Compound with Sigma-1 / H3 receptor double-target activity and preparation method and application thereof

Abstract

The invention relates to a compound with Sigma-1 receptor (sigma 1 receptor) and Histamine 3 (H3) receptor double-target activity as shown in a general formula I or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application of the compound in preparation of drugs for preventing and treating pain-related diseases. The compound as shown in the general formula I provided by the invention has relatively high affinity to a sigma1 receptor and an H3 receptor, can obviously improve neuropathic pain induced by paclitaxel, also shows good analgesic activity in an acetic acid writhing experiment, and has excellent safety.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to indole compounds of general formula I with dual target activity of sigma-1 / H3 receptors or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and their use in the preparation of medicaments for treating pain-related diseases. Background Technology

[0002] Pain is a complex physiological and psychological activity, encompassing unpleasant sensory and emotional experiences, or similar experiences, related to actual or potential tissue damage. Currently, the most common analgesics used clinically for moderate to severe pain are still opioids that act on μ-opioid receptors (MOR), such as fentanyl, alfentanyl, sufentanil, remifentanil, morphine, oxycodone, and buprenorphine. However, while these drugs are highly effective in relieving pain, they all have significant central nervous system and gastrointestinal side effects, including addiction, respiratory depression, nausea, vomiting, constipation, and excessive sedation. Therefore, the development of analgesics without side effects is particularly important and urgent.

[0003] Given the severe side effects of single-target μ-opioid analgesics and the bottlenecks in research targeting single pain targets, multi-target therapeutics offer a new approach. Compared to single-target drugs, multi-target drugs can act on multiple related targets intrinsically linked to the disease. Even if their activity against a single target is lower than that of single-target drugs, the synergistic effect of multi-target regulation enhances the overall effect, resulting in better efficacy and fewer adverse reactions.

[0004] The Sigma-1 receptor (σ1), first discovered in 1976, has attracted considerable attention from the academic and pharmaceutical communities due to its broad biological activity and unique molecular chaperone mechanism, making it one of the emerging and popular drug targets in recent years. Sigma-1 receptors are widely distributed in the central nervous system and peripheral organs, and participate in the regulation of various intracellular neural biological processes. Although the specific mechanism of action of the Sigma-1 receptor is not fully elucidated, current research has found that this receptor can regulate its activity through interactions with various functional proteins, including G protein-coupled receptor families such as the μ-opioid receptor (MOR) and endocannabinoid 1 receptor (CB1R), ion channel receptors such as the NMDA receptor and K+ receptor. + / Ca 2+ These ion chaperone proteins are closely related to the pathogenesis of pain. Multiple ion channels are located at the peripheral end of nociceptors, affecting the excitability of neurons after injury, thereby affecting pain sensation. Therefore, the σ1R system is considered a modulator of pain.

[0005] H3 receptors (H3Rs) are a subtype of histamine receptors, belonging to the G protein-coupled receptor superfamily, and play a wide range of neuroregulatory roles in the central and peripheral nervous systems. H3Rs can act as presynaptic autoreceptors participating in the negative feedback of histamine levels, and also as heteroreceptors regulating interactions with other nonhistaminergic neurotransmitters such as dopamine, norepinephrine, acetylcholine, serotonin, and γ-aminobutyric acid (GABA). H3R antagonists exert analgesic effects in various pain models by blocking H3R activity and increasing the release of histamine and other neurotransmitters. For example, GSK189254 is a highly selective H3R antagonist that can significantly reverse mechanodysia and atypical pain in rodents with neuropathic pain caused by various etiologies, such as chronic compression injury or varicella-zoster virus-induced neuropathic models.

[0006] The development of neuropathic pain involves a multi-pathway synergistic regulatory mechanism. Sigma-1 receptors promote central sensitization by enhancing NMDA receptor activity and the calcium signaling pathway, while H3Rs participate in pain signal transduction by regulating histaminergic neuronal activity. In neuropathic injury models, downregulation of Sigma-1 receptor expression and inhibition of H3R function often coexist, leading to a dual dysregulation of the pain signaling pathway. Designing dual-target sigma-1 / H3 receptor antagonists can simultaneously block the upstream triggering (Sigma-1 receptor) and downstream amplification (H3R) of pain signals, producing a synergistic analgesic effect. This pathological characteristic provides a theoretical basis for the development of dual-target sigma-1 / H3 receptor compounds. Summary of the Invention

[0007] This invention provides compounds with dual target activity against sigma-1 / H3 receptors, which can be used to prepare drugs for treating pain-related diseases. Specifically, they have applications in treating moderate to severe pain, chronic pain, neuralgia, inflammatory pain, nociceptive pain, cancer pain, acute pain, hyperalgesia, and visceral pain.

[0008] This invention provides compounds represented by general formula (I) or pharmaceutically acceptable salts thereof:

[0009]

[0010] Among them, R 1 Selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally R 1a replace;

[0011] R 1a Selected from halogens, C1-C3 alkyl groups, or C1-C3 alkoxy groups;

[0012] R 2R 3 Each is independently selected from hydrogen or halogen;

[0013] m is 0 or 1;

[0014] n is 0 or 1;

[0015] X is CH2 or CHR 6 ;

[0016] R 6 Selected from C1-C6 alkyl, C1-C6 alkoxy or C6-C 10 Aryl;

[0017] The conditions are:

[0018] R 1 R 2 R 3 They are not both hydrogen;

[0019] When R 6 When the components are selected from C1-C6 alkyl or C1-C6 alkoxy, m is 1;

[0020] Not the following compounds:

[0021]

[0022] In some implementations, R 1 Selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally R 1a replace.

[0023] In some implementations, R 1a Selected from halogens.

[0024] In some implementations, R 1a Selected from fluorine.

[0025] In some implementations, R 2 Selected from hydrogen or chlorine.

[0026] In some implementations, R 3 Selected from hydrogen, fluorine, or chlorine.

[0027] In some implementations, m is 0.

[0028] In some implementations, m is 1.

[0029] In some implementations, n is 0 or 1.

[0030] In some implementations, n is 1.

[0031] In some implementations, X is CH2.

[0032] In some implementations, R 6 It is selected from C1-C6 alkyl, C1-C6 alkoxy or phenyl.

[0033] In some implementations, R 6 It is selected from C1-C3 alkyl, C1-C3 alkoxy or phenyl.

[0034] In some implementations, R 6 Selected from methyl, methoxy, or phenyl.

[0035] In some implementations, X is CHR 6 R 6 It is a phenyl group.

[0036] This invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0037] 5-Chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole

[0038] 5-Fluoro-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0039] 5-Fluoro-3-(3-(4-methylpiperidin-1-yl))propyl)-1H-indole

[0040] 4-(3-(5-fluoro-1H-indol-3-yl))propyl)morpholine

[0041] 5-Fluoro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole

[0042] 5-Fluoro-3-(3-(4-methoxypiperidin-1-yl))propyl)-1H-indole

[0043] 5-Methyl-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0044] 5-Methyl-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole

[0045] 5-Methyl-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole

[0046] 5-Methyl-3-(3-(4-methylpiperidin-1-yl))propyl)-1H-indole

[0047] 4-(3-(5-methyl-1H-indol-3-yl))propyl)morpholine

[0048] 5-Methyl-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole

[0049] 3-(3-(4-methoxypiperidin-1-yl))propyl)-5-methyl-1H-indole

[0050] N,N-Diethyl-3-(5-methyl-1H-indol-3-yl)propyl-1-amine

[0051] 5-Methoxy-N-acetyltryptamine-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0052] 5-Methoxy-N-acetyltryptamine-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole

[0053] 6-Chloro-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0054] 6-Chloro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole

[0055] 6-Chloro-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0056] 6-Chloro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole hydrochloride

[0057] 5-Bromo-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0058] 5,7-Difluoro-3-(3-(piperidin-1-yl))propyl)-1H-indole

[0059] 5,7-Difluoro-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole

[0060] 5,7-Difluoro-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole

[0061] 3-(3-(piperidin-1-yl))propyl)-5-(trifluoromethoxy)-1H-indole

[0062] 5-Fluoro-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole

[0063] 5-Fluoro-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole

[0064] N,N-Diethyl-3-(5-fluoro-1H-indol-3-yl)propylamine

[0065] 5-Fluoro-3-(2-(piperidin-1-yl))ethyl)-1H-indole

[0066] 5-Fluoro-3-(2-(pyrrolidone-1-yl))ethyl)-1H-indole

[0067] 5-Fluoro-3-(2-(4-methylpiperazin-1-yl))ethyl)-1H-indole

[0068] 3-(3-(piperidin-1-yl))propyl)-1H-indole

[0069] 3-(3-(pyrrolidone-1-yl))propyl)-1H-indole.

