Tetrahydrofuramide sodium channel modulators and their medical applications

Abstract

The present invention provides a class of substituted tetrahydrofuranformamide derivatives, salts or stereochemical isomers, and pharmaceutical compositions containing the same, as well as their use as Nav inhibitors and their use in the preparation of drugs for treating and / or alleviating pain and pain-related diseases. 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, and low central nervous side effects.

Description

Technical Field

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

[0002] Pain is the sensation produced when the human body is subjected to various noxious stimuli. It is a complex physiological and psychological activity and also 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) classifies 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 and can excite neurons, playing an important biophysical role in the conduction of pain-related signals. They transmit electrical signals through the generation and propagation of action potentials (APs) in the peripheral (PNS) and central nervous systems (CNS). There are 9 types of sodium channels in humans, namely Nav1.1 to Nav1.9. Each sodium channel is formed by an α subunit and one or more β subunits. Although having a high degree of structural and sequence similarity, different subtypes of Nav channels not only have specific tissue distributions but also have different voltage dependencies and activation, inactivation, and recovery kinetics, etc. (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 activities observed under pathological conditions, etc. (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, which is mainly expressed in sensory neurons, located in the region of human chromosome 3p21-22, and 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 in diabetic pain) and tumor necrosis factor α (TNF-α), etc. (Huang Q, et al. Metabolism, 2016, 65(4):463-474; He XH, Zang Y, Chen X, et al. Pain. 2010 Nov;151(2):266-279.). According to a series of animal experiments and human gene evidence, selective inhibition of Nav1.8 can be used for the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, cancer pain, etc., and has become a new type of analgesic therapy. Therefore, Nav1.8 blockers are expected to become a new generation of ideal drugs for the treatment of neuropathic and inflammatory pain.

[0005] Nav inhibitors used in clinical practice have a narrow therapeutic window and limited application range because they lack subtype selectivity and can inhibit sodium channels expressed in the heart and central nervous system. Nav1.8 is mainly distributed in the peripheral nervous system, so selectively inhibiting 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, and fewer side effects. Summary of the Invention

[0006] The present invention provides a substituted tetrahydrofuranformamide derivative, salt or stereochemical isomer and a pharmaceutical composition containing the same. The tetrahydrofuranformamide derivative preferably has a structure represented by 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. Optionally, the compounds of the present invention can be used in the form of acid or base salts. The acid addition salts of the free amino compounds of the present invention can be prepared by methods well 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 adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. 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 their substituted derivatives (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Thus, the term "pharmaceutically acceptable salts" shall include and cover all acceptable salt forms.

[0012] In addition, prodrugs are also included within the scope of the present invention. A prodrug is any covalently bonded carrier that releases the accepted compound in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying a functional group in such a way that the modification can be cleaved by conventional means or decomposed in vivo to yield the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or mercapto group is bonded to any group that detaches when the prodrug is administered to a patient to yield a hydroxyl, amino, or mercapto group.

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

[0014] For stereoisomers, the compounds of the present application may have chiral centers and can exist in the form of racemates, racemic mixtures, as well as individual enantiomers or diastereomers. All isomeric forms are included within the scope of the present invention, including mixtures thereof. In addition, certain 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 similarly included within the scope of the present invention.

[0015] Those skilled in the art should understand that any compound may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. As used in the present invention, in the specification and claims, H refers to hydrogen and includes any stable isotope of hydrogen, i.e., 1 H and D. In the examples where an atom is designated as H, no work has been done to enrich the atoms of a specific isotope of hydrogen, and thus those of ordinary skill in the art should understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen. In the tetrahydrofuran formamide derivatives involved in the present invention, the term "deuteration" means that the atoms at the relevant sites of the compound contain more than the natural proportion (i.e., more than the natural abundance of deuterium) of deuterium atoms. Therefore, any tetrahydrofuran formamide derivative that contains deuterium atoms at a proportion higher than the natural abundance of deuterium at the relevant sites is within the scope of protection of the present invention. For example, it can be understood that the corresponding tetrahydrofuran formamide derivatives having the corresponding deuteration 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 examples of the present invention are all 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 examples, but should be understood as all synthesis methods or routes that can be adopted in the art to obtain the compounds of the present invention, as well as all deuterated reagents that can be used in combination with the foregoing synthesis methods or routes to introduce deuterium atoms into the target molecule.

