CN110511174B - Indolylalkyl piperazine compound and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, relates to an indolyl alkyl piperazine compound and application thereof, and particularly relates to indolyl alkyl piperazine derivative p-5-HT _1A Affinity and action characteristics of receptor and its application in preparing medicine for treating nervous system diseases, especially 5-HT _1A The application in the field of medicines for treating receptor-related nervous system diseases. The indole alkyl piperazine compound has a structure shown in a general formula (I):

wherein R is ₁ 、R ₂ 、R ₃ The definitions of m and n are shown in the specification. The compounds can be used as selective 5-HT _1A Receptor agonists are used for the preparation of medicaments for the treatment of neurological and psychiatric disorders associated with the brain, such as anxiety, depression, schizophrenia and parkinson's disease.

Description

Indole alkyl piperazine compound and application thereof

Technical Field

The present invention relates to the field of medical technology, and relates to indolealkylpiperazine compounds and applications thereof, and specifically to the affinity and action characteristics of indolealkylpiperazine derivatives for 5- _HT1A receptors and their applications in the preparation of drugs for nervous system diseases, especially drugs for nervous system diseases related to 5- _HT1A receptors.

Background Art

Studies have shown that 5-hydroxytryptamine (5-HT), as an important neurotransmitter, participates in the regulation and mediation of a variety of physiological effects through at least 16 different receptor subtypes. According to different pharmacological and functional standards, these receptor subtypes are divided into 7 different subfamilies (5-HT _1-7 ), among which 5-HT _1A receptor is the first receptor to be fully sequenced and widely studied. Studies have shown that 5-HT _1A receptor participates in the regulation of a variety of physiological effects, and its functional disorder can cause a variety of central nervous system diseases.

Anxiety, also known as anxiety neuropathy, is the most common type of neurosis, characterized by the experience of anxiety. According to different external symptoms, anxiety disorders can be divided into two forms: chronic anxiety (generalized anxiety) and acute anxiety (panic disorder). At present, the representative drugs for the treatment of anxiety are mainly 5-HT _1A receptor agonists, such as buspirone. Although the specific mechanism of action has not yet been clarified, it is generally believed that in addition to the presynaptic 5-HT _1A receptor, the 5-HT _1A receptor distributed in the postsynaptic membrane of the limbic area (hippocampus, amygdala, lateral septum) plays a key role in regulating anxiety. The hippocampus and amygdala are the main control areas for regulating emotions and relieving stress, while the lateral septum can transmit nerve impulses from the limbic area to the hypothalamus as a transit station, thereby regulating various physiological responses. 5-HT _1A receptor agonists are believed to inhibit the activity of neurons in the hippocampus and lateral septum by activating G-protein-gated inwardly rectifying potassium ion channels (GIRK), thereby relieving anxiety symptoms.

Depression, also known as depressive disorder, is characterized by significant and persistent low mood as the main clinical symptom. Depending on the severity of the disease, its main clinical manifestations range from melancholy to depression to inferiority and depression, and even pessimism and world-weariness, and finally lead to suicidal behavior. Some patients also have psychiatric symptoms such as anxiety, hallucinations, and delusions. Currently, the main clinical therapeutic drugs include 5-HT _1A receptor agonists, 5-HT reuptake inhibitors (SSRIs), and the combination of the two. Although the specific mechanism of 5-HT _1A receptor agonists in the treatment of depression is unclear, the more recognized view is that the presynaptic 5-HT _1A receptor is desensitized or downregulated, that is, repeated treatment with 5-HT _1A receptor agonists causes the desensitization of the presynaptic 5-HT _1A receptor in the raphe nucleus, thereby relieving the 5-HT neurons that are inhibited by autoreceptor regulation, and ultimately leading to the activation of 5-HT neurons, alleviating the lack of 5-HT in anxiety symptoms. At the same time, the combined use of 5-HT _1A receptor agonists and SSRIs not only alleviates the problem of slow onset of SSRIs alone, but also improves the potential therapeutic effect and accelerates the desensitization of autoreceptors. Vilazodone, a drug approved by the FDA in 2011 for the treatment of major depressive disorder, has 5-HT _1A receptor agonist and 5-HT reuptake inhibitor activity.

Schizophrenia is the most common persistent and chronic major mental illness, with clinical manifestations of positive symptoms and negative symptoms. The former includes hallucinations, delusions, chorea, etc.; the latter mainly refers to cognitive impairment, learning and memory disorders, working memory disorders, etc. With the increasing pressure of work and life, mental problems have a serious adverse impact on the entire society. The early first-generation antipsychotic drugs mainly treat positive symptoms, have poor efficacy on negative symptoms, and have a high incidence of extrapyramidal symptoms (EPS), which are also called classic antipsychotics. Non-classical antipsychotics not only work on positive symptoms, but also have a good therapeutic effect on negative symptoms and can reduce extrapyramidal side effects, but they have no obvious advantages in treating cognitive impairment. Studies have shown that 5-HT _1A receptor agonists can reduce EPS caused by antipsychotic drugs by activating 5-HT _1A receptors in the postsynaptic membrane of the striatum and prefrontal cortex through non-dopaminergic pathways. At the same time, 5-HT _1A receptor antagonists can improve cognitive function by blocking the 5-HT _1A receptors located in the postsynaptic membrane of the medial accumbens or the nucleus of the diagonal zone to relieve the level of acetylcholine or glutamate. Among the current drugs for the treatment of schizophrenia, non-classical antipsychotic drugs with multiple activities such as aripiprazole and ziprasidone all have hypocritical 5-HT _1A receptor activity.

Parkinson's disease (PD), also known as tremor paralysis, is one of the most common neurodegenerative diseases. Clinically, it is mainly characterized by resting tremor, muscle rigidity, bradykinesia and postural reflex disorders. PD not only has a high incidence rate, but is also a lifelong disease. As the onset progresses, patients gradually lose their ability to live and work, and develop non-motor complications such as cognitive impairment and mental confusion, which seriously affect their quality of life. Patients need to take medication for a long time, which brings a heavy burden to their families and society. At present, levodopa (L-DOPA) is the most effective PD treatment drug. It works by converting dopamine into dopamine in the body through dopa decarboxylase. However, since it can cause symptom fluctuations and movement disorders, it is generally hoped that the application of levodopa will be postponed. L-DOPA combined with 5-HT _1A receptor agonists is believed to be able to effectively alleviate the occurrence of movement syndrome. Although the specific mechanism of action remains to be explored, current pharmacological experiments have shown that: 1) L-DOPA may be taken up by serotonin neurons, then converted into dopamine and released into the synaptic cleft. 2) The release of dopamine from serotonin neurons is most likely inhibited by 5-HT _1A receptor agonists through negative feedback regulation, thus ensuring the normal dopamine content in the body.

