTT / HDAC dual inhibitor final product I 1～20 II 1～20 Synthetic route. Reagents and conditions: NH2OH, NaOH, DCM, MeOH, 0℃, 1h.

[0063] As shown in reaction formula 4, intermediate 9a-t (0.60 mmol) was dissolved in a mixed solution of dichloromethane and methanol (9 mL, v / v ratio 1:2), and stirred at 0 °C for 10 min. Then, sodium hydroxide (4.44 mmol) and hydroxylamine aqueous solution (13.32 mmol) were added sequentially, and stirring was continued for 15 min in an ice bath. The reaction was then continued at room temperature. The reaction progress was monitored by TLC. After complete conversion of the starting material, the pH was adjusted to 6-7 with 20% HCl. The reaction solvents dichloromethane and methanol were removed by vacuum distillation. 15 mL of water was added, and the mixture was extracted three times with dichloromethane (15 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the compound was purified by reversed-phase silica gel column chromatography.

[0064] Each intermediate used can be prepared according to (I) to (VI) above, and will not be repeated here.

[0065] Example 1: Preparation of N-hydroxy-4-((4-phenylethylpiperazin-1-yl)methyl)benzamide (compound I1)

[0066]

[0067] Intermediate 9a (200 mg, 0.60 mmol) was dissolved in a mixture of dichloromethane: methanol 9 mL (volume ratio 1:2) and stirred at 0 °C for 10 min, then sodium hydroxide (177.6 mg, 4.44 mmol), aqueous hydroxylamine (879.12 mg, 13.32 mmol) were added successively and stirring was continued in ice bath for 15 min. Then the reaction was continued at room temperature. TLC was used to monitor the progress of the reaction, after the complete conversion of the starting material, the pH was adjusted to 6-7 with 20% HC1, the reaction solvent dichloromethane and methanol were removed under reduced pressure, 15 mL of water was added, extracted with dichloromethane (15 mL) three times, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, purified by reverse phase silica gel column with eluent water: acetonitrile (volume ratio 7:3) to give compound I1 (80 mg, 40%) as a white solid with a melting point of 156.5-158.3 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.02 (s, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.21 - 7.15 (m, 3H), 3.49 (s, 2H), 2.72 - 2.69 (m, 2H), 2.56 - 2.50 (m, 2H), 2.50 - 2.37 (m, 8H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 141.7, 140.4, 131.4, 128.6, 128.6, 128.2, 126.8, 125.8, 61.6, 59.7, 52.7, 52.7, 32.7. LCMS (ESI) m / z: 340.2 [M+H] + .

[0068] Example 2: Preparation of 4-((4-(3,4-dimethoxyphenethyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (Compound I2)

[0069]

[0070] The preparation method is basically the same as Example 1, and compound I2 (200 mg, 51.4%) is obtained in this example as a white solid with a melting point of 78.3-79.2 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.01 (s, 1H), 7.72 - 7.70 (m, 2H), 7.36 (d, J = 7.9 Hz, 2H), 6.82 - 6.81 (m, 2H), 6.71 - 6.69 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.48 (s, 2H), 2.63 (t, J = 7.8 Hz, 2H), 2.48 - 2.46 (m, 2H), 2.46 - 2.38 (m, 8H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 148.5, 147.0, 141.7, 132.9, 131.5, 128.6, 126.8, 120.4, 112.6, 111.8, 61.6, 59.9, 55.5, 55.4, 52.7, 52.7, 32.3. LCMS (ESI) m / z: 400.2 [M+H] + .

[0071] Example 3: Preparation of N-hydroxy-4-((4-(2-(naphthalen-2-yl)ethyl)piperazin-1-yl)methyl)benzamide (Compound I3)

[0072]

[0073] The preparation method is basically the same as in Example 1. Compound I3 (81 mg, 32.4%) is obtained in this example, which is a white solid with a melting point of 147.9-148.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.70 (s, 2H), 7.69 (s, 1H), 7.48 - 7.42 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 3.47 (s, 2H), 2.89 - 2.86 (m, 2H), 2.60 - 2.57 (m, 2H), 2.47 - 2.38 (m, 8H). 13 C NMR (125 MHz, DMSO-d6) δ 164.0, 140.8, 138.2, 133.2, 132.5, 131.6, 128.5, 127.6, 127.6, 127.5, 127.3, 126.6, 126.5, 125.9, 125.2, 61.7, 59.6, 52.7, 52.7, 32.9. LCMS (ESI) m / z: 390.2 [M+H] + .

[0074] Example 4: Preparation of N-hydroxy-4-((4-(2-(naphthalen-1-yl)ethyl)piperazin-1-yl)methyl)benzamide (Compound I4)

[0075]

[0076] The preparation method is basically the same as in Example 1. In this example, compound I4 (170 mg, 29.5%) is obtained as a white solid with a melting point of 198.9-199.3 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.03 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.43 - 7.36 (m, 4H), 3.50 (s, 2H), 3.20 - 3.17 (m, 2H), 2.61 - 2.58 (m, 2H), 2.58 - 2.50 (m, 3H), 2.50 - 2.41 (m, 5H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 141.7, 136.5, 133.4, 131.5, 128.6, 128.6, 126.8, 126.5, 126.0, 125.6, 125.5, 123.6, 61.6, 59.1, 52.7, 52.7, 29.8. LCMS (ESI) m / z: 390.2 [M+H] + .

[0077] Example 5: Preparation of 4-((4-(2-(2,3-dihydrobenzo[l,4]-dioxan-6-yl)ethyl)piperazin-1-yl)methyl)-N-hydroxybenzamide (Compound I5)

[0078]

[0079] The preparation method is basically the same as in Example 1. In this example, compound I5 (196 mg, 50.9%) is obtained as a white solid with a melting point of 178.1-179.0 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.08 (s, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 6.80 - 6.76 (m, 2H), 6.71 (d, J = 8.2 Hz, 1H), 4.26 (t, J = 13.3 Hz, 4H), 3.56 (s, 2H), 2.67 - 2.63 (m, 2H), 2.57 (s, 2H), 2.57 - 2.50 (m, 2H), 2.49 - 2.44 (m, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 143.0, 141.7, 141.5, 133.4, 131.4, 128.6, 126.8, 121.3, 117.0, 116.7, 64.0, 63.9, 61.6, 59.8, 52.7, 31.9. LCMS (ESI) m / z: 398.0 [M+H] + .

