SSRI / 5-HT 1A Dual-target antidepressant formylpiperidine compounds, preparation methods and applications thereof

Abstract

The present invention provides a formylpiperidine compound, a preparation method and an application thereof. The general structural formula of the formylpiperidine compound is shown in formula (I), or its isomer, or its pharmaceutically acceptable salt, ester or prodrug. The formylpiperidine compound described in the present invention is a dual-target inhibitor of 5-HT reuptake and 5-HT 1A receptor, which can overcome the problems of low clinical efficacy, poor metabolic stability and poor safety of existing antidepressant drugs, and is a compound with a novel structure, high efficiency, stability and low toxicity and having an antidepressant effect.

Description

Technical Field

[0001] The present invention relates to the technical field of antidepressant drugs, and particularly relates to an SSRI / 5-HT 1A dual-target antidepressant formylpiperidine compounds, their preparation methods and applications. Background Art

[0002] Depression is a common mental disorder characterized by anhedonia, decreased energy, impaired cognitive function, and even suicidal behavior. It is estimated that 350 million people are affected globally, and according to the World Health Organization, by 2030, depression will become the second-largest disease affecting the quality of human life.

[0003] So far, the mechanism of action of antidepressant drugs has not been fully elucidated. In recent years, the research focus on its pathogenesis has mainly concentrated on monoamine neurotransmitters and receptors, inflammatory responses, neurotrophic factors, etc. Drugs with definite curative effects basically act on the synaptic sites of nerve endings and play a therapeutic role by regulating the levels of neurotransmitters in the synaptic cleft. Biochemical research on its etiology shows that depression is mainly related to five neurotransmitters: central 5-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach), and γ-aminobutyric acid (GABA).

[0004] Antidepressants can be divided into two major categories: early non-selective antidepressants and new selective reuptake inhibitors. Non-selective antidepressants mainly include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs); selective reuptake inhibitors mainly include (1) selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs), such as Fluoxetine and Paroxetine; (2) norepinephrine (NA) reuptake inhibitors (NRIs), such as Reboxitine; (3) noradrenergic and specific 5-HT reuptake inhibitors (NDRIs), such as Mirtazapine; (4) 5-HT and NA dual reuptake inhibitors (SNRIs), such as Venlafaxine and Duloxetine; (5) 5-HT reabsorption promoters, such as Tianeptine, etc.

[0005] Since most of the first-line antidepressant drugs currently used clinically are 5-hydroxytryptamine reuptake inhibitors (SSRI S ), but they have disadvantages such as relatively large side effects, slow onset, poor effectiveness, and large individual differences, resulting in many patients terminating medication during the treatment process. Therefore, there is still a need to develop safe and highly effective antidepressant drugs.

[0006] To address the above-mentioned deficiencies, a strategy that acts simultaneously on 5-HT reuptake and 5-HT receptor subtypes is considered an effective method for shortening the onset time and enhancing the drug efficacy. Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT 1A partial agonists (Feiger, A. Psychopharmacol. Bull. 1996, 32: 659-65). Adding buspirone to standard SSRI treatment induced significant improvement in patients who had previously been unresponsive to standard treatment for depression (Dimitriou, E. J. Clin. Psychopharmacol., 1998, 18: 465-9). The marketed antidepressant vilazodone has a dual-target action of SSRI / 5-HT 1A (J. Med. Chem. 2004, 47, 4684-4692). Its antidepressant onset is faster and side effects are reduced compared to traditional antidepressants, but there are still many deficiencies, such as low drug efficacy, poor clinical metabolism and absorption, etc. (Chin. J. Clin. Pharmacol. 2014, 30, 862-864; J. Clin. Psychiatry, 2011, 72, 1166–1173; P. L. McCormack, Vilazodone: a review in major depressive disorder in adults, Drugs 75(2015)1915e1923). Summary of the Invention

[0007] To solve the above problems, the present invention provides a novel antidepressant compound having selective inhibition of 5-TH reuptake and 50TH 1A receptor dual targets, as well as its preparation method and application, which can overcome the problems of low clinical drug efficacy, poor metabolic stability, and poor safety of existing antidepressants, and is a compound with highly efficient, stable, and low-toxic antidepressant effects.

[0008] To achieve the above invention objective, a first aspect of the present invention provides a formylpiperidine compound, whose structural general formula is shown in formula (Ⅰ), or its isomer, or its pharmaceutically acceptable salt, ester, or prodrug;

[0009]

[0010] Wherein,

[0011] R1 is selected from halogen or cyano;

[0012] R2 is selected from hydrogen, substituted or unsubstituted hydrocarbon group;

[0013] A is selected from a substituted or unsubstituted six-membered ring, and the six-membered ring contains one or more heteroatoms of N, O, and S selected from 0 to 2;

[0014] m and n are independently selected from 0, 1, 2, 3, or 4.

[0015] Preferably, the six-membered ring of A is selected from a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted pyridine, or a substituted or unsubstituted pyrazine.

[0016] Preferably, A is selected from the following groups:

[0017]

[0018] wherein R3, R4, R5, R6, R7, R 3’ , R 4’ , R 5’ , R 6’ , R3” are independently selected from H, halogen, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amide group, or cyano group;

[0019] There are not more than two substituted or unsubstituted amide groups or cyano groups in R3, R4, R5, R6, and R7 at the same time; R 3’ , R 4’ , R 5’ , R 6’ There are not more than two substituted or unsubstituted amide groups or cyano groups in at the same time.

[0020] Preferably, the halogen is selected from F or Cl; and / or, the substituted or unsubstituted hydrocarbon group is selected from a hydrocarbon group with 6 or fewer carbon atoms.

[0021] Preferably, the pharmaceutically acceptable salts include acid addition salts formed by the compound shown in formula (I) and one or more of the following acids: hydrochloric acid, oxalate, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, benzenesulfonic acid, phosphoric acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, and mandelic acid.

[0022] Preferably, the formylpiperidine compounds include the following compounds and their salts:

[0023]

[0024]

[0025]

[0026]

[0027] The second aspect of the present invention provides a preparation method of the formylpiperidine compound described in the above technical solution, comprising the following steps:

[0028] The intermediate compound of formula (V) and the intermediate compound of formula (VI) are subjected to a condensation reaction to obtain the compound of formula (I);

[0029]

[0030] Wherein,

[0031] R1, R2, A, m, and n are as defined in the above technical solution;

[0032] Y is selected from halogen or p-toluenesulfonyloxy.

[0033] Preferably, the preparation method of the intermediate compound of formula (V) comprises the following steps:

[0034] The intermediate compound of formula (II) and the intermediate compound of formula (III) are subjected to a first reaction to generate the intermediate compound of formula (IV); the intermediate compound of formula (IV) is deprotected by Boc to obtain the intermediate compound of formula (V);

[0035]

[0036] Wherein, X is selected from halogen or hydroxyl.

[0037] Preferably, the preparation method of the intermediate compound of formula (VI) comprises:

[0038] (a) When Y is halogen, the preparation method of the intermediate compound of formula (VI) comprises the following steps:

[0039] Under the protection of an inert gas, the intermediate compound of formula (VIII) and the intermediate compound of formula (IX) are subjected to a second reaction to obtain the intermediate compound of formula (VII); the intermediate compound of formula (VII) is reduced to obtain the intermediate compound of formula (VI);

[0040]

[0041] (b) When Y is p-toluenesulfonyloxy, the preparation method of the intermediate compound of formula (VI) comprises the following steps:

[0042] The 4-fluorophenylhydrazine hydrochloride solution and 3,4-dihydro-2H-pyran are subjected to a third reaction to obtain the intermediate compound of formula (X); the intermediate compound of formula (X) and 4-p-toluenesulfonyl chloride are subjected to a substitution reaction to obtain the intermediate compound of formula (VI);

[0043]

[0044] Preferably, the reaction temperature of the condensation reaction is 80°C to 105°C.

[0045] Preferably, in the first reaction, the intermediate compound of formula (III) is added to an excess of the intermediate compound of formula (II), and the reaction is carried out at -5°C to 5°C.

[0046] Preferably, in the second reaction, the intermediate compound of formula (VIII) is added to an excess of the intermediate compound of formula (VII); and / or, in the third reaction, 3,4-dihydro-2H-pyran is added to an excess of 4-fluorophenylhydrazine hydrochloride, and the reaction is carried out at 90°C to 120°C.

[0047] The third aspect of the present invention provides a pharmaceutical composition, comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; the active ingredient comprises the formylpiperidine compound described in the foregoing technical solution or the formylpiperidine compound obtained by the preparation method described in the above technical solution.

[0048] The fourth aspect of the present invention provides an intermediate compound of the formylpiperidine compound described in the foregoing technical solution, comprising a compound having the following structure or its isomer, pharmaceutically acceptable salt, ester or prodrug:

[0049] Intermediate compound of formula (V)

[0050] and / or, intermediate compound of formula (VI)

[0051] and / or, intermediate compound of formula (II)

[0052] and / or, intermediate compound of formula (III)

[0053] and / or, intermediate compound of formula (IV)

[0054] and / or, intermediate compound of formula (VII)

[0055] and / or, intermediate compound of formula (VIII)

[0056] and / or, intermediate compound of formula (IX)

[0057] and / or, intermediate compound of formula (X)

[0058] Wherein,

[0059] R1, R2, A, m, and n are as defined in the formylpiperidine compounds described in the first aspect;

[0060] Y is selected from halogen or p-toluenesulfonyloxy;

[0061] X is selected from halogen or hydroxyl.

[0062] The fifth aspect of the present invention provides the use of the formylpiperidine compounds described in the foregoing technical solutions, the formylpiperidine compounds prepared by the methods described in the foregoing technical solutions, the pharmaceutical combinations described in the foregoing technical solutions, or the intermediate compounds described in the above technical solutions in the preparation of antidepressant drugs.

[0063] Preferably, the antidepressant drug is an antidepressant drug that inhibits the SSRI and 5-HT 1A targets.

