Macrocyclic sodium channel regulator

Abstract

Provided are macrocyclic sodium channel modulators, particularly Nav1.8 channel modulators, which are compounds of Formula I, preferably Formula I1, I2, or I3, isomers, racemate, or pharmaceutically acceptable salts thereof, where the definitions of the groups and substituents are as described in the specification.

Description

TECHNICAL FIELD

[0001] The present invention relates to a macrocyclic sodium channel modulator, in particular a Nav1.8 channel modulator. BACKGROUND

[0002] Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions into excitable cells and play an important role in initiating and propagating the action potential. Voltage-gated sodium channels are ubiquitous in the central and peripheral nervous systems, and are also found in skeletal and cardiac muscle.

[0003] Nav's form a subfamily of the voltage-gated ion channel superfamily and comprise nine isoforms, designated Nav1.1-Nav1.9. The nine isoforms have different tissue localizations. Nav1.4 is the major sodium channel of skeletal muscle, and Nav1.5 is the major sodium channel of cardiac cells. Nav's 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Nav's 1.1, 1.2, 1.3 and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but differs in specific aspects of voltage dependence and kinetic behavior.

[0004] Nav1.8 voltage-gated sodium channels are believed to play a role in a variety of diseases, including neuropathic pain, chronic itch, and inflammatory pain sensation.

[0005] There is still a need for effective inhibitors of Nav1.8 sodium ion channel activity that have selective activity against the Nav1.8 sodium ion channel. Accordingly, the compounds of the present invention are useful for the treatment and prevention of diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium ion channel. SUMMARY

[0006] The present invention provides compounds useful for the treatment and prevention of diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium ion channel.

[0007] In one aspect, the present application provides a compound of the structure of Formula I

[0008]

[0009] isomers, racemates, or pharmaceutically acceptable salts thereof, wherein:

[0010] Ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 9- membered heteroaryl, 10-membered heteroaryl, 11-membered heteroaryl, or 12-membered heteroaryl;

[0011] R1, R2are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, heterocycloalkyl being optionally further substituted with one or more substituents independently selected from the group consisting of hydrogen, hydroxy, C 1-6 alkoxy, haloC

[0012] R3is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 3-6 cycloalkyl, haloC 3-6 cycloalkyloxy, halo 3-7 membered heterocycloalkyl;

[0013] R4, R5, R6are independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, haloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 1-6 alkoxy, haloC 3-6 cycloalkyl, haloC 3-6 cycloalkyloxy, halo 3-7 membered heterocycloalkyl, -NH haloC 1-6 alkyl, -L1-L2-OR9, -L1-(C 2-6 alkylene)-OR9, -L1-L2-NR 10 R 11 , -CO-NR 10 R 11 , -SO2-NR 10 R 11 , -L1-L2-NHS(O)C 1-6 alkyl or L1-L2-R 12 ;

[0014] R9is selected from the group consisting of hydrogen, hydroxy, halogen, C 1-6 alkyl, haloC 1-6 alkyl;

[0015] R 10 , R11 each independently selected from hydrogen, hydroxy, C 1-6 alkyl, 3-7 membered heterocycloalkyl; or R 10 , R 11 and the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl ring;

[0016] R 12 is selected from C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 alkyl, -COOH, -SO2C 1-6 alkyl or -C(O)NR 10 R 11 wherein the 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy;

[0017] L1is selected from a bond, O;

[0018] L2is selected from C 1-6 alkylene;

[0019] Preferably, R4, R5or R5, R6may further form, with the carbon atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl;

[0020] said alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, alkenylene of R4, R5, R6are optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, -NH2, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0021] L is selected from a single bond, -NR 13 -, -S-, -O-, C 1-6 alkylene, C 2-6 alkylene, -X1-(X2) m -, -X1-(X2) m -X3-, -X1-(X2) m -X3-(X4) n -, -(X2) m -X1-(X4) n -, -(X2) m -X1-(X4) n -X3-, -X1-(X2) m -X3-(X4) n -X5-, -(X2) m -X1-(X4)n -X3-(X6) p - X1-(X2) m -X3-(X4) n -X5-(X6) p - X2 m -X1-(X4) n -X3-(X6) p -X5-;

[0022] X1, X3, X5are independently selected from a single bond, -NR 13 - S-, -O- or -CR 14 R 15 -;

[0023] X2, X4, X6are independently selected from -CR 16 R 17 -;

[0024] m, n, p are independently selected from 1, 2, 3 or 4;

[0025] the sum of m, n is 2, 3, 4 or 5;

[0026] the sum of m, n, p is 3, 4 or 5;

[0027] R 13 , R 14 , R 15 , R 16 , R 17 are independently selected from H, C 1-3 alkyl;

[0028] R7, R8are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyloxy, -C 1-6 alkyleneOH, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 alkyl, -C(O)OC 1-6 alkyl, -CO-NR 18 R 19 , -NR 18 R 19 , -N(R 18 R 19 )q, -L1-L2-OR9, -L1-L2-NR 18 R19 -NR9COC 1-6 alkyl, -SO2-NR 18 R 19 -S(=O)=NR 18 )R 19 -S(=O)NR 18 R 19 ;

[0029] q is 0, 1 or 2;

[0030] R 18 , R 19 is independently selected from hydrogen, -OH, -NH2, C 1-6 alkyl, C 3-6 alkoxy, C 18 cycloalkyl, 3-7 membered heterocycloalkyl, or R 19 and R 3-6 together with the nitrogen to which they are attached form a 3-7 membered heterocycloalkyl or C 1-6 cycloalkyl;

[0031] said alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylene of R7, R8is optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, -NH2, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0032] said isomer is an isomer of formula I-YG:

[0033]

[0034] In one embodiment of the application, R1is selected from -CF3.