[0016] Isotopically labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceuticals. In some embodiments, the isotopically labeled compounds and salts are deuterium (D)-labeled. Deuterium (D)-labeled compounds and salts are therapeutically useful and have potential therapeutic advantages over non-D-labeled compounds. Generally, due to the kinetic isotope effects described below, deuterium (D)-labeled compounds and salts can have higher metabolic stability compared to non-isotopically labeled compounds and salts. The higher metabolic stability directly translates into an extended in vivo half-life or a reduced dose, which in most cases will represent a preferred embodiment of the present invention. Isotopically labeled compounds and salts can generally be prepared by carrying out the procedures disclosed in the synthetic schemes, examples, and related descriptions, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants. Deuterium (D)-labeled compounds and salts can manipulate the oxidative metabolic rate of the compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from an isotopic nuclear exchange, which in turn is caused by a change in the ground-state energy of the covalent bond participating in the reaction. The exchange of a heavier isotope generally causes a decrease in the ground-state energy of the chemical bond and thus a reduction in the cleavage of the rate-limiting bond. If the bond cleavage occurs in or near the saddle-point region along the reaction coordinate of a multi-product reaction, the product distribution ratio can be substantially altered.

[0017] According to the specific embodiments disclosed herein of the present invention, those skilled in the art can prepare each specific compound involved in the tetrahydrofuran carboxamide derivatives of the present invention by adopting the same or similar principles and methods.

[0018] The present invention further provides the use of a tetrahydrofuran carboxamide derivative as shown in the present application, its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof or prodrugs thereof in the preparation of an anti-sodium ion channel regulator. Further, the sodium ion channel regulator is a Nav1.8 inhibitor.

[0019] The present invention further provides the use of a tetrahydrofuran carboxamide derivative as shown in the present application, its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof or prodrugs thereof in the preparation of a medicament for treating diseases caused by overexpression of Nav1.8.

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

[0021] The present invention further provides the use of a tetrahydrofuran formamide derivative as shown in the present application, its stereoisomer, hydrate, solvate, polymorph, active metabolite, pharmaceutically acceptable salt or prodrug 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 disease, incontinence and arrhythmia.

[0022] Furthermore, the neuropathic pain is selected from one or more of postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush 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 cephalgia; 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 vulvodynia; the primary pain is selected from fibromyalgia.

[0023] The present invention further provides a pharmaceutical composition, which comprises a therapeutically effective amount of a tetrahydrofuran formamide derivative as shown in the present application, its stereoisomer, hydrate, solvate, polymorph, active metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

[0024] The pure form or a suitable pharmaceutical composition of the compound of the present invention or its pharmaceutically acceptable salt can be administered by any acceptable mode of administering an agent having a similar effect. 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, semi-solid, liquid or gaseous form 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, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated to allow the active ingredient contained therein to be bioavailable after administration of the composition to a patient. The composition to be administered to an individual or patient is in the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and a container containing the compound of the present invention in aerosol form can contain multiple dosage units. The actual methods of preparing such dosage forms are known to those skilled in the art or will be known to them. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt 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. In one aspect, the carrier is particulate, so that the composition is in the form of, for example, a tablet or powder. The carrier can be liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation administration. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the forms regarded 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 usually contain one or more inert diluents or edible carriers. In addition, one or more of the following substances can also be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth 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 silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as peppermint, methyl salicylate or sweet orange flavoring; and coloring agents.

[0026] In the preparation of compositions for oral administration, any common pharmaceutical vehicle can be used. In the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions, and solutions, for example, water, glycols, oils, alcohols, etc.; or in the case of solid compositions, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants, etc. For parenteral compositions, the vehicle will generally comprise at least predominantly sterile water, but other ingredients such as solubilizers, emulsifiers, or additional adjuvants can also be added thereto. Injectable solutions can be prepared, wherein the vehicle comprises a physiological saline solution, a glucose solution, or a mixture of the two. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents, etc. can be employed. Also included are solid form preparations that are intended to be converted into liquid form preparations shortly before use, such as powders for reconstitution.

[0027] When the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, in addition to the substances of the above types, it can also contain a liquid vehicle such as polyethylene glycol or an oil. The pharmaceutical composition can be in liquid form, such as a tincture, syrup, solution, emulsion, or suspension. This liquid can be administered orally or by injection, as two examples. When intended for oral administration, the preferred composition contains, in addition to the compound of the present invention, one or more of a sweetening agent, a preservative, a dye / colorant, and a flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffering agent, a stabilizing agent, and an isotonic agent can be included.

[0028] Regardless of whether the liquid pharmaceutical composition of the present invention is in the form of a solution, suspension, or other similar form, 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 di-glycerides, which can be used as solvents or suspending media), polyethylene glycol, glycerol, propylene glycol, and other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetate, citrate, or phosphate, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0029] The liquid pharmaceutical compositions of the present invention intended for parenteral or oral administration should contain an amount of the compounds of the present invention such that a suitable dose can be obtained. The pharmaceutical compositions of the present invention may be intended for topical administration, in which case the carrier preferably comprises a solution, an emulsion, an ointment or a gel base. For example, the base may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as water and alcohol), and emulsifying and stabilizing agents. Thickeners may be present in the pharmaceutical compositions for topical administration. If transdermal administration is intended, the composition may include a transdermal patch or an iontophoresis device.