[0070] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0071] The present invention also provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0072]

[0073] (S1): Compounds of general formula IA and IB undergo Fischer indole cyclization with an acidic reagent to give intermediate IC;

[0074] (S2): The intermediate IC obtained in step (S1) undergoes a sulfonation reaction with p-methylsulfonyl chloride and a basic reagent to obtain intermediate ID;

[0075] (S3): The intermediate ID obtained in step (S2) undergoes a nucleophilic substitution reaction with the intermediate IE and a basic reagent to obtain the compound of general formula I;

[0076] Among them, X and R 1 R 2 R 3 m and n are as defined above.

[0077] The molar ratio of the general formula IA to the IB compound in step (S1) is 1:(1-5), and the acidic reagent is selected from sulfuric acid, polyphosphoric acid, hydrochloric acid or trifluoroacetic acid;

[0078] The alkaline reagent in step (S2) is selected from triethylamine;

[0079] The alkaline reagent in step (S3) is selected from sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate, and the reaction solvent is selected from acetonitrile, acetone, N,N-dicarboxyformamide or N,N-dicarboxyacetamide.

[0080] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0081] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases mediated by dual targets of the sigma-1 / H3 receptor.

[0082] In some embodiments, the sigma-1 / H3 receptor dual-target mediated disease is a disease antagonistic to the sigma-1 / H3 receptor dual targets.

[0083] In some embodiments, the diseases mediated by the sigma-1 / H3 receptor dual targets are selected from pain-related diseases.

[0084] In some embodiments, the present invention also provides the use of the above-described compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of pain-related diseases.

[0085] In some embodiments, the pain-related diseases are selected from acute pain, chronic pain, intractable pain, cancer pain, specific pain, moderate to severe pain, neuralgia, inflammatory pain, nociceptive pain, hyperalgesia, or visceral pain.

[0086] In some embodiments, the acute pain is selected from acute soft tissue and joint injury pain, postoperative pain, obstetric pain, acute herpes zoster pain, or gout; the chronic pain is selected from soft tissue and joint strain or degenerative pain, intervertebral discogenic pain, or neurogenic pain; the intractable pain is selected from trigeminal neuralgia, postherpetic neuralgia, or intractable headache; the cancer pain is selected from advanced tumor pain or tumor metastasis pain; and the specific pain is selected from thromboangiitis obliterans, intractable angina pectoris, or idiopathic chest and abdominal pain.

[0087] Terminology Definitions and Explanations

[0088] The term "optional" or "optionally" means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event. For example, "optionally" substituted methyl groups with halogens means that the methyl group may be unsubstituted (CH3), monosubstituted (CH2F), polysubstituted (CHF2), or fully substituted (CF3).

[0089] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0090] The compounds of general formula I described in this invention, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, are formulated to be suitable for administration via any appropriate route. The active compound is preferably administered in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the compounds or compositions provided by this invention may be expressed as tablets, capsules, injections, granules, tinctures, lozenges, suppositories, regenerated powders, or liquid formulations.

[0091] The dosage of the compound or composition used in its administration typically varies depending on the severity of pain, the patient's weight, and the relative efficacy of the compound. As a general guideline, a suitable unit dose may be 0.01–1000 mg.

[0092] In addition to the active compound, the pharmaceutical composition provided by this invention may contain one or more excipients, which are selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0093] Pharmaceutical compositions containing active ingredients may be suitable for oral, injectable, or transdermal administration via patch delivery systems, such as tablets, lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, injections, lyophilized powders, or syrups or tinctures. Oral or injectable compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from: sweeteners, flavoring agents, coloring agents, pH adjusters, and preservatives.

[0094] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Aqueous suspensions may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0095] Oil suspensions are prepared by suspending active ingredients in vegetable oil. Oil suspensions may contain thickeners. The aforementioned sweeteners and flavoring agents may also be added.

[0096] The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or media that can be used include water, Green's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin, and then the oil solution is added to a mixture of water and glycerol to form a microemulsion. The injectable solution or microemulsion can be injected into the patient's bloodstream via local injection. Alternatively, the solution and microemulsion can be administered in a manner that maintains a constant circulating concentration of the compound provided by the present invention; to maintain this constant concentration, a continuous intravenous delivery device can be used.

[0097] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension may be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents as described above. The sterile injectable formulation may also be a sterile injectable solution or suspension prepared in a parenteral-acceptable non-toxic diluent or solvent. Furthermore, sterile fixative oils may be used as solvents or suspension media.

[0098] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of compound of formula I, or the type of salt that may be used, can be verified based on conventional treatment protocols.

[0099] The compounds provided by this invention may also contain isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure disclosed herein, except that hydrogen is replaced by "deuterium" or "tritium," or by using... 18 F-fluorine ( 18 F isotope) labeling instead of fluorine, or using 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes, for example, in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. Deuterated compounds generally retain activity comparable to their undeuterated counterparts, and deuteration at certain sites can result in better metabolic stability, thereby providing certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirements).

[0100] The compounds provided by this invention also include various deuterated forms of Formula I compounds. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated forms of Formula I compounds by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare the deuterated forms of Formula I compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0101] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the subject, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0102] Beneficial technical effects of the present invention:

[0103] (1) The compound of general formula I provided by the present invention has a high affinity for σ1 receptor and H3 receptor.

[0104] (2) The compound described in this invention can significantly improve paclitaxel-induced neuropathic pain.

[0105] (3) The compound described in this invention exhibits good analgesic activity in the acetic acid writhing test.

[0106] (4) The compounds described in this invention have shown superior safety in acute toxicity tests.

[0107] Since these in vitro targets and in vivo pharmacological models are closely related to pain, the compounds provided by this invention have the potential to prepare drugs for treating pain-related diseases. Attached Figure Description

[0108] Figure 1 This is a schematic diagram of the mouse acetic acid writhing test results for compound 7.

[0109] Figure 2 This is a schematic diagram showing the change in the inhibition rate of compound 7 over time in a paclitaxel-induced mouse model of neuropathic pain.

[0110] Figure 3 This is a schematic diagram of the experimental results of a mouse model of neuropathic pain induced by paclitaxel (compound 7). Detailed Implementation

[0111] The technical solutions of various embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0112] Test method:

[0113] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements were performed using a Bruker avance III HD 500MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) are expressed in ppm.

[0114] LC-MS measurements were performed using an Agilent 6540Q-TOF (manufacturer: Agilent Technologies Inc., MS model: 6540Q-TOF).

[0115] The following examples are for illustrative purposes only and are not intended to limit the invention.

[0116] A. Compound Synthesis Examples

[0117] Example 15 Synthesis of chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole (1)

[0118]

[0119] Synthesis of S1)3-(5-chloro-1H-indol-3-yl)propyl-1-ol (IF)

[0120] 17.8 g of p-chlorophenylhydrazine hydrochloride, 50 mL of 4% H₂SO₄, and 50 mL of N,N-dimethylacetamide (DMAC) were weighed and added to a 500 mL round-bottom flask. The mixture was heated to 100 °C in an oil bath to completely dissolve the methylhydrazine. Then, 10.08 g of 3,4-dihydropyran was slowly added dropwise, and the mixture was refluxed for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed successively with water (5 × 100 mL), saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain a brown oily product. Finally, the crude product was purified by silica gel chromatography (200-300 mesh, PE / EA = 3:1) to obtain 16 g of a yellow oily product, with a yield of 76.5%.

