Tetrahydrofuramide compounds as sodium channel regulators and their pharmaceutical applications

Abstract

The present invention provides N-(hydroxyalkylpyridyl)tetrahydrofuranformamide compounds, prodrugs, oxides, salts, metal complexes or stereochemical isomers of a sodium channel modulator, and pharmaceutical compositions containing the same, as well as their use as Nav inhibitors and their use in the preparation of drugs for treating and / or alleviating pain and pain-related diseases. The compounds provided by the present invention have the advantages of high metabolic stability, high oral absorption, better bioavailability, better activity, higher selectivity, better pharmacokinetic properties, faster onset, and low cardiac side effects.

Description

Technical Field

[0001] The present invention provides N-(hydroxyalkylpyridyl)tetrahydrofuranformamide derivatives, prodrugs, oxides, salts, metal complexes or stereochemical isomers of a sodium channel modulator, and a pharmaceutical composition containing the same. Specifically, it relates to N-(hydroxyalkylpyridyl)tetrahydrofuranformamide compounds represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing such compounds, as well as their use as Nav inhibitors and their use in the preparation of drugs for treating and / or alleviating pain and pain-related diseases. 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 stimuli that trigger pain disappear, intense or persistent pain will cause physiological dysfunction and seriously affect the quality of life of the living body. Statistical data shows that about one-fifth of the people in the world suffer from moderate to severe chronic pain.

[0003] Pain originates from nociceptors in the peripheral nervous system. This is a free nerve ending widely distributed in the skin, muscles, joints and visceral tissues of the whole body. It can convert the sensed thermal, mechanical or chemical stimuli into nerve impulses (action potentials) and transmit them through the afferent nerve fibers to the cell body part located in the dorsal root ganglia (DRG), and finally transmit them to the higher nerve center to cause pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel opens, causing sodium ion influx, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps in the treatment and relief of 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 behaviors of the nine isoforms are similar but different in the details of their voltage dependence and kinetic behaviors. Nav1.4 is the primary sodium channel in skeletal muscle, and Nav1.5 is the primary sodium channel in 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, and Nav1.3 are mainly distributed in the CNS regions and are related to 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: Currently, the main pain-related targets are Nav1.7, Nav1.8, and Nav1.9. Among them, the application research of Nav1.7 inhibitors in the field of pain is the most extensive, but no relevant clinical trials have been successful so far; Nav1.9 has been less studied, and its mechanism of action in pain is not very clear.

[0005] Nav1.8 is of the TTX-R type, and its encoding gene is SCN10A. It is mainly present in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the upstroke of the action potential is mainly composed of Nav1.8 current. In some models of neuropathic pain research, nerve injury can increase the expression level of Nav1.8 in axons and neuronal cell bodies (Sleeper A.A., et al. J. Neurosci. 2000, 20, 7279 - 7289). Using Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Nav1.8 (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 neuralgia. Based on a series of animal experiments and human gene evidence, selective inhibition of Nav1.8 can be used for the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain, becoming a new type of analgesic therapy.

[0006] Nav inhibitors used in clinical practice have a narrow therapeutic window and limited application scope because they lack subtype selectivity and can inhibit sodium channels expressed in the heart and central nervous system. Nav1.8 is mainly distributed in the peripheral nervous system, so selectively inhibiting Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, good solubility, better pharmacokinetic properties, faster onset, longer-lasting analgesic effect, and less cardiotoxic side effects. SUMMARY OF THE INVENTION

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

[0008] Formula (I)

[0009] Wherein:

[0010] R¹, R², R³ and are the same or different and 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 alkylsulfinyl 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), -(OCH2CH2) n -OH, -(OCH2CH2) n -OCH3; wherein, the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally substituted by one or more R 5 ; 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- to 10-membered cycloalkyl group, or R¹ and R² and the atoms connected thereto form a substituted or unsubstituted 3- to 10-membered heterocyclic group; or R³ and and the atoms connected thereto form a substituted or unsubstituted 3- to 10-membered cycloalkyl group, or R³ and and the atoms connected thereto form a substituted or unsubstituted 3- to 10-membered heterocyclic group; wherein, the substituted 3- to 10-membered cycloalkyl group and the substituted 3- to 10-membered heterocycloalkyl group are each independently optionally substituted by one or more R 5 ;

[0012] Each R 5Same or different, and each independently selected from halogen, hydroxyl, cyano, oxo, amino, amido, alkyl, deuterated alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl;

[0013] R 6 Independently selected from a hydrogen atom, a deuterium atom, alkyl, deuterated alkyl, cycloalkyl;

[0014] R 7 Independently selected from a hydrogen atom, hydroxyl, amino, amido, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, alkylamino, deuterated alkylamino, cycloalkylamino, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, haloacetyl.

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

[0016] Formula (II)

[0017] Wherein:

[0018] R¹, R², R 5 And R 7 Are as defined in general formula (I).

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

[0020] , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。

[0021] The compounds of the present invention are generally used in the form of free acids or free bases. Optionally, the compounds of the present invention can be used in the form of acid or base salts. The acid addition salts of the free amino compounds of the present invention can be prepared by methods well known in the art and can be prepared from organic acids and inorganic acids. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Basic salts include salts formed with carboxylate anions and include salts formed with organic and inorganic cations such as selected from alkali metal ions, alkaline earth metal ions (e.g., lithium, sodium, potassium, magnesium, barium, calcium), and ammonium ions, and their substituted derivatives (e.g., dibenzylamine, benzylamine, 2-hydroxyethylamine, etc.). Thus, the term "pharmaceutically acceptable salts" of general 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 attached carrier that releases a compound of general formula (I) or formula (II) in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying a functional group in such a way that the modification can be cleaved by conventional means or decomposed in vivo to yield the parent compound. Prodrugs include, for example, compounds of the present invention in which a hydroxyl, amino, or mercapto group is bonded to any group that detaches when the prodrug is administered to a patient to yield a hydroxyl, amino, or mercapto group.

[0023] Accordingly, representative examples of prodrugs include, but are not limited to, derivatives of acetates (esters), formates (esters), and benzoates of the alcohol and amine functional groups of the compounds of general 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, the compounds of general formula (I) or formula (II) may have chiral centers and can exist in the form of racemates, racemic mixtures, as well as individual enantiomers or diastereomers. All isomeric forms are included within the scope of the present invention, including mixtures thereof. In addition, certain crystalline forms of the compounds of general formula (I) or formula (II) may exist as polymorphs, which are also included in the present invention. Furthermore, some of the compounds of general formula (I) or formula (II) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of the present invention.

[0025] Those skilled in the art should understand that any compound may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. As used in the present invention, in the specification and claims, H refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D. In the examples where an atom is designated as H, no work has been done on enriching the specific isotope of hydrogen atoms, and thus those of ordinary skill in the art should understand that such hydrogen atoms may be present at approximately the natural abundance concentration of hydrogen. In the tetrahydrofuran formamide derivatives involved in the present invention, the term "deuteration" means that the atoms at the relevant sites of the compound contain more than the natural proportion (i.e., more than the natural abundance of deuterium) of deuterium atoms. Accordingly, any N-(hydroxyalkylpyridyl)tetrahydrofuran formamide derivative that contains deuterium atoms at a proportion higher than the natural abundance of deuterium at the relevant sites is within the scope of protection of the present invention. For example, it can be understood that the corresponding N-(hydroxyalkylpyridyl)tetrahydrofuran formamide derivatives with the corresponding deuteration rate or deuterium content obtained by introducing deuterium atoms using commercially available deuterated reagents by the same or similar chemical synthesis means as shown in the examples of the present invention are all within the scope of protection of the present invention. The chemical synthesis means and deuterated reagents herein are not limited to those exemplified in the examples, but should be understood as all synthetic methods or routes that can be adopted in the art to obtain the compounds of the present invention, as well as all deuterated reagents that can be used in conjunction with the foregoing synthetic methods or routes to introduce deuterium atoms into the target molecule.

