WO2025223193A1 - Amide derivative as sodium channel modulator and use thereof - Google Patents

Abstract

The present invention relates to an amide derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a deuterated derivative thereof, a hydrate thereof, a solvate thereof, or a solvent complex thereof, as a sodium channel modulator. The present invention further provides a pharmaceutically acceptable composition comprising the amide derivative of the present invention, and use of the amide derivative or the composition in the treatment of sodium channel-related diseases, including pain, multiple sclerosis, pathological coughs, etc.

Description

Amide derivatives as sodium channel modulators and their uses Technical Field

This invention relates to the field of biomedical technology, specifically to an amide derivative or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof used as a sodium channel modulator, and its application in the treatment of sodium channel-related diseases.

Background Technology

Pain is a sensation produced when the human body is subjected to various noxious stimuli. It is a complex physiological and psychological activity, as well as a defensive mechanism to protect the body from harm. Clinically, it is one of the most common symptoms. The International Association for the Study of Pain (IASP) classifies pain into nociceptive pain (caused by the activation of corresponding pain receptors in inflamed or damaged tissues, further divided into somatic and visceral pain), neuropathic pain (caused by damage or disease of the nervous system, divided into peripheral and central pain), and psychogenic pain (caused by mental and psychological factors, psychological conflicts, emotional disorders, or mental illnesses, resulting in unpleasant feelings and exaggerated language and behavior to describe pain). Among these, neuropathic pain typically includes pain caused by systemic metabolic damage (postherpetic neuralgia, diabetic neuropathy, and drug-induced neuralgia) and pain caused by discrete nerve damage (post-amputation pain, postoperative nerve damage pain, etc.).

Voltage-gated sodium channels are mainly distributed in the nervous system and excitable cells (such as neurons), playing an important biophysical role in the transmission of pain-related signals. They transmit electrical signals through the generation and propagation of action potentials (APs) in the peripheral (PNS) and central nervous systems (CNS). Humans have nine types of sodium ion channels, Nav1.1 to Nav1.9, each composed of one α subunit and one or more β subunits. Despite their high structural and sequence similarity, different subtypes of Nav channels not only have specific tissue distributions, but also have different voltage dependencies and activation, inactivation and recovery kinetics (Xiaoshuang H, Xueqin J, Gaoxingyu H, et al. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119(30); Eleonora S, Peter W, Raafia M, et al. Cardiovascular research, 2014, 104(2):355-63). Studies have shown that mutations, changes in expression, or inappropriate regulation of these channels can lead to electrical instability of the cell membrane and abnormal spontaneous activity observed under pathological conditions (Chahine M, Chatelier A, Babich O, et al. CNS & Neurological Disorders-Drug Targets, 2008, 7(2): 144-158).

Nav1.8 is a tetrodotoxin (TTX)-insensitive sodium channel encoded by SCN10A, primarily expressed in sensory neurons, located in the 3p21-22 region of human chromosome, and mainly encoding the α subunit. Studies have shown that Nav1.8 plays an important role in neuropathic and chronic inflammatory pain, such as regulating malondialdehyde (a key factor in diabetic pain) and tumor necrosis factor α (TNF-α) (Huang Q, Chen Y, Gong N, et al. Metabolism, 2016, 65(4):463-474; He XH, Zang Y, Chen X, et al. Pain. 2010 Nov; 151(2):266-279.). Nav1.8 blockers hold promise as a new generation of ideal drugs for the treatment of neuropathic and inflammatory pain.

Currently known NaV1.8 blockers lack isotype selectivity. Since not all NaV1.8 positive neurons are nociceptive sensory neurons, some NaV1.8 blockers may act on non-nociceptive sensory neurons, thus limiting their therapeutic efficacy and safety. Therefore, there is an urgent need to develop an effective and highly selective NaV1.8 blocker.

Summary of the Invention

To address the aforementioned technical problems, this invention provides an amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex that can be used as a sodium channel modulator. This derivative exhibits high selectivity, favorable pharmacokinetic properties, high bioavailability, and low side effects, and shows promising application prospects in the treatment of sodium channel-related diseases.

This invention provides the following technical solutions:

The first aspect of this invention provides an amide derivative of Formula I or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof:

in,

A is selected from aryl or heteroaryl containing one or more heteroatoms of N, O, and S;

^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, oxygen, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine.

R is selected from C1-C10 alkyl, halogenated and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogenated and/or deuterated C3-C10 cycloalkyl;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, A is selected from phenyl, pyridine, thiazole, furan, oxazole, isoxazole, and quinoline.

Furthermore, in Equation I, Choose from one of the following structures:

Furthermore, R is preferably trifluoromethyl.

Furthermore, the C5-C10 fused heterocycle is preferably one of the following structures:

Furthermore, the structure of the amide derivative is shown in Formula Ia:

in,

^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, the structure of the amide derivative is as follows:

in,

Q is either N or CH;

^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, and N-hydroxyimide;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, the structure of the amide derivative is shown in formula Id-If:

in,

^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, the structure of the amide derivative is shown in formulas Ig and Ih:

in,

Q is either N or CH;

M is O, S, or N;

^G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 forms a ring with an imide linked to tetrahydrofuran and pyridine;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, the structure of the amide derivative is shown in formulas Ii and Ij:

in,

Q is either N or CH;

M is O, S, or N;

^G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 forms a ring with an imide linked to tetrahydrofuran and pyridine;

_Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens;

When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl;

When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles;

When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl.

Furthermore, in the above general structural formula, _R1X is preferably one of the following structures:

Furthermore, the amide derivative is preferably one of the compounds shown in the following structures:

The second aspect of the present invention provides the use of the amide derivative described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof in the preparation of a medicament for treating, alleviating or preventing sodium channel modulation-related diseases.

Furthermore, the sodium channel is Nav 1.8.

Furthermore, the diseases mentioned include pain, multiple sclerosis, pathological cough, but are not limited to the types of diseases listed above.

Furthermore, the drug may be administered alone or in combination with other therapeutic agents.

Furthermore, the drug can be administered orally, parenterally, intravenously, or transdermally.

A third aspect of the present invention provides a pharmaceutical composition comprising the amide derivative described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof, and a pharmaceutically acceptable carrier or excipient.

The fourth aspect of the present invention provides the use of the pharmaceutical composition described in the third aspect in the preparation of a medicament for treating, alleviating or preventing sodium channel modulation-related diseases.

Furthermore, the sodium channel is Nav 1.8.

Furthermore, the diseases include pain, multiple sclerosis, and pathological cough, but are not limited to the types of diseases listed above; the pain includes acute pain and chronic pain; the acute pain includes, but is not limited to, surgical pain, bone pain, and toothache; and the chronic pain includes, but is not limited to, diabetic neuropathy and herpes zoster neuropathy.

Furthermore, the drug may be administered alone or in combination with other therapeutic agents.

Furthermore, the drug can be administered orally, parenterally, intravenously, or transdermally.

As used herein, unless otherwise stated, the following definitions and terms shall apply.

"R" and "S" are terms used to describe isomers and are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. Naming an asymmetrically substituted carbon atom "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rule, which is well known to those skilled in the art and described in Section E, Stereochemistry, of the International Union of Pure and Applied Chemistry (IUPAC) Rules of Nomenclature for Organic Chemistry.