[0035] In one embodiment of the application, R2is selected from -CH3.

[0036] In one embodiment of the application, R3is selected from -H, -CH3, -OCH3, halogen or -CH2F.

[0037] In one embodiment of the application, R4is selected from hydrogen, halogen, C 1-6 alkyl, C 10 alkoxy, -NR 11 R 1-6 , -NH haloC 1-6 alkyl or -OC 1-6 alkyleneSO2C 1-6 alkyl, preferably, R4is selected from hydrogen, halogen, C 3-6 alkoxy or C 1-6 cycloalkyl.

[0038] In one embodiment of the application, R5is selected from hydrogen or halogen.

[0039] In one embodiment of the application, R6is selected from hydrogen or halogen.

[0040] In one embodiment of the application, the compound, isomers, racemates, or pharmaceutically acceptable salts thereof, is selected from:

[0041]

[0042] wherein R1, R2, R3, R4, R5, R6, R7, R8, L and ring A are as defined above.

[0043] In one embodiment of the application, ring A is selected from

[0044] In one embodiment of the application, the atom of ring A to which NH is attached and the atom of ring A to which L is attached are ortho or meta to each other on ring A.

[0045] In one embodiment of the application, R7, R8are independently selected from H, -C 1-6 alkylene OH, -CO2C 1-6 alkyl, -CONH2, halogen, C 1-6 alkyl-SO2-, C 1-6 alkyl-S(=NH)(=O)-, C 1-6 alkyl NH-SO2-; said alkylene, alkyl groups are optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxy, -NH2, cyano, C 1-6 alkyl, C 1-6 alkoxy.

[0046] In one embodiment of the application, L is selected from -NH-, -O-, -CH2-,

[0047]

[0048] In one embodiment of the application, the structure including but not limited to:

[0049] In one optional embodiment of the application, the application also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0050]

[0051]

[0052]

[0053]

[0054] Definitions of terms:

[0055] In the present application, the term "C 1-6 "alkyl" means a straight or branched chain alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, tert-pentyl, or the like.

[0056] In the present application, the term "C 1-6 "alkylene" means a divalent radical formed by the removal of two hydrogen atoms from a C 1-6 alkyl group, and can be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. Unsubstituted alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0057] In the present application, the term "C 1-6 "alkoxy" means a straight or branched chain alkoxy group having 1-6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. C 1-4 alkoxy is preferred.

[0058] In the present application, the term "C 2-6 "alkenyl" means a straight or branched chain alkenyl group having 2-6 carbon atoms containing one double bond, including, but not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, and the like.

[0059] In the present application, the term "C 3-6 "cycloalkyl" means a cyclic alkyl group having 3-6 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0060] The term "5-10 membered heterocycloalkyl" is a 5-10 membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, S, preferably the 5-10 membered heterocyclic group contains one or more groups selected from NH, CO, C 1-6 alkylene, O, or SO2.

[0061] In the present application, the term "3-8 membered heterocycloalkyl" is a 3-8 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, S, including but not limited to 3-7 membered heterocycloalkyl,

[0062] "3-7 membered heterocycloalkyl" is a 3-7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, S, including but not limited to the following groups:

[0063] In the present application, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0064] In the present application, the term "halo" means substituted with a halogen. HaloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 1-6 alkoxy, haloC 3-6 cycloalkyl, haloC 3-6 cycloalkyloxy, halo3-7 membered heterocycloalkyl means a 3-7 membered heterocycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen group. 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-7 membered heterocycloalkyl means a 3-7 membered heterocycloalkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen group.

[0065] In the present application, the term "oxo" is O.

[0066] In the present application, the term "bond" is -.

[0067] In the present application, "----" is used to depict a chemical bond, which is the point at which a moiety or substituent is attached to a core structure or backbone structure.

[0068] In the present application, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one to several heteroatoms. For example, "heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, pyridine-2(lH)-one, pyridine-2-ol, and the like. The heteroaryl group can be optionally substituted or unsubstituted.

[0069] In the present application, the term "optionally substituted by one or more" or "optionally further substituted by one or more" means that one or more hydrogen atoms on the specified group are replaced by a specified substituent. The specified substituent is the substituent described in the preceding text, or the substituent appearing in the respective embodiment. Unless otherwise specified, a substituted group can have one substituent selected from a specified group at any substitutable position on the group, which can be the same or different at each position.

[0070] In the present application, the term "1-6" means 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality" means 2-6, such as 2, 3, 4, 5, or 6.

[0071] In the present application, the term "substituted" is to be construed as including the specified substituents in the number indicated. When a plurality of substituents is disclosed or claimed, a substituted compound can be singly or multiply substituted independently with one or more of the disclosed or claimed substituents. Independently substituted means that the substituent(s) can be the same or different.

[0072] The compounds of the present application can contain one or more asymmetric centers and can thus occur as isomers, racemates, and the like, where racemates include racemic forms and racemic mixtures; isomers include single enantiomers, diastereomeric mixtures, and individual diastereomers. The present application is meant to include all such isomeric forms of the compounds of Formula I, II, III, or IV.

[0073] Independent synthesis or chromatographic separation of optical isomers and diastereomeric isomers can be achieved, if desired, by appropriate modification of the methods disclosed herein, as is known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which have been derivatized with a reagent containing a sufficiently heavy atom or asymmetric center of known absolute configuration to provide absolute assignment.

[0074] If desired, racemic mixtures of the compounds can be separated so that the single enantiomers are isolated. The separation can be achieved by methods known in the art, for example, by the formation of mixtures of diastereomeric compounds and subsequent separation by standard methods such as fractional crystallization or chromatography.

