Ketone derivatives, processes for their synthesis and uses thereof

Abstract

The application provides a ketone derivative, a synthesis method and use thereof, and belongs to the technical field of drug synthesis. In the application, halogenated benzene compounds and 3-hydroxy-2-pyrazine carboxylic acid are used as raw materials, specific reactions are carried out, and the ketone derivative is obtained. The compound is a Nav1.8 inhibitor, has good analgesic activity, has a quick effect, has a long analgesic time, and has a good application prospect in the preparation of analgesic drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a ketone derivative and a synthesis method and use thereof. BACKGROUND

[0002] Pain is one of the most common symptoms in clinic, and pain lasting more than 3 months is chronic pain. Chronic pain has a serious harm to the physical and mental health, social interaction and quality of life of human beings. According to statistics, about 35%-45% of the general population worldwide suffer from pain, and the incidence of chronic pain in adults is about 30%.

[0003] Analgesics are a class of drugs that mainly act on the nervous system, selectively reduce or eliminate pain and adverse emotional reactions such as mental tension and restlessness caused by pain, but do not affect consciousness and other feelings. Most of the existing drugs have the shortcomings of poor treatment effect and large side effects of long-term use. For example: commonly used opioid drugs have a high risk of addiction and abuse; and non-steroidal anti-inflammatory drugs and tricyclic antidepressants have moderate analgesic effect, and at the same time, can cause a series of adverse reactions, including acute kidney injury, gastroduodenal toxicity and cardiotoxicity. Therefore, the treatment of chronic pain is an unmet health problem, and there is an urgent need for methods to treat or relieve the pain.

[0004] Unlike the mechanism of action of addictive opioid drugs, ion channel drugs mainly affect the formation and conduction of nerve electrophysiological signals by regulating ion channels of nerve cells. This difference in mechanism makes them not addictive.

[0005] The occurrence of pain is closely related to the function of sodium ion channels. Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on cell membranes, composed of alpha and beta subunits, and are important determinants of the excitability of sensory neurons. Nav1.8 is one of the voltage-gated sodium channel subtypes, encoded by the gene SCN10A, and mainly expressed in peripheral neurons. Mutational studies of Nav1.8 have found that it is related to neuropathic pain and pain sensitivity, and plays an important role in chronic neuropathic pain and chronic inflammatory pain. In some animal pain models, the expression level of Nav1.8 mRNA increases in the dorsal root ganglion. In addition, it has been found that intraneural injection of Nav1.8 antisense nucleotides not only reduces spontaneous pain and hyperalgesia in animal pain models, but also reduces mechanical allodynia.

[0006] Sodium ion channels are responsible for the initiation and upstroke of the action potential in excitable cells. By regulating the expression of Nav1.8 and related animal experiments, it is confirmed that Nav1.8 is related to chronic pain. A-803467 is a Nav1.8 selective blocker, which shows promising in preclinical studies of treating chronic pain, but its bioavailability is low, and it does not have good physical and chemical properties, which limits its application. At present, there is no selective Nav1.8 inhibitor applied in clinic. Therefore, it is necessary to develop a new type of small molecule drug targeting Nav1.8 to solve the demand for chronic pain treatment. SUMMARY

[0007] In view of the deficiencies of the prior art, the purpose of the present application is to provide a ketone derivative and a synthesis method and use thereof.

[0008] The present application provides a ketone derivative, its stereoisomer, and its pharmaceutically acceptable salt, and the structural formula of the compound is:

[0009]

[0010] wherein R 1 is selected from C 1-6 alkyl, halogen, cyano, thiol, C 1-6 alkoxy, trifluoromethyl, nitro;

[0011] R 2 is selected from hydrogen, C 1-6 alkyl, halogen, cyano, hydroxyl, trifluoromethyl, nitro;

[0012] R 3 is selected from hydrogen, C 1-3 alkyl, C 1-6 alkoxy, halogen, cyano, hydroxyl, trifluoromethyl;

[0013] R 4 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, hydroxyl, trifluoromethyl;

[0014] R 5 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, hydroxyl.

[0015] Further, the structure of the ketone derivative is as shown in formula II or formula III:

[0016]

[0017] wherein R 1 is selected from C 1-3 alkyl, halogen, trifluoromethyl;

[0018] R 2 selected from hydrogen, C 1-3 alkyl, halogen;

[0019] R 3 selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxyl;

[0020] R 4 selected from hydrogen, C 1-3 alkyl, hydroxyl;

[0021] R 5 selected from hydrogen, C 1-3 alkyl, hydroxyl.