The term "aryl" refers to a monocyclic, bicyclic, or tricyclic system having a total of 5-14 ring carbon atoms, wherein at least one ring in the system is aromatic, and each ring in the system contains 3-7 ring carbon atoms. The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system having a total of 5-14 ring carbon atoms, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms, such as N, O, or S, and each ring contains 3-7 ring members, such as pyridine, thiazole, furan, oxazole, isoxazole, quinoline, etc.

In this invention, the term "halogen" refers to F, Cl, Br, or I.

The term "ester group" refers to -COOR, where R is an alkyl or other non-hydrogen group.

The term "Ci-Cj" refers to the number of carbon atoms i-j in the moiety. For example, "C1-C10 alkyl" means that the alkyl unit has any number of carbon atoms between 1 and 10.

As used herein, "alkyl" refers to a fully saturated straight-chain, branched alkane group. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. Non-limiting examples of exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, n-octyl, etc. Additionally, the term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each ring having 3 to 10 carbon atoms.

The term "substitution" refers to replacing a hydrogen group in a given structure with a specific substituent group. Unless otherwise specified, the optionally substituted group may have a substituent at each substitution position of the group, and when more than one position in any given structure is substituted by a substituent selected from a specified group, the substituents at each position may be the same or different. In some specific embodiments, all three hydrogens in the methyl group are substituted by F to form _-CF3 , or the three hydrogens are substituted by two F and one deuterium to form _-CF2D .

In this invention, the term "carbon heterocycle" refers to a monocycle containing at least one heteroatom, including but not limited to N, O, and S. The ring may be saturated or contain one or more unsaturated bonds.

The term "dialkylamine" is R-NH- _R1 , where R and _R1 are the same or different alkyl groups.

The term "fused heterocycle" contains at least two rings that share an edge, and at least one ring contains one or more heteroatoms.

The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which can be straight-chain or branched, or a combination thereof. The aforementioned C2-C3 alkynyl groups include ethynyl and propynyl. The term "alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, which can be straight-chain or branched, or a combination thereof. The aforementioned C2-C3 alkenyl groups include vinyl, propenyl, 2-methyl-1-propenyl, etc.

Optical isomers, diastereomers, geometric isomers, and tautomers: Some Formula I compounds may contain one or more ring systems, and therefore may have cis and trans isomers. This invention is intended to cover all such cis and trans isomers. The inclusion of an olefinic double bond, unless otherwise specified, means the inclusion of E and Z geometric isomers.

Any enantiomer of a compound of general formula I can be obtained by stereo-oriented synthesis using optically pure starting materials or reagents with known configurations.

Furthermore, compounds of formula I may also include a series of stable isotope-labeled analogs. For example, one or more protons in a compound of formula I may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.

"Pharmaceutically acceptable salt" refers to the acid salt or base salt of the compounds of this invention, which has the desired pharmacological activity and is neither biologically desirable nor otherwise desirable. The salt can form with acids, including but not limited to acetic acid, adipic acid, benzoate, citric acid, camphoric acid, camphor sulfonate, dicarboxylate, dodecyl sulfate, ethanesulfonate, fumarate, glucono-heptate, glycerol phosphate, hemisulfate, heptanate, hexanoate, hydrobromide hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, and oxalate.

By employing the above technical solution, the present invention has at least the following advantages:

This invention provides a novel class of amide derivatives that can serve as sodium channel modulators. These compounds exhibit high inhibitory activity and selectivity against Nav.18, with minimal impact on other sodium ion channels, reducing side effects on the cardiovascular and central nervous systems. This improves the therapeutic efficacy and safety for Nav.18-mediated diseases, facilitating the expansion of clinical applications. Furthermore, the amide derivatives provided by this invention possess superior pharmacokinetic properties, enabling effective absorption, distribution to the target site, and maintenance of appropriate concentrations in vivo for sustained therapeutic effects. They also exhibit high bioavailability, ensuring sufficient drug delivery to and action on target neurons, thereby enhancing therapeutic efficacy. Therefore, these novel amide derivatives show promising application prospects in the preparation of drugs for treating, alleviating, or preventing sodium channel modulation-related diseases.

Detailed Implementation

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items. "Comprising" or "containing" as used herein means that it may include or contain other components in addition to the stated components. "Comprising" or "containing" as used herein may also be replaced with the closed form "is" or "consisting of".

The present invention will be further described below with reference to embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

Example 1

This embodiment relates to the preparation of compounds I-1, 1F1(4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide), and 1F2(4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide). The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 1a (prepared by the method disclosed in example 14 of patent application "WO2021113627") (500 mg, 1.5 mmol) was dissolved in 10 mL of tetrahydrofuran solution, NaH (588 mg, 14.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Deuterium water (1.47 g, 73.5 mmol) was added, and the mixture was stirred for 30 minutes. Then, diethyl bromofluoromethylphosphonate (785 mg, 2.9 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the combined organic layers were washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 1b (400 mg).

(2) Oxaloyl chloride (1.1 mL, 14.0 mmol) and two drops of DMF were added to a mixture of compound 1b (1.0 g, 2.8 mmol) in dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. The solvent was removed from the mixture under reduced pressure. The mixture was then added to dichloromethane (6 mL) containing methyl 4-aminopyridinecarboxylate (640 mg, 4.2 mmol), triethylamine (850 mg, 8.4 mmol), and DMAP (20 mg, 0.1 mmol). The mixture was stirred at room temperature for 4 hours. The solvent was removed from the mixture under reduced pressure. The crude mixture was purified by silica gel column chromatography to obtain 1c (1.1 g, yield: 79.7%).

The characterization data of compound 1c are as follows:

LCMS: 526.1 [M+H],

¹ H NMR (400MHz, DMSO-d ₆ )δ10.76(s,1H),8.58(d,J＝5.5Hz,1H),8.37(d,J＝2.1Hz,1H),7.86(dd,J＝5.5,2.2Hz,1H),7.47(dd,J＝9.8,7.8Hz,1H),7.34(dd,J＝8.5 ,5.9Hz,1H),5.17(d,J＝10.2Hz,1H),4.28(dd,J＝10.2,7.6Hz,1H),4.03(q,J＝7.1Hz,2H),3.87(s,3H),1.60(s,3H),0.81–0.69(m,3H).

(3) Compound 1c (200 mg, 0.38 mmol) was added to 8 mL of methanol-ammonia solution (7 M) at room temperature and stirred overnight. Subsequently, the reaction mixture was concentrated under vacuum to obtain target compound I-1 (170 mg, yield: 89.5%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.74(s,1H),8.50(d,J＝5.5Hz,1H),8.29(d,J＝2.1Hz,1H),8.09(d,J＝2.8Hz,1H),7.84(dd,J＝5.5,2.2Hz,1H),7.65(d,J＝2.8Hz,1H),7.57–7 .39(m,1H),7.43–7.24(m,1H),5.17(d,J＝10.2Hz,1H),4.28(dd,J＝10.2,7.6Hz,1H),2.76(t,J＝7.5Hz,1H),1.60(s,3H),0.76(d,J＝7.3Hz,3H).