[0075] Racemic mixtures of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration, by methods well known in the art.

[0076] In the compounds of general formula I, II, III, the atoms can exhibit their natural isotopic abundances, or one or more of the atoms can be artificially enriched with specific isotopes of the same atomic number but different atomic mass or mass number than the atoms primarily found in nature.

[0077] The present application is intended to include all suitable isotopic variations of the compounds of structural formula I, II, III. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H).

[0078] Isotopically enriched compounds within structural formula I, II, or III can be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and / or intermediates without undue experimentation.

[0079] In yet another aspect of the present application, there is provided a pharmaceutical composition comprising a compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of any one of the above, and a pharmaceutically acceptable carrier.

[0080] In yet another aspect of the present application, there is provided a use of a compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of any one of the above, a pharmaceutical composition in the manufacture of a medicament for treating a condition, a state, or a disease responsive to the inhibition of Nav1.8 channel activity in a mammal in need thereof. The ability of the compounds of the present application to block, partially block, interfere with, reduce, or decrease the activity or expression of Nav1.8 in a subject, "inhibition" encompasses complete and / or partial reduction in channel function, e.g., reduction by at least 10%, in some embodiments, by at least 20%, 30%, 50%, 75%, 95%, 98%, and up to and including 100%.

[0081] More specifically, the compounds of the present application have an activity IC 50 of less than 10 μΜ, more preferably less than 1 μΜ, more preferably less than 50 nM, more preferably less than 10 nM, against the Nav1.8 channel.

[0082] In yet another aspect of the present application, there is provided a use of a compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of any one of the above, a pharmaceutical composition in the manufacture of a medicament for treating, preventing, or managing a pain condition, a cough disorder, an acute itch disorder, or a chronic itch disorder.

[0083] In one embodiment of the application, the condition comprises a method of treating, preventing or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia.

[0084] In one embodiment of the application, the pain comprises neuropathic pain, musculoskeletal pain (preferably osteoarthritic pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain.

[0085] In one embodiment of the application, the neuropathic pain comprises one or more of post-herpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy or diabetic neuropathy, preferably diabetic peripheral neuropathy.

[0086] In one embodiment of the application, the postoperative pain comprises one or more of bunionectomy pain, abdominoplasty pain or hernia repair pain.

[0087] The present application also discloses administering one or more additional therapeutic agents to treat the subject concurrently with, prior to, or after treatment with the compound, isomer, racemate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0088] The present application further discloses the use of any of the above-mentioned compounds, isomers, racemates, or pharmaceutically acceptable salts thereof; or any of the above-mentioned pharmaceutical compositions as a medicament.

[0089] Advantages

[0090] The present application provides a Nav1.8 selective inhibitor with novel structure, excellent pharmacokinetic properties, good drug efficacy and drug development, which can be used for treating, preventing or controlling Nav1.8 related pain conditions, cough disorders, acute itch disorders or chronic itch disorders, and has significant clinical application value. DETAILED DESCRIPTION

[0091] The present application is further described below in conjunction with examples. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of the present application.

[0092] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art, and the experimental materials and reagents used can be obtained from commercial channels.

[0093] Experimental materials and analytical instruments:

[0094] Thin layer analysis (TLC) plate type HSGF-254 (thickness 0.15-0.2 mm, produced by Yantai Chemical Industry Factory); column chromatography silica gel is 200-300 mesh commercial silica gel produced by Qingdao Marine Chemical Factory;

[0095] 1 H-NMR was recorded using a Bruker Avance III-400 nuclear magnetic resonance instrument, with tetramethylsilane (TMS) as the internal standard; the chemical shift is (ppm, δ:), and the proton coupling label is singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m);

[0096] Low-resolution mass spectrometry was recorded using an Agilent 6110 mass spectrometer.

[0097] Abbreviations and notes:

[0098] Boc: tert-butyloxycarbonyl; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TCFH: tetramethylchloroformiurium hexafluorophosphate; NMI: N-methylimidazole; BINAP: 1,1'-binaphthalene-2,2'-bis(diphenylphosphine); CDCl3: chloroform; DMSO: dimethyl sulfoxide.

[0099] Example 1: Preparation of compound P-1

[0100] Example 1: Preparation of compound P-1

[0101]

[0102] The synthetic route of compound P-1 is as follows:

[0103]

[0104] Step 1: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0105] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylic acid (1.0 g, 2.8 mmol) was dissolved in acetonitrile solution, followed by the addition of iodomethane (0.59 g, 4.2 mmol) and potassium carbonate (1.2 g, 8.4 mmol). The reaction was stirred at 80 °C for 2 h. The reaction was monitored for completeness by TLC. The mixture was transferred to a separatory funnel with 100 mL of ethyl acetate and washed 2-3 times with saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. 0.85 g of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was obtained, with a yield of 82.4%. Calculated MSm / z: 368.10; Experimental: 369.12 [M+H] + .

[0106] Step 2: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0107] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylic acid ester (0.80 g, 2.2 mmol) was dissolved in dichloromethane and cooled to 0 °C. Then, a dichloromethane solution of boron tribromide (4.4 mL, 2.0 mol / L) was added, and the mixture was stirred at 0 °C for 4 h. The reaction was monitored by TLC to ensure complete reaction of the starting material. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was transferred to a separatory funnel with 100 mL of ethyl acetate and washed 2-3 times with saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under vacuum and purified by column chromatography to obtain 0.55 g of the pale yellow colloidal compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ester, with a yield of 70.1%. Calculated MSm / z: 354.27; Experimental: 355.08 [M+H] + .