Based on the current status of the prior art, the inventors of this application intend to develop a 5-HT _1A receptor agonist with a novel structure, clear action, and small toxic and side effects, specifically involving an indolealkylpiperazine compound and its application, which may be made into a drug for the treatment of central nervous system diseases such as anxiety, depression, schizophrenia, Parkinson's disease, etc.

Summary of the invention

The object of the present invention is to provide a class of novel indolealkylpiperazine compounds having affinity for 5-HT _1A receptors, especially capable of serving as 5-HT _1A receptor agonists.

Another object of the present invention is to provide a method for preparing the indolealkylpiperazine compound.

The present invention also aims to provide the use of the above compounds in treating neurological and psychiatric diseases related to the brain, such as anxiety, depression, schizophrenia and Parkinson's disease.

The present invention provides an indolealkylpiperazine compound (or "indolealkylpiperazine derivative") represented by the following general formula (I) and its pharmacologically acceptable inorganic or organic salt, crystalline hydrate:

in:

m, n are independently selected from 0, 1, 2, 3 or 4; preferably, m is selected from 1 or 2; n is selected from 3;

The substituent R ₁ is selected from hydrogen, halogen, C ₁ -C ₆ substituted or unsubstituted alkyl, C ₁ -C ₆ substituted or unsubstituted alkoxy, hydroxyl, cyano, preferably F, Cl, hydroxyl, methoxy, cyano;

The substituent R ₂ is absent or located at least one of the 2, 3, 4, 5, and 6 positions, and is unsubstituted, monosubstituted, disubstituted, or polysubstituted. The substituent R ₂ is selected from one, two, or more of the following groups: hydrogen, halogen, nitro, hydroxyl, carboxyl, cyano, amino, C ₁ -C ₆ substituted or unsubstituted alkyl, C ₁ -C ₆ substituted or unsubstituted alkoxy, -SO ₂ CH ₃ group; when R ₂ is disubstituted or trisubstituted, the substituents may be the same or different; preferably, the substituent R ₂ is absent or located at the 4 position, and is methoxy, F, or mesyl;

The substituent _R3 is selected from H, _C1 - _C6 substituted or unsubstituted alkyl, _C3 - _C7 substituted or unsubstituted cycloalkyl or HetAr1, preferably _C5 - _C6 alkyl, 4-methoxycyclohexyl, 4-tetrahydro-2-H-pyranyl, 4-oxocyclohexyl, 4-piperidinyl, hydroxyethyl, hydroxypropyl, 1-methoxy-2-propyl, 1,2-dimethoxy-ethyl;

Unless otherwise specified, the C ₁ -C ₆ alkyl (C ₁ -C ₆ unsubstituted alkyl) described in the present invention is a C ₁ -C ₆ straight or branched alkyl, and refers to an alkyl containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl. C ₁ -C ₆ substituted alkyl means that the C ₁ -C ₆ alkyl may be substituted by 1 to 2 identical or different groups selected from hydroxyl, halogen, C ₁ -C ₃ alkoxy.

Unless otherwise specified, the C ₁ -C ₆ alkoxy group (C ₁ -C ₆ unsubstituted alkoxy group) described in the present invention is a C ₁ -C ₆ straight or branched alkoxy group, which refers to an alkoxy group containing 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy. C ₁ -C ₆ substituted alkoxy groups refer to C ₁ -C ₆ alkoxy groups that may be substituted by 1 to 2 identical or different groups selected from hydroxyl and C ₁ -C ₃ alkoxy groups.

Unless otherwise specified, the C ₃ -C ₇ cycloalkyl (C ₃ -C ₇ unsubstituted cycloalkyl) described in the present invention refers to a cycloalkyl group containing 3-7 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylcyclopentyl, and cyclopropylcyclohexyl. C ₃ -C ₇ substituted cycloalkyl means that the C ₃ -C ₇ cycloalkyl group may be substituted by 1-2 identical or different groups selected from halogen, carbonyl, hydroxyl and C ₁ -C ₃ alkoxy.

Unless otherwise specified, the C ₁ -C ₃ alkoxy group described in the present invention refers to a C ₁ -C ₃ straight-chain or branched alkoxy group, and refers to an alkoxy group containing 1 to 3 carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, and isopropoxy.

Unless otherwise stated, HetAr1 according to the present invention represents a saturated, unsubstituted 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring having 1, 2 or 3 N and/or O and/or S atoms.

Unless otherwise indicated, the term halogen refers to a substituent of the halogen family including, but not limited to, fluorine, chlorine, bromine, or iodine.

The terms "polysubstituted" and "multiple" in the present invention refer to three or more types, and the following also have the same meaning.

As one of the best embodiments, the indolealkylpiperazine derivatives of the present invention are the following specific compounds:

N-(3-pentyl)-2-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-hexyl)-2-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-pentyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-hexyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-hexyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(4-methoxycyclohexyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-pentyl)-2-(4-(3-(5-fluoro-1H-3-indol)propyl)-1-piperazinyl)-N-(5-fluorophenyl)acetamide,

N-(2-pentyl)-2-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-(5-methoxyphenyl)acetamide,

N-(2-pentyl)-2-(4-(3-(5-fluoro-1H-3-indol)propyl)-1-piperazinyl)-N-(5-methylsulfonylphenyl)acetamide,

N-(2-pentyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-pentyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-hexyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-hexyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(4-methoxycyclohexyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-pentyl)-3-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-3-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-hexyl)-3-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-hexyl)-3-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(4-methoxycyclohexyl)-3-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-2-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-hexyl)-2-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-hexyl)-2-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-pentyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-hexyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-hexyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(4-methoxycyclohexyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-2-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-hexyl)-2-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-hexyl)-2-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-pentyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-hexyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-hexyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(4-methoxycyclohexyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-hexyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(3-hexyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(4-methoxycyclohexyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-pentyl)-3-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-pentyl)-3-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-hexyl)-3-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(3-hexyl)-3-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(4-methoxycyclohexyl)-3-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide,

N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-(5-fluorophenyl)acetamide,

N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-(5-methoxyphenyl)acetamide,

N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-(5-methylsulfonylphenyl)acetamide,

N-(4-tetrahydro-2-H-pyranyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(4-oxocyclohexyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(4-piperidinyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-ethanol)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(2-propanol)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(1-methoxy-2-propyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

N-(1,2-dimethoxy-ethyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide,

The indolealkylpiperazine derivatives also include pharmaceutically acceptable salts, solvates, precursor compounds or polymorphs thereof.