[0121] 1 H NMR(500MHz,Chloroform-d)δ8.14(s,1H),7.57(d,J=2.0Hz,1H),7.24(d,J=8.6Hz,1H),7.13(dd,J=8.6, 2.0Hz,1H),6.98(s,1H),3.72(t,J=6.4Hz,2H),2.80(t,J=7.5Hz,2H),1.96(p,J=6.6Hz,2H),1.71(s,1H).

[0122] (+)-ESI-MS:m / z 210.0683(calcd.210.0680for C 11 H 13 ClNO + [M+H] + ).

[0123] Synthesis of S2)3-(5-chloro-1H-indol-3-yl)propyl-4-methylbenzenesulfonate (IG)

[0124] 14.6 g of the reaction product from step S1 was weighed and dissolved in 100 mL of dichloromethane. 14.86 g of triethylamine and 0.89 g of DMAP were added dropwise. 14 g of p-toluenesulfonyl chloride was slowly added with stirring at room temperature. The reaction was allowed to proceed for 4 hours at room temperature, after which the reaction was stopped. The organic phase was washed successively with water (50 mL), saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a dark green oily crude product. Purification was performed using a silica gel chromatography column (200-300 mesh, PE / EA = 6:1) to obtain 19 g of a yellow-green solid, with a yield of 74.8%.

[0125] 1 H NMR(500MHz,Chloroform-d)δ9.14(d,J=7.1Hz,1H),7.74-7.68(m,2H),7.43-7.38(m,3H),7.26(qd,J=7.3,1.6Hz, 2H),7.10(d,J=7.0Hz,1H),4.10(t,J=6.7Hz,2H),3.49(t,J=8.1Hz,2H),2.41(s,3H),2.22(tt,J=8.1,6.7Hz,2H).

[0126] (+)-ESI-MS:m / z 364.0772(calcd.364.0769for C 18 H 19 ClNO3S + [M+H] + ).

[0127] Synthesis of S3)5-chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole

[0128] Weigh 1.45 g of the reaction product from step S2, 1.65 g of potassium carbonate, and 30 mL of acetonitrile into a 100 mL round-bottom flask. Heat the flask to 80 °C in an oil bath and stir. While stirring, add 0.97 g of piperidine hydrochloride. Reflux at 80 °C for 4 hours. After the reaction is complete, cool the reaction system to room temperature and concentrate under reduced pressure to remove the solvent. Dissolve the residue in 30 mL of dichloromethane. Wash the organic phase successively with water (10 mL), saturated brine, and dry with anhydrous sodium sulfate. Concentrate to obtain a brown oily crude product. Purify the crude product using a silica gel chromatography column (200-300 mesh, DCM / MeOH = 15:1) to obtain 0.76 g of a yellow solid, with a yield of 69.1%. Dissolve the product in ethyl acetate solution (with a small amount of methanol added dropwise). While stirring, add EA / HCl dropwise until the pH of the reaction solution reaches approximately 4-5, resulting in the precipitation of a large amount of solid. Stir at room temperature for one hour, filter, and dry to obtain 1 g of hydrochloride solid powder.

[0129] 1 H NMR(500MHz,Chloroform-d)δ8.63(s,1H),7.55(d,J=1.9Hz,1H),7.22(d,J=8.6Hz,1H),7.10(dd,J=8.6,2.0Hz,1H),6.93(d,J=2.3H z,1H),3.47(s,1H),2.69(t,J=7.6Hz,2H),2.40(d,J=7.9Hz,6H),1.90(p,J=7.7Hz,2H),1.61(p,J=5.7Hz,4H),1.44(p,J=5.8Hz,2H).

[0130] (+)-ESI-MS:m / z 277.1473(calcd.277.1466for C 16 H 22 ClN2 + [M+H] + ).

[0131] Example 25 Synthesis of fluoro-3-(3-(piperidin-1-yl)propyl)-1H-indole (2)

[0132] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride; the other steps are basically the same.

[0133] 1H NMR(500MHz,Chloroform-d)δ8.46(s,1H),7.23(td,J=9.2,3.5Hz,2H),6.98(d,J=2.3Hz,1H),6.91(td,J=9.0,2.5H z,1H),2.70(t,J=7.6Hz,2H),2.52-2.35(m,6H),1.92(p,J=7.7Hz,2H),1.62(p,J=5.7Hz,4H),1.45(t,J=5.9Hz,2H).

[0134] (+)-ESI-MS:m / z 261.1769(calcd.261.1762for C 16 H 22 FN2 + [M+H] + ).

[0135] Example 35 Synthesis of 5-fluoro-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole (3)

[0136] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with pyrrolidine. The other steps are basically the same.

[0137] 1 H NMR(500MHz,Chloroform-d)δ8.67(s,1H),7.26-7.22(m,1H),7.19(dd,J=9.7,2.6Hz,1H),6.99(s,1H),6.89(td, J=9.0,2.5Hz,1H),2.71(t,J=7.6Hz,2H),2.63(dt,J=18.8,7.3Hz,6H),1.96(p,J=7.6Hz,2H),1.88-1.78(m,4H).

[0138] (+)-ESI-MS:m / z 247.1611(calcd.247.1605for C 15 H 20 FN2 + [M+H] + ).

[0139] Example 4 Synthesis of 5-fluoro-3-(3-(4-methylpiperazin-1-yl)propyl)-1H-indole (4)

[0140] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with N-methylpiperazine. The other steps are basically the same.

[0141] 1H NMR(500MHz,Chloroform-d)δ8.41(s,1H),7.25-7.20(m,2H),6.99(d,J=2.4Hz,1H),6.91(td,J =9.0,2.5Hz,1H),2.72(t,J=7.6Hz,2H),2.67-2.32(m,10H),2.30(s,3H),1.89(p,J=7.6Hz,2H).

[0142] (+)-ESI-MS:m / z 276.1876(calcd.276.1871for C 16 H 23 FN3 + [M+H] + ).

[0143] Example 55 Synthesis of fluoro-3-(3-(4-methylpiperidin-1-yl)propyl)-1H-indole (5)

[0144] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-methylpiperidine. The other steps are basically the same.

[0145] 1 H NMR(500MHz,Chloroform-d)δ8.45(s,1H),7.26-7.19(m,2H),6.97(d,J=2.3Hz,1H),6.91(td,J=9.0,2.5Hz,1H),2.93(d,J=1 1.9Hz,2H),2.69(t,J=7.6Hz,2H),2.46-2.39(m,2H),1.99-1.87(m,4H),1.63(d,J=13.0Hz,2H),1.30(td,J=12.2,3.6Hz,2H).

[0146] (+)-ESI-MS:m / z 275.1924(calcd.275.1918for C 17 H 24 FN2 + [M+H] + ).

[0147] Example 64 Synthesis of 3-(5-fluoro-1H-indol-3-yl))propyl)morpholine (6)

[0148] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with morpholine. The other steps are basically the same.

[0149] 1H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.26-7.22(m,2H),7.01(d,J=2.4Hz,1H),6.93(td,J=9.1,2.5 Hz,1H),3.74(t,J=4.7Hz,4H),2.74(t,J=7.6Hz,2H),2.43(dd,J=15.9,8.4Hz,6H),1.89(p,J=7.6Hz,2H).

[0150] (+)-ESI-MS:m / z 263.1560(calcd.263.1554for C 15 H 20 FN2O + [M+H] + ).

[0151] Example 75 Synthesis of fluoro-3-(3-(4-phenylpiperidin-1-yl)propyl)-1H-indole (7)

[0152] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-phenylpiperidine. The other steps are basically the same.

