Thiophene piperazine amide derivative, composition and application thereof

Abstract

The present invention discloses a thiophene piperazine amide derivative, a composition and its application. The derivative is a compound as described in the general structural formula (I) or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof; the composition comprises an acylated indoline derivative or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers. The present invention also provides the application of a thiophene piperazine amide derivative or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof in the preparation of a drug for preventing or treating pain diseases. The derivative may have dual activity as a σ1 receptor antagonist and a μ receptor agonist, and can significantly improve formalin-induced pain; when used to treat pain, especially neuralgia, it has the characteristics of high response rate, low side effects, and few adverse reactions, meeting the needs of clinical medication.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a thiophene piperazine amide derivative, a composition and an application thereof. Background Art

[0002] Pain is an unpleasant subjective feeling and emotional experience associated with tissue damage or potential damage. Pain is an internal warning system of the organism that can cause defensive reactions and has a protective effect. However, strong or persistent pain can cause disorders in the body's physiological functions and have direct effects on humans, such as affecting appetite and sleep, reducing quality of life, losing labor, reducing economic benefits, and increasing medical expenses. Pain affects about 20% of the adult population, and many patients do not receive effective treatment and pain relief.

[0003] Neuropathic pain refers to pain directly caused by damage or disease of the somatic sensory nervous system, including peripheral nerve fibers and the central nervous system. It is a type of pain that manifests itself as spontaneous pain, hyperalgesia, abnormal pain, and paresthesia. About 7-10% of people worldwide suffer from neuralgia, and its incidence increases with age. Currently, the main drugs used to treat or alleviate neuropathic pain are: non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anticonvulsants, and opioids.

[0004] The treatment of neuropathic pain is mainly drug therapy assisted by psychological and behavioral therapy and other non-invasive methods. Commonly used drugs in clinical practice include anticonvulsants, antidepressants, 5-hydroxytryptamine (5-HT) and norepinephrine reuptake inhibitors, local anesthetics, opioid analgesics, N-methyl-D-aspartate receptor (NMDA) antagonists, etc. Among them, the first three types of drugs are the first choice for the treatment of neuropathic pain. Currently, the drugs used as the first-line treatment of neuropathic pain include anticonvulsants (gabapentin and pregabalin). These drugs are not metabolized by the liver and are excreted by the kidneys. Therefore, patients with renal insufficiency or who are undergoing renal dialysis need to use them with caution. Common side effects include drowsiness, dizziness, fatigue, weight gain and ataxia. Tricyclic antidepressants (such as amitriptyline, nortriptyline, etc.) and 5-hydroxytryptamine and norepinephrine reuptake inhibitor antidepressants (such as venlafaxine, duloxetine, etc.) have strong side effects and low response rates. Opioids (morphine, fentanyl, tramadol, etc.) are second-line drugs for the treatment of neuropathic pain. Their side effects are very obvious, mainly manifested as respiratory depression, constipation, nausea, etc., and long-term use is prone to drug resistance and addiction. Sigma-1 (σ1) receptors, H3 receptors, cannabinoid receptors, NOP receptors, etc. are new targets that have been studied more in recent years. Biased mu receptor agonists are also a current research hotspot, but the research on these targets is basically in the early stages, and few have entered clinical trials. Therefore, it is of great significance to find new mechanisms of action and study analgesics with high analgesic activity and few side effects.

[0005] σ1 receptor is a new target for the treatment of neuropathic pain that has recently emerged. Many studies have shown that its receptor antagonist itself has analgesic effects. Mice with knockout σ1 receptor gene were insensitive to pain in formalin experiment. When mice were pretreated with σ1 receptor antagonist (haloperidol), formalin-induced pain was significantly attenuated. Similarly, Entrena et al. found that wild-type (WT) mice induced mechanical allodynia in an experiment of central sensitization pain induced by intraplantar injection of capsaicin, while mice with knockout σ1 receptor gene had no obvious pain behavior, and σ1 receptor antagonist inhibited this pain behavior. In recent years, quinolinone, aryl pyrimidine and 6-hydroxypyridazinone derivatives have been synthesized based on σ1 receptor antagonists for the treatment of neuropathic pain. In 2012, Esteve Company of Spain developed compound S1RA, which has the effect of treating neuropathic pain and enhancing the analgesic effect of opioids. Phase II clinical trials are currently underway. However, there are still no marketed drugs based on σ1 receptor for anti-neuralgia.

[0006] The initial use of σ1 receptors for analgesia originated from Chien and Pasternak's discovery that sigma receptors are endogenous anti-opioid systems. Sigma-1 receptor agonists can counteract the analgesic effect mediated by opioid receptors, while on the contrary, their antagonists (such as haloperidol) enhance the analgesic effect of the opioid receptor agonist morphine. In 1992, Carroll et al. found that phenazocine and its derivatives have dual pharmacological activities of sigma-1 receptors and mu receptors through in vitro activity testing, but did not conduct an in vivo analgesic activity evaluation. Based on Carroll's previous research, the Prezzavento research group studied the analgesic effect of phenazocine on the mechanical pain model. The experimental data showed that its analgesic effect could be antagonized by the μ receptor antagonists naloxone, naloxone methyl iodide and σ1 agonist PRE-084, proving that phenazocine acts on both σ1 receptors and μ receptors to produce analgesic effects. This compound has dual pharmacological activity and good analgesic activity, and is expected to be used in the treatment of pain. In 2019, Mónica García proposed the synthesis of spirocycloundecane derivatives based on dual targets of σ1 and μ receptors through pharmacophore fusion method, which has analgesic activity. Therefore, it is of great scientific significance to find analgesics with dual pharmacological activities of σ1 receptor antagonists and μ receptor agonists. Summary of the invention

[0007] One of the purposes of the present invention is to provide a thiophene piperazine amide derivative and a composition, which can have dual activity of σ1 receptor antagonist and μ receptor agonist, and can significantly improve formalin-induced I pain; it is used to treat pain, especially neuralgia, and has the characteristics of high response rate, small side effects, few adverse reactions, etc., meeting the needs of clinical medication.

[0008] The second object of the present invention is to provide the use of thiophene piperazine amide derivatives or pharmaceutically acceptable salts thereof or optical isomers or stereoisomers thereof in the preparation of drugs for preventing or treating pain diseases.

[0009] To achieve the above object, the technical solution adopted by the present invention is: a thiophene piperazine amide derivative, which is a compound having a general structural formula (I) or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof:

[0010]

[0011] Wherein, Q is C or N; n and m are 0, 1 or 2 respectively;

[0012] R1 is selected from halogen, C 1-5 Alkyl, halogen substituted C 1-5 One of the alkyl groups,

[0013] R2, R3, R4, R5 are selected from hydrogen, C 1-5 Alkoxy, substituted C 1-5 Alkoxy, halogen, C 1-5 Alkyl, substituted C 1-5 Alkyl, C 3-7 Cycloalkyl, substituted C 3-7 One of cycloalkyl, phenyl, alkyl-substituted phenyl and heteroaromatic ring.

[0014] Preferably, the C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, pentyl and isopentyl; the C 1-5 The alkoxy group is selected from one of methoxy, ethoxy, propoxy, butoxy and pentoxy.

[0015] Preferably, in R1, the halogen-substituted C 1-5 The alkyl group is selected from dichloromethyl and trifluoromethyl.

[0016] Preferably, the substituted C 1-5 Alkoxy, substituted C 1-5 Alkyl, substituted C 3-7 The substituents in the cycloalkyl group are selected from one or more of amino, hydroxyl, methyl and halogen.

[0017] Preferably, the halogen is fluorine, chlorine, bromine or iodine.

[0018] Preferably, the salt is a pharmaceutically acceptable anionic salt selected from hydrochloride, hydrobromide, hydroiodide, oxalate, citrate, acetate, maleate, fumarate, nitrate, sulfate, bisulfate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate. Preferably, the anionic salt is hydrochloride or oxalate.