(4) Compound I-1 (230 mg) was resolved by chiral column chromatography to give compounds 1F1 (81 mg, yield: 35.2%) and 1F2 (84 mg, yield: 36.4%); chiral resolution conditions:

Instrument: WATERS150 preparative SFC (SFC-26);

Column: ChiralPakAY, 250×30mm I.D., 10μm;

Mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: A:B = 3:1, flow rate: 120 mL/min.

The characterization data of compound 1F1 are as follows:

LCMS:511.1[M+H],

Chiral HPLC analysis results: retention time 1.970 min, purity 100% (column: ChiralPak AY, 150×4.6mm ID, 3μm, mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min).

The characterization data of compound 1F2 are as follows:

LCMS:511.1[M+H];

Chiral HPLC analysis results: retention time 2.317 min, purity 98.5% (column: ChiralPak AY, 150×4.6mm ID, 3μm, mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min).

Example 2

This embodiment involves compounds I-2, 2F1(4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide, and 2F2(4-((2S,3R,4R,5S)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide. The preparation of 2F3(4-((2S,3R,4S,5R)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide and 2F4(4-((2R,3S,4R,5S)-3-(2-(difluoromethoxy-d)-5-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide is carried out according to the following reaction process:

The specific preparation process is as follows:

(1) Triethylamine (52.6 g, 0.52 mol) and 4-acetaminobenzenesulfonyl azide 2b (50 g, 0.20 mol) were added to a mixture of compound 2a (25 g, 0.17 mol) and tetrahydrofuran (1 L). The mixture was stirred at room temperature for 4 hours. The solvent was removed from the mixture under reduced pressure. Then, petroleum ether (500 mL) was added and stirred for 30 minutes. The filtrate was collected and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography to obtain ethyl 2-diazo-3-oxovalerate 2c (27 g, yield: 91.5%). ^1H NMR (400 MHz, CHCl3 _- d) δ 4.29 (q, J = 7.1 Hz, 2H), 2.86 (q, J = 7.4 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H).

(2) To a mixture of compound 2c (25 g, 0.15 mol) and triethylamine (29.7 g, 0.29 mol) in dichloromethane (300 mL), after nitrogen purging three times, trimethylsilyl trifluoromethanesulfonate (49 g, 0.22 mol) was added at 0 °C. The mixture was stirred at 0 °C for 30 minutes, diluted with petroleum ether (500 mL), quenched with saturated sodium bicarbonate, washed with saturated brine, dried with anhydrous sodium sulfate and evaporated to obtain a crude mixture, which can be directly used for the next reaction. Titanium tetrachloride (25 g, 0.13 mol) was slowly added to a mixture of trifluoroacetone (19.8 g, 0.18 mol) and dichloromethane (300 mL) at -78 °C, followed by the crude mixture obtained above. The reaction was maintained at -78 °C for 3 hours, quenched with water, and extracted with dichloromethane (300 mL × 2). The combined organic layers were washed with NaCl aqueous solution, dried over _{anhydrous Na₂SO₄} and evaporated to obtain a crude mixture. The crude mixture was purified by silica gel column chromatography to obtain ethyl (4R, 5S)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (2 d, 10 g, yield: 24.1%). ^¹H NMR (400 MHz, CHCl₃ ₎ -d) δ4.33(q,J＝7.1Hz,2H),4.13(q,J＝7.0Hz,1H),3.99(s,1H),1.42(d,J＝1.2Hz,3H),1.35(t,J＝7.1Hz,3H),1.30(dd,J＝7.0,1.5Hz,3H).

(3) Compound 2d (10 g, 35.5 mmol) was added to a mixture of rhodium acetate dimer (157 mg, 0.35 mmol) and toluene (100 mL) at 100 °C, stirred for 1 hour, and the solvent was removed from the mixture under reduced pressure to give ethyl (4R, 5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2e, 9 g, yield: 100%). ^¹H NMR (400 MHz, CHCl3-d) δ 4.63 (d, J = 1.5 Hz, 1H), 4.26 (t, _J = 7.1 Hz, 2H), 2.62 (q, J = 7.2 Hz, 1H), 2.36 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.25 (dd, J = 7.3, 1.9 Hz, 3H).

(4) After purging the mixture of compound 2e (9.5 g, 37.4 mmol) in dichloromethane (100 mL) three times with nitrogen, add DIPEA (5.8 g, 44.9 mol) and trifluoromethanesulfonic anhydride (10.5 g, 37.4 mmol) at -78 °C, stir at -78 °C for 1 hour, heat to 0 °C and react for 30 minutes, quench with saturated sodium bicarbonate, extract with dichloromethane (200 mL × 2), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate and evaporate to obtain a crude mixture (2f, 14.4 g, yield: 100%), which can be directly used for the next step of the reaction.

(5) To a mixture of compound 2f (3.7 g, 9.5 mmol) and toluene (40 mL), 2 g (1.8 g, 10.5 mmol) of (5-fluoro-2-methoxyphenyl)boronic acid, 0.553 g (0.4 mmol) of tetraphenylphosphine palladium, and 6.1 g (28 mmol) of potassium phosphate were added. After three nitrogen purgings, the mixture was stirred at 100 °C for 2 hours, quenched with water, and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with NaCl aqueous solution, dried _over anhydrous _Na₂SO₄ and evaporated to obtain a crude mixture. The crude mixture was purified by silica gel column chromatography to obtain 2h (1.6 g, yield: 46.3%), LCMS: 362.9 [M+H]; ^¹H NMR (400 MHz, CHCl₃ ₎ -d)δ7.03–6.95(m,1H),6.91–6.85(m,1H),6.83–6.78(m,1H),4.20–4.06( m,2H),3.77(s,3H),1.68(s,3H),1.11(t,J＝7.1Hz,3H),1.08–1.02(m,3H).

(6) At 0°C, a mixture of compound 1.6 g (4.0 mmol) and dichloromethane (15 mL) was added, purged three times with nitrogen, and then 1 M boron tribromide (6.6 mL, 6 mmol) was added. The mixture was stirred for 2 hours, quenched with saturated sodium bicarbonate, and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with NaCl aqueous solution, dried over anhydrous Na₂SO₄ and evaporated to obtain a crude mixture. This crude mixture was then dissolved in dichloromethane (50 mL), and trifluoroacetic acid (1 g, 8.0 mmol) was added. The mixture was stirred at 50°C for 16 hours, allowed to cool naturally to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane (30 mL × 2). The combined organic layers were washed with NaCl aqueous solution and dried over anhydrous _Na₂SO₄ and evaporated to obtain a crude mixture. _4. Dry and evaporate, add petroleum ether (200 mL), stir for 30 minutes, filter and collect the solid to give compound 2i (1.2 g, yield: 95%), LCMS: 302.6 [M+H]; ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.60 (dd, J = 9.0, 3.0 Hz, 1H), 7.54 (dd, J = 9.1, 4.6 Hz, 1H), 7.39 (td, J = 8.8, 3.0 Hz, 1H), 1.64 (s, 3H), 1.45 (dt, J = 6.6, 2.0 Hz, 3H).

(7) Add palladium hydroxide on carbon (1.5 g) to a mixture of compound 2i (6.5 g, 19.34 mmol) and methanol (65 mL). After three hydrogen purgings, the hydrogen pressure in the pressurizing device is increased to 10 psi. Stir at room temperature for 16 hours and filter with diatomaceous earth to obtain crude compound 2j (3.1 g, yield: 42.8%), which can be directly used for the next reaction.

