Tetrahydrofuroylamide compound as sodium channel regulator and application of tetrahydrofuroylamide compound in medicine

Abstract

The invention provides an N-(hydroxyalkyl pyridyl) tetrahydrofuran carboxamide compound, a prodrug, an oxide, a salt, a metal complex or a stereochemical isomer of a sodium channel regulator and a pharmaceutical composition containing the N-(hydroxyalkyl pyridyl) tetrahydrofuran carboxamide compound, the prodrug, the oxide, the salt, the metal complex or the stereochemical isomer. And their use as Nav inhibitors and their use in the preparation of medicaments for the treatment and / or alleviation of 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 cardiac side effect and the like.

Description

Technical Field

[0001] The present invention provides a sodium channel modulator N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivative, prodrug, oxide, salt, metal complex or stereochemical isomer and a pharmaceutical composition containing the same. Specifically, it relates to an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide compound shown in general formula (I), a preparation method thereof and a pharmaceutical composition containing the same, as well as its use as a Nav inhibitor and its use in preparing a drug for treating and / or alleviating pain sensation and pain-related diseases. Background Art

[0002] Pain is a complex physiological activity. Pain can serve as a warning signal to alert the body to potential dangers and plays an indispensable protective role in the normal life activities of the body. At the same time, after the external glare that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the body. Statistics show that about one-fifth of the world's population suffers from moderate to severe chronic pain.

[0003] Pain originates from the nociceptors in the peripheral nervous system. This is a free nerve ending that is widely distributed in the skin, muscles, joints and visceral tissues throughout the body. It can convert the thermal, mechanical or chemical stimulation it senses into nerve impulses (action potentials) and transmit them to the cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to the higher nerve centers, causing pain. The generation and conduction of action potentials in neurons depends on the voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channels are activated, the channels open, causing sodium ions to flow in, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

[0004] Nav forms a subfamily of the voltage-gated ion channel superfamily and includes 9 isoforms, named Nav1.1-Nav1.9. The tissue localization of the nine isoforms is different. The functional behavior of the nine isoforms is similar but different in the details of their voltage dependence and kinetic behavior. Nav1.4 is the primary sodium channel of skeletal muscle, and Nav1.5 is the primary sodium channel of cardiomyocytes. Nav1.1, 1.2, 1.3 and 1.6 are neuronal channels found in the central and peripheral nervous systems. Nav1.1, Nav1.2, Nav1.3 are mainly distributed in the CNS area and are associated with CNS diseases such as epilepsy and local anesthesia; Nav1.4 is mainly distributed in skeletal muscle, and its inhibitors are used as myotonic local anesthetics; Nav1.5 is mainly distributed in cardiomyocytes, and its inhibitors are used to treat arrhythmias; Nav1.6 is involved in movement disorders: At present, the targets related to pain are mainly Nav1.7, Nav1.8 and Nav1.9. Among them, Nav1.7 inhibitors have been most widely studied in the field of pain, but no related clinical trials have been successful so far; Nav1.9 has been less studied, and its mechanism of action in pain is not yet very clear.

[0005] Nav1.8 is TTX-R type, and its coding gene is SCN10A. It is mainly present in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise of action potential is mainly composed of Nav1.8 current. In some models of studying neuropathic pain, nerve damage can increase the expression level of Nav1.8 in axons and neuronal cell bodies (Sleeper AA, et al. J. Neurosci. 2000, 20, 7279-7289). Using Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696). After the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathy. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 can be used to treat various types of pain, including inflammatory pain, neuralgia, postoperative pain, cancer pain, etc., becoming a new type of analgesic therapy.

[0006] 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 higher activity, better selectivity, better solubility, better pharmacokinetic properties, faster onset, more lasting analgesic effect, and less cardiac toxicity. Summary of the invention

[0007] The present invention provides an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide as shown in formula (I), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof:

[0008] Formula (I)

[0009] in:

[0010] R¹, R², R³, and are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an amide group, a nitro group, an alkyl group, a deuterated alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a deuterated alkoxy group, an alkylthio group, an alkyl sulfoxide group, a haloalkyl group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, -O-(heterocyclic group), -O-(cycloalkyl group), -(OCH 2 CH 2 ) n -OH、-(OCH 2 CH 2 ) n -OCH 3 wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more R 5 substituted; n is selected from 1, 2, 3, 4, 5, 6;

[0011] or R¹ and R² and the atoms connected thereto form a substituted or unsubstituted 3-10 membered cycloalkyl group, or R¹ and R² and the atoms connected thereto form a substituted or unsubstituted 3-10 membered heterocyclic group; or R³ and and the atoms connected to them constitute a substituted or unsubstituted 3-10 membered cycloalkyl group, or R³ and and the atoms connected thereto constitute a substituted or unsubstituted 3-10 membered heterocyclic group; wherein the substituted 3-10 membered cycloalkyl group and the substituted 3-10 membered heterocycloalkyl group are each independently optionally substituted by one or more R 5 replaced by;

[0012] Each R 5are the same or different and are each independently selected from halogen, hydroxy, cyano, oxo, amino, amide, alkyl, deuterated alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0013] R 6 are independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, and a cycloalkyl group;

[0014] R 7 Independently selected from hydrogen, hydroxy, amino, amide, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, alkylamino, deuterated alkylamino, cycloalkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, haloacetyl.

[0015] The present invention also provides an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide as shown in formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof:

[0016] Formula (II)

[0017] in:

[0018] R¹, R², R 5 and R 7 As defined in general formula (I).

[0019] The N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives as shown in formula (I) and formula (II) preferably have a structure as shown in any of the following structural formulas:

[0020] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0021] 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. 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" of formula (I) or formula (II) should include and all acceptable salt forms.

[0022] In addition, prodrugs are also included within the scope of the present invention. A prodrug is any covalently bound carrier that releases a compound of Formula (I) or Formula (II) 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 to yield a hydroxyl, amino or sulfhydryl group when the prodrug is administered to a patient.

[0023] Therefore, representative examples of prodrugs include (but are not limited to) acetates, formates and benzoates of alcohol and amine functional groups of compounds of formula (I) or formula (II). 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.

[0024] For stereoisomers, compounds of formula (I) or formula (II) 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, certain crystalline forms of compounds of formula (I) or formula (II) may exist in the form of polymorphs, which are also included in the present invention. In addition, some of the compounds of formula (I) or formula (II) may also form solvates with water or other organic solvents. Such solvates are also similarly included in the scope of the present invention.

[0025] 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. 1H and D. In the embodiments where the atom is designated as H, no work has been 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 N-(hydroxyalkylpyridyl)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 N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives having 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.

[0026] 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.

[0027] According to the specific embodiments disclosed below, those skilled in the art can adopt the same or similar principles and methods to prepare the specific compounds involved in the N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives represented by the general formula (I) or formula (II) of the present invention.

[0028] The present invention further provides a use of N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives as shown in formula (I) or formula (II), stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts thereof or prodrugs thereof in the preparation of anti-sodium ion channel modulators. Further, the sodium ion channel modulator is a Nav1.8 inhibitor.

[0029] The present invention further provides a use of N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives as shown in formula (I) or formula (II), their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of drugs for treating diseases that cause overexpression of Nav1.8.

[0030] The present invention further provides a use of N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives as shown in formula (I) or formula (II), their stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of drugs for treating diseases caused by overexpression of Nav1.8.

[0031] The present invention further provides a use of an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivative as shown in formula (I) or formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a drug 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.

[0032] 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.

[0033] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivative as shown in formula (I) or formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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 used simultaneously with one or more other desired therapeutic agents or medical procedures, before or after them. The specific combination of the therapy (therapeutic agent or procedure) used 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 used can achieve the desired effect on the same disease (e.g., the compounds of the present invention can be used simultaneously with another medicament for the treatment of the same disease), or they can achieve different effects (e.g., controlling any adverse reactions). As used herein, additional therapeutic agents that are usually used to treat or prevent a specific disease or condition are 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; 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.

[0047] 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.

[0048] 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 preparation containing the compounds of the present invention and one or more other active agents, as well as administering a separate pharmaceutical administration preparation 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 is administered with a separate oral administration preparation. In the case of using a separate administration preparation, the compounds of the present invention and one or more additional active agents can be administered substantially at 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0053] 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.

