Long-acting prodrug derivatives of vilazodone, pharmaceutical compositions thereof and uses

Abstract

The present invention belongs to the field of pharmaceutical technology, and particularly relates to a long-acting prodrug derivative of vilazodone, its pharmaceutical composition and uses. The long-acting prodrug derivative of vilazodone includes a compound having the structure shown in formula (I). The long-acting prodrug derivative of vilazodone of the present invention is metabolized by enzymes in vivo to produce vilazodone, so that the fluctuation of the blood drug concentration of vilazodone is small, the effective blood drug concentration is maintained for a long time, the administration frequency can be reduced, and the compliance of patients and the therapeutic effect of diseases can be improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to long-acting prodrug derivatives of vortioxetine, pharmaceutical compositions thereof, and their use in the preparation of drugs for preventing or treating diseases related to serotonin receptors. Background Art

[0002] Depression is a common clinical and severe mental illness, a disease with the core symptoms of persistent and severe mood or mood depression and loss of interest, which may be accompanied by mental retardation, sleep disorders, executive function disorders and abnormal social functions, and in severe cases, suicidal thoughts can be seen.

[0003] Vortioxetine is a novel selective serotonin reuptake inhibitor and an antidepressant with multiple mechanisms. It not only acts on the 5-HT transporter, but also binds to multiple 5-HT receptors. It is a 5-HT1A agonist, a 5-HT1B partial agonist, and antagonizes 5-HT1D, 5-HT7 and 5-HT3, and exerts its pharmacological effects by binding to the corresponding transporters and receptors.

[0004] The Chinese invention patent with the publication number CN109851573B discloses a vortioxetine amino acid amide compound, its preparation method and application. These amide-modified compounds are stable in gastric juice and intestinal juice, and can reduce the promotion of gastrointestinal motility by vortioxetine, thereby reducing the incidence of adverse reactions such as nausea and vomiting. The PCT invention patent application with the publication number WO2017162536A1 discloses a series of vortioxetine amide derivatives and alkyl carbonate derivatives, aiming to enhance the liposolubility of vortioxetine, improve the blood-brain barrier permeability, and prolong its metabolic time.

[0005] The treatment of depression usually requires a long-term process. As the only antidepressant drug that can significantly improve the cognitive function of patients at present, if its long-acting drug can be developed, the dosing interval can be greatly extended, and the treatment effect of depression can be improved. Summary of the Invention

[0006] In view of the above-mentioned deficiencies in the prior art, the present invention synthesizes a series of structurally diverse long-acting prodrug derivatives of vortioxetine, and conducts pharmacokinetic screening in rats. Compounds that can maintain a longer time of stable release of vortioxetine in vivo are found, which can greatly extend the dosing interval of vortioxetine.

[0007] The specific technical solution is as follows:

[0008] The first object of the present invention is to provide a long-acting prodrug derivative of vortioxetine, including a compound having the structure shown in formula (I):

[0009]

[0010] Among them, R1 is selected from the following groups:

[0011] or

[0012] Among them, each R2 is independently selected from methyl, trifluoromethyl or cyano, and m is an integer selected from 0 - 2;

[0013] X is selected from an oxygen atom or a sulfur atom;

[0014] R3 is selected from aryl or heteroaryl, and the aryl is independently substituted by halogen, cyano, trifluoromethyl, nitro, C1 - C4 alkyl, hydroxyl, C1 - C4 alkoxy, amino or C1 - C4 alkylamino, and the number of substituents is 0 - 3. When X is selected from an oxygen atom, the aryl cannot be an unsubstituted phenyl; the heteroaryl is independently substituted by hydroxyl or C1 - C4 alkoxy, and the number of substituents is 0 - 1.

[0015] The long - acting prodrug derivative of vilazodone of the present invention is metabolized by enzymes in vivo to produce vilazodone, which can reduce the fluctuation of the blood drug concentration of vilazodone, maintain the effective blood drug concentration for a long time, reduce the dosing frequency, and improve the compliance of patients.

[0016] Furthermore, R1 is selected from the following groups:

[0017] , , , , .

[0018] Furthermore, R1 is selected from the following groups:

[0019] , , , ,

[0020] , , , ,

[0021] , , ,

[0022] , , ,

[0023] , , ,

[0024] , , ,

[0025] , , , ,

[0026] , , , ,

[0027] , , , ,

[0028] , , , ,

[0029] , , , ,

[0030] , .

[0031] Specifically, the representative compound structures of the compounds of formula (I) in the present invention are shown in Table 1 as follows:

[0032] Table 1 Representative compound structures of the compounds of formula (I)

[0033]

[0034] Furthermore, the prodrug derivatives of vilazodone with long-acting effect also include pharmaceutically acceptable salts of the compounds having the structure shown in formula (I).

[0035] Pharmaceutically acceptable salts refer to inorganic acid salts and organic acid salts that are applicable to contact with human and animal tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, or allergic reactions. Inorganic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, perchloric acid, boric acid, nitric acid, etc. Organic acids that form salts with the amino group of the compound of formula (I) include, but are not limited to, formic acid, acetic acid, butyric acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, lactic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, benzoic acid, fumaric acid, glycerophosphoric acid, gluconic acid, malic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, oxalic acid, oleic acid, palmitic acid, pamoic acid, etc.

[0036] The second object of the present invention is to provide a pharmaceutical composition, which comprises the above-mentioned long-acting prodrug derivative of vilazodone.

[0037] Furthermore, the pharmaceutical composition is administered in a parenteral form.

[0038] Furthermore, the pharmaceutical composition is administered by injection.

[0039] Furthermore, the pharmaceutical composition is administered in the form of intramuscular injection or subcutaneous injection.

[0040] The third object of the present invention is to provide the use of the above-mentioned long-acting prodrug derivative of vilazodone in the preparation of a drug for preventing or treating diseases related to 5-hydroxytryptamine receptors.

[0041] Furthermore, the present invention provides the use of the above-mentioned long-acting prodrug derivative of vilazodone in the preparation of a drug for preventing or treating diseases related to depression.

[0042] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0043] (1) The present invention synthesizes a series of structurally diverse long-acting prodrug derivatives of vilazodone, and conducts in-vivo pharmacokinetic screening in rats, and discovers compounds that can maintain a stable release of vilazodone in the body for a long time, extending the dosing interval;

[0044] (2) The long-acting prodrug derivative of vilazodone provided by the present invention is metabolized by enzymes in the body to produce vilazodone, resulting in small fluctuations in the blood drug concentration of vilazodone and a long maintenance time of the effective blood drug concentration, which can reduce the dosing frequency, improve patient compliance, and the therapeutic effect of the disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a blood concentration-time curve graph of the production of vilazodone by the in-vivo metabolism of Compounds 1, 3, and 4;

[0046] Figure 2 For compounds 14, 24, 41, and 45, the plasma concentration-time curves of vilazodone produced by in vivo metabolism are shown. Detailed implementation manners

[0047] The principles and features of the present invention will be described below in conjunction with embodiments. The examples given are only for explaining the present invention and do not limit the scope of the present invention in any form. Various changes and modifications to the disclosed embodiments will be obvious to those skilled in the art, and changes and modifications, including but not limited to those related to the chemical structure, substituents, derivatives, formulations, and / or methods of the present invention, can be made without departing from the spirit of the present invention and the scope of the appended claims.

[0048] Example 1: Preparation of Compound 1

[0049]

[0050] In a reaction flask, 1.0 g of vilazodone, 0.97 g of benzoyl peroxide, 1.2 g of disodium hydrogen phosphate, and 20 g of DMF were added. The mixture was stirred at 35 °C overnight. After the reaction was completed, 50 g of water was added, and the mixture was extracted with 100 g of dichloromethane. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ (transition to) petroleum ether / ethyl acetate 65 / 35, V / V), and 0.82 g of a solid was obtained, which was Compound 1.