[0153] 1 H NMR(500MHz,Chloroform-d)δ8.17(s,1H),7.31(t,J=7.5Hz,2H),7.29-7.23(m,4H), 7.21(t,J=7.2Hz,1H),7.02(d,J=2.4Hz,1H),6.94(td,J=9.0,2.5Hz,1H),3.09(d,J=1 1.6Hz,2H),2.76(t,J=7.6Hz,2H),2.53(dd,J=10.8,5.2Hz,1H),2.50-2.43(m,2H),2. 07(td,J=11.1,4.1Hz,2H),1.96(p,J=7.7Hz,2H),1.84(td,J=11.2,10.3,3.6Hz,4H).

[0154] (+)-ESI-MS:m / z 337.2084(calcd.337.2075for C 22 H 26 FN2 + [M+H] + ).

[0155] Example 8 Synthesis of 5-fluoro-3-(3-(4-methoxypiperidin-1-yl)propyl)-1H-indole (8)

[0156] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-methoxypiperidine. The other steps are basically the same.

[0157] 1 H NMR(500MHz,Chloroform-d)δ8.28(s,1H),7.25-7.20(m,2H),6.99(d,J=2.4Hz,1H),6.91(td,J=9.0,2.5Hz,1H),3.34(s,3H),3.22(tt,J=8.7,4.0Hz ,1H),2.77(d,J=6.6Hz,2H),2.71(t,J=7.6Hz,2H),2.44-2.38(m,2H),2.1 3(d,J=10.4Hz,2H),1.89(td,J=16.4,15.2,8.6Hz,4H),1.67-1.57(m,2H).

[0158] (+)-ESI-MS:m / z 291.1873(calcd.291.1867for C 17 H 24 FN2O + [M+H] + ).

[0159] Example 9 Synthesis of N,N-diethyl-3-(5-fluoro-1H-indol-3-yl)propyl-1-amine (9)

[0160] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-fluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with diethylamine. The other steps are basically the same.

[0161] 1 H NMR(500MHz,Chloroform-d)δ8.33(s,1H),7.26-7.21(m,2H),7.00(d,J=2.3Hz,1H),6.92(td,J=9.0 ,2.5Hz,1H),2.70(t,J=7.6Hz,2H),2.62-2.52(m,6H),1.87(p,J=7.7Hz,2H),1.03(t,J=7.1Hz,6H).

[0162] (+)-ESI-MS:m / z 249.1767(calcd.249.1762for C 15 H 22 FN2 + [M+H] + ).

[0163] Example 105 Synthesis of fluoro-3-(2-(piperidin-1-yl)ethyl)-1H-indole (10)

[0164] The only difference from Example 1 is that in step S1, p-chlorophenylhydrazine hydrochloride is replaced with p-fluorophenylhydrazine hydrochloride, and 3,4-dihydropyran is replaced with 2,3-dihydrofuran. The other steps are basically the same.

[0165] 1 H NMR(500MHz,Chloroform-d)δ8.34(s,1H),7.23(dt,J=8.6,3.6Hz,2H),7.04(d,J=2.3Hz,1H),6.91(td,J=9.1 ,2.5Hz,1H),2.97-2.90(m,2H),2.70-2.63(m,2H),2.54(s,4H),1.66(p,J=5.6Hz,4H),1.48(p,J=6.0Hz,2H).

[0166] (+)-ESI-MS:m / z 247.1611(calcd.247.1605for C 15 H 20 FN2 + [M+H] + ).

[0167] Example 1 Synthesis of 115-fluoro-3-(2-(pyrrolidone-1-yl)ethyl)-1H-indole (11)

[0168] The only difference from Example 1 is that in step S1, p-chlorophenylhydrazine hydrochloride is replaced with p-fluorophenylhydrazine hydrochloride, 3,4-dihydropyran is replaced with 2,3-dihydrofuran, and piperidine hydrochloride is replaced with pyrrolidine in step S3. The other steps are basically the same.

[0169] 1 H NMR(500MHz,Chloroform-d)δ8.39(s,1H),7.22(ddd,J=8.9,6.2,3.4Hz,2H),7.04(d,J=2.3Hz,1H),6. 90(td,J=9.0,2.5Hz,1H),3.01-2.93(m,2H),2.85-2.80(m,2H),2.73-2.62(m,4H),1.93-1.77(m,4H).

[0170] (+)-ESI-MS:m / z 233.1454(calcd.233.1449for C 14 H 18 FN2 + [M+H] + ).

[0171] Example 125 Synthesis of 5-fluoro-3-(2-(4-methylpiperazin-1-yl)ethyl)-1H-indole (12)

[0172] The only difference from Example 1 is that in step S1, p-chlorophenylhydrazine hydrochloride is replaced with p-fluorophenylhydrazine hydrochloride, 3,4-dihydropyran is replaced with 2,3-dihydrofuran, and in step S3, piperidine hydrochloride is replaced with N-methylpiperazine. The other steps are basically the same.

[0173] 1 H NMR(500MHz,Chloroform-d)δ8.35(s,1H),7.24(d,J=3.3Hz,1H),7.23-7.21(m,1H),7.05(d,J =2.4Hz,1H),6.92(td,J=9.1,2.5Hz,1H),2.94-2.88(m,2H),2.85-2.35(m,10H),2.32(s,3H).

[0174] (+)-ESI-MS:m / z 262.1720(calcd.262.1714for C 15 H 21 FN3 + [M+H] + ).

[0175] Example 13 Synthesis of 5-methyl-3-(3-(piperidin-1-yl)propyl)-1H-indole (13)

[0176] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride; the other steps are basically the same.

[0177] 1 H NMR(500MHz,Chloroform-d)δ8.45(s,1H),7.35(s,1H),7.22(d,J=8.3Hz,1H),6.99(dd,J=8.4,1.6Hz,1H),6.90(d,J=2.3Hz,1 H),2.72(t,J=7.5Hz,2H),2.60-2.46(m,6H),2.45(s,3H),1.97(p,J=7.7Hz,2H),1.67(p,J=5.7Hz,4H),1.45(p,J=5.6Hz,2H).

[0178] (+)-ESI-MS:m / z 257.2018(calcd.257.2012for C 17 H 25 N2 + [M+H] + ).

[0179] Example 14 Synthesis of 5-methyl-3-(3-(pyrrolidone-1-yl)propyl)-1H-indole (14)

[0180] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with pyrrolidine. The other steps are basically the same.

[0181] 1 H NMR(500MHz,Chloroform-d)δ8.24(s,1H),7.38(s,1H),7.23(d,J=8.2Hz,1H),7.00(dd,J=8.2,1.6Hz,1H),6.92(d,J= 2.3Hz,1H),2.77(t,J=7.6Hz,2H),2.60(dd,J=8.8,6.9Hz,6H),2.46(s,3H),1.99(p,J=7.7Hz,2H),1.86-1.77(m,4H).

[0182] (+)-ESI-MS:m / z 243.1861(calcd.243.1856for C 16 H 23 N2 + [M+H] + ).

[0183] Example 15 Synthesis of 5-methyl-3-(3-(4-methylpiperazin-1-yl)propyl)-1H-indole (15)

[0184] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with N-methylpiperazine. The other steps are basically the same.

[0185] 1 H NMR(500MHz,Chloroform-d)δ8.16(s,1H),7.39(s,1H),7.22(d,J=8.2Hz,1H),7.00(dd,J=8.3,1.6Hz,1H) ,6.91(d,J=2.3Hz,1H),2.75(t,J=7.6Hz,2H),2.45(d,J=9.1Hz,11H),2.30(s,5H),1.91(p,J=7.6Hz,2H).

[0186] (+)-ESI-MS:m / z 272.2127(calcd.272.2121for C 17 H 26 N3 + [M+H] + ).

[0187] Example 16 Synthesis of 5-methyl-3-(3-(4-methylpiperidin-1-yl)propyl)-1H-indole (16)

[0188] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-methylpiperidine. The other steps are basically the same.