[0026] Isotopically labeled compounds and salts can be used in a variety of advantageous ways, including as pharmaceuticals. In some embodiments, the isotopically labeled compounds and salts are deuterium (D)-labeled. Deuterium (D)-labeled compounds and salts are therapeutically useful and have potential therapeutic advantages over non-D-labeled compounds. Generally, due to the kinetic isotope effects described below, deuterium (D)-labeled compounds and salts can have higher metabolic stability compared to non-isotopically labeled compounds and salts. Higher metabolic stability directly translates into an extended in vivo half-life or a reduced dose, which in most cases will represent a preferred embodiment of the present invention. Isotopically labeled compounds and salts can generally be prepared by carrying out the procedures disclosed in the synthetic schemes, examples, and related descriptions, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants. Deuterium (D)-labeled compounds and salts can manipulate the oxidative metabolism rate of the compounds through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from an isotopic nuclear exchange, which in turn is caused by a change in the ground-state energy of the covalent bond participating in the reaction. Exchange of a heavier isotope generally causes a decrease in the ground-state energy of the chemical bond and thus a reduction in the cleavage of the rate-limiting bond. If the bond cleavage occurs in or near the saddle-point region along the reaction coordinate of a multi-product reaction, the product distribution ratio can be substantially altered.

[0027] According to the specific examples disclosed hereinafter of the present invention, those skilled in the art can prepare each specific compound involved in the N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamides derivatives represented by the general formula (I) or formula (II) of the present invention by adopting the same or similar principles and methods.

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

[0029] The present invention further provides the use of an N-(hydroxyalkylpyridyl)tetrahydrofurancarboxamide derivative represented by the formula (I) or formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, its pharmaceutically acceptable salts or its prodrugs in the preparation of a medicament for treating diseases caused by overexpression of Nav1.8.

[0030] The present invention further provides the use of an N-(hydroxyalkylpyridyl)tetrahydrofuranformamide derivative represented by formula (I) or formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a medicament for treating diseases caused by overexpression of Nav1.8.

[0031] The present invention further provides the use of an N-(hydroxyalkylpyridyl)tetrahydrofuranformamide derivative represented by formula (I) or formula (II), its stereoisomers, hydrates, solvates, polymorphs, active metabolites, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a medicament for treating any one or more of the diseases including 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] Furthermore, the neuropathic pain is selected from one or several of postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy, trigeminal autonomic cephalgia; the musculoskeletal pain is selected from one or several of osteoarthritis pain, back pain, cold pain, burn pain, toothache; the inflammatory pain is selected from rheumatoid arthritis pain and / or vulvodynia; 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)tetrahydrofuranformamide derivative represented by 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 or suitable pharmaceutical composition of the compound of the present invention or its pharmaceutically acceptable salt can be administered by any acceptable mode of administering agents having a similar effect. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semi-solid, liquid or gaseous forms of preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administering the pharmaceutical composition include (but are not limited to) oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present invention is formulated to allow the active ingredient contained therein to be bioavailable after administration of the composition to a patient. The composition to be administered to an individual or patient is in the form of one or more dosage units, wherein, for example, a tablet can be a single dosage unit, and a container containing the compound of the present invention in aerosol form can contain multiple dosage units. The actual methods of preparing such dosage forms are known to those skilled in the art or will be known to them. The composition to be administered will in any case contain a therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt so as to treat the disease or condition of interest according to the teachings of the present invention.

[0035] The pharmaceutical composition of the present invention can be in solid or liquid form. In one aspect, the carrier is particulate, so that the composition is in the form of, for example, a tablet or powder. The carrier can be liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for, for example, inhalation administration. When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in the forms regarded as solid or liquid herein. For oral solid compositions, the pharmaceutical composition can be formulated into forms such as powders, granules, compressed tablets, pills, capsules, chewable tablets, powder tablets, etc. Such solid compositions usually contain one or more inert diluents or edible carriers. In addition, one or more of the following substances can also be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch, lactose or dextrin; disintegrants, such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, such as magnesium stearate or hydrogenated vegetable oil (Sterotex); glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; flavoring agents, such as mint, methyl salicylate or sweet orange flavoring; and coloring agents.

[0036] In the preparation of compositions for oral administration, any common pharmaceutical vehicle can be used. In the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions, and solutions, for example, water, glycols, oils, alcohols, etc.; or in the case of solid compositions, solid carriers such as starch, sugars, kaolin, lubricants, binders, disintegrants, etc. For parenteral compositions, the vehicle will generally comprise at least predominantly sterile water, but other ingredients such as solubilizers, emulsifiers, or additional adjuvants can also be added thereto. Injectable solutions can be prepared in which the vehicle comprises a physiological saline solution, a glucose solution, or a mixture of the two. Injectable suspensions can also be prepared, in which case appropriate liquid vehicles, suspending agents, etc. can be employed. Also included are solid form preparations that are intended to be converted into a liquid form preparation shortly before use, such as powders for reconstitution.

[0037] When the pharmaceutical composition is in capsule form, such as a gelatin capsule, in addition to substances of the above types, it can also contain a liquid vehicle, such as polyethylene glycol or an oil. The pharmaceutical composition can be in liquid form, such as a tincture, syrup, solution, emulsion, or suspension. This liquid can be administered orally or by injection, as two examples. When intended for oral administration, the preferred composition contains, in addition to the compound of the present invention, one or more of a sweetening agent, a preservative, a dye / colorant, and a flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffering agent, a stabilizing agent, and an isotonic agent can be included.

[0038] Regardless of whether the liquid pharmaceutical composition of the present invention is in solution, suspension, or other similar form, it can include one or more of the following adjuvants: sterile diluents, such as water for injection, physiological saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils (such as synthetic mono- or di-glycerides, which can be used as solvents or suspending media), polyethylene glycol, glycerin, propylene glycol, and other solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffering agents, such as acetate, citrate, or phosphate, and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Physiological saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0039] The liquid pharmaceutical composition of the present invention for parenteral or oral administration should contain a certain amount of the compound of the present invention so as to obtain a suitable dose. The pharmaceutical composition of the present invention may be intended for topical administration, in which case the carrier preferably comprises a solution, an emulsion, an ointment or a gel matrix. For example, the matrix may comprise one or more of the following: paraffin oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as 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 may be administered rectally, for example in the form of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oily matrix as a suitable non-irritating excipient. The said matrix includes (but is not limited to) lanolin, cocoa butter and polyethylene glycol.

[0041] The pharmaceutical composition of the present invention may include various substances that alter the physical form of solid or liquid dosage units. For example, the composition may include substances that form a coating shell around the active ingredient. The substances forming the coating shell are usually inert and may be selected from, for example, sugars, shellac and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0042] The pharmaceutical composition of the present invention in solid or liquid form may include a reagent that binds to the compound of the present invention and thus aids in the delivery of the compound. Suitable reagents having this ability include monoclonal or polyclonal antibodies, proteins or liposomes.

[0043] The pharmaceutical composition of the present invention may consist of dosage units that can be administered in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from colloidal species to systems consisting of pressurized packages. Delivery may be effected by a liquefied or compressed gas, or by a suitable pump system for dispensing the active ingredient. The aerosol of the compound of the present invention may be delivered as a single-phase, two-phase or three-phase system to deliver the active ingredient. The delivery of the aerosol includes the necessary container, actuator, valve, sub-container, etc., which together may form a kit. A person skilled in the art can determine the preferred aerosol without undue experimentation.

[0044] The pharmaceutical compositions of the present invention can be prepared using methods well known in the pharmaceutical art. For example, to prepare a pharmaceutical composition for administration by injection, the compound of the present invention can be combined with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a uniform solution or suspension. A surfactant is a compound that non-covalently interacts with the compound of the present invention, thereby promoting the dissolution or uniform suspension of the compound in an aqueous delivery system. The compound of the present invention can be combined with an acceptable vehicle or solvent such as water, Ringer's solution, and isotonic sodium chloride solution to form a solution. The sterile injectable preparation can be a sterile water-in-oil microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion can be injected into the bloodstream of a patient by topical bolus injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous infusion pump.