[0051] HPLC purity: 97.53%. mp: 109.2 - 110.7 °C. ESI-MS (m / z): 441.18 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 8.06 – 8.00 (m, 2H), 7.60 – 7.53 (m, 1H), 7.49 – 7.42 (m,2H), 7.38 (d, J = 7.9 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.12 – 7.05 (m, 2H), 7.04– 6.99 (m, 1H), 6.88 (ddd, J = 8.0, 6.3, 2.5 Hz, 1H), 6.54 – 6.50 (m, 1H),3.71 – 3.36 (m, 4H), 3.35 – 3.08 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0052] Example 2: Preparation of Compound 2

[0053]

[0054] 8.0 g of Compound 1 was added to 80 mL of methanol, along with 9.67 g of potassium carbonate, and the reaction was carried out overnight at room temperature. The solvent was removed under reduced pressure, 30 g of dichloromethane and 30 g of water were added, and liquid separation was performed. The organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane ~ ethyl acetate / dichloromethane 10 / 90, V / V), and 5.6 g of off-white solid N-hydroxyfulvuthyline was obtained.

[0055] 0.63 g of N-hydroxyfulvuthyline, 0.45 g of 2,4-dimethylbenzoic acid, 0.29 g of DMAP, and 30 mL of dichloromethane were added. While stirring, 0.62 g of DCC was added, and the temperature was raised to 40 °C for reaction for 4 h. After the reaction was completed, the solvent was removed completely, and purification by column chromatography was carried out (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V), and 0.70 g of off-white solid, namely Compound 2, was obtained.

[0056] HPLC purity: 96.20%. mp: 124.5 - 125.7 °C. ESI-MS (m / z): 469.14 [M+Na] + . 1 H NMR(400 MHz, DMSO- d 6) δ 7.64 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.21 –7.16 (m, 2H), 7.13 – 7.04 (m, 4H), 6.92 – 6.87 (m, 1H), 6.38 (dd, J = 8.0, 1.2Hz, 1H), 3.56 – 3.38 (m, 2H), 3.30 – 3.27 (m, 2H), 3.15 – 2.94 (m, 4H), 2.44(s, 3H), 2.28 (s, 6H), 2.21 (s, 3H).

[0057] Example 3: Preparation of Compound 3

[0058]

[0059] 0.78 g of N-hydroxyfulvuthyline, 0.71 g of 4-trifluoromethylbenzoic acid, 0.37 g of DMAP, and 20 mL of dichloromethane were added. While stirring, 0.77 g of DCC was added. After addition, the temperature was raised to 40 °C for reaction for 4 h. After the reaction was completed, the temperature was lowered and filtered, the filtrate was concentrated, and purification by column chromatography was carried out (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V), and 0.80 g of light yellow solid, namely Compound 3, was obtained.

[0060] The HPLC purity is 96.37%. mp: 122.3 - 123.5 °C. ESI-MS (m / z): 509.31 [M+Na] + . 1 1H NMR (400 MHz, DMSO- d 6) δ 8.13 (d, J J = 8.8 Hz, 2H), 7.89 (d, J J = 8.8 Hz, 2H), 7.31 (d, J J=7.6 Hz, 1H), 7.22 – 7.17 (m, 2H), 7.12 – 7.04 (m, 2H), 6.93 – 6.87 (m, 1H),6.38 (dd, J J = 7.8, 1.2 Hz, 1H), 3.59 – 3.39 (m, 2H), 3.37 – 3.29 (m, 2H), 3.20– 2.96 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H).

[0061] Example 4: Preparation of Compound 4

[0062]

[0063] In 20 g of dichloromethane, 0.7 g of N-hydroxyfulvoxetine, 0.46 g of p-toluic acid, 0.69 g of DCC, and 0.33 g of DMAP were added. The mixture was stirred overnight at 35 °C. After the reaction was completed, 20 g of water was added, and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane ~ dichloromethane / methanol 95 / 5, V / V), and the resulting oil was added to 20 mL of n-hexane and stirred vigorously to obtain 0.50 g of a white solid, which was Compound 4.

[0064] The HPLC purity is 97.31%. mp: 122.5 - 123.4 °C. ESI-MS (m / z): 455.16 [M+Na] + . 11H NMR (400 MHz, CDCl3) δ 7.95 – 7.90 (m, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.15 (s, 1H), 7.12 – 7.06 (m, 2H), 7.06 – 7.01 (m, 1H), 6.88 (ddd, J = 8.4, 6.3, 2.4 Hz, 1H), 6.56 – 6.48 (m, 1H), 3.66 – 3.35 (m, 4H), 3.34 – 3.17 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H).

[0065] Example 5: Preparation of Compound 5

[0066]

[0067] To 20 g of dichloromethane, 0.7 g of N-hydroxyfulvoxetine, 0.46 g of 4-cyanobenzoic acid, 0.69 g of DCC, and 0.33 g of DMAP were added. The mixture was stirred overnight at 35 °C. After the reaction was completed, 30 g of water was added, and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was dichloromethane ~ dichloromethane / methanol 95 / 5, V / V). The resulting oil was triturated with 20 mL of n-hexane to obtain 0.48 g of a white solid, which was Compound 5.

[0068] HPLC purity: 97.46%. mp: 103.3 - 104.4 °C. ESI-MS (m / z): 466.17 [M+Na] + . 1 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.07 (m, 2H), 7.79 – 7.71 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 7.11 – 7.06 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.92 – 6.84 (m, 1H), 6.52 (d, J = 7.6 Hz, 1H), 3.66 – 3.37 (m, 4H), 3.35 – 3.18 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0069] Example 6: Preparation of Compound 6

[0070]

[0071] Add 0.70 g of triphosgene and 20 g of dichloroethane to a reaction flask. At 0 - 5 °C, add 0.31 g of 4-methylphenol, and slowly add dropwise 0.75 g of triethylamine. After the addition is complete, stir for 30 min, and then raise the temperature to 50 °C and stir overnight.

[0072] Add 0.80 g of vilazodone, heat up to reflux and react for 8 h. After the reaction is completed, add 50 g of water, separate the layers, and purify the organic layer by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.80 g of a colorless oily substance, which is compound 6.

[0073] HPLC purity: 96.73%. ESI-MS (m / z): 455.22 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ7.40 (d, J = 7.8 Hz, 1H), 7.19 – 7.15 (m, 3H), 7.14 – 7.09 (m, 1H), 7.04 –7.03 (m, 2H), 7.01 – 7.00 (m, 2H), 6.95 – 6.90 (m, 1H), 6.58 (dd, J = 7.9,1.3 Hz, 1H), 3.95 – 3.70 (m, 4H), 3.12 (s, 4H), 2.38 (s, 3H), 2.35 (s, 3H),2.35 (s, 3H).

[0074] Example 7: Preparation of Compound 7

[0075]

[0076] Add 0.70 g of triphosgene to 20 g of dichloroethane, cool down to 0 - 5 °C, add 0.31 g of 4-isopropylphenol, and add dropwise 0.75 g of triethylamine. After the addition is complete, stir for 30 min, and then raise the temperature to 50 °C and stir overnight.

[0077] Add 0.80 g of vilazodone, heat up to reflux and react for 8 h. After the reaction is completed, add 20 g of water, separate the layers, and purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V). Obtain 0.82 g of an oily substance, which is compound 7.

[0078] HPLC purity: 96.89%. ESI-MS (m / z): 483.21 [M+Na] + . 11H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 1H), 7.29 – 7.19 (m, 3H), 7.17 (s, 1H), 6.94 – 6.89 (m, 1H), 6.75 – 6.73 (m, 4H), 6.57 (d, J = 7.8 Hz, 1H), 3.87 – 3.78 (m, 4H), 3.12 (s, 4H), 2.91 – 2.81 (m, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H).

[0079] Example 8: Preparation of Compound 8

[0080]

[0081] 0.70 g of triphosgene was added to 20 g of dichloroethane. At 0 - 5 °C, 0.76 g of 4-chlorophenol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min, and then stirred at 50 °C overnight.

[0082] 0.80 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was performed. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.44 g of white solid, namely Compound 8, was obtained.

[0083] HPLC purity 97.89%. mp: 95.6 - 96.6 °C. ESI-MS (m / z): 475.15 [M+Na] + . 1 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 1H), 7.29 – 7.19 (m, 2H), 7.17 (s, 1H), 7.12 – 7.07 (m, 3H), 7.06 – 7.03 (m, 2H), 6.94 – 6.89 (m, 1H), 6.57 (d, J = 7.8 Hz, 1H), 3.82 (s, 4H), 3.12 (s, 4H) 2.38 (s, 3H), 2.34 (s, 3H).