[0080] Example 6: Preparation of N-hydroxy-3-((4-phenethylpiperazin-1-yl)methyl)benzamide (Compound I6)

[0081]

[0082] The preparation method is basically the same as in Example 1. Compound I6 (178 mg, 31.2%) is obtained in this example, which is a white solid with a melting point of 71.7-72.3 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.08 (s, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 6.80 - 6.76 (m, 2H), 6.71 (d, J = 8.2 Hz, 1H), 4.26 (t, J = 13.3 Hz, 4H), 3.56 (s, 2H), 2.67 - 2.63 (m, 2H), 2.57 (s, 2H), 2.57 - 2.50 (m, 2H), 2.49 - 2.44 (m, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 164.3, 140.5, 138.6, 132.7, 131.5, 128.6, 128.2, 128.2, 127.4, 125.8, 125.4, 61.8, 59.7, 52.7, 52.6, 32.7. LCMS (ESI) m / z: 340.2 [M+H] + .

[0083] Example 7: Preparation of 3-((4-(3,4-dimethoxyphenethyl)piperazin-1-yl)methyl)-N- hydroxybenzamide (Compound I7)

[0084]

[0085] The preparation method is basically the same as in Example 1. Compound I7 (82 mg, 21.6%) is obtained in this example, which is a white solid with a melting point of 73.8-74.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.01 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.44 - 7.37 (m, 2H), 6.83 - 6.81 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.49 (s, 2H), 2.64 (t, J = 7.7 Hz, 2H), 2.59 - 2.50 (m, 2H), 2.49 - 2.36 (m, 8H). 13 CNMR (125 MHz, DMSO-d6) δ 164.2, 148.5, 147.0, 138.6, 132.9, 132.8, 131.5, 128.2, 127.4, 125.4, 120.4, 112.6, 111.8, 61.8, 59.9, 55.5, 55.4, 52.7, 32.3. LCMS (ESI) m / z: 400.0 [M+H] + .

[0086] Example 8: Preparation of N-hydroxy-3-((4-(2-(naphthalen-2-yl)ethyl)piperazin-1-yl)methyl)benzamide (Compound I8)

[0087]

[0088] The preparation method is basically the same as in Example 1. Compound I8 (236 mg, 47.2%) is obtained in this example, which is a white solid with a melting point of 80.2-81.0 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.03 (s, 1H), 7.86 - 7.81 (m, 3H), 7.70 (d, J = 5.7 Hz, 2H), 7.63 (d, J = 7.5 Hz, 1H), 7.48 - 7.37 (m, 5H), 3.48 (s, 2H), 2.89 - 2.86 (m, 2H), 2.61 - 2.58 (m, 2H), 2.56 - 2.50 (m, 2H), 2.47 - 2.39 (m, 6H). 13CNMR (125 MHz, DMSO-d6) δ 164.3, 138.6, 138.2, 133.1, 132.8, 131.6, 131.5, 128.2, 127.6, 127.6, 127.4, 127.4, 127.2, 126.5, 125.9, 125.4, 125.2, 61.8, 59.5, 52.7, 52.7, 32.9. LCMS (ESI) m / z: 390.0 [M+H] + .

[0089] Example 9: Preparation of N-hydroxy-3-((4-(2-(naphthalen-1-yl)ethyl)piperazin-1- yl)methyl)benzamide (Compound I9)

[0090]

[0091] The preparation method is basically the same as in Example 1. Compound I9 (144 mg, 26.2%) is obtained in this example, which is a white solid with a melting point of 91.8-92.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.21 (s, 1H), 9.04 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.45 - 7.37 (m, 4H), 3.50 (s, 2H), 3.20 - 3.17 (m, 2H), 2.61 - 2.58 (m, 2H), 2.58 - 2.50 (m, 2H), 2.50 - 2.41 (m, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 164.3, 138.6, 136.5, 133.4, 132.8, 131.5, 131.5, 128.6, 128.2, 127.4, 126.5, 126.5, 126.0, 125.6, 125.5, 125.4, 123.6, 61.8, 59.1, 52.7, 52.7, 29.8. LCMS (ESI) m / z: 390.0 [M+H] + .

[0092] Example 10: Preparation of 3-((4-(2-(2,3-dihydrobenzo[1,4]-dioxan-6-yl)ethyl)piperazin-1- yl)methyl)-N-hydroxybenzamide (Compound I 10 )

[0093]

[0094] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example 10 (162 mg, 50.6%), white solid, melting point 77.9-78.5°C. 1 H NMR (500 MHz, DMSO-d6) δ 7.66 (d, J = 28.3 Hz, 2H), 7.43 - 7.36 (m, 2H), 6.73 - 6.62 (m, 3H), 4.20 - 4.18 (m, 4H), 3.48 (s, 2H), 2.59 - 2.56 (m, 2H), 2.50 - 2.41 (m, 6H), 2.38 - 2.37 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 164.2, 143.0, 141.5, 138.6, 133.4, 132.8, 131.5, 128.2, 127.4, 125.4, 121.3, 117.0, 116.7, 64.0, 63.9, 61.8, 59.8, 52.7, 31.9. LCMS (ESI) m / z: 398.0 [M+H] + .

[0095] Example 11: Preparation of (E)-N-hydroxy-3-(4-((4-phenethylpiperazin-1-yl)methyl)phenyl)acrylamide (Compound I 11 )

[0096]

[0097] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example 11 (173 mg, 35.5%), white solid, melting point 90.9-91.9°C. 1 H NMR (500 MHz, DMSO-d6) δ 7.66 (d, J = 28.3 Hz, 2H), 7.43 - 7.36 (m, 2H), 6.73 - 6.62 (m, 3H), 4.20 - 4.18 (m, 4H), 3.48 (s, 2H), 2.59 - 2.56 (m, 2H), 2.50 - 2.41 (m, 6H), 2.38 - 2.37 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 162.8, 140.5, 139.9, 138.1, 133.5, 129.3, 128.6, 128.2, 127.4, 125.8, 118.6, 61.7, 59.7, 52.7, 52.7, 32.7. LCMS (ESI) m / z: 366.2 [M+H] + .