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

[0031] The pharmaceutical compositions of the present invention may include various substances which modify the physical form of the solid or liquid dosage units. For example, the composition may include substances which form a coating shell around the active ingredient. The substances forming the coating shell are generally inert and may be selected from, for example, sugars, shellac and other enteric coating agents. Alternatively, the active ingredient may be enclosed in a gelatin capsule.

[0032] The pharmaceutical compositions of the present invention in solid or liquid form may include a reagent which binds to the compounds of the present invention and thus aids in the delivery of the compounds. Suitable reagents having this ability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0033] The pharmaceutical compositions of the present invention may consist of dosage units which can be administered in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from colloidal species to systems consisting of a pressurized package. Delivery may be effected by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredient. The aerosol of the compounds of the present invention may be delivered as a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes the necessary container, actuator, valve, sub-container, etc., which together may form a kit. A person skilled in the art can determine the preferred aerosol without undue experimentation.

[0034] The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical art. For example, to prepare a pharmaceutical composition for administration by injection, the compound of the present invention can be combined 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 non-covalently interacts with the compound of the present invention, thereby promoting the dissolution or uniform suspension of the compound in an aqueous delivery system. The compound of the present invention can be combined with an acceptable vehicle or solvent such as water, Ringer's solution, and isotonic sodium chloride solution to form a solution. The sterile injectable preparation can be a sterile water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion can be injected into the bloodstream of a patient by topical bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous infusion pump.

[0035] The pharmaceutical compositions of the present disclosure can be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. The suspensions can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used. In addition, fatty acids can also be used to prepare injectables.

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

[0037] As used herein, an additional therapeutic agent that is typically administered for treating or preventing a particular disease or condition is referred to as "suitable 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; p-aminophenol derivatives such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium 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, Butorphanol, Dezocine, Nalbuphine and pentazocine). Additionally, non-pharmacological analgesic methods can be used in combination with the administration of one or more compounds of the present invention. For example, anesthesia (intraspinal infusion, nerve block), neurosurgery (neurolysis of CNS pathways), nerve stimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiological (physical therapy, orthopedic devices, diathermy) or psychological (cognitive methods - hypnosis, biofeedback or behavioral methods) methods can also be utilized.

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

[0039] The compounds of the present invention or their pharmaceutically acceptable salts may also be administered simultaneously with, before or after the administration of one or more other therapeutic agents. Such combination therapy includes the administration of a single pharmaceutical dosage formulation containing the compound of the present invention and one or more other active agents, as well as the administration of the compound of the present invention and the individual pharmaceutical dosage formulations of each active agent. For example, the compound of the present invention and another active agent may be administered to a patient together in a single oral dosage composition (such as a tablet or capsule), or each agent may be administered in a separate oral dosage formulation. In the case of separate dosage formulations, the compound of the present invention and one or more additional active agents may be administered substantially at the same time (i.e., simultaneously) or at separate staggered times (i.e., sequentially); combination therapy is to be understood to include all such regimens.

[0040] The compounds and salts of the present invention or their pharmaceutically acceptable compositions may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Thus, in another aspect, the present invention encompasses a composition for coating an implantable device, the implantable device comprising a compound or salt of the present invention as generally described above and the classes and subclasses herein and a carrier suitable for coating the implantable device. In yet another aspect, the present invention encompasses an implantable device coated with a composition comprising a compound or salt of the present invention as generally described above and the classes and subclasses herein and a carrier suitable for coating the implantable device. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polydimethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating may optionally be further coated with a suitable top layer of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release characteristics to the composition.

[0041] As a general guide, the active compounds of the present disclosure are preferably in unit dosage form, or in a form in which the patient can self-administer a single dose. The unit dosage forms of the compounds or compositions of the present disclosure may be tablets, capsules, cachets, vials of liquid medicine, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages may be from 0.1 - 1000 mg.

[0042] In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the different administration methods, 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, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. 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 the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets by mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may not be coated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained-release effect over a longer period.

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

[0046] The present invention features a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which is used for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and central neuropathic pain of irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, non-specific 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 neuropathic pain after stroke), whiplash injury-related conditions, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pudendal, renal colic, biliary tract disease, vascular leg ulcer, 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 motility disorders or a method for reducing their severity.

[0047] On the other hand, the present invention features a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which is used for treating cancerous pain of the femur, 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 headache, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after resection of lower limb, upper limb, breast), 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, childbirth 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, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful obesity, phlebitis pain, Guillain-Barré syndrome pain, leg and moving toe pain, Haglund's syndrome, erythromelalgia, Fabry disease pain, bladder and urogenital system diseases, urinary incontinence, pathological cough, overactive bladder, bladder pain 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 for reducing the severity thereof.