[0019] Preferably, the derivative is:

[0020] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide,

[0021] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)propionamide,

[0022] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)butyramide,

[0023] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide,

[0024] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide,

[0025] 2-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide,

[0026] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide,

[0027] 2-methyl-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide,

[0028] 4-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide,

[0029] 4-Fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide,

[0030] 2-Fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide,

[0031] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0032] N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)acrylamide,

[0033] N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide,

[0034] N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide,

[0035] N-(4-methoxyphenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide,

[0036] N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)furan-2-carboxamide,

[0037] N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0038] N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0039] N-(4-methoxyphenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0040] N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)thiophene-2-carboxamide,

[0041] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide,

[0042] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)propionamide,

[0043] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)butyramide,

[0044] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide,

[0045] 2-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide,

[0046] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide,

[0047] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide,

[0048] 2-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide,

[0049] 4-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide,

[0050] 4-Fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide,

[0051] 2-Fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide,

[0052] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0053] 3-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0054] N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide,

[0055] N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethylethyl)cyclopropanecarboxamide,

[0056] N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide,

[0057] N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)cyclopropanecarboxamide,

[0058] N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide,

[0059] N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide,

[0060] N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide,

[0061] N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)acrylamide,

[0062] N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0063] N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0064] N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide,

[0065] N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl-N-(p-tolyl)furan-2-carboxamide,

[0066] N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)thiophene-2-carboxamide.

[0067] The general reaction formula is as follows:

[0068]

[0069] On the other hand, the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the thiophene piperazine amide derivative or a pharmaceutically acceptable salt thereof or an optical isomer thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients (carriers, excipients, binders, disintegrants, lubricants or sweeteners, etc.).

[0070] The auxiliary materials such as excipients described in the present invention can be calcium hydrogen phosphate; the binder can be selected from corn starch, gelatin, and gum arabic; the disintegrant can be corn starch, potato starch, or alginic acid; the lubricant can be magnesium stearate; when the preparation is in the form of a capsule, in addition to the above-mentioned types of raw materials, it can also contain liquid carriers such as oils and fats.

[0071] The present invention further provides the use of the thiophene piperazine amide derivatives of the present invention or their pharmaceutically acceptable salts or their optical isomers or their stereoisomers in the preparation of drugs for preventing or treating pain diseases.

[0072] Preferably, the pain disease is neuralgia, inflammatory pain, trigeminal neuralgia or cancer pain.

[0073] The synthesis method of the compound of general formula I of the present invention is to first synthesize an amide compound from an aniline compound and a carbon chain containing an acyl chloride, then link it with a thiophene piperazine ring, and finally reduce the carbonyl group and acylate to obtain a series of thiophene piperazine derivatives.

[0074] The effective dose of the compound of the present invention can be taken orally with an inert diluent or a carrier. It can be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral treatment, the compound of the present invention can be used together with an excipient and in the form of tablets, lozenges, capsules, suspensions, syrups, etc. These preparations should contain about 1% to 99% by weight of the active compound or its salt of the present invention, but depending on the dosage form, the active content of these active compounds or their salts is preferably in the range of 4% to 70%.

[0075] The compound of general formula I of the present invention or its salt, each unit dose of active ingredient can provide about 0.01mg to 1000mg, the compound containing general formula I or its salt can be administered by common administration routes, such as oral optional capsules, tablets, syrups and the like; parenteral administration can be in the form of injections such as subcutaneous injection, intramuscular injection, intravenous injection, etc.; topical administration can be in the form of ointment or lotion, or in the form of suppositories for rectal administration, in the form of a patch delivery system for transdermal administration, the total daily dose is usually between about 0.05mg and 2000mg, the specific dosage depends on the specific conditions of the patient, such as health conditions, age, sex, body weight and drug tolerance, can be determined according to the type and severity of the disease or condition by the physician. Those skilled in the art are well aware of the effective doses of commonly used central nervous system drugs, and they can determine the appropriate dose based on these or other factors. For parenteral administration, the compound provided by the present invention can be combined with sterile water or an organic medium to form an injectable solution or suspension.

[0076] In addition, the compounds provided by the present invention and the pharmaceutical compositions composed of the compounds can be used to treat and prevent pain, including acute pain: pain caused by acute injury to soft tissue and joints, postoperative pain, obstetric pain, acute herpes zoster pain, gout, etc.; chronic pain: pain caused by strain or degeneration of soft tissue and joints, intervertebral disc pain, neurogenic pain; intractable pain: trigeminal neuralgia, postherpetic neuralgia, intervertebral disc herniation, intractable headache; cancer pain: pain caused by advanced tumors, pain caused by tumor metastasis; special pain types: thromboangiitis vasculitis pain, intractable angina pectoris, idiopathic chest and abdominal pain, etc.

[0077] In vitro receptor binding tests show that the derivatives provided by the present invention have dual activities of σ1 receptor antagonists and μ receptor agonists. In addition, animal test results also show that in the formalin-induced pain model, the results show that the ED of thiophene piperazine derivatives is 50 The value is lower than that of the positive drug pregabalin, and has good analgesic activity. Therefore, the derivative provided by the present invention has the potential to treat pain, especially neuralgia. When used to treat pain, especially neuralgia, it has the characteristics of high response rate, small side effects, and few adverse reactions, meeting the needs of clinical medication. DETAILED DESCRIPTION

[0078] The present invention is further described in detail below in conjunction with embodiments.

[0079] Example 1

[0080] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)acetamide, the reaction formula is:

[0081]

[0082] The specific preparation process is:

[0083] 1) tert-Butyl 4-(thiophene-2-carbonyl)piperazine-1-carboxylate (Intermediate 1):

[0084]

[0085] 4.37g 2-thiophenecarboxylic acid, 6.07g boc-piperazine, 13.63g HATU, 9.08mL triethylamine, 100mL DMF were added to a 250mL single-mouth bottle in sequence and stirred at room temperature overnight. After the reaction was completed, water was added to quench, extracted with EA, washed with saturated brine, added with anhydrous sodium sulfate, stirred and dried, and the solvent was removed by vacuum distillation. Appropriate amounts of anhydrous ethanol and petroleum ether were added, heated to dissolve, cooled and crystallized, filtered, and the filter cake was washed with petroleum ether, and dried to obtain a white solid with a yield of about 80.7%.

[0086] 2) Piperazine-1-yl(thiophene-2-yl)methanone (Intermediate 2):

[0087]

[0088] 5.0g of tert-butyl 4-(thiophene-2-carbonyl)piperazine-1-carboxylate (intermediate 1) was dissolved in 10mL of dichloromethane, placed in an ice bath and stirred to 0°C; 7.5mL of trifluoroacetic acid was slowly added dropwise and stirred at room temperature for 4 hours. After the reaction was completed, the solvent and excess trifluoroacetic acid were first removed by rotary evaporation, 100mL of water was added for quenching, and then saturated NaHCO3 solution was used for neutralization, extracted with EA, washed with saturated brine, added with anhydrous sodium sulfate, stirred and dried, and the solvent was removed by vacuum distillation. A colorless oil was obtained by column chromatography with EA:PE=3:1~1:1, and the yield was about 75.4%.

[0089] 3) 2-Chloro-N-phenylamide (Intermediate 3):

[0090]

[0091] Dissolve 3.0g aniline and 8.9g K2CO3 in 10mL acetone, place in an ice bath and stir to 0℃; slowly add 4.4g chloroacetyl chloride dropwise and stir at room temperature for 4 hours. After the reaction is completed, add water to quench, extract with EA, wash with dilute NaOH solution and saturated brine respectively, add anhydrous sodium sulfate, stir and dry, remove the solvent by vacuum distillation, add appropriate amount of anhydrous ethanol and petroleum ether, heat to dissolve, cool and crystallize, filter and wash the filter cake with petroleum ether, dry to obtain a white solid, with a yield of about 65.8%.