[0098] Example 12: Preparation of (E)-3-(4-((4-(3,4-dimethoxyphenethyl)piperazin-1-yl)methyl)phenyl)-N-hydroxybenzamide (Compound I 12 )

[0099]

[0100] Preparation method is substantially the same as Example 1, and the compound I 12 (58.2 mg, 29.3%), white solid, melting point 98.1-99.1 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.04 (s, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 15.8 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 6.83 - 6.81 (m, 2H), 6.71 - 6.69 (m, 1H), 6.44 (d, J = 15.8 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.46 (s, 2H), 2.65 - 2.62 (m, 2H), 2.50 - 2.48 (m, 2H), 2.48 - 2.37 (m, 8H). 13 C NMR (125 MHz, DMSO-d6) δ 162.8, 148.6, 147.0, 139.9, 138.1, 133.5, 132.9, 129.3, 127.4, 120.4, 118.6, 112.6, 111.8, 61.7, 59.9, 55.5, 55.4, 52.7, 32.3. LCMS (ESI) m / z: 426.2 [M+H] + .

[0101] Example 13: Preparation of (E)-N-hydroxy-3-(4-((4-(2-(naphthalen-2-yl)ethyl)piperazin-1-yl)methyl)phenyl)benzamide (Compound I 13 )

[0102]

[0103] The preparation method is substantially the same as in Example 1, and Compound I is obtained in this example. 13 (46.5 mg, 23.3%), white solid, melting point 198.9-199.3 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.05 (s, 1H), 7.88-7.83 (m, 3H), 7.74 (s, 1H), 7.54-7.37 (m, 8H), 6.47 (d, J = 15.9 Hz, 1H), 3.60 (s, 2H), 3.16-2.72 (m, 8H), 2.68-2.50 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 162.7, 138.0, 133.1, 131.8, 129.7, 129.7, 127.9, 127.5, 127.5, 127.4, 127.3, 126.7, 126.1, 125.5, 119.0, 60.8, 57.7, 51.5, 50.7, 50.6. LCMS (ESI) m / z: 416.2 [M+H] + .

[0104] Example 14: Preparation of (E)-N-hydroxy-3-(4-((4-(2-(naphthalen-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)benzamide (Compound I 14 )

[0105]

[0106] The preparation method is substantially the same as in Example 1, and Compound I is obtained in this example. 14 (170 mg, 76.2%), white solid, melting point 166.3-167.4 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.07 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.56-7.46 (m, 5H), 7.43-7.37 (m, 2H), 7.33 (d, J = 7.8 Hz, 2H), 6.45 (d, J = 15.8 Hz, 1H), 3.48 (s, 2H), 3.20-3.17 (m, 2H), 2.61-2.58 (m, 2H), 2.58-2.52 (m, 2H), 2.50-2.41 (m, 6H). 13C NMR (125 MHz, DMSO-d6) δ 162.7, 140.0, 138.1, 136.5, 133.5, 133.4, 131.5, 129.3, 129.3, 128.6, 127.4, 126.5, 126.0, 125.6, 125.5, 123.6, 118.6, 61.7, 59.1, 52.7, 52.7, 29.8. LCMS (ESI) m / z: 416.2 [M+H] + .

[0107] Example 15: Preparation of (E)-3-(4-((4-(2-(2,3-dihydrobenzo[l,4]-dioxan-6- yl)ethyl)piperazin-l-yl)methyl)phenyl)-N-hydroxybenzamide (Compound I 15 )

[0108]

[0109] Preparation method is substantially the same as Example 1, the compound I 15 (240 mg, 55.6%) white solid, melting point of 134.1-125.1 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.05 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 15.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 6.73 - 6.69 (m, 2H), 6.64 - 6.62 (m, 1H), 6.44 (d, J = 15.8 Hz, 1H), 4.18 (s, 4H), 3.45 (s, 2H), 2.59 - 2.56 (m, 2H), 2.50 - 2.41 (m, 6H), 2.41 - 2.37 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 162.7, 140.0, 138.1, 136.5, 133.5, 133.4, 131.5, 129.3, 129.3, 128.6, 127.4, 126.5, 126.0, 125.6, 125.5, 123.6, 118.6, 61.7, 59.1, 52.7, 52.7, 29.8. LCMS (ESI) m / z: 416.2 [M+H] + .

[0110] Example 16: Preparation of (E)-N-hydroxy-3-(3-((4-phenethylpiperazin-l- yl)methyl)phenyl)acrylamide (Compound I 16 )

[0111]

[0112] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example. 16 (86.4 mg, 24%), white solid, melting point 84.6-85.8 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.06 (s, 1H), 7.48-7.42 (m, 3H), 7.35 (t, J = 7.5 Hz, 1H), 7.30-7.24 (m, 3H), 7.21-7.15 (m, 3H), 6.47 (d, J = 15.8 Hz, 1H), 3.47 (s, 2H), 2.72-2.69 (m, 2H), 2.50-2.43 (m, 6H), 2.43-2.37 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 162.6, 140.5, 139.1, 138.3, 134.7, 130.0, 128.8, 128.6, 128.2, 127.4, 126.4, 125.8, 119.1, 61.8, 59.7, 52.7, 52.7, 32.8. LCMS (ESI) m / z: 366.2 [M+H] + .

[0113] Example 17: Preparation of (E)-3-(3-((4-(3,4-dimethoxyphenethyl)piperazin-1-yl)methyl)phenyl)-N- hydroxybenzamide (Compound I 17 )

[0114]

[0115] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example. 17 (112.3 mg, 30%), white solid, melting point 83.7-84.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 9.06 (s, 1H), 7.48-7.42 (m, 3H), 7.35 (t, J = 7.5 Hz, 1H), 7.30-7.24 (m, 3H), 7.21-7.15 (m, 3H), 6.47 (d, J = 15.8 Hz, 1H), 3.47 (s, 2H), 2.72-2.69 (m, 2H), 2.50-2.43 (m, 6H), 2.43-2.37 (m, 4H). 13CNMR (125 MHz, DMSO-d6) δ 162.7, 148.5, 147.0, 139.0, 138.3, 134.7, 132.9, 130.0, 128.8, 127.4, 126.4, 120.4, 119.1, 112.6, 111.8, 61.8, 59.9, 55.5, 55.4, 52.7, 32.3. LCMS (ESI) m / z: 426.0 [M+H] + .

