Tetrahydrofuramide sodium channel regulator and application thereof in medicine

Abstract

The invention provides a substituted tetrahydrofuran carboxamide derivative, salt or stereochemical isomer, a pharmaceutical composition containing the substituted tetrahydrofuran carboxamide derivative, application of the substituted tetrahydrofuran carboxamide derivative as a Nav inhibitor and application of the substituted tetrahydrofuran carboxamide derivative in preparation of drugs for treating and / or relieving pain and pain related diseases. The compound provided by the invention has the advantages of high metabolic stability, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic property, quicker effect, low side effect on central nervous system and the like.

Description

Technical Field

[0001] The present invention provides a class of substituted tetrahydrofuran carboxamide derivatives, salts or stereochemical isomers and pharmaceutical compositions containing the same. In particular, the present invention discloses a Nav inhibitor and its use in preparing a drug for treating and / or alleviating pain and pain-related diseases. Background Art

[0002] Pain is a feeling produced by the human body when it is subjected to various harmful stimuli. It is a complex physiological and psychological activity and a defensive mechanism to protect the body from harm. It is one of the most common symptoms in clinical practice. The International Association for the Study of Pain (IASP) divides pain into nociceptive pain, neuropathic pain, and psychogenic pain. Among them, neuropathic pain usually includes pain caused by systemic metabolic damage and pain caused by discrete nerve damage.

[0003] Voltage-gated sodium channels are mainly distributed in the nervous system, can excite neurons, and play an important biophysical role in the conduction of pain-related signals. They transmit electrical signals by generating and propagating action potentials (APs) in the periphery (PNS) and central nervous system (CNS). There are 9 types of sodium ion channels in humans, namely Nav1.1 to Nav1.9, each of which is formed by an α subunit and one or more β subunits. Despite their high structural and sequence similarities, different subtypes of Nav channels not only have specific tissue distributions, but also have different voltage dependencies and activation, inactivation, and recovery dynamics (Xiaoshuang H, et al. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (30); Eleonora S, et al. Cardiovascular research, 2014, 104 (2): 355-63). Studies have shown that mutations, expression changes or inappropriate regulation of these channels can lead to electrical instability of the cell membrane and abnormal spontaneous activity observed in pathological conditions (Chahine M, et al. CNS & Neurological Disorders -Drug Targets, 2008, 7 (2): 144-158).

[0004] Nav1.8 is a tetrodotoxin (TTX)-insensitive sodium channel encoded by SCN10A. It is mainly expressed in sensory neurons and is located in the human chromosome 3p21-22 region. It mainly encodes the α subunit. Studies have shown that Nav1.8 plays an important role in neuropathic and chronic inflammatory pain, such as regulating malondialdehyde (one of the important factors of diabetic pain) and tumor necrosis factor α (TNF-α) (Huang Q, et al. Metabolism, 2016, 65(4):463-474; He XH, ZangY, Chen X, et al. Pain. 2010 Nov; 151(2):266-279.). According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 can be used to treat inflammatory pain, neuralgia, postoperative pain, cancer pain and other types of pain, becoming a new type of analgesic therapy. Therefore, Nav1.8 blockers are expected to become a new generation of ideal neuropathic and inflammatory pain treatment drugs.

[0005] Nav inhibitors used in clinical practice lack subtype selectivity and can inhibit sodium ion channels expressed in the heart and central nervous system, so their therapeutic window is narrow and their application range is limited. Nav1.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with better activity, higher selectivity, better pharmacokinetic properties, faster onset of action and fewer side effects. Summary of the invention

[0006] The present invention provides a substituted tetrahydrofurancarboxamide derivative, salt or stereochemical isomer and a pharmaceutical composition containing the same. The tetrahydrofurancarboxamide derivative preferably has a structure shown in any of the following structural formulas:

[0007] , , ,

[0008] , , ,

[0009] , , .

[0010] The compounds of the present invention are usually used in the form of free acids or free bases. Alternatively, the compounds of the present invention can be used in the form of acid or base salts. Acid addition salts of free amino compounds of the present invention can be prepared by methods known in the art and can be prepared from organic acids and inorganic acids.

[0011] Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Basic salts include salts formed with carboxylate anions, and include salts formed with organic and inorganic cations such as selected from alkali metal ions, alkaline earth metal ions (e.g., lithium, sodium, potassium, magnesium, barium, calcium) and ammonium ions, and substituted derivatives thereof (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Therefore, the term "pharmaceutically acceptable salt" shall include and all acceptable salt forms.

[0012] In addition, prodrugs are also included in the scope of the present invention. A prodrug is any covalently bound carrier that releases the received compound in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner that allows the modifications to decompose by conventional exchange or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino or sulfhydryl group is bound to any group that dissociates when administered to a patient to yield a hydroxyl, amino or sulfhydryl group.

[0013] Therefore, representative examples of prodrugs include (but are not limited to) acetates, formates and benzoates of alcohol and amine functional groups of the compounds of the present invention. In addition, in the case of carboxylic acids (-COOH), esters such as methyl esters, ethyl esters, etc. may be included. In the case of hydroxyl groups, mixed anhydrides such as methoxy, ethoxy, propoxy, tert-butoxy, etc. may be included.

[0014] For stereoisomers, the compounds of the present application may have chiral centers and may exist in the form of racemates, racemic mixtures, and individual enantiomers or diastereomers. All isomeric forms are included in the present invention, including mixtures thereof. In addition, some crystalline forms of the compounds of the present application may exist in the form of polymorphs, which are also included in the present invention. Some of the compounds of the present application may also form solvates with water or other organic solvents. Such solvates are also similarly included in the scope of the present invention.

[0015] It will be understood by those skilled in the art that any compound may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. As used herein, in the specification and claims, H refers to hydrogen, and includes any stable isotope of hydrogen, i.e. 1 H and D. In the embodiments where the atom is designated as H, no work is performed to enrich the atoms of a specific isotope of hydrogen, and therefore it will be understood by those of ordinary skill in the art that such hydrogen atoms may be present at about the natural abundance concentration of hydrogen. In the tetrahydrofurancarboxamide derivatives involved in the present invention, the deuterated means that the atoms at the relevant sites of the compound contain deuterium atoms exceeding the natural ratio (i.e., exceeding the natural abundance of deuterium). Therefore, any tetrahydrofurancarboxamide derivatives containing deuterium atoms at a ratio higher than the natural abundance of deuterium at the relevant sites are within the scope of protection of the present invention. For example, it is understood that the corresponding tetrahydrofurancarboxamide derivatives with the corresponding deuterated rate or deuterium content obtained by introducing deuterium atoms using commercially available deuterated reagents by the same or similar chemical synthesis means as shown in the embodiments of the present invention are within the scope of protection of the present invention. The chemical synthesis means and deuterated reagents herein are not limited to those exemplified in the embodiments, but should be understood to include all synthesis methods or routes that can be used in the art to obtain the compounds of the present invention, as well as all deuterated reagents that can be used in conjunction with the aforementioned synthesis methods or routes to introduce deuterium atoms into the target molecule.