[0048] On the other hand, the present invention features the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions for treating trigeminal neuralgia, migraine treated with botulinum, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliohypogastric neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, stump pain of traumatic neuroma or pain after amputation or a method for reducing the severity thereof.

[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 the compounds disclosed in the present invention or their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed in the present invention.

[0050] Treating one or more of the following in the subject or reducing the severity thereof: one or more of neuropathic pain, optionally one or more of postherpetic 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 hallux valgus resection pain, abdominoplasty pain or hernia repair 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, low side effects, and low central nervous side effects. Therefore, the compounds of the present invention have better pharmaceutical properties.

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

[0053] Unless otherwise specified, the compounds of the present invention are named manually or by chemical structure software, and commercially available compounds use the supplier catalog names.

[0054] On the basis of conforming to common general knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention. Detailed Description of the Invention

[0055] Certain preferred embodiments of the present invention are illustratively shown in the following non-limiting examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. The raw materials can be obtained commercially, 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)pyridinecarboxamide

[0058] The synthetic route is as follows:

[0059]

[0060] Preparation of Intermediate 5:

[0061] Using ethyl 2-diaza-3-oxopentanoate (Intermediate 1) as the raw material, it is prepared by the method disclosed in Example 3 on page 231 of the specification of the 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, and a solution of BBr3 (740 mL, 1 M, 370.0 mmol) was added dropwise, and the reaction was stirred. The reaction was quenched by adding an aqueous sodium bicarbonate solution dropwise at 0 °C. The mixture was extracted with DCM, and 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, it was quenched by adding an aqueous sodium bicarbonate solution, extracted with DCM, dried over anhydrous NaSO4, 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 a 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. Hydrogen gas was pressurized, and the mixture was stirred at a pressure of 60 psi for 8 h. The reaction was monitored by TLC and found to be complete. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, rinsed with MeOH and then with EtOAc. 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, and potassium tert-butoxide (97.6 g, 869.6 mmol) was added in portions. The reaction mixture was stirred at 0 °C for an additional 10 min, then warmed to 10 °C and stirred for 1 h, and then cooled to 5 °C. Then 2M HCl was added to adjust the pH to 1. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain Intermediate 7 (78.3 g). 1H NMR (400 MHz, methanol-d4) δ 6.98 (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 solution was added dropwise to a suspension of Intermediate 7 (20 g, 58.8 mmol) and cesium carbonate (96 g, 298.0 mmol) in acetonitrile (800 mL). The mixture was stirred at 70 °C for 24 h, 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), and 2M LiOH solution (30 mL, 60 mmol) was added dropwise. The mixture was stirred at room temperature for 8 h. Then 3M HCl in MeOH (20 mL) was added dropwise to acidify the solution. The mixture was 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 of DCM, and the temperature was lowered to 2 °C. Oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure, and then concentrated under reduced pressure after adding 10 ml of DCM. The concentrate was dissolved in 20 ml of DCM and added dropwise to a 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) in DCM (40 mL) at room temperature. The mixture was stirred and reacted for 8 h, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol-dichloromethane gave the intermediate, which was directly used in the next reaction.

[0073] The above intermediate was dissolved in methanol ammonia (38.5 mL, 7 M, 269.2 mmol), and the mixture was stirred at room temperature for 24 h. The reaction solution was concentrated under reduced pressure and purified by reversed-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) δ 8.85 (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-MS m / 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)pyridinecarboxamide

[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. Hydrogen gas was pressurized, and the mixture was stirred at a pressure of 60 psi for 8 h. The reaction was monitored by TLC and found to be complete. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, rinsed with MeOH and then with EtOAc. The filtrate was concentrated under reduced pressure to obtain intermediate 9 (91.2 g).

[0080] Preparation of intermediate 10:

[0081] Under nitrogen protection and 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 methyl iodide (3.7 g, 26 mmol) was added portionwise to the reaction mixture. The mixture was stirred for 24 h. MTBE was added, and the mixture was filtered through diatomaceous earth and washed with MTBE. 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 and at room temperature, intermediate 10 (49 g, 133 mmol) was dissolved in 500 mL of THF. Sodium methoxide (30% methanol solution, 3.2 mL, 14 mmol) was added to the reaction mixture, and the mixture was stirred for 4.5 h.

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

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

[0086] Intermediate 11 (1.8 g, 5 mmol) was dissolved in 20 ml of DCM. The temperature was lowered to 2 °C, and oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then concentrated under reduced pressure after adding 10 ml of DCM. The concentrate was dissolved in 20 ml of DCM and added dropwise at room temperature to a 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) in DCM (40 mL). The mixture was stirred and reacted for 8 hr, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol-dichloromethane gave the intermediate, which was directly used in the next reaction.