In the present invention, the pharmaceutically acceptable salt, solvate, prodrug or polymorph is characterized in that the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt;

The inorganic salt may be sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromide or nitrate;

The organic salt may be maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate;

The amino acid salt is arginine, ornithine, lysine, leucine, isoleucine, glycine, cystine, cysteine, tyrosine, alanine, phenylalanine, histidine, serine, threonine, methionine, tryptophan, glutamate, aspartate, valine, methionine, proline or hydroxyproline.

To achieve the above second purpose, the technical solution adopted by the present invention is:

The preparation method of the indole alkyl piperazine derivatives can be synthesized by the following process, comprising the following steps:

Preparation of intermediate 2

Compound 1 reacts with 3,4-dihydropyran at 150° C. in the presence of 4% sulfuric acid to generate compound 2 via Fisher indole synthesis. Compound 2d reacts with cuprous cyanide at 80° C. in N,N-dimethylformamide solvent to generate compound 2e.

Preparation of intermediate 3

Compound 2 reacts with carbon tetrabromide and triphenylphosphine in a dichloromethane solvent to generate compound 3. Compound 3b reacts with boron tribromide in a dichloromethane solvent at -78°C to generate compound 3c.

Preparation of intermediate 5

Compound 4 reacts with a ketone compound corresponding to the R ₃ group and zinc powder activated by hydrochloric acid at 75°C in water under the acidic condition of acetic acid to generate compound 5.

Preparation of intermediate 6

Compound 5 reacts with the corresponding chloroacyl chloride in dichloromethane solvent under alkaline conditions of triethylamine to generate compound 7.

Preparation of intermediate 7

Compound 6 reacts with N-Boc-piperazine at 85°C in acetonitrile solvent under alkaline conditions of potassium carbonate to generate compound 7

Preparation of intermediate 8

Compound 7 reacts with trifluoroacetic acid in dichloromethane solvent to generate compound 8.

Preparation of Compound Ⅰ

Compound 3 reacts with compound 8 in acetonitrile solvent under alkaline conditions of potassium carbonate to generate compound I.

It should be understood that the specific _R1 listed in the above reaction scheme is for example only, and _R1 in the structural formula is not limited thereto, but also includes all R1 mentioned above.

Among them, the preparation method of the pharmaceutically acceptable salt of indolealkylpiperazine derivatives can be prepared according to conventional methods in the art. The compounds of the present invention are usually isolated as is, or in the form of their pharmaceutically acceptable salts, for example, by reacting with inorganic salts, organic salts or amino acid salts under conventional conditions.

The following pharmacological test results illustrate the biological activity of the compounds included in the present invention on serotonin receptors:

1. Compound affinity experimental method: Radioligand binding assay

Compound functional assay method: [ ³⁵ S]GTPγS binding assay

2. The experimental results are shown in Tables 1 and 2:

Table 1 Compound affinity test results

In Table 1, in the column "Inhibition rate %/Ki nM", the data expressed as percentages refer to inhibition rate %, and all other data refer to KinM.

In Table 1, Cis means that the two substituent groups on the cyclohexane are on the same side, and Trans means that the two substituent groups on the cyclohexane are on opposite sides.

In Table 1, - means inactive.

Table 2 Functional test results of some compounds

The results showed that all new compounds showed a certain degree of ability to replace 5-HT _1A receptor isotope ligands and had high 5-HT _1A receptor selectivity. Some compounds showed high 5-HT _1A receptor full agonist activity.

The above compounds of the present invention can be used as lead compounds to further develop 5-HT _1A receptor compounds with good selectivity and high activity, and can be used to prepare potential drugs as 5-HT _1A receptor agonists for treating anxiety, depression, schizophrenia, Parkinson's disease and other diseases.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.

¹ H-NMR was measured with a Varian Mercury Plus 400 Hz instrument; MS was measured with an Agilent 6120 Quadrupole LC/MS. All solvents were redistilled before use, and the anhydrous solvents used were obtained by drying according to standard methods. Unless otherwise specified, all reactions were tracked by TLC, and post-treatments were washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Products were purified by silica gel (200-300 mesh) column chromatography unless otherwise specified; the silica gel (200-300 mesh) was produced by Qingdao Ocean Chemical Plant, and the TLC plate was Qingdao Ocean 0.2 mm GF245 high-efficiency thin-layer chromatography silica gel plate.

Example 1: Preparation of N-(2-pentyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide (FWⅠ-01)

Step 1: Preparation of 3-(5-fluoroindole)propanol (Intermediate 2a)

At room temperature, 4-fluorophenylhydrazine hydrochloride (5g, 3.07×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (3.36ml, 3.7×10 ^{- 2} mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA＝20:1) was performed to obtain 4.56g of a reddish brown oil with a yield of 76%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-fluoroindole (Intermediate 3a)

At 0°C, in a 100ml dry three-necked flask, the intermediate 2a (1g, 3.73×10 ^-3 mol) was dissolved in 30ml of anhydrous dichloromethane, followed by the addition of carbon tetrabromide (1.08ml, 1.11×10 ^-2 mol) and triphenylphosphine (2.91g, 1.11×10 ^-2 mol). 20ml of water was then added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝20:1) to obtain 0.72g of a gray-black oily liquid with a yield of 76%.

Step 3: Preparation of N-(2-pentyl)aniline (Intermediate 5a)

Aniline (1ml, 1.09×10 ^-2 mol), 2-pentanone (0.94g, 1.09×10 ^-2 mol), acetic acid (25ml) and water (2.5ml) were added to a 100ml single-necked flask, and zinc powder activated by hydrochloric acid was added in batches under stirring, and then the temperature was transferred to 75°C and refluxed at this temperature for 12h. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to a weak alkaline environment with ammonia water in an ice bath, pH ≈ 10, and extracted three times with 50ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA = 50: 1) was performed to obtain 1.65g of yellow oil, with a yield of 92.2%.