[0016] Isotope-labeled compounds and salts can be used in a variety of advantageous ways, including as medicines. In some embodiments, isotope-labeled compounds and salts are deuterium (D) labeled. Deuterium (D) labeled compounds and salts are useful in treatment, with potential therapeutic advantages over non-D labeled compounds. Generally, due to the kinetic isotope effect described below, compared with non-isotope-labeled compounds and salts, deuterium (D) labeled compounds and salts can have higher metabolic stability. Higher metabolic stability is directly converted into extended half-life or reduced dosage in vivo, which will represent preferred embodiments of the present invention in most cases. Isotope-labeled compounds and salts can be prepared generally in the following manner: carry out the procedures disclosed in the synthesis scheme, examples and related descriptions, and replace non-isotope-labeled reactants with readily available isotope-labeled reactants. Deuterium (D) labeled compounds and salts can manipulate the oxidative metabolic rate of the compound by the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from isotopic nuclear exchange, which in turn is caused by a change in the ground state energy of the covalent bonds participating in the reaction. The exchange of heavier isotopes generally results in a decrease in the ground state energy of the chemical bond and thus a reduction in rate-limiting bond breakage. If bond breakage occurs in or near a saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be substantially altered.

[0017] According to the specific embodiments disclosed below, those skilled in the art can use the same or similar principles and methods to prepare the specific compounds involved in the tetrahydrofurancarboxamide derivatives of the present invention.

[0018] The present invention further provides a use of a tetrahydrofuran carboxamide derivative, a stereoisomer, a hydrate, a solvate, a polymorph, an active metabolite, a pharmaceutically acceptable salt or a prodrug thereof as shown in the present application in the preparation of an anti-sodium ion channel modulator. Further, the sodium ion channel modulator is a Nav1.8 inhibitor.

[0019] The present invention further provides a use of tetrahydrofurancarboxamide derivatives, stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof as shown in the present application in the preparation of drugs for treating diseases that lead to overexpression of Nav1.8.

[0020] The present invention further provides a use of tetrahydrofurancarboxamide derivatives, stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof as shown in the present application in the preparation of drugs for treating diseases caused by overexpression of Nav1.8.

[0021] The present invention further provides a use of a tetrahydrofurancarboxamide derivative as shown in the present application, its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a medicament for treating any one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and arrhythmia.

[0022] Further, the neuropathic pain is selected from one or more of post-herpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve compression injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy, and trigeminal autonomic headache; the musculoskeletal pain is selected from one or more of osteoarthritis pain, back pain, cold pain, burn pain, and toothache; the inflammatory pain is selected from rheumatoid arthritis pain and / or vulvar pain; the primary pain is selected from fibromyalgia.

[0023] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a tetrahydrofurancarboxamide derivative as shown in the present application, its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier.

[0024] The pure form of the compound of the present invention or its pharmaceutically acceptable salt or a suitable pharmaceutical composition can be administered by any acceptable mode of administering a medicament with similar effects. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administering the pharmaceutical composition include, but are not limited to, oral, topical, transdermal, inhaled, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technology. The pharmaceutical composition of the present invention is formulated to allow the clean ingredients contained therein to be bioavailable after the composition is administered to the patient. The composition to be administered to an individual or patient is in the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, while a container containing the compound of the invention in aerosol form can accommodate multiple dosage units. The actual method of preparing such dosage forms is known to or will become known to those skilled in the art. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, so as to treat the disease or condition of interest according to the teachings of the present invention.

[0025] The pharmaceutical composition of the present invention can be in solid or liquid form. On the one hand, the carrier is a microparticle, so that the composition is in the form of a tablet or powder, for example. The carrier can be a liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation administration. When oral administration is desired, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the forms considered as solid or liquid herein. For oral solid compositions, the pharmaceutical composition can be formulated into forms such as powders, granules, compressed tablets, pills, capsules, chewable tablets, powder tablets, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following substances may be present: binders, such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, xanthan gum or gelatin; excipients, such as starch, lactose or dextrin; disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; flavorings, such as mint, methyl salicylate or orange flavoring; and coloring agents.

[0026] In the preparation of compositions for oral administration, any common pharmaceutical medium can be used, such as water, glycols, oils, alcohols, etc. in the case of oral liquid compositions (such as suspensions, syrups, free agents, emulsions and solutions): or in the case of solid compositions, solid carriers such as starch, sugar, kaolin, lubricants, adhesives, disintegrants, etc. For parenteral compositions, the carrier will generally include at least sterile water in the majority, but other ingredients such as solubilizers, emulsifiers or other adjuvants may also be added thereto. Injectable solutions may be prepared, wherein the carrier includes physiological saline solution, glucose solution or a mixture of the two. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents, etc. may be used. Also included are solid form preparations that are expected to be converted into liquid form preparations shortly before use, such as powders for reconstruction.

[0027] When the pharmaceutical composition is in capsule form, such as a gelatin capsule, in addition to the above-mentioned types of materials, it may also contain a liquid carrier, such as polyethylene glycol or oil. The pharmaceutical composition may be in liquid form, such as a tincture, syrup, solution, emulsion or suspension. This liquid may be taken orally, or delivered by injection, as two examples. When oral administration is desired, the preferred composition contains one or more of a sweetener, a preservative, a dye / colorant and a flavor enhancer in addition to the compounds of the present invention. In the composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersant, a suspending agent, a buffer, a stabilizer and an isotonic agent may be included.

[0028] Whether it is a solution, suspension or other similar form of the liquid pharmaceutical composition of the present invention, it can include one or more of the following adjuvants: sterile diluents, such as water for injection, physiological saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils (such as synthetic mono- or diglycerides, which can be used as solvents or suspension media), polyethylene glycol, glycerol, propylene glycol and other solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tension, such as sodium oxide or dextrose. Parenteral preparations can be packaged in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0029] The liquid pharmaceutical composition of the present invention intended for parenteral administration or oral administration should contain a certain amount of the compound of the present invention so that a suitable dose can be obtained. The pharmaceutical composition of the present invention may be intended to be administered topically, in which case the carrier preferably comprises a solution, emulsion, ointment or gel matrix. For example, this matrix may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (e.g., water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical administration. If transdermal administration is intended, the composition may include a transdermal patch or an iontophoresis device.

[0030] The pharmaceutical composition of the present invention can be administered rectally, for example in the form of a suppository, which will melt in the rectum and release the drug. Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0031] The pharmaceutical composition of the present invention may include various materials that change the physical form of a solid or liquid dosage unit. For example, the composition may include a material that forms a coating shell around the active ingredient. The material that forms the coating shell is generally inert and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0032] Pharmaceutical compositions of the invention in solid or liquid form may include an agent that binds to a compound of the invention and thereby aids in the delivery of the compound. Suitable agents having this capability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0033] The pharmaceutical composition of the present invention can be composed of dosage units that can be administered in the form of an aerosol. The term aerosol is used to represent a variety of systems from colloidal types to systems consisting of pressurized packaging. Delivery can be carried out by liquefied or compressed gas, or by a suitable pump system that distributes the active ingredient. The aerosol of the compound of the present invention can be delivered in a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes necessary containers, starters, valves, sub-containers, etc., which together can form a kit. A person skilled in the art can determine a preferred aerosol without too much experimentation.