[0045] The pharmaceutical compositions of the present disclosure can be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any compatible fixed oil can be used. In addition, fatty acids can also be used to prepare injectables.

[0046] The compounds, salts and pharmaceutically acceptable compositions of the present invention can be used in combination therapies, i.e., the compounds, salts and pharmaceutically acceptable compositions can be administered simultaneously with, before or after one or more other desired therapeutic agents or medical procedures. The specific combinations of therapies (therapeutic agents or procedures) employed in the combination regimens will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapies employed can achieve the desired effect on the same disorder (e.g., a compound of the present invention can be administered simultaneously with another agent for treating the same disorder), or they can achieve different effects (e.g., controlling any adverse reactions). As used herein, an additional therapeutic agent that is normally administered for treating or preventing a particular disease or condition is referred to as "suitable for the disease or condition being treated".For example, exemplary additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; p-aminophenol derivatives such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone)); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine and pentazocine). Additionally, non-pharmacological analgesic methods can be used in combination with the administration of one or more compounds of the present invention. For example, anesthesia (intrathecal infusion, nerve block), neurosurgery (neurolysis of CNS pathways), nerve stimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiological (physical therapy, orthopedic devices, diathermy) or psychological (cognitive methods - hypnosis, biofeedback or behavioral methods) methods can also be utilized.

[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 specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex and diet of the patient; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the individual undergoing the therapy.

[0048] The compounds of the invention or pharmaceutically acceptable salts thereof may also be administered simultaneously with, before or after the administration of one or more other therapeutic agents. Such combination therapy includes the administration of a single pharmaceutical dosage form containing the compound of the invention and one or more other active agents, as well as the administration of the compound of the invention and the individual separate pharmaceutical dosage forms of each active agent. For example, the compound of the invention and another active agent may be administered to a patient together in a single oral dosage composition (e.g., a tablet or capsule), or each agent may be administered in separate oral dosage forms. In the case of separate dosage forms, the compound of the invention and one or more additional active agents may be administered substantially at the same time (i.e., simultaneously) or at separate staggered times (i.e., sequentially); combination therapy is to be understood to include all such regimens.

[0049] The compounds and salts of the invention or their pharmaceutically acceptable compositions may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Thus, in another aspect, the invention encompasses a composition for coating an implantable device, the implantable device comprising a compound or salt of the invention as generally described above and the classes and subclasses herein and a carrier suitable for coating the implantable device. In yet another aspect, the invention encompasses an implantable device coated with a composition comprising a compound or salt of the invention as generally described above and the classes and subclasses herein and a carrier suitable for coating the implantable device. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polydimethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. The coating may optionally be further coated with a suitable top layer of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release properties to the composition.

[0050] As a general guidance, the active compounds of the present disclosure are preferably in the form of unit doses, or in a form that allows the patient to self-administer in a single dose. The unit dose expression of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, bottled potions, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 - 1000 mg.

[0051] In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the different administration methods, the composition may contain 0.1 to 99% by weight of the active compound.

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

[0053] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% - 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% - 98% of a pharmaceutically acceptable excipient. Tablets contain an active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets by mixing. These excipients can be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may not be coated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.

[0054] The present invention relates to N-(hydroxyalkylpyridyl)tetrahydrofuran carboxamide derivatives of formula (I) or formula (II), their prodrugs, their deuterated compounds, pharmaceutical compositions containing the same, and methods of using the composition to inhibit voltage-gated sodium channels in a subject, wherein the voltage-gated sodium channel is Nav1.8.

[0055] The present invention features a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which is used for treating acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, plastic pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpes zoster neuralgia, general neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, mental disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis and central neuropathic pain of irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radiculopathy, sciatica, back pain, non-specific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain (e.g., joint replacement pain, soft tissue surgery pain, hernia repair pain, bunionectomy pain or abdominoplasty pain), cancer pain, including chronic cancer pain and breakthrough cancer pain, stroke (e.g., central neuropathic pain after stroke), whiplash injury-related conditions, fragility fracture, spinal fracture, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, melorheostosis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, disc degeneration / herniation pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, discitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuropathic osteoarthropathy, temporomandibular joint disorder, painful arthroplasty, non-cardiac chest pain, pudendal, renal colic, biliary tract disease, vascular leg ulcer, pain in Parkinson's disease, pain in Alzheimer's disease, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or gastrointestinal motility disorders or a method for reducing their severity.

[0056] On the other hand, the present invention features a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which is used for treating cancerous pain of the femur, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, fibromyalgia, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headache, migraine, tension headache, cluster headache, chronic and acute neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Charcot-Marie-Tooth neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiotherapy-induced neuropathic pain, persistent / chronic postoperative pain (e.g., after amputation, thoracotomy, cardiac surgery), postmastectomy pain, central pain, spinal cord injury pain, post-stroke pain, thalamic pain, phantom limb pain (e.g., after resection of lower limb, upper limb, breast), intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendinitis, injury pain, sports pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, 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, orofacial pain, sinusitis pain, toothache, multiple sclerosis (MS) pain, depression pain, leprosy pain, Behcet's disease pain, painful obesity, phlebitis pain, Guillain-Barré syndrome pain, pain in the legs and moving toes, Haglund's syndrome, erythromelalgia, Fabry disease pain, bladder and urogenital system diseases, urinary incontinence, pathological cough, overactive bladder, bladder pain syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus or angina-induced pain or a method for reducing its severity.

[0057] On the other hand, the present invention features the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions, which are used for treating trigeminal neuralgia, migraine treated with botulinum, cervical radiculopathy, occipital neuralgia, axillary neuropathy, radial neuropathy, ulnar neuropathy, brachial plexopathy, thoracic radiculopathy, intercostal neuralgia, lumbosacral radiculopathy, iliohypogastric neuralgia, pudendal neuralgia, femoral neuropathy, meralgia paresthetica, saphenous neuropathy, sciatic neuropathy, peroneal neuropathy, tibial neuropathy, lumbosacral plexopathy, stump pain of traumatic neuroma or pain after amputation or a method for reducing the severity thereof.

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

[0059] Treating the following in the subject or reducing the severity thereof: one or more of 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 hallux valgus resection pain, abdominoplasty pain or hernia repair 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 persistent analgesic effect, low side effects and low cardiotoxicity. Therefore, the compounds of the present invention have better pharmaceutical properties.

[0061] Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available. Unless otherwise specified, the compounds of the present invention are named manually or by chemical structure software, and commercially available compounds use the supplier catalog names. On the basis of conforming to the common knowledge in the art, the above - mentioned preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention. Detailed Embodiments

[0062] Some preferred embodiments of the present invention are illustratively shown in the following non - restrictive examples. For the experimental methods without specific conditions noted in the following examples, they are carried out according to conventional methods and conditions, or according to the product specifications. The raw materials can be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0063] Example 1.

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

[0065] The synthesis 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. After quenching the reaction with a NaHCO3 solution, the reaction mixture was concentrated under reduced pressure and purified by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether to obtain the intermediate, which was directly used in the next reaction.

[0071] The above 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 the mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain Intermediate 21 (53 g), which was prepared and separated.

[0072] Intermediate 21 was separated on a Prep-100 SFC instrument of a preparative liquid chromatograph with a Chiralpak IB column (mobile phase: 7% MeOH (containing 20 mM ammonia), 93% CO2, 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, isopropylmagnesium chloride (145 mL, 2M THF, 290 mmol) was dissolved in 150 mL of THF, and the temperature was raised to 40 °C. 6-Bromo-2,3-difluorobenzenemethanethiol (28 g, 117 mmol) was added in portions, and the mixture was stirred for 30 min. The reaction solution was cooled to 0 °C, and a solution of triamyl borate (46 mL, 410 mmol) in THF (100 mL) was added dropwise. 2N hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. n-Hexane was added, and the mixture was stirred well to obtain a solid, Intermediate 18 (15 g).