[0084] Example 9: Preparation of Compound 9

[0085]

[0086] 0.70 g of triphosgene, 20 g of dichloroethane. At 0 - 5 °C, 0.67 g of 4-fluorophenol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was completed, stirring was continued in an ice-water bath for 30 min, and then the temperature was raised to 50 °C and stirred overnight.

[0087] 0.80 g of vilazodone was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.33 g of white solid was obtained, which was compound 9.

[0088] HPLC purity 96.15%. mp: 107.6 - 108.4 °C. ESI-MS (m / z): 459.24 [M+Na] + . 1 H NMR(400 MHz, CDCl3) δ 7.37 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.12 – 7.07 (m,3H), 7.07 –7.02 (m, 4H), 6.90 (ddd, J = 8.0, 7.1, 1.6 Hz, 1H), 6.55 (dd, J =7.9, 1.3 Hz, 1H), 3.91 – 3.69 (m, 4H), 3.15 – 3.06 (m, 4H), 2.36 (s, 3H),2.33 (s, 3H).

[0089] Example 10: Preparation of Compound 10

[0090]

[0091] 0.80 g of triphosgene, 20 g of dichloroethane. At 0 - 5 °C, 0.94 g of 2-fluorophenol was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was completed, stirring was continued in an ice-water bath for 30 min, and then the temperature was raised to 50 °C and stirred overnight.

[0092] 1.0 g of vilazodone was added, and the temperature was raised to reflux for reaction for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.58 g of white solid was obtained, which was compound 10.

[0093] HPLC purity 94.23%. mp: 108.5 - 109.3 °C. ESI-MS (m / z): 459.18 [M+Na] + . 11H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.26 – 7.20 (m, 1H), 7.19 – 7.14 (m, 3H), 7.14 – 7.11 (m, 1H), 7.11 – 7.02 (m, 3H), 6.93 – 6.87 (m, 1H), 6.56 (d, J = 7.9 Hz, 1H), 3.96 – 3.70 (m, 4H), 3.18 – 3.08 (m, 4H), 2.37 (s, 3H), 2.33 (s, 3H).

[0094] Example 11: Preparation of Compound 11

[0095]

[0096] 0.70 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, 0.70 g of 4 - cyanophenol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice - water bath for 30 min, and then the temperature was raised to 50 °C and stirred overnight.

[0097] 0.8 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.58 g of white solid, namely Compound 11, was obtained.

[0098] HPLC purity 98.27%. mp: 120.2 - 120.9 °C. ESI - MS (m / z): 466.19 [M + Na] + . 1 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.65 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.32 – 7.25 (m, 2H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.06 – 7.01 (m, 2H), 6.90 (ddd, J = 7.9, 7.1, 1.6 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.90 – 3.70 (m, 4H), 3.16 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0099] Example 12: Preparation of Compound 12

[0100]

[0101] 0.80 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, add 1.2 g of 2 - naphthol, and slowly dropwise add 0.85 g of triethylamine. After the dropwise addition, continue stirring in an ice - water bath for 30 min, and then raise the temperature to 50 °C and stir overnight.

[0102] Add 1.0 g of vilazodone, heat up to reflux and react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.76 g of white solid, which is compound 12.

[0103] HPLC purity: 94.44%. mp: 88.3 - 89.5 °C. ESI - MS (m / z): 491.22 [M + Na] + . 1 H NMR(400 MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.49 – 7.44 (m, 2H), 7.41 – 7.37 (m, 2H), 7.34 – 7.29 (m, 2H),7.17 (s, 1H), 7.14 – 7.09 (m, 1H), 6.95 – 6.87 (m, 1H), 6.59 – 6.54 (m, 1H),4.02 – 3.75 (m, 4H), 3.16 (s, 4H), 2.37 (s, 3H), 2.35 (s, 3H).

[0104] Example 13: Preparation of Compound 13

[0105]

[0106] 0.80 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, add 0.8 g of 4 - hydroxypyridine, and slowly dropwise add 0.85 g of triethylamine. After the dropwise addition, continue stirring in an ice - water bath for 30 min, and then raise the temperature to 50 °C and stir overnight.

[0107] Add 1.0 g of vilazodone, heat up to reflux and react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.34 g of white solid, which is compound 13.

[0108] The HPLC purity is 95.88%. mp: 121.8 - 122.3 °C. ESI-MS (m / z): 420.32 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.39 – 8.33 (m, 1H), 7.75 – 7.71 (m, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.19 – 7.16 (m, 1H), 7.14 (s, 1H), 7.13 – 7.10 (m, 1H), 7.09 – 6.99 (m, 3H), 6.86 (ddd, J = 8.6, 6.7, 2.0 Hz, 1H), 6.52 (dd, J = 7.9, 1.0 Hz, 1H), 3.48 – 3.39 (m, 4H), 3.09 – 3.00 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H).

[0109] Example 14: Preparation of Compound 14

[0110]

[0111] 0.80 g of triphosgene and 20 g of dichloroethane were added. At 0 - 5 °C, 0.8 g of 2 - hydroxypyridine was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice - water bath for 30 min, and then stirred at 50 °C overnight.

[0112] 1.0 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.74 g of a white solid, which was Compound 14.

[0113] The HPLC purity is 96.21%. mp: 125.4 - 126.1 °C. ESI-MS (m / z): 420.31 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.41 – 8.35 (m, 1H), 7.77 (ddd, J = 8.1, 7.4, 2.0 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.19 (ddd, J = 7.3, 4.9, 0.9 Hz, 1H), 7.16 – 7.12 (m, 2H), 7.11 – 7.06 (m, 1H), 7.06 – 7.01 (m, 2H), 6.89 (ddd, J = 8.0, 7.1, 1.6 Hz, 1H), 6.55 (dd, J = 7.9, 1.3 Hz, 1H), 3.92 – 3.71 (m, 4H), 3.18 – 3.05 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H).

[0114] Example 15: Preparation of Compound 15

[0115]

[0116] 1.77 g of Compound 21, 35 mL of tetrahydrofuran, 40 mL of methanol were taken, 0.20 g of palladium on carbon was added, and the mixture was replaced with a hydrogen balloon three times and reacted at room temperature overnight. After the reaction was completed, it was filtered and the filtrate was concentrated. It was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 40 / 60, V / V) to obtain 0.58 g of an off-white solid, namely Compound 15.

[0117] HPLC purity 95.29%. mp: 164.6 - 166.2 °C. ESI-MS (m / z): 434.48 [M+H] + . 1 1H NMR(400 MHz, DMSO- d 6) δ 7.32 (d, J J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.16 – 7.13 (m, 1H), 7.11 – 7.05 (m, 2H), 6.92 – 6.88 (m, 1H), 6.77 – 6.71 (m, 2H), 6.52 – 6.46 (m, 2H), 6.37 (dd, J= 8.0, 1.2 Hz, 1H), 4.93 (s, 2H), 3.76 – 3.51 (m, 4H), 3.03 – 2.97 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H).

[0118] Example 16: Preparation of Compound 16

[0119]

[0120] 1.19 g of vilazodone, 0.61 g of triethylamine, 20 mL of dichloromethane, the temperature was lowered to -10 °C. 0.82 g of 4-methoxyphenyl chloroformate was added, and after the addition was completed, the mixture was kept warm and reacted for 4 h. After the reaction was completed, the reaction was quenched with saturated NaHCO3 solution, separated by liquid-liquid extraction, the organic phase was concentrated until no distillate was obtained, and purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 10 / 90, V / V) to obtain 1.71 g of a white solid, namely Compound 16.

[0121] HPLC purity 95.39%. mp: 135.6 - 136.4 °C. ESI-MS (m / z): 471.30 [M+Na] + . 1 1H NMR (400 MHz, Chloroform- d ) δ 7.36 (d, J = 7.6 Hz, 1H), 7.16 – 7.14 (m, 1H), 7.13 – 7.01 (m, 5H), 6.92 – 6.85 (m, 3H), 6.56 (d, J = 8.0 Hz, 1H), 3.91 – 3.82 (m, 2H), 3.81 – 3.73 (m, 5H), 3.22 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0122] Example 17: Preparation of Compound 17

[0123]

[0124] 1.80 g of Compound 15, 40 mL of dichloromethane, 3 mL of acetone. While stirring, add 1 mL of AcOH, displace with nitrogen three times, heat to 40 °C and react for 16 h. Concentrate to remove dichloromethane, add 40 mL of methanol, 1.74 g of sodium triacetoxyborohydride, and 5 drops of acetic acid, and react overnight at room temperature. After the reaction is completed, concentrate to remove methanol, add 20 mL of water, separate with 20 mL of ethyl acetate, and take the organic phase and concentrate under reduced pressure. Purify by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 12 / 88, V / V) to obtain 0.58 g of a solid, which is Compound 17.

