A tetrahydrofuran derivative and use thereof

Abstract

The application belongs to the technical field of medicine, and specifically discloses a compound shown in formula I and application thereof. The compound has the structure shown in formula I, wherein definitions of each group and substituent group are described in the description. The compound provided by the application can be used as a Nav1.8 inhibitor, and can be used in preparation of a medicine for treating, relieving or preventing pain.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and specifically discloses a tetrahydrofuran derivative compound represented by Formula I, as well as its applications. Background Technology

[0002] Pain originates from nociceptors in the peripheral nervous system, which are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. These receptors convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing 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 depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and alleviate pain.

[0003] Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on the cell membrane, composed of α and β subunits. The α subunit is a functional unit, consisting of four homologous transmembrane domains, each containing six transmembrane hydrophobic α-helices (S1-S6). S1-S4 constitute a voltage receptor, capable of regulating the hydrophilicity of the sodium ion channel between S5 and S6, inducing cell depolarization or hyperpolarization, and completing transmembrane signal transmission. In humans, there are nine different subtypes of the α subunit, named Nav1.1–1.9. Their aberrant inactivation or activation is associated with various neurological, cardiovascular, and muscular diseases, among which the subtypes mainly associated with pain are Nav1.3, Nav1.7, Nav1.8, and Nav1.9. Nav1.7 is present in sympathetic ganglion neurons and peripheral sensory neurons. Nav1.8 and Nav1.9 are expressed only in peripheral sensory neurons. Abnormal activation of these channels can lead to analgesia or abnormal pain, providing potential targets for non-addictive analgesic mechanisms. Nav1.8, a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons, plays a crucial role in pain signal transduction in the peripheral nervous system and is a major selective target for pain treatment. Because Nav1.8 is mainly distributed in pain-sensing neurons, the use of selective Nav1.8 inhibitors is unlikely to cause the adverse reactions common to non-selective Nav1.8 inhibitors. More importantly, Nav1.8 does not participate in central nervous system-related activities, so Nav1.8 inhibitors do not pose addiction problems similar to opioids and do not affect motor function.

[0004] Clinically used Nav inhibitors, lacking subtype selectivity, inhibit sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application. Nav1.8, however, is distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, superior pharmacokinetic properties, faster onset of action, longer-lasting analgesic effect, and fewer cardiotoxic side effects. Summary of the Invention

[0005] The object of this invention is to develop a compound of Formula I, namely a tetrahydrofuran derivative, its tautomer, stereoisomer, pharmaceutically acceptable salt or prodrug, for use as a Nav1.8 inhibitor, for use in the preparation of medicaments for the treatment, relief or prevention of pain.

[0006] Specifically, in a first aspect, the present invention provides a compound, said compound being a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: I In Formula I: R1, R2, and R4 are each independently selected from H, D, fluorine, methyl, and trifluoromethyl, and R1 and R2 are not both H; R3 is selected from deuterated methyl, methyl, trifluoromethyl, and trifluoroethyl.

[0007] Preferably, in Formula I, R1 is selected from D, fluorine, and trifluoromethyl; R2 is selected from D, fluorine, and methyl; and R3 is selected from deuterated methyl.

[0008] More preferably, in Formula I, R1 is selected from D and trifluoromethyl; R2 is selected from D and fluorine.

[0009] As one embodiment, the compound shown in Formula I is selected from compounds represented by any of the following structural formulas:

[0010]

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of the compound of formula I of the present invention, and a pharmaceutically acceptable carrier.

[0012] Thirdly, the present invention provides the use of the compound of Formula I or the pharmaceutical composition of the present invention in the preparation of a medicament, specifically, the use of the medicament in the preparation of a drug that inhibits voltage-gated sodium ion channels and / or in the preparation of a drug for treating, alleviating or preventing diseases related to voltage-gated sodium ion channels.

[0013] Among them, the voltage-gated sodium ion channel is Nav1.8.

[0014] The aforementioned use of voltage-gated sodium ion channels in diseases related to pain is specifically for use in pain-related conditions.