[0054] The present invention relates to N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivatives represented by formula (I) or formula (II), their prodrugs, their deuterated compounds, and pharmaceutical compositions containing them, 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] The compounds provided by the present invention have the advantages of high metabolic stability, better solubility, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic properties, faster onset, more lasting analgesic effect, low side effects and cardiotoxicity, etc. Therefore, the compounds of the present invention have better drugability.

[0061] Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available. Unless otherwise specified, the compounds of the present invention are named manually or by chemical structure software, and commercially available compounds are named according to the supplier's catalog. Based on 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

[0062] 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.

[0063] Example 1.

[0064] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0065] The synthetic route is as follows:

[0066]

[0067]

[0068]

[0069] Preparation of Intermediate 22 and Intermediate 23:

[0070] Rac-1-(5-nitropyridin-2-yl)ethane-1,2-diol (59 g, 320.4 mmol) was dissolved in 2-MeTHF (1 L) and acetone (1 L), p-toluenesulfonic acid (6 g, 34.8 mmol) and 2,2-dimethoxypropane (67.80 g, 650.6 mmol) were added, and the mixture was stirred at room temperature for 16 hours. NaHCO 3 After the reaction was quenched with the solution, the reaction solution was concentrated under reduced pressure and purified by rapid silica gel column chromatography with ethyl acetate-petroleum ether gradient elution to obtain the intermediate, which was directly used in the next reaction.

[0071] The intermediate (60 g, 249 mmol) was dissolved in ethyl acetate (1800 mL). Pd / C (10 wt% loading, wet method, 8.6 g, 8.04 mmol) was added and stirred for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure to obtain intermediate 21 (53 g) for preparation and isolation.

[0072] Intermediate 21 was separated by preparative liquid chromatography on a Prep-100 SFC instrument using a Chiralpak IB column (mobile phase: 7% MeOH (containing 20 mM ammonia), 93% CO 2 , flow rate: 100 ml / min). Intermediate 22 was obtained, ESI-MS m / z 195.2[M+1] + ; Intermediate 23, ESI-MS m / z 195.2[M+1] + .

[0073] Preparation of intermediate 18:

[0074] Under nitrogen protection, dissolve isopropylmagnesium chloride (145 mL, 2M THF, 290 mmol) in 150 ml THF, heat to 40°C, add 6-bromo-2,3-difluoroanisyl sulfide (28 g, 117 mmol) in batches, and stir for 30 min. The reaction solution is cooled to 0°C, and a solution of triamyl borate (46 mL, 410 mmol) in THF (100 ml) is added 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 intermediate 18 (15 g).

[0075] Preparation of intermediate 14:

[0076] Under 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, stirred, and then K was added. 3 PO 4 (300mL, 2M, 600mmol), add tetrakis(triphenylphosphine)palladium(0) (12g, 10.38mmol), heat to 100℃, stir and react for 3hr. Add water to quench, extract with EtOAc, combine the organic layers and concentrate under reduced pressure. Purify by rapid silica gel column chromatography, gradient elution with EtOAc / petroleum ether to obtain intermediate 14 (72g). ESI-MS m / z 397.1[M+1] + .

[0077] Preparation of intermediate 15:

[0078] Intermediate 14 (11 g, 24.3 mmol) was dissolved in DCM (30 mL), cooled to 0 °C with stirring, and BBr was added dropwise. 3 (37 mL, 1 M, 18.5 mmol) solution was stirred for reaction. Sodium bicarbonate aqueous solution was added dropwise at 0°C to quench the reaction. DCM extraction was performed and the organic layer was treated with anhydrous NaSO 4 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, sodium bicarbonate aqueous solution was added to quench, DCM was extracted, and anhydrous NaSO 4 Drying and concentration under reduced pressure gave the desired product in a mixture of diastereoisomers. The crude product was recrystallized twice from DCM-heptane, filtered and dried to give 5.5 g of solid as intermediate 15. ESI-MS m / z 337.0 [M+1] + .

[0079] Preparation of intermediate 16:

[0080] In a hydrogenation reactor, a suspension of intermediate 15 (9.4 g, 28.11 mmol) in MeOH (180 mL) was added and Pd(OH) 2 A suspension of (18.6 g, 20% w / w, 5.82 mmol) in MeOH (40 mL) was added to the reactor. Hydrogen was added under pressure of 60 psi and stirred for 4 hr. Pd(OH) was then added. 2 (18.6 g, 20% w / w, 5.82 mmol), pressurized hydrogen, stirred at 80 psi for 4 hr, TLC detected the reaction was complete. The suspension was filtered through celite under nitrogen atmosphere, rinsed with MeOH and EtOAc, and the filtrate was concentrated under reduced pressure to obtain intermediate 16 (8.3 g).

[0081] Preparation of intermediate 17:

[0082] 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] + .

[0083] Preparation of intermediate 24:

[0084] 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 mixture was stirred for 5 hours. 5 ml of MeOH-5 ml of water solution was added dropwise to the reaction solution, and the mixture was stirred for 30 minutes. Then, lithium hydroxide monohydrate (0.84 g, 20 mmol) was added, and the mixture was stirred for 8 hours. After the reaction was complete by TLC, 1 M hydrochloric acid (20 ml) was added, and MTBE was extracted. The organic layer was washed with saturated NaCl, and anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was dissolved in toluene and concentrated in vacuo, then dissolved in MTBE and concentrated in vacuo again to give the intermediate which was used directly in the next reaction.

[0085] The intermediate (1.9 g, 5 mmol) of the previous step was dissolved in 20 ml of 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, and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then 10 ml of DCM was added to concentrate under reduced pressure. The concentrate was dissolved in 20 ml of DCM and added dropwise to the intermediate 23 (1.49 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol) and Et 3 N (2.2 mL, 15.5 mmol) in DCM (40 mL) solution, 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, to obtain intermediate 24 (3 g). ESI-MS m / z 547.2 [M+1] + .

[0086] Preparation of compound 1:

[0087] The intermediate 24 (1.8 g, 3.33 mmol) was dissolved in DCM (60 mL), TFA (5.2 mL, 6.78 mmol) was added, the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 1 (0.9 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.39(s,1H), 8.71(m,1H), 8.02(m,1H), 7.53(m,1H), 7.24-7.17 (m,2H), 5.33-5.10(m,2H), 4.63-4.54(m,2H), 4.26-4.21(m,1H), 3.65-3.63 (m, 1H), 3.45(m,1H), 2.80-2.77(m,4H), 1.64(s,3H), 0.90-0.71(m,3H)ppm. ESI-MS m / z 507.1[M+1] + .

[0088] Example 2.

[0089] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0090] The synthetic route is as follows:

[0091]

[0092] The preparation process of intermediate 25 is similar to that of intermediate 24, except that intermediate 23 is replaced by intermediate 22 to obtain intermediate 25 (2.9 g). ESI-MS m / z 547.2[M+1] + .

[0093] Preparation of compound 2:

[0094] The intermediate 25 (1.8 g, 3.33 mmol) was dissolved in DCM (60 mL), TFA (5.2 mL, 6.78 mmol) was added, stirred at room temperature for 2 hours, and concentrated under reduced pressure. It was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 2 (1 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.37(s,1H),8.70(m,1H),8.09(m,1H),7.56(m,1H),7.25-7.16(m, 2H), 5.34-5.14(m,2H), 4.73-4.54(m,2H), 4.25-4.30(m,1H), 3.70-3.64(m,1 H), 3.45-3.40(m,1H), 2.81-2.76(m,4H), 1.68(s,3H), 0.91-0.73(m,3H)ppm. ESI-MS m / z 507.1[M+1] + .

[0095] Example 3.

[0096] (2R,3S,4S,5R)-3-(4-fluoro-2,3-dihydrobenzo[b]thiophen-7-yl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0097] The synthetic route is as follows:

[0098]

[0099] Preparation of intermediate 19:

[0100] Under nitrogen protection, dissolve isopropylmagnesium chloride (145mL, 2M THF, 290mmol) in 150ml THF, heat to 40°C, add 1-bromo-4-fluoro-2,3-dihydrobenzo[b]thiophene (27.3g, 117mmol) in batches, and stir for 30min. The reaction solution is cooled to 0°C, and a solution of triamyl borate (46mL, 410mmol) in THF (100ml) is added 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).

