Inhibitors targeting 5-htt / hdac dual targets and preparation method and application thereof

Abstract

The application discloses a kind of inhibitors of targeting 5-HTT / HDAC double target and preparation method and application thereof.The application is based on the principle of rational drug design, and synthesizes novel small-molecule compounds with 5-HTT and HDAC inhibitory activity, multi-targets with potential antidepressant activity.The inhibitors of targeting 5-HTT / HDAC double target have both 5-HTT inhibitor effect and HDAC inhibitory effect, and are a kind of multi-target fluoxetine derivatives with 5-HTT and HDAC synergistically realizing antidepressant.The compound of the application is superior to fluoxetine compound in design strategy, introduces isoxazoles structure that can improve antidepressant activity, improves antidepressant activity, and has good improvement on the shortcomings of long treatment time and large side effects of currently used antidepressant compounds.

Description

TECHNICAL FIELD

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

[0002] Depression (MDD), also known as depressive disorder, is a mental disorder with high incidence, high recurrence and high suicide rate. The clinical manifestations are significant and persistent low mood, loss of appetite, lack of interest, slow thinking, loss of participation in social activities, and severe patients may have hallucinations, even self-harm and suicide behaviors, which seriously endanger human health. With the increase in the number of patients, depression has gradually become a social problem that cannot be ignored. At present, the treatment of depression mainly relies on oral chemical synthesis of drugs, which generally has low efficiency, high addiction, serious adverse reactions, poor patient compliance and other problems, so further research on drugs for treating depression is needed.

[0003] Pharmacophore splicing, i.e. splicing two or more pharmacophores into one molecule, so that the molecule itself or its metabolites act on two or more target points, thereby producing synergistic effect to improve efficacy. Therefore, antidepressant drugs targeting two or more target points can be designed and synthesized to further improve their antidepressant activity. Multi-target antidepressant drugs not only can improve the therapeutic effect, but also can avoid the drug interactions caused by the combination of multiple drugs, have lower side effects, and have important significance in the treatment of depression.

[0004] Histone deacetylase (HDAC) is considered as a new target for antidepressants. Studies have shown that hydroxamic acid is an effective HDAC inhibitor. For example, the patent specification with publication number CN108602812A discloses a bicyclic hydroxamic acid compound which can be used as an inhibitor of histone deacetylase activity in mammals, and can be used for treating mental disorders such as depression. For another example, the patent specification with publication number CN106458856A discloses an inhibitor specific to histone lysine demethylase (LSD1) and histone deacetylase (HDAC), which can be used for treating neurodegenerative diseases such as depression. Vorinostat (SAHA) is one of the classic HDAC inhibitors, and studies have shown that long-term administration of SAHA to depressed mice can effectively alleviate the depressive-like behavior of mice, indicating that HDAC may be an effective therapeutic strategy for the development of antidepressants.

[0005] Fluoxetine (N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, Fluoxetine) is one of the classic monoamine antidepressants, which can improve the content of serotonin (5-HT) in the synaptic cleft by inhibiting serotonin transporter (5-HTT) reuptake, so as to achieve the effect of anti-depression. However, fluoxetine has strong gastrointestinal reactions, headache, insomnia and other side effects, and even can cause nervous system diseases such as hallucinations.

[0006] The fluoxetine is combined with the HDAC inhibitor by the pharmacophore splicing principle to obtain a new antidepressant drug with 5-HTT and HDAC inhibitory activity, so as to improve the anti-depression activity, and has a broad development prospect for improving the treatment effect of anti-depression. In addition, the preparation method and the pharmacological activity of the fluoxetine are also studied. SUMMARY

[0007] The present application provides a kind of 5-HTT / HDAC double target inhibitor, which is superior to fluoxetine compound in design strategy, and introduces hydroxamic acid structure that can improve anti-depression activity, improves anti-depression activity, and has good improvement on the shortcomings of long treatment time and large side effects of currently used antidepressants.

[0008] The 5-HTT / HDAC double target inhibitor, or its pharmaceutically acceptable salt, or its solvate, or its enantiomer, or its diastereomer, the structure of the 5-HTT / HDAC double target inhibitor is as shown in formula (I) or (II):

[0009]

[0010] Wherein:

[0011] R 1 , R 2 are independently selected from straight-chain or cyclic structures containing heteroatoms;

[0012] R 3 is and forms an amide bond with -NH-OH.

[0013] Further, R 1 , R 2 are independently selected from C1-C10 straight-chain alkyl containing nitrogen or oxygen atoms or C1-C10 cyclic structures containing nitrogen or oxygen atoms.

[0014] Further, R 1-CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2CH2O-, and R 1 forms a C-N bond with -NH when R 1 is a nitrogen containing cyclic structure forms a N-N bond with -NH;

[0015] R 2 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2CH2O-, and R 2 forms a C-O bond with R 3 when R 2 is a nitrogen containing cyclic structure forms a N-N bond with R 1 ; 1

[0016] R 3 is then the substituent on the benzene ring is in the para position.

[0017] Still further, R 1 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2CH2O-,

[0018] R 2 ​Selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2 -, -CH2CH2O-, -CH2CH2CH2O-, -CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2O-, -CH2CH2CH2CH2CH2CH2O-,

[0019] Specifically, the inhibitor targeting the dual 5-HTT / HDAC targets is selected from compounds with the following structures: Ia-Ih, IIa-IIh, IIIa-IIIh, or IVa.

[0020]

[0021] Based on the principles of rational drug design, this invention designs and synthesizes novel small molecule compounds with multiple targets and potential antidepressant activity, exhibiting 5-HTT and HDAC inhibitory activities.

[0022] This invention also provides a method for preparing the inhibitor targeting both 5-HTT and HDAC, the synthetic route of which includes:

[0023]

[0024]

[0025] The preparation method includes:

[0026] (S)-(-)-3-chloro-1-phenyl-1-propanol 1 or (R)-(-)-3-chloro-1-phenyl-1-propanol 1' is phototensor reaction to give intermediate 2 or intermediate 2';

[0027] Intermediate 2 or intermediate 2' reacts with potassium phthalimide via a nucleophilic substitution reaction to yield intermediate 3 or intermediate 3';

[0028] Intermediate 3 or intermediate 3' is obtained by hydrazine hydrolysis to yield intermediate 4 or intermediate 4';

[0029] Methyl hydroxybenzoate 5 or methyl hydroxycinnamate 7 undergoes a nucleophilic substitution reaction with bromoalkanes to give intermediates 6a-6e or 8a-8e.

[0030] 1-Boc-piperazine undergoes a nucleophilic substitution reaction with methyl 4-bromobutyrate, methyl 4-bromobenzoate, or methyl 4-bromocinnamate to give intermediates 10, 13, or 16.

[0031] Intermediates 10, 13 or 16 are deprotected to obtain intermediates 11, 14 or 17;

[0032] Intermediates 11, 14 or 17 are subjected to nucleophilic substitution reaction with 1, 2-dibromopropane or 1, 2-dibromobutane to obtain intermediates 12a-12b, 15a-15b or 18a-18b;

[0033] Intermediates 4 is subjected to nucleophilic substitution reaction with intermediates 6a-6e, 8a-8e, 12a-12b, 15a-15b, 18a-18b or (E)-3-(4-formylphenyl) acrylate and haloalkane to obtain intermediates 19a-19f, 20a-20f or 21a-21f; Intermediates 4' is subjected to nucleophilic substitution reaction with intermediates 8a to obtain intermediates 21b';

[0034] Intermediates 19a-19f, 20a-20f and 21a-21f are subjected to amine ester exchange reaction to obtain fluoxetine derivatives Ia-Ih, IIa-IIh, IIIa-IIIh or IVa shown in formula (I) or (II).