[0064] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0065] The formylpiperidine compounds described in the present invention are a novel class of SSRI / 5-HT 1A dual-target inhibitors, which have good inhibitory activities against 5-TH reuptake and 5-HT 1A receptors; they have high hepatic microsomal stability; animal experiments show that the formylpiperidine compounds described in the present invention have more significant in vivo antidepressant activities, and the effective dose concentration is lower than that of the positive drug vilazodone; acute toxicity experiments show that the LD 50 of the formylpiperidine compounds described in the present invention is higher, the safety is better, and there is no risk of genetic toxicity of inducing mutations. It can be seen that the formylpiperidine compounds provided by the present invention are a kind of highly efficient, stable, and low-toxic SSRI / 5-HT 1A dual-target antidepressant compounds and can be used in the preparation of antidepressant drugs. Detailed Embodiments

[0066] In the present invention, the so-called "isomers" include, but are not limited to, enantiomers, diastereomers, mixtures of enantiomers and diastereomers, tautomers, racemic mixtures and mixtures of diastereomers, and pharmaceutically acceptable salts thereof. Unless otherwise specified, when the isomeric components are not specifically indicated, all possible isomers are included.

[0067] In the present invention, the "pharmaceutically acceptable salt" refers to a compound modified by forming an acid or base salt of a small molecule inhibitor that interacts with the β-catenin / BCL9 protein described in the present invention, including but not limited to salts of inorganic acids, selected from, for example, hydrochloride, phosphate, hydrogen phosphate, hydrobromide, sulfate, sulfite, and nitrate; and salts of organic acids, selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and salts of HOOC-(CH2)n-COOH, where n can be any integer from 0 to 4. If the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt (e.g., a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional process for preparing acid addition salts from basic compounds. Those skilled in the art should understand the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation. Similarly, the "pharmaceutically acceptable ester" refers to an ester derivative formed by the small molecule inhibitor described in the present invention, and the "pharmaceutically acceptable prodrug" includes precursor compounds that form the small molecule inhibitor described in the present invention in vivo and in vitro.

[0068] In the present invention, the "aromatic ring" or "aryl" refers to a fully carbonaceous monocyclic or fused polycyclic group of 5 to 12 carbon atoms, having a completely conjugated π electron system. Non-limiting examples of aromatic rings are: benzene ring, biphenyl, naphthalene ring, and anthracene ring. The aromatic ring can be unsubstituted or substituted. The substituents of the aromatic ring can be selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, and halo-C3-C6 cycloalkyl.

[0069] In the present invention, the "heteroaromatic ring" or "heteroaryl" refers to an unsaturated carbocyclic ring having 5 to 12 ring atoms, wherein one or more carbons are replaced by heteroatoms such as oxygen, nitrogen, sulfur, etc. The heteroaromatic ring can be a monocyclic ring or a bicyclic ring, that is, formed by the fusion of two rings. Specific heteroaryl groups can be: pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, morpholinyl, piperidinyl or piperazinyl, thienyl, benzothienyl, pyrazolyl, benzopyrazolyl, indolyl, dioxolanyl, benzo[1,3]dioxolanyl, oxazolyl, benzoxazolyl, furyl, benzofuryl, thiazolyl or benzothiazolyl, etc. The heteroaryl group can be unsubstituted or substituted. The substituents of the heteroaryl group can be selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl.

[0070] In the present invention, the "alkoxy" refers to an -O-alkyl group, wherein the alkyl is as defined above. Examples of the "alkoxy" used in the present invention include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy. The alkoxy can be unsubstituted or substituted.

[0071] In the present invention, the "halogen" or "halogenated" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0072] The formylpiperidine compounds of the present invention have a general structural formula as shown in formula (I), or its isomers, or its pharmaceutically acceptable salts, esters or prodrugs;

[0073]

[0074] Wherein,

[0075] R1 is selected from halogen or cyano;

[0076] R2 is selected from hydrogen or a substituted or unsubstituted hydrocarbon group;

[0077] A is selected from a substituted or unsubstituted six-membered ring, and the six-membered ring contains one or more heteroatoms of N, O and S in an amount of 0 to 2;

[0078] m and n independently are selected from 0, 1, 2, 3 or 4.

[0079] In the present invention, R1 in formula (I) can be any substituent on the indole ring; in some specific embodiments of the present invention, the R1 can be F, Cl or -CN. In some specific embodiments of the present invention, R2 in formula (I) can be H, methyl or propyl.

[0080] In the present invention, when A in formula (I) is a six-membered ring, the six-membered ring may be selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted pyridine, or substituted or unsubstituted pyrazine; in some specific embodiments of the present invention, A may be selected from the following groups:

[0081]

[0082] Wherein, R3, R4, R5, R6, R7, R 3’ 、R 4’ 、R 5’ 、R 6’ 、R3” are independently selected from H, halogen, substituted or unsubstituted hydrocarbon group, substituted or unsubstituted alkoxy group, substituted or unsubstituted amide group, or cyano group; there are not more than two substituted or unsubstituted amide groups or cyano groups among R3, R4, R5, R6, R7 at the same time; R 3’ 、R 4’ 、R 5’ 、R 6’ do not have more than two substituted or unsubstituted amide groups or cyano groups at the same time.

[0083] In some specific embodiments of the present invention, the combination of R3, R4, R5, R6, R7 may be:

[0084] Combination <![CDATA[R3]]> <![CDATA[R4]]> <![CDATA[R5]]> <![CDATA[R6]]> <![CDATA[R7]]> 1 H Cl F H H 2 H Cl Cl H H 3 H F F H H 4 H F Cl H H 5 H F H H H 6 H Cl H H H 7 H Cl F Cl H 8 H H <![CDATA[-OCH3]]> H H 9 H <![CDATA[-CH2]]> F H H 10 H <![CDATA[-OCH3]]> <![CDATA[-OCH3]]> H H 11 H <![CDATA[-OCH3]]> <![CDATA[-OCH3]]> <![CDATA[-OCH3]]> H 12 H H -CN H H 13 H H Sulfonyl H H 14 H H H H Sulfonyl

[0085] In some specific embodiments of the present invention, the combination of R 3’ 、R 4’ 、R 5’ 、R 6’ may be:

[0086] Combination <![CDATA[R 3’ > <![CDATA[R 4’ > <![CDATA[R 5’ > <![CDATA[R 6’ > <![CDATA[R 7’ > 1 H H F Cl H 2 H H F <![CDATA[-OCH3]]> H

[0087] In some specific embodiments of the present invention, R3” may be F or Cl.

[0088] In some specific embodiments of the present invention, the "substituted or unsubstituted hydrocarbon group" in formula (I) may be a saturated or unsaturated hydrocarbon group containing less than 6 C atoms, and its substituents include but are not limited to halogen, H, alkoxy group, cyano group, amino group, and carboxyl group.

[0089] In some specific embodiments of the present invention, the pharmaceutically acceptable salt of the formylpiperidine compound may be the hydrochloride, fumarate, maleate, or oxalate of the formylpiperidine compound; preferably, it is the hydrochloride or oxalate of the formylpiperidine compound.

[0090] The preparation method of the formylpiperidine compound described in the present invention can be prepared according to the following general method:

[0091]

[0092] Among them, R1, R2, A, m, and n are defined as in the above technical solution; Y is selected from halogen or p-toluenesulfonyloxy; X is selected from halogen or hydroxyl group.

[0093] S1, Synthesis of the intermediate compound of formula (V)

[0094] S1-1, When X in the intermediate compound of formula (III) is selected from halogen:

[0095] Dissolve the intermediate compound of formula (II) (1.0 eq) and triethylamine (1.5 eq) in 5 - 10 V of dichloromethane, cool in an ice bath to 0 °C, slowly add dropwise a dichloromethane solution of the intermediate compound of formula (III) (1.0 eq) thereto. After the addition is complete, react at 0 °C in an ice bath for 30 min, then place at room temperature and stir for 3 h. Add 5 V of saturated citric acid solution, stir for 15 min, separate the layers. Extract the aqueous phase with dichloromethane (10 V × 3), combine the organic phases, wash the organic phases with saturated sodium chloride solution (20 V × 3), dry over anhydrous sodium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness, and obtain the intermediate compound of formula (IV) by column chromatography.

[0096] Dissolve the intermediate compound of formula (IV) (1.0 eq) in dichloromethane, slowly add trifluoroacetic acid (2.0 - 4.0 eq), stir at room temperature for 5 - 8 h, monitor the reaction by TLC until completion. Place the reaction solution in an ice - water bath, adjust its pH to approximately 10 - 12 with 20% aqueous NaOH solution, stir for 10 min, separate the layers. Extract the aqueous phase with dichloromethane (10 V × 3), combine the organic phases, wash the organic phases with saturated sodium chloride solution (20 V × 3), dry over anhydrous sodium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness to obtain the intermediate compound of formula (V), with a yield of 70 - 82%.

[0097] S1-2, When X in the intermediate compound of formula (III) is selected from hydroxyl group:

[0098] Dissolve the intermediate compound of formula (II) (1.0 eq), the intermediate compound of formula (III) (1.0 eq), DIPEA (2.0 eq), EDCI (2.0 eq), and DMAP (1.0 eq) in dichloromethane (5 - 10 V), stir at room temperature for 6 - 10 h, monitor the reaction by TLC until completion. Wash the reaction solution successively with water, saturated citric acid solution, water, 20% aqueous NaOH solution, water, and saturated brine, dry over anhydrous sodium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness, and obtain the intermediate compound of formula (IV) by column chromatography.

[0099] Dissolve the intermediate compound of formula (IV) (1.0 eq) in dichloromethane, slowly add trifluoroacetic acid (2.0 - 4.0 eq), stir the reaction at room temperature for 5 - 8 h, monitor the completion of the reaction by TLC. Place the reaction solution in an ice - water bath, adjust its pH to approximately 10 - 12 with 20% aqueous NaOH solution, stir for 10 min, separate the layers. Extract the aqueous phase with dichloromethane (10V × 3), combine the organic phases. Wash the organic phase with saturated sodium chloride solution (20V × 3), dry over anhydrous sodium sulfate for 2 h, filter by suction, and concentrate the filtrate under reduced pressure to dryness to obtain the intermediate compound of formula (V) with a yield of 62 - 75%.