[0108] Step 3: Preparation of methyl (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0109] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylic acid (0.50 g, 1.4 mmol) was dissolved in methanol and cooled to 0 °C. N-bromosuccinimide (0.75 g, 4.2 mmol) was then added. The reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium bicarbonate solution. The mixture was transferred to a separatory funnel with 100 mL of ethyl acetate and washed 2-3 times with saturated brine. After drying over anhydrous sodium sulfate, the solution was concentrated under reduced pressure and purified by column chromatography to give 0.38 g of methyl (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid, in 62.6% yield. Calculated MSm / z: 433.17; Experimental: 434.10 [M+H] + Step 4: Preparation of methyl (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid.

[0110] Methyl (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.38 g, 0.88 mmol) was dissolved in acetonitrile solution, followed by the addition of iodomethane (0.19 g, 1.3 mmol) and potassium carbonate (0.36 g, 2.6 mmol). The reaction was stirred at 80 °C for 2 h. The reaction was monitored for completeness by TLC. The mixture was transferred to a separatory funnel with 100 mL of ethyl acetate and washed 2-3 times with saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated under vacuum. 0.30 g of the pale yellow oily compound (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (76.2%) was obtained. Calculated MSm / z: 447.20; Experimental: 448.30 [M+H] + .

[0111] Step 5: Preparation of (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0112] Methyl (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.30 g, 0.67 mmol) was dissolved in tetrahydrofuran, cooled to 0 °C, then potassium tert-butoxide (150 mg, 1.34 mmol) was added, the mixture was stirred for 2 h, then the reaction was moved to room temperature. The system was adjusted to pH 3 with dilute hydrochloric acid (2.0 mol / L), then the system was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine 2-3 times. Dried over anhydrous sodium sulfate and concentrated under reduced pressure in vacuum. A light yellow solid compound (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was obtained, 0.25 g, with a yield of 86.5%. MS m / z calcd for C19H19F6NO5: 433.17; found: 434.51 [M+H] + .

[0113] Step 6: Preparation of methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5- nitrobenzoate

[0114] Into a 100 mL Schlenk tube was added methyl 4-bromo-2-fluoro-5-nitrobenzoate (1.0 g, 3.6 mmol), tert-butyl carbamate (0.63 g, 5.4 mmol), cesium carbonate (3.5 g, 10.8 mmol), Xantphos (0.42 g, 0.72 mmol), tris(dibenzylideneacetone)dipalladium (330 mg, 0.36 mmol) sequentially. Nitrogen was replaced for three times, then toluene (20 mL) was added with a syringe. 100 °C for 6 h, monitor by spotting on a plate until the reaction was complete. The system was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine 2-3 times. Dried over anhydrous sodium sulfate and concentrated under reduced pressure, then purified by column chromatography to obtain a yellow solid methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5-nitrobenzoate 0.55 g, with a yield of 48.6%. MS m / z calcd for C14H14F2N3O6: 314.27; found: 315.56 [M+H] + .

[0115] Step 7: Preparation of methyl 5-amino-4-((tert-butoxycarbonyl)amino)-2- fluorobenzoate

[0116] Methyl 4-((tert-butoxycarbonyl)amino)-2-fluoro-5-nitrobenzoate (0.55 g, 1.75 mmol) was dissolved in methanol (10 mL), palladium carbon catalyst (50% content, 0.12 g, 20% wt) was added, and the reaction was carried out at room temperature and normal pressure for 4 h with a hydrogen balloon. The reaction was monitored by spotting on a plate until completion. Filtration under suction and concentration under reduced pressure gave methyl 5-amino-4-((tert-butoxycarbonyl)amino)-2-fluorobenzoate 0.35 g in white gum, with a yield of 57.8%. MS m / z calcd for C15H17FN3O4: 284.29; found: 285.58 [M+H] + .

[0117] Step 8: Preparation of methyl 4-amino-5-((2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2- fluorobenzoate

[0118] A 100 mL vial was charged with (2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (90 mg, 0.23 mmol), methyl 5-amino-4-((tert-butoxycarbonyl)amino)-2-fluorobenzoate (68 mg, 0.28 mmol), TCFH (150 mg, 0.46 mmol), NMI (70 mg, 0.92 mmol), acetonitrile (30 mL). The reaction was carried out at room temperature for 3 h. The reaction was monitored by spotting on a plate until completion. The system was transferred to a separatory funnel with 100 mL ethyl acetate, and washed with saturated brine 2-3 times. Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give methyl 4-amino-5-((2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2- fluorobenzoate 105 mg in white solid, with a yield of 65.2%. MS m / z calcd for C25H25BrF6N3O5: 699.44; found: 700.50 [M+H] + .

[0119] Step 9: Preparation of methyl 4-amino-5-((2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2- fluorobenzoate

[0120] Methyl 5-((2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-4-((tert- butoxycarbonyl)amino)-2-fluorobenzoate (105 mg, 0.15 mmol) was dissolved in ethyl acetate (10 mL), and hydrogen chloride ethyl acetate solution (10 mL, 4.0 mol / L) was added. The reaction was carried out at room temperature for 6 h. The reaction was monitored by spotting on silica gel plate until it was completed. The pH of the system was adjusted to 8 by adding saturated sodium bicarbonate solution. The system was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine for 2-3 times. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give methyl 4-amino-5-((2R,3S,4S,5R)-3-(5-bromo-3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)- 2-fluorobenzoate 70 mg as a colorless gum in 77.8% yield. MS m / z calcd for C25H25BrF7NO5 599.32; found 600.41 [M+H] + .