[0092] 4) N-phenyl-2-(4-(thiophene-2-carbonyl)piperazin-1-yl)acetamide (Intermediate 4):

[0093]

[0094] Take a single-necked flask and add 1.69g of piperazine-1-yl (thiophene-2-yl) ketone (intermediate 2), 150mL of acetone and 1.96g of 2-chloro-N-phenylamide (intermediate 3), 4.07g of K2CO3 in turn, and react at room temperature for 8h. After the reaction is completed, add water to quench, extract with an appropriate amount of EA, wash 3 times with saturated brine, and dry the organic phase with anhydrous sodium sulfate. Remove the solvent by distillation under reduced pressure, pass through a column with PE:EA=1:1, and obtain about 2.63g of white solid, with a yield of 79.9%.

[0095] 5) N-(2-(4-(Thien-2-ylmethyl)piperazin-1-yl)ethyl)aniline (Intermediate 5):

[0096]

[0097] 2.0 g of intermediate 4 and 100 mL of anhydrous THF were added to a single-necked flask, stirred in an ice bath for 15 min to cool to 0°C, then 1.37 g of LiAlH4 was slowly added, and the mixture was transferred to an oil bath and refluxed at 65°C for 4 h. After the reaction was completed, the mixture was cooled in an ice bath, ethanol was slowly added to quench the reaction, extracted with EA, washed with 5% NaOH solution and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The mixture was filtered through a column with PE:EA=1:2 to obtain 1.55 g of a colorless oil with a yield of 85.0%.

[0098] 6) N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide

[0099]

[0100] 0.35 g of intermediate 5, 0.18 g of triethylamine and 50 mL of DCM were added to a single-necked flask, stirred for 15 min in an ice bath, cooled to 0 °C, and 0.13 g of acetyl chloride was slowly added dropwise, and continued to stir in an ice bath for 1 h. After the reaction was completed, saturated NaHCO3 was added to quench, extracted with DCM, washed with saturated NaHCO3 solution and saturated brine in sequence, dried with anhydrous sodium sulfate, and the solvent was removed by rotation; first rinsed with PE:EA=1:2, and then passed through a column with DCM:MeOH=25:1 to obtain 0.31 g of a yellow-brown transparent oil with a yield of 77.5%.

[0101] 1H NMR(400MHz,Chloroform-d)δ7.38(dd,J=8.2,6.5Hz,2H),7.34–7.28(m,1H),7.21–7.16(m,3H),6.92(dd,J=5.0,3.4Hz,1H),6 .88(dd,J=3.4,1.1Hz,1H),3.81(t,J=7.0Hz,2H),3.69(s,2H),2.47(t,J=7.0Hz,10H),1.80(s,3H).MS(ESI)m / z=344.2([M+H] + ).

[0102] Example 2

[0103] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)propionamide

[0104] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "propionyl chloride" and following the method of Example 1 for the rest of the process.

[0105] 1 H NMR(400MHz,Chloroform-d)δ7.42–7.27(m,3H),7.23–7.10(m,4H),6.94–6.87(m,2H),3.81(t,J=7.1Hz,2H), 3.75–3.63(m,2H),2.55–2.38(m,10H),2.01(q,J=7.4Hz,2H),1.01(t,J=7.4Hz,3H).MS(ESI)m / z=358.2([M+H] + ).

[0106] Example 3

[0107] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)butyramide

[0108] The target compound was prepared by using butyryl chloride instead of acetyl chloride in step 6) of Example 1 and the other steps were carried out according to the method of Example 1.

[0109] 1H NMR (400MHz, Chloroform-d) δ7.41–7.34(m,2H),7.34–7.28(m,1H),7.22–7.14(m,3H),6.92(dd,J=5.0,3.4Hz,1H),6.88(dd,J=3.4,1.1Hz,1H),3.81(t ,J=7.0Hz,2H),3.69(d,J=0.8Hz,2H),2.65–2.24(m,10H),1.97(t,J=7.4Hz, 2H),1.56(h,J=7.4Hz,2H),0.79(t,J=7.4Hz,3H).MS(ESI)m / z=372.2([M+H] + ).

[0110] Example 4

[0111] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide

[0112] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "cyclopropylcarbonyl chloride" and following the method of Example 1 for the rest of the process.

[0113] 1 H NMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.34–7.28(m,1H),7.26–7.21(m,3H),6.96–6.92(m,2H),3.94–3.82(m,4H),2.8 3–2.53(m,10H),1.26(qd,J=7.6,3.2Hz,1H),0.96(qd,J=4.4,3.1Hz,2H),0.59(dq,J=7.0,3.7Hz,2H).MS(ESI)m / z=370.3([M+H] + ).

[0114] Example 5

[0115] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)acrylamide

[0116] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "propenyl chloride" and following the method of Example 1 for the rest of the process.

[0117] 1H NMR(400MHz,Chloroform-d)δ7.44–7.26(m,3H),7.22–7.11(m,3H),6.95–6.83(m,2H),6.33(dd,J=16.8,2.0Hz,1H),5.97(dd,J=16.8,10 .3Hz,1H),5.48(dd,J=10.3,2.1Hz,1H),3.90(dd,J=7.5,6.6Hz,2H),3.69(d,J=0.8Hz,2H),2.59–2.30(m,10H).MS(ESI)m / z=356.2([M+H] + ).

[0118] Example 6

[0119] Preparation of 2-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide

[0120] The target compound was prepared by substituting "methoxyacetyl chloride" for "acetyl chloride" in step 6) of Example 1, and following the method of Example 1 for the rest of the process.

[0121] 1 H NMR(400MHz,Chloroform-d)δ7.42–7.33(m,3H),7.23(dd,J=4.9,1.5Hz,1H),7.20–7.14(m,2H),6.95–6.90(m,2H),3.84 (t,J=6.9Hz,2H),3.81–3.77(m,2H),3.70(s,2H),3.30(s,3H),2.56(dd,J=13.2,6.2Hz,10H).MS(ESI)m / z=374.3([M+H] + ).

[0122] Example 7

[0123] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide

[0124] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "benzoyl chloride" and following the method of Example 1 for the rest of the process.

[0125] 1H NMR(400MHz,Chloroform-d)δ7.28–7.23(m,2H),7.21(dd,J=5.0,1.3Hz,1H),7.20–7.15(m,3H),7.15–7.09(m,3H),7.07–7.02(m,2H),6. 92(dd,J=5.0,3.4Hz,1H),6.89(dd,J=3.5,1.1Hz,1H),4.04(t,J=7.0Hz,2H),3.70(s,2H),2.73–2.31(m,10H).MS(ESI)m / z=406.2([M+H] + ).

[0126] Example 8

[0127] Preparation of 2-methyl-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide

[0128] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "o-methylbenzoyl chloride" and following the method of Example 1 for the rest of the process.

[0129] 1 H NMR(400MHz,Chloroform-d)δ7.22(dd,J=5.0,1.3Hz,1H),7.11(d,J=7.4Hz,2H),7.03(q,J=10.2,8.5Hz,5H),6.93(dd,J=5.0,3.4H z,2H),6.89(d,J=3.8Hz,2H),4.10(dt,J=16.5,8.2Hz,2H),3.71(s,2H),2.65–2.40(m,10H),2.34(s,3H).MS(ESI)m / z=420.3([M+H] + ).

[0130] Example 9

[0131] Preparation of 4-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide

[0132] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "p-methoxybenzoyl chloride" and following the method of Example 1 for the rest of the process.

[0133] 1H NMR(400MHz,Chloroform-d)δ7.26–7.16(m,5H),7.14–7.08(m,1H),7.07–7.03(m,2H),6.92(dd,J=5.1,3.4Hz,1H),6.88(dd,J=3.4, 1.2Hz,1H),6.65–6.59(m,2H),4.05–3.98(m,2H),3.71(s,3H),3.69(d,J=0.8Hz,2H),2.69–2.36(m,10H).MS(ESI)m / z=436.2([M+H] + ).

[0134] Example 10

[0135] Preparation of 4-fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide

[0136] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "p-fluorobenzoyl chloride" and following the method of Example 1 for the rest of the process.

[0137] 1 H NMR(400MHz,Chloroform-d)δ7.25(q,J=5.4,4.1Hz,2H),7.23–7.16(m,3H),7.16–7.09(m,1H),7.07–7.00(m,2H),6.95–6.87(m, 2H),6.81(td,J=8.8,2.6Hz,2H),4.02(q,J=4.8,2.4Hz,2H),3.70(d,J=2.6Hz,2H),2.75–2.23(m,10H).MS(ESI)m / z=424.2([M+H] + ).