(8) At 0°C, sodium tert-butoxide (1.48 g, 15 mmol) was added to a mixture of compound 2j (1.3 g, 3.8 mmol) and tetrahydrofuran (13 mL). The mixture was stirred at room temperature for 30 minutes. The pH was adjusted to 1-2 with 2 M hydrochloric acid under ice bath conditions. The mixture was quenched with water and extracted with ethyl acetate (200 × 2). The combined organic layers were washed with NaCl aqueous solution, dried _over anhydrous _Na₂SO₄ and evaporated to obtain crude compound 2k (1.7 g), which was used directly in the next step of the reaction.

(9) Compound 2k (1.7 g, 5.2 mmol) was dissolved in 25 mL of tetrahydrofuran solution, and NaH (1.26 g, 52 mmol) was added. The mixture was stirred at room temperature for 30 minutes, followed by the addition of deuterium water (5.2 g, 260 mmol). After stirring for another 30 minutes, diethyl bromofluoromethylphosphonate (2.8 g, 10.4 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 2l (1.4 g), which was directly used in the next reaction. LCMS: 374.1 [M+H]; ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.34(dd,J＝10.0,2.9Hz,1H),7.26–7.13(m,2H),4.80(d,J＝10.1Hz,1H),4.03 (dd,J＝10.2,7.3Hz,1H),2.66(t,J＝7.4Hz,1H),1.50(s,3H),0.78–0.62(m,3H).

(10) Oxaloyl chloride (2.3 g, 18.7 mmol) and two drops of DMF were added to a mixture of compound 2l (1.4 g, 3.7 mmol) in dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The mixture was then added to dichloromethane (6 mL) containing methyl 4-aminopyridinecarboxylate (855 mg, 5.6 mmol), triethylamine (1.13 g, 11.2 mmol), and DMAP (23 mg, 0.1 mmol). The mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. The crude mixture was purified by silica gel column chromatography to give 2m (1.0 g, yield: 53.3%). LCMS: 508.1 [M+H].

(11) At room temperature, 2m of compound (600mg, 1.1mmol) was added to 17mL of methanol-ammonia solution (7M) and stirred overnight. Subsequently, the reaction mixture was concentrated under vacuum to obtain the target compound I-2 (300 mg, yield: 55.5%), LCMS: 493.1 [M+H]; ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 8.58 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 5.4, 2.2 Hz, 1H), 7.39 (dd, J = 9.9, 2.8 Hz, 1H), 7.31–7.20 (m, 2H), 5.76 (s, 1H), 5.20 (d, J = 10.1 Hz, 1H), 4.27 (dd, J = 10.1, 7.5 Hz, 1H), 3.91–3.82 (m, 4H), 1.61 (s, 3H), 0.80–0.69 (m, 3H).

(12) Compound I-2 (400 mg) was separated by chiral column using method 1 (MGⅡpreparative SFC (SFC-14), column: Whelk O1 (S,S), 250×30 mm I.D., 10 μm, mobile phase A: supercritical CO2, mobile phase B: Ethanol, gradient ratio: A:B＝55:45, flow rate: 60 mL/min) to obtain compounds 2F1 (118 mg) and 2F2 (107 mg);

Compound I-2 (400 mg) was separated by method 2: chiral column resolution (MG II preparer SFC (SFC-13), column: Cellulose-2, 250×30 mm I.D., 10 μm, mobile phase A: supercritical CO2, mobile phase B: Isopropanol, gradient ratio: A:B＝7:3, flow rate: 80 mL/min) to obtain compounds 2F3 (63 mg) and 2F4 (48 mg).

The characterization data of compound 2F1 are as follows:

LCMS: 493.1 [M+H];

Chiral HPLC analysis results: retention time 0.899 min, purity 100% (column: Whelk O1(S,S), 250×4.6mm ID, 5μm, mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: B = 40%, flow rate: 2.5 mL/min).

The characterization data of compound 2F2 are as follows:

LCMS: 493.1 [M+H];

¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),8.50(d,J＝5.5Hz,1H),8.30(d,J＝2.2Hz,1H),8.09(d,J＝2.8Hz,1H),7.85(dd,J＝5.5,2.2Hz,1H),7.64(d,J＝2.8Hz,1H),7.39(dd, J＝9.9,2.8Hz,1H),7.34–7.20(m,2H),5.19(d,J＝10.1Hz,1H),4.27(dd,J ＝10.1,7.5Hz,1H),2.78(t,J＝7.5Hz,1H),1.61(s,3H),0.83–0.68(m,3H).

Chiral HPLC analysis results: retention time 1.368 min, purity 99.5%. Column: Whelk O1 (S,S), 250×4.6 mm ID, 5 μm; mobile phase A: supercritical _CO2 ; mobile phase B: ethanol; gradient ratio: B = 40%; flow rate: 2.5 mL/min.

The characterization data of compound 2F3 are as follows:

LCMS: 493.1 [M+H];

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(s,1H),8.48(d,J＝5.6Hz,1H),8.24(d,J＝2.2Hz,1H),8.08(s,1H),7.63(s,2H),7.24(d,J＝6.4Hz,3H),4 .66(d,J＝10.2Hz,1H),3.66(d,J＝10.7Hz,1H),2.91(dd,J＝12.4,6.5Hz,1H),1.46(s,3H),0.93(d,J＝6.8Hz,3H).

Chiral HPLC analysis results: retention time 2.965 min, purity 100% (column: Cellulose-2, 150×4.6mm ID, 3μm, mobile phase A: supercritical _CO2 , mobile phase B: isopropanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min).

The characterization data of compound 2F4 are as follows:

LCMS: 493.1 [M+H];

Chiral HPLC analysis results: retention time 3.302 min, purity 97.68% (column: Cellulose-2, 150×4.6mm ID, 3μm, mobile phase A: supercritical _CO2 , mobile phase B: isopropanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min).

Example 3

This embodiment relates to the preparation of compounds I-3, 3F1(2R,3S,4S,5R)-N-(2-(1H-tetrazol-5-yl)pyridin-4-yl)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and 3F2(2S,3R,4R,5S)-N-(2-(1H-tetrazol-5-yl)pyridin-4-yl)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 1b (1.5 g, 1.8 mmol) and compound 4-aminopyridinecarboxynitrile (685 mg, 5.7 mmol) were dissolved in 20 mL of dichloromethane at room temperature. Triethylamine (1.16 g, 11.5 mmol) and DMAP (123 mg, 0.2 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 12–14 hours. After the reaction was completed, the mixture was purified by column chromatography to give 1 g of the target product 3a, with a yield of 53%.

(2) In a single-necked round-bottom flask, starting material 3a (700 mg, 1.4 mmol) was dissolved in 7 mL of acetonitrile, and trimethylsilyl azide (205 mg, 1.8 mmol) was added. Subsequently, phosphorus oxychloride (220 mg, 1.4 mmol) was added, and the reaction mixture was heated to 100 °C and reacted at this temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, and dried over anhydrous sodium sulfate or anhydrous magnesium sulfate. Purification by column chromatography yielded 260 mg of the target product I-3, in a yield of 35.4%.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),8.61(d,J＝5.6Hz,1H),8.19(d,J＝2.0Hz,1H),7.90(dd,J＝5.6,2.1Hz,1H),7.51–7.42(m,1H),7.38–7. 31(m,1H),5.18(d,J＝10.1Hz,1H),4.28(dd,J＝10.2,7.7Hz,1H),2.75(t,J＝7.5Hz,1H),1.59(s,3H),0.81–0.73(m,3H).