[0035] The present application also provides use of the inhibitor targeting 5-HTT / HDAC dual targets, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof in preparation of an antidepressant drug. The target of the antidepressant drug is 5-HTT.

[0036] As a general inventive concept, the present application also provides an antidepressant drug containing a safe and effective amount of the inhibitor targeting 5-HTT / HDAC dual targets, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an enantiomer thereof, or a diastereomer thereof. The antidepressant drug can further comprise at least one of a pharmacologically acceptable salt, an excipient, a carrier.

[0037] Compared with the prior art, the present application has the following beneficial effects:

[0038] The inhibitor targeting 5-HTT / HDAC dual targets of the present application has both 5-HTT inhibitor effect and HDAC inhibitor effect, and is a kind of multi-target fluoxetine derivative realizing antidepressant effect in cooperation with 5-HTT and HDAC. DETAILED DESCRIPTION

[0039] 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 conventional conditions, or according to the conditions suggested by the manufacturers.

[0040] (I) Synthesis of intermediates 2, 3, 4 and 2', 3', 4'

[0041]

[0042] Reaction Scheme 1: Synthesis of intermediates 2, 3, 4 and 2', 3', 4'. Reaction reagents and conditions: (a) Ph3P, DIAD, THF, 0 °C - r.t., 12 h; (b) KI, DMSO, 70 °C, 13 h; (c) NH2NH2.H2O, DCM, MeOH, r.t., 8 h.

[0043] As shown in Reaction Scheme 1, into a 100 mL round-bottom flask equipped with a magnetic stirrer, (S)-(-)-3-chloro-1-phenyl-1-propanol 1 (10.0 mmol, 1705 mg), triphenylphosphine Ph3P (10.0 mmol, 2620 mg), p-trifluoromethylphenol (10.0 mmol, 1620 mg) and THF (30 mL) were added successively, and stirred at 0 °C. Then a solution of DIAD (10.0 mmol, 2022 mg) in THF (15 mL) was added dropwise slowly using a constant pressure dropping funnel, and the reaction was continued at room temperature for 12 h after the addition was completed. The reaction progress was monitored by TLC with n-hexane as the developing agent. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography with n-hexane as the eluent to give intermediate 2 (2795 mg, 89%) as a colorless transparent liquid.

[0044] Into a 100 mL round-bottom flask equipped with a magnetic stirrer, intermediate 2 (5.0 mmol, 1571 mg), potassium phthalimide (10.0 mmol, 1850 mg), potassium iodide KI (0.5 mmol, 83 mg) and DMSO (30 mL) were added successively, and the reaction was carried out at 70 °C for 13 h. The reaction progress was monitored by TLC with n-hexane: ethyl acetate (volume ratio 4:1) as the developing agent. After the reaction was completed, water (20 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (20 mL x 3), then washed with water (20 mL), saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The product was purified by column chromatography with n-hexane: ethyl acetate (volume ratio 20:1) as the eluent to give intermediate 3 (1510 mg, 71%) as a white solid.

[0045] Into a 100 mL round-bottom flask equipped with a magnetic stir bar was added intermediate 3 (5.0 mmol, 2125 mg), hydrazine hydrate (10.0 mmol, 500 mg) and DCM / MeOH (40 mL, 1:1 by volume) sequentially. The reaction mixture was stirred at room temperature for 8 h. The reaction progress was monitored by TLC with dichloromethane:methanol (30:1 by volume) as eluent. After the reaction was completed, the solvent was removed by distillation under reduced pressure. Water (20 mL) was added to the reaction mixture, which was extracted with DCM (20 mL). The pH of the aqueous layer was adjusted to 12 with NaOH solution (10%) and extracted with DCM (20 mL x 3). The organic layers were combined and washed with water (20 mL), saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography with dichloromethane:methanol (100:1 by volume) as eluent to give intermediate 4 (1121 mg, 76%) as a light yellow transparent liquid.

[0046] Intermediate 4' was prepared according to Reaction Scheme 1 and the same procedure as described above by changing the reactants.

[0047] (ii) Synthesis of intermediates 6a-e and 8a-e

[0048]

[0049] Reaction Scheme 2: Synthesis of intermediates 6a-e and 8a-e. Reaction reagents and conditions: (a) K2CO3, acetone, 60 °C, 8 h.

[0050] As shown in Reaction 2, into a 50 mL round-bottom flask equipped with a magnetic stir bar was added methyl p-hydroxybenzoate 5 (3.0 mmol, 456 mg), 1,2-dibromoethane (12.0 mmol), potassium carbonate (9.0 mmol, 1242 mg) and acetone (15 mL). The reaction mixture was stirred at 60 °C for 8 h. The reaction progress was monitored by TLC with n-hexane:ethyl acetate (5:1 by volume) as eluent. After the reaction was completed, the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography with n-hexane:ethyl acetate (20:1 by volume) as eluent to give intermediate 6a (450 mg, 58%) as a white solid.

[0051] Intermediates 6b, 6c, 6d, 6e, 8a, 8b, 8c, 8d, 8e were prepared according to Reaction Scheme 2 and the same procedure as described above by changing the reactants.

[0052] (iii) Synthesis of intermediates 12a-b, 15a-b and 18a-b

[0053]

[0054] Reaction Scheme 3: Synthesis of intermediates 12a-b, 15a-b and 18a-b. Reagents and conditions: (a) TEA, DCM, r.t., 6 h. (b) HC1.dioxane, MeOH, 0 °C, 12 h; (c) K2CO3, DMF, 60 °C, 8 h; (d) DIPEA, KI, CH3CN, 50 °C, 5 h; (e) DIPEA, KI, DCM, 50 °C, 5 h.

[0055] As shown in Reaction 3, to a 50 mL round bottom flask equipped with magnetic stirring was added 1-Boc-piperazine 9 (3.0 mmol, 558 mg), methyl 4-bromobutyrate (3.0 mmol, 540 mg), triethylamine (6.0 mmol, 606 mg) and DCM (20 mL). The reaction was allowed to proceed at room temperature for 6 h. The reaction progress was monitored by TLC using dichloromethane:methanol (5:1 by volume) as eluent. After completion of the reaction, the reaction solvent was removed under reduced pressure and the product was purified by column chromatography using dichloromethane:methanol (30:1 by volume) as eluent to obtain the intermediate 10 as a clear liquid (421 mg, 48%).

[0056] To a 100 mL round bottom flask equipped with magnetic stirring was added 1-Boc-piperazine 9 (6.0 mmol, 1116 mg), methyl p-chloromethyl benzoate (5.0 mmol, 920 mg), N,N-diisopropylethylamine DIPEA (10.0 mmol, 1290 mg), potassium iodide (0.5 mmol, 83 mg) and acetonitrile (30 mL) and allowed to react at 50 °C for 5 h. The reaction progress was monitored by TLC using n-hexane:ethyl acetate (3:2 by volume) as eluent. After completion of the reaction, the solvent was removed under reduced pressure and the product was purified by column chromatography using n-hexane:ethyl acetate (6:1 by volume) as eluent to obtain the intermediate 13 as a clear liquid (1768 mg, 88%).