[0087] The above intermediate was dissolved in methanol ammonia (38.5 mL, 7 M, 269.2 mmol), and the mixture was stirred at room temperature for 24 hr. The reaction solution was concentrated under reduced pressure, EtOAc (10 mL) was added, and the mixture was heated 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), and the mixture was stirred and cooled to 0 °C. A solution of BBr3 (10 mL, 1 M, 10 mmol) was added dropwise, and the mixture was stirred and reacted for 12 hr. The reaction was quenched by adding an aqueous sodium bicarbonate solution at 0 °C. The mixture was extracted with DCM, and the organic layer was dried over anhydrous NaSO4 and concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether gave Intermediate 13 (2.2 g). ESI-MS m / z 458.8 [M-1] - 。

[0090] Preparation of Compound 2:

[0091] A suspension of intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) 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. The reaction was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain an 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 h. Concentrated under reduced pressure, water was added, 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) δ 8.86 (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)pyridinecarboxamide

[0094] The synthetic route is as follows:

[0095]

[0096] Preparation of intermediate 18:

[0097] Under nitrogen protection, isopropylmagnesium chloride (145 mL, 2 M THF, 290 mmol) was dissolved in 150 mL of THF, the temperature was raised to 40 °C, and 6-bromo-2,3-difluorobenzyl methyl sulfide (28 g, 117 mmol) was added in batches and stirred for 30 min. The reaction solution was cooled to 0 °C, and a solution of triamyl borate (46 mL, 410 mmol) in THF (100 mL) 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 well to obtain a solid intermediate 18 (15 g).

[0098] Preparation of intermediate 4:

[0099] It is prepared from ethyl 2-diaza-3-oxopentanoate (Intermediate 1) by the method disclosed in Example 3 on page 231 of the specification of the patent application "WO2021113627".

[0100] Preparation of Intermediate 14:

[0101] Under a nitrogen atmosphere, Intermediate 4 (78 g, 201.93 mmol) was dissolved in 400 ml of toluene. Intermediate 18 (45.6 g, 223.5 mmol) was added to the solution and stirred. Subsequently, K3PO4 (300 mL, 2 M, 600 mmol) was added, and 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 h. The reaction was quenched by adding water, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave 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), and the solution was stirred and cooled to 0 °C. A solution of BBr3 (37 mL, 1 M, 18.5 mmol) was added dropwise, and the reaction was stirred. The reaction was quenched by adding an aqueous sodium bicarbonate solution dropwise at 0 °C. The mixture was extracted with DCM, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was dissolved in DCM (40 mL), trifluoroacetic acid (4 mL, 52 mmol) was added dropwise, and then the reaction solution was heated to 45 °C. After the reaction was completed, the reaction was quenched by adding an aqueous sodium bicarbonate solution, the mixture was extracted with DCM, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the desired product in a mixture of diastereomers. The crude product was recrystallized twice from DCM-heptane, filtered and dried to obtain 5.5 g of a 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. Hydrogen gas was pressurized, and the mixture was stirred at a pressure of 60 psi for 4 h. Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) was added again, hydrogen gas was pressurized, and the mixture was stirred at a pressure of 80 psi for 4 h. TLC was used to detect the completion of the reaction. The suspension was filtered through diatomaceous earth 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 and 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 methyl iodide (1.85 g, 13 mmol) was added portionwise to the reaction solution. The mixture was stirred for 24 h. MTBE was added, and the mixture was filtered through diatomaceous earth, washed with MTBE. 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 and at room temperature, Intermediate 17 (5.1 g, 13.3 mmol) was dissolved in 50 mL of THF. Sodium methoxide (30% methanol solution, 0.32 mL, 1.3 mmol) was added to the reaction solution, and the mixture was stirred for 5 h.

[0110] To the reaction solution, a solution of 5 mL of MeOH - 5 mL of water was added dropwise, and the mixture was stirred for 30 min. Then lithium hydroxide monohydrate (0.84 g, 20 mmol) was added, and the mixture was stirred for 8 h. After the reaction was complete as detected by TLC, 1 M hydrochloric acid (20 mL) was added, and the mixture was extracted with MTBE. 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 vacuo, then dissolved in MTBE and concentrated again in vacuo to obtain an intermediate, which was directly used in the next step of the reaction.

[0111] The intermediate from the previous step (1.9 g, 5 mmol) was dissolved in 20 mL of DCM, and the temperature was lowered 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 in sequence, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure, and then concentrated again with 10 mL of DCM under reduced pressure. The concentrate was dissolved in 20 mL of DCM and added dropwise at room temperature to a 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) in 40 mL of DCM. The mixture was stirred for 8 h, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol - dichloromethane gave an intermediate, which was directly used in the next reaction.