(3) Compound I-3 (251 mg) was resolved by chiral column chromatography to give compounds 3F1 (124 mg, yield: 49.4%) and 3F2 (95 mg, yield: 37.8%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak IH, 100×4.6mm I.D., 3μm;

Mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min.

The characterization data of compound 3F1 are as follows:

LCMS: 534.3 [M+H];

Chiral HPLC analysis results: retention time 2.474 min, purity 98.5%.

The characterization data of compound 3F2 are as follows:

LCMS: 534.3 [M+H];

Chiral HPLC analysis results: retention time 1.538 min, purity 100%.

Example 4

The preparation of compounds I-8, 8F1(2R,3S,4S,5R)-3-[2-(deuterated difluoromethoxy)-3,4-difluorophenyl]-N-[2-((Z)-N'-methoxyformamidinyl)pyridin-4-yl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and 8F2(2S,3R,4R,5S)-3-[2-(deuterated difluoromethoxy)-3,4-difluorophenyl]-N-[2-((Z)-N'-methoxyformamidinyl)pyridin-4-yl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and the reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 3a (800 mg, 1.6 mmol), diisopropylethylamine (1.26 g, 9.8 mmol), mercaptoacetic acid (598 mg, 6.5 mmol), and methoxyamine hydrochloride (829 mg, 4.8 mmol) were dissolved in 10 mL of isopropanol. The reaction system was heated to 80 °C and stirred overnight. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate and purified by column chromatography to give the target product I-8 (800 mg, yield 91.4%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),8.44(d,J＝5.6Hz,1H),8.10(d,J＝2.1Hz,1H),7.77–7.67(m,1H),7.56–7.44(m,2H),7.37–7.27(m,1H),6.08(s ,2H),5.13(d,J＝10.6Hz,1H),4.28(dd,J＝10.3,7.5Hz,1H),3.79(s,3H),2.85–2.70(m,2H),1.60(s,3H),0.76(d,J＝7.3Hz,3H).

(2) Compound I-8 (775 mg) was resolved by chiral column chromatography to give compounds 8F1 (233 mg, yield: 30.1%) and 8F2 (292 mg, yield: 37.7%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak IH, 100×4.6mm I.D., 3μm;

Mobile phase A: supercritical _CO2 , mobile phase B: ethanol, gradient ratio: B = 5-40%, flow rate: 2.5 mL/min.

The characterization data of compound 8F1 are as follows:

LCMS: 540.6 [M+H];

Chiral HPLC analysis results: retention time 3.299 min, purity 99.7%.

The characterization data of compound 8F2 are as follows:

LCMS: 540.6 [M+H];

Chiral HPLC analysis results: retention time 1.409 min, purity 100%.

Example 5

This embodiment relates to the preparation of compounds I-24, 24F14-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid, and 24F24-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 5a (prepared by the method disclosed in example 3 of patent application "WO2021113627") (30 g, 0.08 mol) was dissolved in 250 mL of acetonitrile, and deuterated iodomethane (24.6 g, 0.17 mol) and cesium carbonate (82.9 g, 0.25 mol) were added at 0 °C. The reaction mixture was heated to room temperature and stirred overnight for 24 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to dryness. Compound 5b was given in 76.3% yield.

(2) Compound 5b (12.0 g, 0.05 mol) was dissolved in 200 mL of tetrahydrofuran, and potassium tert-butoxide (20.7 g, 0.21 mol) was added. The reaction mixture was stirred at room temperature until the reaction was complete. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate to give crude compound 5c (11.92 g), in 98% yield.

(3) Compound 5c (580 mg, 1.6 mmol) and methyl 4-aminopyridinecarboxylate (370 mg, 2.4 mmol) were dissolved in 10 mL of dichloromethane, and triethylamine (492 mg, 4.9 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was complete, the product was washed with saturated brine and extracted with ethyl acetate. The product was purified by column chromatography to obtain the target product 5d (320 mg, yield 40.1%).

(4) Compound 5d (1.6 g, 3.3 mmol) was added to a single-necked flask, followed by 20 mL of methanol, 5 mL of tetrahydrofuran, and 5 mL of water, and then lithium hydroxide (313 mg, 13.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 5-6 with 3N hydrochloric acid, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to give the target product I-24 (1.1 g, 70.7% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.76(s,1H),8.56(d,J＝5.5Hz,1H),8.34(d,J＝2.1Hz,1H),7.91–7.82(m,1H),7.16(d,J＝7.4Hz,2H),5. 12(d,J＝10.2Hz,1H),4.26(dd,J＝10.2,7.7Hz,1H),2.78(t,J＝7.5Hz,1H),1.61(s,3H),0.80–0.64(m,3H).

(5) Compound I-24 (409 mg) was resolved by chiral column chromatography to give compounds 24F1 (224 mg, yield: 54.7%) and 24F2 (255 mg, yield: 62.3%); chiral resolution conditions:

Instrument: Shimadzu LC-20AT;

Chromatographic column: CHIRALPAK IK, 0.46 cm I.D. × 15 cm L;

Mobile phase: Hexane/IPA/TFA = 45/55/0.1 (V/V/V) (n-hexane/isopropanol/trifluoroacetic acid, volume ratio 45:55:0.1), flow rate: 1.0 mL/min.

The characterization data of compound 24F1 are as follows:

LCMS: 478.6 [M+H];

Chiral HPLC analysis results: retention time 3.050 min, purity 94.316%.

The characterization data of compound 24F2 are as follows:

LCMS: 478.6 [M+H];

Chiral HPLC analysis results: retention time 4.505 min, purity 99.3%.

Example 6

This embodiment relates to the preparation of compounds I-25, 25F14-((2R,3S,4S,5R)-3-(2-(deuterated difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid, and 25F24-((2S,3R,4R,5S)-3-(2-(deuterated difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 1c (3.2 g, 6.6 mmol) was added to a single-necked flask, followed by 35 mL of methanol, 10 mL of tetrahydrofuran, and 10 mL of water, and then lithium hydroxide (630 mg, 26.0 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the pH was adjusted to 5-6 with 3N hydrochloric acid, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to give the target product I-25 (2.8 g, yield 65.7%).

¹ H NMR (400MHz, DMSO-d ₆ )δ10.73(s,1H),8.56(d,J＝5.5Hz,1H),8.34(d,J＝2.1Hz,1H),7.85(dd,J＝5.5,2.1Hz,1H),7.53–7.43(m,1H),7.38–7. 30(m,1H),5.16(d,J＝10.2Hz,1H),4.29(dd,J＝10.2,7.6Hz,1H),2.76(t,J＝7.5Hz,1H),1.60(s,3H),0.80–0.73(m,3H).