[0075] Preparation of Intermediate 14:

[0076] Under a nitrogen atmosphere, Intermediate 4 (78 g, 201.93 mmol) was dissolved in 400 mL of toluene. Intermediate 18 (45.6 g, 223.5 mmol) was added to the solution, and the mixture was stirred. Subsequently, K3PO4 (300 mL, 2M, 600 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 g, 10.38 mmol) were added. The temperature was raised to 100 °C, and the mixture was stirred and reacted for 3 h. The reaction was quenched by adding water, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave Intermediate 14 (72 g). ESI-MS m / z 397.1 [M+1] + 。

[0077] Preparation of Intermediate 15:

[0078] Intermediate 14 (11 g, 24.3 mmol) was dissolved in DCM (30 mL), and the mixture was stirred and cooled to 0 °C. A solution of BBr3 (37 mL, 1M, 18.5 mmol) was added dropwise, and the mixture was stirred and reacted. The reaction was quenched by adding an aqueous sodium bicarbonate solution at 0 °C. The mixture was extracted with DCM, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was dissolved in DCM (40 mL), and trifluoroacetic acid (4 mL, 52 mmol) was added dropwise. Then the reaction solution was heated to 45 °C. After the reaction was completed, the reaction was quenched by adding an aqueous sodium bicarbonate solution, and the mixture was extracted with DCM, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the desired product in a mixture of diastereomers. The crude product was recrystallized twice from DCM-heptane, filtered, and dried to obtain 5.5 g of a solid, 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 a suspension of Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) in MeOH (40 mL) was added to the reactor. Hydrogen gas was pressurized, and the mixture was stirred at a pressure of 60 psi for 4 h. Then, Pd(OH)2 (18.6 g, 20% w / w, 5.82 mmol) was added again, hydrogen gas was pressurized, and the mixture was stirred at a pressure of 80 psi for 4 h. The reaction was monitored by TLC and found to be complete. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, rinsed with MeOH and then with EtOAc. The filtrate was concentrated under reduced pressure to obtain intermediate 16 (8.3 g).

[0081] Preparation of intermediate 17:

[0082] Under nitrogen protection and at room temperature, intermediate 16 (1 g, 2.82 mmol) was dissolved in 15 mL of acetonitrile. Potassium carbonate (2 g, 14.4 mmol) was added, and methyl iodide (1.85 g, 13 mmol) was added to the reaction mixture in portions. The mixture was stirred for 24 h. MTBE was added, and the mixture was filtered through diatomaceous earth and washed with MTBE. The filtrate was concentrated under reduced pressure to obtain a solid, which was intermediate 17 (0.9 g). ESI-MS m / z 385.1 [M+1] + 。

[0083] Preparation of intermediate 24:

[0084] Under nitrogen protection and at room temperature, intermediate 17 (5.1 g, 13.3 mmol) was dissolved in 50 ml of THF. Sodium methoxide (30% methanol solution, 0.32 mL, 1.3 mmol) was added to the reaction mixture, and the mixture was stirred for 5 h. A solution of 5 ml of MeOH - 5 ml of water was added dropwise to the reaction mixture, and the mixture was stirred for 30 min. Then, lithium hydroxide monohydrate (0.84 g, 20 mmol) was added, and the mixture was stirred for 8 h. After the reaction was monitored by TLC and found to be complete, 1 M hydrochloric acid (20 ml) was added, and the mixture was extracted with MTBE. The organic layer was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene and concentrated in vacuo, and then dissolved in MTBE and concentrated again in vacuo to obtain an intermediate, which was directly used in the next reaction.

[0085] Dissolve the intermediate from the previous step (1.9 g, 5 mmol) in 20 ml of DCM, cool to 2 °C, and sequentially add oxalyl chloride (2.2 mL, 25 mmol) and DMF (35.5 μL, 0.5 mmol) dropwise to the reaction solution, then stir at room temperature for 1.5 hr. Concentrate the reaction solution under reduced pressure, and then add 10 ml of DCM and concentrate again under reduced pressure. Dissolve the concentrate in 20 ml of DCM and add dropwise to a solution of intermediate 23 (1.49 g, 7.62 mmol), DMAP (35.6 mg, 0.3 mmol), and Et3N (2.2 mL, 15.5 mmol) in DCM (40 mL) at room temperature. Stir the reaction for 8 hr, concentrate under reduced pressure, add water, extract with DCM, and dry over anhydrous sodium sulfate. Purify by flash silica gel column chromatography with a methanol - dichloromethane gradient elution to obtain intermediate 24 (3 g). ESI-MS m / z 547.2 [M+1] + 。

[0086] Preparation of Compound 1:

[0087] Dissolve the intermediate 24 from the previous step (1.8 g, 3.33 mmol) in DCM (60 mL), add TFA (5.2 mL, 6.78 mmol), stir at room temperature for 2 hours, and concentrate under reduced pressure. Purify by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 1 (0.9 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (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-(methylthio)phenyl)-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 refers to the preparation of Intermediate 24, with the difference 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] Dissolve the above Intermediate 25 (1.8 g, 3.33 mmol) in DCM (60 mL), add TFA (5.2 mL, 6.78 mmol), stir and react at room temperature for 2 hours, and concentrate under reduced pressure. Purify by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 2 (1 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.37 (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, 1H), 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, isopropylmagnesium chloride (145 mL, 2 M THF, 290 mmol) was dissolved in 150 mL of THF, and the temperature was raised to 40 °C. 1-Bromo-4-fluoro-2,3-dihydrobenzothiophene (27.3 g, 117 mmol) was added in portions, and the mixture was stirred for 30 min. The reaction solution was cooled to 0 °C, and a solution of triamyl borate (46 mL, 410 mmol) in THF (100 mL) was added dropwise. 2N hydrochloric acid was added to adjust the pH to 1, and the mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. n-Hexane was added, and the mixture was stirred well to obtain the solid intermediate 19 (18.3 g).

[0101] Preparation of Intermediate 20:

[0102] Under a nitrogen atmosphere, Intermediate 4 (15.6 g, 40.39 mmol) was dissolved in 400 mL of toluene. Intermediate 19 (8.85 g, 44.7 mmol) was added to the solution, and the mixture was stirred. Subsequently, K3PO4 (60 mL, 2 M, 120 mmol) was added, and tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) was added. The temperature was raised to 100 °C, and the mixture was stirred and reacted for 3 h. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave Intermediate 20 (72 g). ESI-MS m / z 391.1 [M+1] + 。

[0103] Preparation of Intermediate 21:

[0104] Compound 20 (30 g, 76.25 mmol) was dissolved in 100 mL of ethanol. Pd / C (10% loading, 100 g, 94 mmol) was added, and hydrogen was passed through. The hydrogenation reaction was carried out at room temperature for 10 h; Pd / C (10% loading, 100 g, 94 mmol) was added again, and hydrogen was passed through for another 10 h of hydrogenation reaction. The mixture was filtered through diatomaceous earth, washed with DCM, water was added, and the mixture was extracted with DCM. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether was directly used for 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 the mixture was stirred and reacted for 6 h. The reaction was quenched with a saturated aqueous solution of NH4Cl, the pH was adjusted under 2N hydrochloric acid conditions, and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. Purification by flash silica gel column chromatography with gradient elution of EtOAc / petroleum ether gave Intermediate 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 of DCM, and the temperature was cooled to 2 °C. Oxalyl chloride (4.4 mL, 50 mmol) and DMF (71 μL, 1 mmol) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure, and then concentrated under reduced pressure after adding 20 mL of DCM. The concentrate was dissolved in 40 mL of DCM and added dropwise to a solution of Intermediate 23 (2.8 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol), and Et3N (4.4 mL, 31 mmol) in DCM (80 mL) at room temperature. The mixture was stirred and reacted for 8 h, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with a methanol-dichloromethane gradient elution gave Intermediate 26 (4.3 g). ESI-MS m / z 541.2 [M+1] + 。