[0112] The intermediate from the previous step was dissolved in methanol ammonia (38.5 mL, 7 M, 269.2 mmol), and the reaction was stirred at room temperature for 24 h. The reaction solution was concentrated under reduced pressure, EtOAc (10 mL) was added, and the mixture was heated to 60 °C to dissolve. The solution was cooled to 50 °C, 6 mL of heptane was added dropwise, and a solid precipitated. It was purified by reverse-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.9 g of compound 3. 1H NMR (400 MHz, methanol-d4) δ 8.81 (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-methylsulfinyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide

[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 of THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. A NaHCO3 solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. It was purified by flash silica gel column chromatography with gradient elution of methanol-dichloromethane 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)pyridinecarboxamide

[0121] The synthetic route is as follows:

[0122]

[0123] Preparation of compound 5:

[0124] A suspension of intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) 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. The reaction was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain an 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 h. 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) δ 8.86 (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)pyridinecarboxamide

[0127] The synthetic route is as follows:

[0128]

[0129] Preparation of compound 6:

[0130] A suspension of intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) in acetonitrile (120 mL) was added dropwise with a solution of (R)-3-iodotetrahydrofuran (0.37 g, 1.86 mmol) in 10 mL of acetonitrile. The reaction mixture was stirred at 65 °C for 12 h, concentrated under reduced pressure to obtain an intermediate, and 50 mL of THF was added. TBAF (20 mL, 1 M THF solution) was added to the above solution, and the mixture was stirred for 2 h. The mixture was concentrated under reduced pressure, water was added, and the product was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by preparative reverse-phase 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 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)pyridinecarboxamide

[0133] The synthetic route is as follows:

[0134]

[0135] Preparation of intermediate 19:

[0136] Under nitrogen protection, isopropylmagnesium chloride (145 mL, 2 M THF, 290 mmol) was dissolved in 150 mL of THF, and the temperature was raised to 40 °C. 1-Bromo-4-fluoro-2,3-dihydrobenzo[b]thiophene (27.3 g, 117 mmol) was added in portions, and the mixture was stirred for 30 min. The reaction mixture was cooled to 0 °C, and a solution of triamyl borate (46 mL, 410 mmol) in THF (100 mL) was added dropwise. 2N hydrochloric acid was added to adjust the pH to 1, and the product was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. n-Hexane was added, and the mixture was stirred thoroughly to obtain a solid intermediate 19 (18.3 g).

[0137] Preparation of intermediate 20:

[0138] Under a nitrogen atmosphere, intermediate 4 (15.6 g, 40.39 mmol) was dissolved in 400 ml of toluene. Intermediate 19 (8.85 g, 44.7 mmol) was added to the solution, and the mixture was stirred. Subsequently, K3PO4 (60 mL, 2 M, 120 mmol) was added, and 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 h. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave 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. Pd / C (10% loading, 100 g, 94 mmol) was added, and hydrogen was bubbled through. The hydrogenation reaction was carried out at room temperature for 10 h. Pd / C (10% loading, 100 g, 94 mmol) was replenished, and hydrogen was bubbled through for another 10 h. The mixture was filtered through diatomaceous earth, washed with DCM, water was added, and the mixture was extracted with DCM. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether was carried out directly for 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 the reaction was stirred for 6 h. The reaction was quenched with saturated aqueous solution, adjusted to pH under 2N hydrochloric acid conditions, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave intermediate 21 (6.1 g). 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 of DCM. The temperature was cooled to 2 °C, and oxalyl chloride (4.4 mL, 50 mmol) and DMF (71 μL, 1 mmol) were successively added dropwise to the reaction solution. The mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure, and then 20 ml of DCM was added and concentrated under reduced pressure. The concentrate was dissolved in 40 ml of DCM and added dropwise at room temperature to a solution of methyl 4-aminopicolinate (2.3 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol), and Et3N (4.4 mL, 31 mmol) in DCM (80 mL). The reaction was stirred for 8 h, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol-dichloromethane gave the intermediate, which was directly used in the next reaction.