[0022] Further, the ketone derivative comprises the following structural formula:

[0023]

[0024] The present application also provides a method for preparing the ketone derivative, its stereoisomer, and its pharmaceutically acceptable salt, comprising the following steps:

[0025]

[0026] (1) reacting compound A, compound B, a nitrogen nucleophile, a base, and a catalyst to obtain intermediate C;

[0027] (2) reacting intermediate C, a base, and an azide reagent to obtain intermediate D;

[0028] (3) reacting intermediate D, compound E, an alkylating reagent, and a reducing agent to obtain compound F, i.e., the ketone derivative;

[0029] wherein X is selected from halogen.

[0030] Further, in step (1), the molar ratio of compound A, compound B, the nitrogen nucleophile, the base, and the catalyst is 1:0.5-1.5:0.5-1:10-15:0.1-0.5; the nitrogen nucleophile is (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine; the base is an organic base or an inorganic base; the catalyst is a metal catalyst; the solvent of the reaction is an organic solvent; the temperature of the reaction is 180-220℃, and the time is 10-20 minutes.

[0031] In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.1-0.5:1-1.5; the base is an organic base or an inorganic base; the azidation reagent is diphenyl phosphorazide; the solvent of the reaction is a mixture of an organic solvent and an inorganic solvent; the reaction condition is that the reaction is first carried out at 10-40℃ for 0.5-1.5 hours, and then at 60-100℃ for 0.5-1.5 hours;

[0032] In step (3), the molar ratio of the intermediate D, the compound E, the alkylating reagent and the reducing agent is 1:5-7:4-6:8-10; the alkylating reagent is magnesium methoxide; the reducing agent is sodium borohydride; the solvent of the reaction is an organic solvent; the reaction condition is that the reaction is first carried out at 50-60℃ for 2-4 hours, and then at 10-40℃ for 20-40 minutes.

[0033] Further, in step (1), the molar ratio of the compound A, the compound B, the nitrogen nucleophile, the base and the catalyst is 1:1:0.7:13:0.3; the base is potassium carbonate; the catalyst is cuprous iodide; the solvent of the reaction is N,N'-dimethylformamide; the reaction temperature is 200℃, and the reaction time is 15 minutes;

[0034] In step (2), the molar ratio of the intermediate C, the base and the azidation reagent is 1:0.3:1.1; the base is triethylamine; the solvent of the reaction is a mixture of tetrahydrofuran and water; the reaction condition is that the reaction is first carried out at 20-30℃ for 1 hour, and then at 80℃ for 1 hour;

[0035] In step (3), the molar ratio of the intermediate D, the compound E, the alkylating reagent and the reducing agent is 1:6:5:9; the solvent of the reaction is methanol; the reaction condition is that the reaction is first carried out at 55℃ for 3 hours, and then at 20-30℃ for 30 minutes.

[0036] Further, after the reaction of step (1) is completed, the following purification step is further included: the reaction solution is diluted with ethyl acetate; the organic phase is washed with water and 10% LiCl aqueous solution, dried, filtered, and concentrated to obtain the intermediate C;

[0037] In step (2), the feeding mode of the reaction is that the intermediate C, the azidation reagent and the base are added into tetrahydrofuran, the reaction is first carried out at 20-30℃ for 1 hour, water is added, and then the reaction is carried out at 80℃ for 1 hour;

[0038] In step (3), the feeding mode of the reaction is that the intermediate D, the compound E and the alkylating reagent are added into methanol, the reaction is first carried out at 55℃ for 3 hours, the reducing agent is added, and then the reaction is carried out at 20-30℃ for 30 minutes;

[0039] After the reaction of step (3) is completed, the following purification step is included: adjusting the pH to 7 with concentrated hydrochloric acid, removing the solvent, extracting with ethyl acetate, aqueous hydrochloric acid, aqueous potassium hydroxide, drying, concentrating, and obtaining the ketone derivative.

[0040] The present application also provides the use of the above ketone derivative, its stereoisomer, and its pharmaceutically acceptable salt in the preparation of an analgesic drug.

[0041] Further, the analgesic drug is a non-addictive analgesic drug, and the non-addictive analgesic drug includes a chronic neuropathic pain drug and a chronic inflammatory pain drug.

[0042] The present application also provides a pharmaceutical composition which is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the above ketone derivative, its stereoisomer, and its pharmaceutically acceptable salt as an active ingredient.

[0043] In the present application, the compounds and derivatives provided are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, OH) nomenclature system.

[0044] Definitions of terms used in the present application: Unless otherwise indicated, the initial definition of a group or term provided herein applies to that group or term throughout the specification; terms not specifically defined herein have a meaning as would be given to them by one of ordinary skill in the art in light of the disclosure and context, and should not be limited to a specialized meaning unless expressly so defined. Among others:

[0045] "Substituted" means that a hydrogen atom in a molecule is replaced by another different atom or molecule;

[0046] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a～b Alkyl means any alkyl group of from "a" to "b" carbon atoms. For example, C 1～6 Alkyl means any alkyl group of from "a" to "b" carbon atoms. For example, C 1-4 Alkyl means any alkyl group of from "a" to "b" carbon atoms. For example, C

[0047] "Alkyl" means a saturated hydrocarbon chain having the specified number of members. Alkyl groups can be straight-chained or branched, and the alkyl groups can be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl).