[0108] Preparation of Compound 3:

[0109] The above Intermediate 26 (2.7 g, 5 mmol) was dissolved in DCM (100 mL), and TFA (7.8 mL, 10.17 mmol) was added. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 3 (1.9 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.77 (m, 1H), 8.12 (m, 1H), 7.54 (m, 1H), 7.25 - 7.16 (m, 2H), 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 refers to the preparation of Intermediate 26, with the difference 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] Dissolve the above Intermediate 27 (1.8 g, 3.33 mmol) in DCM (60 mL), add TFA (5.2 mL, 6.78 mmol), stir and react at room temperature for 2 hours, and concentrate under reduced pressure. Purify by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 4 (1 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.29 (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, 1H), 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 the raw material, it is prepared by the method disclosed in Example 3 on page 231 of the specification of the patent application "WO2021113627". Intermediate 5:

[0125] 1 1H NMR (400 MHz, chloroform-d) δ 6.89 - 6.80 (m, 2H), 4.18 - 4.10 (m, 2H), 3.91 (s, 3H), 3.77 - 3.46 (m, 1H), 1.68 (s, 3H), 1.14 (t, 3H), 1.07 (dd, 3H) ppm, ESI-MS m / z 381.02 [M+1] + .

[0126] Preparation of Intermediate 6:

[0127] Intermediate 5 (220 g, 486 mmol) was dissolved in DCM (600 mL), stirred and cooled to 0 °C. A solution of BBr3 (740 mL, 1 M, 370.0 mmol) was added dropwise, and the mixture was stirred for reaction. The reaction was quenched by adding an aqueous sodium bicarbonate solution dropwise at 0 °C. The mixture was extracted with DCM, and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was dissolved in DCM (800 mL), trifluoroacetic acid (80 mL, 1038 mmol) was added dropwise, and then the reaction solution was heated to 45 °C. After the reaction was completed, it was quenched by adding an aqueous sodium bicarbonate solution, extracted with DCM, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the desired product in a mixture of diastereoisomers. The crude product was recrystallized twice from DCM - heptane, filtered and dried to obtain 124 g of a solid as Intermediate 6. ESI-MS m / z 321.5 [M+1] + 。

[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 a suspension of Pd(OH)2 (185.5 g, 20% w / w, 58.2 mmol) in MeOH (400 mL) was added to the reactor. Hydrogen was pressurized, and the mixture was stirred at a pressure of 60 psi for 8 h. The reaction was monitored by TLC and found to be complete. The suspension was filtered through diatomaceous earth under a nitrogen atmosphere, rinsed with MeOH and then with EtOAc, 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 methyl iodide (3.7 g, 26 mmol) was added portionwise to the reaction solution. The mixture was stirred for 24 h. MTBE was added, and the mixture was filtered through diatomaceous earth and washed with MTBE. The filtrate was concentrated under reduced pressure to obtain a solid as Intermediate 10 (1.8 g). ESI-MS m / z 369.1 [M+1] + 。

[0132] Preparation of Intermediate 11:

[0133] Under nitrogen protection and at room temperature, Intermediate 10 (49 g, 133 mmol) was dissolved in 500 ml of THF, and sodium methoxide (30% methanol solution, 3.2 mL, 14 mmol) was added to the reaction solution, followed by stirring for 4.5 hours.

[0134] To the reaction solution, a solution of 50 ml of MeOH - 50 ml of water was added dropwise, and the mixture was stirred for 30 minutes. Then, lithium hydroxide monohydrate (8.4 g, 200 mmol) was added, and the reaction was stirred for 8 hours. After TLC detection showed complete reaction, 1 M hydrochloric acid (220 ml) was added, and the mixture was extracted with MTBE. The organic layer was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (4 L) and concentrated in vacuo, then dissolved in MTBE (4 L) and concentrated again in vacuo to obtain Intermediate 11 as an oil, which was directly used in the next step of the reaction.

[0135] Preparation of Intermediate 28 (Control Compound CP1):

[0136] Intermediate 11 (3.7 g, 10 mmol) was dissolved in 40 ml of DCM, and the temperature was lowered to 2 °C. Oxalyl chloride (2.2 mL, 25 mmol) and DMF (71 μL, 1 mmol) were added dropwise to the reaction solution in sequence, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then concentrated again after adding 20 ml of DCM. The concentrate was dissolved in 40 ml of DCM and added dropwise to a solution of Intermediate 23 (2.8 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol), and Et3N (4.4 mL, 31 mmol) in 80 mL of DCM at room temperature. The reaction was stirred for 8 hours, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM, followed by drying over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol - dichloromethane gave the intermediate, which was directly used in the next step of the reaction.

[0137] The intermediate from the previous step (3.6 g, 6.66 mmol) was dissolved in DCM (100 mL), TFA (10.5 mL, 13.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. Purification by reverse - phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave Intermediate 28 (2.1 g). 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). The temperature was lowered to 0 °C, and boron tribromide (5 mL, 1 M solution in DCM, 5 mmol) was added. The mixture 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. Purification by flash silica gel column chromatography with a methanol-dichloromethane gradient elution gave 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 K2CO3 (0.32 g, 2.3 mmol) were added. The reaction mixture was stirred at room temperature for 1 hr and then at 60 °C for 12 hr. The mixture was filtered and concentrated under reduced pressure. Purification by reversed-phase preparative HPLC (mobile phase: 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 5 (0.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (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-MS m / 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] For the preparation process of Intermediate 49, refer to the preparation of Intermediate 28. The difference is that Intermediate 23 is replaced with Intermediate 22 to obtain Intermediate 49 (2.2 g). ESI-MS m / z 491.2 [M+1] + 。

[0147] For the preparation process of Intermediate 50, refer to the preparation of Intermediate 29. The difference is that Intermediate 28 is replaced with 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), and 1-bromo-2-(2-methoxyethoxy)ethane (0.38 g, 2.1 mmol) and K2CO3 (0.32 g, 2.3 mmol) were added. The reaction mixture was stirred at room temperature for 1 hr, then heated to 60 °C and stirred for 12 hr. After filtration and concentration 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 6 (0.4 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (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-MS m / 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 h, concentrated under reduced pressure to obtain an intermediate. Water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reverse-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.28 g of Compound 7. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (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 h, concentrated under reduced pressure to obtain an intermediate. Water was added, and the mixture was extracted with DCM. The organic layer was concentrated under reduced pressure and purified by reverse-phase preparative chromatography (mobile phase: 25% methanol:acetonitrile (1:1), 75% CO2) to obtain 0.29 g of Compound 8. 11H NMR (400 MHz, DMSO-d6) δ 10.41 (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 of THF / 50 ml of 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 of THF and added dropwise to the above reaction solution. The mixture was stirred at room temperature for 2 h. Concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, and the organic layers were combined. Concentrated under reduced pressure to obtain Intermediate 30.

[0170] Preparation of Intermediate 31:

[0171] Intermediate 30 (8.5 g, 30.16 mmol) was placed in DMF (50 mL), and tert-butyldimethylchlorosilane (7 g, 46.44 mmol), imidazole (6 g, 88.14 mmol) and DMAP (0.73 g, 5.98 mmol) were added. The reaction mixture was heated at 60 °C for 16 hours. After the reaction was completed, the temperature was lowered, and the reaction was quenched by adding ice water (500 mL), followed by extraction with EtOAc. The extract was washed with saturated sodium chloride, and the organic layers were combined. The solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography with gradient elution of ethyl acetate - petroleum ether 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 and added to the above reaction solution. The mixture was refluxed for 3 hours. The reaction mixture was filtered through diatomaceous earth while hot, and the filter cake was washed with 1 L of hot water. The filtrate was concentrated under reduced pressure, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure to obtain Intermediate 32 (23 g).