[0100] S2, Synthesis of the intermediate compound of formula (VI)

[0101] S2 - 1, When Y in the intermediate compound of formula (VI) is selected from halogen

[0102] Place aluminum trihalide (2.0 eq) in dichloromethane (5V), place it in an ice - water bath, and dropwise add a dichloromethane solution (1V) of the intermediate compound of formula (IX) (1.5 eq) at 0 °C. After dropping, stir until the aluminum trihalide dissolves. Continue under nitrogen protection, and dropwise add a dichloromethane solution of the intermediate compound of formula (VIII) (1.0 eq) to the above reaction system at 0 °C. After dropping, stir for about 30 min and then react at room temperature for 6 - 10 h. Monitor the completion of the reaction by TLC. Pour the reaction solution into ice - water (8 - 10V) in batches, stir, solids precipitate, filter by suction, and dry to obtain the intermediate compound of formula (VI).

[0103] S2 - 1, When Y in the intermediate compound of formula (VI) is selected from p - toluenesulfonyloxy

[0104] Dissolve 4 - fluorophenylhydrazine hydrochloride (1.0 eq) in a 5V mixed solution of 4% dilute sulfuric acid / N,N - dimethylacetamide (1:1), slowly add 3,4 - dihydro - 2H - pyran (1.0 eq) at 100 °C. After dropping, continue the reaction for 3 h, monitor the completion of the reaction by TLC (petroleum ether:ethyl acetate = 1:1). Cool to room temperature, add 5V ethyl acetate, stir for 15 min, then separate the layers. Extract the aqueous phase with ethyl acetate (2V × 3), combine the organic phases. Wash the organic phase with saturated sodium chloride solution (5V × 3), dry over anhydrous magnesium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness, and dry under vacuum to obtain a brown oily intermediate compound of formula (X) directly for the next step.

[0105] Dissolve the intermediate compound of formula (Ⅹ) (1.0 eq), triethylamine (1.5 eq), and 4-dimethylaminopyridine (0.1 eq) in 5V of dichloromethane. Slowly add dropwise a solution of 5V of p-toluenesulfonyl chloride (1.2 eq) in dichloromethane to the above solution at 0 °C, and then continue the reaction at room temperature for 8 h. Monitor the reaction by TLC (petroleum ether:ethyl acetate = 3:1). After the reaction is complete, add 2V of water, stir for 15 min, and then separate the layers. Wash the organic phase successively with 1N dilute hydrochloric acid (5V × 3) and saturated sodium chloride solution (5V × 3), dry over anhydrous magnesium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness, recrystallize twice from isopropanol, and dry in vacuo to obtain the intermediate compound of formula (Ⅵ) as a white solid, with a yield of 78%.

[0106] S3, Synthesis of the compound of formula (Ⅰ)

[0107] Dissolve the intermediate compound of formula (Ⅵ) (1.2 eq), the intermediate compound of formula (Ⅵ) (1.0 eq), and anhydrous potassium carbonate (2.5 eq) in acetonitrile (10V). Heat the reaction mixture under reflux at an external temperature of 90 °C overnight. Monitor the reaction by TLC (dichloromethane:methanol = 10:1). After the reaction is complete, filter by suction, concentrate the filtrate under reduced pressure to dryness, add 20V of dichloromethane and 20V of water, stir for 15 min, and then separate the layers. Extract the aqueous phase with dichloromethane (10V × 3), and combine the organic phases. Wash the combined organic phases with saturated sodium chloride solution (20V × 3), dry over anhydrous sodium sulfate for 2 h, filter by suction, concentrate the filtrate under reduced pressure to dryness, and perform column chromatography (dichloromethane:methanol = 50:1) to obtain the compound of formula (Ⅰ).

[0108] There is no limitation on the order between steps S1 and S2 in the present invention, as long as the intermediate compound of formula (Ⅵ) and the intermediate compound of formula (Ⅵ) can be obtained separately.

[0109] The present invention also protects the intermediate compounds or their isomers, pharmaceutically acceptable salts, esters or prodrugs involved in the above preparation method, including but not limited to the intermediate compound of formula (Ⅴ) and / or, the intermediate compound of formula (Ⅵ) and / or, the intermediate compound of formula (Ⅱ) and / or, the intermediate compound of formula (Ⅲ) and / or, the intermediate compound of formula (Ⅳ) and / or, the intermediate compound of formula (Ⅶ) and / or, the intermediate compound of formula (Ⅷ) and / or, the intermediate compound of formula (Ⅸ) and / or, the intermediate compound of formula (Ⅹ)

[0110] Wherein,

[0111] R1, R2, A, m, and n are as defined in the formylpiperidine compounds described in the above technical solution;

[0112] Y is selected from halogen or p-toluenesulfonyloxy;

[0113] X is selected from halogen or hydroxy.

[0114] The present invention also provides a pharmaceutical composition, wherein the active component comprises the formylpiperidine compound described in the above technical solution or the formylpiperidine compound obtained by the preparation method described in the above technical solution, and pharmaceutically acceptable excipients.

[0115] In the present invention, the pharmaceutically acceptable excipients include, but are not limited to, conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and flavoring agents, sweeteners, etc. may be added when necessary. The pharmaceutical composition of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injections, and the drugs in the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0116] The present invention also provides the use of the formylpiperidine compound described in the above technical solution, the formylpiperidine compound prepared by the method described in the above technical solution, the pharmaceutical composition described in the above technical solution or the intermediate compound described in the above technical solution in the preparation of an antidepressant; in the present invention, the antidepressant is preferably a drug that inhibits SSRI and 5-HT 1A Targeted antidepressant drugs.

[0117] The formylpiperidine compound of the present invention or the pharmaceutical composition comprising the formylpiperidine compound of the present invention can be administered to patients in need of such treatment by oral administration, injection, etc. The dosage of the formylpiperidine compound of the present invention can be varied according to the route of administration, the age, weight, sex, type and severity of the disease to be treated, etc., and the dosage can be 0.5-200 mg / kg body weight / day.

[0118] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be understood as limiting the scope of protection of the present invention. The experimental methods in the following embodiments that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. All raw materials that do not specify the synthesis method are purchased from manufacturers such as Exploration Platform, Aladdin, and Sigma-Aldrich, and are all analytically pure.

[0119] Example 1

[0120] (3-Chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-1) and its salts preparation

[0121]

[0122] 4-Boc-aminomethylpiperidine (5.40 mmol), 3-chloro-4-fluorobenzoyl chloride (5.40 mmol), and triethylamine (8.10 mmol) were operated according to step S1-1 to obtain the oily intermediate compound 5 (4.33 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain the off-white intermediate compound 6. The intermediate compound 5 (4.33 mmol) and the intermediate compound 6 (3.61 mmol) were operated according to step S3 to prepare 1.20 g of (3-chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 58%.

[0123] Preparation of compound I-1 maleate

[0124] Compound I-1 was dissolved in 10 ml of dichloromethane, and a solution of maleic acid (2.96 mmol) dissolved in 5 ml of acetone was slowly added dropwise thereto. White solid was precipitated by stirring at room temperature, and filtered by suction to obtain 1.12 g of white solid.

[0125] Preparation of compound I-1 oxalate

[0126] Compound I-1 was dissolved in 10 ml of dichloromethane, and a solution of oxalic acid (2.96 mmol) dissolved in 5 ml of acetone was slowly added dropwise thereto. White solid was precipitated by stirring at room temperature, and filtered by suction to obtain 1.05 g of white solid.

[0127] 11H NMR (400 MHz, DMSO-d6) δ 10.99 (d, J = 2.3 Hz, 1H), 8.24 (s, 2H), 7.66 (dd, J = 7.3, 2.1 Hz, 1H), 7.54 (t, J = 8.9 Hz, 1H), 7.44 (ddd, J = 8.5, 4.8, 2.1 Hz, 1H), 7.36 (ddd, J = 15.5, 9.4, 3.6 Hz, 2H), 7.28 (d, J = 2.3 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 6.05 (s, 2H), 4.46 (s, 1H), 3.56 (s, 1H), 3.16–2.72 (m, 7H), 1.99–1.63 (m, 5H), 1.29–1.14 (m, 2H).

[0128] ESI-MS: [M+H] + : 446.20 [M+1] + 。

[0129] Example 2

[0130] Preparation of (3,4-dichlorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-2)

[0131]

[0132] 4-Boc-aminomethylpiperidine (0.84 mmol), 3,4-dichlorobenzoyl chloride (0.84 mmol), and triethylamine (1.26 mmol) were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.68 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.68 mmol) and intermediate compound 6 (0.57 mmol) were operated according to step S3 to prepare 220 mg of (3,4-dichlorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 68%.

[0133] 11H NMR (400 MHz, DMSO-d6) δ 10.89 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.43–7.24 (m, 3H), 7.22 (d, J = 2.3 Hz, 1H), 6.92 (td, J = 9.2, 2.5 Hz, 1H), 4.46 (d, J = 12.7 Hz, 1H), 3.52 (d, J = 13.2 Hz, 1H), 3.37 (s, 2H), 3.03 (d, J = 14.1 Hz, 1H), 2.76 (s, 1H), 2.79–2.67 (m, 2H), 2.61 (t, J = 7.1 Hz, 2H), 2.48 (d, J = 6.4 Hz, 2H), 1.86–1.64 (m, 4H), 1.14 (d, J = 10.8 Hz, 2H).

[0134] ESI-MS: [M+H] + : 462.00 [M+1] + 。

[0135] Example 3

[0136] (3,4-Difluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-3) and its salts preparation

[0137]

[0138] 4-Boc-aminomethylpiperidine (0.84 mmol), 3,4-difluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 183 mg of (3,4-difluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 61%.

[0139] Preparation of compound I-3 oxalate

[0140] Compound I-3 was dissolved in 5 ml of dichloromethane, and an acetone solution of oxalic acid (0.47 mmol) dissolved in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 150 mg of a white solid.