[0189] 1 H NMR(500MHz,Chloroform-d)δ8.10(s,1H),7.38(s,1H),7.23(d,J=8.2Hz,1H),7.00(dd,J=8.2,1.6Hz,1H),6.92(d,J=2.3Hz,1H),2.96(d,J=8.5 Hz,2H),2.74(t,J=7.6Hz,2H),2.50-2.41(m,5H),1.96(dd,J=14.1,9.0H z,4H),1.64(d,J=10.8Hz,2H),1.41-1.27(m,3H),0.93(d,J=6.0Hz,3H).

[0190] (+)-ESI-MS:m / z 271.2174(calcd.271.2169for C 18 H 27 N2 + [M+H] + ).

[0191] Example 174 Synthesis of 4-(3-(5-methyl-1H-indol-3-yl)propyl)morpholine hydrochloride (17)

[0192] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with morpholine. The other steps are basically the same.

[0193] 1 H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.40(s,1H),7.23(d,J=8.2Hz,1H),7.02(dd,J=8.2,1.7Hz,1H) ,6.93(d,J=2.3Hz,1H),3.78-3.72(m,4H),2.77(t,J=7.6Hz,2H),2.49-2.43(m,9H),1.92(p,J=7.6Hz,2H).

[0194] (+)-ESI-MS:m / z 259.1810(calcd.259.1805for C 16 H 23 N2O + [M+H] + ).

[0195] Example 18 Synthesis of 5-methyl-3-(3-(4-phenylpiperidin-1-yl)propyl)-1H-indole (18)

[0196] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-phenylpiperidine. The other steps are basically the same.

[0197] 1 H NMR (600MHz, Chloroform-d) δ7.93 (s, 1H), 7.42 (dd, J=1.8, 1.0Hz, 1H), 7.31 (t, J= 7.6Hz,2H),7.25(s,2H),7.24(s,1H),7.23-7.19(m,1H),7.03(dd,J=8.3,1.6Hz,1 H),6.96(d,J=2.2Hz,1H),3.13-3.07(m,2H),2.81-2.75(m,2H),2.54-2.48(m,3H) ,2.48(s,3H),2.06(td,J=11.1,4.6Hz,2H),2.01-1.93(m,2H),1.88-1.82(m,4H).

[0198] (+)-ESI-MS:m / z 333.2324(calcd.333.2325for C 23 H 29 N2 + [M+H] + ).

[0199] Example 19 Synthesis of 3-(3-(4-methoxypiperidin-1-yl)propyl)-5-methyl-1H-indole (19)

[0200] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-methoxypiperidine. The other steps are basically the same.

[0201] 1 H NMR(500MHz,Chloroform-d)δ8.08(s,1H),7.39(s,1H),7.22(d,J=8.2Hz,1H),7.01(dd,J=8.3,1.6Hz,1H),6.91(d,J=2.3Hz,1H),3 .35(s,3H),3.23(tt,J=9.1,4.3Hz,1H),2.832.71(m,4H),2.47-2.42(m,5H),2.17(s,2H),1.92(p,J=7.6Hz,4H),1.69-1.58(m,2H).

[0202] (+)-ESI-MS:m / z 287.2123(calcd.287.2118for C 18 H 27 N2O + [M+H] + ).

[0203] Example 20 Synthesis of N,N-diethyl-3-(5-methyl-1H-indol-3-yl)propyl-1-amine (20)

[0204] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methylphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with diethylamine. The other steps are basically the same.

[0205] 1 H NMR(500MHz,Chloroform-d)δ8.15(s,1H),7.39(s,1H),7.23(d,J=8.2Hz,1H),7.01(dd,J=8.4,1.6Hz,1H),6.93(d,J =2.2Hz,1H),2.74(t,J=7.2Hz,2H),2.59(q,J=7.2Hz,6H),2.47(s,3H),1.91(p,J=7.7Hz,2H),1.05(t,J=7.2Hz,6H).

[0206] (+)-ESI-MS:m / z 245.2018(calcd.245.2012for C 16 H 25 N2 + [M+H] + ).

[0207] Example 2 Synthesis of 15-methoxy-N-acetyltryptamine-3-(3-(piperidin-1-yl)propyl)-1H-indole (21)

[0208] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methoxyphenylhydrazine hydrochloride; the other steps are basically the same.

[0209] 1 H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.23(d,J=8.8Hz,1H),7.00(d,J=2.5Hz,1H),6.94(s,1H),6.82(dd,J=8.7,2.5Hz,1H),3.85(s,3H) ,2.71(t,J=7.5Hz,2H),2.59-2.49(m,6H),2.49-2.45(m,1H),1.99(p,J =7.8Hz,2H),1.68(p,J=5.7Hz,4H),1.55(p,J=5.7Hz,1H),1.45(s,2H).

[0210] (+)-ESI-MS:m / z 273.1966(calcd.273.1961for C 17 H 25 N2O + [M+H] + ).

[0211] Example 2. Synthesis of 225-methoxy-N-acetyltryptamine-3-(3-(4-phenylpiperidin-1-yl)propyl)-1H-indole (22)

[0212] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-methoxyphenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with p-4-phenylpiperidine. The other steps are basically the same.

[0213] 1 H NMR(600MHz,Chloroform-d)δ7.97(s,1H),7.33-7.29(m,2H),7.26-7.23(m,3H) ),7.22-7.19(m,1H),7.06(d,J=2.4Hz,1H),6.98(d,J=2.2Hz,1H),6.86(dd,J=8 .8,2.4Hz,1H),3.88(s,3H),3.12-3.07(m,2H),2.80-2.74(m,2H),2.54-2.47(m ,3H),2.09-2.03(m,2H),2.02-1.95(m,2H),1.84(td,J=11.3,10.4,3.6Hz,4H).

[0214] (+)-ESI-MS:m / z 349.2309(calcd.349.2274for C 23 H 29 N2O + [M+H] + ).

[0215] Example 23 Synthesis of 6-chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole (23)

[0216] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 3-chlorophenylhydrazine hydrochloride; the other steps are basically the same.

[0217] 1H NMR(500MHz,Chloroform-d)δ8.76(s,1H),7.45(d,J=8.4Hz,1H),7.31(d,J=1.8Hz,1H),7.04(dd,J=8.4,1.9Hz,1H),6. 90(d,J=1.2Hz,1H),2.73-2.66(m,2H),2.51-2.37(m,6H),1.96-1.88(m,2H),1.63(p,J=5.6Hz,4H),1.48-1.41(m,2H).

[0218] (+)-ESI-MS:m / z 277.1473(calcd.277.1466for C 16 H 22 ClN2 + [M+H] + ).

[0219] Example 24 Synthesis of 6-chloro-3-(3-(4-phenylpiperidin-1-yl)propyl)-1H-indole (24)

[0220] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 3-chlorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-phenylpiperidine. The other steps are basically the same.

[0221] 1 H NMR(600MHz,Chloroform-d)δ8.26 / 8.15(s,1H),7.32-7.28(m,2H),7.25-7.22(m,3H),7.22-7.18(m,1H),7.10-7.03(m,2H),6.99(dd,J=15.6,2.4 Hz,1H),3.14-3.06(m,2H),3.01 / 2.76(t,J=7.6Hz,2H),2.54-2.45(m,3H ),2.10-2.02(m,2H),2.00-1.94(m,2H),1.84(tq,J=7.4,3.6,2.7Hz,4H).

[0222] (+)-ESI-MS:m / z 353.1809(calcd.353.1779for C 22 H 26 ClN2 + [M+H] + ).

[0223] Example 25 Synthesis of 6-chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole (25)

[0224] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 2-chlorophenylhydrazine hydrochloride; the other steps are basically the same.