[0015] The pain-related diseases mentioned are selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and primary pain.

[0016] The neuropathic pain mentioned therein is selected from postherpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuropathic pain, nerve compression injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, neuropathic pain caused by drug therapy, neuropathic pain caused by cancer chemotherapy, neuropathic pain caused by antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy, or trigeminal autonomic headache.

[0017] The inflammatory pain mentioned above is selected from rheumatoid arthritis pain.

[0018] The musculoskeletal pain mentioned above is selected from osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0019] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0020] Through extensive and in-depth research, the inventors unexpectedly discovered a class of compounds with excellent therapeutic, alleviating, or preventative properties for painful diseases. Based on this discovery, the present invention was completed.

[0021] the term

[0022] Unless otherwise specified, the following terms used in this application (including the specification and claims) have the definitions given below.

[0023] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0024] "Alkyl (alone or as part of other groups)" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of 1 to 12 carbon atoms, composed solely of carbon and hydrogen atoms. Alkyl groups are preferably C1-C6 alkyl groups (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. In this application, alkyl is also intended to include substituted alkyl groups, i.e., one or more positions of an alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by the same or different halogens. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0025] "alkylene" refers to the divalent group of an alkyl group, such as -CH2-, -CH2CH2- and -CH2CH2CH2-.

[0026] "Alkoxy group (alone or as part of other groups)" refers to an alkyl group having an oxygen group attached thereto, having an alkyl O- structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy group" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0027] "Thioalkyl" refers to an alkyl group in which the carbon atom is replaced by S, S(O) or S(O)2.

[0028] "Alkenyl (alone or as part of other groups)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In this invention, "C2-C6 alkenyl" refers to an alkenyl group containing 2, 3, 4, 5, or 6 carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In this invention, alkenyl groups include substituted alkenyl groups.

[0029] "Alkenyl" refers to an alkenyl group with two connection points. For example, "vinylene" represents the group -CH=CH-. Alkenyl groups can also be in an unsubstituted form or in a substituted form with one or more substituents.

[0030] "Alynyl group (alone or as part of other groups)" refers to a straight-chain or branched hydrocarbon chain containing two or more carbon atoms and characterized by having one or more triple bonds, typically having 2 to 20 carbon atoms. In this invention, "C2-6 alkynyl group" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alynyl groups include, but are not limited to, ethynyl, propynyl, and 3-hexynyl. One of the carbon atoms in the triple bond may optionally be the linking point for an alkynyl substituent. In this invention, alkynyl groups also include substituted alkynyl groups.

[0031] "Imyynyl" refers to an alkynyl group with two connection points. For example, "ethynyl" indicates the group: -C≡C-. Imyynyl can also be in an unsubstituted form or a substituted form with one or more substituents.

[0032] "Aliphatic groups" refer to straight-chain, branched, or cyclic hydrocarbon groups, including saturated and unsaturated groups such as alkyl, alkenyl, and alkynyl groups.

[0033] "Aromatic ring system" refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0034] "Aryl (alone or as part of other groups)" refers to a monovalent group in an aromatic ring system. Representative aryl groups include phalloaromatic systems such as phenyl, naphthyl, and anthracene; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimide, naphthylimide, or tetrahydronaphthyl, etc. In this invention, the aryl group is preferably a C6-C12 aryl group. In this invention, the aryl group is also intended to include substituted aryl groups.

[0035] "Arylalkyl" or "arylalkyl group" refers to an alkyl moiety in which one or more hydrogen atoms are replaced by aryl groups. Arylalkyl groups include groups in which one or more hydrogen atoms are replaced by aryl groups, and aryl and alkyl groups are defined as described above. Examples of "arylalkyl" or "arylalkyl group" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, diphenylmethyl, and triphenylmethyl, etc.

[0036] "Aryloxy group" refers to -O-(aryl), where the aryl moiety is as defined in this article.