[0034] The pharmaceutical composition of the present invention can be made using methods well known in the pharmaceutical field. For example, a pharmaceutical composition to be administered by injection can be prepared by combining the compound of the present invention with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a uniform solution or suspension. A surfactant is a compound that interacts non-covalently with the compound of the present invention, thereby promoting the dissolution or uniform suspension of the compound in an aqueous delivery system. A solution can be formed by combining the compound of the present invention with an acceptable solvent or solvent, such as water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that can maintain a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0035] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0036] The compounds, salts and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, i.e., the compounds, salts and pharmaceutically acceptable compositions can be administered simultaneously with, before or after one or more other desired therapeutic agents or medical procedures. The specific combination of the therapy (therapeutic agent or procedure) employed in the combination regimen will take into account the compatibility of the desired therapeutic agent and / or procedure and the desired therapeutic effect to be achieved. It should also be understood that the therapy employed can achieve the desired effect on the same condition (e.g., the compounds of the present invention can be administered simultaneously with another agent for treating the same condition), or they can achieve different effects (e.g., controlling any adverse reactions).

[0037] As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated." For example, exemplary additional therapeutic agents include, but are not limited to, non-opioid analgesics (indoles, such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones, such as Nabumetone; oxicams, such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids, such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates, such as Aspirin, Choline magnesium trisalicylate, trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone); or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, In some embodiments, the analgesic agent may be administered in combination with the administration of one or more compounds of the invention. For example, anesthesia (intraspinal infusion, nerve block), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiology (physical therapy, orthopedic devices, diathermy), or psychology (cognitive methods - hypnosis, biofeedback or behavioral methods) methods may also be utilized.

[0038] The compounds of the invention, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and timing of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the individual undergoing therapy.

[0039] The compounds of the present invention or their pharmaceutically acceptable salts may also be administered at the same time, before or after administering one or more other therapeutic agents. This combination therapy includes administering a single pharmaceutical administration formulation containing the compounds of the present invention and one or more other active agents, as well as administering a separate pharmaceutical administration formulation of the compounds of the present invention and each active agent. For example, the compounds of the present invention and another active agent can be administered to the patient together with a single oral administration composition (e.g., tablets or capsules), or each agent can be administered with a separate oral administration formulation. In the case of using a separate administration formulation, the compounds of the present invention and one or more additional active agents can be administered at substantially the same time (i.e., simultaneously) or at a separate staggered time (i.e., successively); combination therapy should be understood to include all of these schemes.

[0040] The compounds and salts of the present invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Therefore, on the other hand, the present invention comprises compositions for coating implantable devices, the implantable devices comprising compounds or salts of the present invention as generally described above and classes and subclasses herein and carriers suitable for coating the implantable devices. On still another hand, the present invention comprises implantable devices coated with compositions, the compositions comprising compounds or salts of the present invention as generally described above and classes and subclasses herein and carriers suitable for coating the implantable devices. The coating is typically a biocompatible polymeric material, such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating can optionally be further coated with a suitable top layer of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or a combination thereof to impart controlled release properties to the composition.

[0041] As a general guide, the active compounds of the present disclosure are preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the compounds or compositions of the present disclosure can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid formulations. Suitable unit doses can be 0.1-1000 mg.

[0042] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0043] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0044] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0045] The present invention relates to tetrahydrofuran carboxamide derivatives and prodrugs thereof and deuterated compounds thereof shown in the present application, and pharmaceutical compositions containing the same, as well as methods for using the compositions to inhibit voltage-gated sodium channels of a subject, wherein the voltage-gated sodium channel is Nav1.8.

[0046] The present invention is characterized in that the compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition is used to treat acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and irritable bowel syndrome in a subject. Pathological pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, hernia repair pain, bunionectomy pain, or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, stroke (e.g., central nervous system pathological pain after stroke), swaying pain, Whiplash-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, osteomyelitis oleaginosus, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperosteogeny, disc degeneration / hernia pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease , mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolisthesis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pubic, renal colic, biliary tract disease, vascular leg ulcers, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal dysmotility or methods of reducing the severity thereof.

[0047] In another aspect, the invention features a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in treating femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal pain, cerebrospinal fluid (TFP), schizophrenia, schizophrenia, leukemia ... Geminid neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, persistent / chronic postoperative pain (e.g., post-amputation, post-thoracotomy, post-cardiac surgery), post-mastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., post-amputation of lower limbs, upper limbs, breasts), intractable pain, acute pain, acute postoperative pain, acute Musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendinitis, injury pain, sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, trauma pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, oral and facial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy Pain, Behcet's disease pain, obesity pain, phlebitis pain, Guillain-Barré syndrome pain, leg and mobile toe pain, Haglund's syndrome, erythromelalgia, Fabry disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, overactive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus or angina-induced pain or a method of reducing its severity.

[0048] In another aspect, the invention features a compound of the invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating or reducing the severity of trigeminal neuralgia, migraine treated with botulinum toxin, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, ilioglossal neuralgia, pudendal neuralgia, femoral neuropathy, paresthesia meralgia, saphenous neuropathy, sciatica, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, traumatic neuroma stump pain, or post-amputation pain in a subject.

[0049] A method for treating chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia in a subject or reducing the severity thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0050] Treating or lessening the severity of one or more of the following in the subject: neuropathic pain, optionally one or more of post-herpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy, or diabetic neuropathy; musculoskeletal pain, optionally osteoarthritis pain; acute pain, acute postoperative pain; postoperative pain, optionally one or more of bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain; or visceral pain.

[0051] The compounds provided by the present invention have the advantages of high metabolic stability, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic properties, faster onset of action, low side effects and central nervous system side effects, etc. Therefore, the compounds of the present invention have better drugability.

[0052] Unless otherwise specified, the reagents and starting materials used in the present invention are commercially available.

[0053] Unless otherwise specified, the compounds of the present invention were named manually or using chemical structure software, and commercially available compounds were named according to supplier catalog names.

[0054] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0055] Certain preferred embodiments of the present invention are illustratively shown in the following non-limiting examples. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the commercial specifications. The raw materials can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to the methods described herein.

[0056] Example 1.

[0057] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-methoxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0058] The synthetic route is as follows:

[0059]

[0060] Preparation of intermediate 5:

[0061] Using ethyl 2-diaza-3-oxopentanoate (intermediate 1) as raw material, it was prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627". Intermediate 5:

[0062] 1H NMR (400 MHz, CHLOROFORM-d) δ 6.89-6.80 (m, 2H), 4.18-4.10 (m, 2H), 3.91 (s, 3H), 3.77-3.46 (m, 1H), 1.68 (s, 3H), 1.14 (t, 3H), 1.07 (dd, 3H) ppm, ESI-MS m / z 381.02 [M+1]+.