[0101] Preparation of intermediate 20:

[0102] Under 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, stirred, and then K was added. 3 PO 4 (60mL, 2M, 120mmol), add tetrakis(triphenylphosphine)palladium(0) (2.5g, 2.1mmol), heat to 100℃, stir and react for 3hr. Add water to quench, extract with EtOAc, combine the organic layers and concentrate under reduced pressure. Purify by rapid silica gel column chromatography, gradient elution with EtOAc / petroleum ether to obtain intermediate 20 (72g). ESI-MS m / z 391.1[M+1] + .

[0103] Preparation of intermediate 21:

[0104] 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.

[0105] 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. 4 The mixture was quenched with aqueous Cl solution, pH adjusted with 2N hydrochloric acid, and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography with EtOAc / petroleum ether gradient elution to obtain intermediate 21 (6.1 g). ESI-MS m / z 363.3 [M-1] - .

[0106] Preparation of intermediate 26:

[0107] 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, and stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 20 ml DCM was added to concentrate under reduced pressure. The concentrate was dissolved in 40 ml DCM and added dropwise to intermediate 23 (2.8 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol) and Et 3 N (4.4 mL, 31 mmol) in DCM (80 mL) solution, 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, to obtain intermediate 26 (4.3 g). ESI-MS m / z 541.2 [M+1] + .

[0108] Preparation of compound 3:

[0109] The intermediate 26 (2.7 g, 5 mmol) was dissolved in DCM (100 mL), TFA (7.8 mL, 10.17 mmol) was added, stirred at room temperature for 2 hours, and concentrated under reduced pressure. It was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 3 (1.9 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.31(s,1H), 8.77(m,1H), 8.12(m,1H), 7.54(m,1H), 7.25-7.16(m,2 H), 5.35-5.09(m,2H), 4.71-4.61(m,2H), 4.27-4.20(m,1H), 3.66-3.61 (m, 1H), 3.45-3.21(m,3H), 2.81-2.78(m,3H), 1.70(s,3H), 0.91-0.75(m,3H)ppm. ESI-MS m / z 501.1[M+1] + .

[0110] Example 4.

[0111] (2R,3S,4S,5R)-3-(4-fluoro-2,3-dihydrobenzo[b]thiophen-7-yl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0112] The synthetic route is as follows:

[0113]

[0114] The preparation process of intermediate 27 is similar to that of intermediate 26, except that intermediate 23 is replaced by intermediate 22 to obtain intermediate 27 (2.7 g). ESI-MS m / z 541.2[M+1] + .

[0115] Preparation of compound 4:

[0116] The intermediate 27 (1.8 g, 3.33 mmol) from the previous step was dissolved in DCM (60 mL), TFA (5.2 mL, 6.78 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. It was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 4 (1 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.29(s,1H),8.71(m,1H),7.99(m,1H),7.49(m,1H),7.24-7.11(m, 2H), 5.32-4.99(m,2H), 4.75-4.56(m,2H), 4.28-4.18(m,1H), 3.66-3.61(m,1 H), 3.45-3.21(m,3H), 2.81-2.78(m,3H), 1.70(s,3H), 0.89-0.74(m,3H)ppm. ESI-MS m / z 501.1[M+1] + .

[0117] Example 5.

[0118] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-methoxyethoxy)ethoxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0119] The synthetic route is as follows:

[0120]

[0121]

[0122]

[0123] Preparation of intermediate 5:

[0124] 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:

[0125] 1 H 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] + .

[0126] Preparation of intermediate 6:

[0127] Intermediate 5 (220 g, 486 mmol) was dissolved in DCM (600 mL), stirred and cooled to 0 °C, and BBr was added dropwise. 3 (740 mL, 1 M, 370.0 mmol) solution was stirred for reaction. Sodium bicarbonate aqueous solution was added dropwise at 0°C to quench the reaction. DCM was used for extraction, and the organic layer was treated with anhydrous NaSO 4 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 was extracted, and anhydrous NaSO 4 Drying and concentration under reduced pressure gave the desired product in a mixture of diastereoisomers. The crude product was recrystallized twice from DCM-heptane, filtered and dried to give 124 g of solid as Intermediate 6. ESI-MS m / z 321.5 [M+1] + .

[0128] Preparation of intermediate 9:

[0129] In a hydrogenation reactor, a suspension of intermediate 6 (90 g, 281.07 mmol) in MeOH (1800 mL) was added and Pd(OH) 2 A suspension of (185.5 g, 20% w / w, 58.2 mmol) in MeOH (400 mL) was added to the reactor. Hydrogen was pressurized and stirred at 60 psi for 8 hours. 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).

[0130] Preparation of intermediate 10:

[0131] 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 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 10 (1.8 g). ESI-MS m / z 369.1 [M+1] + .

[0132] Preparation of intermediate 11:

[0133] 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.

[0134] To the reaction solution, 50 ml of MeOH-50 ml of water solution was added dropwise, and the reaction was stirred for 30 min. Then, lithium hydroxide monohydrate (8.4 g, 200 mmol) was added and the reaction was stirred for 8 hr. After TLC detection, 1 M hydrochloric acid (220 ml) was added, MTBE was extracted, and the organic layer was washed with saturated NaCl and anhydrous Na 2 SO 4 Dry, filter and concentrate 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 give intermediate 11 as an oil, which was used directly in the next reaction.

[0135] Preparation of intermediate 28 (reference compound CP1):

[0136] Intermediate 11 (3.7 g, 10 mmol) was dissolved in 40 ml DCM, cooled to 2°C, and oxalyl chloride (2.2 mL, 25 mmol) and DMF (71 μL, 1 mmol) were added dropwise to the reaction solution, and stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 20 ml DCM was added to concentrate under reduced pressure. The concentrate was dissolved in 40 ml DCM and added dropwise to intermediate 23 (2.8 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol) and Et 3 N (4.4 mL, 31 mmol) in DCM (80 mL) solution, stirred for 8 hours, concentrated under reduced pressure, added with water, extracted with DCM, dried over anhydrous sodium sulfate, purified by rapid silica gel column chromatography, gradient elution with methanol-dichloromethane, to obtain the intermediate, which was directly used in the next step.

[0137] The intermediate (3.6 g, 6.66 mmol) from the previous step was dissolved in DCM (100 mL), TFA (10.5 mL, 13.5 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The intermediate 28 (2.1 g) was obtained by purification by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia). ESI-MS m / z 491.2 [M+1] + .

[0138] Preparation of intermediate 29:

[0139] Intermediate 28 (0.8 g, 1.63 mmol) was dissolved in DCM (20 mL), cooled to 0 °C, tribromoborane (5 mL, 1 M solution in DCM, 5 mmol) was added, and the reaction was stirred for 20 min. The reaction solution was quenched with MeOH (20 mL) and then concentrated in vacuo. The residue was dissolved in MeOH (30 mL) and the pH was adjusted to pH 9 with 2 M aqueous sodium hydroxide solution. Rapid silica gel column chromatography was used for purification with a methanol-dichloromethane gradient elution to obtain intermediate 29 (0.6 g). ESI-MS m / z 477.2 [M+1] + .

[0140] Preparation of compound 5:

[0141] Intermediate 29 (1 g, 2 mmol) was dissolved in DMF (100 mL), and 1-bromo-2-(2-methoxyethoxy)ethane (0.38 g, 2.1 mmol) and K 2 CO 3 (0.32 g, 2.3 mmol). The reaction solution was stirred at room temperature for 1 hr, then heated to 60°C and stirred for 12 hr. Filtered, concentrated under reduced pressure, and purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 5 (0.5 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),8.66(m,1H),8.01(m,1H),7.41(m,1H),7.23-7.15(m, 2H), 5.32-5.09(m,2H), 4.65-4.51(m,2H), 4.35-4.20(m,2H), 3.65-3.40(m,6H),3.26(s,3H),2.81- 2.67(m,1H),1.60(s,3H),0.77-0.70(m,3H)ppm.ESI-MSm / z 579.2[M+1] + .