Step 4: Preparation of N-(2-pentyl)-N-phenyl-3-chloropropionamide (Intermediate 6a)

In a single-necked flask, the intermediate 5a (2.5 g, 1.5 × 10 ^-2 mol) and triethylamine (2.54 ml, 1.83 × 10 ^-2 mol) were dissolved in 50 ml of anhydrous dichloromethane. A dichloromethane solution containing 3-chloropropionyl chloride (1.79 ml, 1.83 × 10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75 ° C and the reaction was continued for 8 hours. After the reaction was completed, 30 ml of dichloromethane was added, and the mixture was washed three times with 30 ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 30:1) to obtain 2.91 g of a white solid with a yield of 76.4%.

Step 5: Preparation of N-(2-pentyl)-3-(4-Boc-1-piperazinyl)-N-phenylpropanamide (Intermediate 7a)

Dissolve the intermediate 6a (5 g, 1.97×10 ^-2 mol) and N-Boc-piperazine (3.67 g, 1.97×10 ^-2 mol) in acetonitrile, then add potassium carbonate (3.27 g, 2.36×10 ^-2 mol), raise the temperature to 85°C, and maintain the reaction for 8 hours. After the reaction is completed, remove the acetonitrile under reduced pressure, then add 30 ml of water, and extract three times with 30 ml of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and column chromatography (DCM:MeOH=50:1) to obtain 7.01 g of light yellow solid with a yield of 88.1%.

Step 6: Preparation of N-(2-pentyl)-3-(1-piperazinyl)-N-phenylpropanamide trifluoroacetate (Intermediate 8a)

In a single-necked flask, the intermediate 7a (5 g, 1.24×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 4.12 g of a white solid was obtained with a yield of 91.3%.

Step 7: Preparation of N-(2-pentyl)-3-(4-(3-(5-fluoro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide

At room temperature, intermediate 8a (1 g, 2.75×10 ^-3 mol) and intermediate 3a (0.96 g, 2.75×10 ^-3 mol) and potassium carbonate (0.76 g, 5.54×10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM:MeOH=10:1) to obtain 1.05 g of a white solid with a yield of 79.5%.

Example 2-8: Compounds FWI-02-FWI-08

Example 1 was repeated, except that different raw materials were used in step 3 and different raw materials were used in step 5 to prepare compounds FWI-02-FWI-08. Compounds FWI-02 and FWI-03 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 by column chromatography (PE:EA=30:1).

The details are shown in the following table:

Step 3:

Step 5:

Examples 9-11: Compounds FWI-09-FWI-11

Example 1 was repeated, except that different raw materials were used in step 3 to prepare compounds FWI-09-FWI-11. The specific details are as follows:

Example 12: Preparation of N-(2-pentyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide (FW I-12)

Step 1: Preparation of 3-(5-chloroindole)propanol (Intermediate 2c)

At room temperature, 4-chlorophenylhydrazine hydrochloride (5g, 2.79×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (4.46ml, 2.79×10 ^{- 2} mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 4.20g of an oily substance with a yield of 72%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-chloroindole (Intermediate 3d)

At 0°C, in a 100ml dry three-necked flask, the intermediate 2c (1g, 4.78×10 ^-3 mol) was dissolved in 30ml of anhydrous dichloromethane, followed by the addition of carbon tetrabromide (0.84ml, 1.43×10 ^-2 mol) and triphenylphosphine (2.26g, 1.43×10 ^-2 mol). 20ml of water was then added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝20:1) to obtain 1.00g of a gray-black oily liquid with a yield of 77%.

Step 3: Preparation of N-(2-pentyl)aniline (Intermediate 5a)

Aniline (2.94g, 0.03mol), 2-pentanone (2.58g, 0.03mol), acetic acid (25ml) and water (2.5ml) were added to a 100ml single-necked flask, and zinc powder activated by hydrochloric acid was added in batches under stirring, and then the mixture was transferred to 75°C and refluxed at this temperature for 12h. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to a weak alkaline environment with ammonia water in an ice bath, pH ≈ 10, and extracted three times with 50ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA＝50:1) was performed to obtain 3.06g of yellow oil, with a yield of 62.6%.

Step 4: Preparation of N-(2-pentyl)-N-phenyl-2-chloroacetamide (Intermediate 6a)

In a single-necked flask, the intermediate 5a (5g, 3.07×10 ^-2 mol) and triethylamine (4.74ml, 3.42×10 ^-2 mol) were dissolved in 50ml of anhydrous dichloromethane. A dichloromethane solution containing chloroacetyl chloride (2.72ml, 3.42×10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75°C and the reaction was continued for 8h. After the reaction was completed, 30ml of dichloromethane was added, and the mixture was washed three times with 30ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝30:1) to obtain 6.6g of a white solid with a yield of 90.3%.

Step 5: Preparation of N-(2-pentyl)-2-(4-Boc-1-piperazinyl)-N-phenylacetamide (Intermediate 7a)

Dissolve the intermediate 6a (6 g, 2.51×10 ^-2 mol) and N-Boc-piperazine (4.20 g, 2.51×10 ^-2 mol) in acetonitrile, then add potassium carbonate (4.68 g, 3.76×10 ^-2 mol), raise the temperature to 85°C, and maintain the reaction for 8 hours. After the reaction is completed, remove the acetonitrile under reduced pressure, then add 30 ml of water, and extract three times with 30 ml of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and column chromatograph (DCM:MeOH=50:1) to obtain 7.5 g of a light yellow solid with a yield of 77%.

Step 6: Preparation of N-(2-pentyl)-2-(1-piperazinyl)-N-phenylacetamide trifluoroacetate (Intermediate 8a)

In a single-necked flask, the intermediate 7a (6 g, 1.54×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 6.08 g of a white solid was obtained with a yield of 98.0%.

Step 7: Preparation of N-(2-pentyl)-2-(4-(3-(5-chloro-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide

At room temperature, intermediate 8a (1 g, 2.48 × 10 ^-3 mol) and intermediate 3d (0.93 g, 2.85 × 10 ^-3 mol) and potassium carbonate (0.85 g, 4.96 × 10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM: MeOH = 10:1) to obtain 1.13 g of a white solid with a yield of 82.8%.

Examples 13-23: Compounds FWI-13-FWI-23

Example 12 was repeated, except that different raw materials were used in step 3 and different raw materials were used in step 5 to obtain compounds FWI-13-FWI-23. Compounds FWI-20 and FWI-21, FWI-22 and FWI-23 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 by column chromatography (PE:EA=30:1).