[0116] Example 18: Preparation of (E)-N-hydroxy-3-(3-((4-(2-(naphthalen-2- yl)ethyl)piperazin-1-yl)methyl)phenyl)benzamide (Compound I 18 )

[0117]

[0118] Preparation method is substantially the same as Example 1, the compound I 18 (111.5 mg, 43.7%), white solid, melting point 95.9-96.9 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.06 (s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.48 - 7.29 (m, 8H), 6.48 (d, J = 15.9 Hz, 1H), 3.47 (s, 2H), 2.88 (t, J = 8.0 Hz, 2H), 2.60 (t, J = 7.9 Hz, 2H), 2.50 - 2.39 (m, 8H). 13 C NMR (125 MHz, DMSO-d6) δ 162.7, 139.0, 138.3, 138.3, 138.2, 134.7, 133.1, 131.6, 130.0, 128.8, 127.6, 127.6, 127.4, 127.4, 127.2, 126.5, 125.9, 125.2, 119.1, 61.8, 59.5, 52.7, 52.7, 32.9. LCMS (ESI) m / z: 416.0 [M+H] + .

[0119] Example 19: Preparation of (E)-N-hydroxy-3-(3-((4-(2-(naphthalen-1- yl)ethyl)piperazin-1-yl)methyl)phenyl)benzamide (Compound I 19 )

[0120]

[0121] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example. 19 (212, mg, 61.6%), white solid, melting point 94.5-95.4°C. 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.07 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54 - 7.31 (m, 9H), 6.49 (d, J = 15.8 Hz, 1H), 3.48 (s, 2H), 3.19 (t, J = 7.9 Hz, 2H), 2.61 - 2.58 (m, 3H), 2.58 - 2.50 (m, 2H), 2.50 - 2.41 (m, 5H). 13 C NMR (125 MHz, DMSO-d6) δ 162.7, 139.1, 138.3, 136.5, 134.7, 133.4, 131.5, 130.0, 128.8, 128.6, 127.4, 126.5, 126.4, 126.0, 125.6, 125.5, 123.6, 119.1, 61.8, 59.1, 52.7, 52.7, 29.8. LCMS (ESI) m / z: 416.0 [M+H] + .

[0122] Example 20: Preparation of (E)-3-(3-((4-(2-(2,3-dihydrobenzo[l,4]-dioxan-6-yl)ethyl)piperazin-l-yl)methyl)phenyl)-N-hydroxybenzamide (Compound I) 20 )

[0123]

[0124] The preparation method is basically the same as in Example 1, and Compound I is obtained in this example. 20 (155 mg, 46.5%), white solid, melting point 90.4-91.2°C. 1 H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.06 (s, 1H), 7.47 - 7.42 (m, 3H), 7.36 - 7.28 (m, 2H), 6.73 - 6.69 (m, 2H), 6.63 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 15.5 Hz, 1H), 4.18 (s, 4H), 3.46 (s, 2H), 2.59 - 2.56 (m, 2H), 2.50 - 2.41 (m, 6H), 2.41 - 2.38 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 162.7, 143.0, 141.5, 139.1, 138.3, 134.7, 133.4, 130.0, 128.8, 127.4, 126.4, 121.3, 119.1, 117.0, 116.7, 64.0, 63.9, 61.8, 59.8, 52.7, 31.9. LCMS (ESI) m / z: 424.0 [M+H] + .

[0125] Example 21: Preparation of N-hydroxy-4-((5-(2-(naphthalen-2-yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)benzamide (Compound II1)

[0126]

[0127] The preparation method is basically the same as in Example 1. Compound II1 (90.1 mg, 35%) is obtained in this example, which is a white solid with a melting point of 81.7-82.7 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.04 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.28 - 7.15 (m, 5H), 3.55 (s, 2H), 2.71 (t, J = 7.8 Hz, 2H), 2.56 - 2.50 (m, 8H), 2.29 (d, J = 5.5 Hz, 2H), 2.23 (d, J = 7.5 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 142.7, 140.6, 131.3, 128.6, 128.2, 128.2, 126.8, 125.8, 59.4, 59.3, 58.5, 56.9, 41.3, 34.7. LCMS (ESI) m / z: 366.0 [M+H] + .

[0128] Example 22: Preparation of N-hydroxy-4-((5-(2-(naphthalen-2-yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)benzamide (Compound II2)

[0129]

[0130] The preparation method is basically the same as in Example 1. Compound II2 (170 mg, 85%) is obtained in this example, which is a white solid with a melting point of 192.4-193.3 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.01 (s, 1H), 7.87 - 7.81 (m, 3H), 7.73 - 7.69 (m, 3H), 7.49 - 7.40 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 3.53 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.68 - 2.65 (m, 2H), 2.61 - 2.54 (m, 6H), 2.33 (d, J = 6.5 Hz, 2H), 2.22 (d, J = 6.5 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 142.6, 138.3, 133.1, 131.6, 131.3, 128.2, 127.6, 127.5, 127.4, 127.3, 126.8, 126.5, 125.9, 125.2, 59.4, 59.3, 58.5, 56.6, 41.3, 34.7. LCMS (ESI) m / z: 416.0 [M+H] + .

[0131] Example 23: Preparation of N-hydroxy-4-((5-(2-(naphthalen-1-yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(1H)-yl)methyl)benzamide (Compound II3)

[0132]

[0133] The preparation method is basically the same as in Example 1. Compound II3 (123 mg, 47.1%) is obtained in this example, which is a white solid with a melting point of 98.6-99.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.01 (s, 1H), 7.87 - 7.81 (m, 3H), 7.73 - 7.69 (m, 3H), 7.49 - 7.40 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 3.53 (s, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.68 - 2.65 (m, 2H), 2.61 - 2.54 (m, 6H), 2.33 (d, J = 6.5 Hz, 2H), 2.22 (d, J = 6.5 Hz, 2H). 13CNMR (125 MHz, DMSO-d6) δ 164.2, 142.7, 136.6, 133.4, 131.5, 131.3, 128.6, 128.2, 126.8, 126.5, 126.4, 126.0, 125.6, 125.5, 123.6, 59.5, 59.2, 58.5, 56.2, 41.4, 31.7. LCMS (ESI) m / z: 416.0 [M+H] + .