[0138] Embodiment 11

[0139] Preparation of 2-fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide

[0140] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "o-fluorobenzoyl chloride" and following the method of Example 1 for the rest of the process.

[0141] 1H NMR(400MHz,Chloroform-d)δ7.23–7.12(m,5H),7.09(d,J=9.0Hz,3H),6.93(ddd,J=13.2,11.6,5.5Hz,3H ),6.77(t,J=8.8Hz,1H),4.04(t,J=7.1Hz,2H),3.71(s,2H),2.67–2.26(m,10H).MS(ESI)m / z=424.2([M+H] + ).

[0142] Example 12

[0143] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0144] The target compound was prepared by substituting 2-furoyl chloride for acetyl chloride in step 6) of Example 1 and following the method of Example 1 for the rest of the process.

[0145] 1 H NMR(400MHz,Chloroform-d)δ7.42–7.32(m,3H),7.30(d,J=1.7Hz,1H),7.26–7.21(m,2H),7.20(dd,J=5.1,1.3Hz,1H),6.94–6.84(m,2H ),6.15(dt,J=3.3,1.5Hz,1H),5.64(d,J=3.5Hz,1H),3.96(t,J=7.0Hz,2H),3.68(s,2H),2.66–2.30(m,10H).MS(ESI)m / z=396.2([M+H] + ).

[0146] Example 13

[0147] Preparation of N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)-N-(p-tolyl)acrylamide

[0148] The target compound was prepared by replacing "aniline" in step 3) of Example 5 with "p-toluidine" and following the method of Example 5 for the rest of the process.

[0149] 1H NMR(400MHz,Chloroform-d)δ7.20(dd,J=13.4,6.4Hz,3H),7.07(d,J=7.7Hz,2H),6.96–6.84(m,2H),6.32(d,J=16.8Hz,1H),6.00(dd,J=16.9, 10.3Hz,1H),5.47(d,J=10.3Hz,1H),3.88(t,J=7.2Hz,2H),3.70(s,2H),2.51(dd,J=17.9,9.8Hz,10H),2.37(s,3H).MS(ESI)m / z=370.2([M+H] + ).

[0150] Embodiment 14

[0151] Preparation of N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)acrylamide

[0152] Substitute "p-fluoroaniline" for "aniline" in step 3) of Example 5, and prepare the target compound according to the method of Example 5 in other processes.

[0153] 1 H NMR(400MHz,Chloroform-d)δ7.39–7.33(m,2H),7.22(dd,J=5.1,1.3Hz,1H),7.20– 7.14(m,2H),6.94(dd,J=5.1,3.4Hz,1H),6.90(dt,J=3.5,1.0Hz,1H),6.35(dd,J=16 .7,2.0Hz,1H),5.97(dd,J=16.7,10.3Hz,1H),5.53(dd,J=10.3,2.0Hz,1H),3.87(t ,J=6.8Hz,2H),3.70(d,J=0.8Hz,2H),2.57–2.39(m,10H).MS(ESI)m / z=374.2([M+H] + ).

[0154] Embodiment 15

[0155] Preparation of N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)acrylamide

[0156] Substitute "p-chloroaniline" for "aniline" in step 3) of Example 5, and prepare the target compound according to the method of Example 5 in other processes.

[0157] 1H NMR(400MHz,Chloroform-d)δ7.25–7.16(m,3H),7.12–7.03(m,2H),6.94(dd,J=5.0,3.4Hz,1H),6.91–6.83(m,1H),6.35(dd,J=16.8,2.0Hz,1H),5.9 6(dd,J=16.8,10.4Hz,1H),5.52(dd,J=10.3,2.0Hz,1H),3.87(t,J=6.9Hz ,2H),3.70(d,J=0.8Hz,2H),2.58–2.36(m,10H).MS(ESI)m / z=390.1([M+H] + ).

[0158] Example 16

[0159] Preparation of N-(4-methoxyphenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazine-1-yl)ethyl)acrylamide

[0160] Substitute "p-methoxyaniline" for "aniline" in step 3) of Example 5, and prepare the target compound according to the method of Example 5 in other processes.

[0161] 1 H NMR(400MHz,Chloroform-d)δ7.23(d,J=5.0Hz,1H),7.16–7.08(m,2H),6.97–6.87(m,4H),6.38–6.29(m,1H),6.06–5.96(m,1H),5. 49(d,J=10.3Hz,1H),3.92–3.85(m,2H),3.85(d,J=2.3Hz,3H),3.72(d,J=2.2Hz,2H),2.64–2.38(m,10H).MS(ESI)m / z=386.2([M+H] + ).

[0162] Embodiment 17

[0163] Preparation of N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)furan-2-carboxamide

[0164] Substitute "p-toluidine" for "aniline" in step 3) of Example 12, and prepare the target compound according to the method of Example 12 in other processes.

[0165] 1H NMR(400MHz,Chloroform-d)δ7.33(s,1H),7.22–7.17(m,2H),7.12(dd,J=8.3,2.2Hz,2H),6.96–6.87(m,2H),6.17(d,J=3.6Hz,1H),5.63(s ,1H),5.30(d,J=2.2Hz,1H),3.98–3.91(m,2H),3.70(d,J=2.2Hz,2H),2.66–2.42(m,10H),2.39(d,J=2.2Hz,3H).MS(ESI)m / z=410.2([M+H] + ).

[0166] Embodiment 18

[0167] Preparation of N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0168] Substitute "p-fluoroaniline" for "aniline" in step 3) of Example 12, and prepare the target compound according to the method of Example 12 in other processes.

[0169] 1 H NMR(400MHz,Chloroform-d)δ7.35(d,J=2.0Hz,1H),7.34(d,J=2.2Hz,1H),7.30(dd,J =1.7,0.8Hz,1H),7.23–7.20(m,2H),7.19(d,J=2.1Hz,1H),6.93(dd,J=5.1,3.3Hz,1H) ,6.89(dd,J=3.4,1.2Hz,1H),6.24(dd,J=3.5,1.7Hz,1H),5.97(d,J=3.5Hz,1H),3.94 (t,J=6.8Hz,2H),3.70(d,J=0.8Hz,2H),2.68–2.32(m,10H).MS(ESI)m / z=414.2([M+H] + ).

[0170] Embodiment 19

[0171] Preparation of N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0172] Substitute "p-chloroaniline" for "aniline" in step 3) of Example 12, and prepare the target compound according to the method of Example 12 in other processes.

[0173] 1H NMR(400MHz,Chloroform-d)δ7.32(d,J=1.7Hz,1H),7.27–7.21(m,3H),7.13–7.04(m,2H),6.94(dd,J=5.0,3.4Hz,1H),6.90(dd,J=3.5, 1.1Hz,1H),6.22(dd,J=3.6,1.7Hz,1H),5.82(s,1H),3.94(t,J=6.8Hz,2H),3.71(s,2H),2.62–2.38(m,10H).MS(ESI)m / z=430.1([M+H] + ).

[0174] Embodiment 20

[0175] Preparation of N-(4-methoxyphenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0176] Substitute "p-methoxyaniline" for "aniline" in step 3) of Example 12, and prepare the target compound according to the method of Example 12 in other processes.

[0177] 1 H NMR(400MHz,Chloroform-d)δ7.37(dd,J=1.8,0.8Hz,1H),7.24(dd,J=5.1,1.3Hz,1H),7.22–7.15(m,2H),6.98–6.89(m,4H),6.20(dd,J =3.6,1.7Hz,1H),5.63(s,1H),3.96(t,J=6.9Hz,2H),3.87(s,3H),3.73(d,J=0.8Hz,2H),2.65–2.44(m,10H).MS(ESI)m / z=426.2([M+H] + ).

[0178] Embodiment 21

[0179] Preparation of N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)thiophene-2-carboxamide

[0180] The target compound was prepared by replacing the "acetyl chloride" in step 6) of Example 1 with "2-thenoyl chloride" and following the method of Example 1 for the rest of the process.