[0144] The above intermediate was dissolved in methanol ammonia (77 mL, 7 M, 538 mmol), and the reaction was stirred at room temperature for 24 h. The reaction solution was concentrated under reduced pressure, EtOAc (20 mL) was added, and the mixture was heated to 60 °C to dissolve. The solution was cooled to 50 °C, and 12 mL of heptane was added dropwise to obtain the intermediate. Purification by reversed-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) gave 1.5 g of compound 7. 1H NMR (400 MHz, methanol-d4) δ 8.85 (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)pyridinecarboxamide

[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 of THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. A NaHCO3 solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol - dichloromethane gave 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)pyridinecarboxamide

[0153] The synthetic route is as follows:

[0154]

[0155] Preparation of Compound 9:

[0156] A suspension of Intermediate 13 (0.4 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) in acetonitrile (120 mL) was prepared. 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 h, concentrated under reduced pressure to obtain an 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 h. After concentration 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 0.18 g of Compound 9. ESI-MS m / z 542.2 [M+1] + .

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

[0158] In vitro test example: The effects of the compound on Nav1.8, Nav1.4, and Nav1.6 ion channels were tested. Nav1.8 ion channels were expressed on HEK293 cells, and Nav1.4 and Nav1.6 ion channels were expressed on HEK293 or ND7 / 23 cells respectively. After the Nav1.8, Nav1.4, and Nav1.6 currents were stabilized, the magnitudes of the corresponding ion channel currents before and after the application of the compound were compared to obtain the inhibitory activity and selectivity of the compound for the Nav1.8 ion channel.

[0159] 1. Experimental Instruments

[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 (Axoninstruments)

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

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

[0164] 5) Glass Microelectrode Puller: PC-10 (NARISHIGE)

[0165] 6) Microelectrode Glass Capillary: B12024F

[0166] 2. Experimental procedures

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

[0168] All test compounds and the control compound CP were dissolved in dimethyl sulfoxide (DMSO), and the stock solution concentration was 10 mM. The compound solution for Nav1.8 inhibition activity test contained 1 μM tetrodotoxin (TTX, Affix Scientific). It was diluted with extracellular fluid and freshly prepared as required concentrations according to the serial dilution method.

[0169] Preparation of intracellular and extracellular solutions:

[0170] Intracellular fluid (mM): Aspartic acid, 140; , 2; EGTA, 11; HEPES, 10; pH 7.2 (titrated with CsOH).

[0171] Extracellular fluid (mM): NaCl, 137; KCl, 4; , 1.8; , 1; HEPES, 10; Glucose, 10; pH 7.4 (titrated with NaOH).

[0172] 2.2 Electrophysiology

[0173] 1) After the compounds were prepared into solutions with specified concentrations, the drug solutions were added to each pipette in ascending order of concentration, and each pipette was labeled.

[0174] 2) The cells were transferred to the perfusion chamber. Positive pressure was applied inside the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the aspiration device was adjusted to the three-way state, and then negative pressure was applied to the electrode to form a high-resistance seal with the cell. Negative pressure was continuously applied to rupture the cell membrane and form a current path.

[0175] 3) After the whole-cell break-in current was stable, perfusion with different concentrations was carried out in sequence. If the current was stable for at least one minute, the next concentration could be perfused. The perfusion time for each concentration was no more than five minutes.

[0176] 4) The perfusion chamber was washed. It was rinsed in descending order of drug solution concentration, and each concentration of the drug solution was rinsed for 20 s. Finally, it was rinsed with extracellular fluid for 1 min.

[0177] 3. Pilot-scale scheme (resting state)

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

[0179] 4. Data analysis

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

[0181] The inhibitory activities of the example compounds against Nav1.8, Nav1.4, and Nav1.6 were determined by the above tests, and the measured values 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 against 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 relatively high inhibitory effects on Nav1.8 channel activity and had relatively high selectivity indices (therapeutic indices). In particular, the inhibitory effects of Compound 3 and Compound 7 on Nav1.8 were approximately 10 times that of the control compound CP. The Nav1.4 therapeutic indices of Compound 3 and Compound 7 were more than 15 times greater than that of the control compound CP; the Nav1.6 therapeutic indices of Compound 1 and Compound 3 were more than 19 times greater than 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 do not participate in the processes of inflammatory pain and neuropathic pain, but can cause adverse reactions. Therefore, the example compounds can be prepared into drugs for preventing / treating the symptoms / diseases caused by overexpression of Nav1.8, and have higher therapeutic indices and lower central nervous side effects.

[0185] Effect Example 2 Pharmacokinetic evaluation

[0186] SD rats were used as test animals, and the LC / MS / MS method was applied to determine the drug concentrations in the plasma of SD rats at different time points after intragastric administration of the compounds in the examples. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0187] 1) Test drugs

[0188] Compound 1, Compound 3 and Compound 7 of the examples.

[0189] 2) Test animals

[0190] 16 SD rats, 4 in each group, with half males and half females. After fasting overnight without water deprivation, they were given intragastric administration respectively.

[0191] 3) Drug preparation

[0192] Weighed a certain amount of the compounds in the examples respectively, and added the administration lysate: 5% DMSO + 10% Solutol + 85% normal saline to prepare a homogeneous solution of 0.2 mg / mL.