The details are as follows:

Step 3:

Step 5

Example 24: Preparation of N-(2-pentyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide (FW I-24)

Step 1: Preparation of 3-(5-methoxyindole)propanol (Intermediate 2b)

At room temperature, 4-methoxyphenylhydrazine hydrochloride (5g, 2.86×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (4.35ml, 2.86×10 ^-2 mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 4.63g of an oily substance with a yield of 79%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-methoxyindole (Intermediate 3b)

At 0°C, in a 100ml dry three-necked flask, the intermediate 2b (1g, 4.88×10 ^-3 mol) was dissolved in 30ml of anhydrous dichloromethane, followed by the addition of carbon tetrabromide (0.82ml, 1.46×10 ^-2 mol) and triphenylphosphine (2.21g, 1.46×10 ^-2 mol). 20ml of water was then added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝20:1) to obtain 0.93g of a gray-black oily liquid with a yield of 71%.

Step 3: Preparation of N-(2-pentyl)aniline (Intermediate 5a)

Aniline (1ml, 1.09×10 ^-2 mol), 2-pentanone (0.94g, 1.09×10 ^-2 mol), acetic acid (25ml) and water (2.5ml) were added to a 100ml single-necked flask, and zinc powder activated by hydrochloric acid was added in batches under stirring, and then the mixture was transferred to 75°C and refluxed at this temperature for 12h. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to a weak alkaline environment with ammonia water in an ice bath, pH ≈ 10, and extracted three times with 50ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA＝50:1) was performed to obtain 1.65g of yellow oil, with a yield of 92.2%.

Step 4: Preparation of N-(2-pentyl)-N-phenyl-3-chloropropionamide (Intermediate 6a)

In a single-necked flask, the intermediate 5a (2.5 g, 1.5 × 10 ^-2 mol) and triethylamine (2.54 ml, 1.83 × 10 ^-2 mol) were dissolved in 50 ml of anhydrous dichloromethane. A dichloromethane solution containing 3-chloropropionyl chloride (1.79 ml, 1.83 × 10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75 ° C and the reaction was continued for 8 hours. After the reaction was completed, 30 ml of dichloromethane was added, and the mixture was washed three times with 30 ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 30:1) to obtain 2.91 g of a white solid with a yield of 76.4%.

Step 5: Preparation of N-(2-pentyl)-3-(4-Boc-1-piperazinyl)-N-phenylpropanamide (Intermediate 7a)

Dissolve the intermediate 6a (5 g, 1.97×10 ^-2 mol) and N-Boc-piperazine (3.67 g, 1.97×10 ^-2 mol) in acetonitrile, then add potassium carbonate (3.27 g, 2.36×10 ^-2 mol), raise the temperature to 85°C, and maintain the reaction for 8 hours. After the reaction is completed, remove the acetonitrile under reduced pressure, then add 30 ml of water, and extract three times with 30 ml of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and column chromatography (DCM:MeOH=50:1) to obtain 7.01 g of light yellow solid with a yield of 88.1%.

Step 6: Preparation of N-(2-pentyl)-3-(1-piperazinyl)-N-phenylpropanamide trifluoroacetate (Intermediate 8a)

In a single-necked flask, the intermediate 7a (5 g, 1.24×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 4.12 g of a white solid was obtained with a yield of 91.3%.

Step 7: Preparation of N-(2-pentyl)-3-(4-(3-(5-methoxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide

At room temperature, intermediate 8a (1 g, 2.75×10 ^-3 mol) and intermediate 3b (0.99 g, 2.75×10 ^-3 mol) and potassium carbonate (0.76 g, 5.54×10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM:MeOH=10:1) to obtain 1.12 g of a white solid with a yield of 82.9%.

Examples 25-32: Compounds FWI-25-FWI-32

Example 24 was repeated, except that different raw materials were used in step 3 and different raw materials were used in step 5 to obtain compounds FWI-25-FWI-32. Compounds FWI-31 and FWI-32 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 by column chromatography (PE:EA=30:1).

The details are as follows:

Step 3:

Step 5:

Example 33: Preparation of N-(2-pentyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide (FW I-33)

Step 1: Preparation of 3-(5-methoxyindole)propanol (Intermediate 2b)

At room temperature, 4-methoxyphenylhydrazine hydrochloride (5g, 2.86×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (4.35ml, 2.86×10 ^-2 mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 4.63g of an oily substance with a yield of 79%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-hydroxyindole (Intermediate 3c)

[Step a] At 0°C, in a 100ml dry three-necked flask, the intermediate 2b (1g, 4.88×10 ^-3 mol) was dissolved in 30ml of anhydrous dichloromethane, followed by the addition of carbon tetrabromide (0.82ml, 1.46×10 ^-2 mol) and triphenylphosphine (2.21g, 1.46×10 ^-2 mol). 20ml of water was then added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA=20:1) to obtain 0.93g of a gray-black oily liquid with a yield of 71%.

[Step b] Under nitrogen protection, the oily substance (1g, 3.75×10 ^{- 3} mol) of the previous step was dissolved in 30ml of anhydrous dichloromethane in a 100ml dry three-necked flask, cooled to -40°C with a dry ice-ethyl acetate system, and then 3ml of boron tribromide dichloromethane solution was added with a glass syringe, slowly raised to 0°C, and the reaction was continued for 2 hours. After the reaction was completed, it was cooled to -40°C again, and water was slowly added dropwise to quench the reaction. Subsequently, 20ml of water was added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 0.77g of an oily liquid with a yield of 81%.

Step 3: Preparation of N-(2-pentyl)aniline (Intermediate 5a)

Aniline (1ml, 1.09×10 ^-2 mol), 2-pentanone (0.94g, 1.09×10 ^-2 mol), acetic acid (25ml) and water (2.5ml) were added to a 100ml single-necked flask, and zinc powder activated by hydrochloric acid was added in batches under stirring, and then the temperature was transferred to 75°C and refluxed at this temperature for 12h. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to a weak alkaline environment with ammonia water in an ice bath, pH ≈ 10, and extracted three times with 50ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE: EA = 50: 1) was performed to obtain 1.65g of yellow oil, with a yield of 92.2%.

Step 4: Preparation of N-(2-pentyl)-N-phenyl-3-chloropropionamide (Intermediate 6a)

In a single-necked flask, the intermediate 5a (2.5 g, 1.5 × 10 ^-2 mol) and triethylamine (2.54 ml, 1.83 × 10 ^-2 mol) were dissolved in 50 ml of anhydrous dichloromethane. A dichloromethane solution containing 3-chloropropionyl chloride (1.79 ml, 1.83 × 10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75 ° C and the reaction was continued for 8 hours. After the reaction was completed, 30 ml of dichloromethane was added, and the mixture was washed three times with 30 ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE: EA = 30:1) to obtain 2.91 g of a white solid with a yield of 76.4%.