[0181] 1H NMR(400MHz,Chloroform-d)δ7.39–7.34(m,3H),7.29–7.24(m,3H),7.20(dd,J=5.0,1.2Hz,1H),6.92(dd,J=5.0,3.4Hz,1H),6.88(dt,J=3.4,1.0Hz,1H), 6.75(dd,J=5.0,3.8Hz,1H),6.64(dd,J=3.8,1.2Hz,1H),3.97(dd,J=7.6,6.6 Hz,2H),3.69(d,J=0.8Hz,2H),2.66–2.35(m,10H).MS(ESI)m / z=412.2([M+H] + ).

[0182] Embodiment 22

[0183] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide

[0184] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and following the method of Example 1 for the rest of the process.

[0185] 1 HNMR (400MHz, CDCl3) δ7.13–7.05(m,4H),6.97–6.87(m,4H),3.83(s,3H),3.81–3.73(m,2H),2.85(d,J=11.4Hz,2H),2.51–2.41(m ,4H),1.90(t,J=10.8Hz,2H),1.81(s,3H),1.57(d,J=12.5Hz,2H),1.50–1.38(m,1H),1.28–1.17(m,2H).MS(ESI)m / z=358.2([M+H] + ).

[0186] Embodiment 23

[0187] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)propionamide

[0188] Substitute "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, substitute "propionyl chloride" for "acetyl chloride" in step 6) of Example 1, and prepare the target compound according to the method of Example 1 in other processes.

[0189] 1H NMR (400MHz, CDCl3) δ7.43–7.36(m,2H),7.36–7.27(m,1H),7.19(dd,J=5.1,3.2Hz,2H),7. 06(dd,J=8.7,5.2Hz,2H),6.93–6.85(m,2H),3.83(t,J=7.1Hz,2H),2.85(d,J=11.1Hz,2H) ,2.46(t,J=7.4Hz,4H),2.03(q,J=7.3Hz,2H),1.90(t,J=11.1Hz,2H),1.56(d,J=12.6Hz,2 H),1.48–1.39(m,1H),1.27–1.14(m,2H),1.03(t,J=7.4Hz,3H).MS(ESI)m / z=372.2([M+H] + ).

[0190] Embodiment 24

[0191] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)butyramide

[0192] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "butyryl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0193] 1 H NMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.35–7.28(m,1H),7.21–7.16(m, 2H),7.10(dd,J=5.1,1.2Hz,1H),6.89(dd,J=5.1,3.4Hz,1H),6.82–6.76(m,1H),3 .83(t,J=7.0Hz,2H),2.99(dd,J=9.0,6.9Hz,2H),2.72–2.28(m,12H),1.98(t,J=7 .4Hz,2H),1.57(q,J=7.4Hz,2H),0.80(t,J=7.4Hz,3H).MS(ESI)m / z=386.3([M+H] + ).

[0194] Embodiment 25

[0195] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide

[0196] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "cyclopropylcarbonyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0197] 1 H NMR(400MHz,Chloroform-d)δ7.40(t,J=7.6Hz,2H),7.36–7.24(m,3H),7.10(dd,J =5.2,1.2Hz,1H),6.89(dd,J=5.1,3.4Hz,1H),6.79(d,J=3.5Hz,1H),3.86(t,J=7. 1Hz,2H),3.00(q,J=8.9,8.2Hz,2H),2.78–2.27(m,12H),1.32–1.22(m,1H),0.98( dp,J=6.5,3.7,3.3Hz,2H),0.58(dq,J=7.0,3.7Hz,2H).MS(ESI)m / z=384.3([M+H] + ).

[0198] Embodiment 26

[0199] Preparation of 2-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide

[0200] The target compound was prepared by replacing the "2-thiophenecarboxylic acid" in step 1) of Example 1 with "2-thiopheneacetic acid", and replacing the "acetyl chloride" in step 6) of Example 1 with "methoxyacetyl chloride". The other processes were prepared according to the method of Example 1.

[0201] 1 H NMR(400MHz,Chloroform-d)δ7.45–7.32(m,3H),7.23–7.16(m,2H),7.10(dd,J=5.1,1.2Hz,1H),6.90(dd,J=5.1,3.4Hz,1H),6.80(dt,J=3.4,1.0Hz, 1H),3.84(t,J=6.8Hz,2H),3.72(s,2H),3.31(s,3H),3.05–2.95(m,2H),2 .73–2.63(m,2H),2.51(dd,J=15.5,8.7Hz,10H).MS(ESI)m / z=388.3([M+H] + ).

[0202] Embodiment 27

[0203] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)acrylamide

[0204] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "acryloyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0205] 1 H NMR(400MHz,Chloroform-d)δ7.47–7.29(m,3H),7.17(d,J=7.6Hz,2H),7.11(d,J =5.1Hz,1H),6.90(dd,J=5.2,3.4Hz,1H),6.80(d,J=3.5Hz,1H),6.33(dd,J=16.9 ,2.0Hz,1H),5.97(dd,J=16.8,10.3Hz,1H),5.50(dd,J=10.3,2.0Hz,1H),3.93(t ,J=7.1Hz,2H),3.08–3.02(m,2H),2.78–2.56(m,12H).MS(ESI)m / z=370.2([M+H] + ).

[0206] Embodiment 28

[0207] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide

[0208] Substitute "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, substitute "benzoyl chloride" for "acetyl chloride" in step 6) of Example 1, and prepare the target compound according to the method of Example 1 in other processes.

[0209] 1 H NMR(400MHz,Chloroform-d)δ7.30–7.23(m,2H),7.23–7.16(m,3H),7.16–7.08(m,4H),7.07–7.02(m,2H),6.90(dd,J=5.1,3.4Hz,1H ),6.81(dt,J=3.3,1.1Hz,1H),4.07(t,J=7.0Hz,2H),3.02(dd,J=8.7,7.1Hz,2H),2.74–2.34(m,12H).MS(ESI)m / z=420.2([M+H]+).

[0210] Embodiment 29

[0211] Preparation of 2-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide

[0212] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "o-methylbenzoyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0213] 1 H NMR(400MHz,Chloroform-d)δ7.19–7.09(m,3H),7.09–6.97(m,5H),6.97–6.85(m,3H),6.81(d,J=3.4Hz,1H),4.07 (d,J=7.0Hz,2H),3.01(t,J=7.8Hz,2H),2.61(dt,J=33.9,8.6Hz,12H),2.37(s,3H).MS(ESI)m / z=434.3([M+H]+).

[0214] Embodiment 30

[0215] Preparation of 4-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide

[0216] The target compound was prepared by replacing the "2-thiophenecarboxylic acid" in step 1) of Example 1 with "2-thiopheneacetic acid", and replacing the "acetyl chloride" in step 6) of Example 1 with "p-methoxybenzoyl chloride". The other processes were prepared according to the method of Example 1.

[0217] 1 H NMR(400MHz,Chloroform-d)δ7.26–7.19(m,4H),7.16–7.09(m,2H),7.09–7.04(m,2H),6.90(dd,J=5.1,3.4Hz,1H),6.81(dt,J=3.4,1.0H z,1H),6.66–6.60(m,2H),4.04(t,J=7.1Hz,2H),3.72(s,3H),3.00(dd,J=9.0,6.7Hz,2H),2.68–2.41(m,12H).MS(ESI)m / z=450.2([M+H] + ).

[0218] Embodiment 31

[0219] Preparation of 4-fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide

[0220] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "p-toluocarbonyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0221] 1 H NMR(400MHz,Chloroform-d)δ7.29–7.22(m,2H),7.22–7.18(m,2H),7.17–7.13(m,1H),7.13–7.09(m,1H),7.07–7.02(m,2H),6.90(dd, J=5.1,3.4Hz,1H),6.85–6.77(m,3H),4.05(t,J=7.0Hz,2H),3.02(dd,J=9.0,6.8Hz,2H),2.74–2.41(m,12H).MS(ESI)m / z=438.3([M+H] + ).