[0142] Example 6.

[0143] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-(2-methoxyethoxy)ethoxy)phenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0144] The synthetic route is as follows:

[0145]

[0146] The preparation process of intermediate 49 is similar to that of intermediate 28, except that intermediate 23 is replaced by intermediate 22 to obtain intermediate 49 (2.2 g). ESI-MS m / z 491.2[M+1] + .

[0147] The preparation process of intermediate 50 is similar to that of intermediate 29, except that intermediate 28 is replaced by intermediate 49 to obtain intermediate 50 (0.3 g). ESI-MS m / z 477.2[M+1] + .

[0148] Preparation of compound 6:

[0149] Intermediate 50 (1 g, 2 mmol) was dissolved in DMF (100 mL), 1-bromo-2-(2-methoxyethoxy)ethane (0.38 g, 2.1 mmol) and K 2 CO 3 (0.32 g, 2.3 mmol). The reaction solution was stirred at room temperature for 1 hr, then heated to 60°C and stirred for 12 hr. Filtered, concentrated under reduced pressure, and purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 6 (0.4 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.35(s,1H),8.70(m,1H),8.06(m,1H),7.47(m,1H),7.25-7.14(m, 2H), 5.36-5.11(m,2H), 4.70-4.53(m,2H), 4.40-4.23(m,2H), 3.71-3.43(m,6H),3.29(s,3H),2.86-2.70 (m, 1H),1.65(s,3H),0.78-0.71(m,3H)ppm. ESI-MSm / z 579.2[M+1] + .

[0150] Example 7.

[0151] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0152] The synthetic route is as follows:

[0153]

[0154] Preparation of compound 7:

[0155] Intermediate 29 (0.43 g, 0.9 mmol) and cesium carbonate (1 g, 3 mmol) were suspended in acetonitrile (120 mL), (S)-3-iodotetrahydrofuran (0.37 g, 1.86 mmol) was dissolved in 10 ml of acetonitrile and added dropwise to the above reaction solution. The reaction was stirred at 60°C for 12 hours and concentrated under reduced pressure to obtain the intermediate. Water was added and 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% CO 2 ), to obtain 0.28 g of compound 7. 1 H NMR (400 MHz, DMSO-d 6 )δ10.33(s,1H),8.59(m,1H),8.08(m,1H),7.45(m,1H),7.22-7.16(m, 2H),5.34-5.10(m,2H),4.64-4.55(m,2H),4.36-4.21(m,4H),3.66-3.34(m,3H),2.92-2.66(m,4H),1.61(s,3H),0.78-0.77(m,3H)ppm. ESI-MS m / z 547.2[M+1] + .

[0156] Example 8.

[0157] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0158] The synthetic route is as follows:

[0159]

[0160] Preparation of compound 8:

[0161] Intermediate 29 (0.43 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. The reaction was stirred at 60°C for 12 hr and concentrated under reduced pressure to obtain the intermediate. Water was added and 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 0.29 g of compound 8. 1 H NMR (400 MHz, DMSO-d 6 )δ10.41(s,1H),8.62(m,1H),8.11(m,1H),7.54(m,1H),7.30-7.17(m, 2H),5.44-5.15(m,2H),4.71-4.56(m,2H),4.43-4.24(m,4H),3.73-3.35(m,3H),2.93-2.67(m,4H),1.65(s,3H),0.80-0.76(m,3H)ppm. ESI-MS m / z 547.2[M+1] + .

[0162] Example 9.

[0163] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0164] The synthetic route is as follows:

[0165]

[0166]

[0167]

[0168] Preparation of intermediate 30:

[0169] (S)-2-Amino-1-(5-nitropyridin-2-yl)ethanol (50 g, 273 mmol) was dissolved in 150 ml THF / 50 ml water, triethylamine (5.5 g, 54.6 mmol) was added, and the reaction solution was stirred and cooled to 10°C. Di-tert-butyl dicarbonate (35.8 g, 163.8 mmol) was dissolved in 50 ml THF and added dropwise to the above reaction solution, and stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, and the organic layers were combined. The solution was concentrated under reduced pressure to obtain intermediate 30.

[0170] Preparation of intermediate 31:

[0171] Intermediate 30 (8.5 g, 30.16 mmol) was dissolved in DMF (50 mL), and tert-butyldimethylsilyl chloride (7 g, 46.44 mmol), imidazole (6 g, 88.14 mmol) and DMAP (0.73 g, 5.98 mmol) were added, and the reaction mixture was heated at 60 ° C for 16 hours. After the reaction was completed, the temperature was lowered, ice water (500 mL) was added to quench, and EtOAc was extracted. The organic layers were combined after washing with saturated sodium chloride. The mixture was concentrated under reduced pressure and purified by rapid silica gel column chromatography with ethyl acetate-petroleum ether gradient elution to obtain intermediate 31 (7.7 g).

[0172] Preparation of intermediate 32:

[0173] Intermediate 31 (25 g, 62.9 mmol) was suspended in 1 L of 90% ethanol, 24 g of ammonium chloride was dissolved in 500 mL of water, added to the above reaction solution, and refluxed for 3 hours. The mixture was filtered through hot celite, the filter cake was washed with 1 L of hot water, concentrated under reduced pressure, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure to obtain intermediate 32 (23 g).

[0174] The preparation process of intermediate 33 refers to the preparation of intermediate 30, except that (S)-2-amino-1-(5-nitropyridine-2-yl)ethanol is replaced with (R)-2-amino-1-(5-nitropyridine-2-yl)ethanol to obtain intermediate 33.

[0175] The preparation process of intermediate 34 is similar to that of intermediate 31, except that intermediate 30 is replaced by intermediate 33 to obtain intermediate 34.

[0176] The preparation process of intermediate 35 refers to the preparation process of intermediate 32, except that intermediate 31 is replaced by intermediate 34 to obtain intermediate 35.

[0177] Preparation of intermediate 36:

[0178] Intermediate 11 (3.7 g, 10 mmol) was dissolved in 40 ml DCM, cooled to 2 °C, and oxalyl chloride (2.2 mL, 25 mmol) and DMF (71 μL, 1 mmol) were added dropwise to the reaction solution, and stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and then 20 ml DCM was added to concentrate under reduced pressure. The concentrate was dissolved in 40 ml DCM and added dropwise to intermediate 32 (5.3 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol) and Et 3N (4.4 mL, 31 mmol) in DCM (80 mL), stirred for 8 hours, concentrated under reduced pressure, added with water, extracted with DCM, dried over anhydrous sodium sulfate, and purified by rapid silica gel column chromatography with a methanol-dichloromethane gradient elution to obtain intermediate 36 (4.3 g).

[0179] Preparation of compound 9:

[0180] Intermediate 36 (4.2 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hr. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0181] The intermediate (3.9 g, 6.66 mmol) from the previous step was dissolved in DCM (50 mL), TFA (10.5 mL, 13.5 mmol) was added, the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 9 (2.9 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.37 (s,1H), 8.65(m,1H), 8.03(m,1H), 7.42 (m,1H), 7.20-7.11(m,2H), 5.45(m,1H), 5.07(m,1H), 4.71-4.62(m,1H) ,3.95(m,3H),3.42-2.99(m,3H),2.77(m,1H),1.59(s,3H),0.75(m,3H) ppm. ESI-MS m / z 490.2[M+1] + .

[0182] Example 10.

[0183] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0184] The synthetic route is as follows:

[0185]

[0186] The preparation process of intermediate 37 refers to the preparation process of intermediate 36, except that intermediate 32 is replaced by intermediate 35 to obtain intermediate 37.

[0187] Preparation of compound 10:

[0188] Intermediate 37 (4.2 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 ° C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hours. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0189] The intermediate (3.9 g, 6.66 mmol) from the previous step was dissolved in DCM (50 mL), TFA (10.5 mL, 13.5 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 10 (2.2 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.37 (s,1H), 8.65(m,1H), 8.03 (m,1H), 7.42 (m,1H), 7.20- 7.11 (m,2H), 5.45(m,1H), 5.07(m,1H), 4.71-4.62(m,1H), 3.95 (m,3H),3.42-2.99(m,3H),2.77(m,1H),1.59(s,3H),0.75(m,3H) ppm.ESI-MSm / z 490.2[M+1] + .