[0048] "Alkoxy" represents the above-mentioned alkyl group having the specified number of carbon atoms attached through an oxygen bridge, unless otherwise specified. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy.

[0049] "Halogen" is fluorine, chlorine, bromine or iodine.

[0050] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the application. Unless otherwise specified, all tautomeric forms of the compounds of the application are within the scope of the application.

[0051] Unless otherwise specified, structures depicted herein are also meant to include solvates of the compounds, solvates being a physical association of a compound with one or more solvent molecules; the physical association involving varying degrees of ionic and covalent bonding, including hydrogen bonding; and the solvent molecules being those of a pharmaceutically acceptable solvent that are in no way toxic at the dosages contemplated; suitable examples of which include, but are not limited to, isopropanol, ethanol, methanol, polyethylene glycols, DMSO, acetone, acetic acid, and ethanolamine; "hydrates" are solvates wherein the solvent molecule is H2O;

[0052] The term "pharmaceutically acceptable" means that which is generally compatible with pharmaceutical administration and with the other ingredients in a pharmaceutical formulation, and which is physiologically acceptable to the recipient.

[0053] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid and / or base salts of the foregoing compounds and stereoisomers thereof, and include anionic, cationic, and zwitterionic salts. These salts can be formed by conventional means. Such salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsylate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mesylate, methylbromide, methylnitrate, methylsulfate, napsylate, nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and the like. The salts of the present application can be prepared by conventional means.

[0054] In addition, the compounds of the present application can be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain components such as diluents, carriers, pH modifiers, sweeteners, flavoring agents, coloring agents, and additional active agents;

[0055] The compounds of the application can be administered by any suitable mode including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intradermal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intraocular, intralesional or subcutaneous administration.

[0056] The present technical solution has the beneficial technical effects that:

[0057] The present application provides a ketone derivative and a synthesis method thereof, the ketone derivative is used for treating non-addictive chronic pain, has fast effect, long analgesic time, and has a wide application prospect in preparation of non-addictive chronic analgesic drugs.

[0058] In addition, the ketone derivative synthesized in the present application has inhibitory activity on Nav1.8 and belongs to a Nav1.8 inhibitor. It is known to those skilled in the art that the Nav1.8 inhibitor has good analgesic activity and can be used for extensive pain treatment. The ketone derivative in the present application has a wide application prospect in preparation of non-addictive chronic analgesic drugs as the Nav1.8 inhibitor.

[0059] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0060] The above content of the present application is further described in detail through the specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0061] Figure 1 Mechanical pain threshold-time curve of compound 1-5 in the CFA pain model.

[0062] Figure 2 Mechanical pain threshold-time curve of compound 6-9 in the CFA pain model.

[0063] Figure 3 Area under curve (AUC) of mechanical pain threshold-time curve of compound 1-9 in the CFA pain model.

[0064] Figure 4 Inhibition rate of compound 1 on resting state Nav1.8 current and time-current response curve.

[0065] Figure 5Inhibition rate of compound 1 on semi-inactivated Nav1.8 current and time-current curve. DETAILED DESCRIPTION

[0066] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products.

[0067] The structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is given in units of HT6 (ppm). The NMR measurement uses a fcuker NEO (400 MHz) nuclear magnetic instrument, the solvent is deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS). The MS measurement uses a Waters Q-TOF-Premier. The high performance liquid chromatography (HPLC) analysis uses Shimadzu's LC-20AD.

[0068] The "room temperature (rt)" referred to in the present application is 25±5°C.

[0069] Example 1, method for preparing the ketone derivative of the present application

[0070] According to the following synthetic route, the ketone derivative is prepared:

[0071]

[0072] The synthetic conditions involved are as follows:

[0073] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, N,N'-dimethylformamide (DMF), 200°C, 15 min;

[0074] S2: triethylamine, diphenyl phosphorazide, tetrahydrofuran, 80°C~rt, 2h;

[0075] S3: methyl magnesium, sodium borohydride, methanol, 55°C~rt, 3h~0.5h;

[0076] The specific synthetic process involved is as follows:

[0077] Step 1: preparation of intermediate 1a

[0078]

[0079] To a microwave reactor was added 4-chloroisopropylbenzene (1 g, 6.47 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (905.98 mg, 6.47 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (643.91 mg, 4.53 mmol), copper(I) iodide (369.48 mg, 1.94 mmol) and potassium carbonate (11.62 g, 84.07 mmol) mixed in 10 mL of DMF; microwave irradiation at 200 °C for 15 minutes; the reaction was diluted with ethyl acetate (100 mL); the organic phase was washed with water and 10% aqueous LiCl solution; dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure; after removing the solvent, intermediate 1a was obtained as a colorless oily liquid (1.43 g). Yield 88%. ESI [M+H] + : 259.1038.