[0057] Following the same procedure as described above in Reaction Scheme 3 and replacing the substrates, the intermediates 16 were prepared.

[0058] To a 50 mL round bottom flask equipped with magnetic stirring was added the intermediate 10 (1.5 mmol, 429 mg), HC1.dioxane solution (8 mL) and methanol (8 mL). The reaction was allowed to proceed at room temperature for 12 h. The reaction progress was monitored by TLC using dichloromethane:methanol (5:1 by volume) as eluent. After completion of the reaction, the reaction solvent was removed under reduced pressure and the mixture was shaken with ethyl acetate, filtered, washed with ethyl acetate and dried to obtain the intermediate 11 as a clear liquid (333 mg, 98%).

[0059] Following the same procedure as described above in Reaction Scheme 3 and replacing the substrates, the intermediates 14, 17 were prepared.

[0060] To a 50 mL round bottom flask equipped with magnetic stirring was added intermediate 11 (3.0 mmol, 666 mg), 1,2-dibromoethane (12.0 mmol), potassium carbonate (9.0 mmol, 1242 mg) and DMF (15 mL) and reacted at 60 °C for 8 h. The reaction progress was monitored by TLC with dichloromethane:methanol (30:1 by volume) as eluent. After completion of the reaction, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3) and then washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and purified by column chromatography using dichloromethane:methanol (120:1 by volume) as eluent to obtain a clear yellow liquid, intermediate 12a (433 mg, 47%).

[0061] Following the same procedure as described above, intermediates 12b, 15a-b, 18a-b were prepared by changing the substrates according to Reaction Scheme 3.

[0062] (iv) Synthesis of intermediates 19a-f, 20a-f, 21a-f and 21b'

[0063]

[0064] Reaction Scheme 4: Synthesis of intermediates 19a-f, 20a-f, 21a-f and 21b'. Reaction reagents and conditions: (a) Cs2CO3, TBAI, DMF, 90 °C, 12 h; (b) K2CO3, DMF, 70 °C; (c) K2CO3, KI, CH3CN, 65 °C; (d) K2CO3, DMF, 40 °C; (e) Cs2CO3, DMF, 70 °C; (f) CH3COOH, (CH3COO)3BHNa, DCE, r.t.

[0065] As shown in Reaction 4, to a 50 mL round bottom flask equipped with magnetic stirring was added fluoxetine intermediate 4 (1.5 mmol, 443 mg), methyl bromoacetate (1.5 mmol), cesium carbonate (2.0 mmol, 653 mg), tetrabutylammonium iodide TBAI (0.15 mmol, 55 mg) and DMF (15 mL) and reacted at 90 °C for 12 h. The reaction progress was monitored by TLC with dichloromethane:methanol (30:1 by volume) as eluent. After completion of the reaction, water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3) and then washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure and purified by column chromatography using dichloromethane:methanol (100:1 by volume) as eluent to obtain a clear yellow liquid, intermediate 19a (356 mg, 56%).

[0066] Following the same procedure as described above, by changing the substrates, intermediates 19b-f, 20a-h, 21b-h, 21b' were prepared.

[0067] Into a 100 mL round bottom flask with magnetic stirring, was added intermediate fluoxetine intermediate 4 (0.96 mmol, 283 mg), (E)-3-(4-formylphenyl) acrylate (0.8 mmol, 152 mg), acetic acid (1.6 mmol, 96 mg), a few drops of DMF and 1,2-dichloroethane DCE (20 mL), and reacted at room temperature for 1 h. Then sodium triacetoxyborohydride (2.56 mmol, 543 mg) was added and reacted at room temperature for 2 h. The reaction progress was monitored by TLC with dichloromethane:methanol (30:1 by volume) as eluent. After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (10 mL), then neutralized with NaHCO3 solution (10 mL) and acetic acid was extracted with dichloromethane (20 mL x 3), followed by washing the organic phase with saturated brine (20 mL x 2), removing the solvent under reduced pressure, and purifying by column chromatography with dichloromethane:methanol (100:1 by volume) as eluent, to finally obtain intermediate 21a as a colorless transparent liquid (326 mg, 87%).

[0068] (V) Preparation of 5-HTT / HDAC dual inhibitor final products Ia-h, IIa-h, IIIa-h and IVa

[0069]

[0070] Scheme 5: Synthetic route of 5-HTT / HDAC dual inhibitor final products Ia-h, IIa-h, IIIa-h and IVa. Reagents and conditions: (a) NH2OH, NaOH, DCM, MeOH, 0 °C, 1 h.

[0071] As shown in Scheme 5, into a 50 mL round bottom flask with magnetic stirring, was added intermediate 19a (0.2 mmol) and a mixed solution of dichloromethane and methanol (DCM:MeOH = 1:2, 9 mL in total), the reaction solution was cooled to 0 °C, then hydroxylamine aqueous solution (6.0 mmol) and NaOH solid (2.0 mmol) were added, and reacted at 0 °C for 1-4 h. The reaction progress was monitored by TLC with dichloromethane:methanol (15:1 by volume) as eluent. After the reaction was completed, dilute hydrochloric acid (1 mol / L) was first added to the reaction solution to adjust the pH to 7, the solvent was removed under reduced pressure, and thin layer chromatography preparation plate was used for purification to obtain the compound.

[0072] Each of the intermediates used can be prepared according to (I)-(V) described above, which will not be repeated here.

[0073] Example 1: Preparation of (R)-N-hydroxy-2-((3-phenyl-3-(4(trifluoromethyl) phenoxy)propyl)amino)acetamide (Compound la)

[0074]

[0075] Into a 50 mL round bottom flask equipped with magnetic stirring was added intermediate 19a (0.2 mmol) and a mixture of dichloromethane and methanol (DCM / MeOH = 1:2, total 9 mL). The reaction was cooled to 0 °C, then NH2OH-H2O (6.0 mmol, 612 mg) and NaOH solid (2.0 mmol, 80 mg) were added, and the reaction was allowed to proceed at 0 °C for 1-4 h. The reaction progress was monitored by TLC, using dichloromethane:methanol (15:1 by volume) as the eluent. After the reaction was completed, dilute hydrochloric acid (1 mol / L) was added to the reaction to adjust the pH to 7, and the solvent was removed by reduced pressure concentration. The product was purified by TLC-preparative plate using dichloromethane:methanol (15:1 by volume) as the eluent, and then washed with n-hexane and ethyl acetate to obtain compound la (38 mg, 19%) as a yellow liquid. 1 H NMR (500 MHz, Chloroform-d) δ 11.68 (s, 1H), 10.09 (s, 1H), 7.41 (d, J = 7.7 Hz, 2H), 7.35 - 7.27 (m, 5H), 6.87 (t, J = 9.8 Hz, 2H), 5.23 (s, 1H), 3.26 (s, 2H), 2.76 (s, 2H), 2.16 (ddd, J = 21.1, 12.0, 4.2 Hz, 1H), 2.06 - 1.95 (m, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 173.0, 160.6, 141.1, 128.9, 128.0, 126.9, 126.9, 126.9, 125.9, 115.9, 78.6, 50.9, 46.0, 39.0. HRMS calcd for C 18 H 19 F3N2O3 369.1 [M+H] + , found 369.1.