[0190] Example 11.

[0191] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d 3 )phenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0192] The synthetic route is as follows:

[0193]

[0194]

[0195] Preparation of intermediate 38:

[0196] Intermediate 9 (5 g, 14.11 mmol) was dissolved in 50 ml DCM, and triethylamine (1.71 g, 16.94 mmol) was added. The temperature was lowered to 5°C. Deuterated iodomethane (2.5 g, 16.94 mmol) was dissolved in 5 ml DCM and added dropwise to the reaction solution. The temperature was raised to room temperature and stirred for 2 hours. Saturated aqueous ammonium chloride was added to quench the reaction, and the organic layer was washed with saturated sodium chloride and concentrated under reduced pressure to obtain intermediate 38 (4.9 g).

[0197] Preparation of intermediate 39:

[0198] The preparation process of intermediate 39 refers to the preparation process of intermediate 36, except that intermediate 11 is replaced by intermediate 38 to obtain intermediate 39.

[0199] Preparation of compound 11:

[0200] Intermediate 39 (4.3 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 ° C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hours. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0201] The intermediate (4 g, 6.67 mmol) from the previous step was dissolved in DCM (50 mL), TFA (10.5 mL, 13.5 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The compound 11 (2.5 g) was obtained by purification by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia). 1 H NMR (400 MHz, DMSO-d 6 )δ10.39 (s,1H), 8.68(m,1H), 8.10(m,1H), 7.46 (m,1H), 7.24-7.12(m,2H), 5.48(m,1H), 5.11(m,1H), 4.75-4.67(m,1H), 3.48-3.01(m,3H) , 2.80(m,1H) ,1.63(s,3H) ,0.78(m,3H) ppm. ESI-MS m / z 493.2[M+1] + .

[0202] Example 12.

[0203] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d 3)phenyl)-N-(6-((R)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0204] The synthetic route is as follows:

[0205]

[0206] Preparation of intermediate 40:

[0207] The preparation process of intermediate 40 refers to the preparation process of intermediate 36, except that intermediate 11 is replaced by intermediate 38, and intermediate 32 is replaced by intermediate 35 to obtain intermediate 40.

[0208] Preparation of compound 12:

[0209] Intermediate 40 (4.3 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 ° C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hours. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step reaction.

[0210] The intermediate (4 g, 6.67 mmol) was dissolved in DCM (50 mL), TFA (10.5 mL, 13.5 mmol) was added, the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 12 (3.0 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.38 (s,1H), 8.67(m,1H), 8.11(m,1H), 7.45 (m,1H), 7.23-7.10(m,2H), 5.46(m,1H), 5.09(m,1H), 4.73-4.66(m,1H), 3.47-2.98(m,3H) , 2.78(m,1H) ,1.61(s,3H) ,0.77(m,3H) ppm. ESI-MS m / z 493.2[M+1] + .

[0211] Example 13.

[0212] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0213] The synthetic route is as follows:

[0214]

[0215] Preparation of intermediate 41:

[0216] The preparation process of intermediate 41 refers to the preparation process of intermediate 36, except that intermediate 11 is replaced by intermediate 17 to obtain intermediate 41.

[0217] Preparation of compound 13:

[0218] Intermediate 41 (4.25 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, stirred for 1.5 hr, diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0219] The intermediate (4.8 g, 6.67 mmol) from the previous step was dissolved in DCM (50 mL), TFA (10.5 mL, 13.5 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 13 (3.3 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.38 (s,1H), 8.67 (m,1H), 8.11 (m,1H), 7.45 (m,1H), 7.23-7.13(m,2H), 5.46(m,1H), 5.10(m,1H), 4.76-4.65(m,1H), 3.66-2.91(m,3H), 2.79-2.48(m,4H), 1.62(s,3H), 0.80(m,3H) ppm. ESI-MS m / z506.1[M+1] + .

[0220] Example 14.

[0221] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((R)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0222] The synthetic route is as follows:

[0223]

[0224] Preparation of intermediate 42:

[0225] The preparation process of intermediate 42 refers to the preparation process of intermediate 36, except that intermediate 11 is replaced by intermediate 17, and intermediate 32 is replaced by intermediate 35 to obtain intermediate 41.

[0226] Preparation of compound 14:

[0227] Intermediate 42 (4.25 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hr. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0228] The intermediate (2.4 g, 3.4 mmol) from the previous step was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 14 (1.6 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.40 (s,1H), 8.71 (m,1H), 8.14 (m,1H), 7.50 (m,1H), 7.27-7.15(m,2H), 5.49(m,1H), 5.13(m,1H), 4.80-4.68(m,1H), 3.65-2.90(m,3H), 2.82-2.51(m,4H), 1.65(s,3H), 0.81(m,3H) ppm. ESI-MS m / z 506.1[M+1] + .

[0229] Example 15.

[0230] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxy)ethoxy)phenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0231] The synthetic route is as follows:

[0232]

[0233]

[0234] Preparation of intermediate 43:

[0235] Intermediate 36 (1.2 g, 1.63 mmol) was dissolved in DCM (20 mL), cooled to 0 °C, tribromoborane (5 mL, 1 M solution in DCM, 5 mmol) was added, and the reaction was stirred for 20 min. The reaction solution was quenched with MeOH (20 mL) and then concentrated in vacuo. The residue was dissolved in MeOH (30 mL) and the pH was adjusted to pH 9 with 2 M aqueous sodium hydroxide solution. Rapid silica gel column chromatography with a methanol-dichloromethane gradient elution gave intermediate 43 (0.5 g).

[0236] Preparation of intermediate 44:

[0237] Intermediate 43 (1.4 g, 2 mmol) was dissolved in DMF (100 mL), 1-bromo-2-methoxyethane (0.29 g, 2.1 mmol) and K 2 CO 3 (0.32 g, 2.3 mmol). The reaction solution was stirred at room temperature for 1 hr, then heated to 60°C and stirred for 12 hr. Filtered, concentrated under reduced pressure, and purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain intermediate 44 (0.6 g).

[0238] Preparation of compound 15:

[0239] Intermediate 44 (4.4 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, stirred for 1.5 hr, diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0240] The intermediate (2.2 g, 3.4 mmol) from the previous step was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure. It was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 15 (1.6 g). 1 H NMR (400 MHz, DMSO-d 6)δ10.49(s,1H), 8.75(s,1H), 8.12(m,1H), 7.54(m,1H) ,7.25-7.12(m,2H),5.13(m,1H),4.63(s,1H),3.97(m,3H),3.64(m,1H),3.40-3.18(m,4H),2.77(m,1H),1.64(s,3H),0.80-0.68 (m,3H) ppm. ESI-MS m / z 506.1[M+1] + .

[0241] Example 16.

[0242] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxy)ethoxy)phenyl)-N-(6-((R)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0243] The synthetic route is as follows:

[0244]

[0245]

[0246] Preparation of intermediate 45:

[0247] The preparation process of intermediate 45 refers to the preparation process of intermediate 43, except that intermediate 36 is replaced by intermediate 37 to obtain intermediate 45.

[0248] Preparation of intermediate 46:

[0249] The preparation process of intermediate 46 refers to the preparation process of intermediate 44, except that intermediate 43 is replaced by intermediate 45 to obtain intermediate 46.

[0250] Preparation of compound 16:

[0251] Intermediate 46 (4.4 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hr. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0252] The intermediate (2.2 g, 3.4 mmol) from the previous step was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, the mixture was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 16 (1.7 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.43(s,1H),8.69(s,1H),8.05(m,1H),7.49(m,1H),7.18-7.06(m,2H),5.07(m,1H),4.58(s,1 H),3.92(m,3H),3.58(m,1H),3.38-3.15(m,4H),2.72(m,1H),1.60(s,3H),0.78-0.66(m,3H)ppm. ESI-MS m / z 506.1[M+1] + .

[0253] Example 17.

[0254] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0255] The synthetic route is as follows:

[0256]

[0257] Preparation of compound 17:

[0258] Compound 9 (3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 17 (1.6 g).