[0134] Example 24: Preparation of 4-((5-(3,4-dimethoxyphenethyl)octahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-N-hydroxybenzamide (Compound II4)

[0135]

[0136] The preparation method is basically the same as in Example 1. Compound II4 (55 mg, 26.9%) is obtained in this example, which is a white solid with a melting point of 73.2-74.1 °C. 1 H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J = 5.6 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 6.72 (d, J = 8.1 Hz, 1H), 3.72 (d, J = 14.7 Hz, 6H), 3.54 (s, 2H), 2.64 (t, J = 7.8 Hz, 2H), 2.56 - 2.53 (m, 8H), 2.30 (d, J = 6.9 Hz, 2H), 2.22 (d, J = 6.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.1, 148.5, 147.0, 142.6, 133.1, 131.4, 128.2, 126.8, 120.3, 112.6, 111.8, 59.4, 59.3, 58.5, 57.1, 55.5, 55.4, 41.3, 34.3. LCMS (ESI) m / z: 426.0 [M+H] + .

[0137] Example 25: Preparation of 4-((5-(2-(2,3-dihydrobenzo[l,4]-dioxan-6-yl)ethyl)octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-N-hydroxybenzamide (Compound II5)

[0138]

[0139] The preparation method is substantially the same as in Example 1. In this example, compound II5 (59 mg, 30%) is obtained as a white solid with a melting point of 92.1-92.9 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 6.73-6.71 (m, 2H), 6.66-6.64 (m, 1H), 4.19 (s, 4H), 3.55 (s, 2H), 2.60-2.51 (m, 10H), 2.27-2.22 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 164.2, 143.0, 142.7, 141.5, 133.5, 131.3, 128.2, 126.8, 121.2, 117.0, 116.6, 64.0, 63.9, 59.4, 59.3, 58.5, 57.0, 41.3, 33.8. LCMS (ESI) m / z: 424.0 [M+H] + .

[0140] Example 26: Preparation of N-hydroxy-3-((5-phenethyl octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)benzamide (Compound II6)

[0141]

[0142] The preparation method is substantially the same as in Example 1. In this example, compound II6 (92.4 mg, 38.9%) is obtained as a white solid with a melting point of 80.8-81.8 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.03 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 6.73-6.71 (m, 2H), 6.66-6.64 (m, 1H), 4.19 (s, 4H), 3.55 (s, 2H), 2.60-2.51 (m, 10H), 2.27-2.22 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 164.3, 140.6, 139.6, 132.7, 131.1, 128.6, 128.2, 128.2, 127.0, 125.8, 125.2, 59.3, 59.3, 58.7, 56.9, 41.3, 34.7. LCMS (ESI) m / z: 366.0 [M+H] + .

[0143] Example 27: Preparation of N-hydroxy-3-((5-(2-(naphthalen-2-yl)ethyl) octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)benzamide (Compound II7)

[0144]

[0145] The preparation method is basically the same as in Example 1. Compound II7 (104.8 mg, 56%) is obtained in this example, which is a white solid with a melting point of 91.1-92.0 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.04 (s, 1H), 7.87 - 7.81 (m, 3H), 7.71 (d, J = 19.6 Hz, 2H), 7.61 (d, J = 7.5 Hz, 1H), 7.49 - 7.36 (m, 5H), 3.53 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 2.57 (s, 6H), 2.35 (d, J = 5.7 Hz, 2H), 2.20 (d, J = 5.3 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.3, 140.6, 139.6, 132.7, 131.1, 128.6, 128.2, 128.2, 127.0, 125.8, 125.2, 59.3, 59.3, 58.7, 56.9, 41.3, 34.7. LCMS (ESI) m / z: 366.0 [M+H] + .

[0146] Example 28: Preparation of N-hydroxy-3-((5-(2-(naphthalen-l-yl)ethyl) octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)benzamide (Compound II8)

[0147]

[0148] The preparation method is substantially the same as in Example 1. In this example, compound II8 (82.8 mg, 41.4%) was obtained as a white solid with a melting point of 88.2-89.3 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.11 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.56 - 7.36 (m, 6H), 3.55 (s, 2H), 3.19 (t, J = 7.8 Hz, 2H), 2.67 - 2.58 (m, 8H), 2.36 (d, J = 7.4 Hz, 2H), 2.24 (d, J = 7.1 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.3, 139.6, 136.6, 133.4, 132.8, 131.5, 131.1, 128.6, 128.2, 127.0, 126.5, 126.5, 126.0, 125.6, 125.5, 125.2, 123.7, 59.4, 59.3, 58.7, 56.2, 41.4, 31.7. LCMS (ESI) m / z: 416.0 [M+H] + .

[0149] Example 29: Preparation of 3-((5-(3,4-dimethoxyphenethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)-N-hydroxybenzamide (Compound II9)

[0150]

[0151] The preparation method is substantially the same as in Example 1. In this example, compound II9 (65.6 mg, 33.8%) was obtained as a white solid with a melting point of 73.9-74.6 °C. 1 H NMR (500 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.44 - 7.36 (m, 2H), 6.82 (d, J = 9.5 Hz, 2H), 6.72 (d, J = 7.4 Hz, 1H), 3.72 (d, J = 15.3 Hz, 6H), 3.54 (s, 2H), 2.64 (t, J = 10.0 Hz, 2H), 2.59 - 2.53 (m, 8H), 2.32 (d, J = 8.2 Hz, 2H), 2.21 (d, J = 5.5 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 164.3, 148.5, 147.0, 139.6, 133.1, 132.8, 131.1, 128.2, 127.0, 125.2, 120.3, 112.6, 111.8, 59.4, 59.3, 58.7, 57.1, 55.5, 55.4, 41.4, 34.3. LCMS (ESI) m / z: 426.0 [M+H] + .