[0037] "Heteroalkyl" refers to a substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given; for example, C1-C6 heteroalkyl refers to the number of carbon atoms in the chain, ranging from 1 to 6 carbon atoms. For example, the -CH2OCH2CH3 group is called a "C3" heteroalkyl. Connection to the rest of the molecule can be via heteroatoms or carbon atoms in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.

[0038] A “carbocyclic system” refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which each ring is fully saturated or contains one or more unsaturated units, but none of the rings are aromatic.

[0039] "Carbocyclic group" refers to a monovalent group in a carbocyclic system. Examples include cycloalkyl (cyclopentyl, cyclobutyl, cyclopropyl, cyclohexyl, etc.) and cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, etc.).

[0040] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring, having 3-12, preferably 3-10, and more preferably 3-8 ring atoms. The cycloalkyl group may optionally be substituted with one or more substituents, wherein each substituent is independently a hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0041] “Cycloalkoxy” refers to a group of the formula -OR, where R is a cycloalkyl group as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. “Cycloalkylalkyl” refers to a cycloalkyl group where the cycloalkyl and alkyl groups are -(cycloalkyl)-alkyl groups as disclosed herein. “Cycloalkylalkyl” is bonded to the parent molecule structure via the cycloalkyl group.

[0042] A "heteroaromatic ring system" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (6-12-membered), or polycyclic system in which at least one ring is aromatic and contains at least one heteroatom (e.g., N, O, or S); and the other rings are not heterocyclic groups (as defined below). In some cases, the aromatic ring containing a heteroatom contains 1, 2, 3, or 4 ring heteroatoms. At least one ring is heteroaromatic, and the remaining rings may be saturated, partially unsaturated, or fully unsaturated.

[0043] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8- or 10-membered), or tricyclic group with 5 to 12 ring atoms, containing at least one aromatic ring with 1, 2, or 3 heteroatoms selected from N, O, or S, and the remaining ring atoms being C. It should be clearly stated that the heteroaryl group's bonding point should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazole groups, azole group, iso azole group, thiazolyl group, isothiazol group, Diazolyl, thiadiazolyl, pyrazinyl, thiopheneyl, furanyl, pyranyl, pyridyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiopheneyl, benzothiopheneyl, benzoimidazolyl, benzo[] azole, benzo[ Diazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indoleyl, isoyindolyl, triazolyl, triazinyl, quinoxalinyl, purineyl, quinazolinyl, quinazinyl, naphthidyl, pteridyl, carbazoleyl, aza basalt, diazoxide Compounds such as acridine and aryl. Heteroaryl refers to a heteroaryl group having two linkage sites.

[0044] A "heterocyclic system" refers to a monocyclic, bicyclic, or polycyclic system in which at least one ring is saturated or partially unsaturated (but not aromatic) and contains at least one heteroatom. Heterocyclic systems can be attached to side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can optionally be substituted.

[0045] "Heterocyclic group" refers to a monovalent group in a heterocyclic system, usually a stable monocyclic (e.g., 3-8 ternary, i.e., 3, 4, 5, 6, 7 or 8 ternary), bicyclic (e.g., 5-12 ternary, i.e., 5, 6, 7, 8, 9, 10, 11 or 12 ternary), or polycyclic (e.g., 7-14 ternary, i.e., 7, 8, 9, 10, 11, 12, 13 or 14 ternary), including fused rings, spirocyclic and / or bridged ring structures, which are saturated or partially unsaturated, and contain a carbon atom and one, two, three or four heteroatoms independently selected from N, O and S. Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolylalkyl, pyrrolidoneyl, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolylalkyl, piperazineyl, dioxalyl, dioxopentyl, diachexenyl, oxachexenyl, thiaachexenyl, morpholinyl, and quininecycloyl; (2) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2 3,4-Tetrahydro-2,6-diazanaphthalene. A heterocyclic group refers to a heterocyclic group having two linking sites. In this invention, the heterocyclic group is preferably bicyclic, with one ring being a heteroaryl group, and linked to other parts of the general formula through the heteroaryl group. In this invention, the heterocyclic group is preferably a 5-6 member monocyclic heterocyclic group or an 8-10 member bicyclic heterocyclic group.