[0121] Step 10: Preparation of methyl (2R,3S,3aS,15aR)-6,7,11-trifluoro-5-methoxy-2,3- dimethyl-15-oxo-2-(trifluoromethyl)-3,3a,9,14,15,15a-hexahydro-2H-4,8- (methyl)benzo[b]furo[2,3-f][1,4]diazocin-12-carboxylate

[0122] To a 100 mL Schlenk tube was added methyl 4-amino-5-((2R,3S,4S,5R)-3-(5-bromo-3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)- 2-fluorobenzoate (50 mg, 0.083 mmol), cesium carbonate (82 mg, 0.42 mmol), BINAP (5.2 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium (4.0 mg, 0.004 mmol). Nitrogen was purged for three times, followed by the addition of toluene (20 mL) via syringe. The reaction was heated at 100 °C for 12 h, monitored by spotting on silica gel TLC until completion. The reaction mixture was transferred to a separatory funnel with 100 mL ethyl acetate and washed with saturated brine 2-3 times. Dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to give methyl (2R,3S,3aS,15aR)-6,7,11 -trifluoro-5-methoxy-2,3-dimethyl-15-oxo-2- (trifluoromethyl)-3,3a,9,14,15,15a-hexahydro-2H-4,8-(methyl)benzo[b]furo[2,3- f][l,4]diazocin-12-carboxylate 35 mg, 72.0% yield. MS m / z calc 518.41 ; found 519.23 [M+H] + .

[0123] 1 H NMR (400 MHz, CDC13-d) δ 9.52 (s, 1H), 8.12 (s, 1H), 7.32 (dd, J = 6.8, 2.3 Hz, 2H), 7.26 (s, 1H), 5.64 (d, J = 10.1 Hz, 1H), 4.31 (t, J = 9.3 Hz, 1H), 3.97 (d, J = 2.7 Hz, 3H), 3.94 (s, 3H), 2.86 (p, J = 7.7 Hz, 1H), 1.60 (s, 3H), 0.87 (dd, J = 7.9, 2.6 Hz, 3H).

[0124] Example 2: Preparation of compound P-2

[0125]

[0126]

[0127] Into a 35 mL sealed tube was added (2R,3S,3aS,15aR)-6,7,11-trifluoro-5-methoxy- 2,3-dimethyl-15-oxo-2-(trifluoromethyl)-3,3a,9,14,15,15a-hexahydro-2H-4,8- (methyl)benzo[b]furo[2,3-f][1,4]diazocin-12-carboxylic acid methyl ester (Compound P-1, 35 mg, 0.067 mmol), ammonium hydroxide solution (10.0 mL, 7.0 mol / L), 60 °C sealed tube reaction for 24 h. TLC detection of the reaction was complete. The system was cooled to room temperature, concentrated under reduced pressure to give white solid (2R,3S,3aS,15aR)-6,7,11-trifluoro-5-methoxy-2,3-dimethyl-15-oxo-2- (trifluoromethyl)-3,3a,9,14,15,15a-hexahydro-2H-4,8-(methyl)benzo[b]furo[2,3- f][1,4]diazocin-12-carboxamide 15 mg, yield 55.0%. MS m / z calcd for: 503.13; found: 504.16 [M+H] + .

[0128] 1 H NMR (400 MHz, CDC13-d) δ 9.10 (s, 1H), 8.17 (s, 1H), 7.88 - 7.80 (m, 2H), 7.43 - 7.22 (m, 3H), 5.65 (d, J = 10.1 Hz, 1H), 4.34 (t, J = 9.3 Hz, 1H), 3.98 (d, J = 2.7 Hz, 3H), 2.85 (p, J = 7.7 Hz, 1H), 1.62 (s, 3H), 0.87 (dd, J = 7.9, 2.6 Hz, 3H).

[0129] Biological part test:

[0130] Test example: the blocking activity of the compound of the present application on sodium ion channel 1.8 (Nav1.8)

[0131] 1. Detection method: whole cell manual patch clamp technique to detect the effect of the compound on voltage-gated Nav1.8 channel current

[0132] 2. Preparation and analysis of the test compound

[0133] Blank control: take an appropriate amount of DMSO and add it to the extracellular fluid to obtain an extracellular fluid containing 0.1% DMSO as a blank control working solution.

[0134] Test compound: An appropriate amount of test compound was weighed, dissolved in DMSO to obtain a test compound stock solution, and then further diluted with extracellular solution to obtain test compound working solutions with different final concentrations of 10 nM, 50 nM, 0.1 μM, 1 μM and 10 μM (the concentration of DMSO in the working solution was not more than 0.3%).

[0135] 3. Cell culture

[0136] A CHO cell line stably expressing Nav1.8 (Gene information: SCN10A, NM_006514; SCN1B, NM_199037; SCN3B, NM_018400) was used for cell culture and passage in cell culture dishes using HAM'S / F-12 medium (containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B and 100 μg / mL Zeocin), and the cell culture incubator temperature was 37°C and the carbon dioxide concentration was 5%. In order to maintain the electrophysiological activity of the cells, the cell density in the culture dish should not exceed 80%.

[0137] Before patch clamp detection, the cells were separated by 0.25% trypsin-EDTA, and 6.5 x 10 3 cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL), and after tetracycline induction for 24-72 hours, the test was detected.

[0138] 4. Electrophysiological experiment

[0139] (1) Liquid for electrophysiological experiment

[0140] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH 7.4 adjusted with NaOH.

[0141] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH 7.2 adjusted with CsOH.