[0125] HPLC purity 98.65%. mp: 155.6 - 156.3 °C. ESI-MS (m / z): 476.40 [M+H] + . 1 H NMR(400 MHz, DMSO-d 6 ) δ 8.33 – 8.13 (m, 1H), 7.44 – 7.30 (m, 2H), 7.23 – 7.20(m, 1H), 7.18 – 7.04 (m, 3H), 6.94 – 6.87 (m, 1H), 6.82 – 6.77 (m, 1H), 6.52– 6.45 (m, 1H), 6.43 – 6.34 (m, 1H), 5.26 (d, J = 8.8 Hz, 1H), 3.82 – 3.51(m, 4H), 3.52 – 3.40 (m, 1H), 3.12 – 2.91 (m, 4H), 2.29 (s, 3H), 2.22 (s,3H), 1.08 (d, J = 6.4 Hz, 6H).

[0126] Example 18: Preparation of Compound 18

[0127]

[0128] 1.20 g of Compound 16, 40 mL of dichloromethane, at 0 - 5 °C, dropwise add 6 mL of boron tribromide dichloromethane solution (1 M). After the addition is complete, react at room temperature for 5 h. After the reaction is completed, quench the reaction with saturated NaHCO3 solution, and concentrate the organic phase until there is no distillate. Purify by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 30 / 70, V / V) to obtain 1.05 g of an off-white solid, which is Compound 18.

[0129] HPLC purity 95.33%. mp: 180.4 - 181.1 °C. ESI-MS (m / z): 457.39 [M+Na] + .1 H NMR (400 MHz, Chloroform- d ) δ 7.35 (d, J J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.16 – 7.14 (m,1H), 7.12 – 7.08 (m, 1H), 7.02 (d, J J = 2.0 Hz, 1H), 6.95 – 6.89 (m, 3H), 6.69 –6.65 (m, 2H), 6.57 (d, J J = 8.0 Hz, 1H), 5.77 (s, 1H), 3.94 – 3.75 (m, 4H), 3.26– 3.08 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0130] Example 19: Preparation of Compound 19

[0131]

[0132] 0.80 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, add 0.8 g of 3-hydroxypyridine, and slowly add dropwise 0.85 g of triethylamine. After the addition is complete, continue to stir in an ice-water bath for 30 min, and then raise the temperature to 50 °C and stir overnight.

[0133] Add 1.0 g of vilazodone, raise the temperature to reflux and react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.64 g of a white solid, which is Compound 19.

[0134] HPLC purity 96.91%. mp: 136.2 - 136.8 °C. ESI-MS (m / z): 420.27 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.50 – 8.40 (m, 2H), 7.57 – 7.50 (m, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.31 (ddd, J = 8.5, 4.8, 0.7 Hz, 1H), 7.15 (s, 1H), 7.13 – 6.94 (m, 3H), 6.90 (ddd, J = 8.1, 7.0, 1.8 Hz, 1H), 6.55 (dd, J = 8.0, 1.6 Hz, 1H), 4.02 – 3.69 (m, 4H), 3.18 – 3.06 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0135] Example 20: Preparation of Compound 20

[0136]

[0137] 0.80 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, add 1.2 g of 3-hydroxyquinoline, and slowly add dropwise 0.85 g of triethylamine. After the addition is complete, continue to stir for 30 min in an ice-water bath, and then raise the temperature to 50 °C and stir overnight.

[0138] Add 1.0 g of vortioxetine, raise the temperature to reflux and react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.64 g of white solid, which is Compound 20.

[0139] HPLC purity 96.11%. mp: 148.0 - 148.6 °C. ESI-MS (m / z): 470.25 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.7 Hz, 1H), 8.15 – 8.09 (m, 1H), 7.99 (d, J = 2.6 Hz, 1H), 7.84 – 7.76 (m, 1H), 7.68 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.55 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.18 – 7.15 (m, 1H), 7.13 – 7.02 (m, 3H), 6.91 (ddd, J = 8.0, 6.9, 1.8 Hz, 1H), 6.56 (dd, J = 7.9, 1.3 Hz, 1H), 4.01 – 3.71 (m, 4H), 3.22 – 3.09 (m, 4H), 2.36 (s, 3H), 2.34 (s, 3H).

[0140] Example 21: Preparation of Compound 21

[0141]

[0142] 1.19 g of vilazodone, 0.61 g of triethylamine, 30 mL of dichloromethane, the temperature was lowered to -10 °C. 0.89 g of p-nitrophenyl chloroformate was added, and after the addition was completed, it was kept warm for 5 - 10 min, and then the temperature was raised to room temperature and reacted for 4 h. After the reaction was completed, the reaction was quenched with saturated NaHCO3 solution, separated by liquid-liquid extraction, and the organic phase was concentrated until there was no distillate. Purification by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V) gave 1.80 g of a pale yellow solid, which is Compound 21.

[0143] HPLC purity 96.36%. mp: 136.6 - 137.2 °C. ESI-MS (m / z): 464.39 [M+H] + . 1 1H NMR(400 MHz, DMSO- d 6) δ 8.29 – 8.22 (m, 2H), 7.48 – 7.41 (m, 2H), 7.32 (d, J= 7.6Hz, 1H), 7.23 – 7.19 (m, 1H), 7.17 – 7.04 (m, 3H), 6.94 – 6.88 (m, 1H), 6.38(dd, J = 8.0, 1.2 Hz, 1H), 3.82 – 3.68 (m, 2H), 3.66 – 3.54 (m, 2H), 3.10 –2.96 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H).

[0144] Example 22: Preparation of Compound 22

[0145]

[0146] 0.45 g of triphosgene and 40 mL of dichloroethane were used, and the temperature was lowered in an ice-water bath. 0.90 g of p-trifluoromethylphenol was added, 0.91 g of triethylamine was added dropwise. After the addition was complete, the mixture was kept warm for 5 - 10 min and then heated to room temperature and reacted for 7 h. 1.46 g of vilazodone was added and the reaction was carried out at 80 °C overnight. After the reaction was completed, it was concentrated until no distillate was obtained, and purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 1.31 g of a white solid, namely Compound 22.

[0147] HPLC purity 98.48%. mp: 87.7 - 88.2 °C. ESI-MS (m / z): 509.21 [M+Na] + . 1 H NMR(400 MHz, DMSO- d 6) δ 7.75 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.32 (d, J =7.6 Hz, 1H), 7.22 – 7.05 (m, 1H), 7.18 – 7.05 (m, 3H), 6.95 – 6.88 (m, 1H),6.42 – 6.36 (m, 1H), 3.81 – 3.67 (m, 2H), 3.64 – 3.50 (m, 2H), 3.08 – 2.98(m, 4H), 2.29 (s, 3H), 2.22 (s, 3H).

[0148] Example 23: Preparation of Compound 23

[0149]

[0150] 0.71 g of triphosgene, 30 mL of dichloroethane, and the temperature was lowered using an ice-water bath. 1.09 g of 4-hydroxyquinoline was added, 1.52 g of triethylamine was added dropwise. After the addition was complete, the mixture was kept warm for 5 - 10 min, then heated to room temperature and reacted overnight. Then, 0.90 g of vilazodone was added, and the temperature was raised to 80 °C and reacted for 8 h. After the reaction was completed, it was concentrated until no distillate was obtained. Purification by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 20 / 80, V / V) gave 0.20 g of a pale white solid, which was Compound 23.