[0141] 1 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.57 (s, 2H), 7.62–7.46 (m, 2H), 7.38–7.25 (m, 4H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.45 (s, 1H), 3.56 (s, 1H), 3.06 (s, 1H), 2.96 (t, J = 7.8 Hz, 2H), 2.87 (d, J = 6.5 Hz, 2H), 2.81–2.66 (m, 2H), 1.98 (p, J = 7.9 Hz, 3H), 1.76 (d, J = 52.7 Hz, 3H), 1.21 (d, J = 12.2 Hz, 2H).

[0142] ESI-MS: [M+H] + : 430.10 [M+1] + 。

[0143] Example 4

[0144] (3-Chloro-4-fluorophenyl)(4-(((4-(5-fluoro-1H-indol-3-yl)butyl)amino)methyl)piperidin-1-yl)methanone (I-4) and its salts preparation

[0145]

[0146] 4-Boc-aminomethylpiperidine (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 5-Fluoroindole, 4-chlorobutyryl chloride, aluminum trichloride, etc., were operated according to step S2-1 to obtain an oily intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 140 mg of (3-chloro-4-fluorophenyl)(4-(((4-(5-fluoro-1H-indol-3-yl)butyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 44%.

[0147] Preparation of compound I-4 oxalate

[0148] Compound I-4 was dissolved in 5 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 125 mg of a white solid.

[0149] 11H NMR (400 MHz, Chloroform-d) δ 9.09 (d, J = 7.0 Hz, 1H), 7.76 (dd, J = 4.9, 2.2 Hz, 1H), 7.62 (ddd, J = 8.6, 5.0, 2.3 Hz, 1H), 7.35–7.28 (m, 2H), 7.23 (s, 1H), 7.13–7.03 (m, 2H), 3.79–3.70 (m, 2H), 3.28–3.16 (m, 3H), 2.75–2.66 (m, 4H), 2.62 (ddd, J = 12.6, 6.0, 4.5 Hz, 1H), 2.53 (ddd, J = 12.6, 6.0, 4.5 Hz, 1H), 1.86–1.67 (m, 7H), 1.59–1.50 (m, 2H).

[0150] ESI-MS: [M+H] + : 460.20 [M+1] + 。

[0151] Example 5

[0152] (3-Chloro-4-fluorophenyl)(4-(((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)methyl)piperidin-1-yl)methanone (I-5) and its salts preparation

[0153]

[0154] 4-Boc-aminomethylpiperidine (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to Step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 5-Fluoroindole, chloroacetyl chloride, aluminum trichloride, etc., were operated according to Step S2-1 to obtain an oily intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to Step S3 to prepare 120 mg of (3-chloro-4-fluorophenyl)(4-(((2-(5-fluoro-1H-indol-3-yl)ethyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 40%.

[0155] Preparation of compound I-5 oxalate

[0156] Compound I-5 was dissolved in 5 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. A white solid was precipitated by stirring at room temperature, and filtered by suction to obtain 98 mg of a white solid.

[0157] 11H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.68 (s, 2H), 7.67 (dd, J = 7.1, 2.0 Hz, 1H), 7.55 (t, J = 8.9 Hz, 1H), 7.45 (ddd, J = 8.5, 4.7, 2.0 Hz, 1H), 7.42–7.30 (m, 3H), 6.97 (td, J = 9.2, 2.5 Hz, 1H), 4.48 (s, 1H), 3.58 (s, 1H), 3.32–2.65 (m, 8H), 2.46–1.52 (m, 3H), 1.25 (d, J = 12.5 Hz, 3H).

[0158] ESI-MS: [M+H] + : 432.10 [M+1] + 。

[0159] Example 6

[0160] (3-Chloro-4-fluorophenyl)(4-(((5-(5-fluoro-1H-indol-3-yl)pentyl)amino)methyl)piperidin-1-yl)methanone (I-6) and its salts preparation

[0161]

[0162] 4-Boc-aminomethylpiperidine (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 5-Fluoroindole, 5-chlorovaleryl chloride, aluminum trichloride, etc., were operated according to step S2-1 to obtain an oily intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 132 mg of (3-chloro-4-fluorophenyl)(4-(((5-(5-fluoro-1H-indol-3-yl)pentyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 44%.

[0163] Preparation of compound I-6 fumarate

[0164] Compound I-6 was dissolved in 5 ml of dichloromethane, and a solution of fumaric acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 106 mg of a white solid.

[0165] 11H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.59 (s, 2H), 7.66 (dd, J = 7.2, 2.0 Hz, 1H), 7.54 (t, J = 8.9 Hz, 1H), 7.44 (ddd, J = 8.5, 4.7, 2.0 Hz, 1H), 7.35 (dd, J = 8.8, 4.6 Hz, 1H), 7.27 (dd, J = 10.1, 2.6 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.92 (td, J = 9.2, 2.6 Hz, 1H), 3.56 (s, 1H), 3.08 (s, 1H), 2.92 (d, J = 7.7 Hz, 1H), 2.86 (s, 4H), 2.69 (dd, J = 15.2, 7.6 Hz, 2H), 2.12 (s, 2H), 1.97 (s, 1H), 1.83 (s, 2H), 1.66 (dp, J = 13.9, 7.6 Hz, 5H), 1.39 (p, J = 7.8 Hz, 2H), 1.22 (d, J = 12.7 Hz, 3H).

[0166] ESI-MS: [M + H] + : 474.10 [M + 1] + 。

[0167] Example 7

[0168] (4-Fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-7) and its salts preparation

[0169]

[0170] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 126 mg of (4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 42%.

[0171] Preparation of compound I-7 oxalate

[0172] Dissolve compound I-7 in 7 ml of dichloromethane, slowly add dropwise to it an acetone solution of oxalic acid (1.1 eq) dissolved in 3 ml of acetone, stir at room temperature to precipitate a white solid, and filter by suction to obtain 110 mg of a white solid.

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.74 (s, 2H), 7.47 (dt, J = 7.9, 3.5 Hz, 2H), 7.40–7.17 (m, 6H), 6.94 (td, J = 9.2, 2.6 Hz, 1H), 4.46 (s, 1H), 3.58 (s, 1H), 2.96 (t, J = 7.9 Hz, 2H), 2.91–2.66 (m, 5H), 1.99 (p, J = 7.5 Hz, 3H), 1.77 (d, J = 44.8 Hz, 3H), 1.20 (d, J = 13.2 Hz, 2H).

[0174] ESI-MS: [M+H] + : 474.10 [M+1] + 。

[0175] Example 8

[0176] (4-Chlorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-8) and its salts preparation

[0177]

[0178] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-chlorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 144 mg of (4-chlorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 48%.

[0179] Preparation of compound I-8 oxalate

[0180] Dissolve compound I-8 in 7 ml of dichloromethane, slowly add dropwise to it an acetone solution of oxalic acid (1.1 eq) dissolved in 3 ml of acetone, stir at room temperature to precipitate a white solid, and filter by suction to obtain 128 mg of a white solid.

[0181] 1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.71 (s, 2H), 7.59–7.50 (m, 2H), 7.46–7.40 (m, 2H), 7.35 (ddd, J = 17.1, 9.5, 3.6 Hz, 2H), 7.27 (d, J = 2.3 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.46 (s, 1H), 3.56 (s, 1H), 3.06 (s, 1H), 3.02–2.85 (m, 4H), 2.75 (t, J = 7.3 Hz, 2H), 2.10–1.90 (m, 3H), 1.84 (s, 2H), 1.70 (s, 1H), 1.34–1.02 (m, 2H).

[0182] ESI-MS: [M+H] + : 428.20 [M+1] + 。

[0183] Example 9

[0184] (3,5-Dichloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (I-9) and its salts preparation

[0185]

[0186] 4-Boc-aminomethylpiperidine (0.84 mmol), 3,5-dichloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol) were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 168 mg of (3,5-dichloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 50%.

[0187] Preparation of compound I-9 hydrochloride

[0188] Compound I-9 was dissolved in 10 ml of ethyl acetate, and 2N hydrochloric acid ethyl acetate solution (1.1 eq) was slowly added dropwise thereto. White solid was precipitated by stirring at room temperature, and filtered by suction to obtain 130 mg of white solid.

[0189] 1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 2.5 Hz, 1H), 8.76 (s, 2H), 7.68 (d, J = 6.4 Hz, 2H), 7.40–7.25 (m, 3H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 4.43 (s, 1H), 3.53 (s, 1H), 3.07 (s, 1H), 2.94 (s, 2H), 2.90–2.70 (m, 5H), 2.10–1.95 (m, 3H), 1.85 (s, 1H), 1.73 (s, 1H), 1.24 (tq, J = 12.2, 6.5, 4.6 Hz, 2H).

[0190] ESI-MS: [M+H] + : 480.10 [M + 1] + 。

[0191] Example 10

[0192] Preparation of 3-(3-(((1-(3-chloro-4-fluorobenzoyl)piperidin-4-yl)methyl)amino)propyl)-1H-indole-5-carbonitrile (I-10) and its salts

[0193]

[0194] 4-Boc-aminomethylpiperidine (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), and triethylamine (1.26 mmol) were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 5-Cyanoindole, 3-chloropropionyl chloride, aluminum trichloride, etc. were operated according to step S2-1 to obtain an oily intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to step S3 to prepare 134 mg of 3-(3-(((1-(3-chloro-4-fluorobenzoyl)piperidin-4-yl)methyl)amino)propyl)-1H-indole-5-carbonitrile with a yield of 51%.

[0195] Preparation of the oxalate salt of compound I-10

[0196] Compound I-10 was dissolved in 5 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 2 ml of acetone was slowly added dropwise thereto. White solid precipitated upon stirring at room temperature, and was filtered by suction to obtain 120 mg of white solid.

[0197] 11H NMR (600 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.20 (s, 2H), 8.12 (s, 1H), 7.62 (dd, J = 7.2, 2.1 Hz, 1H), 7.55–7.48 (m, 2H), 7.43 (dd, J = 8.3, 1.6 Hz, 1H), 7.43–7.37 (m, 2H), 5.76 (s, 1H), 4.43 (s, 1H), 3.53 (s, 1H), 3.05 (s, 1H), 2.93 (d, J = 8.8 Hz, 2H), 2.85 (d, J = 6.0 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.96 (p, J = 7.6 Hz, 2H), 1.90 (s, 1H), 1.79 (s, 1H), 1.65 (s, 1H), 1.19 (s, 2H).