[0142] (2) Patch clamp detection

[0143] The voltage stimulation protocol for whole-cell patch-clamp recording of sodium currents is as follows: After whole-cell sealing, the cell voltage is clamped at -120 mV. First, the voltage is stepped from -130 mV to -10 mV in 10 mV increments, held for 5 s, and then a 0 mV depolarization pulse is applied to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of sodium currents are detected using a dual-pulse mode. First, a first depolarization pulse (TP1) is applied to 0 mV for 50 ms to detect the resting state sodium current. Then, the voltage is adjusted to Vhalf, held for 5 s, then restored to -120 mV, held for 20 ms, and then a second depolarization pulse (TP2) is applied to 0 mV for 50 ms to detect the half-inactivated state sodium current. Finally, the clamp voltage is restored to -120 mV. Data is collected repeatedly every 20 s to observe the effect of the drug on the peak sodium current in the two different states. The test data were acquired by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0144] The patch-clamp procedure begins by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, is then placed into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. Next, the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to aspirate and create a high-resistance seal (GΩ). Fast capacitance compensation is then performed, and continued negative pressure is applied to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0145] Once the sodium current recorded in whole cells stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before moving to the next concentration. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, while a peristaltic pump was used for fluid replacement during recording. The current detected in the solution without the compound served as a control for each cell. Each concentration was measured independently in duplicate using at least two cells. All electrophysiological experiments were performed at room temperature.

[0146] 5. Data Analysis

[0147] First, the peak sodium current after each drug concentration was applied was recorded. compound Peak current of blank control control Normalize, and then calculate the inhibition rate corresponding to each drug concentration under different states, i.e. The inhibition rate of each concentration was averaged.

[0148] The dose-effect curve was fitted using Hill equation: Y = Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)), where Bottom and Top represent the minimum and maximum values of inhibition, respectively, X represents the logarithmic value of compound concentration, Y represents the Peak-current compound / Peak-current Control The numerical value, IC 50 represents the drug concentration that produces a half-inhibitory effect, and HillSlope represents the Hill coefficient.

[0149] The percentage block activity of some compounds of the present application on Nav1.8 channel is shown in Table 1-3. TP1 is Resting state, TP2 is Half-inactivated state.

[0150] Table 1 Percentage block activity of some compounds of the present application on Nav1.8 channel at the concentration of 100 nM

[0151]

[0152] Table 2 Percentage block activity of some compounds of the present application on Nav1.8 channel at the concentration of 10 nM

[0153]

[0154] Table 3 Activity IC 50 value (nM) of representative compounds on Nav1.8 channel

[0155]

[0156] hERG activity test:

[0157] 1. Sample preparation

[0158] Blank control preparation: Take an appropriate amount of DMSO into the extracellular fluid to obtain extracellular fluid containing 0.3% DMSO as blank control working solution.

[0159] Positive control preparation: Weigh an appropriate amount of Cisapride, dissolve it with an appropriate amount of dimethyl sulfoxide (DMSO), and then dilute it with extracellular fluid to prepare working solutions with concentrations of 1000 nM, 100 nM, 10 nM, 1 nM and 0.1 nM (ensure the concentration of DMSO is 0.3%).

[0160] Test article preparation: The appropriate amount of test article was weighed into a vial and dissolved in DMSO. The test article was then diluted with extracellular solution to achieve a final concentration of 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM. The final concentration of DMSO in each of the working solutions was 0.3%.

[0161] 2. Cell Culture

[0162] The HEK-293 cell line stably expressing hERG potassium channel was purchased from Creacell (Cat. No. A-0320). The cells were cultured and passaged in cell culture flasks using DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418. The cell culture incubator was set at 37 °C with 5% CO2. The cell density must not exceed 80% to maintain the electrophysiological activity of the cells.

[0163] Before patch clamp assay, cells were detached with TrypLE Express and resuspended in extracellular solution at a concentration of 4 x 105 cells / mL. TM Express, 4 x 105 cells were plated onto coverslips in 24-well plates (final volume: 500 μL) and incubated for 18 hours before testing. 3

[0164] 3. Electrophysiological Recordings

[0165] Extracellular solution: K-007-1, 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2 6H2O, 2 mM CaCl2 2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4 2H2O, pH 7.4 adjusted with NaOH.

[0166] Intracellular solution: K-002-2, 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2 6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH 7.2 adjusted with KOH.

[0167] ​Patch-clamp assay: The voltage stimulation protocol for whole-cell patch-clamp recording of hERG currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -80 mV. The clamp voltage is depolarized from -80 mV to -50 mV and maintained for 0.5 s (as leakage current detection), then stepped to 30 mV and maintained for 2.5 s, and then rapidly restored to -50 mV and maintained for 4 s to excite the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. A 0.5 s stimulation at -50 mV is used as the leakage current detection. Experimental data are acquired using an IPA amplifier (Sutter Instrument) and stored in SutterPatch (with IgorPro) software.

[0168] The patch-clamp procedure begins by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, is then placed into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. Next, the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to aspirate and create a high-resistance seal (GΩ). Fast capacitance compensation is then performed, and continued negative pressure is applied to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0169] Once the hERG current recorded in whole cells stabilized, drug administration began. Each drug concentration was administered for 5 minutes (or until the current stabilized) before moving to the next concentration. Multiple concentrations were measured for each test compound. A coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solution and working solution of the test compound were perfused sequentially from low to high concentration through the recording bath using gravity perfusion, with fluid exchange performed using a peristaltic pump during recording. The current detected in the compound-free solution for each cell served as its control group. Each concentration was measured independently in triplicate using at least three cells. All electrophysiological experiments were performed at room temperature.

[0170] 4. Data Analysis

[0171] First, the peak tail current after each drug concentration was applied was recorded. compound Peak tail current (and blank control) control Normalize, and then calculate the inhibition rate corresponding to each drug concentration. The average inhibition rate was calculated for each concentration.