[0225] 1 H NMR(500MHz,Chloroform-d)δ8.38(s,1H),7.47(d,J=7.9Hz,1H),7.17(d,J=6.7Hz,1H),7.04(d,J=2.2Hz,1H),7.03(d,J= 7.8Hz,1H),2.78-2.71(m,2H),2.59-2.43(m,6H),1.98(dt,J=15.5,7.7Hz,2H),1.66(p,J=5.7Hz,4H),1.50-1.41(m,2H).

[0226] (+)-ESI-MS:m / z 277.1475(calcd.277.1466for C 16 H 22 ClN2 + [M+H] + ).

[0227] Example 26 Synthesis of 6-chloro-3-(3-(4-phenylpiperidin-1-yl)propyl)-1H-indole (26)

[0228] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 2-chlorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with 4-phenylpiperidine. The other steps are basically the same.

[0229] 1 H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.54(d,J=7.9Hz,1H),7.32(t,J=7.5Hz,2H),7.25(dt,J=10.0,2.8Hz,2H),7.20(d,J=7.2Hz,2H),7.09 -7.03(m,2H),3.15-3.04(m,2H),2.80(t,J=7.6Hz,2H),2.57-2.43(m,3H ),2.06(td,J=11.0,4.0Hz,2H),1.97(p,J=7.7Hz,2H),1.89-1.79(m,4H).

[0230] (+)-ESI-MS:m / z 353.1809(calcd.353.1779for C 22 H 26 ClN2 + [M+H] + ).

[0231] Example 27 Synthesis of 5-bromo-3-(3-(piperidin-1-yl)propyl)-1H-indole (27)

[0232] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with p-bromophenylhydrazine hydrochloride; the other steps are basically the same.

[0233] 1 H NMR(500MHz,Chloroform-d)δ8.39(s,1H),7.72(d,J=1.8Hz,1H),7.24(dd,J=8.6,1.9Hz,1H),7.19(d,J=8.6Hz ,1H),2.70(t,J=7.6Hz,2H),2.50-2.32(m,6H),1.96-1.84(m,2H),1.61(p,J=5.7Hz,4H),1.43(d,J=6.5Hz,2H).

[0234] (+)-ESI-MS:m / z 321.0970(calcd.321.0961for C 16 H 22 BrN2 + [M+H] + ).

[0235] Example 28 Synthesis of 3-(3-(piperidin-1-yl)propyl)-1H-indole (28)

[0236] The only difference from Example 1 is that in step S1, p-chlorophenylhydrazine hydrochloride is replaced with phenylhydrazine hydrochloride; the other steps are basically the same.

[0237] 1 H NMR(500MHz,Chloroform-d)δ8.30(s,1H),7.61(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.18(t,J=7.6Hz,1H),7.11(t,J=7.5Hz,1H ),6.95(d,J=2.4Hz,1H),2.77(t,J=7.6Hz,2H),2.50-2.35(m,6H),1.95(p,J=7.7Hz,2H),1.62(p,J=5.6Hz,4H),1.50-1.39(m,2H).

[0238] (+)-ESI-MS:m / z 243.1861(calcd.243.1856for C 16 H 23 N2 + [M+H] + ).

[0239] Example 29 Synthesis of 3-(3-(pyrrolidone-1-yl)propyl)-1H-indole (29)

[0240] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with phenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with pyrrolidine. The other steps are basically the same.

[0241] 1 H NMR(500MHz,Chloroform-d)δ8.36(s,1H),7.61(d,J=7.8Hz,1H),7.34(d,J=8.1Hz,1H),7.21-7.15(m,1H),7.10(t,J= 7.5Hz,1H),6.96(d,J=2.3Hz,1H),2.80(t,J=7.7Hz,2H),2.59-2.53(m,6H),1.98(p,J=7.7Hz,2H),1.86-1.76(m,4H).

[0242] (+)-ESI-MS:m / z 229.1705(calcd.229.1699for C 15 H 21 N2 + [M+H] + ).

[0243] Example 305. Synthesis of 7-difluoro-3-(3-(piperidin-1-yl)propyl)-1H-indole (30)

[0244] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 2,4-difluorophenylhydrazine hydrochloride; the other steps are basically the same.

[0245] 1 H NMR(500MHz,Chloroform-d)δ8.48(s,1H),7.06-6.97(m,2H),6.70(ddd,J=11.3,9.4,2.2Hz,1H),2.68( t,J=7.6Hz,2H),2.51-2.30(m,6H),1.89(p,J=7.7Hz,2H),1.61(p,J=5.6Hz,4H),1.44(q,J=6.1Hz,2H).

[0246] (+)-ESI-MS:m / z 279.1664(calcd.279.1667for C 16 H 21 F2N2 + [M+H] + ).

[0247] Example 315,7-Difluoro-3-(3-(pyrrolidone-1-yl)propyl)-1H-indole (31)

[0248] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 2,4-difluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with pyrrolidine. The other steps are basically the same.

[0249] 1 H NMR (500MHz, Chloroform-d) δ8.84 (s, 1H), 7.02 (dd, J = 9.2, 2.2 Hz, 1H), 6.99 (s, 1H), 6.70 (ddd, J = 11. 3,9.4,2.2Hz,1H),2.71(t,J=7.5Hz,2H),2.60-2.49(m,6H),1.92(p,J=7.7Hz,2H),1.85-1.74(m,4H).

[0250] (+)-ESI-MS:m / z 265.1534(calcd.265.1511for C 15 H 19 F2N2 + [M+H] + ).

[0251] Example 325,7-Difluoro-3-(3-(4-methylpiperazin-1-yl)propyl)-1H-indole Synthesis (32)

[0252] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 2,4-difluorophenylhydrazine hydrochloride, and piperidine hydrochloride in step S3 is replaced with N-methylpiperazine. The other steps are basically the same.

[0253] 1 H NMR(500MHz,Chloroform-d)δ9.11(s,1H),7.01(dd,J=9.2,2.2Hz,1H),6.99(d,J=2.3Hz,1H),6.69(ddd ,J=11.4,9.5,2.2Hz,1H),2.69(t,J=7.5Hz,2H),2.64-2.36(m,10H),2.29(s,3H),1.86(p,J=7.7Hz,2H).

[0254] (+)-ESI-MS:m / z 294.1780(calcd.294.1776for C 16 H 22 F2N3 + [M+H] + ).

[0255] Example 333 Synthesis of 3-(3-(piperidin-1-yl)propyl)-5-(trifluoromethoxy)-1H-indole (33)

[0256] The only difference from Example 1 is that p-chlorophenylhydrazine hydrochloride in step S1 is replaced with 4-trifluoromethoxyphenylhydrazine hydrochloride; the other steps are basically the same.

[0257] 1 H NMR (600MHz, DMSO-d6) δ11.24(s,1H),10.37(s,1H),7.51(d,J=2.3Hz,1H),7.43(d, J=8.7Hz,1H),7.35(d,J=2.3Hz,1H),7.07-7.01(m,1H),3.41-3.36(m,2H),3.08-2. 97(m,2H),2.81(tdd,J=12.3,9.2,3.7Hz,2H),2.73(t,J=7.4Hz,2H),2.12-2.03(m, 2H),1.85-1.71(m,4H),1.67(dt,J=13.2,3.6Hz,1H),1.35(qt,J=12.1,4.4Hz,1H).

[0258] (+)-ESI-MS:m / z 327.1681(calcd.327.1679for C 17 H 22 F3N2 + [M+H] + ).

[0259] Table 1. Compound numbers and structural formulas prepared in Examples 1-33

[0260]

[0261]

[0262] B. Pharmacological Examples

[0263] Example 34: Preparation of sigma-1 receptor membrane and determination of ligand affinity

[0264] Preparation of Sigma-1 receptor membrane

[0265] The guinea pig was decapitated and the entire brain was quickly removed on ice. The tissue was collected into a centrifuge tube, and buffer A (10 mM Tris-HCl buffer containing 320 mM sucrose solution, pH 7.4) was added. The mixture was homogenized and centrifuged at 2000g, 4°C for 10 min. The supernatant was discarded. The centrifugation was repeated once. The precipitate was then stored at -80°C for later use.