[0152] Example 30: Preparation of 3-((5-(2-(2,3-dihydrobenzo[l,4]-dioxan-6-yl)ethyl) octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-N-hydroxybenzamide (Compound II 10 )

[0153]

[0154] Preparation method is substantially the same as Example 1, and the compound II 10 (76.8 mg, 48.5%), white solid, melting point 77.2-78.2 °C. 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.68 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.44 - 7.36 (m, 2H), 6.73 - 6.64 (m, 3H), 4.19 (s, 4H), 3.54 (s, 2H), 2.66 - 2.56 (m, 8H), 2.29 (d, J = 7.6 Hz, 2H), 2.21 (d, J = 7.6 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.3, 148.5, 147.0, 139.6, 133.1, 132.8, 131.1, 128.2, 127.0, 125.2, 120.3, 112.6, 111.8, 59.4, 59.3, 58.7, 57.1, 55.5, 55.4, 41.4, 34.3. LCMS (ESI) m / z: 426.0 [M+H] + .

[0155] Example 31: Preparation of (E)-N-hydroxy-3-(4-((5-phenethyl octahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 11 )

[0156]

[0157] The preparation method is basically the same as in Example 1, and Compound II is obtained in this example. 11 (60 mg, 30%), white solid, melting point 83.8-84.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.30 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.50 - 7.17 (m, 9H), 6.44 (d, J = 15.0 Hz, 1H), 3.53 (d, J = 10.4 Hz, 2H), 2.72 - 2.69 (m, 2H), 2.57 - 2.52 (m, 8H), 2.27 (d, J = 30.1 Hz, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 160.3, 140.5, 131.4, 129.9, 128.8, 128.6, 128.5, 128.2, 127.4, 125.8, 59.4, 59.2, 58.5, 56.8, 41.3, 34.6. LCMS (ESI) m / z: 392.0 [M+H] + .

[0158] Example 32: Preparation of (E)-N-hydroxy-3-(4-((5-(2-(naphthalen-2- yl)ethyl)octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 12 )

[0159]

[0160] The preparation method is basically the same as in Example 1, and Compound II is obtained in this example. 12 (42.5 mg, 25%), white solid, melting point 89.3-89.9 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.30 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.50 - 7.17 (m, 9H), 6.44 (d, J = 15.0 Hz, 1H), 3.53 (d, J = 10.4 Hz, 2H), 2.72 - 2.69 (m, 2H), 2.57 - 2.52 (m, 8H), 2.27 (d, J = 30.1 Hz, 4H). 13C NMR (125 MHz, DMSO-d6) δ 162.8, 136.5, 133.4, 131.5, 129.9, 128.9, 128.6, 128.5, 127.4, 126.5, 126.5, 126.0, 125.6, 125.5, 123.6, 59.5, 59.2, 58.5, 56.2, 41.4, 31.6. LCMS (ESI) m / z: 422.0 [M+H] + .

[0161] Example 33: Preparation of (E)-N-hydroxy-3-(4-((5-(2-(naphthalen-1- yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 13 )

[0162]

[0163] Preparation method is substantially the same as Example 1, and the compound II 13 (60 mg, 30%) is obtained in this example, white solid, melting point of 92.4-93.4 °C. 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.64 - 7.32 (m, 8H), 6.45 (d, J = 15.8 Hz, 1H), 3.54 (d, J = 10.4 Hz, 2H), 3.21 (t, J = 7.9 Hz, 2H), 2.68 (t, J = 7.7 Hz, 4H), 2.60 (s, 2H), 2.54 - 2.53 (m, 2H), 2.36 - 2.26 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 162.8, 136.5, 133.4, 131.5, 129.9, 128.9, 128.6, 128.5, 127.4, 126.5, 126.5, 126.0, 125.6, 125.5, 123.6, 59.5, 59.2, 58.5, 56.2, 41.4, 31.6. LCMS (ESI) m / z: 422.0 [M+H] + .

[0164] Example 34: Preparation of (E)-3-(4-((5-(3,4-dimethoxyphenethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)-N-hydroxyacrylate (Compound II 14 )

[0165]

[0166] The preparation method is basically the same as in Example 1. In this example, compound II was obtained. 14 (62.6 mg, 34.8%), yellow solid, melting point 79.8-80.4 °C. 1 H NMR (500MHz, DMSO-d6) δ7.76–7.63(m,1H),7.50–7.22(m,4H),6.83(d,J=8.4Hz,2H),6.72(d,J=7.5Hz,1H),6.45(d,J=5.0Hz,1H), 3.72(d,J=15.1Hz,6H),3.55(d,J=9.9Hz,2H),2.66–2.59(m,8H),2.55–2.54(m,2H),2.36(d,J=8.2Hz,2H),2.28(d,J=6.6Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ160.3,148.6,147.1,132.8,131.4,129.9,128.9,128.5,127.4,122.1, 120.3,112.6,111.8,59.3,59.2,58.5,56.8,55.5,55.4,41.2,34.0.LCMS(ESI)m / z:452.0[M+H] + .

[0167] Example 35: (E)-3-(4-((5-(2-(2,3-dihydrobenzo[1,4]-dioxane-6-yl)ethyl)octahydropyrrolyl[3,4-C]pyrrole-2(1H)-yl)methyl)phenyl)-N-hydroxyacrylate (Compound II) 15 Preparation of )

[0168]

[0169] The preparation method is basically the same as in Example 1. In this example, compound II was obtained. 15 (62.4 mg, 32.3%), white solid, melting point 87.3-88.1 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.10 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.50 - 7.31 (m, 4H), 6.73 - 6.64 (m, 3H), 6.44 (d, J = 15.8 Hz, 1H), 4.19 (s, 4H), 3.54 (d, J = 10.5 Hz, 2H), 2.59 - 2.52 (m, 10H), 2.28 - 2.24 (m, 4H). 13 CNMR (125 MHz, DMSO-d6) δ 160.3, 143.0, 141.5, 133.5, 131.4, 131.3, 129.9, 128.8, 128.5, 127.4, 121.3, 117.0, 116.6, 64.0, 63.9, 59.4, 59.2, 58.6, 56.9, 41.3, 33.8. LCMS (ESI) m / z: 450.0 [M+H] + .