[0222] Embodiment 32

[0223] Preparation of 2-fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide

[0224] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "p-fluorocarbonyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0225] 1 H NMR (400MHz, Chloroform-d) δ7.24–7.05(m,8H),6.95(t,J=7.6Hz,1H),6.92–6.88(m,1H),6.79(dd,J=16. 2,6.2Hz,2H),4.05(t,J=6.9Hz,2H),3.07–2.95(m,2H),2.75–2.34(m,12H).MS(ESI)m / z=438.3([M+H]+).

[0226] Embodiment 33

[0227] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0228] Substitute "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, substitute "2-furoyl chloride" for "acetyl chloride" in step 6) of Example 1, and prepare the target compound according to the method of Example 1 in other processes.

[0229] 1 H NMR(400MHz,Chloroform-d)δ7.41–7.35(m,3H),7.31(dd,J=1.8,0.8Hz,1H),7.26(d,J=2 .1Hz,1H),7.24(t,J=1.8Hz,1H),7.11(dd,J=5.1,1.2Hz,1H),6.90(dd,J=5.1,3.4Hz,1H) ,6.80(dt,J=3.4,1.1Hz,1H),6.16(dd,J=3.5,1.7Hz,1H),5.65(d,J=3.4Hz,1H),3.98(t, J=7.0Hz,2H),2.99(dd,J=8.9,6.8Hz,2H),2.68–2.35(m,12H).MS(ESI)m / z=410.2([M+H] + ).

[0230] Embodiment 34

[0231] Preparation of 3-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0232] The target compound was prepared by replacing the "2-thiophenecarboxylic acid" in step 1) of Example 1 with "2-thiopheneacetic acid", and replacing the "acetyl chloride" in step 6) of Example 1 with "3-methylfuran-2-carbonyl chloride". The other processes were prepared according to the method of Example 1.

[0233] 1 H NMR(400MHz,Chloroform-d)δ7.31–7.24(m,2H),7.22–7.16(m,1H),7.13–7.09(m,3H),6.93–6.87(m,2H),6.81–6.79(m,1H ),6.12(d,J=1.7Hz,1H),4.02–3.94(m,2H),3.04–2.97(m,2H),2.68–2.44(m,12H),2.21(s,3H).MS(ESI)m / z=424.3([M+H] + ).

[0234] Embodiment 35

[0235] Preparation of N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide

[0236] Substitute "p-chloroaniline" for "aniline" in step 3) of Example 25, and prepare the target compound according to the method of Example 25 in other processes.

[0237] 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.6Hz,2H),7.28–7.22(m,2H),7.11–7.09(m,1H),6.90–6.88(m,1H),6.81–6.76(m,1H),3.82(t,J=6.9Hz,2H), 3.05–2.94(m,2H),2.72–2.59(m,2H),2.47(dd,J=12.0,5.2Hz,10H),1.31–1 .17(m,1H),1.05–0.94(m,2H),0.63–0.59(m,2H).MS(ESI)m / z=418.3([M+H] + ).

[0238] Embodiment 36

[0239] Preparation of N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethylethyl)cyclopropanecarboxamide

[0240] Substitute "p-methoxyaniline" for "aniline" in step 3) of Example 25, and prepare the target compound according to the method of Example 25 in other processes.

[0241] 1 H NMR(400MHz,Chloroform-d)δ7.23–7.16(m,2H),7.10–7.07(m,1H),6.93–6.86(m,3H),6.80–6.78(m,1H),5.58(s,1H),3.81(s,5H),3.05 –2.96(m,2H),2.67–2.60(m,2H),2.58–2.38(m,10H),1.33–1.22(m,1H),1.01–0.92(m,2H),0.59–0.54(m,2H).MS(ESI)m / z=414.3([M+H] + ).

[0242] Embodiment 37

[0243] Preparation of N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide

[0244] Substitute "p-fluoroaniline" for "aniline" in step 3) of Example 25, and prepare the target compound according to the method of Example 25 in other processes.

[0245] 1 H NMR(400MHz,Chloroform-d)δ7.34–7.23(m,2H),7.14–7.04(m,3H),6.90–6.87(m,1H),6.80–6.78(m,1H),3.82(t,J=7.0Hz,2H),2.99(dd,J= 8.6,7.1Hz,2H),2.72–2.59(m,2H),2.57–2.34(m,10H),1.26–1.20(m,,1H),1.00–0.96(m,2H),0.62–0.57(m,2H).MS(ESI)m / z=402.2([M+H] + ).

[0246] Embodiment 38

[0247] Preparation of N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)cyclopropanecarboxamide

[0248] Substitute "p-toluidine" for "aniline" in step 3) of Example 25, and prepare the target compound according to the method of Example 25 in other processes.

[0249] 1 H NMR(400MHz,Chloroform-d)δ7.23–7.12(m,4H),7.09(dd,J=5.1,1.2Hz,1H),6.89(dd,J=5.1,3.4Hz,1H),6.80–6.78(m,1H),3.86–3.79(m,2H),3.02 –2.94(m,2H),2.65–2.59(m,2H),2.56–2.42(m,10H),2.36(s,3H),1.34–1. 22(m,1H),0.98–0.96(m,2H),0.59–0.54(m,2H).MS(ESI)m / z=398.3([M+H] + ).

[0250] Embodiment 39

[0251] Preparation of N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)acrylamide

[0252] Substitute "p-chloroaniline" for "aniline" in step 3) of Example 27, and follow the method of Example 27 for the rest of the process to prepare the target compound.

[0253] 1 H NMR(400MHz,Chloroform-d)δ7.38–7.31(m,2H),7.20–7.13(m,2H),7.13–7.07(m,2H),6.90–6.88(m,1H),6.83–6.77(m,1H),6.37–6.32(m,1H), 6.00–5.93(m,1H),5.53–5.50(m,1H),3.87(t,J=6.8Hz,2H),3.00–2.96( m,2H),2.64–2.60(m,2H),2.66–2.48(m,12H).MS(ESI)m / z=404.0([M+H] + ).

[0254] Embodiment 40

[0255] Preparation of N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)acrylamide

[0256] Substitute "p-methoxyaniline" for "aniline" in step 3) of Example 27, and prepare the target compound according to the method of Example 27 in other processes.

[0257] 1 H NMR(400MHz,Chloroform-d)δ7.14–7.05(m,3H),6.96–6.85(m,3H),6.81–6.76(m,1H),6.31(dd,J=16.8,2.1Hz,1H),5.99(dd,J=16.8,10.3 Hz,1H),5.47(dd,J=10.3,2.1Hz,1H),3.87(t,J=7.0Hz,2H),3.82(s,3H),3.02–2.95(m,2H),2.67–2.38(m,12H).MS(ESI)m / z=400.2([M+H] + ).

[0258] Embodiment 41

[0259] Preparation of N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)acrylamide

[0260] Substitute "p-fluoroaniline" for "aniline" in step 3) of Example 27, and prepare the target compound according to the method of Example 27 in other processes.

[0261] 1 H NMR(400MHz,Chloroform-d)δ7.23–7.15(m,2H),7.13–7.02(m,3H),6.89(dd,J=5.1,3.4Hz,1H),6.80–6.78(m,1H),6.34(dd,J=16.8,2.0Hz,1H),5 .95(dd,J=16.8,10.3Hz,1H),5.50(dd,J=10.3,2.0Hz,1H),3.87(t,J=6.8 Hz,2H),3.05–2.91(m,2H),2.73–2.26(m,12H).MS(ESI)m / z=388.3([M+H] + ).

[0262] Embodiment 42

[0263] Preparation of N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)-N-(p-tolyl)acrylamide

[0264] Substitute "p-toluidine" for "aniline" in step 3) of Example 27, and follow the method of Example 27 for the rest of the process to prepare the target compound.