[0076] Example 2: Preparation of (R)-N-hydroxy-3-((3-phenyl-3-(4(trifluoromethyl) phenoxy)propyl)amino)propanamide (Compound lb)

[0077]

[0078] The preparation method is basically the same as in Example 1, and Compound lb (62 mg, 31%) is obtained as a yellow liquid in this example.1 HNMR (500 MHz, Chloroform-d) δ 12.06 (s, 1H), 9.97 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 4.3 Hz, 4H), 7.23 (dt, J = 8.6, 3.9 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 5.26 (dd, J = 7.9, 4.2 Hz, 1H), 2.84 (s, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.29 (s, 2H), 2.19 (dq, J = 14.1, 6.9 Hz, 1H), 2.12 - 2.02 (m, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 173.0, 160.7, 141.1, 128.9, 128.0, 126.9, 126.9, 126.9, 125.9, 122.8, 115.9, 78.6, 52.0, 50.9, 46.0, 39.0. HRMS calcd for C 19 H 21 F3N2O3 383.2 [M+H] + , found 383.2.

[0079] Example 3: Preparation of (R)-N-hydroxy-4-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)butanamide (Compound Ic)

[0080]

[0081] The preparation method is basically the same as in Example 1, and Compound Ic (58 mg, 29%) is obtained in this example, which is a yellow-brown liquid. 1 HNMR (400 MHz, Chloroform-d) δ 9.27 (s, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.31 (s, 5H), 6.88 (d, J = 8.2 Hz, 2H), 5.35 (s, 1H), 5.27 - 5.20 (m, 1H), 4.05 (s, 2H), 3.35 (s, 2H), 2.16 (s, 2H), 2.04 (dd, J = 25.2, 8.1 Hz, 2H), 1.91 (s, 2H). 13C NMR (125 MHz, Chloroform-d) δ 171.0, 160.4, 140.5, 129.0, 128.2 127.0, 126.9, 126.9, 126.9, 125.8, 123.1 (d, J = 32.7 Hz), 115.9, 78.4, 64.0, 50.9, 38.7, 38.0, 25.1. HRMS calcd for C 20 H 23 F3N2O3 397.2 [M + H] + , found 397.2.

[0082] Example 4: Preparation of (R)-N-hydroxy-5-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)pentanamide (Compound Id)

[0083]

[0084] The preparation method is basically the same as in Example 1, and Compound Id (56 mg, 28%) is obtained in this example, which is a yellow-brown liquid. 1 HNMR (500 MHz, Chloroform-d) δ 12.29 (s, 1H), 9.67 (s, 1H), 7.41 (s, 2H), 7.31 (s, 4H), 7.25 (s, 1H), 6.87 (s, 2H), 5.39 (d, J = 41.8 Hz, 1H), 5.27 - 5.19 (m, 1H), 4.11 - 3.87 (m, 2H), 3.33 (s, 2H), 2.31 - 2.11 (m, 2H), 2.11 - 1.92 (m, 2H), 1.78 - 1.44 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 171.0, 160.4, 140.5, 129.0, 128.2 127.0, 126.9, 126.9, 126.9, 125.8, 123.1 (d, J = 32.7 Hz), 115.9, 78.4, 64.0, 50.9, 38.7, 38.0, 25.1. HRMS calcd for C 21 H 25 F3N2O3 397.2 [M + H] + , found 397.2.

[0085] Example 5: Preparation of (R)-N-hydroxy-6-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)hexanamide (Compound Ie)

[0086]

[0087] The preparation method is basically the same as in Example 1. In this example, compound Ie (70 mg, 35%) is obtained as a yellow-brown liquid. 1 HNMR (500 MHz, Chloroform-d) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.1 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 5.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 5.48 (dd, J = 8.0, 4.9 Hz, 1H), 3.89 (t, J = 6.5 Hz, 2H), 3.11 (q, J = 6.7, 6.2 Hz, 2H), 2.08 (dq, J = 14.2, 6.7 Hz, 1H), 1.96 - 1.87 (m, 3H), 1.49 (h, J = 7.8, 7.3 Hz, 4H), 1.29 - 1.23 (m, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 160.4, 157.1, 140.5, 129.0, 128.2, 126.9, 126.9, 125.8, 123.1 (d, J = 33.2 Hz), 115.9, 78.6, 64.7, 38.8, 38.1, 28.6, 25.3, 24.9, 18.5. HRMS calcd for C 22 H 27 F3N2O3 425.2 [M+H] + , found 425.2.

[0088] Example 6: Preparation of (R)-N-hydroxy-7-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)heptanamide (Compound If)

[0089]

[0090] The preparation method is basically the same as in Example 1. In this example, compound If (48 mg, 24%) is obtained as a yellow-brown solid with a melting point of 54.5-55.8 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.64 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 5.1 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 5.48 (dd, J = 8.0, 4.9 Hz, 1H), 3.89 (t, J = 6.5 Hz, 2H), 3.15 - 3.08 (m, 2H), 2.08 (dq, J = 14.2, 7.0 Hz, 1H), 1.93 (d, J = 7.3 Hz, 2H), 1.91 (s, 1H), 1.48 (dt, J = 14.3, 6.8 Hz, 4H), 1.29 - 1.22 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 174.2, 160.4, 156.8, 140.6, 129.0, 128.2, 127.0, 127.0, 126.9, 125.8, 123.2 (d, J = 32.4 Hz), 115.9, 78.7, 64.8, 51.6, 38.9, 38.1, 34.0, 28.8, 25.6, 24.7. HRMS calcd for C 23 H 29 F3N2O3439.2 [M+H] + , found 439.2.

[0091] Example 7: Preparation of (R)-N-hydroxy-4-(4-(3-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)propyl)piperazin-l-yl)butanamide (Compound Ig)

[0092]

[0093] The preparation method is basically the same as in Example 1, and Compound Ig (40 mg, 20%) is obtained in this example, which is a yellow-brown solid with a melting point of 57.9-59 °C. 1H NMR (400 MHz, Chloroform-d) δ 11.98 (s, 1H), 9.95 (s, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 4.3 Hz, 4H), 7.28 (d, J = 4.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.32 (dd, J = 8.3, 4.6 Hz, 1H), 4.12 (dd, J = 21.5, 11.2 Hz, 4H), 4.03 (s, 2H), 3.44 (dt, J = 9.6, 5.2 Hz, 4H), 3.31 (s, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.43 (s, 4H), 2.19 (dt, J = 14.6, 7.2 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.97 (s, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 160.4, 140.8, 128.9, 127.9, 126.8, 126.8, 126.8, 126.7, 125.8, 123.3, 122.8 (d, J = 32.6 Hz), 122.5, 115.8, 78.4, 61.2, 50.1, 41.7, 38.4, 38.1, 35.2, 34.2. HRMS calcd for C 27 H 37 F3N4O3 523.3 [M+H] + , found 523.3.