[0172] The dose-response curve was fitted using the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50- Bottom + (Top - Bottom) * (X / HillSlope)), where Bottom and Top are the minimum and maximum values of the inhibition, X is the logarithm of the compound concentration, and Y is the peak tail current compound / Peak tail current Control Value, IC 50 represents the drug concentration that produces half-maximal inhibition, and HillSlope represents the Hill coefficient.

[0173] Liver microsomal stability test:

[0174] 1. Sample preparation

[0175] Test compound and positive control compound stock solution: The test compound and positive control compound (dextromethorphan) were dissolved in DMSO to prepare 1 mM intermediate stock solution. The intermediate stock solution was then diluted with acetonitrile (ACN) to prepare 200 μM working solution.

[0176] Phosphate buffer: 8.709 g of potassium phosphate dibasic (K2HPO4) was dissolved in 950 mL of water, and the pH of the solution was adjusted to 7.4 with hydrochloric acid, and then water was added to make up to 1000 mL. After filtration with a 0.22 μm filter, it was stored in a 4°C refrigerator for use.

[0177] Incubation matrix working solution: After thawing the various species of liver microsomes (protein concentration 20 mg / mL) in a 37°C water bath, they were diluted with the phosphate buffer solution to obtain a liver microsome working solution having a protein concentration of 0.629 mg / mL.

[0178] NADPH working solution: A 5 mM NADPH solution was prepared using the above phosphate buffer solution for use.

[0179] Reaction termination solution: A 1 mg / mL terfenadine / tolbutamide stock solution was prepared using DMSO, and then diluted with a mixture of 50% methanol / 50% acetonitrile to prepare a reaction termination solution containing 5 / 10 ng / mL (terfenadine / tolbutamide) internal standard.

[0180] 2. Incubation and detection

[0181] Take 238.5 μL of different species of liver microsomes working solution into 1.1 mL microtiter tube, add 1.5 μL of the test compound working solution or positive control compound (dextromethorphan) working solution (200 μM) respectively, mix well, and pre-incubate in 37 degree water bath for 5 min. Add 60 μL of NADPH solution to start the reaction, mix well, and at 0, 5, 15, 30 and 60 min time points after the reaction, take 30 μL of the reaction solution and add to 300 μL of reaction termination solution. After vortexing all time point samples for 1 min, centrifuge at 4000 rpm at 4 degree for 15 min. Take the supernatant for LC-MS / MS analysis.

[0182] 3. Data analysis

[0183] The slope (ke) is measured by plotting the natural logarithm of the remaining amount of the compound against time, and T is calculated according to the first order kinetic formula. 1 / 2 and intrinsic clearance (CL int ):

[0184] The remaining amount of the compound is calculated as follows:

[0185]

[0186] C t = C0* e -ke*t

[0187] lnC t = lnC o – ke * t

[0188] According to the above formula, when , then

[0189] Intrinsic clearance CL int (μL / min / mg protein) = 0.693*1000 / T 1 / 2 / protein concentration (0.5 mg protein / mL)

[0190]

[0191] It is assumed that the unbound portion (Fu) in the liver microsomal mixture is 100%.

[0192]

[0193] The following physiological variables are used for prediction calculation:

[0194]

[0195] Solubility test:

[0196] The solubility of representative compounds was tested in this experimental example.

[0197] In vivo pharmacokinetic test in rats:

[0198] In vivo pharmacokinetic evaluation of rats was performed by single intravenous injection in this experimental example.

[0199] 1. Test method and condition: Male SD rats, all animals were fasted overnight, and were administered with 1 mg / kg of the test compound by single intravenous injection.

[0200] 2. Sampling information: Whole blood was collected at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0 and 24 h after administration, and was placed in a micro centrifuge tube containing EDTA-K2 anticoagulant. The supernatant was obtained after centrifugation at 4°C and 4000 rpm for 5 min, and was stored in a refrigerator at -75°C±15°C.

[0201] 3. Detection information: The drug concentration in plasma at different time points was detected by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software.

[0202] The above examples are numbered and correspond to the structural formula, and are only used to illustrate the technical solutions of the present application, but not to limit it. Although the present application has been described in detail with reference to the foregoing examples, it should be understood by those skilled in the art that the technical solutions recorded in the foregoing examples can be modified, or some or all of the technical features can be replaced equivalently, without departing from the spirit and essence defined in the claims of the present application.