(2) Compound I-25 (488 mg) was resolved by chiral column chromatography to give compounds 25F1 (244 mg, yield: 50.0%) and 25F2 (234 mg, yield: 48.0%); chiral resolution conditions:

Instrument: Shimadzu LC-20AT;

Chromatographic column: CHIRALPAK IK, 0.46 cm I.D. × 25 cm L;

Mobile phase: Hexane/EtOH/DEA/TFA = 50/50/0.5/0.1 (V/V/V) (n-hexane/isopropanol/diethylamine/trifluoroacetic acid), flow rate: 1.0 mL/min.

The characterization data of compound 25F1 are as follows:

LCMS: 512.3 [M+H];

Chiral HPLC analysis results: retention time 3.679 min, purity 95.8%.

The characterization data of compound 25F2 are as follows:

LCMS: 512.3 [M+H];

Chiral HPLC analysis results: retention time 4.646 min, purity 99.3%.

Example 7

This embodiment relates to the preparation of compounds I-38, 38F1 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(deuterated methoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide, and 38F2 2-carbamoyl-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(deuterated methoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 7a (2 g, 13.1 mmol) was reacted with Boc anhydride (3.1 g, 14.4 mmol), triethylamine (4 g, 39.4 mmol) and 4-dimethylaminopyridine (160 mg, 1.31 mmol) at room temperature for 3 hours to give the target product 7b (2.8 g, yield 84.8%).

(2) Compound 7b (2.8 g, 11.1 mmol) was dissolved in 30 mL of dichloromethane (DCM) and reacted with m-CPBA (15.3 g, 88.8 mmol) overnight at room temperature. The product was washed with saturated brine and extracted with ethyl acetate. The product was purified by column chromatography to obtain the target product 7c (1.77 g, yield 59.6%).

(3) Compound 7c (1.77 g, 6.6 mmol) was dissolved in 20 mL of dichloromethane (DCM), and 5 mL of TFA was added and reacted overnight at room temperature to obtain the target product 7d (1 g of crude product).

(4) Compound 5c (130 mg, 0.85 mmol) was dissolved in 2.5 mL of dichloromethane. Oxaloyl chloride (360 mg, 2.82 mmol) and a catalytic amount of DMF were added under ice bath conditions. After stirring for 1 hour, the solvent was evaporated to dryness. The residue was redissolved in dichloromethane, and compound 7d (200 mg, 0.56 mmol), triethylamine (171 mg, 1.7 mmol), and 4-dimethylaminopyridine (3.8 mg, 0.03 mmol) were added and dissolved in 15 mL of dichloromethane. After reacting at room temperature for 2 hours, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target product 7e (74 mg, yield 25.8%).

(5) Compound 7e (250 mg, 0.49 mmol) was added to 8 mL of methanol-ammonia solution (7 M) at room temperature and stirred overnight. Subsequently, after routine post-processing, the target compound I-38 (170 mg, yield 70.5%) was purified by column chromatography.

^1H NMR(400MHz,Chloroform-d)δ11.07(s,1H),8.87(s,1H),8.28(dd,J＝7.2,3.3Hz,1H),8.23–8.14(m,2H),7.11–7.02(m,1H),6.98–6.86 (m,1H),6.15(s,1H),5.03(d,J＝11.0Hz,1H),4.09(dd,J＝11.1,8.1Hz,1H),2.82–2.69(m,1H),1.69(s,3H),0.80(dd,J＝7.7,2.3Hz,3H).

(6) Compound I-38 (150 mg) was resolved by chiral column chromatography to give compounds 38F1 (49 mg, yield: 36.7%) and 38F2 (54 mg, yield: 36.0%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak IH, 100×4.6mm I.D., 3μm;

Mobile phase: Mobile phase A: supercritical _CO2 , Mobile phase B: ethanol, Gradient ratio: B = 5-40%, Flow rate: 2.5 mL/min.

The characterization data of compound 38F1 are as follows:

LCMS: 493.2 [M+H];

Chiral HPLC analysis results: retention time 2.972 min, purity 99.2%.

The characterization data of compound 38F2 are as follows:

LCMS: 493.2 [M+H];

Chiral HPLC analysis results: retention time 2.442 min, purity 100%.

Example 8

This embodiment relates to the preparation of compounds I-39, 39F14-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide-5-deuterium, and 39F24-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide-5-deuterium. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 8a (14 g, 26.3 mmol) was dissolved in dichloroethane (DCE, 80 mL) at room temperature. N-bromosuccinimide (4.68 g, 26.3 mmol) was added to the solution in a single batch. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the product in the aqueous phase was extracted with ethyl acetate, and the organic extracts were combined and washed with saturated brine. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, giving crude product 8b (16 g, 99.1% yield).

(2) Compound 8b (1g, 4.3mmol), sodium deuterate (11.2g, 17.4mmol), Pd2(dba)3 (199mg, 0.2mmol) and tert-butylphosphine (88mg, 0.4mmol) were added to a single-necked flask, and 6mL of DMSO was added as solvent. The reaction was carried out at about 80℃ for 4 hours under nitrogen protection. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target product 8c (500mg, yield 75.1%).

(3) Compound 5c (800 mg, 2.2 mmol) was dissolved in 10 mL of dichloromethane. Oxaloyl chloride (1.4 g, 11.2 mmol) and a catalytic amount of DMF were added under ice bath conditions. After stirring for 1 hour, the solvent was evaporated to dryness. The residue was redissolved in DCM, and compound 8c (343 mg, 2.2 mmol), triethylamine (679 mg, 6.7 mmol), and 4-dimethylaminopyridine (14 mg, 0.1 mmol) were added and dissolved in 50 mL of dichloromethane. After reacting at room temperature for 2 hours, the reaction was quenched with water. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target product 8d (550 mg, yield 49.9%).

(4) Compound 8d (550 mg, 1.1 mmol) was added to 16 mL of methanol-ammonia solution (7 M) at room temperature and stirred overnight. Subsequently, the reaction mixture was concentrated under vacuum, and after routine post-treatment, the target compound I-39 (170 mg, yield 70.5%) was purified by column chromatography.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.74(s,1H),8.51(t,J＝2.8Hz,1H),8.30(d,J＝2.7Hz,1H),8.08(d,J＝2.8Hz,1H),7.63(d,J＝2.9Hz,1H),7.24–7.10(m ,2H),5.12(d,J＝10.2Hz,1H),4.27(dd,J＝10.2,7.6Hz,1H),2.84–2.73(m,1H),1.62(s,3H),0.74(dd,J＝7.2,2.6Hz,3H).

(5) Compound I-39 (258 mg) was resolved by chiral column chromatography to give compounds 39F1 (124 mg, yield: 48.1%) and 39F2 (107 mg, yield: 41.4%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak AD, 150×4.6mm I.D., 3μm;

Mobile phase: Mobile phase A: supercritical _CO2 , Mobile phase B: ethanol, Gradient ratio: B = 5-40%, Flow rate: 2.5 mL/min.

The characterization data of compound 39F1 are as follows:

LCMS: 477.9 [M+H];

Chiral HPLC analysis results: retention time 1.688 min, purity 98.7%.

The characterization data of compound 39F2 are as follows:

LCMS: 477.9 [M+H];

Chiral HPLC analysis results: retention time 1.553 min, purity 100%.