[0080] Step 2: Preparation of intermediate 1b

[0081]

[0082] Intermediate 1a (1 g, 3.87 mmol), diphenyl phosphorazide (1.23 g, 4.45 mmol) and triethylamine (117.54 mg, 1.16 mmol) were dissolved in tetrahydrofuran (35 mL) and the mixture was stirred at room temperature for 1 hour; to the mixture was added water (6 ml) and stirred at 80 °C for 1 hour; after the reaction was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35 mL); the layers were separated and the aqueous layer was extracted with ethyl acetate (35 mL x 3) and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35 mL); the washed organic phase was dried over sodium sulfate; filtered and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. A colorless oily liquid was obtained (595 mg). Yield 67%. ESI [M+H] + : 230.1249.

[0083] Step 3: Preparation of compound 1

[0084]

[0085] Intermediate 1b (100 mg, 0.44 mmol) and 3,4-dimethoxybenzaldehyde (434.86 mg, 2.62 mmol) were dissolved in 4 mL of methanol, and magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; then sodium borohydride (148.50 mg, 3.93 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid (0.05 M, 4 mL); the aqueous phase was neutralized with aqueous potassium hydroxide (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 1 was obtained as a white solid (124 mg). Yield 75%, purity 99.7%. ESI [M+H] + : 380.1929.

[0086] NMR data of compound 1: 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 5.3 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.17 - 7.14 (m, 2H), 6.89 (dt, J = 1.8, 0.9 Hz, 1H), 6.86 (ddt, J = 8.5, 1.7, 0.8 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 4.72 (dt, J = 5.2, 0.8 Hz, 2H), 3.86 (d, J = 1.6 Hz, 6H), 2.85 (tt, J = 7.3, 6.3 Hz, 1H), 1.27 (d, J = 6.6 Hz, 6H).

[0087] Example 2, method for preparing the ketone derivatives of the application

[0088] On the basis of Example 1, this example describes the preparation of compound 2, as follows:

[0089]

[0090] Intermediate 1b (100 mg, 0.44 mmol) and p-fluorobenzaldehyde (324.79 mg, 2.62 mmol) in example 1 were dissolved in 4 mL of methanol, and magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; then sodium borohydride (148.50 mg, 3.93 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous KOH solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried with anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 2 was obtained as a white solid (122 mg). Yield 83%, purity 99.6%. ESI [M+H] + : 338.1624.

[0091] NMR data of compound 2: 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.35 (ddt, J = 7.8, 3.5, 0.9 Hz, 2H), 7.26 - 7.23 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 1.0 Hz, 1H), 7.15 - 7.10 (m, 3H), 7.08 (t, J = 5.2 Hz, 1H), 4.75 (dt, J = 5.3, 0.9 Hz, 2H), 2.85 (tt, J = 7.3, 6.3 Hz, 1H), 1.27 (d, J = 6.6 Hz, 6H).

[0092] Example 3, method for preparing the ketone derivatives of the invention

[0093] On the basis of example 1, this example carries out the preparation of compound 3, as follows:

[0094]

[0095] Intermediate 1b (100 mg, 0.44 mmol) and p-methoxybenzaldehyde (356.28 mg, 2.62 mmol) in example 1 were dissolved in 4 mL of methanol, and magnesium methoxide (188.35 mg, 2.18 mmol) was added, and the mixture was stirred at 55 °C for 3 h; then sodium borohydride (148.50 mg, 3.93 mmol) was slowly added to the mixture, and the reduction was continued at room temperature for 30 min; the pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous K0H solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 3 was obtained as a white solid (117 mg). Yield 77%, purity 99.7%. ESI [M+H] + : 350.1824.

[0096] NMR data of compound 3: 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.20 - 7.14 (m, 4H), 7.08 (t, J = 5.2 Hz, 1H), 6.86 - 6.81 (m, 2H), 4.75 (dt, J = 5.2, 0.9 Hz, 2H), 3.80 (s, 3H), 2.85 (tt, J = 7.3, 6.3 Hz, 1H), 1.27 (d, J = 6.6 Hz, 6H).