[0198] ESI-MS: [M+H] + : 453.10 [M+1] + 。

[0199] Example 11

[0200] (3-Chloro-4-fluorophenyl)(4-((3-(5-fluoro-1H-indol-3-yl)propyl)amino)piperidin-1-yl)methanone (I-11) and its salts preparation

[0201]

[0202] 4-Boc-aminopiperidine (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol) were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 150 mg of (3-chloro-4-fluorophenyl)(4-((3-(5-fluoro-1H-indol-3-yl)propyl)amino)piperidin-1-yl)methanone, with a yield of 60%.

[0203] Preparation of compound I-11 hydrochloride

[0204] Compound I-11 was dissolved in 12 ml of ethyl acetate, and 2N hydrochloric acid ethyl acetate solution (1.1 eq) was slowly added dropwise thereto. White solid was precipitated by stirring at room temperature, and filtered by suction to obtain 130 mg of white solid.

[0205] 1 1H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 2.7 Hz, 1H), 9.07 (s, 2H), 7.66 (dd, J = 7.1, 2.1 Hz, 1H), 7.62–7.51 (m, 1H), 7.49–7.25 (m, 4H), 6.94 (td, J = 9.2, 2.6 Hz, 1H), 4.52 (s, 1H), 3.65 (s, 1H), 3.14 (s, 1H), 3.09–2.62 (m, 6H), 2.30–1.82 (m, 4H), 1.59 (s, 2H).

[0206] ESI-MS: [M+H] + : 432.20 [M+1] + 。

[0207] Example 12

[0208] (3-Chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)(methyl)amino)methyl)piperidin-1-yl)methanone (II-1) and its salts preparation

[0209]

[0210] tert-Butyl methyl(piperidin-4-ylmethyl)carbamate (0.84 mmol), 3-chloro-4-fluorobenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 165 mg of (3-chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)(methyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 62%.

[0211] Preparation of compound II-1 oxalate

[0212] Compound II-1 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 4 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 154 mg of a white solid.

[0213] 11H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.53 (s, 1H), 7.65 (dd, J = 7.1, 1.9 Hz, 1H), 7.54 (t, J = 8.9 Hz, 1H), 7.47–7.40 (m, 1H), 7.44–7.32 (m, 2H), 7.31 (s, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.44 (s, 1H), 3.54 (s, 1H), 3.05 (d, J = 48.2 Hz, 6H), 2.82–2.63 (m, 7H), 2.04 (s, 3H), 1.80 (s, 1H), 1.68 (s, 1H), 1.21 (td, J = 7.2, 2.7 Hz, 2H).

[0214] ESI-MS: [M+H] + : 460.10 [M+1] + 。

[0215] Example 13

[0216] (3-Chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)(propyl)amino)methyl)piperidin-1-yl)methanone (II-2) and its salts preparation

[0217]

[0218] Synthesize I-1 (1.0 mmol) according to the synthesis method of I-1, and then operate I-1 and 3-bromopropane (1.0 mmol) according to step S3 to obtain 303 mg of (3-chloro-4-fluorophenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)(propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 62%.

[0219] Preparation of compound II-2 oxalate

[0220] Dissolve compound II-2 in 10 ml of dichloromethane, slowly add dropwise an acetone solution of oxalic acid (1.1 eq) dissolved in 5 ml of acetone thereto, stir at room temperature to precipitate a white solid, and filter by suction to obtain 289 mg of a white solid.

[0221] 11H NMR (400 MHz, DMSO-d6) δ 11.03 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.1, 2.1 Hz, 1H), 7.58–7.49 (m, 1H), 7.46–7.29 (m, 5H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.43 (s, 1H), 3.51 (s, 1H), 3.11 (t, J = 8.3 Hz, 2H), 3.06–2.90 (m, 5H), 2.74 (q, J = 12.6, 9.9 Hz, 3H), 2.17–1.46 (m, 8H), 1.18 (d, J = 12.8 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0222] ESI-MS: [M+H] + : 488.20 [M+1] + 。

[0223] Example 14

[0224] (4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone (Ⅲ-1) and its salts preparation

[0225]

[0226] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-methoxybenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 140 mg of (4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(4-methoxyphenyl)methanone, with a yield of 59%.

[0227] Preparation of compound Ⅲ-1 oxalate

[0228] Compound Ⅲ-1 was dissolved in 6 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 2 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 132 mg of a white solid.

[0229] 11H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.58 (s, 2H), 7.44–7.18 (m, 5H), 7.18–6.85 (m, 3H), 3.82 (s, 3H), 3.17–2.62 (m, 7H), 2.08–1.55 (m, 5H), 1.19 (d, J = 12.4 Hz, 2H).

[0230] ESI-MS: [M+H] + : 424.20 [M+1] + 。

[0231] Example 15

[0232] (4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(p-tolyl)methanone

[0233] Preparation of (Ⅲ-2) and its salts

[0234]

[0235] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-methylbenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol) were operated according to Step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to Step S3 to prepare 144 mg of (4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(p-tolyl)methanone, with a yield of 61%.

[0236] Preparation of compound Ⅲ-2 oxalate

[0237] Compound Ⅲ-2 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 130 mg of a white solid.

[0238] 11H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.48 (s, 2H), 7.41–7.24 (m, 7H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.46 (s, 3H), 3.01–2.82 (m, 5H), 2.76 (t, J = 7.4 Hz, 3H), 2.37 (s, 3H), 1.98 (p, J = 7.7 Hz, 3H), 1.76 (s, 2H), 1.19 (s, 2H).

[0239] ESI-MS: [M+H] + : 408.30 [M+1] + 。

[0240] Example 16

[0241] Preparation of (4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(4-fluoro-3-methylphenyl)methanone (Ⅲ-3) and its salts

[0242]

[0243] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-fluoro-3-methylbenzoyl chloride (0.84 mmol), and triethylamine (1.26 mmol) were operated according to Step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to Step S3 to prepare 151 mg of (4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(4-fluoro-3-methylphenyl)methanone with a yield of 61%.

[0244] Preparation of the oxalate salt of compound Ⅲ-3

[0245] Compound Ⅲ-3 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 143 mg of a white solid.

[0246] 11H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.35 (ddd, J = 17.4, 9.4, 3.6 Hz, 3H), 7.29–7.20 (m, 3H), 6.94 (td, J = 9.2, 2.5 Hz, 1H), 4.46 (s, 2H), 3.61 (s, 1H), 3.03 (s, 1H), 2.98–2.87 (m, 2H), 2.87–2.68 (m, 5H), 2.29 (d, J = 2.0 Hz, 3H), 1.96 (p, J = 8.5, 8.1 Hz, 3H), 1.78 (s, 3H), 1.31–1.08 (m, 3H).

[0247] ESI-MS: [M+H] + : 426.20 [M+1] + 。

[0248] Example 17

[0249] (4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(3-fluoro-4-methoxyphenyl)methanone (Ⅲ-4) and its salts preparation

[0250]

[0251] 4-Boc-aminomethylpiperidine (0.84 mmol), 3-fluoro-4-methoxybenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 164 mg of (4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(3-fluoro-4-methoxyphenyl)methanone, with a yield of 64%.

[0252] Preparation of compound Ⅲ-4 oxalate

[0253] Compound Ⅲ-4 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 153 mg of a white solid.

[0254] 11H NMR (400 MHz, DMSO-d6) δ 11.01 (d, J = 2.3 Hz, 1H), 8.64 (s, 1H), 7.41–7.16 (m, 7H), 6.95 (td, J = 9.1, 2.6 Hz, 1H), 4.47 (s, 9H), 3.91 (s, 2H), 3.17–2.64 (m, 7H), 1.99 (p, J = 7.8 Hz, 3H), 1.76 (s, 2H), 1.21 (p, J = 11.7 Hz, 2H).

[0255] ESI-MS: [M+H] + : 442.20 [M+1] + 。

[0256] Example 18

[0257] Preparation of (3,4-dimethoxyphenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (Ⅲ-5) and its salts

[0258]

[0259] 4-Boc-aminomethylpiperidine (0.84 mmol), 3,4-dimethoxybenzoyl chloride (0.84 mmol), and triethylamine (1.26 mmol) were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to step S3 to prepare 158 mg of (3,4-dimethoxyphenyl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 60%.

[0260] Preparation of the oxalate salt of compound Ⅲ-5

[0261] Compound Ⅲ-5 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 140 mg of a white solid.

[0262] 1H NMR (400 MHz, DMSO-d6) δ 11.00 (d, J = 2.1 Hz, 1H), 8.62 (s, 2H), 7.40–7.24 (m, 3H), 7.09–6.87 (m, 4H), 4.24 (s, 3H), 3.81 (d, J = 8.8 Hz, 7H), 3.05–2.82 (m, 5H), 2.76 (t, J = 7.4 Hz, 2H), 2.06–1.88 (m, 3H), 1.77 (s, 2H), 1.21 (dt, J = 22.5, 12.1 Hz, 2H).

[0263] ESI-MS: [M+H] + : 454.20 [M+1] + 。

[0264] Example 19

[0265] (4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone (Ⅲ-6) and its salts preparation

[0266]

[0267] 4-Boc-aminomethylpiperidine (0.84 mmol), 3,4,5-trimethoxybenzoyl chloride (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-1 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 174 mg of (4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone, with a yield of 62%.

[0268] Preparation of compound Ⅲ-6 hydrochloride

[0269] Compound Ⅲ-6 was dissolved in 15 ml of ethyl acetate, and 2N hydrochloric acid ethyl acetate solution (1.1 eq) was slowly added dropwise thereto. It was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 150 mg of a white solid.