[0151] HPLC purity 98.85%. mp: 178.6 - 179.2 °C. ESI-MS (m / z): 470.40 [M+H] + . 1 H NMR(400 MHz, DMSO- d 6) δ 8.88 (d, J = 4.8 Hz, 1H), 8.08 – 8.01 (m, 2H), 7.84 – 7.77(m, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 7.6 Hz,1H), 7.24 – 7.16 (m, 2H), 7.14 – 7.05 (m, 2H), 6.96 – 6.89 (m, 1H), 6.39 (dd, J = 8.0, 1.2 Hz, 1H), 3.98 – 3.83 (m, 2H), 3.72 – 3.57 (m, 2H), 3.17 – 3.01(m, 4H), 2.30 (s, 3H), 2.23 (s, 3H).

[0152] Example 24: Preparation of Compound 24

[0153]

[0154] 0.71 g of triphosgene, 30 mL of dichloroethane, and the temperature was lowered using an ice-water bath. 1.09 g of 2-hydroxyquinoline was added, 1.52 g of triethylamine was added dropwise. After the addition was complete, the mixture was kept warm for 5 - 10 min, then heated to room temperature and reacted overnight. 0.90 g of vilazodone was added, and the temperature was raised to 80 °C and reacted for 8 h. After the reaction was completed, it was concentrated until no distillate was obtained. Purification by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 20 / 80, V / V) gave 0.32 g of a pale white solid, which was Compound 24.

[0155] The HPLC purity is 96.89%. mp: 89.8 - 91.5 °C. ESI-MS (m / z): 492.31 [M+Na] + . 1 1H NMR(400 MHz, DMSO- d 6) δ 8.48 – 8.43 (m, 1H), 8.03 – 7.98 (m, 1H), 7.91 – 7.85 (m,1H), 7.80 – 7.73 (m, 1H), 7.64 – 7.54 (m, 1H), 7.34 (dd, J = 8.0, 6.4 Hz, 2H),7.24 – 7.16 (m, 2H), 7.14 – 7.06 (m, 2H), 6.95 – 6.89 (m, 1H), 6.39 (dd, J =8.0, 1.2 Hz, 1H), 3.85 – 3.69 (m, 2H), 3.68 – 3.52 (m, 2H), 3.11 – 3.00 (m,4H), 2.30 (s, 3H), 2.23 (s, 3H).

[0156] Example 25: Preparation of Compound 25

[0157]

[0158] 0.80 g of triphosgene, 20 g of dichloroethane, at 0 - 5 °C, add 1.2 g of 4-hydroxyisoquinoline, and slowly dropwise add 0.85 g of triethylamine. After the addition is complete, continue to stir for 30 min in an ice-water bath, and then raise the temperature to 50 °C and stir overnight.

[0159] Add 1.0 g of vilazodone, raise the temperature to reflux and react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 1.1 g of a yellow solid, which is Compound 25.

[0160] The HPLC purity is 96.65%. mp: 131.4 - 132.2 °C. ESI-MS (m / z): 470.22 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 0.5 Hz, 1H), 8.45 (s, 1H), 8.02 (dd, J = 8.2, 0.9 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.64 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.18 – 7.15 (m, 1H), 7.14 – 7.06 (m, 2H), 7.04 (ddd, J = 7.8, 1.4, 0.6 Hz, 1H), 6.91 (ddd, J = 8.0, 6.1, 2.6 Hz, 1H), 6.59 – 6.53 (m, 1H), 4.05 (s, 2H), 3.82 (s, 2H), 3.26 – 3.10 (m, 4H), 2.37 (s, 3H), 2.34 (s, 3H).

[0161] Example 26: Preparation of Compound 26

[0162]

[0163] 0.80 g of triphosgene and 20 g of dichloroethane were added. At 0 - 5 °C, 1.1 g of 8-hydroxy-imidazo[1,2-a]pyridine was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice-water bath for 30 min, and then the temperature was raised to 50 °C and stirred overnight.

[0164] 1.0 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.95 g of solid, which was Compound 26.

[0165] HPLC purity: 95.15%. mp: 163.5 - 165.1 °C. ESI-MS (m / z): 459.22 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 6.8, 1.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.16 – 7.12 (m, 1H), 7.12– 7.00 (m, 4H), 6.89 (ddd, J = 8.0, 6.7, 2.0 Hz, 1H), 6.79 – 6.72 (m, 1H), 6.56 (dd, J = 7.9, 1.1 Hz, 1H), 4.06 – 3.72 (m, 4H), 3.23 – 3.09 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H).

[0166] Example 27: Preparation of Compound 27

[0167]

[0168] 0.80 g of triphosgene and 20 g of dichloroethane were added. At 0 - 5 °C, 1.5 g of 4-bromophenol was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min, and then stirred at 50 °C overnight.

[0169] 1.0 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.93 g of a white solid, which was Compound 27.

[0170] HPLC purity 96.07%. mp: 100.9 - 101.6 °C. ESI-MS (m / z): 519.07 [M+Na] + . 11H NMR (400 MHz, CDCl3) δ 7.55 – 7.50 (m, 2H), 7.49 – 7.44 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.11 – 7.06 (m, 1H), 7.04 – 7.00 (m, 3H), 6.89 (ddd, J = 8.0, 7.0, 1.7 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.87 – 3.69 (m, 4H), 3.13 – 3.07 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0171] Example 28: Preparation of Compound 28

[0172]

[0173] 0.80 g of triphosgene and 20 g of dichloroethane were added. At 0 - 5 °C, 0.93 g of 2,3 - dihydroxypyridine was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice - water bath for 30 min, and then stirred at 50 °C overnight.

[0174] 1.0 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added, and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 1.1 g of a white solid, which was Compound 28.

[0175] HPLC purity: 95.41%. mp: 139.6 - 140.7 °C. ESI - MS (m / z): 436.25 [M + H] + . 1 1H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 7.71 – 7.21 (m, 4H), 7.20 – 7.12 (m, 1H), 7.12 – 6.92 (m, 2H), 6.89 (ddd, J = 8.0, 6.8, 2.0 Hz, 1H), 6.63 – 6.43 (m, 1H), 6.25 (dd, J = 7.4, 6.6 Hz, 1H), 4.47 – 3.50 (m, 4H), 3.50 – 2.76 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H).

[0176] Example 29: Preparation of Compound 29

[0177]

[0178] 0.80 g of triphosgene, 20 g of dichloroethane. At 0 - 5 °C, 1.0 g of 5 - methoxy - 3 - hydroxypyridine was added, and 0.85 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice - water bath for 30 min, and then the temperature was raised to 50 °C and stirred overnight.

[0179] 1.0 g of vilazodone was added, and the temperature was raised to reflux for 8 h. After the reaction was completed, 30 g of water was added and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.41 g of solid was obtained, which was compound 29.

[0180] HPLC purity: 97.35%. mp: 146.3 - 147.1 °C. ESI - MS (m / z): 450.24 [M + H] + . 1 H NMR(400 MHz, CDCl3) δ 8.15 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 2.2 Hz, 1H), 7.34 –7.28 (m, 2H), 7.21 (s, 1H), 7.16 – 7.13 (m, 1H), 7.11 – 7.05 (m, 2H), 6.94 –6.88 (m, 1H), 6.38 (dd, J = 7.9, 1.4 Hz, 1H), 3.81 (s, 3H), 3.77 – 3.50 (m,4H), 3.03 (s, 4H), 2.29 (s, 3H), 2.21 (s, 3H).

[0181] Example 30: Preparation of Compound 30

[0182]

[0183] 0.35 g of triphosgene, 20 g of dichloromethane. At 0 - 5 °C, 0.39 g of benzenethiol was added, and 0.72 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice - water bath for 30 min, and then the temperature was raised to room temperature and stirred overnight.

[0184] 0.7 g of vilazodone was added and the reaction was carried out for 8 h. After the reaction was completed, 30 g of water was added and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), 20 mL of n - hexane was added and stirred vigorously to obtain 0.51 g of white solid, which was compound 30.

[0185] The HPLC purity is 96.56%. mp: 132.6 - 133.2 °C. ESI-MS (m / z): 457.13 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ7.56 – 7.49 (m, 2H), 7.43 – 7.37 (m, 3H), 7.36 (d, J = 7.8Hz, 1H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.89 (ddd, J= 7.9, 7.2, 1.5 Hz, 1H), 6.54 (dd, J = 7.9, 1.4 Hz, 1H), 3.79 (s, 4H), 3.10(s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0186] Example 31: Preparation of Compound 31

[0187]

[0188] 0.35 g of triphosgene and 20 g of dichloromethane were added. At 0 - 5 °C, 0.45 g of p-fluorothiophenol was added, and 0.72 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min, and then stirred at room temperature overnight.