[0063] Preparation of intermediate 6:

[0064] Intermediate 5 (220 g, 486 mmol) was dissolved in DCM (600 mL), stirred and cooled to 0 ° C, BBr3 (740 mL, 1 M, 370.0 mmol) solution was added dropwise, and the reaction was stirred. Sodium bicarbonate aqueous solution was added dropwise at 0 ° C to quench the reaction. DCM extraction, the organic layer was dried over anhydrous NaSO4, and concentrated under reduced pressure. The product was dissolved in DCM (800 mL), trifluoroacetic acid (80 mL, 1038 mmol) was added dropwise, and then the reaction solution was heated to 45 ° C. After the reaction was completed, sodium bicarbonate aqueous solution was added to quench, DCM extraction, anhydrous NaSO4 was dried, and concentrated under reduced pressure to obtain the desired product in a mixture of diastereoisomers. The crude product was recrystallized twice from DCM-heptane, filtered and dried to obtain 124 g of solid as intermediate 6. ESI-MS m / z 321.5[M+1] + .

[0065] Preparation of intermediate 7:

[0066] In a hydrogenation reactor, a suspension of intermediate 6 (90 g, 281.07 mmol) in MeOH (1800 mL) was added, and a suspension of Pd(OH)2 (185.5 g, 20% w / w, 58.2 mmol) in MeOH (400 mL) was added to the reactor. Pressurized hydrogen was stirred at 60 psi for 8 hours, and the reaction was complete when detected by TLC. The suspension was filtered through celite under a nitrogen atmosphere, rinsed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain the intermediate (91.2 g).

[0067] The above intermediate (91.2 g, 257.4 mmol) was dissolved in THF (1000 mL), the solution was cooled to 0°C, potassium tert-butoxide (97.6 g, 869.6 mmol) was added in batches, the reaction solution was stirred at 0°C for 10 min, heated to 10°C and stirred for 1 hr, cooled to 5°C, and then 2M HCl was added to adjust the pH to 1). Water was added and extracted with EtOAc. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to obtain intermediate 7 (78.3 g). 1H NMR (400MHz, methanol-d4) δ6.98(m,1H), 6.67(m,1H), 4.96(m,1H), 4.16(m,1H), 2.80(m,1H), 1.57(m,3H), 0.75(m,3H)ppm. ESI-MS m / z 339.0[M-1]-.

[0068] Preparation of intermediate 8:

[0069] 1-Bromo-2-(2-methoxyethoxy)ethane (54.5 g, 298.0 mmol) was dissolved in 200 ml of acetonitrile, and the intermediate 7 (20 g, 58.8 mmol) and cesium carbonate (96 g, 298.0 mmol) were added dropwise to a suspension of acetonitrile (800 mL). The mixture was stirred at 70°C for 24 hours, filtered, and concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0070] The above intermediate was dissolved in ethanol (600 mL), 2M LiOH solution (30 mL, 60 mmol) was added dropwise, and the mixture was stirred at room temperature for 8 hours. 3M HCl in MeOH (20 mL) was added dropwise to acidify the mixture, filtered, and concentrated under reduced pressure to obtain intermediate 8 (18.1 g). ESI-MS m / z 441.1 [M-1] - .

[0071] Preparation of compound 1:

[0072] Intermediate 8 (2.2 g, 5 mmol) was dissolved in 20 ml DCM, cooled to 2 °C, oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution, and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then 10 ml DCM was added and concentrated under reduced pressure. The concentrate was dissolved in 20 ml DCM, and added dropwise to a DCM (40 mL) solution of 4-aminopicolinic acid methyl ester (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol) and Et3N (2.2 mL, 15.5 mmol) at room temperature, stirred for 8 hours, concentrated under reduced pressure, added water, extracted with DCM, and dried over anhydrous sodium sulfate. Purified by rapid silica gel column chromatography, gradient elution with methanol-dichloromethane, the intermediate was obtained, and used directly in the next reaction.

[0073] The above intermediate was dissolved in methanolic ammonia (38.5 mL, 7 M, 269.2 mmol), stirred at room temperature for 24 h, and the reaction solution was concentrated under reduced pressure and purified by reverse phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 1.3 g of compound 1. 1H NMR (400 MHz, chloroform-d) δ8.85 (s, 1H), 8.41 (m, 1H), 8.14 (m, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.08 (m, 1H), 6.89 (m, 1H), 5.76 (m, 1H), 4.98 (m, 1H), 4.38-4.11 (m, 3H), 3.77-3.40 (m, 6H), 3.24 (s, 3H), 2.84 (m, 1H), 1.68(s,3H), 0.76(m,3H) ppm. ESI-MSm / z 562.5[M+1]+.

[0074] Example 2.

[0075] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-hydroxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0076] The synthetic route is as follows:

[0077]

[0078] Preparation of intermediate 9:

[0079] In a hydrogenation reactor, a suspension of intermediate 6 (90 g, 281.07 mmol) in MeOH (1800 mL) was added, and a suspension of Pd(OH)2 (185.5 g, 20% w / w, 58.2 mmol) in MeOH (400 mL) was added to the reactor. Pressurized hydrogen was stirred at 60 psi for 8 hours, and the reaction was complete when detected by TLC. The suspension was filtered through celite under a nitrogen atmosphere, rinsed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate 9 (91.2 g).

[0080] Preparation of intermediate 10:

[0081] Under nitrogen protection, at room temperature, intermediate 9 (2 g, 5.64 mmol) was dissolved in 20 mL of acetonitrile, potassium carbonate (4 g, 28.8 mmol) was added, and iodomethane (3.7 g, 26 mmol) was added to the reaction solution in batches, and stirred for 24 hours. MTBE was added, filtered through diatomaceous earth, washed with MTBE, and the filtrate was concentrated under reduced pressure to obtain a solid intermediate 10 (1.8 g). ESI-MS m / z 369.1 [M+1] +.

[0082] Preparation of intermediate 11:

[0083] Under nitrogen protection, at room temperature, intermediate 10 (49 g, 133 mmol) was dissolved in 500 ml THF, sodium methoxide (30% methanol solution, 3.2 mL, 14 mmol) was added to the reaction solution, and the reaction was stirred for 4.5 hr.

[0084] In the reaction solution, a solution of 50ml MeOH-50ml water was added dropwise, and the reaction was stirred for 30min, then lithium hydroxide monohydrate (8.4g, 200mmol) was added, and the reaction was stirred for 8hr. After TLC detection reaction was complete, 1M hydrochloric acid (220ml) was added, MTBE was extracted, the organic layer was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (4L) and concentrated in a vacuum, then dissolved in MTBE (4L) and concentrated in a vacuum again, to obtain an oily intermediate 11, which was directly used in the next step reaction.