Step 5: Preparation of N-(2-pentyl)-3-(4-Boc-1-piperazinyl)-N-phenylpropanamide (Intermediate 7a)

Dissolve the intermediate 6a (5 g, 1.97×10 ^-2 mol) and N-Boc-piperazine (3.67 g, 1.97×10 ^-2 mol) in acetonitrile, then add potassium carbonate (3.27 g, 2.36×10 ^-2 mol), raise the temperature to 85°C, and maintain the reaction for 8 hours. After the reaction is completed, remove the acetonitrile under reduced pressure, then add 30 ml of water, and extract three times with 30 ml of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and column chromatography (DCM:MeOH=50:1) to obtain 7.01 g of light yellow solid with a yield of 88.1%.

Step 6: Preparation of N-(2-pentyl)-3-(1-piperazinyl)-N-phenylpropanamide trifluoroacetate (Intermediate 8a)

In a single-necked flask, the intermediate 7a (5 g, 1.24×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 4.12 g of a white solid was obtained with a yield of 91.3%.

Step 7: Preparation of N-(2-pentyl)-3-(4-(3-(5-hydroxy-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylpropanamide

At room temperature, intermediate 8a (1 g, 2.75×10 ^-3 mol) and intermediate 3c (0.95 g, 2.75×10 ^-3 mol) and potassium carbonate (0.76 g, 5.54×10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM:MeOH=10:1) to obtain 1.08 g of a white solid with a yield of 82.4%.

Examples 34-41: Compounds FWI-34-FWI-41

Example 33 was repeated, except that different raw materials were used in step 3 and different raw materials were used in step 5 to obtain compounds FWI-34-FWI-41. Compounds FWI-40 and FWI-41 are a pair of cis-trans isomers, and their corresponding intermediates were obtained in step 4 by column chromatography (PE:EA=30:1).

The details are as follows:

Step 3:

Step 5:

Example 42: Preparation of N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide (FW I-42)

Step 1: Preparation of 3-(5-cyanoindole)propanol (Intermediate 2e)

[Step a] At room temperature, 4-bromophenylhydrazine hydrochloride (5g, 2.24×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (5.55ml, 2.86×10 ^-2 mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 4.36g of an oily substance with a yield of 77%.

[Step b] At room temperature, the oily substance (1g, 3.94×10 ^-3 mol) of the previous step was dissolved in N,N-dimethylformamide (50ml) in a single-necked flask, and cuprous cyanide (1.10g, 1.18×10 ^-2 mol) was added, and the reaction was heated to 130°C and maintained for 6h. After the reaction was completed, the reaction solution was poured into 100ml of water and extracted with 20ml of ethyl acetate 5 times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA=20:1) to obtain 0.71g of an oily substance with a yield of 90%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-cyanoindole (Intermediate 3e)

At 0°C, in a 100ml dry three-necked flask, the intermediate 2 (1g, 5.00×10 ^-3 mol) was dissolved in 30ml of anhydrous dichloromethane, followed by the addition of carbon tetrabromide (0.80ml, 1.50×10 ^-2 mol) and triphenylphosphine (2.15g, 1.50×10 ^-2 mol). 20ml of water was then added, and the mixture was extracted three times with 20ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝20:1) to obtain 0.93g of a gray-black oily liquid with a yield of 71%.

Step 3: Preparation of N-(2-pentyl)aniline (Intermediate 5a)

Aniline (2.94g, 0.03mol), 2-pentanone (2.58g, 0.03mol), acetic acid (25ml) and water (2.5ml) were added to a 100ml single-necked flask, and zinc powder activated by hydrochloric acid was added in batches under stirring, and then the mixture was transferred to 75°C and refluxed at this temperature for 12h. After the reaction was completed, the reaction solution was cooled to room temperature, and then adjusted to a weak alkaline environment with ammonia water in an ice bath, pH ≈ 10, and extracted three times with 50ml of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA＝50:1) was performed to obtain 3.06g of yellow oil, with a yield of 62.6%.

Step 4: Preparation of N-(2-pentyl)-N-phenyl-2-chloroacetamide (Intermediate 6a)

In a single-necked flask, the intermediate 5a (5g, 3.07×10 ^-2 mol) and triethylamine (4.74ml, 3.42×10 ^-2 mol) were dissolved in 50ml of anhydrous dichloromethane. A dichloromethane solution containing chloroacetyl chloride (2.72ml, 3.42×10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75°C and the reaction was continued for 8h. After the reaction was completed, 30ml of dichloromethane was added, and the mixture was washed three times with 30ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝30:1) to obtain 6.6g of a white solid with a yield of 90.3%.

Step 5: Preparation of N-(2-pentyl)-2-(4-Boc-1-piperazinyl)-N-phenylacetamide (Intermediate 7a)

Intermediate 6a (6 g, 2.51×10 ^-2 mol) and N-Boc-piperazine (4.20 g, 2.51×10 ^-2 mol) were dissolved in acetonitrile, and potassium carbonate (4.68 g, 3.76×10 ^-2 mol) was added. The temperature was raised to 85°C and the reaction was maintained for 8 hours. After the reaction was completed, the acetonitrile was removed under reduced pressure, and then 30 ml of water was added and extracted three times with 30 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (DCM:MeOH=50:1) to obtain 7.5 g of a light yellow solid with a yield of 77%.

Step 6: Preparation of N-(2-pentyl)-2-(1-piperazinyl)-N-phenylacetamide trifluoroacetate (Intermediate 8a)

In a single-necked flask, the intermediate 7a (6 g, 1.54×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 6.08 g of a white solid was obtained with a yield of 98.0%.

Step 7: Preparation of N-(2-pentyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide

At room temperature, intermediate 8a (1 g, 2.48 × 10 ^-3 mol) and intermediate 3e (0.75 g, 2.85 × 10 ^-3 mol) and potassium carbonate (0.85 g, 4.96 × 10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM: MeOH = 10:1) to obtain 0.97 g of a white solid with a yield of 82.7%.

Examples 43-55, 58, 60, 61: Compounds FWI-43-FWI-55, FWI-58, FWI-60, FWI-61

Example 42 was repeated, except that different raw materials were used in step 3 and step 5 to obtain compounds FWI-43-FWI-55, FWI-58, FWI-60, and FWI-61. Compounds FWI-50 and FWI-51, FWI-52 and FWI-53 are a pair of cis-trans isomers, and their corresponding intermediates were obtained by column chromatography (PE:EA=30:1) in step 4.