[0097] Example 4, method for preparing the ketone derivative of the application

[0098] This example also provides a method for synthesizing a ketone derivative, the synthetic route of which is as follows:

[0099]

[0100] The synthetic conditions involved are as follows:

[0101] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, DMF, 200 °C, 15 min;

[0102] S2: triethylamine, diphenyl phosphorazide, tetrahydrofuran, 80 °C - rt, 2 h;

[0103] S3: magnesium methoxide, sodium borohydride, methanol, 55 °C - rt, 3 h - 0.5 h;

[0104] The specific synthetic process involved is as follows:

[0105] Step 1: Preparation of intermediate 4a

[0106]

[0107] Into a microwave reactor was added 4-chloro-o-xylene (1 g, 7.11 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (996.36 mg, 7.11 mmol), (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine (708.14 mg, 4.98 mmol), copper(I) iodide (406.34 mg, 2.13 mmol) and potassium carbonate (12.78 g, 92.45 mmol) mixed in 10 mL of DMF; microwave irradiation at 200 °C for 15 min; the reaction was diluted with ethyl acetate (100 mL); the organic phase was washed with water and 10% aqueous LiCl solution; dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure; after removal of the solvent, intermediate 1a was obtained as a colorless oily liquid (1.7 g). Yield 90%. ESI [M+H] + : 245.0881.

[0108] Step 2: Preparation of intermediate 4b

[0109]

[0110] Intermediate 4a (1.00 g, 4.09 mmol), diphenyl phosphorazide (1.30 g, 4.71 mmol) and triethylamine (124.29 mg, 1.23 mmol) were dissolved in tetrahydrofuran (35 mL) and the mixture was stirred at room temperature for 1 h; to the mixture was added water (6 ml) and stirred at 80 °C for 1 h; after the reaction was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35 mL); the layers were separated and the aqueous layer was extracted with ethyl acetate (35 mL x 3) and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35 mL); the washed organic phase was dried over sodium sulfate; filtered and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. A colorless oily liquid (644 mg) was obtained. Yield 73%. ESI [M+H] + : 216.1092.

[0111] Step 3: Preparation of compound 4

[0112]

[0113] Intermediate 4b (100 mg, 0.46 mmol) and p-fluorobenzaldehyde (345.95 mg, 2.79 mmol) were dissolved in 4 mL of methanol, and magnesium methoxide (200.63 mg, 2.32 mmol) was added. The mixture was stirred at 55 °C for 3 hours. Then sodium borohydride (158.18 mg, 4.18 mmol) was slowly added to the mixture, and the reduction was continued at room temperature for 30 minutes. The pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was evaporated under reduced pressure. Water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL). The organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL). The aqueous phase was neutralized with aqueous K0H solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 4 was obtained as a white solid (115 mg). Yield 78%, purity 99.7%. ESI [M+H] + : 324.1467.

[0114] NMR data of compound 4: 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.2 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.36 - 7.30 (m, 3H), 7.22 (dd, J = 8.1, 2.1 Hz, 1H), 7.10 - 7.04 (m, 2H), 7.01 (dq, J = 8.2, 1.1 Hz, 1H), 4.66 (dt, J = 5.3, 0.8 Hz, 2H), 2.28 (s, 3H), 2.11 (s, 3H).

[0115] Example 5, method for preparing the ketone derivatives of the application

[0116] On the basis of Example 4, this example describes the preparation of compound 5, as follows:

[0117]

[0118] Intermediate 4b (100 mg, 0.46 mmol) and 3,4-dimethoxybenzaldehyde (457.70 mg, 2.79 mmol) in example 4 were dissolved in 4 mL of methanol, and magnesium methoxide (200.63 mg, 2.32 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; then sodium borohydride (158.18 mg, 4.18 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous KOH solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 5 was obtained as a white solid (131 mg). Yield 77%, purity 99.8%. ESI [M+H] + : 366.1773.

[0119] NMR data of compound 5: 1 H NMR (500 MHz, Chloroform-d) δ 7.70 (t, J = 5.3 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.1, 2.1 Hz, 1H), 7.01 (dq, J = 8.2, 1.1 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 4.61 (dt, J = 5.3, 0.8 Hz, 2H), 3.84 (d, J = 5.3 Hz, 6H), 2.28 (s, 3H), 2.11 (s, 3H).

[0120] Example 6, method for preparing the ketone derivatives of the invention

[0121] On the basis of example 4, the preparation of compound 6 was carried out in this example, as follows:

[0122]

[0123] Intermediate 4b (100 mg, 0.46 mmol) and 4-isopropylbenzaldehyde (413.10 mg, 2.79 mmol) in example 4 were dissolved in 4 mL of methanol, and magnesium methoxide (200.63 mg, 2.32 mmol) was added, and the mixture was stirred at 55 °C for 3 h; then sodium borohydride (158.18 mg, 4.18 mmol) was slowly added to the mixture, and the reduction was continued at room temperature for 30 min; the pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous KOH solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 6 was obtained as a white solid (130 mg). Yield 81%, purity 99.6%. ESI [M+H] + : 348.2031.