[0046] "Heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group, wherein the definitions of heterocyclic group and alkyl group are as described above.

[0047] "Alkylamine group" refers to a group having an alkyl-NR- structure, where R is H, or an alkyl, cycloalkyl, aryl, heteroaryl, etc. as described above.

[0048] "Cycloalkylamine" refers to the formula -NR a R b Group, wherein R a H, alkyl as defined herein, or cycloalkyl as defined herein, R b cycloalkyl as defined herein, or R a and R b Together with the N atom it is attached to, it forms a 3-10 member N-containing monocyclic or bicyclic heterocyclic group, such as a tetrahydropyrrole group. As used in this invention, a C3-C8 cycloalkanamine group refers to an amine group containing 3-8 carbon atoms.

[0049] In this invention, "ester group" refers to having a -C(O)-OR or RC(O)-O- structure, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, as defined above.

[0050] In this invention, the term "amide group" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in the dialkylamine segment.

[0051] In this invention, the term "sulfonamide group" refers to a group having the structure -SO2NRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in the dialkylamine segment.

[0052] "Ketocarbonyl" refers to RC (=O)-, where R is an alkyl, cycloalkyl, etc., as mentioned above.

[0053] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0054] In this invention, each of the above-mentioned groups such as alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cyclohexaalkyl, alkenyl, alkyne, heterocycle, and heterocyclic can be substituted or unsubstituted.

[0055] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where Ra R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic, or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic ring, can be optionally substituted. Such substituents include (but are not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea, etc.

[0056] "Cyano" refers to the -CN group.

[0057] "Nitro" refers to -NO2.

[0058] "Hydroxy group" refers to -OH.

[0059] "Amino" refers to -NH2 or RNH-, where R is a ketone carbonyl, sulfonyl, sulfonamide, Ra-C(=O)-, RaRbN-C(=O)-, etc., where Ra and Rb are alkyl, cycloalkyl, aryl or heteroaryl, etc.

[0060] "Halogen (halogenated)" refers to any halogen group, such as -F, -Cl, -Br or -I.

[0061] "Deuterated compounds" refer to compounds in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0062] In this invention, the term "multiple" independently refers to 2, 3, 4, or 5.

[0063] The structural formula of the carbamate group is -NH-C(=O)-OR, where R is an alkyl, aryl, heteroaryl, etc.

[0064] Active ingredients

[0065] As used herein, the terms “compound of the invention” or “active ingredient of the invention” are used interchangeably to refer to a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (such as a deuterated compound), or prodrug thereof. The term also includes racemic mixtures and optical isomers.

[0066] The compound of formula I has the following structure: I The groups are defined above.

[0067] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0068] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0069] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0070] The prodrugs and solvates (or solvents) of the compounds in this invention are also within the scope of this invention.

[0071] The term "prodrug" here refers to a compound that, in the course of treating a related disease, undergoes a metabolic or chemical transformation to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0072] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0073] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0074] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as described in the text. Such “very pure” compounds of this invention are also included as part of this invention.

[0075] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixture, pure, or very pure form. The definition of the compounds of this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0076] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0077] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0078] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0079] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0080] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, or 14C, are relatively easy to prepare and detect, making them the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0081] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0082] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective for such a long period of time, and is used here for the purposes described above.

[0083] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0084] In another preferred embodiment, in the compound, any one of the groups corresponds to the group in the specific compound.

[0085] Preparation method

[0086] The following schemes and examples describe methods for preparing compounds of formula I. Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing the reaction scheme may be altered to promote the reaction or avoid unwanted byproducts.

[0087] The preparation method of the compound of Formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0088] Typically, in the preparation process, the reactions are carried out under inert gas protection and in appropriate solvents.

[0089] Pharmaceutical Compositions and Administration

[0090] The pharmaceutical composition described in this invention is used for the prevention and / or treatment of painful diseases.