[0189] 0.7 g of vilazodone was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.41 g of a white solid, which was Compound 31.

[0190] The HPLC purity is 96.30%. mp: 164.7 - 165.5 °C. ESI-MS (m / z): 474.98 [M+Na] + . 1 H NMR(400MHz, CDCl3) δ 7.53 – 7.43 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.16 (s,1H), 7.14 – 7.05 (m, 3H), 7.05 – 6.99 (m, 2H), 6.93 – 6.86 (m, 1H), 6.55 (dd,J = 8.1, 1.6 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0191] Example 32: Preparation of Compound 32

[0192]

[0193] 0.35 g of triphosgene and 20 g of dichloromethane were added. At 0 - 5 °C, 0.63 g of 4-(trifluoromethyl)benzenethiol was added, and 0.60 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min in an ice - water bath and then stirred at room temperature overnight.

[0194] 0.7 g of vilazodone was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.32 g of a white solid, which was Compound 32.

[0195] HPLC purity: 94.95%. mp: 132.3 - 133.5 °C. ESI - MS (m / z): 525.07 [M + Na] + . 1 H NMR(400MHz, CDCl3) δ 7.35 – 7.31 (m, 2H), 7.27 – 7.24 (m, 2H), 7.14 (s, 1H),7.08 – 7.05 (m, 2H), 7.04 – 7.02 (m, 2H), 6.89 – 6.84 (m, 1H), 6.50 (d, J =7.9 Hz, 1H), 3.49 – 3.29 (m, 4H), 3.21 – 3.07 (m, 4H), 2.35 (s, 3H), 2.30 (s,3H).

[0196] Example 33: Preparation of Compound 33

[0197]

[0198] 0.80 g of triphosgene and 20 g of dichloromethane were added. At 0 - 5 °C, 0.68 g of 4 - mercaptobenzonitrile was added, and 0.82 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred for 30 min in an ice - water bath and then stirred at room temperature overnight.

[0199] 1.0 g of vilazodone was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.35 g of a white solid, which was Compound 33.

[0200] The HPLC purity is 97.06%. mp: 163.3 - 164.1 °C. ESI-MS (m / z): 482.07 [M+Na] + . 1 1H NMR(400MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.64 – 7.59 (m, 2H), 7.35 (d, J = 8.0Hz, 1H), 7.15 (s, 1H), 7.11 – 6.94 (m, 3H), 6.92 – 6.84 (m, 1H), 6.54 (dd, J= 8.0, 1.6 Hz, 1H), 3.78 (s, 4H), 3.11 (s, 4H), 2.36 (s, 3H), 2.31 (s, 3H).

[0201] Example 34: Preparation of Compound 34

[0202]

[0203] 0.50 g of triphosgene and 20 g of dichloromethane were taken. At 0 - 5 °C, 0.50 g of 4-methyl-benzenethiol was added, and 0.70 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min, and then stirred at room temperature overnight.

[0204] 0.8 g of vilazodone was added and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.40 g of a white solid, which was Compound 34.

[0205] The HPLC purity is 95.21%. mp: 145.0 - 145.7 °C. ESI-MS (m / z): 471.08 [M+Na] + . 1 1H NMR(400MHz, CDCl3) δ 7.43 – 7.38 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 – 7.18(m, 2H), 7.16 (s, 1H), 7.12 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.93 – 6.87(m, 1H), 6.55 (dd, J = 7.9, 1.4 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.37 (s,3H), 2.36 (s, 3H), 2.32 (s, 3H).

[0206] Example 35: Preparation of Compound 35

[0207]

[0208] 0.49 g of triphosgene, 20 mL of dichloromethane. Cooled in an ice-water bath, 1.00 g of vilazodone was added, and 0.67 g of triethylamine was added dropwise. After the addition was complete, it was kept warm for 5 - 10 min, and then the temperature was raised to room temperature and reacted overnight. 0.72 g of 2-chlorobenzenethiol was added, and the reaction was carried out overnight at room temperature. There was intermediate remaining, 0.5 mL of triethylamine was added, and the temperature was raised to 40 °C and reacted for 5 h. After the reaction was completed, it was concentrated until there was no distillate, and purified by column chromatography (petroleum ether ~ ethyl acetate / petroleum ether 3 / 97, V / V) to obtain 0.85 g of a white solid, which was Compound 35.

[0209] HPLC purity 96.38%. mp: 134.4 - 134.9 °C. ESI-MS (m / z): 491.11 [M+Na] + . 1 1H NMR(400 MHz, Chloroform- d ) δ 7.47 – 7.42 (m, 2H), 7.39 – 7.34 (m, 3H), 7.17 – 7.14(m, 1H), 7.11 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.94 – 6.87 (m, 1H), 6.55(dd, J = 8.0, 1.2 Hz, 1H), 3.88 – 3.66 (m, 4H), 3.20 – 3.01 (m, 4H), 2.36 (s,3H), 2.32 (s, 3H).

[0210] Example 36: Preparation of Compound 36

[0211]

[0212] 0.80 g of triphosgene, 20 g of dichloromethane. At 0 - 5 °C, 0.64 g of 2-fluorobenzenethiol was added, and 0.82 g of triethylamine was added dropwise slowly. After the addition was complete, it was stirred in an ice-water bath for 30 min, and then stirred at room temperature overnight.

[0213] 1.0 g of vilazodone was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.45 g of a white solid, which was Compound 36.

[0214] The HPLC purity is 98.75%. mp: 157.9 - 148.5 °C. ESI-MS (m / z): 453.12 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.60 (m, 1H), 7.52 (dd, J = 8.1, 1.8 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.32 – 7.24 (m, 1H), 7.16 (d, J = 1.6 Hz, 1H), 7.13 – 7.06 (m, 1H), 7.06 – 6.95 (m, 2H), 6.94 – 6.87 (m, 1H), 6.55 (dd, J = 8.1, 1.7 Hz, 1H), 3.90 – 3.73 (m, 4H), 3.10 (s, 4H), 2.35 (s, 3H), 2.31 (s, 3H).

[0215] Example 37: Preparation of Compound 37

[0216]

[0217] 0.70 g of triphosgene and 20 g of dichloromethane were added. At 0 - 5 °C, 0.58 g of 2-chlorothiophenol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min, and then stirred at room temperature overnight.

[0218] 0.80 g of vilazodone was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and the layers were separated. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.42 g of a white solid, which was Compound 37.

[0219] The HPLC purity is 98.16%. mp: 144.5 - 145.2 °C. ESI-MS (m / z): 491.16 [M+Na] + . 11H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.8, 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 1.8 Hz, 1H), 7.48 – 7.22 (m, 3H), 7.16 (d, J = 1.6 Hz, 1H), 7.12 – 6.93 (m, 3H), 6.94– 6.84 (m, 1H), 6.55 (dd, J = 8.1, 1.7 Hz, 1H), 3.91 – 3.74 (m, 4H), 3.12 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0220] Example 38: Preparation of Compound 38

[0221]

[0222] 0.70 g of triphosgene, 20 g of dichloromethane, at 0 - 5 °C, 0.76 g of 4-bromobenzenethiol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice-water bath for 30 min, and then the mixture was stirred at room temperature overnight.

[0223] 0.80 g of vortioxetine was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.75 g of a white solid was obtained, which was Compound 38.

[0224] HPLC purity 98.30%. mp: 135.6 - 136.2 °C. ESI-MS (m / z): 534.98 [M+Na] + . 1 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.49 (m, 2H), 7.41 – 7.34 (m, 3H), 7.16 (s, 1H), 7.12 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.94 – 6.86 (m, 1H), 6.55 (dd, J = 7.9, 1.1 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0225] Example 39: Preparation of Compound 39

[0226]

[0227] 0.70 g of triphosgene, 20 g of dichloromethane. At 0 - 5 °C, 0.64 g of naphthalenethiol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice - water bath for 30 min, and then the mixture was stirred at room temperature overnight.

[0228] 0.80 g of vilazodone was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.58 g of white solid, that is, compound 39, was obtained.