[0170] Example 36: Preparation of (E)-N-hydroxy-3-(3-((5-phenethyl octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 16 )

[0171]

[0172] Preparation method is substantially the same as Example 1, the compound II 16 (65 mg, 36%) was obtained as a yellow solid with a melting point of 75.6-76.6 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 9.10 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.50 - 7.31 (m, 4H), 6.73 - 6.64 (m, 3H), 6.44 (d, J = 15.8 Hz, 1H), 4.19 (s, 4H), 3.54 (d, J = 10.5 Hz, 2H), 2.59 - 2.52 (m, 10H), 2.28 - 2.24 (m, 4H). 13 CNMR (125 MHz, DMSO-d6) δ 160.3, 143.0, 141.5, 133.5, 131.4, 131.3, 129.9, 128.8, 128.5, 127.4, 121.3, 117.0, 116.6, 64.0, 63.9, 59.4, 59.2, 58.6, 56.9, 41.3, 33.8. LCMS (ESI) m / z: 450.0 [M+H] + .

[0173] Example 37: Preparation of (E)-N-hydroxy-3-(3-((5-(2-(naphthalen-2- yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 17 ) was prepared according to the procedure described in Example 1.

[0174]

[0175] Example 37: Preparation of (E)-N-hydroxy-3-(3-((5-(2-(naphthalen-2- yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 17 (50 mg, 30%), yellow solid, m.p. 84.6-85.5 °C. 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.83 - 7.63 (m, 6H), 7.46 - 7.29 (m, 6H), 6.48 (d, J = 16.3 Hz, 1H), 3.53 (d, J = 13.3 Hz, 2H), 2.90 (s, 2H), 2.70 - 2.54 (m, 8H), 2.37 (d, J = 18.2 Hz, 2H), 2.25 (d, J = 29.5 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 138.1, 133.1, 131.6, 131.5, 129.6, 129.6, 128.8, 127.6, 127.6, 127.4, 127.3, 127.2, 126.5, 125.9, 125.2, 119.1, 59.4, 59.2, 59.1, 56.4, 41.2, 34.6. LCMS (ESI) m / z: 442.0 [M+H] + .

[0176] Example 37: Preparation of (E)-N-hydroxy-3-(3-((5-(2-(naphthalen-2- yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 18 ) was prepared according to the procedure described in Example 1.

[0177]

[0178] Example 37: Preparation of (E)-N-hydroxy-3-(3-((5-(2-(naphthalen-2- yl)ethyl)octahydropyrrolo[3,4-C]pyrrol-2(lH)-yl)methyl)phenyl)acrylate (Compound II 18 (60 mg, 35%), yellow solid, m.p. 89.1-89.9 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.63 - 7.31 (m, 8H), 6.48 (d, J = 16.0 Hz, 1H), 3.55 (d, J = 13.7 Hz, 2H), 2.68 - 2.50 (m, 10H), 2.39 - 2.25 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 162.7, 140.0, 136.5, 133.4, 131.5, 129.6, 128.8, 128.6, 128.5, 126.5, 126.5, 126.2, 126.0, 125.6, 125.5, 123.6, 119.1, 59.5, 59.3, 59.3, 59.1, 41.3, 31.6. LCMS (ESI) m / z: 442.0 [M+H] + .

[0179] Example 39: Preparation of (E)-3-(3-((5-(3,4-dimethoxyphenethyl)octahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)phenyl)-N-hydroxyacrylate (Compound II 19 )

[0180]

[0181] Preparation method is substantially the same as Example 1, and the compound II 18 (130 mg, 72%) was obtained as a yellow solid with a melting point of 86.9-87.9 °C. 1 H NMR (500 MHz, DMSO-d6) δ 7.76 (d, J = 5.3 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.50 - 7.34 (m, 3H), 6.85 (d, J = 7.9 Hz, 2H), 6.74 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 15.9 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.62 (d, J = 8.4 Hz, 2H), 2.95 - 2.70 (m, 10H), 2.58 - 2.54 (m, 2H), 2.45 - 2.43 (d, J = 9.3 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 148.6, 147.3, 132.8, 131.5, 129.8, 129.7, 128.9, 128.7, 128.5, 122.7, 120.4, 112.5, 112.5, 111.9, 58.9, 58.4, 58.1, 56.0, 55.5, 55.5, 40.7, 33.0. LCMS (ESI) m / z: 452.0 [M+H] + .

[0182] Example 40: Preparation of (E)-3-(3-((5-(2-(2,3-dihydrobenzo[l,4]- dioxan-6-yl)ethyl)octahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)phenyl)-N- hydroxyacrylate (Compound II 20 )

[0183]

[0184] Preparation method is substantially the same as Example 1, and the compound II 20 (98 mg, 59%) was obtained as a yellow solid with a melting point of 79.9-80.4 °C. 1 H NMR (500 MHz, DMSO-d6) δ 7.76 (d, J = 5.2 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.46 - 7.29 (m, 3H), 6.73 - 6.71 (m, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 15.8 Hz, 1H), 4.19 (s, 4H), 3.55 (d, J = 13.3 Hz, 2H), 2.61 - 2.57 (m, 7H), 2.53 - 2.50 (m, 3H), 2.31 - 2.23 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 143.0, 141.5, 139.7, 139.6, 133.4, 131.5, 129.6, 129.6, 128.8, 128.6, 128.5, 121.3, 117.0, 116.6, 64.0, 63.9, 59.4, 59.3, 59.1, 56.9, 41.3, 33.7. LCMS (ESI) m / z: 450.0 [M+H] + .

[0185] Pharmacodynamics experiment

[0186] 1. Determination of the inhibitory activity of the compound on HDAC6

[0187] 1.1 Experimental method

[0188] The enzyme activity was detected in 96-well or 384-well flat-bottom microplate using fluorescence detection method with Ac-Lys-Tyr-Lys(Ac)-AMC and Boc-Lys(Ac)-AMC as substrates. After deacetylation by HDAC6, the product AMC was hydrolyzed by trypsin and the fluorescence signal was detected under the excitation of 355 nm and the emission of 460 nm. The initial velocity of the reaction was calculated by detecting the change of fluorescence signal over time. According to the initial activity of the sample and the test results, the inhibition rate of the compound at different concentrations was calculated, and the IC50was calculated according to different inhibition rates. 50 .