[0091] Compounds of Formula I can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of Formula I is taken simultaneously or subsequently. When a compound of Formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and a compound of Formula I is preferred. Drug combination also includes taking a compound of Formula I with one or more other known drugs during overlapping time periods. When a compound of Formula I is used in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than the dosage of either drug alone.

[0092] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release or nano-formulations.

[0093] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0094] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0095] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0096] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0097] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0098] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0099] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0100] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0101] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0102] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0103] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0104] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0105] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound of general formula I or its crystal form, a pharmaceutically acceptable salt, hydrate or solvate of the present invention, thereby forming a pharmaceutical composition.

[0106] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound of formula I described herein, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition described herein for the treatment or prevention or relief of pain.

[0107] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0108] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0109] The technical solution of the present invention will be further described below, but the scope of protection of the present invention is not limited thereto.

[0110] Example 1

[0111] The compound structural formula provided in this embodiment is as follows: PY-01.

[0112] The synthetic route for the above compound PY-01 is as follows: .

[0113] Synthesis steps: 1. Synthesis of Compound 2

[0114] Compound 1 (3.27 g, 0.01 mol) was dissolved in anhydrous tetrahydrofuran, then cooled to -10 °C, and sodium deuterated borohydride (0.41 g, 0.01 mol) was added in portions. The reaction was carried out for 3 hours, and then 0.1 mL of deuterated methanol was added dropwise while maintaining the temperature at -10 °C, followed by 1 mL of water. Ethyl acetate was then added, and the mixture was washed with saturated brine. The organic phase was collected, dried, and evaporated to dryness. The solution was then passed through a column chromatography column to obtain 3.1 g of the product.

[0115] Compounds 3-6 were further prepared from compound 2, and the experimental procedures for synthesizing the target compound of Example 1 were carried out according to the method disclosed in patent (CN117794921A). Finally, 560 mg of the target compound (PY-01) of Example 1 was obtained.

[0116] Example 2

[0117] The compound structural formula provided in this embodiment is as follows: PY-16.

[0118] The synthetic route for the above compound PY-16 is as follows: .

[0119] Synthesis steps:

[0120] 1. Synthesis of Compound 7

[0121] Compound 1 (3.27 g, 0.01 mol) was dissolved in anhydrous tetrahydrofuran, then cooled to -10°C, and methyl magnesium chloride (10 mL, 0.01 mol, 1.0 mol / L) was added dropwise. The reaction was carried out for 2 hours, then the temperature was maintained at -10°C, and 0.1 mL of methanol was added dropwise, followed by 1 mL of water. Ethyl acetate was then added, and the mixture was washed with saturated brine. The organic phase was collected, dried, and evaporated to dryness. The solution was then passed through a column chromatography to give 1.92 g of the product, which was compound 7.

[0122] Compounds 8-11 were further prepared from compound 7, and 176 mg of the target compound (PY-16) of Example 2 was finally synthesized.

[0123] The listed compounds PY-01 to PY-24 were specifically synthesized in accordance with the synthesis methods disclosed in Examples 1 and 2 and Patent (CN117794921A).

[0124] Experimental Example 1: In vitro testing

[0125] The compounds prepared in this invention were subjected to in vitro tests. The in vitro test examples investigated the effects of the compounds on the Nav1.8, Nav1.4, and Nav1.6 ion channels. Nav1.8 and Nav1.4 / Nav1.6 ion channels were expressed in HEK293 cells. After the Nav1.8 and Nav1.4 / Nav1.6 currents stabilized, the magnitudes of the corresponding ion channel currents before and after compound application were compared to obtain the inhibitory activity and selectivity of the compounds on the Nav1.8 ion channel.

[0126] 1. Experimental Apparatus 1) Patch-clamp amplifier: patch clamp PC 505B (WARNER instruments) / MultiClamp 700A (Axoninstrument); 2) Digital-to-analog converter: Digidata1 440 A (Axon CN S) / Digidata1 550 A (Axoninstruments); 3) Microcontroller: MP 225 (SUTTER instrument); 4) Inverted microscope: TL4 (Olympus); 5) Glass microelectrode pulling instrument: PC 10 (NARISHIGE); 6) Microelectrode glass capillary: B12024F;

[0127] 2. Experimental Procedure

[0128] 2.1 Preparation of experimental compounds and intracellular / extracellular solutions All test compounds and control compounds CP or CP1 were dissolved in dimethyl sulfoxide (DMSO) and the solution was stored at a concentration of 10 mM.