[0265] 1 H NMR(400MHz,Chloroform-d)δ7.18(d,J=8.1Hz,2H),7.14–6.98(m,3H),6.89(dd,J=5.1,3 .4Hz,1H),6.79(dd,J=3.4,1.1Hz,1H),6.32(dd,J=16.8,2.1Hz,1H),5.99(dd,J=16.8,10. 3Hz,1H),5.46(dd,J=10.3,2.1Hz,1H),3.88(t,J=7.1Hz,2H),2.98(dd,J=8.5,7.2Hz,2H) ,2.70–2.58(m,2H),2.52(dd,J=12.9,5.9Hz,10H),2.36(s,3H).MS(ESI)m / z=384.3([M+H] + ).

[0266] Embodiment 43

[0267] Preparation of N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0268] Substitute "p-chloroaniline" for "aniline" in step 3) of Example 33, and prepare the target compound according to the method of Example 33 in other processes.

[0269] 1 H NMR(400MHz,Chloroform-d)δ7.38–7.26(m,3H),7.22–7.14(m,2H),7.09(d,J=4.9Hz,1H),6.92–6.86(m,1H),6.79(d,J=3.6Hz,1H),6. 22(d,J=3.6Hz,1H),5.96(d,J=3.7Hz,1H),3.93(t,J=6.7Hz,2H),2.98(t,J=7.9Hz,2H),2.70–2.33(m,12H).MS(ESI)m / z=444.0([M+H] + ).

[0270] Embodiment 44

[0271] Preparation of N-(4-methoxyphenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)furan-2-carboxamide

[0272] Substitute "p-methoxyaniline" for "aniline" in step 3) of Example 33, and prepare the target compound according to the method of Example 33 in other processes.

[0273] 1 H NMR(400MHz,Chloroform-d)δ7.34–7.32(m,1H),7.18–7.13(m,2H),7.10–7.08(m,1H),6.92–6.86(m,3H),6.80–6.78(m,1H) ,6.17–6.14(m,1H),3.93(t,J=6.8Hz,2H),3.83(s,3H),2.99(t,J=6.8Hz,2H),2.66–2.44(m,12H).MS(ESI)m / z=440.3([M+H] + ).

[0274] Embodiment 45

[0275] Preparation of N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide

[0276] Substitute "p-fluoroaniline" for "aniline" in step 3) of Example 33, and prepare the target compound according to the method of Example 33 in other processes.

[0277] 1 H NMR(400MHz,Chloroform-d)δ7.30–7.28(m,1H),7.26–7.21(m,2H),7.12–7.04(m,3H),6.91–6.87(m,1H),6.81–6.78(m,1H),6. 20(dd,J=3.6,1.6Hz,1H),5.84(s,1H),3.94(t,J=6.8Hz,2H),3.04–2.95(m,2H),2.67–2.42(m,12H).MS(ESI)m / z=428.3([M+H] + ).

[0278] Embodiment 46

[0279] Preparation of N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl-N-(p-tolyl)furan-2-carboxamide

[0280] Substitute "p-toluidine" for "aniline" in step 3) of Example 33, and prepare the target compound according to the method of Example 33 in other processes.

[0281] 1 H NMR(400MHz,Chloroform-d)δ7.33–7.31(m,1H),7.21–7.15(m,2H),7.14–7.07(m,3H),6.91–6.88(m,1H),6.81–6.79(m,1H),6.1 8–6.15(m,1H),5.62(s,1H),3.95(t,J=7.2Hz,2H),3.07–2.93(m,2H),2.72–2.44(m,12H),2.39(s,3H).MS(ESI)m / z=424.3([M+H] + ).

[0282] Embodiment 47

[0283] Preparation of N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazine-1-yl)ethyl)thiophene-2-carboxamide

[0284] The target compound was prepared by substituting "2-thiopheneacetic acid" for "2-thiophenecarboxylic acid" in step 1) of Example 1, and "2-thiophenecarboxoyl chloride" for "acetyl chloride" in step 6) of Example 1. The other processes were carried out according to the method of Example 1.

[0285] 1 H NMR(400MHz,Chloroform-d)δ7.38(td,J=4.6,2.6Hz,3H),7.31–7.26(m,3H),7.10(dd,J=5.1,1.3Hz,1H),6.90(dd,J=5.2,3.4Hz,1H),6.80(dd,J=3.4,1. 1Hz, 1H), 6.75 (dd, J=5.0, 3.7Hz, 1H), 6.64 (dd, J=3.9, 1.2Hz, 1H), 3.99 (t, J= 7.0Hz,2H),3.03–2.96(m,2H),2.72–2.37(m,12H).MS(ESI)m / z=426.2([M+H] + ).

[0286] The structural formula of the compound prepared in the above examples is shown in Table 1 below:

[0287] Table 1 Structural formulas of the compounds prepared in Examples 1-47

[0288]

[0289]

[0290]

[0291]

[0292] Embodiment 48

[0293] Preparation of Sigma-1 (Cellular) Receptor Membranes and Determination of Ligand Affinity

[0294] Preparation of sigma-1 (cell) receptor membrane: CHO-sigma-1 cells were taken out of a -80°C freezer and thawed naturally. The cells were centrifuged at 1000 g for 10 min, and the precipitate was added with homogenate A. The mixture was mixed with a vortex mixer and centrifuged at 50,000 g, 4°C for 15 min. The supernatant was discarded, the precipitate was taken, and the A buffer was added again for washing. The centrifugation was repeated three times. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0295] Receptor binding experimental materials: isotope ligand 3H-Pentazocine (catalog number: NET 1056) and MICROSCINTPS scintillation fluid (catalog number: 94-1249C) were purchased from Perkin-Elmer; fine GF / C filter membrane (catalog number: 1822-047) was purchased from Whatman; haloperidol and Tris were purchased from Sigma-Aldrich; all cells were cell lines cultured in the cell room of the pharmacology laboratory, and hamster ovary cells transfected with corresponding receptor proteins were purchased from Perkin-Elmer and GenScript.

[0296] Experimental instruments: pH meter (model PHS-3C) was purchased from Shanghai Jingke; precision electronic balance (model MS105DU) was purchased from METTLER TOLEDO; liquid scintillation counter (model 425-304) was purchased from HIDEX of Finland; MicroBeta liquid scintillation instrument (model 2450-0010) was purchased from Perkin-Elmer; high-speed disperser (model IKA-T10) was purchased from IKA.

[0297] Experimental methods

[0298] (I) Preparation of solutions required for the experiment

[0299] For preparation of sigma-1, μ: 50 mM Tris-HCl buffer: Dissolve 96.8 g Tris in deionized water to a total volume of 4000 ml, adjust pH to 7.5 with HCl, dilute to 16000 mL, pH = 7.4;

[0300] (II) CHO-sigma-1 receptor competition binding assay

[0301] Step 1: First, use the prepared membrane to make a suspension of 8 mg / ml membrane using homogenate A for later use;

[0302] Step 2: Add 100 μl of membrane preparation to each reaction tube;

[0303] Step 3: Add 100 μl of solution A to the total binding tube (TB) and 100 μl of haloperidol (final concentration 1.0×10 -5 M), add 100 μl of test compound to each test compound tube (SB);

[0304] Step 4: Add 4 nM of radioligand to each reaction tube 3 H]-Pentazocine 10 μl;

[0305] Step 5: Incubate each reaction tube at 25°C for 120 min. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The Whatman test paper GF / C plate is soaked in 0.5% PEI for more than 1 hour in advance. After filtration, the filter membrane is dried in an oven at 60°C, and 45 μl of scintillation fluid is added after the bottom membrane is attached. The upper membrane is sealed and allowed to stand.

[0306] Step 6: Place the scintillation vial into a liquid scintillation counter for counting.

[0307] (III) Data processing and statistical analysis

[0308]

[0309] TB: total binding constant

[0310] NB: nonspecific binding constant

[0311] SB: binding constant of the compound

[0312] Embodiment 49

[0313] Mu (cell) receptor functional assay

[0314] Experimental materials: DAMGO (Sigma-Aldrich), IBMX (SIGMA), DPBS (Shanghai Rongbai), HTRF kit (Cisbio Bioassays, 62AM9PEC). CHO-K1 cells stably expressing human MOR.

[0315] Solution preparation:

[0316] (A) Cell growth medium: 10% FBS, 1% PBS were added to 90% DMEM, and G418 was added to a final concentration of 500 μg / mL and stored at 4°C until use.