The details are as follows:

Step 3:

Step 5:

Examples 56, 57, 59: Compounds FWI-56, FWI-57, FWI-59

Example 42 was repeated, except that different raw materials were used in step 3 to prepare compounds FWI-56, FWI-57, and FWI-59. The details are as follows:

Step 3

Example 62: Preparation of N-(2-ethanol)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide (FW I-62)

Step 1: Preparation of 3-(5-cyanoindole)propanol (Intermediate 2e)

[Step a] At room temperature, 4-bromophenylhydrazine hydrochloride (5g, 2.24×10 ^-2 mol) was dissolved in a mixture of acetonitrile (50ml) and 4% sulfuric acid (50ml) in a single-necked flask, and 3,4-dihydropyran (5.55ml, 2.86×10 ^-2 mol) was slowly added dropwise under stirring. After the addition was completed, the reaction was heated to 150°C and maintained for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, the excess acetonitrile was distilled off under reduced pressure, and then 50ml of ethyl acetate was added to the remaining mixture and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain 4.36g of an oily substance with a yield of 77%.

[Step b] At room temperature, the oily substance (1g, 3.94×10 ^-3 mol) in the previous step was dissolved in N,N-dimethylformamide (50ml) in a single-necked flask, and cuprous cyanide (1.10g, 1.18×10 ^-2 mol) was added. The reaction was heated to 130°C and maintained for 6h. After the reaction was completed, the reaction solution was poured into 100ml of water and extracted with 20ml of ethyl acetate 5 times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA=20:1) to obtain 0.71g of an oily substance with a yield of 90%.

Step 2: Preparation of 3-(3-bromopropyl)-1-H-5-cyanoindole (Intermediate 3e)

At 0°C, the intermediate 2e (1 g, 5.00×10 ^-3 mol) was dissolved in 30 ml of anhydrous dichloromethane in a 100 ml dry three-necked flask, followed by the addition of carbon tetrabromide (0.80 ml, 1.50×10 ^-2 mol) and triphenylphosphine (2.15 g, 1.50×10 ^-2 mol). 20 ml of water was then added, and the mixture was extracted three times with 20 ml of dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA=20:1) to obtain 0.93 g of a gray-black oily liquid with a yield of 71%.

Step 3: Preparation of N-[2-(tert-butyldimethylsilyloxy)ethyl]aniline (Intermediate 5b)

[Step a] Add iodobenzene (1.11 ml, 0.01 mol), aminoethanol (0.93 ml, 0.012 mol), potassium hydroxide (1.12 g, 0.02 mol), iodide (0.19 g, 1×10 ^-3 mol) and water into a sealed tube, and then heat the reaction solution to 100° C. After the reaction, add 50 ml of water, extract with ethyl acetate three times, combine the organic phases, dry with anhydrous sulfuric acid, concentrate, and perform column chromatography (PE:EA=10:1) to obtain 0.85 g of colorless oil with a yield of 62%.

[Step b] At room temperature, the colorless oily compound (1.5 g, 1.09×10 ^-2 mol) was dissolved in dichloromethane (20 ml) in a single-necked flask, and imidazole (0.89 g, 1.3×10 ^-2 mol) was slowly added under stirring, and stirring was continued for 10 minutes, and then tert-butyldimethylsilyl chloride (1.96 g, 1.3×10 ^-2 mol) was added to the reaction solution, and the reaction was carried out at room temperature for 10 hours. After the reaction was completed, 30 ml of water was added, and then ethyl acetate was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (PE:EA=20:1) was performed to obtain colorless oily intermediate 4, 2.32 g, with a yield of 84.6%.

Step 4: Preparation of N-[2-(tert-butyldimethylsilyloxy)ethyl]-N-phenyl-2-chloroacetamide (Intermediate 6b)

In a single-necked flask, the intermediate 5b (5g, 1.99×10 ^-2 mol) and triethylamine (5.42ml, 2.99×10 ^-2 mol) were dissolved in 50ml of anhydrous dichloromethane. A dichloromethane solution containing chloroacetyl chloride (3.11ml, 2.99×10 ^-2 mol) was added dropwise under ice bath conditions. After the addition was completed, the temperature was gradually raised to room temperature. After stirring for 30 minutes, the temperature was transferred to 75°C and the reaction was continued for 8h. After the reaction was completed, 30ml of dichloromethane was added, and the mixture was washed three times with 30ml of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE:EA＝30:1) to obtain 5.5g of a white solid with a yield of 85.3%.

Step 5: Preparation of N-(2-pentyl)-2-(4-Boc-1-piperazinyl)-N-phenylacetamide (Intermediate 7b)

The intermediate 6b (6 g, 1.83 × 10 ^-2 mol) and N-Boc-piperazine (5.74 g, 1.83 × 10 ^-2 mol) were dissolved in acetonitrile, and potassium carbonate (6.40 g, 2.75 × 10 ^-2 mol) was added, and the temperature was raised to 85 ° C. The reaction was maintained for 8 hours. After the reaction was completed, the acetonitrile was removed under reduced pressure, and then 30 ml of water was added, and extracted three times with 30 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatography (DCM: MeOH = 50: 1) was performed to obtain 6.1 g of a light yellow solid with a yield of 70%.

Step 6: Preparation of N-(2-pentyl)-2-(1-piperazinyl)-N-phenylacetamide trifluoroacetate (Intermediate 8b)

In a single-necked flask, the intermediate 7b (6 g, 1.26×10 ^-2 mol) was dissolved in 50 ml of dichloromethane, and 30 ml of trifluoroacetic acid was added dropwise under stirring. After completion, the reaction was continued at room temperature for 3 h. After the reaction was completed, the excess solvent was removed under reduced pressure, and the product was washed three times with 30 ml of petroleum ether and 30 ml of ether respectively. After filtration and drying, 3.13 g of a white solid was obtained, with a yield of 94.1%.

Step 7: Preparation of N-(2-ethanol)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide

At room temperature, intermediate 8b (1 g, 2.65×10 ^-3 mol) and intermediate 3e (0.59 g, 2.65×10 ^-3 mol) and potassium carbonate (1.05 g, 5.68×10 ^-3 mol) were added to a single-necked flask containing 50 ml of acetonitrile solution, and the reaction was heated to 75°C and stirred under reflux for 12 h. After the reaction was completed, the excess acetonitrile was removed, 30 ml of water was added, and 30 ml of dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and column chromatographed (DCM:MeOH=10:1) to obtain 0.95 g of a white solid with a yield of 80.8%.