[0124] NMR data of compound 6: 1 H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J = 8.2 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.27 - 7.19 (m, 3H), 7.17 - 7.13 (m, 2H), 7.01 (dq, J = 8.2, 1.1 Hz, 1H), 4.66 (dt, J = 5.3, 0.9 Hz, 2H), 2.90 - 2.78 (m, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.28 (d, J = 6.6 Hz, 6H).

[0125] Example 7, method for preparing the ketone derivative of the application

[0126] This example also provides a method for synthesizing a ketone derivative, the synthetic route of which is as follows:

[0127]

[0128] The synthetic conditions involved are as follows:

[0129] S1: potassium carbonate, (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine, cuprous iodide, DMF, 200 °C, 15 min;

[0130] S2: triethylamine, diphenyl phosphorazide, tetrahydrofuran, 80 °C - rt, 2 h;

[0131] S3: magnesium methoxide, sodium borohydride, methanol, 55 °C - rt, 3 h - 0.5 h;

[0132] The specific synthesis procedure involved is as follows:

[0133] Step 1: Preparation of intermediate 7a

[0134]

[0135] Into a microwave reactor was added p-chloromethylbenzene (1 g, 7.90 mmol), 3-hydroxy-2-pyrazinecarboxylic acid (1.11 g, 7.90 mmol), (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (786.62 mg, 5.53 mmol), copper(I) iodide (451.37 mg, 2.37 mmol) and potassium carbonate (14.19 g, 102.70 mmol) mixed in 10 mL of DMF; microwave irradiation at 200 °C for 15 min; the reaction was diluted with ethyl acetate (100 mL); the organic phase was washed with water and 10% aqueous LiCl; dried over anhydrous MgS04, filtered and the filtrate was concentrated under reduced pressure; after removal of the solvent, intermediate 7a was obtained as a colorless oil (1.7 g). Yield 93%. ESI [M+H] + : 231.0725.

[0136] Step 2: Preparation of intermediate 7b

[0137]

[0138] Intermediate 7a (1.00 g, 4.34 mmol), diphenyl phosphorazide (1.37 g, 5.00 mmol) and triethylamine (131.86 mg, 1.30 mmol) were dissolved in tetrahydrofuran (35 mL) and the mixture was stirred at room temperature for 1 h; to the mixture was added water (6 ml) and stirred at 80 °C for 1 h; after the reaction was cooled to room temperature, it was diluted with saturated aqueous sodium carbonate solution (35 mL); the layers were separated and the aqueous layer was extracted with ethyl acetate (35 mL x 3) and the combined organic extracts were washed with saturated aqueous sodium chloride solution (35 mL); the washed organic phase was dried over sodium sulfate; filtered and the filtrate was concentrated under reduced pressure; the crude residue was purified by flash column chromatography on silica gel. Intermediate 7b was obtained as a colorless oily liquid (612 mg). Yield 70%. ESI [M+H] + : 202.0936.

[0139] Step 3: Preparation of compound 7

[0140]

[0141] Intermediate 7b (100 mg, 4.47 mmol) and 3,4-dimethylbenzaldehyde (400 mg, 26.84 mmol) were dissolved in 4 mL of methanol, and magnesium methoxide (214.61 mg, 2.48 mmol) was added. The mixture was stirred at 55 °C for 3 hours, then sodium borohydride (169.20 mg, 4.47 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes. The pH of the mixture was adjusted to 7 with concentrated HC1, and the solvent was removed by evaporation under reduced pressure. Water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL). The organic phase was extracted with aqueous HC1 solution (0.05 M, 4 mL). The aqueous extract was neutralized with aqueous potassium hydroxide solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried with anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 7 was obtained as a white solid (114 mg). Yield 72%, purity 99.6%. ESI [M+H] + : 320.1718.

[0142] NMR data of compound 7: 1 H NMR (500 MHz, Chloroform-d) δ 7.66 (t, J = 5.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.13 - 7.06 (m, 3H), 7.04 - 6.98 (m, 2H), 4.58 (dt, J = 5.3, 0.9 Hz, 2H), 2.37 (d, J = 0.8 Hz, 3H), 2.27 (d, J = 1.0 Hz, 3H), 2.21 (s, 3H).

[0143] Example 8, method for preparing ketone derivatives of the present application

[0144] On the basis of Example 7, the preparation of compound 8 was carried out as follows:

[0145]

[0146] Intermediate 7b (100 mg, 0.50 mmol) and 3,4-dimethoxybenzaldehyde (495.48 mg, 2.98 mmol) in example 7 were dissolved in 4 mL of methanol, and magnesium methoxide (214.61 mg, 2.48 mmol) was added, and the mixture was stirred at 55 °C for 3 hours; then sodium borohydride (169.20 g, 4.47 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with aqueous hydrochloric acid (0.05 M, 4 mL); the aqueous extract was neutralized with aqueous potassium hydroxide (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried with anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 8 was obtained as a white solid (115 mg). Yield 66%, purity 99.8%. ESI [M+H] + : 352.1616.