[0085] Preparation of intermediate 12 (reference compound CP):

[0086] Intermediate 11 (1.8 g, 5 mmol) was dissolved in 20 ml DCM, cooled to 2 °C, oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution, and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then 10 ml DCM was added and concentrated under reduced pressure. The concentrate was dissolved in 20 ml DCM and added dropwise to a DCM (40 mL) solution of methyl 4-aminopicolinate (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol) and Et3N (2.2 mL, 15.5 mmol) at room temperature, stirred for 8 hours, concentrated under reduced pressure, added water, extracted with DCM, and dried over anhydrous sodium sulfate. Purified by rapid silica gel column chromatography, gradient elution with methanol-dichloromethane, the intermediate was obtained and used directly in the next reaction.

[0087] The above intermediate was dissolved in methanolic ammonia (38.5 mL, 7 M, 269.2 mmol), stirred at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, EtOAc (10 mL) was added, the temperature was raised to 60°C to dissolve, the solution was cooled to 50°C, and 6 ml of heptane was added dropwise to obtain 1.0 g of intermediate 12. ESI-MS m / z 474.4 [M+1] + .

[0088] Preparation of intermediate 13:

[0089] Intermediate 12 (3.4 g, 7.08 mmol) was dissolved in DCM (70 mL), cooled to 0°C with stirring, and BBr3 (10 mL, 1 M, 10 mmol) solution was added dropwise. The reaction was stirred for 12 hours. Sodium bicarbonate aqueous solution was added dropwise at 0°C to quench the reaction. DCM extraction was performed, the organic layer was dried over anhydrous NaSO4, and concentrated under reduced pressure. Rapid silica gel column chromatography was used for purification, and ethyl acetate-petroleum ether gradient elution was used to obtain intermediate 13 (2.2 g). ESI-MS m / z 458.8 [M-1] - .

[0090] Preparation of compound 2:

[0091] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) were suspended in acetonitrile (120 mL), (2-(2-bromoethoxy)ethoxy)-tert-butyl-dimethylsilane (0.53 g, 1.86 mmol) was dissolved in 10 ml of acetonitrile and added dropwise to the above reaction solution, stirred at 65°C for 12 hours, and concentrated under reduced pressure to obtain the intermediate, and 50 ml of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution and stirred for 2 hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reverse phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.2 g of compound 2. 1H NMR (400 MHz, chloroform-d) δ8.86 (s, 1H), 8.42 (m, 1H), 8.09 (m, 1H), 7.95 (m, 1H), 7.08 (m, 1H), 6.90 (m, 1H), 4.99 (m, 1H), 4.38-4.05 (m, 6H), 3.85 (s, 2H), 2.76 (m, 1H), 2.36 (s, 1H), 1.66-1.56 (m, 3H), 0.76-0.72 (m, 3H) ppm. ESI-MS m / z 548.2[M+1]+.

[0092] Example 3.

[0093] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0094] The synthetic route is as follows:

[0095]

[0096] Preparation of intermediate 18:

[0097] Under nitrogen protection, isopropylmagnesium chloride (145mL, 2M THF, 290 mmol) was dissolved in 150ml THF, the temperature was raised to 40°C, 6-bromo-2,3-difluoroanisyl sulfide (28g, 117 mmol) was added in batches, and stirred for 30min. The reaction solution was cooled to 0°C, and a solution of triamyl borate (46mL, 410mmol) in THF (100ml) was added dropwise. 2N hydrochloric acid was added to adjust the pH to 1, extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. n-hexane was added and stirred thoroughly to obtain a solid intermediate 18 (15g).

[0098] Preparation of intermediate 4:

[0099] Using ethyl 2-diaza-3-oxopentanoate (intermediate 1) as raw material, it was prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627".

[0100] Preparation of intermediate 14:

[0101] Under nitrogen atmosphere, intermediate 4 (78 g, 201.93 mmol) was dissolved in 400 ml toluene, intermediate 18 (45.6 g, 223.5 mmol) was added to the solution, stirred, then K3PO4 (300 mL, 2M, 600 mmol) was added, tetrakis(triphenylphosphine)palladium(0) (12 g, 10.38 mmol) was added, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. Water was added to quench, EtOAc was extracted, and the organic layers were combined and concentrated under reduced pressure. Rapid silica gel column chromatography was used for purification, and EtOAc / petroleum ether gradient elution was used to obtain intermediate 14 (72 g). ESI-MS m / z 397.1[M+1]+.

[0102] Preparation of intermediate 15:

[0103] Intermediate 14 (11 g, 24.3 mmol) was dissolved in DCM (30 mL), cooled to 0 °C with stirring, and BBr3 (37 mL, 1 M, 18.5 mmol) solution was added dropwise, and the reaction was stirred. Aqueous sodium bicarbonate solution was added dropwise at 0 °C to quench the reaction. DCM extraction was performed, the organic layer was dried over anhydrous NaSO4, and concentrated under reduced pressure. The product was dissolved in DCM (40 mL), trifluoroacetic acid (4 mL, 52 mmol) was added dropwise, and the reaction solution was heated to 45 °C. After the reaction was completed, aqueous sodium bicarbonate solution was added to quench, DCM extraction was performed, anhydrous NaSO4 was dried, and the mixture was concentrated under reduced pressure to obtain the desired product in a mixture of diastereoisomers. The crude product was recrystallized twice from DCM-heptane, filtered and dried to obtain 5.5 g of solid as intermediate 15. ESI-MS m / z 337.0 [M+1] + .

[0104] Preparation of intermediate 16:

[0105] In a hydrogenation reactor, a suspension of intermediate 15 (9.4 g, 28.11 mmol) in MeOH (180 mL) was added, and a suspension of Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) in MeOH (40 mL) was added to the reactor. Pressurized hydrogen was stirred at 60 psi for 4 hrs, and then Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) was added, and pressurized hydrogen was stirred at 80 psi for 4 hrs. The reaction was complete after TLC detection. The suspension was filtered through celite under a nitrogen atmosphere, rinsed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate 16 (8.3 g).

[0106] Preparation of intermediate 17:

[0107] Under nitrogen protection, at room temperature, intermediate 16 (1 g, 2.82 mmol) was dissolved in 15 mL of acetonitrile, potassium carbonate (2 g, 14.4 mmol) was added, and iodomethane (1.85 g, 13 mmol) was added to the reaction solution in batches, and the reaction was stirred for 24 hours. MTBE was added, filtered through diatomaceous earth, washed with MTBE, and the filtrate was concentrated under reduced pressure to obtain a solid intermediate 17 (0.9 g). ESI-MS m / z 385.1 [M+1] +.

[0108] Preparation of compound 3:

[0109] Under nitrogen protection, at room temperature, intermediate 17 (5.1 g, 13.3 mmol) was dissolved in 50 ml THF, sodium methoxide (30% methanol solution, 0.32 mL, 1.3 mmol) was added to the reaction solution, and the reaction was stirred for 5 hr.