[0270] 11H NMR (400 MHz, DMSO-d6) δ 11.00 (d, J = 2.4 Hz, 1H), 8.63 (s, 2H), 7.41–7.26 (m, 3H), 6.95 (td, J = 9.2, 2.6 Hz, 1H), 6.68 (s, 2H), 4.46 (s, 1H), 3.82 (s, 6H), 3.72 (s, 3H), 3.11–2.66 (m, 7H), 2.09–1.92 (m, 4H), 1.80 (s, 2H), 1.33–1.12 (m, 3H).

[0271] ESI-MS: [M+H] + : 484.30 [M+1] + 。

[0272] Example 20

[0273] Preparation of 4-(4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzonitrile (IV-1) and its salts

[0274]

[0275] 4-Boc-aminomethylpiperidine (0.84 mmol), 4-cyanobenzoic acid (0.84 mmol), and triethylamine (1.26 mmol) were operated according to step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 158 mg of 4-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzonitrile, with a yield of 65%.

[0276] Preparation of the oxalate salt of compound IV-1

[0277] Compound IV-1 was dissolved in 7 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 140 mg of a white solid.

[0278] 11H NMR (600 MHz, DMSO-d6) δ 10.96 (d, J = 2.5 Hz, 1H), 8.58 (s, 1H), 7.98–7.91 (m, 2H), 7.59–7.54 (m, 2H), 7.38–7.20 (m, 3H), 6.91 (td, J = 9.1, 2.6 Hz, 1H), 4.44 (d, J = 12.9 Hz, 1H), 3.41 (d, J = 13.4 Hz, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.92 (d, J = 15.8 Hz, 2H), 2.89–2.67 (m, 5H), 1.94 (tt, J = 11.5, 5.8 Hz, 3H), 1.82 (d, J = 13.0 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.19 (dt, J = 37.2, 11.4 Hz, 2H).

[0279] ESI-MS: [M+H] + : 419.20 [M+1] + 。

[0280] Example 21

[0281] Preparation of 4-(4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzamide (IV-2) and its salts

[0282]

[0283] 4-Boc-aminomethylpiperidine (0.84 mmol), terephthalic acid monoamide (0.84 mmol), and triethylamine (1.26 mmol) were operated according to Step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to Step S3 to prepare 160 mg of 4-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzamide, with a yield of 63%.

[0284] Preparation of the oxalate salt of compound IV-2

[0285] Compound IV-2 was dissolved in 7 ml of dichloromethane, and an acetone solution of oxalic acid (1.1 eq) dissolved in 3 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 154 mg of a white solid.

[0286] 1 1H NMR (400 MHz, DMSO-d6) δ 11.02–10.93 (m, 1H), 8.78 (s, 1H), 7.94 (dd, J = 7.8, 1.2 Hz, 1H), 7.79 (td, J = 7.7, 1.3 Hz, 1H), 7.64 (td, J = 7.7, 1.2 Hz, 1H), 7.54 (dd, J = 7.7, 1.2 Hz, 1H), 7.37–7.16 (m, 3H), 6.90 (td, J = 9.2, 2.5 Hz, 1H), 5.17 (s, 2H), 4.48 (d, J = 13.0 Hz, 1H), 3.30 (d, J = 13.5 Hz, 1H), 3.06 (s, 1H), 2.98–2.76 (m, 5H), 2.71 (t, J = 7.4 Hz, 2H), 2.04–1.81 (m, 4H), 1.68 (d, J = 13.1 Hz, 1H), 1.17 (tt, J = 12.2, 8.7 Hz, 2H).

[0287] ESI-MS: [M+H] + : 437.20 [M+1] + 。

[0288] Example 22

[0289] Preparation of 2-(4-(((3-(5-Fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzamide (IV-3) and its salts

[0290]

[0291] 4-Boc-aminomethylpiperidine (0.84 mmol), o-formamidobenzoic acid (0.84 mmol), triethylamine (1.26 mmol) were operated according to Step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to Step S3 to prepare 152 mg of 2-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)benzamide, with a yield of 60%.

[0292] Preparation of the oxalate salt of compound IV-3

[0293] Dissolve compound IV-3 in 7 ml of dichloromethane, and slowly add dropwise thereto an acetone solution of oxalic acid (1.1 eq) dissolved in 3 ml of acetone. Stir at room temperature to precipitate a white solid, and filter by suction to obtain 141 mg of a white solid.

[0294] 1 H NMR (600 MHz, DMSO-d6) δ 11.03–10.95 (m, 1H), 8.78 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.79 (td, J = 7.7, 1.2 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.41–7.21 (m, 3H), 6.91 (td, J = 9.1, 2.5 Hz, 1H), 5.16–4.21 (m, 5H), 3.40–3.26 (m, 1H), 3.06 (d, J = 11.4 Hz, 1H), 2.99–2.90 (m, 2H), 2.85 (tt, J = 7.3, 3.8 Hz, 3H), 2.72 (t, J = 7.4 Hz, 2H), 2.05–1.81 (m, 4H), 1.69 (d, J = 13.0 Hz, 1H), 1.18 (dqd, J = 24.4, 13.3, 12.0, 5.1 Hz, 2H).

[0295] ESI-MS: [M+H] + : 419.60 [M - 28] + 。

[0296] Example 23

[0297] (6-Chloro-5-fluoropyridin-2-yl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (V-1) and its salts Preparation

[0298]

[0299] 4-Boc-aminomethylpiperidine (0.84 mmol), 2-chloro-3-fluoropyridine-6-carboxylic acid (0.84 mmol), and triethylamine (1.26 mmol) were operated according to Step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to Step S3 to prepare 168 mg of (6-chloro-5-fluoropyridin-2-yl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone, with a yield of 65%.

[0300] Preparation of Compound V-1 Oxalate

[0301] Compound V-1 was dissolved in 8 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) in 4 ml of acetone was slowly added dropwise thereto. The mixture was stirred at room temperature to precipitate a white solid, which was filtered by suction to obtain 155 mg of a white solid.

[0302] 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (d, J = 2.3 Hz, 1H), 8.06 (t, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.4, 3.5 Hz, 1H), 7.36–7.18 (m, 3H), 6.91 (td, J = 9.2, 2.6 Hz, 1H), 4.43 (d, J = 13.1 Hz, 1H), 4.03 (s, 3H), 3.64 (d, J = 13.5 Hz, 1H), 3.03 (d, J = 25.2 Hz, 1H), 2.97–2.61 (m, 7H), 1.94 (dt, J = 15.2, 7.3 Hz, 3H), 1.83 (d, J = 13.4 Hz, 1H), 1.69 (d, J = 13.1 Hz, 1H), 1.20 (qd, J = 12.2, 4.5 Hz, 2H).

[0303] ESI-MS: [M+H] + : 447.00 [M+1] + .

[0304] Example 24

[0305] Preparation of 6-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-carbonyl)pyridinecarboxamide (V-2) and Its Salt

[0306]

[0307] 4-Boc-aminomethylpiperidine (0.84 mmol), 2-formamido-6-pyridinecarboxylic acid (0.84 mmol), and triethylamine (1.26 mmol) were operated according to Step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc. were operated according to Step S2-2 to obtain an off-white intermediate compound 6. Intermediate compound 5 (0.70 mmol) and intermediate compound 6 (0.58 mmol) were reacted according to Step S3 to prepare 165 mg of 6-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidine-1-carbonyl)pyridinecarboxamide, with a yield of 65%.

[0308] Preparation of Compound V-2 Oxalate

[0309] Compound V-2 was dissolved in 8 ml of dichloromethane, and a solution of oxalic acid (1.1 eq) dissolved in 4 ml of acetone was slowly added dropwise thereto. A white solid was precipitated by stirring at room temperature, and then filtered by suction to obtain 155 mg of a white solid.

[0310] 1H NMR (400 MHz, DMSO-d6) δ 10.98–10.93 (m, 1H), 8.15–8.05 (m, 2H), 7.91 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 6.0, 2.8 Hz, 1H), 7.31 (ddd, J = 17.4, 9.4, 3.6 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H), 6.91 (td, J = 9.2, 2.6 Hz, 1H), 4.48 (d, J = 13.1 Hz, 1H), 3.05 (t, J = 12.6 Hz, 1H), 2.97–2.89 (m, 2H), 2.83 (dd, J = 17.5, 4.9 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 2.08 (s, 2H), 1.94 (d, J = 7.5 Hz, 2H), 1.85 (d, J = 13.0 Hz, 1H), 1.67 (d, J = 12.5 Hz, 1H), 1.33 –1.17 (m, 2H).

[0311] ESI-MS: [M+H] + : 438.60 [M+1] + 。

[0312] Example 25

[0313] (5-Chloropyrazin-2-yl)(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-yl)methanone (Ⅵ-1) Preparation

[0314]

[0315] 4-Boc-aminomethylpiperidine (0.84 mmol), (5-chloro-2-pyrazinecarboxylic acid (0.84 mmol), triethylamine (1.26 mmol), were operated according to step S1-2 to obtain an oily intermediate compound 5 (0.70 mmol). 4-Fluorophenylhydrazine hydrochloride (123.0 mol), 3,4-dihydro-2H-pyran (123.0 mol), etc., were operated according to step S2-2 to obtain an off-white intermediate compound 6. The intermediate compound 5 (0.70 mmol) and the intermediate compound 6 (0.58 mmol) were operated according to step S3 to prepare 152 mg of 6-(4-(((3-(5-fluoro-1H-indol-3-yl)propyl)amino)methyl)piperidin-1-carbonyl)pyridinecarboxamide, with a yield of 62%.

[0316] 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (d, J = 2.4 Hz, 1H), 8.81 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.4 Hz, 1H), 7.37–7.21 (m, 3H), 6.91 (td, J = 9.2, 2.5 Hz, 1H), 4.45 (d, J = 13.0 Hz, 1H), 3.98 (s, 2H), 3.70 (d, J = 13.5 Hz, 1H), 3.04 (d, J = 11.5 Hz, 1H), 2.97–2.89 (m, 2H), 2.89–2.78 (m, 3H), 2.72 (t, J = 7.4 Hz, 2H), 2.00–1.92 (m, 2H), 1.85 (d, J = 13.3 Hz, 1H), 1.68 (d, J = 12.9 Hz, 1H), 1.20 (qd, J = 12.3, 4.3 Hz, 2H).