[0147] NMR data of compound 8: 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.31 (t, J = 5.3 Hz, 1H), 7.25 - 7.19 (m, 3H), 7.14 - 7.08 (m, 2H), 6.91 - 6.83 (m, 2H), 6.82 (d, J = 8.6 Hz, 1H), 4.72 (dt, J = 5.3, 0.9 Hz, 2H), 3.86 (d, J = 2.2 Hz, 6H), 2.35 (s, 3H).

[0148] Example 9, method for preparing the ketone derivatives of the application

[0149] On the basis of example 7, the preparation of compound 9 was carried out as follows:

[0150]

[0151] Intermediate 7b (100 mg, 0.50 mmol) and 4-isopropylbenzaldehyde (441.90 mg, 2.98 mmol) in 4 mL of methanol were stirred at 55 °C for 3 hours; then sodium borohydride (169.20 g, 4.47 mmol) was slowly added to the mixture, and the reduction reaction was continued at room temperature for 30 minutes; the pH value of the mixture was adjusted to 7 with concentrated HCl, and the solvent was removed by evaporation under reduced pressure; water (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate (4 mL); the organic phase was extracted with hydrochloric acid aqueous solution (0.05 M, 4 mL); the water extract was neutralized with potassium hydroxide aqueous solution (1 M, 0.2 mL), and finally extracted with ethyl acetate (4 mL). The organic phase was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. Compound 9 was obtained as a white solid (133 mg). Yield 80%, purity 99.6%. ESI [M+H] + : 334.1875.

[0152] NMR data of compound 9: 1 H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.25 - 7.15 (m, 7H), 7.14 - 7.04 (m, 3H), 4.75 (dt, J = 5.3, 0.9 Hz, 2H), 2.89 - 2.82 (m, 1H), 2.35 (d, J = 0.9 Hz, 3H), 1.27 (d, J = 6.6 Hz, 6H).

[0153] The beneficial effects of the present application are demonstrated by the following experimental examples.

[0154] Experimental Example 1, testing the analgesic activity of ketone derivatives in a complete Freund's adjuvant (CFA) induced inflammatory pain model

[0155] 1. Experimental method

[0156] (1) Experimental animal modeling: ICR mice (purchased from Chengdu Dashuo Experimental Animal Co., Ltd., 6-8 weeks old, weighing about 25 g, male, adapted to the experimental environment for three days) were randomly divided into model (model) group, positive control group and drug group, 6 in each group. The left foot of each mouse was given 20 microliters of CFA to model and trigger inflammatory pain.

[0157] (2) Treatment: One day after modeling, the mechanical pain threshold of each group before administration was measured with an electronic pain tester, and the corresponding drug was dissolved with a solvent combination of DMSO: Tween 80: physiological saline = 1:1:8;

[0158] The drug group: dissolve compounds 1-9 in the above solvent combination respectively, then intraperitoneally inject 13 mM, 0.2 mL of the dose for administration;

[0159] The model group: give the same dose of the solvent combination of DMSO: Tween 80: physiological saline = 1:1:8;

[0160] The positive control group: dissolve indomethacin in the above solvent combination, then intraperitoneally inject 13 mM, 0.2 mL of the dose for administration;

[0161] (3) Data statistics: 30 min, 60 min, 120 min, 180 min, 240 min and 300 min after administration, respectively, measure the mechanical pain threshold of the left foot of each mouse, measure three times at each time point, and take the average value into the statistical data.

[0162] 2、Experimental results

[0163] The results are shown in the following table: Figures 1-2 The analgesic activity of compound 1, compound 2 and compound 7 is better than that of the positive control indomethacin. Among them, compound 1 reaches the best analgesic effect 60 min after administration, and can last for about 5 h; compared with indomethacin, compound 1 has a faster onset, a longer action time and a higher analgesic intensity; and it can be found that the area under the curve (AUC%) of compound 1 is better than that of indomethacin. Figure 3

[0164] Therefore, it is concluded that compound 1 has the advantages of fast onset, good analgesic effect and long duration of drug efficacy in analgesia.