[0110] In the reaction solution, a solution of 5ml MeOH-5ml water was added dropwise, the reaction was stirred for 30min, then lithium hydroxide monohydrate (0.84g, 20mmol) was added, and the reaction was stirred for 8hr. After TLC detection reaction was complete, 1M hydrochloric acid (20ml) was added, MTBE was extracted, the organic layer was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated in a vacuum, then dissolved in MTBE and concentrated in a vacuum again, to obtain an intermediate, which was directly used in the next step reaction.

[0111] The intermediate (1.9 g, 5 mmol) of the previous step was dissolved in 20 ml DCM, cooled to 2 °C, and oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were added dropwise to the reaction solution in sequence, and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then 10 ml DCM was added to concentrate under reduced pressure. The concentrate was dissolved in 20 ml DCM, and added dropwise to a DCM (40 mL) solution of 4-aminopicolinic acid methyl ester (1.15 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol) and Et3N (2.2 mL, 15.5 mmol) at room temperature, stirred for 8 hours, concentrated under reduced pressure, added water, extracted with DCM, and dried over anhydrous sodium sulfate. Purified by rapid silica gel column chromatography, gradient elution with methanol-dichloromethane, the intermediate was obtained, and used directly in the next reaction.

[0112] The intermediate of the previous step was dissolved in methanolic ammonia (38.5 mL, 7 M, 269.2 mmol), stirred at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, EtOAc (10 mL) was added, the temperature was raised to 60°C to dissolve, the solution was cooled to 50°C, 6 ml of heptane was added dropwise, a solid was precipitated, and purified by reverse phase preparative chromatography (mobile phase: 25% methanol: acetonitrile (1:1), 75% CO2) to obtain 0.9 g of compound 3. 1HNMR (400 MHz, methanol-d4) δ8.81 (m, 1H), 8.57 (m, 1H), 8.21 (m, 1H), 7.46-7.20 (m, 2H), 5.125.12 (m, 1H), 4.56 (m, 1H), 3.14 (m, 1H), 2.78 (m, 3H), 1.93 (m, 3H), 0.91(m,3H)ppm. ESI-MS m / z 490.2[M+1]+.

[0113] Example 4.

[0114] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0115] The synthetic route is as follows:

[0116]

[0117] Preparation of compound 4:

[0118] Compound 3 (1 g, 2 mmol) was dissolved in 15 ml THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and stirred at room temperature for 1.5 hr. NaHCO3 solution was added, extracted with DCM, and dried over anhydrous sodium sulfate. Rapid silica gel column chromatography was performed, and gradient elution with methanol-dichloromethane was used to obtain 0.6 g of compound 4. ESI-MS m / z 506.2 [M+1] + .

[0119] Example 5.

[0120] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0121] The synthetic route is as follows:

[0122]

[0123] Preparation of compound 5:

[0124] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) were suspended in acetonitrile (120 mL), (2-(2-bromoethoxy)ethoxy)-tert-butyl-dimethylsilane (0.53 g, 1.86 mmol) was dissolved in 10 ml of acetonitrile and added dropwise to the above reaction solution, stirred at 65°C for 12 hours, and concentrated under reduced pressure to obtain the intermediate, and 50 ml of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution and stirred for 2 hours. The mixture was concentrated under reduced pressure, water was added, and DCM was used for extraction. The organic layer was concentrated under reduced pressure and purified by reverse phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.2 g of compound 2. 1H NMR (400 MHz, chloroform-d) δ8.86 (s, 1H), 8.42 (m, 1H), 8.09 (m, 1H), 7.95 (m, 1H), 7.08 (m, 1H), 6.90 (m, 1H), 4.99 (m, 1H), 4.38-4.05 (m, 6H), 3.85 (s, 2H), 2.76 (m, 1H), 2.36 (s, 1H), 1.66-1.56 (m, 3H), 0.76-0.72 (m, 3H) ppm. ESI-MS m / z 548.2[M+1]+.

[0125] Example 6.

[0126] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0127] The synthetic route is as follows:

[0128]

[0129] Preparation of compound 6:

[0130] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) were suspended in acetonitrile (120 mL), (R)-3-iodotetrahydrofuran (0.37 g, 1.86 mmol) was dissolved in 10 ml of acetonitrile and added dropwise to the above reaction solution, stirred at 65°C for 12 hours, and concentrated under reduced pressure to obtain the intermediate, and 50 ml of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution and stirred for 2 hours. The mixture was concentrated under reduced pressure, water was added, and DCM was extracted. The organic layer was concentrated under reduced pressure and purified by reverse phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.20 g of compound 6. 1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 8.89 (s, 1H), 8.47 (m, 1H), 8.13 (m, 1H), 7.99 (m, 1H), 7.12 (m, 1H), 6.94 (m, 1H), 5.01 (m, 1H), 4.39-4.06 (m, 4H), 3.89-3.65 (m, 2H), 2.84-2.23 (m, 3H), 1.72-1.61 (m, 3H), 0.84-0.72 (m, 3H) ppm. ESI-MS m / z 530.2[M+1]+.

[0131] Example 7.

[0132] 4-((2R,3S,4S,5R)-3-(4-fluoro-2,3-dihydrobenzo[b]thiophen-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0133] The synthetic route is as follows:

[0134]

[0135] Preparation of intermediate 19:

[0136] Under nitrogen protection, dissolve isopropylmagnesium chloride (145mL, 2M THF, 290 mmol) in 150ml THF, heat to 40°C, add 1-bromo-4-fluoro-2,3-dihydrobenzo[b]thiophene (27.3g, 117 mmol) in batches, and stir for 30min. Cool the reaction solution to 0°C, and add a solution of triamyl borate (46mL, 410mmol) in THF (100ml) dropwise. Add 2N hydrochloric acid to adjust the pH to 1, extract with DCM, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Add n-hexane and stir thoroughly to obtain a solid as intermediate 19 (18.3g).

[0137] Preparation of intermediate 20:

[0138] Under nitrogen atmosphere, intermediate 4 (15.6 g, 40.39 mmol) was dissolved in 400 ml toluene, intermediate 19 (8.85 g, 44.7 mmol) was added to the solution, stirred, then K3PO4 (60 mL, 2 M, 120 mmol) was added, tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) was added, the temperature was raised to 100 ° C, and the reaction was stirred for 3 hours. Water was added to quench, EtOAc was extracted, and the organic layers were combined and concentrated under reduced pressure. Rapid silica gel column chromatography was used for purification, and EtOAc / petroleum ether gradient elution was used to obtain intermediate 20 (72 g). ESI-MS m / z 391.1[M+1]+.

[0139] Preparation of intermediate 21:

[0140] Compound 20 (30 g, 76.25 mmol) was dissolved in 100 ml of ethanol, and Pd / C (10% loading, 100 g, 94 mmol) was added, and hydrogen was passed through. The reaction was carried out at room temperature for 10 hours. Pd / C (10% loading, 100 g, 94 mmol) was further added, and hydrogen was passed through. The reaction was carried out for 10 hours. Filtered through diatomaceous earth, washed with DCM, added with water, extracted with DCM, and the organic layers were combined and concentrated under reduced pressure. Purified by rapid silica gel column chromatography, eluted with EtOAc / petroleum ether gradient, and used directly in the next step.