[0129] The compound solution used for the Nav1.8 inhibitory activity assay contained 1 μM tetrodotoxin (TTX, Affix Scientific). It was diluted with extracellular fluid, prepared fresh for immediate use, and diluted to the required concentration using the fractional dilution method.

[0130] Preparation of intracellular and extracellular fluids: Intracellular fluid (mM): Aspartic acid, 140; 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration).

[0131] Extracellular fluid (mM): NaCl, 137; KCl, 4; 1.8; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration).

[0132] 2.2 Electrophysiology 1) After the compound is prepared into a solution of a specified concentration, the solution is added to each pipe in order of increasing concentration, and each pipe is labeled.

[0133] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and bring the electrode tip into contact with the cell. Adjust the three-way valve of the suction device to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current pathway.

[0134] 3) After the cell membrane rupture current stabilizes, perform perfusion at different concentrations sequentially. If the current stabilizes for at least one minute, proceed to the next concentration. The perfusion time for each concentration should not exceed five minutes.

[0135] 4) Clean the perfusion tank, rinsing from high to low drug concentration, rinsing for 20 seconds for each concentration. Finally, rinse with extracellular fluid for 1 minute.

[0136] 3. Pilot-scale design (resting state)

[0137] Cells were clamped at 80 mV and then depolarized to 10 mV using a square wave lasting 10 milliseconds to obtain Nav1.8, Nav1.4, and Nav1.6 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. Once the reaction stabilized, the blocking strength was calculated.

[0138] 4. Data Analysis

[0139] Data acquisition and analysis will be performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stability refers to the current changing within a finite range over time. The magnitude of the stable current is used to calculate the effect of the compound at that solubility.

[0140] The inhibitory activity of the compounds in the examples against Nav1.8, Nav1.4, and Nav1.6 was determined by the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 1 below:

[0141] Table 1

[0142] Experimental Example 2: Preclinical Rat Pharmacokinetic Study

[0143] 1. Experimental materials and equipment

[0144] Healthy adult male SD rats, 6-8 weeks old, weighing 200-300 grams, were purchased from Vital River Company; EDTA-Na2 anticoagulant; analytical balance, animal weighing scale, magnetic stirrer, refrigerated centrifuge, single-channel manual pipette, etc.

[0145] 2. Experimental Procedure

[0146] 1) Drug preparation: Accurately weigh approximately 10 mg of the sample to be tested, dissolve it in 5% DMSO (converted), then add 10% Solutol HS-15 and 85% physiological saline, sonicate, vortex mix to obtain a solution with a concentration of 1 mg / mL; prepare fresh immediately before use.

[0147] Pipette 0.2 mL of the sample into a 1.5 mL centrifuge tube and store at -80°C for analysis of the concentration of the drug solution.

[0148] 2) Animal preparation: Animals were housed in rat cages and fasted for at least 10 hours starting the day before the experiment, but water was allowed. On the day of the experiment, each animal was weighed and marked on its tail. Blank blood samples were collected before drug administration. Blood was collected via tail vein.

[0149] 3) Administration: Route of administration: Oral gavage (po); Dosage: 10 mg / kg; Dosage volume: 10 mL / kg; Procedure: Hold the rat upright with your left hand wearing a bite-proof glove. Insert a 16-gauge gavage needle into the throat through the mouth. Once you feel no obvious resistance, insert the needle and then inject the medication into the stomach.

[0150] 4) Sample Collection: Whole blood (0.1 ml) was collected from the test animals before drug administration and at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after drug administration. The samples were mixed by inverting the tubes 3-4 times, centrifuged at 10000 g for 5 min at 4℃ to separate the plasma, and stored at -80℃ for later analysis. Blood was collected via tail vein.