[0259] 1 H NMR (400 MHz, DMSO-d 6)δ10.37(s,1H), 8.67(m,1H), 8.06 (m,1H), 7.45 (m,1H), 7.23-7.12 (m,2H), 5.47(m,1H), 5.10(m,1H), 4.74-4.64(m,1H), 3.97(m,3H), 3.43-3.01(m,3H), 2.80(m, 1H), 1.60(s,3H),1.24(s,9H), 0.77(m,3H) ppm. ESI-MS m / z546.2[M+1] + .

[0260] Example 18.

[0261] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0262] The synthetic route is as follows:

[0263]

[0264] Preparation of compound 18:

[0265] Compound 10 (3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 18 (1.7 g).

[0266] 1 H NMR (400 MHz, DMSO-d 6 )δ10.36(s,1H), 8.66(m,1H), 8.06 (m,1H), 7.46 (m,1H), 7.21-7.13 (m,2H), 5.48(m,1H), 5.12(m,1H), 4.75-4.66(m,1H), 3.98(m,3H), 3.45-3.02(m,3H), 2.82(m,1H), 1.61 (s, 3H), 1.23(s,9H), 0.78(m,3H) ppm. ESI-MS m / z546.2[M+1] + .

[0267] Example 19.

[0268] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d 3 )phenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0269] The synthetic route is as follows:

[0270]

[0271] Preparation of compound 19:

[0272] Compound 11 (3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 19 (1.5 g).

[0273] 1 H NMR (400 MHz, DMSO-d 6 )δ10.37(s,1H), 8.66(m,1H), 8.06 (m,1H), 7.46 (m,1H), 7.24-7.13 (m,2H), 5.48(m,1H), 5.11(m,1H), 4.75-4.64(m,1H), 3.45-3.01(m,3H), 2.82(m,1H), 1.61(s,3H), 1.25(s, 9H), 0.78(m,3H) ppm. ESI-MS m / z 549.3[M+1] + .

[0274] Example 20.

[0275] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d 3 )phenyl)-N-(6-((R)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0276] The synthetic route is as follows:

[0277]

[0278] Preparation of compound 20:

[0279] Compound 12 (3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 20 (1.4 g).

[0280] 1 H NMR (400 MHz, DMSO-d 6 )δ10.40(s,1H),8.68(m,1H),8.07(m,1H),7.47(m,1H),7.26-7.14 (m, 2H),5.50(m,1H),5.13(m,1H),4.77-4.66(m,1H),3.46-3.03(m,3H),2.85(m,1H),1.63(s,3H),1.25 (s, 9H),0.79(m,3H) ppm. ESI-MS m / z 549.3[M+1] + .

[0281] Example 21.

[0282] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0283] The synthetic route is as follows:

[0284]

[0285] Preparation of compound 21:

[0286] Compound 13 (3.1 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 21 (1.7 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.41 (s,1H), 8.70 (m,1H), 8.13 (m,1H), 7.48 (m,1H), 7.26-7.14(m,2H), 5.51(m,1H), 5.13(m,1H), 4.79-4.66(m,1H), 3.67-2.91(m,3H), 2.89-2.51(m,4H), 1.65 (s, 3H), 1.24(s,9H), 0.82(m,3H) ppm. ESI-MS m / z 562.2[M+1] + .

[0287] Example 22.

[0288] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-N-(6-((R)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0289] The synthetic route is as follows:

[0290]

[0291] Preparation of compound 22:

[0292] Compound 14 (3.1 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 22 (1.6 g). 1 H NMR (400 MHz, DMSO-d6 )δ10.42 (s,1H), 8.72 (m,1H), 8.12 (m,1H), 7.49 (m,1H), 7.28-7.14(m,2H), 5.52(m,1H), 5.14(m,1H), 4.80-4.65(m,1H), 3.69-2.92(m,3H), 2.87-2.49(m,4H), 1.63(s, 3H), 1.23(s,9H), 0.81(m,3H) ppm. ESI-MS m / z 562.2[M+1] + .

[0293] Example 23.

[0294] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxy)ethoxy)phenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0295] The synthetic route is as follows:

[0296]

[0297] Preparation of compound 23:

[0298] Compound 15 (3.3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. Stirred at room temperature for 8 hours, then warmed to 50 ° C, stirred and reacted for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 23 (1.8 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.47(s,1H),8.76(s,1H),8.11(m,1H),7.52(m,1H),7.23-7.11(m,2H),5.10(m,1H),4.61(s,1H),3.95(m,3H),3.61 (m,1H),3.38-3.15(m,4H),2.74(m,1H),1.61(s,3H),1.24(s,9H),0.78-0.65(m,3H)ppm.ESI-MS m / z 590.3[M+1] + .

[0299] Example 24.

[0300] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxy)ethoxy)phenyl)-N-(6-((R)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0301] The synthetic route is as follows:

[0302]

[0303] Preparation of compound 24:

[0304] Compound 16 (3.3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. Stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 24 (1.6 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.48(s,1H),8.77(s,1H),8.13(m,1H),7.54(m,1H),7.25-7.13(m,2H),5.12(m,1H),4.63(s,1H),3.97(m,3H),3.63 (m,1H),3.40-3.16(m,4H),2.76(m,1H),1.64(s,3H),1.25(s,9H),0.79-0.66(m,3H)ppm.ESI-MS m / z 590.3[M+1] + .

[0305] Example 25.

[0306] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0307] The synthetic route is as follows:

[0308]

[0309] Preparation of compound 25:

[0310] Compound 1 (1 g, 2 mmol) was dissolved in 15 ml THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H 2 O 2 (0.2 g, 35%, 2 mmol), stirred at room temperature for 1.5 hr, and NaHCO was added 3 The solution was extracted with DCM and dried over anhydrous sodium sulfate. Purification was performed by rapid silica gel column chromatography with gradient elution of methanol-dichloromethane to obtain 0.4 g of compound 25. ESI-MS m / z 523.1 [M+1] + .

[0311] Example 26.

[0312] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxyphenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0313] The synthetic route is as follows:

[0314]

[0315] Preparation of compound 26:

[0316] The preparation process of compound 26 is similar to that of compound 25, except that compound 1 is replaced by compound 2 to obtain compound 26. ESI-MS m / z 523.1[M+1] + .

[0317] Example 27.

[0318] (2R,3S,4S,5R)-3-(1-oxo-4-fluoro-2,3-dihydrobenzo[b]thiophen-7-yl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0319] The synthetic route is as follows:

[0320]

[0321] Preparation of compound 27:

[0322] Compound 3 (1 g, 2 mmol) was dissolved in 15 ml THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H 2 O 2 (0.2 g, 35%, 2 mmol), stirred at room temperature for 1.5 hr, and NaHCO was added 3The solution was extracted with DCM and dried over anhydrous sodium sulfate. Purification was performed by rapid silica gel column chromatography with gradient elution of methanol-dichloromethane to obtain 0.5 g of compound 27. ESI-MS m / z 517.1 [M+1] + .

[0323] Example 28.

[0324] (2R,3S,4S,5R)-3-(1-oxo-4-fluoro-2,3-dihydrobenzo[b]thiophen-7-yl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0325] The synthetic route is as follows:

[0326]

[0327] Preparation of compound 28:

[0328] The preparation process of compound 28 is similar to that of compound 27, except that compound 3 is replaced by compound 4 to obtain compound 28. ESI-MS m / z 517.1[M+1] + .

[0329] Example 29.

[0330] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxyphenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0331] The synthetic route is as follows:

[0332]

[0333] Preparation of compound 29:

[0334] Compound 13 (1 g, 2 mmol) was dissolved in 15 ml THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H 2 O 2 (0.2 g, 35%, 2 mmol), stirred at room temperature for 1.5 hr, and NaHCO was added 3 The solution was extracted with DCM and dried over anhydrous sodium sulfate. Purification was performed by rapid silica gel column chromatography with gradient elution of methanol-dichloromethane to obtain 0.45 g of compound 29. ESI-MS m / z 522.1[M+1] + .

[0335] Example 30.

[0336] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxyphenyl)-N-(6-((R)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0337] The synthetic route is as follows:

[0338]

[0339] Preparation of compound 30:

[0340] The preparation process of compound 30 is similar to that of compound 29, except that compound 13 is replaced by compound 14 to obtain compound 30. ESI-MS m / z 522.1[M+1] + .