[0317] ESI-MS: [M+H] + : 430.00 [M+1] + .

[0318] Example 26, Inhibitory Effect of the Compound on 5-HT Reuptake and 5-HT 1A Receptor Binding Experiment

[0319] The method of using cell monoclonal technology and radioactive ligand binding experiment was used to conduct in vitro screening research on the new compound with a clear target, and this method can be objectively, accurately and quickly used for the corresponding bioactivity evaluation.

[0320] Specifically, the in vitro activity screening of the compound was carried out by the research methods reported in (Mulheron, J.G. et al. (1994), J. Biol. Chem., 269: 12954 - 12962. and Perovic, S. and Muller, W.E.G. (1995), Arzneim - Forsch. Drug Res., 45: 1145 - 1148.). At the same time, vilazodone with effective 5 - HT reuptake / 5 - HT 1A dual activity (English name: Vilazodone) was used as a positive control, and the 5 - HT reuptake / 5 - HT 1A receptor binding experiment was carried out on the invented compound. The specific method is as follows:

[0321] 1. Establishment of 5 - HT transporter (hSERT) stable cell line

[0322] The HEK 293 cells were transfected with the pcDNA3.0 - hSERT vector plasmid. 48 hours after transfection, the G418 - selective DMEM culture medium was added to culture the cells. After 3 weeks, the cells showing G418 resistance were presented by serial dilution to obtain stably transfected monoclonal cells, and then amplified and cultured with the culture medium containing G418. The expression of 5 - HT transporter on the monoclonal cells was verified by the 5 - HT reuptake experiment, and finally a stable cell line that could stably express the 5 - HT transporter protein was obtained.

[0323] 2. 5 - HT reuptake test

[0324] The test compounds (formylpiperidine compounds prepared in Examples 1 - 25) and the positive control drug (vilazodone) were dissolved in DMSO to 0.01 mol / L respectively, and then diluted to 1000 μmol / L with deionized water. 50 μl of the test compound (or positive drug) and 430 μl of the cells were added to the reaction tube. After incubation in a 30 °C water bath for 10 min, radioactive [3H] -5-HT 20 μl was added to make the final concentration of the test compound (or positive drug) 1 μmol / L. After incubation in a 30 °C water bath for 10 min, it was immediately transferred to an ice bath to terminate the reaction. On a BRANDEL 24-well cell sample collector, it was rapidly filtered through a GF / B glass fiber filter paper and washed 3 times with ice-cold washing buffer (50 mM Tris, 5 mM EDTA, pH 7.4). After the filter paper was dried, it was placed in a 0.5 ml centrifuge tube, 500 μl of lipophilic scintillation fluid was added, and the radioactivity was measured by a MicroBeta liquid scintillation counter. The experiments were divided into: total reuptake tube (blank control), non-specific reuptake tube (1 μmol / L positive drug), and sample reuptake tube (1 μmol / L test compound). Two replicates were measured for each concentration, and three independent experiments were performed. The percent inhibition of reuptake of each compound was calculated according to the following formula:

[0325]

[0326] 3. 5-HT 1A Receptor binding assay

[0327] 5-HT 1A Cell transfection: In this experiment, CHO cells were transfected with a plasmid vector containing the 5-HT 1A receptor protein gene using the calcium phosphate transfection method. From the transfected cells, through culturing in a medium containing G418, and screening for cell monoclonal and radioactive culture binding experiments, a stable cell line capable of stably expressing the 5-HT 1A receptor protein was finally obtained. For cell culture, the cells were centrifuged at 1000 rpm for 5 min, the culture medium was discarded, the cells were collected, and stored in a -20 °C refrigerator for later use. During the experiment, they were resuspended with Tris-HCl reaction buffer (pH 7.7).

[0328] 5-HT 1A Receptor binding competition assay:

[0329] Add 10 μL each of the compound to be tested, the positive control drug, and the radioactive isotope ligand [3H]8-OH-DPAT, and 80 μL of receptor protein into the reaction tube, so that the final concentrations of the test compound and the positive drug are both 1 μmol / L. After incubating in a water bath at 37 °C for 15 min, immediately transfer it to an ice bath to terminate the reaction; on a Millipore cell sample collector, quickly filter through a GF / C glass fiber filter paper, and wash with 3 mL of eluent (50 mM Tris-HCl, pH 7.7) three times, dry in a microwave oven for 8 - 9 min, transfer the filter paper to a 0.5 mL centrifuge tube, and add 500 μL of lipophilic scintillation fluid. Keep it in the dark and stand for more than 30 min, and measure the radioactivity with a Beckman LS-6500 type multi-functional liquid scintillation counter. Measure two replicates for each concentration and conduct three independent experiments. Calculate the inhibition rate percentage of each compound on the binding of the isotope ligand according to the aforementioned formula.

[0330] 4. Results:

[0331] The 5-HT reuptake inhibition effect and 5-HT 1A receptor binding test results of the test compound and the positive control drug are shown in Table 1.

[0332] Table 1 5-HT reuptake inhibition / 5-HT 1A receptor binding ability

[0333]

[0334]

[0335] It can be seen from the experimental results that the formylpiperidine compounds provided by the present invention have good inhibitory activity and affinity for 5-HT reuptake and 5-HT 1A receptors, and their inhibitory activity and affinity are equivalent to or better than those of the positive control drug Vilazodone. Among them, compounds IV-2 and V-2 have significantly better inhibitory activity on 5-HT reuptake and 1A affinity for 5-HT receptors than the positive control drug Vilazodone.

[0336] Microsomal stability experiments of the compound in Example 27 in mice and human liver

[0337] Conduct microsomal metabolic stability experiments on the compound to preliminarily investigate its metabolic stability.

[0338] Experimental method:

[0339] Prepare stock solutions of the test samples (formylpiperidine compounds prepared in Examples 1 - 25) and the positive control (vilazodone) at a concentration of 10 mM using DMSO as the solvent. Dilute the stock solutions to a concentration of 0.25 mM with 70% acetonitrile. Prepare an NADPH solution composed of 6.5 mM NADP, 16.5 mM glucose - 6 - phosphate, and 3 U / mL glucose - 6 - phosphate dehydrogenase. The quenching agent consists of acetonitrile, tolbutamide, and propanol (as the internal standard). The buffer is 100 mM potassium phosphate buffer containing 3.3 mM MgCl2. Place a mixture containing 0.5 mg / mL liver microsomal protein and 1 μM test sample / positive control in the buffer and incubate with mixing.

[0340] Add 80 μL aliquots of each incubation mixture to 400 μL of the quenching reagent to precipitate proteins and prepare the initial samples. After vortexing the samples, add 20 μL aliquots of the NADPH solution. Add 80 μL of the NADPH solution to 320 μL of the incubation mixture to initiate the reaction. Incubate the mixture with gentle shaking in a 37°C water bath. At 0, 10, 30, and 90 min respectively, transfer 100 μL of the mixture to a 96 - well plate containing 400 μL of the quenching agent. After centrifugation (4000 rpm, 15 min), take 80 μL of the supernatant and add it to a 96 - well plate pre - filled with 160 μL of ultrapure water, and analyze using LC - MS / MS.

[0341] Calculate T according to the following formula 1 / 2 and CLint, where the slope is measured using the percentage of the remaining compound and the natural logarithm of time, and V / M is equal to 1 / protein concentration.

[0342]

[0343] The results are shown in Table 2:

[0344] Table 2 Results of the stability experiments of the compounds in mouse and human liver microsomes

[0345]

[0346]

[0347] It can be seen from the experimental results that: the formylpiperidine compounds provided by the present invention have good stability in the stability experiments of human and mouse liver microsomes, and their metabolic stability is equivalent to or better than that of the positive control drug vilazodone. Among them, the metabolic stability of compounds IV - 2 and V - 2 in human and mouse liver microsomes is significantly better than that of vilazodone.

[0348] In - vivo antidepressant results of the compound in Example 28

[0349] The tail suspension test and forced swimming test of mice in the "behavioral despair model" and the learned helplessness model were used. Vilazodone was used as the positive control drug to preliminarily study the in vivo antidepressant effects of compounds with 5-HT reuptake and 5-HT 1A dual activity.

[0350] 1. Mouse tail suspension test

[0351] Experimental method:

[0352] 156 male ICR mice were evenly and randomly divided into 10 groups according to body weight: blank control group, positive drug group (vilazodone) (30.0 mg / kg), compound test groups (30.0 mg / kg). They were administered by gavage at 10 ml / kg, and the blank control group was given the same volume of normal saline. Among them, the compound test groups selected compounds I-1, I-2, I-3, II-1, II-2, IV-1, IV-2, V-1, and V-2 prepared in the above examples.

[0353] One hour after administration, the mouse's tail was fixed with medical tape about 2 cm from the end, and the mouse was hung upside down in the tail suspension box, with its head about 5 cm from the bottom of the box. After the mouse was suspended for 2 minutes, observation immediately began. The observation lasted for 4 minutes, and the immobile time of the mouse within these 4 minutes was accumulated (the mouse stopped struggling in the air or only had minor limb movements). The improvement rate was calculated using the formula:

[0354]

[0355] The results are shown in Table 3:

[0356] Table 3 Effects of single oral administration of compounds on mouse tail suspension test

[0357]

[0358] * Compared with the blank group, P < 0.05, there was a significant difference; ** compared with the blank group, P < 0.01, there was a highly significant difference.

[0359] Note: P represents the statistical deviation.

[0360] In the mouse tail suspension test, all of the above 9 compounds could significantly shorten the immobile time of the suspended mouse. At the dose of 10 mg / kg, the pharmacodynamic effects of 7 compounds such as IV-2 and V-2 were stronger than those of the positive drug vilazodone at the same dose, and there was a highly significant difference compared with the blank group, indicating that the above compounds all have strong in vivo antidepressant activity.

[0361] 2. Mouse Forced Swimming Test

[0362] Experimental method:

[0363] 156 male ICR mice were evenly and randomly divided into 10 groups according to body weight: blank control group, vilazodone (20.0 mg / kg), compound test groups (5.0 mg / kg). They were given intragastric administration at 10 ml / kg, and the blank control group was given the same volume of normal saline. Among them, the compound test groups selected compounds I-1, I-2, I-3, II-1, II-2, IV-1, IV-2, V-1, and V-2 prepared in the above examples.