[0266] σ1 receptor competitive binding assay

[0267] Step 1: Add 50 μL of Tris-HCl buffer to the total binding tube (TB), and add 50 μL of Maloperidol (final concentration 1.0 × 10⁻⁶) to the nonspecific binding tube (NB). -5 50 μL of the test compound was added to each specific binding tube (CB) containing the test compound.

[0268] Step 2: Add 100 μL of standard binding buffer (500 mL Tris-HCl buffer, containing 1.02 g MgCl2·6H2O, 14.6 mg EDTA, pH = 7.4) to each reaction tube.

[0269] Step 3: First, prepare a 500 mg / mL membrane suspension using Tris-HCl buffer for later use.

[0270] Step 4: Add 50 μL of the membrane preparation to each reaction tube.

[0271] Step 5: Add radioactive ligands to each reaction tube separately. 3 H](+)-pentazocine 50μL (final concentration 4nM).

[0272] Step 6: Incubate each reaction tube at 25°C for 135 min, filter under reduced pressure using a GF / B filter membrane pretreated with 0.5% PEI, wash thoroughly 3 times with ice-cold Tris buffer, transfer the filter membrane to a scintillation tube, add 1 mL of toluene scintillation solution, and let stand at room temperature in the dark for 6 h.

[0273] Step 7: Place the scintillation tube into the liquid scintillation counter for counting.

[0274] Data processing and statistical analysis:

[0275]

[0276] Wherein, TB: total binding constant; NB: non-specific binding constant; CB: compound-specific binding constant. The results are shown in Table 2 below.

[0277] Example 35: Determination of ligand affinity for H3

[0278] H3 receptor surface plasmon resonance experiment

[0279] Step 1: Test chip printing

[0280] Using Biodot TMThe AD1520 spotting instrument spots the test solution onto the surface of the 3D photocrosslinked chip, with four replicate spots for each sample. Four positive control spots (containing rapamycin standard) are also spotted at the four corners of the array. After spotting, the chip is vacuum dried and then transferred to a UV curing device for photocuring. Subsequently, it is sequentially washed with N,N-dimethylformamide, anhydrous ethanol, and ultrapure water, each for 15 minutes with shaking. After nitrogen drying, the flow path chamber cover is installed for later use.

[0281] Step 2: Protein Processing

[0282] Commercial protein preparations (HRH3 and FKBP12 proteins) were purified by dialysis: the protein solutions were placed in a dialysis apparatus, and the surfactants and glycerol in the original storage solution were removed by phosphate-buffered saline (PBS). The solutions were then concentrated using ultrafiltration centrifuge tubes, and the protein concentration was determined by the BCA method and stored for later use.

[0283] Step 3: On-machine testing and real-time monitoring

[0284] Five concentration gradients were prepared by diluting the protein stock solution with PBST buffer (pH 7.4, containing 0.1% Tween 20): 1×10⁻⁶. -8 M, 4×10 -8 M, 16×10 -8 M, 64×10 -8 M and 256×10 -8 M. Samples were injected and analyzed sequentially in ascending order of concentration, with PBST used as the mobile phase throughout the experiment. During the molecular interaction detection phase, the analyte was passed through the chip surface at a flow rate of 0.5 μL / s, and the binding reaction was carried out at 4 °C, with binding and dissociation times set to 600 seconds and 360 seconds, respectively. Subsequently, chip regeneration was performed using glycine-hydrochloric acid buffer at pH 2.0.

[0285] To ensure experimental reliability, rapamycin (positive control) and DMSO (negative control) were pre-dotted onto the chip. After testing, a regeneration step was performed before injecting 100 nM FKBP12 standard protein. By analyzing the binding signal and response data of the control sites, the chip performance and detection system were validated for quality control, thereby ensuring the stability of the experimental system and the reliability of the data.

[0286] Data processing and statistical analysis

[0287] The resonance signal (RU) is monitored in real time to generate binding and dissociation curves. Kinetic parameters (binding rate K) are calculated by fitting the curves. a Dissociation rate K d ) and affinity constant (K D =K d / Ka According to K) D Value determines binding strength: strong binding (K) D 10 -8 ~10 -6 M); combined with (K) D 10 -6 ~10 -3 M); extremely weak / no binding (K) D >10 -3 The results are shown in Table 2 below.

[0288] Table 2. In vitro experimental results of the compounds on sigma-1 and H3 receptors.

[0289]

[0290]

[0291]

[0292] Note: *The concentration of each test compound is 10 μM. "-" indicates not detected.

[0293] Based on the in vitro sigma-1 receptor activity assay results, 17 compounds (1, 2, 5, 7, 8, 16, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 30) showed strong affinity for the sigma-1 receptor target (K). i <100 nM). Further evaluation of the affinity of these 17 compounds for the H3R target was conducted using surface plasmon resonance (SPR) spectroscopy. The results showed that compounds (7, 18, 26, 27, 30) exhibited strong affinity for both the sigma-1 and H3 receptor dual targets (K0). i or K D <100nM).

[0294] Example 36 Mouse Acetic Acid Writhing Test

[0295] ICR mice, weighing 22-32g, were randomly divided into a negative control group, a model group, a positive control group (BD-1063 and JNJ5207852, dissolved in physiological saline), and various dose groups of the test compounds (solvent: physiological saline), with 6 mice in each group. The negative control group and model group were administered the corresponding solvent, physiological saline, subcutaneously; the positive control group was administered the corresponding positive control drug subcutaneously; and the various dose groups of the test compounds were administered the corresponding doses of the compounds subcutaneously, with an administration volume of 10mL / kg. Five minutes after subcutaneous administration, the mice were intraperitoneally given 1% acetic acid, and the number of writhing episodes within 45 minutes was recorded. The results of the compound detection were compared with those of the model detection, and the writhing inhibition rate (maximum analgesic effect percentage, MPE%) was used as the objective criterion for determining whether an analgesic effect was present.

[0296] Data processing and statistical analysis

[0297] Maximum analgesic effect percentage (MPE%) = (Wc - Wt) / Wc × 100%, where Wc and Wt represent the mean number of writhing movements in the model group and the drug-treated group, respectively. Experimental data are expressed as Mean ± SEM and statistical analysis was performed using GraphPad Prism software. After normality and homogeneity of variance tests, one-way ANOVA combined with Dunnett's test was used to compare differences between groups, and the effect of ED was calculated using nonlinear regression. 50 The results are shown in Tables 3 and 4 below.

[0298] Table 3. Analgesic effects of sigma-1 / H3 receptor dual-target compounds in the acetic acid writhing model.

[0299]

[0300]

[0301] Table 4. Half-maximal effective dose of Sigma-1 / H3 receptor dual-target compounds in the acetic acid writhing model.

[0302]

[0303] The positive control drugs (BD-1063 and JNJ5207852) and the five sigma-1 / H3 receptor dual-target compounds all exerted analgesic effects in a dose-dependent manner. All dual-target compounds showed significantly higher analgesic potency than the positive control, with compound 7 exhibiting strong analgesic activity (ED). 50 <1 mg / kg), with analgesic activity more than 98.5 times stronger than the positive control drug. The dose-response relationship of compound 7 in the mouse acetic acid writhing model is as follows: Figure 1 As shown, under the same analgesic effect, the effective dose of 7 was significantly lower than that of the positive control drugs BD-1063 and JNJ5207852. This result is consistent with the design strategy of dual-target drugs, which is to reduce drug dose-related side effects by reducing the effective dose while maintaining analgesic activity.

[0304] Example 37: Paclitaxel-induced mouse model of neuropathic pain

[0305] ICR mice, weighing 22-32g, were randomly divided into a negative control group, a model group, and various dose groups of the test compound, with 6 mice in each group. The negative control group and the model group were administered physiological saline subcutaneously, while the various dose groups of the test compound were administered the corresponding dose of the compound subcutaneously.