[0094] Example 8: Preparation of (R)-N-hydroxy-4-(4-(4-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)butyl)piperazin-l-yl)butanamide (Compound Ih)

[0095]

[0096] The preparation method is basically the same as in Example 1, and Compound Ih (34 mg, 17%) is obtained in this example, which is a yellow-brown solid with a melting point of 62.7-64.2 °C. 1H NMR (400 MHz, Chloroform-d) δ 12.04 (s, 1H), 9.96 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 4.3 Hz, 4H), 7.30 (d, J = 4.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.35 (dd, J = 8.3, 4.6 Hz, 1H), 4.19 (dt, J = 24.8, 12.3 Hz, 4H), 3.90 (s, 2H), 3.44 (dt, J = 14.5, 7.4 Hz, 4H), 3.37 (s, 2H), 2.94 (t, J = 6.8 Hz, 2H), 2.71 - 2.64 (m, 2H), 2.57 (s, 4H), 2.46 (s, 2H), 2.21 (dt, J = 13.9, 6.8 Hz, 1H), 2.03 (dtd, J = 14.2, 7.2, 4.7 Hz, 1H), 1.88 (s, 4H). 13 CNMR (125 MHz, Chloroform-d) δ 165.1, 160.2, 140.2, 128.9, 128.1, 126.8, 126.8, 126.8, 126.7, 125.7, 123.2, 123.0 (d, J = 26.8 Hz), 122.8, 115.8, 78.0, 63.9, 63.3, 62.2, 61.7, 50.1, 39.4, 38.1, 37.6, 29.7, 28.9, 25.0. HRMS calcd for C 28 H 39 F3N4O3 537.3 [M+H] + , found 537.3.

[0097] Example 9: Preparation of (R)-N-hydroxy-4-(((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)methyl)benzamide (Compound Ila)

[0098]

[0099] The preparation method is basically the same as that in Example 1, and Compound Ila (64 mg, 32%) is obtained in this example, which is a brown solid with a melting point of 81.5-83.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.99 (s, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.37 (t, J = 7.0 Hz, 4H), 7.32 (d, J = 7.7 Hz, 2H), 7.25 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 5.61 - 5.54 (m, 1H), 3.76 (s, 2H), 2.67 - 2.59 (m, 2H), 2.13 (dt, J = 12.6, 6.7 Hz, 1H), 1.98 - 1.92 (m, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 165.1, 160.2, 140.4, 131.2, 128.8, 128.0, 127.2, 127.2, 127.1, 126.7, 126.7, 125.7, 125.4, 122.8 (d, J = 32.0 Hz), 115.8, 83.8, 78.0, 45.5, 37.2, 22.7. HRMS calcd for C 24 H 23 F3N2O3 445.2 [M+H] + , found 445.2.

[0100] Example 10: Preparation of (R)-N-hydroxy-4-(2-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)ethoxy)benzamide (Compound lib)

[0101]

[0102] The preparation method is basically the same as that in Example 1, and Compound lib (60 mg, 30%) is obtained in this example, which is a white solid with a melting point of 76.7-77.8 °C. 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.91 (s, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.56 (dd, J = 7.7, 5.3 Hz, 1H), 4.04 (t, J = 5.5 Hz, 2H), 2.87 (t, J = 5.5 Hz, 2H), 2.67 (t, J = 5.9 Hz, 2H), 2.11 (dq, J = 14.1, 6.8 Hz, 1H), 1.93 (dq, J = 13.3, 7.0 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 165.8, 161.2, 160.5, 140.7, 129.0, 128.6, 128.0, 126.9, 126.8, 126.8, 125.9, 124.3, 123.2 (d, J = 40.5 Hz), 122.8, 115.9, 114.2, 78.6, 66.8, 48.3, 46.2, 38.0. HRMS calcd for C 25 H 25 F3N2O4475.2[M+H] + , found 475.2.

[0103] Example 11: Preparation of (R)-N-hydroxy-4-(3-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)propoxy)benzamide (Compound IIc)

[0104]

[0105] The preparation method is substantially the same as in Example 1, and the compound IIc (52 mg, 26%) is obtained in this example, which is a white solid with a melting point of 84.9-85.8 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.90 (s, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.56 (dd, J = 7.7, 5.2 Hz, 1H), 4.06 (tt, J = 9.4, 4.8 Hz, 2H), 2.66 (dq, J = 12.9, 6.2 Hz, 4H), 2.11 (dq, J = 13.6, 7.4 Hz, 1H), 1.93 (dq, J = 13.3, 7.1 Hz, 1H), 1.85 (p, J = 6.4 Hz, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 166.9, 162.6, 160.6, 140.9, 131.8, 129.0, 128.1, 127.0, 126.9, 126.9, 125.9, 123.4, 123.0 (d, J = 32.7 Hz), 123.0, 115.9, 114.2, 78.8, 67.3, 52.0, 48.6, 46.1, 38.7. HRMS calcd for C 26 H 27 F3N2O4 489.2 [M+H] + , found 489.2.

[0106] Example 12: Preparation of (R)-N-hydroxy-4-(4-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)butoxy)benzamide (Compound IId)

[0107]

[0108] The preparation method is basically the same as in Example 1, and Compound IId (56 mg, 28%) is obtained in this example, which is a white solid with a melting point of 83.0-84.9 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 5.48 (dd, J = 7.8, 5.0 Hz, 1H), 4.04 (t, J = 6.1 Hz, 1H), 4.01 - 3.95 (m, 2H), 3.17 - 3.07 (m, 2H), 2.09 (dq, J = 14.0, 7.2 Hz, 1H), 1.92 (dq, J = 12.6, 7.3 Hz, 1H), 1.79 - 1.72 (m, 1H), 1.67 (dq, J = 21.5, 7.8, 7.0 Hz, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.0, 163.0, 160.4, 156.8, 140.5, 131.7, 129.0, 128.2, 127.0, 127.0, 126.9, 126.9, 125.8, 123.2 (d, J = 36.4 Hz), 122.6, 115.9, 114.2, 78.7, 68.0, 64.9, 52.0, 29.8, 28.9, 22.6. HRMS calcd for C 27 H 29 F3N2O 4503.2 [M+H] + , found 503.2.

[0109] Example 13: Preparation of (R)-N-hydroxy-4-((5-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)pentyl)oxy)benzamide (Compound lie)

[0110]

[0111] The preparation method is basically the same as in Example 1, and the compound lie (72 mg, 36%) is obtained in this example, which is a brown solid with a melting point of 83.5-85.6 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.28 (s, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.42 - 7.37 (m, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.56 (dd, J = 7.8, 5.2 Hz, 1H), 3.98 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.53 (dt, J = 6.6, 4.2 Hz, 2H), 2.11 (dq, J = 14.0, 6.9 Hz, 1H), 1.93 (dt, J = 13.6, 6.3 Hz, 1H), 1.69 (p, J = 6.6 Hz, 2H), 1.43 (tt, J = 13.4, 5.6 Hz, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 165.7, 161.6, 160.4, 140.4, 129.0, 128.7, 128.1, 126.8, 126.8, 125.9, 124.0, 123.0, 122.8, 115.9, 114.3, 77.9, 67.6, 48.9, 45.4, 29.8, 28.6, 23.4, 14.3. HRMS calcd for C 28 H 31 F3N2O4 517.2 [M+H] + , found 517.2.