[0341] Example 31.

[0342] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0343] The synthetic route is as follows:

[0344]

[0345] Preparation of intermediate 47:

[0346] The preparation process of intermediate 47 is similar to that of intermediate 44, except that 1-bromo-2-methoxyethane is replaced with (S)-3-iodotetrahydrofuran to obtain intermediate 47.

[0347] Preparation of compound 31:

[0348] Intermediate 47 (4.5 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 ° C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, and stirred for 1.5 hours. Diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0349] The intermediate (2.3 g, 3.4 mmol) from the previous step was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The mixture was purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to give compound 31 (1.66 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.42(s,1H),8.62(m,1H),8.13(m,1H),7.50 (m,1H),7.26-7.17(m,2H),5.37-5.10(m,2H),4.68-4.55(m,2H),4.39-4.23(m,4H),3.70- 3.31(m,3H),2.94-2.63(m,4H),1.65(s,3H),0.83-0.77(m,3H)ppm. ESI-MS m / z 546.2[M+1] + .

[0350] Example 32.

[0351] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((S)-2-amino-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0352] The synthetic route is as follows:

[0353]

[0354] Preparation of intermediate 48:

[0355] The preparation process of intermediate 48 is similar to that of intermediate 44, except that 1-bromo-2-methoxyethane is replaced with (R)-3-iodotetrahydrofuran to obtain intermediate 48.

[0356] Preparation of compound 32:

[0357] Intermediate 48 (4.5 g, 5.9 mmol) was dissolved in 50 ml THF, nitrogen atmosphere, cooled to 5 °C, TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, warmed to room temperature, stirred for 1.5 hr, diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0358] The intermediate (2.3 g, 3.4 mmol) from the previous step was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, the reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. The compound 32 (1.5 g) was obtained by purification by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia). 1 H NMR (400 MHz, DMSO-d 6 )δ10.40(s,1H),8.61(m,1H),8.12(m,1H),7.51 (m,1H),7.25-7.18(m,2H),5.36-5.11(m,2H),4.66-4.56(m,2H),4.38-4.22(m,4H),3.69- 3.30(m,3H),2.91-2.62(m,4H),1.64(s,3H),0.81-0.77(m,3H)ppm. ESI-MS m / z 546.2[M+1] + .

[0359] Example 33.

[0360] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0361] The synthetic route is as follows:

[0362]

[0363] Preparation of compound 33:

[0364] Compound 32 (3.3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 33 (1.8 g). 1 H NMR (400 MHz, DMSO-d 6)δ10.43(s,1H), 8.61(m,1H), 8.14(m,1H), 7.51(m,1H), 7.25- 7.16 (m,2H), 5.38-5.11(m,2H), 4.70-4.54(m,2H), 4.40-4.24(m,4H), 3.72-3.30(m,3H),2.96- 2.65 (m,4H),1.66(s,3H),1.26(s,9H),0.84-0.76(m,3H)ppm. ESI-MS m / z602.3[M+1] + .

[0365] Example 34.

[0366] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0367] The synthetic route is as follows:

[0368]

[0369] Preparation of compound 34:

[0370] Compound 31 (3.3 g, 6.13 mmol) was dissolved in 20 ml DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and stirred at room temperature. Tert-butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 hours, then warmed to 50 ° C and stirred for 2 hours. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. Concentrated under reduced pressure. Purified by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain compound 34 (1.8 g). 1 H NMR (400 MHz, DMSO-d 6 )δ10.41(s,1H), 8.63(m,1H), 8.13(m,1H), 7.49(m,1H), 7.26- 7.17(m,2H), 5.38-5.11(m,2H), 4.66-4.56(m,2H), 4.38-4.22(m,4H), 3.69-3.31(m,3H),2.95- 2.63 (m,4H),1.66(s,3H),1.25(s,9H),0.81-0.76(m,3H)ppm. ESI-MS m / z602.3[M+1] + .

[0371] Example 35.

[0372] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylsulfoxyphenyl)-N-(6-((S)-2-(tert-butylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0373] The synthetic route is as follows:

[0374]

[0375] Preparation of compound 35:

[0376] The preparation process of compound 35 is similar to that of compound 29, except that compound 13 is replaced by compound 21 to obtain compound 35. ESI-MS m / z 578.2[M+1] + .

[0377] Example 36.

[0378] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((S)-2-(trifluoroacetylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0379] The synthetic route is as follows:

[0380]

[0381] Preparation of compound 36:

[0382] Compound 9 (2.74 g, 5.6 mmol) was dissolved in 20 ml methanol, triethylamine (3 ml, 21.5 mmol) was added, and the mixture was stirred at room temperature. Ethyl trifluoroacetate (1.3 g, 9 mmol) was then added, the reaction solution was heated to 50 ° C, stirred for 15 hours, and the reaction was complete after TLC monitoring. The organic solvent was evaporated under reduced pressure, water was added, and the pH was adjusted to 3-4 with hydrochloric acid. The organic layer was extracted with ethyl acetate, washed with saturated sodium chloride solution, separated, and concentrated under reduced pressure. Compound 36 (1.9 g) was obtained by purification by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia). 1 H NMR (400 MHz, DMSO-d 6)δ10.43 (s,1H), 8.69 (m,1H), 8.07 (m, 1H), 7.46 (m,1H), 7.24-7.13(m,2H), 5.48(m,1H), 5.11(m,1H), 4.73-4.65(m,1H), 3.98(m,3H), 3.84- 3.51(m,2H), 3.45-3.00(m,1H), 2.81(m,1H) ,1.60(s,3H) ,0.78(m,3H) ppm. ESI-MS m / z 586.2[M+1] + .

[0383] Example 37.

[0384] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2-(trifluoroacetylamino)-1-hydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0385] The synthetic route is as follows:

[0386]

[0387] Preparation of compound 37:

[0388] Compound 10 (2.74 g, 5.6 mmol) was dissolved in 20 ml methanol, triethylamine (3 ml, 21.5 mmol) was added, and the mixture was stirred at room temperature. Ethyl trifluoroacetate (1.3 g, 9 mmol) was then added, the reaction solution was heated to 50 ° C, stirred for 15 hours, and the reaction was complete after TLC monitoring. The organic solvent was evaporated under reduced pressure, water was added, and the pH was adjusted to 3-4 with hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride solution, the organic layer was separated, and the mixture was concentrated under reduced pressure. Compound 37 (1.7 g) was obtained by purification by reverse phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia). 1 H NMR (400 MHz, DMSO-d 6 )δ10.45 (s,1H), 8.70 (m,1H), 8.11 (m, 1H), 7.49 (m,1H), 7.31-7.14(m,2H), 5.52(m,1H), 5.13(m,1H), 4.75-4.66(m,1H), 4.02(m,3H), 3.86- 3.50(m,2H), 3.47-3.02(m,1H), 2.83(m,1H) ,1.61(s,3H) ,0.79(m,3H) ppm. ESI-MS m / z 586.2[M+1] + .

[0389] Intermediate 28 is the reference compound CP1.

[0390] Prepare the control compound CP with reference to the above example:

[0391] .

[0392] Effect Example 1 Determination of Nav1.8 Inhibitory Activity and Ion Channel Selectivity

[0393] The effects of the example compounds on Nav1.8, Nav1.4 and Nav1.5 ion channels were tested in vitro. Nav1.8, Nav1.4 and Nav1.5 ion channels were expressed in HEK293 cells. After the currents of Nav1.8, Nav1.4 and Nav1.5 were stabilized, the sizes of the corresponding ion channel currents before and after the application of the compounds were compared to obtain the inhibitory activity and selectivity of the compounds on Nav1.8 ion channels.