Example 63: Compound FWI-63

Example 62 was repeated, except that different starting materials were used in step 3 to obtain compound FWI-63. The details are shown in the following table:

The chemical structure of the target product synthesized by the present invention is shown in Table 3. The chemical structure of the target product was characterized by hydrogen nuclear magnetic spectrum and mass spectrometry.

Table 3 Chemical structure, H NMR spectrum and mass spectrum data of target products

Example 64: Pharmacological Example

Affinity experiment:

1. Drug configuration

The test compound, 5-HT _1A receptor positive drug 5-hydroxytryptamine, and 5-HT _2A receptor positive drug butaclmol were dissolved in DMSO to 0.01 mol/L, and then diluted to 100 μmol/L with deionized water.

2. Materials for receptor binding experiments

5-HT _1A receptor isotope ligand [ ³ H]8-OH-DPAT, 5-HT _2A receptor isotope ligand [3H]Ketanserin (purchased from PE), (+)5-hydroxytrptamine, (+)-Butaclamol hydrochloride (purchased from Sigma), GF/B glass fiber filter paper (purchased from Whatman), lipid-soluble scintillation fluid: PPO, POPOP (purchased from Shanghai Reagent Factory No. 1), toluene (purchased from Sinopharm Chemical Reagent Co., Ltd.), Tris was packaged by Jitai Technology Co., Ltd. Cells: HEK-293 cells stably expressing 5-HT _1A receptor and 5-HT _2A receptor were cultured with DMEM + 10% serum cell culture medium for 3-5 days, and then the cells were harvested with PBS, centrifuged at -4 degrees and 3000 rpm for 10 minutes, and the supernatant was discarded. The cell bodies were harvested and stored in a -80 degree refrigerator. Resuspended with Tris-Cl (pH 7.4) during the experiment.

3. Receptor competition binding assay

Add 10 μL of the compound to be tested and the radioactive ligand and 80 μL of the receptor protein to the reaction tube, so that the final concentration of the test compound and the positive drug is 10 μmol/L. After incubation in a water bath at 37°C for 15 minutes, immediately move to an ice bath to terminate the reaction; on a Millipore cell sample collector, quickly filter through GF/B glass fiber filter paper, wash 3 times with 3 ml of eluent (50 mM Tris-HCl, pH 7.7), dry in a microwave oven for 8 to 9 minutes, move the filter paper into a 0.5 mL centrifuge tube, and add 500 μL of fat-soluble scintillation fluid. Keep it in the dark for more than 30 minutes, and count and measure the radioactivity. Calculate the inhibition percentage of each compound on the binding of the isotope ligand. Compounds with an inhibition rate higher than 80% are subjected to a series of receptor binding tests to determine the half inhibition amount (IC50, the concentration of the compound required to inhibit 50% of the positive control drug from binding to the receptor). Two pairs of tubes are measured for each concentration, and each compound is tested twice independently.

The inhibition rate calculation formula is as follows:

Functional experiment:

1. Experimental Materials

[ ³⁵ S]GTPγS; GF/C glass fiber filter paper; lipid-soluble scintillation fluid; Gpp(NH)p(10-2); GDP(4*10-3); RB buffer. Cells: HEK293 cells expressing 5-HT _1A receptor protein. Positive drug: 5-HT

2. Experimental Methods

1) The cells were disrupted with 50 mM Tris, pH 7.4, and centrifuged at 1000 × g, 4°C for 10 min. The supernatant was centrifuged again at 36,000 × g, 4°C for 30 min. The precipitate (cell membrane) was retained and resuspended with 50 mM Tris, pH 7.4. The protein concentration was measured by BCA method.

2) GTPγS binding assay was performed in 200μl buffer system, 30μg protein per tube, reaction buffer was 50mMTris, Ph 7.4, 5mM MgCl2, 1mM EDTA, 100mM NaCl, 1mM DTT, Ph 7.5. The reaction system contained 40μM GDP, 100μM Gpp(NH)p was added to the non-specific tube, and different concentrations of the test drug were added to the test tube. For the detection of antagonistic function, different concentrations of the test drug and 5-HT (5-HT _1A ) were added to the test tube. 0.1nM [ ³⁵ S]GTPγS was added to each tube, and the tube was placed in a 30℃ water bath for 20min. The tube was taken out and placed on ice to terminate the reaction, filtered through a GF/C membrane, dried and placed in a 0.5ml EP tube, 500μl of fat-soluble scintillation fluid was added, and the radioactivity was measured using a MicroBeta liquid scintillation instrument. Each concentration was repeated in triplicate, and at least 2 independent experiments were performed.

The calculation formula is: [ ³⁵ S]GTPγS Bound (% above basal) = 100 × (sample dpm - basal dpm) / (basal dpm - non-specific dpm) %

Concentration-effect curves were fitted using software and _EC50 or _IC50 values were calculated.

Claims (6)

1. Compounds of formula (I)

The compound is selected from: N-(4-tetrahydro-2-H-pyranyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide N-(1-methoxy-2-propyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide N-(1,2-Dimethoxy-ethyl)-2-(4-(3-(5-cyano-1H-3-indolyl)propyl)-1-piperazinyl)-N-phenylacetamide. 2. A pharmaceutically acceptable salt of the compound of claim 1. 3. The pharmaceutically acceptable salt according to claim 2, characterized in that the pharmaceutically acceptable salt is an inorganic salt, an organic salt or an amino acid salt; The inorganic salt is: sodium salt, hydrochloride, trifluoroacetate, sulfate, phosphate, diphosphate, hydrobromide or nitrate; The organic salt is maleate, acetate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate, or oxalate; The amino acid salt is arginine, ornithine, lysine, leucine, isoleucine, glycine, cystine, cysteine, tyrosine, alanine, phenylalanine, histidine, serine, threonine, methionine, tryptophan, glutamate, aspartate, valine, methionine, proline or hydroxyproline. 4. Use of the compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2 in the preparation of a medicament for treating diseases associated with 5-HT _1A receptor. 5. The use according to claim 4, characterized in that the disease is a neurological and psychiatric disease related to the brain. 6. The use according to claim 5, characterized in that the disease is anxiety, depression, schizophrenia and Parkinson's disease.