[0141] The above intermediate (7.8 g, 20 mmol) and potassium tert-butoxide (6.5 g, 58 mmol) were dissolved in tert-butanol (250 mL) and stirred for 6 h. The aqueous solution was quenched, the pH was adjusted to 2N hydrochloric acid, and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The intermediate 21 (6.1 g) was obtained by rapid silica gel column chromatography with EtOAc / petroleum ether gradient elution. ESI-MS m / z 363.3 [M-1] -.

[0142] Preparation of compound 7:

[0143] Intermediate 21 (3.7 g, 10 mmol) was dissolved in 40 ml DCM, cooled to 2 °C, and oxalyl chloride (4.4 mL, 50 mmol) and DMF (71 μL, 1 mmol) were added dropwise to the reaction solution in sequence, and stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 20 ml DCM was added and concentrated under reduced pressure. The concentrate was dissolved in 40 ml DCM, and added dropwise to a DCM (80 mL) solution of 4-aminopicolinic acid methyl ester (2.3 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol) and Et3N (4.4 mL, 31 mmol) at room temperature, stirred for 8 hr, concentrated under reduced pressure, added water, extracted with DCM, and dried over anhydrous sodium sulfate. Purified by rapid silica gel column chromatography, gradient elution with methanol-dichloromethane, the intermediate was obtained, and used directly in the next reaction.

[0144] The intermediate was dissolved in methanolic ammonia (77 mL, 7 M, 538 mmol), stirred at room temperature for 24 hours, the reaction solution was concentrated under reduced pressure, EtOAc (20 mL) was added, the temperature was raised to 60°C to dissolve, the solution was cooled to 50°C, and 12 ml of heptane was added dropwise to obtain the intermediate. Reverse phase preparative chromatography was used for purification (mobile phase: 25% methanol: acetonitrile (1:1), 75% CO2) to obtain 1.5 g of compound 7. 1HNMR (400 MHz, methanol-d4) δ8.85 (m, 1H), 8.62 (m, 1H), 8.26 (m, 1H), 7.51-7.24 (m, 2H), 5.16 (m, 1H), 4.61 (m, 1H), 3.29 (m, 5H), 1.97 (m, 3H), 0.95 (m, 3H) ppm. ESI-MS m / z 484.2[M+1]+.

[0145] Example 8.

[0146] 4-((2R,3S,4S,5R)-3-(4-fluoro-1-oxo-2,3-dihydrobenzo[b]thiophen-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0147] The synthetic route is as follows:

[0148]

[0149] Preparation of compound 8:

[0150] Compound 7 (1 g, 2 mmol) was dissolved in 15 ml THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and stirred at room temperature for 1.5 hr. NaHCO3 solution was added, extracted with DCM, and dried over anhydrous sodium sulfate. Rapid silica gel column chromatography was performed, and gradient elution with methanol-dichloromethane was used to obtain 0.5 g of compound 8. ESI-MS m / z 500.1 [M+1] + .

[0151] Example 9.

[0152] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-hydroxyethoxy)ethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

[0153] The synthetic route is as follows:

[0154]

[0155] Preparation of compound 9:

[0156] Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) were suspended in acetonitrile (120 mL), 2-iodo-1,1,1-trifluoroethane (0.39 g, 1.86 mmol) was dissolved in 10 ml of acetonitrile and added dropwise to the above reaction solution. The reaction was stirred at 65°C for 12 hours and concentrated under reduced pressure to obtain the intermediate. 50 ml of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution and stirred for 2 hours. The solution was concentrated under reduced pressure, water was added, and DCM was extracted. The organic layer was concentrated under reduced pressure and purified by reverse phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.18 g of compound 9. ESI-MS m / z 542.2 [M+1] + .

[0157] Effect Example 1 Determination of Nav1.8 Inhibitory Activity and Ion Channel Selectivity

[0158] The effects of the example compounds on Nav1.8, Nav1.4 and Nav1.6 ion channels were tested in vitro. Nav1.8 ion channels were expressed in HEK293 cells, and Nav1.4 and Nav1.6 ion channels were expressed in HEK293 or ND7 / 23 cells, respectively. After the currents of Nav1.8 and Nav1.4 and Nav1.6 were stabilized, the sizes of the corresponding ion channel currents before and after the application of the compounds were compared, and the inhibitory activity and selectivity of the compounds on Nav1.8 ion channels could be obtained.

[0159] 1. Experimental Equipment

[0160] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axon instrument)

[0161] 2) Digital to analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments)

[0162] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0163] 4) Inverted microscope: TL4 (Olympus)

[0164] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0165] 6) Microelectrode glass capillary: B12024F

[0166] 2. Experimental Procedure

[0167] 2.1 Preparation of experimental compounds and intracellular and extracellular solutions

[0168] All test compounds and control compound CP were dissolved in dimethyl sulfoxide (DMSO) and the solution was stored at a concentration of 10 mM. The compound solution used for Nav1.8 inhibitory activity test contained 1 μM tetrodotoxin (TTX, Affix Scientific). Dilute with extracellular fluid, prepare before use, and prepare to the required concentration according to the multiple dilution method.

[0169] Preparation of intracellular and extracellular fluids:

[0170] Intracellular fluid (mM): aspartate, 140; ,2; EGTA,11; HEPES,10; pH7.2 (CsOH titration).

[0171] Extracellular fluid (mM): NaCl, 137; KCl, 4; ,1.8; ,1; HEPES,10; glucose,10; pH7.4 (NaOH titration).

[0172] 2.2 Electrophysiology

[0173] 1) After the compound is prepared into a solution of specified concentration, add the solution into each channel in order from low to high concentration and mark each channel.

[0174] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, touch the tip of the electrode to the cell, adjust the three-way valve of the vacuum device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current path.

[0175] 3) After the cell membrane permeation current is stable, different concentrations are perfused in sequence. If the current is stable for at least one minute, the next concentration can be perfused. The perfusion time for each concentration should not exceed five minutes.

[0176] 4) Clean the perfusion tank. Rinse the cells according to the concentration of the drug solution from high to low, and rinse for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

[0177] 3. Pilot Plan (Quiet State)

[0178] The cells were clamped at -80 mV, and then depolarized to 10 mV with a 10 ms square wave to obtain Nav1.8, Nav1.4, and Nav1.6 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. When the reaction stabilized, the intensity of the blockade was calculated.

[0179] 4. Data Analysis

[0180] Data collection and analysis will be performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stabilization refers to the change of current over time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound at this concentration.

[0181] The inhibitory activity of the example compounds on Nav1.8, Nav1.4 and Nav1.6 was determined by the above test. Value and SI (therapeutic index), SI1.4=(Nav1.4 ) / (Nav1.8 );SI1.6=(Nav1.6 ) / (Nav1.8 ), the experimental results are shown in Table 1.