[0112] Example 14: Preparation of (R)-N-hydroxy-4-((6-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)hexyl)oxy)benzamide (Compound If)

[0113]

[0114] The preparation method is basically the same as in Example 1, and Compound If (66 mg, 33%) is obtained in this example, which is a brown solid with a melting point of 82.0-83.8 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.94 (dd, J = 8.9, 3.0 Hz, 2H), 5.57 - 5.53 (m, 1H), 3.98 (t, J = 6.5 Hz, 2H), 2.57 (dd, J = 9.4, 4.7 Hz, 2H), 2.49 - 2.41 (m, 2H), 2.08 (dq, J = 13.7, 7.1, 6.2 Hz, 1H), 1.89 (dt, J = 12.9, 6.3 Hz, 1H), 1.69 (ddd, J = 21.3, 14.3, 6.8 Hz, 2H), 1.51 (dt, J = 14.4, 6.8 Hz, 1H), 1.43 - 1.35 (m, 3H), 1.32 (dd, J = 12.6, 6.3 Hz, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.0, 163.0, 160.4, 156.8, 140.5, 131.7, 129.0, 128.2, 127.0, 126.9, 125.8, 123.4, 123.1, 122.6, 115.9, 114.2, 78.7, 68.0, 64.9, 52.0, 38.9, 38.1, 29.8, 28.9, 22.6. HRMS calcd for C 29 H 33 F3N2O4 531.2 [M+H] + , found 531.2.

[0115] Example 15: Preparation of (R)-N-hydroxy-4-((4-(3-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)propyl)piperazin-1-yl)methyl)benzamide (Compound IIg)

[0116]

[0117] The preparation method is basically the same as in Example 1. Compound IIg (42 mg, 21%) is obtained in this example, which is a white solid with a melting point of 85.4-86.2 °C. 1H NMR (500 MHz, Chloroform-d) δ 12.20 (s, 1H), 10.05 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.34 - 7.31 (m, 4H), 7.29 - 7.26 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 5.23 (dd, J = 8.4, 4.3 Hz, 1H), 4.85 (s, 1H), 4.13 (dt, J = 13.2, 5.4 Hz, 4H), 3.55 (s, 2H), 3.47 (s, 4H), 3.38 (q, J = 6.2 Hz, 2H), 2.39 (s, 4H), 2.23 - 2.15 (m, 1H), 2.11 (dt, J = 13.5, 7.0 Hz, 1H), 1.94 (q, J = 6.1 Hz, 2H). 13 CNMR (125 MHz, Chloroform-d) δ 167.1, 160.5, 143.3, 140.9, 129.7, 128.9, 128.0, 126.8, 126.8, 125.8, 123.4, 122.9, 122.5, 115.8, 78.4, 62.6, 53.7, 52.8, 52.1, 50.3, 41.8, 38.4, 29.7. HRMS calcd for C 31 H 37 F3N4O3 571.3 [M+H] + , found 571.3.

[0118] Example 16: Preparation of (R)-N-hydroxy-4-((4-(4-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)butyl)piperazin-l-yl)methyl)benzamide (Compound IIh)

[0119]

[0120] The preparation method is basically the same as in Example 1. Compound IIh (36 mg, 18%) is obtained in this example, which is a white solid with a melting point of 89.8-91.5 °C. 1H NMR (500 MHz, Chloroform-d) δ 12.17 (s, 1H), 10.55 (s, 1H), 8.03 - 7.97 (m, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.40 (s, 2H), 7.35 - 7.31 (m, 4H), 7.29 - 7.27 (m, 1H), 6.89 (d, J = 8.7 Hz, 2H), 5.24 (dd, J = 8.3, 4.2 Hz, 1H), 4.85 (s, 1H), 4.11 (s, 2H), 4.06 (s, 2H), 3.55 (s, 2H), 3.52 - 3.41 (m, 4H), 3.38 (q, J = 6.2 Hz, 2H), 2.39 (s, 2H), 2.19 (dt, J = 14.4, 6.7 Hz, 1H), 2.10 (dd, J = 13.7, 6.1 Hz, 1H), 1.68 (s, 4H), 1.57 (s, 2H). 13 CNMR (125 MHz, Chloroform-d) δ 167.0, 160.4, 155.1, 143.2, 140.8, 129.6, 128.9, 128.8, 127.8, 126.7, 126.7, 125.7, 122.7 (d, J = 32.6 Hz), 115.7, 78.3, 63.1, 62.5, 52.7, 52.0, 50.0, 41.6, 38.3, 32.1, 29.5. HRMS calcd for C 32 H 39 F3N4O3 585.3 [M+H] + , found 585.3.

[0121] Example 17: Preparation of (R,E)-N-hydroxy-3-(4-(((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)methyl)phenyl)acrylamide (Compound IIIa)

[0122]

[0123] The preparation method is basically the same as in Example 1, and the compound IIIa (50 mg, 25%) is obtained in this example, which is a yellow solid with a melting point of 90.9-93.3 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.99 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.46 - 7.42 (m, 2H), 7.39 (s, 1H), 7.37 (d, J = 7.1 Hz, 2H), 7.35 - 7.30 (m, 4H), 7.25 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.41 (d, J = 15.8 Hz, 1H), 5.58 (dd, J = 7.8, 5.3 Hz, 1H), 3.68 (s, 2H), 2.59 (dd, J = 13.2, 6.2 Hz, 2H), 2.11 (dq, J = 13.6, 7.1 Hz, 1H), 1.97 - 1.90 (m, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 164.0, 160.4, 140.5, 138.9, 134.4 (d, J = 32.5 Hz), 129.1, 128.9, 128.1, 126.8, 126.8, 125.9, 125.5, 123.4, 123.0, 122.7, 115.9, 78.2, 45.4, 37.4, 29.8. HRMS calcd for C 26 H 25 F3N2O3 471.2 [M+H] + , found 471.2.

[0124] Example 18: Preparation of (R,E)-N-hydroxy-3-(4-(2-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)ethoxy)phenyl)acrylamide (Compound IIIb)

[0125]

[0126] The preparation method is basically the same as in Example 1, and Compound IIIb (46 mg, 23%) is obtained in this example, which is a brown solid with a melting point of 80.5-82.7 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.96 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.3 Hz, 3H), 7.33 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.30 (d, J = 15.7 Hz, 1H), 5.56 (dd, J = 7.7, 5.3 Hz, 1H), 4.02 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 5.2 Hz, 2H), 2.68 (t, J = 6.1 Hz, 2H), 2.11 (dq, J = 13.8, 6.7 Hz, 1H), 1.93 (dq, J = 12.9, 7.0 Hz, 1H). 13 CNMR (125 MHz, Chloroform-d) δ 177.7, 168.8, 160.4, 159.7, 140.6, 133.5, 129.4, 129.0, 128.1, 126.9, 126.8, 125.9, 123.4, 123.0 (d, J = 30.0 Hz), 115.9, 114.7, 78.5, 62.0, 48.3, 46.1, 39.9. HRMS calcd for C 27 H 27 F3N2O4 501.2 [M+H] + , found 501.2.