[0151] Specific procedure: Fix the rat in a restraint device, ensuring its tail is fully exposed. Wipe the rat's tail with alcohol to allow the skin to absorb the alcohol, resulting in significant venous dilation. Select suitable veins from both sides and insert the needle approximately one-third of the way from the tail tip. Use an insulin syringe, inserting the needle with the bevel facing upwards. Once the skin is pierced, immediately move the needle parallel to the vein. You should feel minimal resistance as the needle slides through the vein and observe blood return in the syringe, indicating successful insertion. Draw approximately 0.1-0.2 ml of whole blood. After removing the needle, apply pressure to stop the bleeding.

[0152] 3. Sample Analysis

[0153] Preparation of standard curve: Take 25 μL of rat blank plasma into centrifuge tubes, add 25 μL of prepared standard series solution (prepared with methanol), and then add 200 μL of internal standard solution (prepared with methanol). Vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃.

[0154] Unknown plasma sample processing: Take 25 μL of drug-containing rat plasma, add 25 μL of methanol and 200 μL of internal standard solution sequentially, vortex to mix for 2 min, and centrifuge at 10000g for 10 min at 4℃. Take the supernatant for LC / MS detection.

[0155] 4. Data Processing

[0156] A quantitative detection method for the analyte was established using Shimadzu liquid chromatography and Triple Quad™ 6500+AB mass spectrometry. The concentration of the parent drug in plasma was determined. Blood drug concentration-time curves were plotted, and the main pharmacokinetic parameters were calculated using a non-compartmental model in WinNonlin Phoenix software.

[0157] The pharmacokinetic results are shown in Table 2 below:

[0158] Table 2

[0159] The positive control compounds in Tables 1 and 2, and the structures of CD3-suzetrigine are as follows: ; .

[0160] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A tetrahydrofuran derivative, characterized in that, The compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: I In Formula I: R1, R2, and R4 are each independently selected from H, D, fluorine, methyl, and trifluoromethyl, and R1 and R2 are not both H; R3 is selected from deuterated methyl, methyl, trifluoromethyl, and trifluoroethyl.

2. The tetrahydrofuran derivative according to claim 1, characterized in that, In Formula I, R1 is selected from D, fluorine, and trifluoromethyl; R2 is selected from D, fluorine, and methyl; and R3 is selected from deuterated methyl.

3. The tetrahydrofuran derivative according to claim 1 or 2, characterized in that, In Formula I, R1 is selected from D and trifluoromethyl; R2 is selected from D and fluorine.

4. The tetrahydrofuran derivative according to claim 1, characterized in that, The compound is selected from any of the compounds shown in the following structural formulas: ； 。 5. A pharmaceutical composition, characterized in that, The compound comprising a preventive and / or therapeutically effective amount of any one of claims 1-4, and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1-4 or a pharmaceutical composition according to claim 5, characterized in that, Use in the preparation of a medicament, the medicament being used in the preparation of a drug for inhibiting voltage-gated sodium ion channels and / or in the preparation of a drug for treating, alleviating or preventing diseases related to voltage-gated sodium ion channels.

7. The use according to claim 6, characterized in that, The voltage-gated sodium ion channel is Nav1.

8.

8. The use according to claim 6, characterized in that, The voltage-gated sodium ion channel is used for pain-related diseases.

9. The use according to claim 8, characterized in that, The pain-related diseases mentioned are selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, and primary pain.

10. The use according to claim 9, characterized in that, The neuropathic pain described herein is selected from postherpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathy, trigeminal neuralgia, oral burn syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuropathic pain, nerve compression injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug-induced neuropathic pain, cancer chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain, post-spinal cord injury pain, primary small fiber neuropathy, primary sensory neuropathy, or trigeminal autonomic headache; and / or, The inflammatory pain described is selected from rheumatoid arthritis pain; and / or, The musculoskeletal pain mentioned refers to pain from osteoarthritis, back pain, cold pain, burn pain, or toothache.

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