[0182] Table 1: IC of the Example compounds for inhibition of Nav1.8 channel activity 50 and therapeutic index SI

[0183]

[0184] From the above results, it can be seen that all the tested compounds showed a relatively high inhibitory effect on the activity of Nav1.8 channels, and had a high selectivity index (therapeutic index), especially the inhibitory effect of compound 3 and compound 7 on Nav1.8 was about 10 times that of the control compound CP, the Nav1.4 therapeutic index of compound 3 and compound 7 was greater than 15 times that of the control compound CP; the Nav1.6 therapeutic index of compound 1 and compound 3 was greater than 19 times that of the control compound CP. Nav1.6 is expressed in central nervous system cells, and Nav1.4 is expressed in skeletal muscle cells. Nav1.6 and Nav1.4 ion channels are not involved in the process of inflammatory pain and neuropathic pain, but can cause adverse reactions. Therefore, the example compounds can be prepared for the treatment of drug symptoms / disease prevention / treatment drugs for diseases caused by overexpression of Nav1.8, and have a higher therapeutic index and lower central nervous system side effects.

[0185] Effect Example 2 Pharmacokinetic Evaluation

[0186] SD rats were used as test animals, and the drug concentration in plasma at different time points after oral administration of the example compounds was determined by LC / MS / MS method. The pharmacokinetic behavior of the disclosed compounds in SD rats was studied, and their pharmacokinetic characteristics were evaluated.

[0187] 1) Experimental drugs

[0188] Example Compound 1, Compound 3 and Compound 7.

[0189] 2) Experimental animals

[0190] Sixteen SD rats, 4 in each group, half male and half female, were administered with oral administration after fasting overnight but not water restriction.

[0191] 3) Drug preparation

[0192] A certain amount of the example compounds were weighed respectively, and a lysozyme solution of 5% DMSO + 10% Solutol + 85% saline was added to prepare a 0.2 mg / mL uniform solution.

[0193] 4) Drug administration

[0194] The dosage was 2 mg / kg and the administration volume was 10.0 mL / kg.

[0195] 5) Operation

[0196] Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the eye sockets and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

[0197] Determination of the content of the test compound in the plasma of SD rats after administration of different concentrations of the drug: Take the plasma samples of SD rats at different times after administration, dilute 10 times with acetonitrile solution containing internal standard, vortex mix, and centrifuge at 3700 rpm for 10 minutes. After the supernatant is mixed with water in a ratio of 1:1, take 0.5 μL of the supernatant for LC / MS / MS analysis.

[0198] 6) Pharmacokinetic parameter results

[0199] Table 2: Pharmacokinetic parameters of the example compounds in SD rats

[0200]

[0201] The experiment found that the metabolic parameters of the control compound had obvious male-female differences, while compound 1, compound 3 and compound 7 had no obvious male-female differences. From the above results, it can be seen that all the tested compounds have better exposure than the control compound. Especially compound 3 C max It is 1.6 times that of the control compound. Compound 1 AUC 0-t The experimental results show that the example compound has better metabolic parameters, and there is no gender difference in metabolic parameters, so it can be used by a wider population in clinical practice and has higher drug safety.

[0202] Effect Example 3 Evaluation of drug efficacy in mouse incision pain model

[0203] Mice were used as test animals. After oral administration of the example compounds, the efficacy of the disclosed compounds on the mouse incision pain model was studied to evaluate their in vivo efficacy.

[0204] 1) Modeling:

[0205] Grouping: The experimental animals were BALB / c mice, 8 in each group, half male and half female. Before modeling, 8 animals were randomly selected as the sham operation group after excluding abnormal animals based on the PWT basal value, and 8 animals in each drug group were surgically modeled. After surgery, the animals were grouped again according to the pain threshold (PWT) before drug administration.

[0206] Under isoflurane anesthesia, a 0.5 cm long longitudinal skin incision was made with a blade at about 0.2 cm distal to the tibiotalar joint on the plantar surface of the left hind foot, extending to the toes; the plantar muscle was separated, slightly raised, and then longitudinally cut, taking care not to damage the muscle origin and insertion. The incision was sutured horizontally with 5-0 nylon thread (2 stitches) as the model group and the efficacy evaluation group; in addition, healthy normal mice were selected as the normal group.

[0207] 2) Solvent: The solvent used for the example compound and the control compound CP was 5% DMSO + 10% Solutol + 85% Saline

[0208] 3) Dosage method and frequency:

[0209] Model group: vehicle was orally administered once a day.

[0210] Normal group: vehicle was orally administered once a day.

[0211] Experimental group: oral administration, once a day, dose: 60 mpk.

[0212] 4) Mechanical pain threshold measurement: The mechanical pain threshold before modeling was measured before modeling; the mechanical pain threshold before drug administration was measured 2.5 h after modeling. Oral administration was performed after the measurement, and the mechanical pain threshold was measured 2 h after drug administration. The measurement position was within the surgical incision position. Each animal was measured 3 times, with an interval of 3-5 minutes each time, and the average value was taken.

[0213] 5) Data analysis: The relevant data were collated in GraphPad Prism 6.0 and analyzed using One-way ANOVA. The analysis method used was Tukey's test for significant differences between groups.

[0214] Table 3: Pharmacodynamic results of the example compounds on the mouse incision pain model

[0215]

[0216] The above results show that the example compounds all show excellent pain-suppressing effects. And the pain-suppressing effects of the example compounds are better than those of the control compound CP. The experimental results show that the example compounds have better analgesic efficacy, lower dosage, and lower central nervous system side effects than existing clinical treatment methods.

[0217] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that all aspects be considered as illustrative and not restrictive, that reference is made to the embodiments of the appended claims rather than to the foregoing embodiments, that references are made only to the appended claims rather than to the foregoing examples, and that all changes that come within the meaning and scope of equivalents of the claims are therefore intended to be included herein.

[0218] All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the event of inconsistency, the present disclosure, including the definitions, will control.

Claims

1. A compound, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is represented by any of the following structural formulas: , , , , , , , , .

2. A pharmaceutical composition comprising an effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

3. Use of the pharmaceutical composition according to claim 2 or the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating, preventing or alleviating voltage-gated sodium channel-related diseases.

4. The related disease according to claim 3 is selected from chronic pain or acute pain.

5. The related disease according to claim 3 is selected from intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia.

6. According to claim 3, the related disease is selected from one or more of neuropathic pain, post-herpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy.

7. The related disease according to claim 3 is selected from musculoskeletal pain, postoperative pain or visceral pain.

8. The associated disease according to claim 7, wherein the musculoskeletal pain is selected from osteoarthritis pain.

9. The related disease according to claim 4, wherein the acute pain is selected from acute postoperative pain.

10. The related disease according to claim 7, wherein the postoperative pain is selected from bunionectomy pain, abdominoplasty pain or hernia repair pain.

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