[0229] HPLC purity: 97.37%. mp: 148.3 - 149.7 °C. ESI - MS (m / z): 485.11 [M + H] + . 1 H NMR(400 MHz, CDCl3) δ 8.06 – 8.03 (m, 1H), 7.88 – 7.80 (m, 3H), 7.57 (dd, J = 8.5,1.8 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H),7.12 – 7.06 (m, 1H), 7.06 – 7.00 (m, 2H), 6.90 (ddd, J = 7.9, 7.1, 1.6 Hz,1H), 6.55 (dd, J = 7.9, 1.3 Hz, 1H), 3.86 – 3.76 (m, 4H), 3.12 (s, 4H), 2.36(s, 3H), 2.32 (s, 3H).

[0230] Example 40: Preparation of compound 40

[0231]

[0232] 0.70 g of triphosgene, 20 g of dichloromethane. At 0 - 5 °C, 0.51 g of 4 - hydroxythiophenol was added, and 0.75 g of triethylamine was slowly added dropwise. After the addition was complete, stirring was continued in an ice - water bath for 30 min, and then the mixture was stirred at room temperature overnight.

[0233] 0.80 g of vilazodone was added, and the reaction was continued for 8 h. After the reaction was completed, 30 g of water was added, and liquid - liquid separation was carried out. The organic phase was purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V), and 0.47 g of solid, that is, compound 40, was obtained.

[0234] The HPLC purity is 94.76%. mp: 193.9 - 195.7 °C. ESI-MS (m / z): 473.08 [M+Na] + . 1 1H NMR(400MHz, CDCl3) δ10.45 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.33 – 7.29 (m,1H), 7.29 – 7.25 (m, 2H), 7.15 (d, J = 0.7 Hz, 1H), 7.11 – 7.06 (m, 1H), 7.06– 7.00 (m, 2H), 6.93 – 6.87 (m, 1H), 6.74 – 6.70 (m, 1H), 6.55 (dd, J = 7.9,1.4 Hz, 1H), 3.81 (s, 4H), 3.11 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0235] Example 41: Preparation of Compound 41

[0236]

[0237] 0.46 g of triphosgene, 30 mL of dichloromethane, the temperature was lowered in an ice-water bath, 0.92 g of vortioxetine was added, and 0.92 g of triethylamine was added dropwise. After the dropwise addition was completed, it was kept warm for 5 - 10 min, and the temperature was raised to room temperature and reacted for 7 h. 0.38 g of 4-mercaptopyridine was added, and the reaction was continued overnight. After the reaction was completed, it was concentrated until there was no distillate. Purification by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 15 / 85, V / V) gave 0.32 g of an off-white solid, which is Compound 41.

[0238] The HPLC purity is 96.38%. mp: 153.7 - 154.4 °C. ESI-MS (m / z): 436.28 [M+H] + . 1 1H NMR(400 MHz, DMSO- d 6) δ 8.59 – 8.53 (m, 2H), 7.52 – 7.48 (m, 2H), 7.31 (d, J = 8.0Hz, 1H), 7.24 – 7.19 (m, 1H), 7.16 – 7.05 (m, 3H), 6.95 – 6.88 (m, 1H), 6.37(dd, J= 8.0, 1.2 Hz, 1H), 3.72 – 3.60 (m, 4H), 3.06 - 2.96 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H).

[0239] Example 42: Preparation of Compound 42

[0240]

[0241] 0.50 g of triphosgene, 30 mL of dichloromethane, cooled in an ice - water bath, add 1.00 g of vilazodone, and dropwise add 1.00 g of triethylamine. After the addition is complete, keep warm for 5 - 10 min, then raise the temperature to room temperature and react for 7 h. Add 0.77 g of 2,4,6 - trichlorobenzenethiol and continue to react overnight. After the reaction is completed, concentrate until there is no distillate. Purify by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 0.60 g of a off - white solid, which is Compound 42.

[0242] HPLC purity 97.24%. mp: 173.5 - 174.7 °C. ESI - MS (m / z): 559.14 [M + Na] + . 1 1H NMR(400 MHz, DMSO - d 6) δ 7.84 (s, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.15 – 7.05 (m, 3H), 6.94 – 6.88 (m, 1H), 6.37 (dd, J = 8.0, 1.4 Hz, 1H), 3.76– 3.52 (m, 4H), 3.10 – 2.86 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H).

[0243] Example 43: Preparation of Compound 43

[0244]

[0245] Add 0.56 g of 4 - methoxythiophenol to 0.70 g of triphosgene and 20 g of dichloromethane at 0 - 5 °C, and slowly dropwise add 0.75 g of triethylamine. After the addition is complete, continue to stir in an ice - water bath for 30 min, and then raise the temperature to room temperature and stir overnight.

[0246] Add 0.80 g of vilazodone, and continue the reaction for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.46 g of white solid, which is compound 43.

[0247] HPLC purity: 99.18%. mp: 124.5 - 125.2 °C. ESI-MS (m / z): 465.11 [M+H] + . 1 H NMR(400MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 – 7.13(m, 1H), 7.13 – 7.06 (m, 1H), 7.05 – 6.95 (m, 2H), 6.95 – 6.90 (m, 2H), 6.90– 6.85 (m, 1H), 6.55 (dd, J = 8.0, 1.6 Hz, 1H), 3.82 (s, 3H), 3.80 – 3.61 (m,4H), 3.10 (s, 4H), 2.36 (s, 3H), 2.32 (s, 3H).

[0248] Example 44: Preparation of Compound 44

[0249]

[0250] 0.50 g of triphosgene, 60 mL of dichloromethane, cool in an ice-water bath, add 0.57 g of 6-mercaptopurine, and dropwise add 1.04 g of triethylamine. After the addition is complete, keep warm for 5 - 10 min, then raise the temperature to room temperature and react for 7 h. Add 1.00 g of vilazodone and continue the reaction overnight. After the reaction is completed, concentrate until there is no distillate. Purify by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 10 / 90, V / V) to obtain 0.44 g of off-white solid, which is compound 44.

[0251] HPLC purity: 95.74%. mp: 235.8 - 237.2 °C. ESI-MS (m / z): 499.11 [M+Na] + . 1 H NMR(400 MHz, DMSO- d 6) δ 13.93 (s, 1H), 8.48 (s, 1H), 8.24 (d, J = 3.6 Hz, 1H), 7.30(d, J= 7.6 Hz, 1H), 7.22 – 7.18 (m, 1H), 7.15 – 7.04 (m, 3H), 6.96 – 6.87 (m,1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.98 – 3.34 (m, 4H), 3.18 – 2.95 (m, 4H),2.28 (s, 3H), 2.19 (s, 3H).

[0252] Example 45: Preparation of Compound 45

[0253]

[0254] 0.50 g of triphosgene, 30 mL of dichloromethane, cooled in an ice-water bath, 1.00 g of vortioxetine was added, and 1.00 g of triethylamine was added dropwise. After the dropwise addition, it was kept warm for 5 - 10 min, and the temperature was raised to room temperature and reacted for 7 h. 0.37 g of 2-mercaptopyridine was added, and the reaction was continued overnight. After the reaction was completed, it was concentrated until there was no distillate. Purified by column chromatography (the elution ratio of the eluent was petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V), and 0.46 g of off-white solid was obtained, which was Compound 45.

[0255] HPLC purity 95.30%. mp: 135.8 - 137.2 °C. ESI-MS (m / z): 458.19 [M+Na] + . 1 H NMR(400 MHz, DMSO- d 6) δ 8.57 – 8.48 (m, 1H), 7.87 – 7.79 (m, 1H), 7.68 – 7.64 (m,1H), 7.40 – 7.35 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.16– 7.04 (m, 3H), 6.94 – 6.86 (m, 1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.70 –3.56 (m, 4H), 3.08 – 2.89 (m, 4H), 2.29 (s, 3H), 2.22 (s, 3H).

[0256] Example 46: Preparation of Compound 46

[0257]

[0258] 0.50 g of triphosgene, 30 mL of dichloromethane, cooled in an ice-water bath, add 1.00 g of vilazodone, and slowly add dropwise 1.00 g of triethylamine. After the addition is complete, keep warm for 5 - 10 min, then raise the temperature to room temperature and react for 7 h. Add 0.38 g of 2-mercaptothiophene and continue to react overnight. After the reaction is completed, concentrate until no distillate is obtained. Purify by column chromatography (the elution ratio of the eluent is petroleum ether ~ ethyl acetate / petroleum ether 5 / 95, V / V) to obtain 0.57 g of an off-white solid, which is compound 46.