[0174] For the preparation process of Intermediate 33, refer to the preparation of Intermediate 30, with the difference that (S)-2-amino-1-(5-nitropyridin-2-yl)ethanol was replaced by (R)-2-amino-1-(5-nitropyridin-2-yl)ethanol to obtain Intermediate 33.

[0175] For the preparation process of Intermediate 34, refer to the preparation of Intermediate 31, with the difference that Intermediate 30 was replaced by Intermediate 33 to obtain Intermediate 34.

[0176] For the preparation process of Intermediate 35, refer to the preparation of Intermediate 32, with the difference that Intermediate 31 was 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 of DCM, and the temperature was lowered to 2 °C. Oxalyl chloride (2.2 mL, 25 mmol) and DMF (71 μL, 1 mmol) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and then concentrated under reduced pressure after adding 20 ml of DCM. The concentrate was dissolved in 40 ml of DCM and added dropwise at room temperature to a solution of Intermediate 32 (5.3 g, 14.5 mmol), DMAP (70 mg, 0.6 mmol) and Et3N (4.4 mL, 31 mmol) in DCM (80 mL). The mixture was stirred for 8 hours, concentrated under reduced pressure, water was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. The residue was purified by flash silica gel column chromatography with gradient elution of methanol - dichloromethane 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was then raised to room temperature, and the mixture was stirred for 1.5 h. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solutions. The solvent was evaporated under reduced pressure to obtain the intermediate, which was directly used in the next step.

[0181] The above intermediate (3.9 g, 6.66 mmol) was dissolved in DCM (50 mL), and TFA (10.5 mL, 13.5 mmol) was added. The mixture was stirred at room temperature for 2 h, and the solvent was evaporated 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 9 (2.9 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (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] For the preparation process of Intermediate 37, refer to the preparation of Intermediate 36, with the difference 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 1.5 hr. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. It was concentrated under reduced pressure to obtain the intermediate, which was directly used in the next step of the reaction.

[0189] The intermediate from the previous step (3.9 g, 6.66 mmol) was dissolved in DCM (50 mL), and TFA (10.5 mL, 13.5 mmol) was added. The reaction 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 10 (2.2 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (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] + 。

[0190] Example 11.

[0191] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)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 of DCM, and triethylamine (1.71 g, 16.94 mmol) was added. The temperature was lowered to 5 °C. Iodomethane-d3 (2.5 g, 16.94 mmol) was dissolved in 5 ml of DCM and added dropwise to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 2 h. Saturated aqueous ammonium chloride was added to quench the reaction. 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] For the preparation process of Intermediate 39, refer to the preparation of Intermediate 36, with the difference that Intermediate 11 was 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 1.5 h. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solution. It was concentrated under reduced pressure to obtain an intermediate, which was directly used for the next reaction.

[0201] The intermediate from the previous step (4 g, 6.67 mmol) was dissolved in DCM (50 mL), and TFA (10.5 mL, 13.5 mmol) was added. The reaction 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 11 (2.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (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-d3)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] For the preparation process of Intermediate 40, refer to the preparation of Intermediate 36. The difference is that Intermediate 11 is replaced with Intermediate 38, and Intermediate 32 is replaced with 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 1.5 hr. Diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain an intermediate, which was directly used in the next step of the reaction.

[0210] The above intermediate (4 g, 6.67 mmol) was dissolved in DCM (50 mL), and TFA (10.5 mL, 13.5 mmol) was added. The reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. Purified by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 12 (3.0 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (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-(methylthio)phenyl)-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] For the preparation process of Intermediate 41, refer to the preparation of Intermediate 36. The difference is that Intermediate 11 is replaced with 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was then raised to room temperature, and the mixture was stirred for 1.5 h. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. It was concentrated under reduced pressure to obtain an intermediate, which was directly used in the next step.

[0219] The above intermediate (4.8 g, 6.67 mmol) was dissolved in DCM (50 mL), and TFA (10.5 mL, 13.5 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 13 (3.3 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (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 / z 506.1 [M + 1] + 。

[0220] Example 14.

[0221] (2R,3S,4S,5R)-3-(3,4-Difluoro-2-(methylthio)phenyl)-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] For the preparation process of Intermediate 42, refer to the preparation of Intermediate 36. The difference is that Intermediate 11 is replaced with Intermediate 17, and Intermediate 32 is replaced with 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C. TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the mixture was stirred for 1.5 h. Diluted with EtOAc and washed with saturated aqueous sodium bicarbonate 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 from the previous step (2.4 g, 3.4 mmol) was dissolved in DCM (30 mL), and TFA (5.3 mL, 6.8 mmol) was added. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Purified by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 14 (1.6 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (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). The temperature was lowered to 0 °C, and boron tribromide (5 mL, 1 M solution in DCM, 5 mmol) was added. The mixture 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. Purification by flash 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 K2CO3 (0.32 g, 2.3 mmol) were added. The reaction solution was stirred at room temperature for 1 hr and then at 60 °C for 12 hr. It was filtered and concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase: 0% to 100% MeCN / water containing 0.1% ammonia) gave Intermediate 44 (0.6 g).

[0238] Preparation of Compound 15:

[0239] Intermediate 44 (4.4 g, 5.9 mmol) was dissolved in 50 mL of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the mixture was stirred for 1.5 hr. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and saturated sodium chloride solutions. Concentration under reduced pressure gave an intermediate, which was directly used in the next step.

[0240] The intermediate from the previous step (2.2 g, 3.4 mmol) was dissolved in DCM (30 mL), and TFA (5.3 mL, 6.8 mmol) was added. The mixture was stirred at room temperature for 2 hr and then concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase: 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 15 (1.6 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (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] For the preparation process of Intermediate 45, refer to the preparation of Intermediate 43. The difference is that Intermediate 36 is replaced with Intermediate 37 to obtain Intermediate 45.

[0248] Preparation of Intermediate 46:

[0249] For the preparation process of Intermediate 46, refer to the preparation of Intermediate 44. The difference is that Intermediate 43 is replaced with 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 1.5 hr. Diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. Concentrated under reduced pressure to obtain an intermediate, which was directly used in the next step of the reaction.

[0252] The above intermediate (2.2 g, 3.4 mmol) was dissolved in DCM (30 mL), TFA (5.3 mL, 6.8 mmol) was added, and the reaction was stirred at room temperature for 2 hours and concentrated under reduced pressure. Purified by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) to obtain Compound 16 (1.7 g). 11H NMR (400 MHz, DMSO-d6) δ 10.43 (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, 1H), 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 of DMF, and anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added. The mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solvent was removed under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 17 (1.6 g).

[0259] 1 1H NMR (400 MHz, DMSO-d6) δ 10.37 (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 / z 546.2 [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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solvent was evaporated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase: 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 18 (1.7 g).

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (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 / z 546.2 [M + 1] + 。

[0267] Example 19

[0268] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)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 of DMF, and anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added. The mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2 N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solution 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 19 (1.5 g).