Example 9

This embodiment relates to the preparation of compounds I-40, 40F15-bromo-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxycarboxamide)pyridinecarboxamide, and 40F25-bromo-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxycarboxamide)pyridinecarboxamide. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 5c (1 g, 2.8 mmol) was dissolved in 15 mL of dichloromethane. Oxaloyl chloride (1.4 g, 10.9 mmol) and a catalytic amount of DMF were added under ice bath conditions. After stirring for 1 hour, the solvent was evaporated to dryness. The residue was redissolved in DCM, and compound 8b (500 mg, 2.2 mmol), triethylamine (659 mg, 6.52 mmol), and 4-dimethylaminopyridine (14 mg, 0.1 mmol) were added and dissolved in 20 mL of dichloromethane. After reacting at room temperature for 2 hours, the reaction was quenched with water. The mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target product 9a (650 mg, yield 52.5%).

(2) Compound 9a (300 mg, 0.5 mmol) was added to a single-necked flask, along with 3 mL THF, 1 mL MeOH and 1 mL water, and lithium hydroxide (25 mg, 1.1 mmol). The mixture was reacted at room temperature for 1 hour. After the reaction was completed, the solvent was evaporated, and the pH was adjusted to acidic by adding 2N HCl. The mixture was extracted with dichloromethane (DCM), and the organic phase was dried over anhydrous sodium sulfate. The product was purified by column chromatography to obtain the target product 9b (200 mg, yield 68.3%).

(3) Compound 9b (200 mg, 0.4 mmol) was added to a single-necked flask, dissolved in 2 mL of dichloromethane, and tert-butylcalcium hypochlorite (92 mg, 0.8 mmol) was added. After reacting for 1 hour, the mixture was rotary evaporated to dryness, and the residue was dissolved in 1 mL of DCM. 2 mL of ammonia water was added, and the reaction was allowed to proceed for 5 minutes. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The target product I-40 (142 mg, yield 71.1%) was obtained by column chromatography.

¹ H NMR (400MHz, DMSO-d ₆ )δ8.80–8.68(m,1H),7.51(s,1H),7.21–7.09(m,3H),4.81(d,J＝10.7Hz,1H),4 .02(dd,J＝10.8,7.6Hz,1H),2.70–2.59(m,1H),1.54(s,4H),0.69–0.64(m,3H).

(4) Compound I-40 (142 mg) was resolved by chiral column chromatography to give compounds 40F1 (31 mg, yield: 21.8%) and 40F2 (35 mg, yield: 24.6%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak AD, 150×4.6mm I.D., 3μm;

Mobile phase: Mobile phase A: supercritical _CO2 , Mobile phase B: isopropanol, Gradient ratio: B = 5-40%, Flow rate: 2.5 mL/min.

The characterization data of compound 40F1 are as follows:

LCMS: 556.2 [M+H];

Chiral HPLC analysis results: retention time 1.956 min, purity 100%.

The characterization data of compound 40F2 are as follows:

LCMS: 556.2 [M+H];

Chiral HPLC analysis results: retention time 2.405 min, purity 100%.

Example 10

This embodiment relates to the preparation of compounds I-41 and 41F1 2-carbamoyl-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(deuteromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine-1-oxide-5-deuterium and 41F2 2-carbamoyl-4-((2S,3R,4R,5S)-3-(3,4-difluoro-2-(deuteromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine-1-oxide-5-deuterium. The reaction process is as follows:

The specific preparation process is as follows:

(1) Compound 8c (1800 mg, 5.2 mmol) and Boc anhydride (12.3 g, 10.4 mmol, 2.0 equivalence) were added to a single-necked flask and dissolved in 10 mL of dichloromethane. Triethylamine (1.6 g, 15.6 mmol) and 4-dimethylaminopyridine (64 mg, 0.5 mmol) were then added to the solution. The reaction mixture was stirred at room temperature for 4 hours under nitrogen protection. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The crude product was purified by column chromatography to give approximately the target product 10a (600 mg, yield 45.3%).

(2) Compound 10a (1.6 g, 6.3 mmol) was added to a single-necked flask and dissolved in 30 mL of dichloromethane. m-chloroperoxybenzoic acid (8.8 g, 50.6 mmol) was added to this solution. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated sodium sulfite solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure using a rotary evaporator. The crude product was purified by column chromatography to give the target product 10b (1.5 g, yield 89.2%).

(3) Compound 10b (1.5 g, 5.6 mmol) was added to a single-necked flask and dissolved in 30 mL of dichloromethane. Trifluoroacetic acid (10 mL) was added to the solution, and the reaction mixture was stirred overnight at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to neutral with triethylamine. The reaction solution was concentrated and dried by rotary evaporator to obtain the target product 10c, which was directly used in the next step of the reaction without purification.

(4) Compound 5c (2.2 g, 6.2 mmol) was dissolved in 30 mL of dichloromethane. Oxaloyl chloride (3.0 g, 23.7 mmol) and a catalytic amount of DMF were added under ice bath conditions. After stirring for 1 hour, the solvent was evaporated to dryness. The residue was redissolved in dichloromethane, and compound 10c (800 mg, 4.7 mmol), triethylamine (1.4 g, 14.2 mmol), and 4-dimethylaminopyridine (29 mg, 0.24 mmol) were added and dissolved in 35 mL of dichloromethane. After reacting at room temperature for 2 hours, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target product 10d (1.4 g, yield 58.0%).

(5) Compound 10d (1.4 g, 2.76 mmol) was added to 40 mL of methanol-ammonia solution (7 M) at room temperature and stirred overnight. Subsequently, the product I-41 (500 mg, yield: 36.7%) was purified by column chromatography.

¹ H NMR (400MHz, DMSO-d ₆ )δ10.84(s,1H),10.61(d,J＝4.6Hz,1H),8.59–8.50(m,1H),8.38–8.30(m,1H),8.26(d,J＝4.6Hz,1H),7.24–7.13 (m,2H),5.11(d,J＝10.2Hz,1H),4.26(t,J＝9.0Hz,1H),2.78(t,J＝7.5Hz,1H),1.62(s,3H),0.74(d,J＝7.3Hz,3H).

(6) Compound I-41 (210 mg) was resolved by chiral column chromatography to give compounds 41F1 (80 mg, yield: 38.1%) and 41F2 (88 mg, yield: 41.9%); chiral resolution conditions:

Instrument: Waters UPC2 analytical SFC (SFC-H);

Chromatographic column: ChiralPak IH, 100×4.6mm I.D., 3μm;

Mobile phase: Mobile phase A: supercritical _CO2 , Mobile phase B: ethanol, Gradient ratio: B = 5-40%, Flow rate: 2.5 mL/min.

The characterization data of compound 41F1 are as follows:

LCMS: 494.0 [M+H];

Chiral HPLC analysis results: retention time 3.025 min, purity 95.8%.

The characterization data of compound 41F2 are as follows:

LCMS: 494.0 [M+H];

Chiral HPLC analysis results: retention time 2.520 min, purity 100%.

Similarly, compounds 42F1, 43F1, 44F1, 45F1, 46F1, 47F1, 48F1, 49F1, 50F1, 51F1, 52F1, 53F1, 54F1, and 55F1 were prepared according to the synthesis method of Example 9.