[0306] Experimental mice were allowed free movement on an elevated metal mesh platform within a transparent plexiglass box (size: 20×30×15cm) to acclimatize to their environment. After 30 minutes, progressively increasing pressure was applied to the left hind paw of each mouse using an instrument. When a paw withdrawal response was observed, the device automatically recorded the mechanical withdrawal threshold (MWT). This test was repeated three times per animal (with an experimental interval of 30 seconds). A 6 mg / mL paclitaxel stock solution was prepared by mixing polyoxyethylene castor oil and anhydrous ethanol in a 1:1 ratio, and then diluted 30 times with physiological saline to obtain a 0.2 mg / mL working solution. Mice with a suitable MWT were selected before the experiment, and a peripheral neuralgia model was established by intraperitoneal injection of paclitaxel (2 mg / kg / day) for five consecutive days. MWT was retested on day 6 of modeling to verify model success. Subsequently, successfully modeled animals were subcutaneously injected with different doses of the compound or physiological saline as controls. MWT changes were dynamically monitored at multiple time points at 0, 15, 30, 45, 60, 90, and 120 minutes after drug administration.

[0307] Data processing and statistical analysis

[0308] Maximum possible percentage effect (%MPE) = (MWT1 - MWT2) / (MWT3 - MWT2) × 100%, where MWT1 refers to the maximum threshold after drug treatment, MWT2 refers to the threshold after modeling, and MWT3 refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated using the area under the curve (AUC). The AUC (min*g) describing the change of mechanical withdrawal threshold over time was calculated using GraphPad Prism software using an approximate trapezoidal rule. The results are shown in Table 5 below. Figure 2 and Figure 3 As shown.

[0309] Depend on Figure 2 and Figure 3 It was found that after the successful establishment of the paclitaxel-induced neuropathic pain model in mice, the mechanical withdrawal threshold of the model group mice was significantly reduced. Compound 7 significantly reversed paclitaxel-induced neuropathic pain in a dose-dependent manner, and the highest analgesic inhibition rate was reached 45 minutes after administration. The analgesic inhibition rates (MPE%) at 0.0125 mg / kg, 0.05 mg / kg, and 0.2 mg / kg were 24.72%, 48.56%, and 74.75%, respectively. The ED was calculated by nonlinear fitting using GraphPad Prism software. 50 The value is 0.06 mg / kg.

[0310] Table 5 shows the half-maximal effective dose of compound 7 in a paclitaxel-induced neuropathic pain model.

[0311] compound <![CDATA[ED 50 (95% confidence interval, mg / kg) 7 0.06(0.04-0.07)

[0312] Example 38 Acute Toxicity Test

[0313] ICR mice, weighing 22-32g, were randomly divided into groups of 6 mice per group and each group was assigned a dose of the test compound. The mice were administered a single dose of 1000mg / kg and 250mg / kg (0.1mL / 10g, suspended in physiological saline), and the toxicity and mortality were observed for 7 consecutive days.

[0314] The LD values ​​of each compound were calculated using the Bliss method. 50 Values, and based on the mouse acetic acid writhing test, ED 50 The therapeutic index (TI = LD) was calculated based on the results. 50 / ED 50 The results are shown in Table 6 below.

[0315] Table 6 Results of acute toxicity tests for compound 7

[0316]

[0317] The results showed that compound 7 did not cause mouse mortality when administered via gavage at 1000 mg / kg or subcutaneously at 250 mg / kg, and its LD50 was [not specified]. 50 Compound 7 demonstrated superior safety and therapeutic window in acute toxicity studies at doses greater than 1000 mg / kg (ig) or 250 mg / kg (sc), with therapeutic indices greater than 1000.

Claims

1. A compound represented by general formula (Ⅰ) or a pharmaceutically acceptable salt thereof: in, R 1 Selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally R 1a replace; R 1a Selected from halogens, C1-C3 alkyl groups, or C1-C3 alkoxy groups; R 2 R 3 Each is independently selected from hydrogen or halogen; m is 0 or 1; n is 0 or 1; X is CH2 or CHR 6 ; R 6 Selected from C1-C6 alkyl, C1-C6 alkoxy or C6-C 10 Aryl; The conditions are: R 1 R 2 R 3 They are not both hydrogen; When R 6 When the components are selected from C1-C6 alkyl or C1-C6 alkoxy, m is 1; Not the following compounds:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 1 Selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally R 1a Replace; and / or, R 1a Selected from halogens; or, R 1a Selected from fluorine.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein, R 2 Selected from hydrogen or chlorine.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein, R 3 Selected from hydrogen, fluorine, or chlorine.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from C1-C6 alkyl, C1-C6 alkoxy, or phenyl; or, R 6 Selected from C1-C3 alkyl, C1-C3 alkoxy, or phenyl; or, R 6 Selected from methyl, methoxy, or phenyl; or, X is CHR. 6 R 6 It is a phenyl group.

6. The following compounds or their pharmaceutically acceptable salts: 5-Chloro-3-(3-(piperidin-1-yl)propyl)-1H-indole 5-Fluoro-3-(3-(piperidin-1-yl))propyl)-1H-indole 5-Fluoro-3-(3-(4-methylpiperidin-1-yl))propyl)-1H-indole 4-(3-(5-fluoro-1H-indol-3-yl))propyl)morpholine 5-Fluoro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole 5-Fluoro-3-(3-(4-methoxypiperidin-1-yl))propyl)-1H-indole 5-Methyl-3-(3-(piperidin-1-yl))propyl)-1H-indole 5-Methyl-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole 5-Methyl-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole 5-Methyl-3-(3-(4-methylpiperidin-1-yl))propyl)-1H-indole 4-(3-(5-methyl-1H-indol-3-yl))propyl)morpholine 5-Methyl-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole 3-(3-(4-methoxypiperidin-1-yl))propyl)-5-methyl-1H-indole N,N-Diethyl-3-(5-methyl-1H-indol-3-yl)propyl-1-amine 5-Methoxy-N-acetyltryptamine-3-(3-(piperidin-1-yl))propyl)-1H-indole 5-Methoxy-N-acetyltryptamine-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole 6-Chloro-3-(3-(piperidin-1-yl))propyl)-1H-indole 6-Chloro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole 6-Chloro-3-(3-(piperidin-1-yl))propyl)-1H-indole 6-Chloro-3-(3-(4-phenylpiperidin-1-yl))propyl)-1H-indole hydrochloride 5-Bromo-3-(3-(piperidin-1-yl))propyl)-1H-indole 5,7-Difluoro-3-(3-(piperidin-1-yl))propyl)-1H-indole 5,7-Difluoro-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole 5,7-Difluoro-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole 3-(3-(piperidin-1-yl))propyl)-5-(trifluoromethoxy)-1H-indole 5-Fluoro-3-(3-(pyrrolidone-1-yl))propyl)-1H-indole 5-Fluoro-3-(3-(4-methylpiperazin-1-yl))propyl)-1H-indole N,N-Diethyl-3-(5-fluoro-1H-indol-3-yl)propylamine 5-Fluoro-3-(2-(piperidin-1-yl))ethyl)-1H-indole 5-Fluoro-3-(2-(pyrrolidone-1-yl))ethyl)-1H-indole 5-Fluoro-3-(2-(4-methylpiperazin-1-yl))ethyl)-1H-indole 3-(3-(piperidin-1-yl))propyl)-1H-indole 3-(3-(pyrrolidone-1-yl))propyl)-1H-indole.

7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Use of the compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention or treatment of diseases mediated by dual targets of the sigma-1 / H3 receptor.

9. The use according to claim 8, wherein, The diseases mediated by the sigma-1 / H3 receptor dual target are selected from pain-related diseases.

10. The use according to claim 9, wherein, The pain-related diseases mentioned are selected from acute pain, chronic pain, intractable pain, cancer pain, special pain, moderate to severe pain, neuralgia, inflammatory pain, nociceptive pain, hyperalgesia, or visceral pain.

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