[0189] 1.2 Experimental results

[0190] Table 1 shows the inhibition activity results of the compounds of Examples I1-I 20 and II1-II 20 on HDAC6.

[0191] Table 1

[0192]

[0193] From the experimental results (Table 1), most of the forty examples showed significant inhibition activity on HDAC6, among which I2, I3, I4, I5, I 11 , I 12 , I 14 , I 15 , I 16 , I 17 , I 18 , I 19 , I 20 , II1, II2, II3, II4, II7, II8, II9, II 11 , II 12 , II 13 , II 14 , II 15 , II 16 , II 17 , II 18 , II 20 , II 50 The IC50of twenty-nine examples on HDAC6 were stronger than that of the positive control drug vorinostat. Among them, the examples I3, I 12 , I 15 , I 16 , I 18 , I 19 , I 20 , II1, II2, II3, II4, II11 12 13 14 15 16 17 18 The half-inhibitory concentration of HDAC6 of the nineteen compounds is less than 0.5 μM.

[0194] 2. Determination of the inhibitory activity of the preferred compounds on 5-HTT

[0195] 2.1 Experimental method

[0196] In this study, the HEK cell line expressing 5-HTT receptor was used. After trypsin digestion, the 5-HTT cells were resuspended in DMEM + 10% Dialyzed FBS medium and inoculated into 384-well plates at 3000 cells / well and cultured overnight. After the cells adhered, the culture medium in the 384-well plate was centrifuged and aspirated. The test compound (1000 nM) diluted in different concentrations was prepared in advance with 1x Assay Buffer and added to the corresponding wells of the 384-well plate. After centrifugation, the plate was incubated at 37°C for 60 min. After incubation, the values were detected at 450 nm excitation and 528 nm reading using a microplate reader. The inhibition rate of the test compound was calculated according to the absorbance of the test compound.

[0197] 2.2 Experimental results

[0198] Table 2 shows the inhibitory activity of the preferred compounds on 5-HTT.

[0199] Table 2

[0200]

[0201] According to the experimental results (Table 2), among the nineteen example compounds, eight example compounds had an inhibition rate of 5-HTT of more than 50% at a concentration of 1000 nM. Among them, compounds I3, I 18 19 17 18 showed significant inhibitory effect, and compound I 18 showed the strongest inhibitory effect, with the highest inhibition rate of 78.76%.

[0202] In summary, compounds I3, I 12 15 16 18 19 20 ​​​​​​​​​​​​​​​, II1, II2, II3, II4, II 11 , II 12 , II 13 , II 14 , II 15 , II 16 , II 17 , II 18 The inhibitory activity against HDAC6 is superior to the positive control drug, vorinostat. More importantly, compounds I3, I 18 , I 19 , II 17 , II 18 showed strong inhibitory activity against 5-HTT. In addition, compounds II3, II 12 , II 13 also showed good inhibitory activity against 5-HTT. Based on the above activity data, we can reasonably speculate that compounds I2, I3, I4, I5, I 11 , I 12 , I 14 , I 15 , I 16 , I 17 , I 18 , I 19 , I 20 , II1, II2, II3, II4, II7, II8, II9, II 11 , II 12 , II 13 , II 14 , II 15 , II 16 , II 17 , II 18 , II 20 may exert stronger antidepressant effects in vivo than vorinostat. Compounds that act on both HDAC and 5-HTT may exhibit stronger antidepressant efficacy than existing drugs by inhibiting two important antidepressant pathways in the central nervous system.

[0203] Furthermore, it is understood that various modifications and changes can be made to the application by those skilled in the art upon reading the above description of the application, which modifications and changes are also intended to fall within the scope of the claims which follow.

Claims

1. 5-HTT / HDAC dual inhibitor, or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the 5-HTT / HDAC dual inhibitor is shown in formula (I) or (II): in: R 1 for R 2 R 3 Each is an independent C1-C10 chain alkyl group; R 4 for It also forms an amide bond with -NH-OH.

2. The 5-HTT / HDAC dual inhibitor according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 R 3 Each is an alkyl group with a C1-C5 chain.

3. The 5-HTT / HDAC dual inhibitor according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 R 3 Each is independently selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, or -CH2CH2CH2CH2CH2-; R 4 For opposite or interposition 4. The 5-HTT / HDAC dual inhibitor according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 -CH2CH2-; R 3 It is -CH2-.

5. The 5-HTT / HDAC dual inhibitor according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, The 5-HTT / HDAC dual inhibitor is selected from compounds with the following structures:

6. The method for preparing the 5-HTT / HDAC dual inhibitor according to any one of claims 1-5, characterized in that, The synthetic route includes: The preparation method includes the following steps: Acid 1 with aromatic groups is reduced to intermediate alcohol 2 by lithium aluminum hydride; Intermediate alcohol 2 undergoes a nucleophilic substitution reaction with p-toluenesulfonyl chloride to give intermediate 3; 4. Methyl chloromethylbenzoate or methyl chloromethylcinnamate undergoes a nucleophilic substitution reaction with 1-Boc-piperazine or 2-Boc-octahydropyrrolyl[3,4-C]pyrrole to give intermediate 5 or 6. The protecting group of intermediate 5 or 6 is removed to obtain intermediate 7 or 8; Intermediate 7 or 8 undergoes a nucleophilic substitution reaction with intermediate 3 to yield intermediate 9 or 10; Intermediate 9 or 10 undergoes an amino-ester exchange reaction to obtain a 5-HTT / HDAC dual inhibitor as shown in formula (I) or (II).

7. The use of the 5-HTT / HDAC dual inhibitor or its pharmaceutically acceptable salt according to any one of claims 1-5 in the preparation of antidepressants.

8. The application according to claim 7, characterized in that, The target of the antidepressant is 5-HTT.

9. An antidepressant, characterized in that, Contains a safe and effective amount of the 5-HTT / HDAC dual inhibitor as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof.

10. The antidepressant according to claim 9, characterized in that, The antidepressant also includes at least one of the following: a pharmacologically acceptable salt, excipient, or carrier.

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