[0317] (B) Cryopreservation solution: Just before use, add 5% DMSO to 95% FBS.

[0318] (C) Assay buffer: Just before use, add IBMX to DPBS to a final concentration of 0.5 mM.

[0319] (D) cAMP-d2 working solution: Dilute the cAMP-d2 stock solution 20-fold with lysis binding buffer to prepare the cAMP-d2 working solution. The working solution can be placed at 4°C for 24 hours.

[0320] (E) Anti-cAMP antibody-cryptate working solution: Dissolve Anti-cAMP

[0321] The antibody-cryptate stock solution was diluted 20 times to prepare the anti-cAMP antibody-cryptate working solution; the working solution can be placed at 4°C for 24 hours.

[0322] Experimental methods:

[0323] Resuscitate cells in a 37°C sterile water bath and shake gently until all ice has melted (approximately 1 min). Transfer the cells to be revived to a sterile centrifuge tube and add 5-10 mL of complete medium preheated at 37°C without the selective antibiotic G418. Allow the cells to settle naturally for 5 min, centrifuge at 900 rpm for 5 min, and discard the medium. Resuspend the centrifuged cells in fresh medium and culture them in a 37°C incubator containing 5% CO2 until the cells reach 80-90%, then subculture or prepare for drug screening experiments. CHO-K1 cells are suspended in PBS buffer and centrifuged at 2000 rpm for 10 min. Resuspend the cell pellet in HAMF12 medium containing 0.5 mM IBMX and add it to 96-well ProxiPlates (5 μL / well, 3000 cells / well). Add 0.5μM forskolin (1μL / well) and target compound (4μL / well, 0.5% DMSO) in sequence to a final volume of 10μL, and incubate at 37°C for 45min. Use a micropipette to add 5μL of cAMP-d2 working solution and 5μL Anti-cAMP antibody-cryptate working solution to the corresponding wells of the reaction plate, cover with a lid, and incubate in the dark at room temperature for 1h. Place in a plate reader and read. The final value is the ratio of OD665nm to OD620nm. While detecting the compounds, prepare a cAMP standard curve according to the method described in the kit. The results in Table 1 show that the compounds prepared in Example 5, Example 12, Example 25, and Example 27, respectively, have a good agonist effect on the μ receptor, and "++++" indicates EC 50 Value is less than 500nM, “+++” indicates EC 50 Value 500-1000nM, "++" indicates EC 50 Value 1000-10000nM, "+" indicates EC 50 The value is greater than 10000nM. At the same time, this type of compound has a good affinity for σ1 receptors at a concentration of 10μM.

[0324] Table 1 Results of the functional test of the target compound on μ receptor and the affinity results for σ1 receptor (inhibition rate of each receptor when the compound concentration is 10 μM)

[0325]

[0326]

[0327] Embodiment 50

[0328] Formalin-induced pain model

[0329] (1) Experimental animal information

[0330] SD male rats, 6-8 weeks old, 230-280 g, were provided by Shanghai Xipu-Bikai Experimental Animal Co., Ltd.

[0331] (2) Main reagents

[0332] The tested positive drugs: pregabalin; purified water, purchased from Hangzhou Wahaha; PEG400, purchased from Will Chemical; normal saline, purchased from Shijiazhuang Siyao; formaldehyde solution, purchased from Sigma-Adrich.

[0333] (3) Experimental instruments

[0334] The electronic balance (model: TP6001N) was purchased from Shanghai Precision Scientific Instrument Co., Ltd.;

[0335] The precision electronic balance (model: BS224s) was purchased from Sartorius Scientific Instruments (Beijing) Co., Ltd.;

[0336] The automatic pain analysis system (model: ANTE) was purchased from Zhenghua, Huaibei, Anhui.

[0337] (4) Experimental methods

[0338] Male SPF SD rats with qualified body weight were randomly divided into a model group (i.e., solvent group), a control group, and each dose group of the test compound, with 8 rats in each group. According to the different doses of each group, different concentration solutions were prepared for administration, the model group was given the corresponding solvent, and the control group was given the corresponding positive control drug.

[0339] Before the test, the rats were allowed to adapt to the experimental device for 10 minutes. One hour after the end of the administration, 75 μL of 5% formalin solution (containing 1.85% formaldehyde) was subcutaneously injected into the right hind foot of the rats to establish the model. The formation of a skin mound was considered a successful model. If the injected foot bled, the animal was discarded.

[0340] The software automatically recorded the number of paw lifts in 1-minute time periods from 0 to 60 minutes after modeling, and then analyzed and calculated the total number of paw lifts in the first phase (1-10 minutes) and the second phase (10-60 minutes) based on the software results.

[0341] (5) Data processing

[0342]

[0343] If the dose effect showed obvious dose dependence, the dose-analgesic effect curve could be analyzed by nonlinear fitting method using GraphPad Prism 6.0 software and the ED 50 .

[0344] (6) Experimental results

[0345] Table 2 Results of acute toxicity test and formalin-induced pain test of preferred compounds

[0346]

[0347] The results showed that compared with pregabalin, the compounds prepared in Example 5, Example 12, Example 25 and Example 27 respectively showed good analgesic effect in the formalin-induced pain experiment, and ED 50 Are lower.

[0348] C. Preparation Examples

[0349] Example 51: Tablet

[0350]

[0351] The raw materials and auxiliary materials are sieved through an 80-mesh sieve for later use. The prescribed amount of active ingredients, microcrystalline cellulose, lactose, and povidone K30 are weighed and added to a high-speed mixing tablet machine. The mixture is stirred at a low speed and evenly mixed. An appropriate amount of purified water is added. The mixture is stirred at a low speed and granulated at a high speed. The wet granules are dried at 60°C for 3 hours, sieved through a 24-mesh sieve, and the prescribed amount of sodium carboxymethyl starch, silicon dioxide, and magnesium stearate are added. The mixture is mixed and tableted by a rotary tablet press.

[0352] Example 52: Injection

[0353] A parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the present invention in 10% by volume propylene glycol and water.

Claims

1. A thiophene piperazine amide derivative, characterized in that: The derivatives are: N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)propionamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)butyramide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide, 2-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acetamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide, 2-methyl-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide, 4-methoxy-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide, 4-Fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide, 2-Fluoro-N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)benzamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)acrylamide, N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide, N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide, N-(4-methoxyphenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)acrylamide, N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)furan-2-carboxamide, N-(4-fluorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(4-chlorophenyl)-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(4-methoxyphenyl)-N-(2-(4-(thien-2-ylmethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-phenyl-N-(2-(4-(thiophen-2-ylmethyl)piperazin-1-yl)ethyl)thiophene-2-carboxamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)propionamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)butyramide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide, 2-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acetamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide, 2-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide, 4-methoxy-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide, 4-Fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide, 2-Fluoro-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)benzamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, 3-methyl-N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide, N-(4-methoxyphenyl)-N-(2-(4-(2-(thien-2-yl)ethyl)piperazin-1-yl)ethylethyl)cyclopropanecarboxamide, N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)cyclopropanecarboxamide, N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)cyclopropanecarboxamide, N-(4-chlorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide, N-(4-methoxyphenyl)-N-(2-(4-(2-(thien-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide, N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)acrylamide, N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)-N-(p-tolyl)acrylamide, N-(4-chlorophenyl)-N-(2-(4-(2-(thien-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(4-methoxyphenyl)-N-(2-(4-(2-(thien-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(4-fluorophenyl)-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)furan-2-carboxamide, N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl-N-(p-tolyl)furan-2-carboxamide, N-phenyl-N-(2-(4-(2-(thiophen-2-yl)ethyl)piperazin-1-yl)ethyl)thiophene-2-carboxamide.

2. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises a therapeutically effective amount of the thiophene piperazine amide derivative according to claim 1, and one or more pharmaceutically acceptable carriers.

3. Use of the thiophene piperazine amide derivatives according to claim 1 in the preparation of drugs for preventing or treating pain diseases.

4. The use according to claim 3, wherein the pain disease is neuralgia.

Images