Claims

1. A compound of the structure of Formula I isomers, racemates, or pharmaceutically acceptable salts thereof, wherein: ring A is selected from phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 9- membered heteroaryl, 10-membered heteroaryl, 11-membered heteroaryl, or 12- membered heteroaryl; R1, R2are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 3-6 cycloalkyl, halo3-7 membered heterocycloalkyl, which alkyl, alkoxy, cycloalkyl, heterocycloalkyl groups are optionally further substituted with one or more substituents independently selected from hydrogen, hydroxy, C 1-6 alkoxy. R3is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl; R4, R5, R6are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halogenated C 1-6 alkyl, halogenated C 2-6 alkenyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NH halogenated C 1-6 alkyl, -L1-L2-OR9, -L1-(C 2-6 alkenylene)-OR9, -L1-L2-NR 10 R 11 , -CO-NR 10 R 11 , -SO2-NR 10 R 11 , -L1-L2-NHS(O)C 1-6 alkyl or L1-L2-R 12 ; R9is selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, haloC 1-6 alkyl; R 10 , R 11 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl, 3-7 membered heterocycloalkyl; or R 10 , R 11 and the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyl group; R 12 selected from C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 alkyl, -COOH, -SO2C 1-6 alkyl or -C(O)NR 10 R 11 wherein the 5-6 membered heteroaryl can be optionally further substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy; L1is selected from a bond, O; L2is selected from C 1-6 alkylene; Preferably, R4, R5or R5, R6may further be ringed with the carbon atom to which they are attached to form a 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl; The alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, and alkenyl groups described in R4, R5, and R6 are optionally selected from hydrogen, halogen, hydroxyl, -NH2, cyano, and C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; L is selected from the group consisting of a single bond, -NR 13 -, -S-, -O-, C 1-6 alkylene, C 2-6 alkenylene, -X1-(X2) m -, -X1-(X2) m -X3-, -X1-(X2) m -X3-(X4) n -, -(X2) m -X1-(X4) n -, -(X2) m -X1-(X4) n -X3-, -X1-(X2) m -X3-(X4) n -X5-, -(X2) m -X1-(X4) n -X3-(X6) p -, X1-(X2) m -X3-(X4) n -X5-(X6) p -, -(X2) m -X1-(X4) n -X3-(X6) p -X5-; X1, X3, X5are independently selected from a single bond, -NR 13 -, -S-, -O- or -CR 14 R 15 -; X2, X4, X6are independently selected from -CR 16 R 17 -; m, n, p are independently selected from 1, 2, 3, or 4; the sum of m, n is 2, 3, 4, or 5; the sum of m, n, p is 3, 4, or 5; R 13 , R 14 , R 15 , R 16 , R 17 is independently selected from H, C 1-3 alkyl; R7, R8are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkyloxy, -C 1-6 alkyleneOH, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NH halogenated C 1-6 alkyl, -C(O)O C 1-6 alkyl, -CO-NR 18 R 19 , -NR 18 R 19 , -N(R 18 R 19 )q, -L1-L2-OR9, -L1-L2-NR 18 R 19 , -NR9COC 1-6 alkyl, -SO2-NR 18 R 19 , -S(=O)=NR 18 )R 19 , -S(=O)NR 18 R 19 ; q is 0, 1, or 2; R 18 , R 19 are independently selected from hydrogen, -OH, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, or R 18 , R 19 are taken together to form a 3-7 membered heterocycloalkyl or C 3-6 cycloalkyl; R7, R8, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, alkylene groups are optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, -NH2, cyano, C 1-6 alkyl, C 1-6 alkoxy; the isomer is of the structure of Formula I-YG:

2. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R1is selected from -CF3.

3. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R2is selected from -CH3.

4. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R3is selected from -H, -CH3, -OCH3, halogen, or -CH2F.

5. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R4is selected from hydrogen, halogen, C 1-6 alkoxy, halogen-C 1-6 alkoxy, -NR 10 R 11 , -NH halogen-C 1-6 alkyl or -OC 1-6 alkylene-SO2C 1-6 alkyl, preferably R4is selected from hydrogen, halogen, C 1-6 alkoxy or C 3-6 cycloalkyl.

6. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R5is selected from hydrogen or halogen; preferably, R6is selected from hydrogen or halogen.

7. The compound, isomers, racemates, or pharmaceutically acceptable salts thereof, according to claim 1, selected from: wherein, R1, R2, R3, R4, R5, R6, R7, R8, L, and ring A are as defined in claim 1.

8. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: Ring A is selected from 9. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: the atom of ring A to which NH is attached and the atom of ring A to which L is attached are ortho or meta to each other on ring A.

10. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: R7, R8are independently selected from H, -C 1-6 alkylene OH, -CO2C 1-6 alkyl, -CONH2, halogen, C 1-6 alkyl-SO2-, C 1-6 alkyl-S(=NH)(=O)-, C 1-6 alkyl NH-SO2-; said alkylene, alkyl groups are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, hydroxy, -NH2, cyano, C 1-6 alkyl, C 1-6 alkoxy.

11. The compound, isomers, racemates, or pharmaceutically acceptable salts thereof, according to claim 1, wherein: L is selected from -NH-, -O-, -CH2-, 12. The compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of claim 1, wherein: Structure including, but not limited to:

13. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising a compound, isomers, racemates, or pharmaceutically acceptable salts thereof, according to any one of claims 1-12, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 13, and a pharmaceutically acceptable carrier.

16. Use of a compound, isomers, racemates, or pharmaceutically acceptable salts thereof, according to any one of claims 1-12, a compound, or a pharmaceutically acceptable salt thereof, according to claim 13, or a pharmaceutical composition according to any one of claims 14-15, in the manufacture of a medicament for treating a condition, a state, or a disease responsive to inhibition of Nav1.8 channel activity in a mammal in need thereof.

17. Use of a compound, isomers, racemates, or pharmaceutically acceptable salts thereof, according to any one of claims 1-12, a compound, or a pharmaceutically acceptable salt thereof, according to claim 13, or a pharmaceutical composition according to any one of claims 14-15, in the manufacture of a medicament for treating, preventing, or managing a pain condition, a cough condition, an acute itch condition, or a chronic itch condition; preferably, the condition comprises chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia, or a method of reducing the severity thereof. Preferably, the pain comprises neuropathic pain, musculoskeletal pain (preferably osteoarthritic pain), acute pain (preferably acute postoperative pain), postoperative pain, or visceral pain; Preferably, the neuropathic pain comprises one or more of postherpetic neuralgia, small-fiber neuropathy, idiopathic small-fiber neuropathy, or diabetic neuropathy, preferably diabetic peripheral neuropathy; Preferably, the postoperative pain comprises one or more of bunionectomy pain, abdominoplasty pain, or hernia repair pain; Preferably, the subject is treated with one or more additional therapeutic agents concurrently with, prior to, or subsequent to treatment with the compound, isomer, racemate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

18. Use of a compound, isomer, racemate, or pharmaceutically acceptable salt thereof, of any one of claims 1-12, a compound or pharmaceutically acceptable salt thereof of claim 13, or a pharmaceutical composition of any one of claims 14-15 as a medicament.

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