[0259] HPLC purity 95.76%. mp: 123.8 - 125.2 °C. ESI-MS (m / z): 463.19 [M+Na] + . 1 H NMR(400 MHz, DMSO- d 6) δ 7.80 (dd, J J = 5.2, 1.2 Hz, 1H), 7.31 (d, J J = 7.6 Hz, 1H),7.25 (dd, J J = 3.6, 1.2 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.15 – 7.05 (m, 4H), 6.94– 6.88 (m, 1H), 6.37 (dd, J = 8.0, 1.2 Hz, 1H), 3.68 – 3.55 (m, 4H), 3.11 –2.91 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H).

[0260] Example 47: Preparation of compound 47

[0261]

[0262] 0.70 g of triphosgene, 20 g of dichloromethane, at 0 - 5 °C, add 0.47 g of p-isopropylbenzenethiol, and slowly add dropwise 0.75 g of triethylamine. After the addition is complete, continue to stir in an ice-water bath for 30 min, then raise the temperature to room temperature and stir overnight.

[0263] Add 0.80 g of vilazodone and continue to react for 8 h. After the reaction is completed, add 30 g of water and separate the layers. Purify the organic phase by column chromatography (the elution ratio of the eluent is petroleum ether ~ petroleum ether / ethyl acetate 90 / 10, V / V) to obtain 0.53 g of a white solid, which is compound 47.

[0264] The HPLC purity is 96.41%. mp: 63.2 - 63.9 °C. ESI-MS (m / z): 477.19 [M+H]+. 1H NMR(400 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.8 Hz, 1H), 7.27 – 7.24 (m, 2H), 7.15 (s, 1H), 7.11 – 7.06 (m, 1H), 7.05 – 7.00 (m, 2H), 6.92 – 6.86 (m, 1H), 6.54 (dd, J = 7.9, 1.3 Hz, 1H), 3.78 (s, 4H), 3.10 (s, 4H), 2.91 (dq, J = 13.9, 6.9 Hz, 1H), 2.36 (s, 3H), 2.32 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H).

[0265] Experiment: Pharmacokinetic Behavior of Vortioxetine Derivatives in Rats

[0266] Experimental animals: Male SD rats, purchased from Jinan Pengyue Laboratory Animal Breeding Co., Ltd., weighing 180 - 220 g, 3 rats in each group.

[0267] The oily or waxy prodrug compounds were administered as an oily solution. Preparation method of the oily solution: Dissolve the oily or waxy vortioxetine prodrug derivative in soybean oil for injection to prepare an oil solution of 40 mg / mL (calculated as vortioxetine).

[0268] The crystalline solid was administered as an aqueous suspension. Preparation method of the aqueous suspension: Dissolve CMC-Na and Tween 20 in ultrapure water to prepare an aqueous solution containing 1.5% CMC-Na and 0.4% Tween 20. After passing the solid vortioxetine prodrug derivative through a 200-mesh sieve, add an appropriate amount to the above aqueous solution to prepare a suspension of 40 mg / mL (calculated as vortioxetine).

[0269] Each group of rats was intramuscularly injected with the above drugs at a dose of 20 mg / kg. Blood was collected from the orbital cavity before dosing and at 15 min, 1 h, 6 h, 1 d, 2 d, 3 d, 5 d, 7 d, 9 d, 11 d, 14 d, 18 d, 21 d, 25 d, and 28 d after dosing. Each blood collection was 0.25 mL and placed in an EP tube pre-treated with heparin. Centrifuge at 12,000 rpm for 5 min, and take the plasma and store it frozen at -80 °C for detection.

[0270] Bio - sample pretreatment: 50 μL of plasma containing the drug was added with 50 μL of internal standard (agomelatine, 2 ng / mL) and 150 μL of methanol, vortexed for 1 min, centrifuged at 12000 rpm for 5 min, and the supernatant was taken for injection analysis.

[0271] Detection instrument:

[0272] Ultra - high performance liquid chromatography system: Ultimate3000 (Thermo Fisher Scientific, USA);

[0273] Triple quadrupole tandem mass spectrometer: TSQ Quantiva (Thermo Fisher Scientific, USA);

[0274] Data acquisition: Xcalibur (Thermo Fisher Scientific, USA);

[0275] Mass spectrometry conditions: The ion source was electrospray ionization source (ESI); ionization voltage was 5000 V; temperature was 500 °C; sheath gas was 50 Arb; auxiliary gas was 50 Arb; detection was in positive ion mode, and the scanning time was 200 ms.

[0276] The main pharmacokinetic parameters of the prodrug compound metabolized to vilazodone in vivo are shown in Table 2.

[0277] Table 2 Main pharmacokinetic parameters of the prodrug compound metabolized to vilazodone in vivo

[0278]

[0279] Note: "~" indicates that due to the lack of a downward trend in the vilazodone concentration over 28 days, "T1 / 2(d)" and "AUC 0-∞ " could not be calculated.

[0280] As can be seen from Table 2, the half - life of vilazodone free base in vivo is 2.09 days, and the half - life of the prodrug compound of the present invention metabolized to vilazodone in vivo is significantly prolonged.

[0281] The first category, hydroxylamine compounds (Compounds 1 - 5), the half - life of vilazodone release is 6.06 - 19.34 days, with an average of 12.11 days. The drug concentrations of the representative compounds 1, 3, and 4 metabolized to vilazodone in vivo over time are shown in Table 3, and their plasma concentration - time curves of vilazodone metabolized in vivo are as Figure 1 shown.

[0282] Table 3 Drug concentrations of prodrug compounds 1, 3, and 4 metabolized to vilazodone over time

[0283]

[0284] Note: The drug concentration of each compound in the table is the average of the drug concentrations in the blood of three rats.

[0285] As can be seen from Table 3 and Figure 1 it can be known that Compounds 1, 3, and 4 can all achieve sustained release of vilazodone in the body for 21 days (>1 ng / mL). The drug peak concentration of Compound 1 is relatively high, and the concentration fluctuates greatly in the early stage. The vilazodone concentrations of Compounds 3 and 4 fluctuate little, and stable release of vilazodone can be achieved.

[0286] The second category is carbamate / thiocarbamate. Compounds 6 - 29 are carbamates, and the half-life of vilazodone release is 2.30 - 196.97 days, with an average of 22.8 days. Compounds 30 - 47 are thiocarbamates, and the half-life of vilazodone release is 4.23 - 1153.1 days, with an average of 97.6 days. The drug concentrations of representative Compounds 14, 24, 41, and 45 that metabolize to produce vilazodone in the body over time are shown in Table 4, and the plasma concentration-time curves of vilazodone produced by their metabolism in the body are as Figure 2 shown.

[0287] Table 4 Drug Concentrations of Prodrugs Compounds 14, 24, 41, and 45 that Metabolize to Produce Vilazodone over Time

[0288]

[0289] Note: The drug concentration of each compound in the table is the average of the drug concentrations in the blood of three rats.

[0290] As can be seen from Table 4 and Figure 2 it can be known that Compounds 14, 24, 41, and 45 can all achieve sustained release of vilazodone in the body for >28 days (>10 ng / mL), and the vilazodone concentration fluctuates little, with stable drug release.

[0291] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A long-acting prodrug derivative of vilazodone, characterized in that, Comprising a compound having the structure shown in formula (I): Wherein, R1 is selected from the following groups: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 2. The fluoxetine long-acting prodrug derivative according to claim 1, characterized in that, Also included are pharmaceutically acceptable salts of the compound having the structure shown in formula (I).

3. A pharmaceutical composition, characterized in that, Comprising the valiforine long-acting prodrug derivative as claimed in claim 1 or 2.

4. The pharmaceutical composition according to claim 3, characterized in that, Administered in a parenteral form.

5. Use of a valiforine long-acting prodrug derivative as claimed in claim 1 or 2 in the preparation of a medicament for preventing or treating a disease related to a serotonin receptor.

6. The use according to claim 5, characterized in that, The diseases include depression.

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