[0193] 4) Administration

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

[0195] 5) Operations

[0196] Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored at -20 °C for determination. The blood collection to centrifugation process was carried out under ice bath conditions. They were allowed to eat 2 hours after administration.

[0197] Determined the content of the compound to be measured in the plasma of SD rats after administration of drugs at different concentrations: Took the plasma samples of SD rats at each time point after administration, diluted them 10 times with the acetonitrile solution containing the internal standard, vortex-mixed, and centrifuged at 3700 rpm for 10 minutes. After mixing the supernatant with water at a ratio of 1:1, 0.5 μL of the supernatant was taken for LC / MS / MS analysis.

[0198] 6) Results of pharmacokinetic parameters

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

[0200]

[0201] It was found in the experiment that there were significant gender differences in the metabolic parameters of the control compounds, while there were no significant gender differences in Compounds 1, 3, and 7. From the above results, it can be seen that all the tested compounds had better exposure levels than the control compounds. In particular, Compound 3 C max was 1.6 times that of the control compound, and the AUC of Compound 1 0-t was 2.2 times that of the control compound. The experimental results showed that the compounds of the examples had better metabolic parameters, and there were no gender differences in the metabolic parameters, so they had a wider range of clinical user groups and higher drug safety.

[0202] Effect Example 3 Pharmacodynamic Evaluation of Mouse Incision Pain Model

[0203] Using mice as the test animals, after administering the compounds of the examples by gavage, the pharmacodynamic effects of the compounds of the present disclosure on the mouse incision pain model were studied to evaluate their in vivo pharmacodynamic effects.

[0204] 1) Modeling:

[0205] Grouping: The test animals were BALB / c mice, with 8 mice in each group, half male and half female. Before modeling, according to the PWT baseline value, abnormal animals were excluded, and then 8 mice were randomly selected as the sham operation group, and 8 animals in each dosing group were subjected to surgical modeling. After the surgery, the animals were re-grouped according to the pain threshold (PWT) before drug administration.

[0206] Anesthetized with isoflurane, at about 0.2 cm distal to the tibio-talar joint on the plantar surface of the left hind paw, a 0.5 cm long longitudinal skin incision was made with a scalpel towards the toes; the plantar muscles were separated and slightly elevated, and then longitudinally incised, taking care not to damage the origin and insertion of the muscles. The incision was sutured intermittently horizontally with 5-0 nylon thread (2 stitches), serving as the model group and the pharmacodynamic evaluation group; in addition, healthy normal mice were selected as the normal group.

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

[0208] 3) Administration method and frequency:

[0209] Model group: Oral administration of the solvent, once a day.

[0210] Normal group: Oral administration of the solvent, once a day.

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

[0212] 4) Measurement of mechanical pain threshold: Measure the mechanical pain threshold before modeling; measure the mechanical pain threshold before drug administration 2.5 h after modeling. After the measurement, administer the drug orally and measure the mechanical pain threshold 2 h after drug administration. The measurement location is inside the surgical incision site. Measure each animal 3 times, with an interval of 3 - 5 minutes each time, and take the average value.

[0213] 5) Data analysis: Relevant data were sorted out in GraphPad Prism 6.0 and analyzed using One-way ANOVA. The Tukey method was selected for the significance test of inter-group comparison.

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

[0215]

[0216] The above results show that the compounds in the examples all exhibit excellent pain inhibitory effects. And the pain inhibitory effect of the compounds in the examples is better than that of the control compound CP. The experimental results show that the compounds in the examples have better analgesic efficacy, lower drug dosage, and lower central nervous side effects compared with the existing clinical treatment methods.

[0217] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is expected that all aspects are illustrative rather than restrictive, referring to the appended claims rather than the foregoing embodiments, citing references only for the additional claims rather than the above examples, and all variations falling within the meaning and scope of the equivalence of the claims are thus expected 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 case of inconsistency, the present disclosure including the definitions will prevail.

Claims

1. A compound, 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 as claimed in claim 1 and a pharmaceutically acceptable excipient.

3. Use of the pharmaceutical composition as claimed in claim 2 or the compound, stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1 in the manufacture of a medicament for treating, preventing or alleviating a voltage-gated sodium channel-related disease.

4. The related disease as claimed in claim 3 is selected from chronic pain or acute pain.

5. The related disease as claimed in 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. The related disease as claimed in claim 3 is selected from one or more of neuropathic pain, postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy.

7. The related disease as claimed in claim 3 is selected from musculoskeletal pain, postoperative pain or visceral pain.

8. The related disease as claimed in claim 7, wherein the musculoskeletal pain is selected from osteoarthritis pain.

9. The related disease as claimed in claim 4, wherein the acute pain is selected from acute postoperative pain.

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

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