[0364] One day before the experiment, the mice were pre-screened by swimming. The mice were placed in a glass cylinder with a water depth of 10 cm (height 20 cm, diameter 14 cm), the water temperature was 25 °C, and they were allowed to swim for 6 min. Animals with a stop swimming time between 70 - 160 seconds were selected for the formal experiment. Mice in each group were given corresponding drugs continuously for one week. One hour after the last administration, the mouse swimming experiment was carried out. The animals were placed in the above environment to swim for 6 min, and the cumulative time that the mice stopped swimming and remained motionless in the last 4 min within 6 min was recorded. The t-test method was used for statistical processing of the data. The results are shown in Table 4:

[0365] Table 4 Results of oral administration for one week on mouse forced swimming test

[0366]

[0367] * Compared with the blank group, P < 0.05, there was a significant difference; ** compared with the blank group, P < 0.01, there was a highly significant difference. Note: P represents the statistical deviation.

[0368] In the mouse forced swimming test, the above 9 compounds could significantly shorten the immobile time of the mice during swimming. The pharmacological effects of 6 compounds such as IV-2 and V-2 were stronger than those of the positive drug at a lower dose than the positive drug, and there was a highly significant difference compared with the blank group, indicating that the formylpiperidine compounds provided by the present invention have strong in vivo antidepressant activity and potential higher safety.

[0369] 3. Learned Helplessness Experiment

[0370] 3.1 Principle

[0371] This model is an animal model of depression. When the animal is placed in an inescapable aversive stimulus environment, it will produce a despair behavior, manifested as no longer avoiding the stimulus and interfering with subsequent adaptive responses. At this time, the catecholamine level in the animal's brain decreases, which is recognized as a depressive state, and antidepressants can counteract this state. The learned helplessness model is sensitive to various antidepressants used for sub-chronic (3 - 7 days), including tricyclic antidepressants, monoamine oxidase inhibitors, monoamine reuptake inhibitors, and atypical antidepressants.

[0372] 3.2 Experimental method

[0373] The animals were grouped. On the first day, inescapable electroshock was performed to make pre-shock animals. The pre-shock animals received foot electrostimulation of 0.8 mA x 15 s, once per minute, for a total of 60 times. The control group rats were only placed in the box without electrostimulation for the same time. Medication started on the second day. The medication groups were divided into a positive drug group (vilazodone: 60 mg / kg and venlafaxine: 30 mg / kg), IV - 2, V - 2: 10, 5, 2.5 mg / kg, and they were continuously administered for one week. 24 h after the last administration, a conditioned avoidance experiment was performed. The measured indexes were the number of successful avoidances and the latency of escape.

[0374] 3.3 Results

[0375] As shown in Table 5, in the conditioned avoidance experiment one week later, the escape latency of the animals in the normal control group was significantly shortened, and the number of successful avoidances was very high; after the inescapable electroshock stimulation, the animals in the model group showed obvious despair behavior, the escape latency was significantly prolonged, and the number of successful avoidances was greatly reduced; vilazodone (60 mg / kg), venlafaxine (30 mg / kg), and IV - 2, V - 2 at two doses (5 mg / kg and 10 mg / kg) significantly shortened the escape latency, and the number of successful avoidances was significantly increased. It shows that IV - 2 and V - 2 can counteract this depressive state, and the effective dose is lower than that of the marketed drugs vilazodone and venlafaxine (5 - HT / NA dual reuptake inhibitors).

[0376] Table 5 Results of the learned helplessness experiment in rats (n = 10)

[0377]

[0378] * Compared with the blank group, P < 0.05, there is a significant difference; ** compared with the blank group, P < 0.01, there is a highly significant difference. Note: P represents the statistical deviation.

[0379] Example 29 Acute toxicity test

[0380] Test animals: 20 ICR mice, 10 males and 10 females.

[0381] Test method: The approximate LD reported on page 1814 of "Modern Pharmacological Experimental Methods" edited by Zhang Juntian and published by the United Publishing House of China Medical University and Peking Union Medical College in 1998 was adopted. 50 Determination method, preliminary screening, and statistical analysis using the Bliss method.

[0382] Results: The LD50 values of compounds IV-2 and V-2 after single oral administration to mice were 50 2300 mg / kg and 2500 mg / kg respectively, and the LD50 of the positive drug vilazodone was 50 2000 mg / kg. The compounds of the present invention have better safety.

[0383] Example 30 Bacterial Reverse Mutation Test

[0384] Bacterial strains: Salmonella typhimurium histidine auxotrophic mutant strains TA97, TA98, TA100, and TA102.

[0385] Test method: The method reported in the literature of Maron DM et al: (1983) Mutay Res. 113, 173-216 was adopted.

[0386] Results: The experiment included two parts: -S9 and +S9. In the -S9 test system, TA98 and in the +S9 test system, TA97 had antibacterial effects at 5000 μg / plate. Other doses had no antibacterial effects on all strains, and the growth background was good. At all tested doses, whether in the -S9 or +S9 experimental systems, IV-2 and V-2 did not cause any significant increase in the number of revertant colonies, and the Ames test was negative.

[0387] The experimental results suggest that compounds IV-2 and V-2 have no mutagenic effects and a low risk of genetic toxicity.

[0388] Example 31 Antidepressant Pharmaceutical Composition 1

[0389] The compound V-1 prepared in Example 23 was mixed with a filler and a disintegrant, granulated, and tabletted to obtain Pharmaceutical Composition 1 with compound V-1 as the active ingredient.

[0390] Example 32 Antidepressant Pharmaceutical Composition 2

[0391] The compound V-2 prepared in Example 24 was mixed with water, filtered, and packaged to obtain Pharmaceutical Composition 2 with compound V-2 as the active ingredient.

[0392] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A formylpiperidine compound or a pharmaceutically acceptable salt thereof, with the general structural formula shown as formula (I); Wherein, R1 is selected from halogen or cyano; R2 is selected from hydrogen, methyl or propyl; A is selected from the following groups: Wherein R3, R4, R5, R6, R7, R3’, R4’, R5’, R6’, R3” are independently selected from H, halogen, unsubstituted hydrocarbon group, unsubstituted alkoxy group, unsubstituted amide group or cyano; the unsubstituted hydrocarbon group is selected from hydrocarbon groups with 6 or fewer carbon atoms; The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy; There are not more than two unsubstituted amide groups or cyano groups simultaneously among R3, R4, R5, R6, R7; there are not more than two unsubstituted amide groups or cyano groups simultaneously among R3’, R4’, R5’, R6’; m and n are independently selected from 0, 1, 2, 3 or 4.

2. The formylpiperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The halogen is selected from F or Cl.

3. The formylpiperidine compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salts include acid addition salts formed by the compound shown in formula (I) and one or more of the following acids: hydrochloric acid, oxalic acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, benzenesulfonic acid, phosphoric acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid and mandelic acid.

4. The formylpiperidine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, Selected from the following compounds:

5. A preparation method of the formylpiperidine compound according to any one of claims 1-4, comprising the following steps: The intermediate compound of formula (V) and the intermediate compound of formula (VI) are subjected to a condensation reaction to obtain the compound of formula (I); Wherein, R1, R2, A, m, n are defined as in any one of claims 1-4; Y is selected from halogen or p-toluenesulfonyloxy.

6. The preparation method according to claim 5, characterized in that, The preparation method of the intermediate compound of formula (V) comprises the following steps: The intermediate compound of formula (II) and the intermediate compound of formula (III) carry out a first reaction to generate the intermediate compound of formula (IV); the intermediate compound of formula (IV) is deprotected from Boc to obtain the intermediate compound of formula (V); Wherein, X is selected from halogen or hydroxyl.

7. The preparation method according to claim 5 or 6, characterized in that, The preparation method of the intermediate compound of formula (VI) comprises: (a) When Y is halogen, the preparation method of the intermediate compound of formula (VI) comprises the following steps: Under the protection of an inert gas, the intermediate compound of formula (VIII) and the intermediate compound of formula (IX) carry out a second reaction to obtain the intermediate compound of formula (VII); the intermediate compound of formula (VII) is reduced to obtain the intermediate compound of formula (VI); (b) When Y is p-toluenesulfonyloxy, the preparation method of the intermediate compound of formula (VI) comprises the following steps: 4-Fluorophenylhydrazine hydrochloride solution and 3,4-dihydro-2H-pyran carry out a third reaction to obtain the intermediate compound of formula (X); the intermediate compound of formula (X) and 4-p-toluenesulfonyl chloride carry out a substitution reaction to obtain the intermediate compound of formula (VI); 8. The preparation method according to claim 5, characterized in that, The reaction temperature of the condensation reaction is 80°C to 105°C.

9. The preparation method according to claim 6, characterized in that, In the first reaction, the intermediate compound of formula (III) is added to an excess of the intermediate compound of formula (II), and the reaction is carried out at -5°C to 5°C.

10. The preparation method according to claim 7, characterized in that, In the second reaction, the intermediate compound of formula (VIII) is added to an excess of the intermediate compound of formula (VII); And / or, in the third reaction, 3,4-dihydro-2H-pyran is added to an excessive amount of 4-fluorophenylhydrazine hydrochloride, and the reaction is carried out at 90 °C to 120 °C.

11. A pharmaceutical composition, characterized in that, Comprising at least one active ingredient and one or more pharmaceutically acceptable excipients; the active ingredient comprises the formylpiperidine compound according to any one of claims 1-4 or the formylpiperidine compound obtained by the preparation method according to any one of claims 5-10.

12. Use of the formylpiperidine compound according to any one of claims 1-4, the formylpiperidine compound prepared by the method according to any one of claims 5-10, or the pharmaceutical composition according to claim 11 in the preparation of an antidepressant drug.

13. The application according to claim 12, wherein The antidepressant drug is an antidepressant drug that inhibits the SSRI and 5-HT 1A targets.

Images