[0394] 1. Experimental Equipment

[0395] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axon instrument)

[0396] 2) Digital to analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments)

[0397] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0398] 4) Inverted microscope: TL4 (Olympus)

[0399] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0400] 6) Microelectrode glass capillary: B12024F

[0401] 2. Experimental Procedure

[0402] 2.1 Preparation of experimental compounds and intracellular and extracellular solutions

[0403] All test compounds and control compounds CP or CP1 were dissolved in dimethyl sulfoxide (DMSO) and the solution was stored at a concentration of 10 mM. The compound solution used for the Nav1.8 inhibitory activity test contained 1 μM tetrodotoxin (TTX, AffixScientific). Dilute with extracellular fluid, prepare before use, and prepare to the required concentration according to the multiple dilution method.

[0404] Preparation of intracellular and extracellular fluids:

[0405] Intracellular fluid (mM): aspartate, 140; , 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration).

[0406] Extracellular fluid (mM): NaCl, 137; KCl, 4; ,1.8; ,1; HEPES,10; glucose,10; pH7.4 (NaOH titration).

[0407] 2.2 Electrophysiology

[0408] 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.

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 3. Pilot program (resting state)

[0413] 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 Nav1.5 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 response stabilized, the intensity of the blockade was calculated.

[0414] 4. Data Analysis

[0415] Data collection and analysis will be performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stabilization refers to the current variation over time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound at this solubility.

[0416] The inhibitory activity of the example compounds on Nav1.8, Nav1.4 and Nav1.5 was determined by the above test, and the measured IC 50 Value and SI (therapeutic index), SI 1.4 =(Nav1.4 IC 50 ) / (Nav1.8 IC 50 );SI 1.5 =(Nav1.5 IC 50 ) / (Nav1.8 IC 50 ), Example Compound Nav1.8 IC 50 All are less than 10nM. The experimental results are shown in Table 1.

[0417] Table 1: IC of the Example compounds for inhibition of Nav1.8 channel activity 50 and therapeutic index SI

[0418]

[0419] From the above results, it can be seen that all the tested compounds showed a relatively high inhibitory effect on Nav1.8 channel activity and had a high selectivity index (therapeutic index), especially compounds 1, 11, 17, 36, and 37, whose inhibitory effects on Nav1.8 were about 3 times more than the control compound CP1; compounds 1, 9, 11, 13, 17, 19, 23, 36, and 37, whose inhibitory effects on Nav1.8 were about 3 times more than the control compound CP. The Nav1.4 therapeutic index of compounds 1, 11, 36, and 37 was greater than 5 times that of the control compound CP1; the Nav1.4 therapeutic index of compounds 1, 9, 11, 13, 14, 17, 19, 23, 36, and 37 was greater than 5 times that of the control compound CP. The Nav1.5 therapeutic index of compounds 1, 11, 13, 17, 36, and 37 was greater than 5 times that of the control compound CP1. Nav1.5 is expressed in myocardial cells, and Nav1.4 is expressed in skeletal muscle cells. Nav1.5 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 as preventive / therapeutic drugs for treating symptoms / diseases caused by overexpression of Nav1.8, and have a higher therapeutic index and lower cardiac side effects.

[0420] Effect Example 2 Pharmacokinetic Evaluation

[0421] 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.

[0422] 1) Experimental drugs

[0423] Example compound 1, compound 11 and compound 19, and reference compound CP.

[0424] 2) Experimental animals

[0425] Sixteen SD rats, 4 in each group, half male and half female, were administered with oral administration after fasting overnight but not water restriction.

[0426] 3) Drug preparation

[0427] 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.

[0428] 4) Drug administration

[0429] The dosage was 2 mg / kg and the administration volume was 10.0 mL / kg.

[0430] 5) Operation

[0431] 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.

[0432] 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.

[0433] 6) Pharmacokinetic parameter results

[0434] Table 2: Pharmacokinetic parameters of the example compounds in SD rats

[0435]

[0436] The above test found that the metabolic parameters of the control compound had obvious male-female differences, while compound 1, compound 11 and compound 19 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. In particular, compound 1 C max It is 1.9 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, and the clinical use of the compound is wider and the drug safety is higher.

[0437] Effect Example 3 Evaluation of drug efficacy in mouse incision pain model

[0438] 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.

[0439] 1) Modeling:

[0440] 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.

[0441] 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 elevated, and then longitudinally cut, taking care not to damage the muscle origin and insertion. The incision was sutured with 5-0 nylon thread interrupted horizontally (2 stitches), as the model group and the efficacy evaluation group; in addition, healthy normal rats were selected as the normal group.

[0442] 2) Solvent: The solvent used for the example compound and the control compound CP1 was 5% DMSO + 10% Solutol + 85% Saline

[0443] 3) Dosage method and frequency:

[0444] Model group: Oral administration of vehicle, once a day.

[0445] Normal group: Oral administration of vehicle, once a day.

[0446] Experimental group: oral administration, once a day, dose: 60mpk.

[0447] 4) Mechanical pain threshold measurement: The mechanical pain threshold was measured before modeling; the mechanical pain threshold was measured before drug administration 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.

[0448] 5) Data analysis: The relevant data were sorted in GraphPad Prism6.0 and analyzed by One-way ANOVA. The analysis method used was Tukey's test for significant difference between groups.

[0449] Table 3: Pharmacodynamic results of the example compounds on the mouse incision pain model

[0450]

[0451] 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 CP1. The experimental results show that the example compounds have better analgesic efficacy, lower dosage, and lower cardiac side effects than existing clinical treatment methods.

[0452] Effect Example 4 hERG Test

[0453] To evaluate the risk of QT prolongation in electrocardiogram (ECG), HEK293 cells expressing human ether-a-go-go related gene (hERG) channel were used to investigate the expression of delayed rectifier K, which plays an important role in ventricular repolarization. + Current (I Kr )’s role.

[0454] Three concentrations of the test article working solution were prepared: 0.3, 3, and 30 µM. Visual inspection showed no precipitation. The experiment tested three concentrations of 0.3, 3, and 30 µM, and two groups of cells were tested for each concentration to evaluate the effect of the test article on hERG current. Using a fully automated patch clamp system, the I current induced by the cell being held at a membrane potential of -80 mV, a 2-second depolarizing stimulus of +50 mV, and a further 2-second repolarizing stimulus of -50 mV was recorded by the whole-cell patch clamp method. Kr After the generated current stabilized, the extracellular fluid containing the test substance dissolved at the target concentration (NaCl: 137mmol / L, KCl: 4mmol / L, CaCl 2 : 1.8mmol / L, MgCl 2 - 6H 2O: 1mmol / L, glucose: 10mmol / L, HEPES: 10mmol / L, pH 7.4) was applied to cells at room temperature for 10 minutes. Kr The absolute value of the maximum tail current was measured using analysis software based on the current value of the resting membrane potential. Further, the inhibition rate of the maximum tail current before the application of the test substance was calculated, and compared with the medium application group (0.1% DMSO solution), the effect of the test substance on I Kr impact.

[0455] For each cell, the inhibition percentage of each concentration of the test product was calculated from the recorded current response using the following formula:

[0456] (1 – peak tail current recorded after perfusion of test article / positive control / peak tail current (starting current) recorded after perfusion of vehicle control) × 100%.

[0457] Table 4 Average current inhibition rate of the example compounds at 0.3-30 μM

[0458]

[0459] From the inhibition rate results in Table 4, it can be seen that the inhibition rates of Example compounds 1, 11, 19, and 36 are significantly lower than those of the control compound CP1, especially the inhibition rate of 11 is less than half of that of CP1. The test results show that the risk of prolonging the QT interval of the electrocardiogram of the Example compounds is very small compared with the control compound CP1, that is, the Example compounds have lower cardiotoxicity and lower side effects in clinical practice.

[0460] 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.

[0461] 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 tetrahydrofurancarboxamide 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: (i) an effective amount of the tetrahydrofurancarboxamide compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1; and (ii) a pharmaceutically acceptable excipient.

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

4. The method of claim 3, wherein the voltage-gated sodium channel-related disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or arrhythmia.

5. The use according to claim 4, wherein the neuropathic pain is selected from 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, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy or trigeminal autonomic headache.

6. The use according to claim 4, wherein the musculoskeletal pain is selected from osteoarthritis pain, back pain, cold pain, burn pain or toothache.

7. The use according to claim 4, wherein the inflammatory pain is selected from rheumatoid arthritis pain or vulvar pain.

8. The use according to claim 4, wherein the primary pain is selected from fibromyalgia.

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