[0127] Example 19: Preparation of (R,E)-N-hydroxy-3-(4-(3-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)propoxy)phenyl)acrylamide (Compound IIIc)

[0128]

[0129] The preparation method is basically the same as in Example 1. Compound IIIc (60 mg, 30%) is obtained in this example, which is a brown solid with a melting point of 76.5-78.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.07 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.35 (dq, J = 15.7, 7.7 Hz, 5H), 7.28 - 7.24 (m, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.31 (d, J = 15.7 Hz, 1H), 5.48 (dd, J = 7.7, 4.8 Hz, 1H), 4.06 (dt, J = 13.2, 6.2 Hz, 4H), 3.11 (dd, J = 9.4, 3.3 Hz, 2H), 2.08 (dq, J = 14.7, 7.2 Hz, 1H), 2.02 - 1.94 (m, 2H), 1.91 (dd, J = 13.0, 5.5 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 175.4, 160.3, 156.8, 140.5, 136.0, 129.6, 129.0, 128.2, 126.9, 126.9, 125.8, 125.5, 123.4, 123.1 (d, J = 32.9 Hz), 115.9, 114.7, 114.7, 78.5, 61.7, 38.8, 38.1, 29.0, 22.8. HRMS calcd for C 28 H 29 F3N2O4 515.2 [M+H] + , found 515.2.

[0130] Example 20: Preparation of (R,E)-N-hydroxy-3-(4-(4-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)butoxy)phenyl)acrylamide (Compound IIId)

[0131]

[0132] The preparation method is basically the same as in Example 1, and Compound IIId (58 mg, 29%) is obtained in this example, which is a brown solid with a melting point of 78.8-79.5 °C. 1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.08 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.5 Hz, 3H), 7.27 (d, J = 7.2 Hz, 1H), 7.23 (dd, J = 10.6, 5.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 15.6 Hz, 1H), 5.48 (dd, J = 7.8, 4.9 Hz, 1H), 3.99 (dt, J = 12.1, 6.0 Hz, 4H), 3.12 (d, J = 5.9 Hz, 2H), 2.09 (dq, J = 14.0, 6.9 Hz, 1H), 1.92 (dq, J = 12.8, 7.2 Hz, 1H), 1.79 - 1.71 (m, 2H), 1.67 (dt, J = 13.1, 6.0 Hz, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.9, 160.7, 144.6, 141.0, 129.9, 128.9, 128.0, 127.4, 126.9, 126.9, 125.9, 123.4, 123.0 (d, J = 32.7 Hz), 115.9, 115.5, 114.9, 78.8, 67.5, 51.7, 48.8, 46.1, 39.0, 29.8. HRMS calcd for C 29 H 31 F3N2O4 529.2 [M+H] + , found 529.2.

[0133] Example 21: Preparation of (R,E)-N-hydroxy-3-(4-((5-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)pentyl)oxy)phenyl)acrylamide (Compound IIIe)

[0134]

[0135] The preparation method is basically the same as in Example 1, and Compound IIIe (56 mg, 28%) is obtained in this example, which is a brown solid with a melting point of 90.7-91.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.00 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.37 (t, J = 6.1 Hz, 3H), 7.33 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.30 (d, J = 15.7 Hz, 1H), 5.47 (dd, J = 7.4, 4.7 Hz, 1H), 3.95 (dt, J = 16.2, 6.0 Hz, 4H), 3.16 - 3.06 (m, 2H), 2.13 - 2.01 (m, 1H), 1.99 - 1.87 (m, 1H), 1.72 (dt, J = 13.1, 6.4 Hz, 2H), 1.58 (p, J = 6.5 Hz, 2H), 1.50 - 1.37 (m, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.9, 160.9, 160.4, 156.8, 144.7, 140.5, 129.9, 129.1, 128.2, 127.2, 127.0, 126.9, 125.8, 123.2 (d, J = 33.2 Hz), 115.9, 114.9, 78.7, 67.6, 64.6, 51.7, 38.8, 38.1, 29.8, 25.9. HRMS calcd for C 30 H 33 F3N2O4 543.2 [M+H] + , found 543.2.

[0136] Example 22: Preparation of (R,E)-N-hydroxy-3-(4-((6-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)hexyl)oxy)phenyl)acrylamide (Compound IIIf)

[0137]

[0138] The preparation method is basically the same as in Example 1, and Compound IIIf (66 mg, 33%) is obtained in this example, which is a brown solid with a melting point of 84.0-86.2 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.10 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 6.2 Hz, 3H), 7.34 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 7.0 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 15.9 Hz, 1H), 5.48 (dd, J = 6.9, 5.0 Hz, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.92 (t, J = 6.5 Hz, 2H), 3.16 - 3.05 (m, 2H), 2.08 (td, J = 13.9, 8.0 Hz, 1H), 1.91 (td, J = 12.1, 6.7 Hz, 1H), 1.76 - 1.62 (m, 2H), 1.54 (dt, J = 13.4, 7.1 Hz, 2H), 1.37 (dt, J = 13.1, 7.6 Hz, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 167.7, 160.8, 160.1, 156.6, 144.4, 140.3, 129.6, 128.8, 127.9, 126.9, 126.7, 126.7, 125.6, 123.0 (d, J = 35.5 Hz), 115.6, 114.7, 78.5, 67.7, 64.6, 51.5, 38.6, 37.9, 29.6, 28.7, 22.4. HRMS calcd for C 31 H 35 F3N2O4 557.3 [M+H] + , found 557.3.

[0139] Example 23: Preparation of (R,E)-N-hydroxy-3-(4-((4-(3-((3-phenyl-3-(4- (trifluoromethyl)phenoxy)propyl)amino)propyl)piperazin-1-yl)methyl)phenyl)acrylamide (Compound IIIg)

[0140]

[0141] The preparation method is basically the same as in Example 1. Compound IIIg (46 mg, 23%) is obtained in this example, which is a white solid with a melting point of 84.0-85.1 °C. 1H NMR (500 MHz, Chloroform-d) δ 11.92 (s, 1H), 9.97 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.36 - 7.34 (m, 2H), 7.32 (d, J = 8.7 Hz, 4H), 7.28 (s, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 16.0 Hz, 1H), 5.23 (dd, J = 8.4, 4.2 Hz, 1H), 4.83 (s, 1H), 4.18 - 4.08 (m, 4H), 3.51 (s, 2H), 3.47 (s, 4H), 3.38 (q, J = 5.8 Hz, 2H), 2.39 (s, 4H), 2.23 - 2.16 (m, 1H), 2.14 - 2.07 (m, 1H), 1.98 - 1.89 (m, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.6, 160.4, 154.7, 144.6, 140.7, 140.5, 129.6, 128.9, 128.2, 128.0, 126.8, 126.8, 125.8, 122.9 (d, J = 32.6 Hz), 117.6, 115.8, 78.3, 64.7, 62.6, 51.8, 50.4, 44.9, 41.0, 38.2, 29.7. HRMS calcd for C 33 H 39 F3N4O3 597.3 [M+H] + , found 597.3.