[0273] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (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-d3)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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. 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-d6) δ 10.40 (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-(methylthio)phenyl)-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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. 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). 11H NMR (400 MHz, DMSO-d6) δ 10.41 (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-(methylthio)phenyl)-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 of DMF, and anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added. The mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solvent was removed under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase: 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 22 (1.6 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.42 (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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solvent was evaporated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave Compound 23 (1.8 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.47 (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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solvent was concentrated under reduced pressure. Purification by reverse-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave compound 24 (1.6 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (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-methylsulfinylphenyl)-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 of THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. A NaHCO3 solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. Purification by flash silica gel column chromatography with gradient elution of methanol-dichloromethane gave 0.4 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-methylsulfinylphenyl)-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] For the preparation process of Compound 26, refer to the preparation of Compound 25. The difference is that Compound 1 is replaced with 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 of THF, cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added, and the mixture was stirred at room temperature for 1.5 h. Then, NaHCO3 solution was added, and the mixture was extracted with DCM and dried over anhydrous sodium sulfate. It was purified 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] For the preparation process of Compound 28, refer to the preparation of Compound 27. The difference is that Compound 3 is replaced with 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-methylsulfinylphenyl)-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 of THF, and cyanuric chloride (0.15 g, 0.8 mmol) and H2O2 (0.2 g, 35%, 2 mmol) were added. The mixture was stirred at room temperature for 1.5 h, then a NaHCO3 solution was added, and it was extracted with DCM and dried over anhydrous sodium sulfate. It was purified by flash silica gel column chromatography with gradient elution of methanol-dichloromethane to obtain 0.45 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-methylsulfinylphenyl)-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] For the preparation process of Compound 30, refer to the preparation of Compound 29. The difference is that Compound 13 is replaced with 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] For the preparation process of Intermediate 47, refer to the preparation of Intermediate 44. The difference is 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C. TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution, and the temperature was raised to room temperature. The mixture was stirred for 1.5 h. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. It was concentrated under reduced pressure to obtain an intermediate, which was directly used in the next step.

[0349] The above intermediate (2.3 g, 3.4 mmol) was dissolved in DCM (30 mL), and 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 31 (1.66 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (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] For the preparation process of Intermediate 48, refer to the preparation of Intermediate 44. The difference is 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 of THF. Under a nitrogen atmosphere, the temperature was lowered to 5 °C, and TBAF (12.6 mL, 1 M in THF, 12.6 mmol) was added to the reaction solution. The temperature was raised to room temperature, and the reaction was stirred for 1.5 h. It was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. It was concentrated under reduced pressure to obtain an intermediate, which was directly used in the next step of the reaction.

[0358] The above intermediate (2.3 g, 3.4 mmol) was dissolved in DCM (30 mL), and TFA (5.3 mL, 6.8 mmol) was added. The reaction 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 32 (1.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. The solution 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 33 (1.8 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.43 (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 / z 602.3 [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 of DMF, anhydrous potassium carbonate (0.47 g, 3.37 mmol) was added, and the mixture was stirred at room temperature. tert-Butyl bromide (0.84 g, 6.13 mmol) was dissolved in 5 ml of DCM and slowly added dropwise to the reaction solution. The mixture was stirred at room temperature for 8 h, then heated to 50 °C and stirred for 2 h. The reaction was quenched with 2N hydrochloric acid, diluted with DCM, extracted, and washed with saturated sodium chloride solution. It was concentrated under reduced pressure. Purification by reversed-phase preparative HPLC (mobile phase 0% to 100% MeCN / water containing 0.1% ammonia) gave compound 34 (1.8 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (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 / z 602.3 [M+1] + 。

[0371] Example 35.

[0372] (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methylsulfinylphenyl)-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] For the preparation process of compound 35, refer to the preparation of compound 29, with the difference that compound 13 was 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-(trifluoroacetamido)-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 of methanol, and triethylamine (3 ml, 21.5 mmol) was added. The mixture was stirred at room temperature. Then ethyl trifluoroacetate (1.3 g, 9 mmol) was added, and the reaction solution was heated to 50 °C and stirred for 15 h. The reaction was monitored by TLC until completion. The organic solvent was removed by evaporation under reduced pressure. Water was added, and the pH was adjusted to 3 - 4 with hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution. The organic layer was separated 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 36 (1.9 g). 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (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-(trifluoroacetamido)-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 of methanol, and triethylamine (3 ml, 21.5 mmol) was added. The mixture was stirred at room temperature. Then ethyl trifluoroacetate (1.3 g, 9 mmol) was added, and the reaction solution was heated to 50 °C and stirred for 15 h. The reaction was monitored by TLC until completion. 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, and the organic layer was washed with saturated sodium chloride solution. The organic layer was separated 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 37 (1.7 g). 1 1H NMR (400 MHz, DMSO-d6) δ 10.45 (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 was the control compound CP1.

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

[0391] 。

[0392] Effect Example 1 Determination of Nav1.8 inhibitory activity and ion channel selectivity

[0393] In vitro test the effects of the compounds on Nav1.8 and Nav1.4, Nav1.5 ion channels. Express Nav1.8 and Nav1.4, Nav1.5 ion channels on HEK293 cells. After the Nav1.8 and Nav1.4, Nav1.5 currents were stabilized, compare the magnitudes of the corresponding ion channel currents before and after the application of the compounds to obtain the inhibitory activity and selectivity of the compounds for the Nav1.8 ion channel.

[0394] 1. Experimental instruments

[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 (Axoninstruments)

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

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

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

[0400] 6) Microelectrode glass capillary: B12024F

[0401] 2. Experimental procedures

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

[0403] All test compounds and control compounds CP or CP1 were dissolved in dimethyl sulfoxide (DMSO), and the stock solution concentration was 10 mM. The compound solution for Nav1.8 inhibition activity testing contained 1 μM tetrodotoxin (TTX, Affix Scientific). It was diluted with extracellular fluid and used immediately, and was prepared into the required concentration according to the serial dilution method.

[0404] Preparation of intracellular and extracellular solutions:

[0405] Intracellular fluid (mM): Aspartic acid, 140; , 2; EGTA, 11; HEPES, 10; pH 7.2 (titrated with CsOH).

[0406] Extracellular fluid (mM): NaCl, 137; KCl, 4; , 1.8; , 1; HEPES, 10; Glucose, 10; pH 7.4 (titrated with NaOH).

[0407] 2.2 Electrophysiology

[0408] 1) After the compound was prepared into a solution with a specified concentration, the drug solutions were added to each tube in ascending order of concentration, and each tube was labeled.

[0409] 2) The cells were transferred to the perfusion chamber, positive pressure was applied inside the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the aspiration device was adjusted to the three-way state, and then negative pressure was applied to the electrode to form a high-resistance seal with the cell. Negative pressure was continuously applied to rupture the cell membrane and form a current path.

[0410] 3) After the current of cell membrane rupture is stable, perfusions with different concentrations are carried out in sequence. If the current is stable for at least one minute, the next concentration can be used for perfusion. The perfusion time for each concentration does not exceed five minutes.

[0411] 4) Wash the perfusion chamber. Rinse it in the order of decreasing drug solution concentration, with each concentration of the drug solution rinsed for 20 s. Finally, rinse it with extracellular fluid for 1 min.

[0412] 3. Pilot-scale scheme (resting state)

[0413] Clamp the cell at -80 mV, and then depolarize it to 10 mV with a 10-ms square wave to obtain Nav1.8, Nav1.4, and Nav1.5 currents. This procedure is repeated every 5 s. Detect the maximum current induced by the square wave. After it is stable, perfuse the test compound. When the reaction is stable, calculate the blocking intensity.

[0414] 4. Data analysis

[0415] Data acquisition and analysis will be performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stability means that the current changes within a limited range over time. The magnitude of the current after stability is used to calculate the effect of the compound at this concentration.

[0416] The inhibitory activities of the example compounds against Nav1.8, Nav1.4, and Nav1.5 are determined through the above tests, and the measured IC 50 values 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 ). The Nav1.8 IC 50 values of the example compounds are all less than 10 nM. The experimental results are shown in Table 1.