Test Example 1

Using the known Nav1.8 inhibitor A-803467 as a control, the inhibitory activity of the above compounds against Nav1.8 was tested, as follows:

(1) Place the small glass slide containing cells from the culture dish into the perfusion tank of the micromanipulation stage. Use a ×10 objective lens to locate the tip of the glass electrode and center it in the field of view. Use the micromanipulator to move the electrode down while adjusting the coarse adjustment knob to slowly bring the electrode closer to the cell. Use the micromanipulator's fine adjustment setting to gradually bring the electrode closer to the cell surface. Apply negative pressure to form a seal with a resistance higher than 1 G between the electrode tip and the cell membrane.

(2) Compensation was performed on the instantaneous capacitive current Cfast in voltage-clamp mode. With the membrane potential clamped at -60mV, compensation was performed on the slow capacitive current Cslow, cell membrane capacitance (Cm), and input membrane resistance (Ra). After cell stabilization, the clamping voltage was changed to -80mV for 200ms; the sampling frequency was set to 20kHz, and the filtering frequency to 10kHz. Leakage current was detected when the depolarized membrane potential reached -80mV.

(3) Current stimulation method: After clamping the cells at -80mV, a depolarization command voltage of -10mV was applied for 20ms to open the channel. Stimulation was performed every 10 seconds. The instantaneous peak current at the depolarization voltage was the magnitude of the Nav1.8 sodium channel current.

(4) Testing the inhibitory effect of Nav1.8 current: First, the Nav1.8 current measured in normal extracellular fluid was used as the baseline. After the Nav1.8 current remained stable for at least 5 minutes, the solution containing the test compound was sequentially perfused around the cells from low to high concentration. After the recorded current tended to stabilize, the last 5 Nav1.8 current values were recorded, and their average value was taken as the final current value at the specific concentration.

(5) Data Analysis: The current suppression percentage is calculated using the following formula:

Peak current inhibition rate = [1 - (peak current size compound - peak current size positive control) / (peak current size blank control - peak current size positive control)] × 100%;

The dose-response curve was fitted using Graphpad Prism 8.0 software and the _IC50 value was calculated.

The test results are shown in Table 1 below:

Table 1

The inhibitory activity test results for Nav1.8 show that the novel amide derivatives provided by this invention have good inhibitory activity against Nav1.8, and compounds 1F1, 1F2, and 2F1 exhibit significantly better inhibitory activity against Nav1.8 than A-803467. Among them, compound 1F1 has an _IC50 value of less than 0.0016 μM, demonstrating extremely high inhibitory activity against Nav1.8.

Test Example 2

Using the known Nav1.8 inhibitor VX-548 as a control, the pharmacokinetic studies of the above compounds in rats were conducted as follows:

Experimental animals: Male SD rats (purchased from SPF Laboratory Animal Technology Co., Ltd.), age: 6-8 weeks, weight: 180-300 grams.

Administration: Intravenous (IV, 1 mg/kg); Oral (PO, 10 mg/kg).

Blood collection time points: IV (0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h); PO (0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24h).

All blood samples were transferred to plastic microcentrifuge tubes containing anticoagulant and centrifuged at 4000g, 4℃ for 5 min. The supernatant was then transferred to microcentrifuge tubes without anticoagulant. Plasma was stored at -75±15℃. LC-MS/MS analysis was performed after pretreatment.

Pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software.

The test results are shown in Table 2 below:

Table 2

Furthermore, as shown in Table 2, the novel amide derivatives provided by this invention not only exhibit high selectivity for Nav.18, but also possess advantages such as better pharmacokinetic properties and high bioavailability, which are beneficial for improving the therapeutic efficacy and safety of Nav.18-mediated diseases and expanding the clinical application scope of the drug.

The embodiments described above are merely preferred examples to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims (18)

Amide derivatives of Formula I or their pharmaceutically acceptable salts, stereoisomers, deuterated derivatives, hydrates, solvates, or solvent complexes:
in, A is selected from aryl or heteroaryl containing one or more heteroatoms of N, O, and S; ^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, oxygen, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine. R is selected from C1-C10 alkyl, halogenated and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogenated and/or deuterated C3-C10 cycloalkyl; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof, characterized in that A is selected from phenyl, pyridine, thiazole, furan, oxazole, isoxazole, quinoline. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof, characterized in that, in formula I, Choose from one of the following structures:
According to claim 1, the amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof is characterized in that R is trifluoromethyl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the C5-C10 fused heterocycle is selected from one of the following structures:
According to claim 1, the amide derivative or its pharmaceutically acceptable salt, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the structure of the amide derivative is as shown in Formula Ia:
in, ^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the structure of the amide derivative is as shown in formulas Ib and Ic:
in, Q is either N or CH; ^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, and N-hydroxyimide; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the structure of the amide derivative is as shown in formula Id-If:
in, ^G1 , ^G2 , and ^G3 are independently selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 and/or ^G2 form a ring with an imide linked to tetrahydrofuran and pyridine; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the structure of the amide derivative is as shown in formulas Ig and Ih:
in, Q is either N or CH; M is O, S, or N; ^G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 forms a ring with an imide linked to tetrahydrofuran and pyridine; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. According to claim 1, the amide derivative or its pharmaceutically acceptable salt, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the structure of the amide derivative is as shown in formulas Ii and Ij:
in, Q is either N or CH; M is O, S, or N; ^G1 is selected from hydrogen, deuterium, halogen, carboxyl, ester, amide, sulfonamide, tetrazolium, methyltetrazole, acylsulfonamide, imide, N-hydroxyimide, or ^G1 forms a ring with an imide linked to tetrahydrofuran and pyridine; _Y1 , _Y2 , _Y3 , and _Y4 are independently selected from hydrogen, deuterium, and halogens; When X is O, NH or S, _R1 is selected from C1-C10 alkyl, halogen and/or deuterated C1-C10 alkyl, C3-C10 cycloalkyl, halogen and/or deuterated C3-C10 cycloalkyl; When X is N, _R1X is selected from C3-C7 carbon heterocycles, C1-C6 dialkylamines, and C5-C10 fused heterocycles; When X is C, _R1X is selected from C2-C3 alkynyl, C2-C3 alkenyl, C3-C4 cycloalkyl, C5-C6 aryl, and C5-C6 heteroaryl. The amide derivative according to any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof, is characterized in that _R1X is selected from one of the following structures:
According to claim 1, the amide derivative or its pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof is characterized in that the amide derivative is one of the compounds shown in the following structures:








The use of an amide derivative of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate or solvent complex thereof in the preparation of a medicament for treating, alleviating or preventing diseases related to sodium channel modulation. A pharmaceutical composition characterized by comprising an amide derivative as described in any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, deuterated derivative, hydrate, solvate, or solvent complex thereof, and a pharmaceutically acceptable carrier or excipient. The use of the pharmaceutical composition of claim 14 in the preparation of a medicament for treating, alleviating or preventing sodium channel modulation-related diseases. The application according to claim 13 or 15 is characterized in that the sodium channel is Nav 1.8. The application according to claim 13 or 15 is characterized in that the disease includes pain, multiple sclerosis, and pathological cough; the pain includes acute pain and chronic pain; the acute pain includes, but is not limited to, surgical pain, bone pain, and toothache; and the chronic pain includes, but is not limited to, diabetic neuropathy and herpes zoster neuropathy. The application according to claim 13 or 15 is characterized in that the drug is administered alone or in combination with other therapeutic agents.