[0142] Example 24: Preparation of (R,E)-N-hydroxy-3-(4-((4-(4-((3-phenyl-3-(4-(trifluoromethyl)phenoxy)propyl)amino)butyl)piperazin-1-yl)methyl)phenyl)acrylamide (Compound IIIh)

[0143]

[0144] The preparation method is basically the same as in Example 1, and the compound IIIh (36 mg, 18%) is obtained in this example, which is a white solid with a melting point of 93.5-94.6 °C. 1H NMR (500 MHz, Chloroform-d) δ 12.10 (s, 1H), 10.47 (s, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 4.7 Hz, 2H), 7.32 (d, J = 8.4 Hz, 4H), 7.28 (d, J = 1.9 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 16.0 Hz, 1H), 5.24 (dd, J = 8.5, 4.4 Hz, 1H), 4.85 (s, 1H), 4.10 (t, J = 5.3 Hz, 2H), 4.06 (d, J = 4.6 Hz, 2H), 3.81 (s, 2H), 3.51 (s, 2H), 3.47 (s, 4H), 3.37 (q, J = 6.1 Hz, 2H), 2.39 (s, 4H), 2.15 - 2.07 (m, 1H), 2.01 (q, J = 6.5 Hz, 1H), 1.68 (s, 2H). 13 C NMR (125 MHz, Chloroform-d) δ 167.6, 160.5, 155.4, 144.6, 140.9, 140.5, 133.5, 129.6, 128.9, 128.1, 127.9, 126.8, 126.8, 125.8, 122.8 (d, J = 32.7 Hz), 117.6, 115.8, 78.4, 64.5, 62.6, 52.8, 50.2, 41.7, 38.4, 33.2, 29.4, 27.7. HRMS calcd for C 34 H 41 F3N4O3 611.3 [M+H] + , found 611.3.

[0145] Example 25: Preparation of (S,E)-N-hydroxy-3-(4-(2-((3-phenyl-3-(4-(trifluoromethyl) phenoxy)propyl)amino)ethoxy)phenyl)acrylamide (Compound IVa)

[0146]

[0147] The preparation method is basically the same as in Example 1, and Compound IVa (46 mg, 23%) is obtained in this example, which is a white solid with a melting point of 81.7-82.5 °C. 1H NMR (500 MHz, DMSO-d6) δ 7.54 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.42 - 7.38 (m, 3H), 7.33 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.94 - 6.92 (m, 2H), 6.31 (d, J = 15.8 Hz, 1H), 5.58 - 5.55 (m, 1H), 4.03 (t, J = 5.5 Hz, 2H), 2.90 - 2.88 (m, 2H), 2.70 (t, J = 6.9 Hz, 2H), 2.16 - 2.09 (m, 1H), 1.97 - 1.91 (m, 1H). 13 C NMR (125 MHz, DMSO-d6) δ 163.1, 160.6, 159.6, 141.0, 138.0, 129.0, 128.6, 127.7, 127.4, 126.8 (q, 4 J = 3.6 Hz), 126.0, 125.5 (d, 1 J = 270 Hz), 121.5 (q, 3 J = 31.25 Hz), 116.5, 116.1, 114.9, 77.5, 67.3, 47.9, 45.3, 37.9. HRMS calcd for C 27 H 27 F3N2O4501.2 [M + H] + , found 501.2.

[0148] Pharmacodynamic experiments

[0149] 1. Determination of the inhibitory activity of compounds on 5-HTT

[0150] 1.1 Experimental method

[0151] The ICE-5HTT-HEK cell line is constructed in advance by integrating the human SLC6A4 gene into the genome of HEK293 cells to stably express 5-HTT receptors. The ICE-5HTT-HEK cell line is plated into 384-well plates overnight, and after the cells adhere, the culture medium in the 384-well plate is centrifuged and removed. Different concentrations of the test compound (10 nM and 1000 nM) prepared in advance with 1x Assay Buffer are added to the corresponding wells of the 384-well plate, and after centrifugation, incubation is carried out at 37°C for 30 min. Then 16 μL of detection reagent prepared with 1x HBSS is added to the wells containing the test compound, and after centrifugation, incubation is carried out at 37°C for 60 min. After incubation is complete, the values are detected at 450 nm excitation and 528 nm reading using an enzyme marker. Using the positive drug fluoxetine as a control, the inhibition rate of the test compound is calculated based on the absorbance of the test compound.

[0152] 1.2 Experimental results

[0153] Table 1 shows the results of the inhibition activity of the example compounds on 5-HTT.

[0154] Table 1

[0155]

[0156] According to the inhibition activity test results (Table 1), at a concentration of 1000 nM, the inhibition rates of compounds la, lib, lie, Ilia, Illb and IVa on 5-HTT reached more than 50%, and the inhibition rates were 72.20%, 68.80%, 55.82%, 72.74%, 86.03% and 98.93%, respectively. Among them, compound IVa showed the strongest inhibitory effect, even better than the positive control drug fluoxetine.

[0157] 2. Determination of the inhibition activity of the compound on HDAC6

[0158] 2.1 Experimental method

[0159] The HDAC6 inhibition activity test is based on a fluorescence method. First, the acetylated amino acid substrate Ac-Lys-Tyr-Lys(Ac)-AMC is incubated with human HDAC6. After the substrate is deacetylated, the obtained AMC product is detected by a fluorescence detector at 355 nm excitation and 460 nm reading. According to the initial activity of the sample and the test results, the inhibition rate of the compound at different concentrations is calculated, and the IC 50 value is calculated according to different inhibition rates.

[0160] Table 2 shows the results of the inhibitory activity of the compounds of Examples Ia-Ih, IIa-IIh, IIIa-IIIh and IVa against HDAC6.

[0161] Table 2

[0162]

[0163] 2.2 Experimental results

[0164] According to the results of the inhibitory activity test (Table 2), most of the compounds showed significant inhibitory effect against HDAC6. In the test of HDAC6 inhibitory activity, compounds Ie, lib, lie, lie, lif, lig and IVa are better active compounds, with IC 50 values of 0.20 μM, 0.28 μM, 0.22 μM, 0.32 μM, 0.47 μM, 0.30 μM and 0.23 μM, respectively, which are comparable to or even better than the IC 50 value of the positive control drug, vorinostat.

[0165] In summary, the inhibitory activity of compounds Ie, lib, lie, lie, lif, lig and IVa against HDAC6 is comparable to that of the positive control drug, vorinostat. More importantly, compounds Ia, lib, lie, Ilia, Illb and IVa showed better 5-HTT inhibitory activity, and compound IVa showed better 5-HTT inhibitory activity than the positive control drug, fluoxetine. Based on the above activity data, we can reasonably speculate that compounds Ia, Ie, lib, lie, lie, lif, lig, Ilia, Illb and IVa can exert stronger antidepressant effect than vorinostat in vivo. Active compounds that act on both HDAC and 5-HTT can exhibit stronger antidepressant efficacy than existing drugs by inhibiting two important antidepressant pathways in the central nervous system.

[0166] It should also be understood that various changes and modifications can be made to the application described herein, and such changes and modifications are also intended to fall within the scope of the application as defined by the following claims, made using the knowledge provided from this detailed description of the application.

Claims

1. An inhibitor targeting 5-HTT / HDAC dual targets or a pharmaceutically acceptable salt thereof, characterized in that, The inhibitor targeting 5-HTT / HDAC dual targets is selected from compounds Ic-Id, IIa-IIc, IIe-IIf, IIIa-IIIb or Iva as shown in the following structures:

2. Use of the inhibitor targeting 5-HTT / HDAC dual targets or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an antidepressant drug.

3. An antidepressant medicament, characterized by comprising a combination of the compound of claim 1 and a selective serotonin reuptake inhibitor. The inhibitor targeting 5-HTT / HDAC dual targets or a pharmaceutically acceptable salt thereof according to claim 1 in a safe and effective amount.

4. The antidepressant medicament according to claim 3, characterized in that, The antidepressant drug further comprises at least one of a pharmacologically acceptable salt, an excipient, a carrier.

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