[0417] Table 1: IC 50 of the inhibitory effect of the example compounds on Nav1.8 channel activity and the therapeutic index SI

[0418]

[0419] From the above results, it can be seen that all the tested compounds showed relatively high inhibitory effects on Nav1.8 channel activity and had relatively high selectivity indices (therapeutic indices). In particular, the inhibitory effects of compounds 1, 11, 17, 36, and 37 on Nav1.8 were more than 3 times that of the control compound CP1; the inhibitory effects of compounds 1, 9, 11, 13, 17, 19, 23, 36, and 37 on Nav1.8 were more than 3 times that of the control compound CP. The Nav1.4 therapeutic indices of compounds 1, 11, 36, and 37 were more than 5 times greater than that of the control compound CP1; the Nav1.4 therapeutic indices of compounds 1, 9, 11, 13, 14, 17, 19, 23, 36, and 37 were more than 5 times greater than that of the control compound CP. The Nav1.5 therapeutic indices of compounds 1, 11, 13, 17, 36, and 37 were more than 5 times greater than that of the control compound CP1. Nav1.5 is expressed in cardiomyocytes, and Nav1.4 is expressed in skeletal muscle cells. The Nav1.5 and Nav1.4 ion channels do not participate in the processes of inflammatory pain and neuropathic pain, but can cause adverse reactions. Therefore, the compounds of the examples can be prepared into drugs for preventing / treating the symptoms / diseases of 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] Using SD rats as the test animals, the LC / MS / MS method was used to measure the drug concentrations in the plasma of SD rats at different times after intragastric administration of the compounds of the examples. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0422] 1) Test drugs

[0423] Compound 1, Compound 11, and Compound 19 of the examples, and the control compound CP.

[0424] 2) Test animals

[0425] 16 SD rats, 4 in each group, with an equal number of males and females. After fasting overnight without water restriction, they were intragastrically administered drugs respectively.

[0426] 3) Drug preparation

[0427] Weighed a certain amount of the compounds of the examples respectively, and added the administration lysate: 5% DMSO + 10% Solutol + 85% normal saline to prepare a homogeneous solution of 0.2 mg / mL.

[0428] 4) Drug administration

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

[0430] 5) Operation

[0431] Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored at -20 °C for further measurement. The blood collection to centrifugation process was carried out under ice bath conditions. Food was given 2 hours after drug administration.

[0432] Determine the content of the compound to be measured in the plasma of SD rats after administration of different concentrations of the drug: Take the plasma samples of SD rats at each time point after drug administration, dilute them 10 times with an acetonitrile solution containing an internal standard, vortex mix, and centrifuge at 3700 rpm for 10 minutes. After mixing the supernatant with water at a ratio of 1:1, 0.5 μL of the supernatant was taken for LC / MS / MS analysis.

[0433] 6) Results of pharmacokinetic parameters

[0434] Table 2: Pharmacokinetic parameters of the compound pair in Example in SD rats

[0435]

[0436] The above experiments found that there were significant male-female differences in the metabolic parameters of the control compound, while there were no obvious male-female differences in Compound 1, Compound 11, and Compound 19. From the above results, it can be seen that all the tested compounds had better exposure levels than the control compound. In particular, the exposure of Compound 1 C max was 1.9 times that of the control compound, and the AUC of Compound 1 0-t was 2.3 times that of the control compound. The experimental results showed that the compounds in the examples had better metabolic parameters, and there were no gender differences in the metabolic parameters, so they had a wider range of clinical use and higher drug safety.

[0437] Effect Example 3: Pharmacodynamic evaluation of the mouse incision pain model

[0438] Using mice as the test animals, after administering the compounds in the examples by gavage, the pharmacodynamic effects of the compounds in the present disclosure on the mouse incision pain model were studied to evaluate their in vivo pharmacodynamic effects.

[0439] 1) Modeling:

[0440] Grouping: The test animals were BALB / c mice, with 8 mice in each group, half male and half female. Before modeling, according to the basic value of PWT, 8 abnormal animals were excluded, and 8 animals were randomly selected as the sham operation group, and 8 animals in each administration group were subjected to surgical modeling. After the operation, the animals were re-grouped according to the pain threshold (PWT) before drug administration.

[0441] Isoflurane anesthesia was performed. At about 0.2 cm distal to the tibio-talar joint on the plantar surface of the left hind paw, a longitudinal skin incision 0.5 cm long was made with a blade extending towards the toes; the plantar muscles were dissected, slightly elevated, and then incised longitudinally, taking care not to damage the origins and insertions of the muscles. The incision was sutured discontinuously horizontally with 5-0 nylon thread (2 stitches), which served as the model group and the pharmacodynamic 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) Administration method and frequency:

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

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

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

[0447] 4) Measurement of mechanical pain threshold: The mechanical pain threshold before modeling was measured before modeling; the mechanical pain threshold before drug administration was measured 2.5 h after modeling. After the measurement was completed, the drug was administered orally, and the mechanical pain threshold was measured 2 h after drug administration. The measurement position was inside the surgical incision. 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 out in GraphPad Prism 6.0 and analyzed using One-way ANOVA. The Tukey method was selected for the significance test of the differences between groups.

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

[0450]

[0451] The above results show that the example compounds all exhibited excellent pain inhibitory effects. And the pain inhibitory effect of the example compounds was better than that of the control compound CP1. The experimental results show that the example compounds have better analgesic efficacy, lower drug dosage, and lower cardiac side effects compared with the existing clinical treatment methods.

[0452] Effect Example 4 hERG test

[0453] To evaluate the risk of electrocardiogram QT interval prolongation, HEK293 cells expressing the human ether-a-go-go related gene (hERG) channels were used to study the effect on the delayed rectifier K + current (I Kr ) which plays an important role in ventricular repolarization.

[0454] Three concentrations of the test article working solutions were prepared: 0.3, 3, and 30 μM. Visual inspection showed no precipitation. The test was conducted at 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 an automated patch clamp system, after holding the cells at a membrane potential of -80 mV by whole-cell patch clamp method, a depolarizing stimulus of +50 mV for 2 seconds was given, and then a repolarizing stimulus of -50 mV for 2 seconds was further given to evoke I Kr . After the generated current was stabilized, the extracellular fluid (NaCl: 137 mmol / L, KCl: 4 mmol / L, CaCl2: 1.8 mmol / L, MgCl2 - 6H2O: 1 mmol / L, glucose: 10 mmol / L, HEPES: 10 mmol / L, pH 7.4) dissolved with the test substance at the target concentration was applied to the cells at room temperature for 10 minutes. From the obtained I Kr , the absolute value of the maximum tail current was measured using analysis software based on the current value at the resting membrane potential. Further, the inhibition rate relative to the maximum tail current before the application of the test substance was calculated and compared with the medium application group (0.1% DMSO solution) to evaluate the effect of the test substance on I Kr .

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

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

[0457] Table 4 Mean current inhibition rate of the compounds in the examples under the conditions of 0.3 - 30 μM

[0458]

[0459] From the inhibition rate results in Table 4, it can be seen that the inhibition rates of the compounds 1, 11, 19, and 36 in the examples were significantly lower than that of the control compound CP1. In particular, the inhibition rate of 11 was less than half of that of CP1. The test results indicate that the risk of electrocardiogram QT interval prolongation of the compounds in the examples is much smaller than that of the control compound CP1, that is, the compounds in the examples 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 and can be embodied in other specific forms without departing from its essential attributes. Therefore, it is expected that all aspects are illustrative rather than restrictive, that the embodiments are to be construed with reference to the appended claims rather than the foregoing embodiments, that the citations are to the appended claims rather than the foregoing examples, and that all variations falling within the meaning and scope of the equivalence of the claims are thus expected 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 case of inconsistencies, the present disclosure, including the definitions, will prevail.

Claims

1. A compound, stereoisomer or 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 compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or (ii) a pharmaceutically acceptable excipient.

3. Use of the compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 2 in the preparation of a medicament for the treatment, prevention or alleviation of voltage-gated sodium channel-related diseases.

4. The use according to claim 3, wherein the voltage-gated sodium channel-related diseases include: Chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, multiple sclerosis, Charcot-Marie-Tooth disease, incontinence and arrhythmia.

5. The use according to claim 4, wherein the neuropathic pain includes one or more of postherpetic 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 crush 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, trigeminal autonomic cephalgia.

6. The use according to claim 4, wherein the musculoskeletal pain includes one or more of osteoarthritis pain, back pain, cold pain, burn pain, toothache.

7. The use according to claim 4, wherein the inflammatory pain includes rheumatoid arthritis pain and / or vulvodynia.

8. The use according to claim 4, wherein the primary pain includes fibromyalgia.

Images