[0165] Experimental example 2, test the effect of ketone derivatives on Nav1.8 current

[0166] 1、Experimental method

[0167] The effect of compound 1 on Nav1.8 current at concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM and 0.1 μM was determined by manual patch clamp test, and the specific process was as follows:

[0168] (1) Before the start of the electrophysiological experiment, the Nav1.8 (SCN10A: NP_006505; SCN3B: NP_060870) cell strain should be kept within 70% of the maximum density of the logarithmic growth phase;

[0169] (2) All reagents were preheated to 37°C before use, and the patch clamp detection experiment was carried out after the cells were well adhered;

[0170] ​(3) Using Patchmaster software to collect and store Nav1.8 sodium current data on the computer through EPC-10 amplifier;

[0171] (4) Using forceps to take the cell climbing sheet out of the cell culture dish, adding extracellular fluid, and placing it in the bath on the inverted microscope stage;

[0172] (5) Using P-1000 microelectrode puller to pull glass microtubules, filling 1 / 3 volume of glass microtubules (recording electrodes) with intracellular fluid, and placing them in the electrode holder;

[0173] (6) Using electric micro-manipulator (Scientifica-Double 1U) to contact the recording electrode to the cell surface, at this time the membrane test window shows a decrease in the current value represented by the seal test pulse due to the sudden increase in electrode resistance, remove the positive pressure, and apply a negative pressure of 0.5 cm H2O, observe the rapid rise of the seal resistance until it reaches gigohm seal. After the seal resistance between the recording electrode and the cell membrane is >1 GΩ, give negative pressure to break the membrane and form a whole-cell recording mode, and after the membrane is stable, compensate for the membrane capacitance (Cs) and series resistance (Rs);

[0174] The stimulation program is: 1) The clamping voltage is -120 mV, a -120~ -10 mV, 10 mV step, 8000 ms duration square wave train stimulation, then step to -10 mV, time is 30 ms, and finally restore to -120 mV. Taking the membrane potential as the abscissa and the relative current I / Imax as the ordinate, a Boltzmann process I / Imax = 1 / {1+exp[(V-V1 / 2) / k]} is used for fitting to obtain the steady-state inactivation curve (V1 / 2 is the condition pulse voltage when the channel is half inactivated, and k is the slope factor);

[0175] 2) The clamping voltage is -120 mV, depolarization to 0 mV, time course is 40 ms, stimulating the resting state current of sodium channel, then step to the condition pulse voltage when the channel is half inactivated, time course is 8000 ms, repolarization to -120 mV, time course is 30 ms, then depolarization to 0 mV, time course is 40 ms, stimulating the half-inactivated state current of sodium channel, and finally restoring to -120 mV, recording the current every 20 s. At room temperature, record the Nav1.8 sodium channel current before adding drugs, and after the control current value reaches steady state, i.e. the recent 4 consecutive current recording lines coincide, use cumulative drug addition method to detect the effect of negative (0.1% DMSO) and 5 drug concentrations (from low to high) on the current.

[0176] 2、Experimental results

[0177] In two independent repeated tests, the inhibitory effect of the test compound on Nav1.8 channel was detected, the original data of Nav1.8 current peak was extracted from PatchMaster software, and the calculation formula of current inhibition rate was as follows: peak current inhibition rate=(1-peak current compound / peak current vehicle), the inhibition rate of compound 1 on Nav1.8 current and the time-current response curve. Among them, the inhibition rate of compound 1 on resting state Nav1.8 current at 10 μM concentration was: 80.50±3.88%, and the inhibition rate of compound 1 on semi-inactivated state Nav1.8 current was: 85.74±4.66%.

[0178] In conclusion, the present application provides a ketone derivative and a synthesis method and use thereof. In the present application, halogenated benzene compounds and 3-hydroxy-2-pyrazine carboxylic acid are used as raw materials, and after specific reactions, the ketone derivative is obtained. This compound is a Nav1.8 inhibitor, has good analgesic activity, fast onset, good analgesic effect, long drug efficacy duration, and has a good application prospect in the preparation of non-addictive analgesic drugs.

Claims

1. The following ketone derivatives, stereoisomers thereof, pharmaceutically acceptable salts thereof, characterized in that, The ketone derivative comprises the following structural formula: 。 2. A method of preparing the ketone derivative, stereoisomer thereof, pharmaceutically acceptable salt thereof according to claim 1, characterized by, The method comprises the following steps: (1) reacting compound A, compound B, a nitrogen nucleophile, a base and a catalyst to obtain intermediate C; (2) reacting intermediate C, a base and an azidation reagent to obtain intermediate D; (3) reacting intermediate D, compound E, an alkylating reagent and a reducing agent to obtain compound F, i.e. the ketone derivative; X is selected from halogen; Compound F is the following compound: 。 3. The method of claim 2, wherein, In step (1), the molar ratio of compound A, compound B, the nitrogen nucleophile, the base and the catalyst is 1:0.5-1.5:0.5-1:10-15:0.1-0.5; the nitrogen nucleophile is (1R,2R)-N,N'-dimethylcyclohexane-1,2-diamine; the base is an organic base or an inorganic base; the catalyst is a metal catalyst; the solvent of the reaction is an organic solvent; the temperature of the reaction is 180-220 DEG C, and the time is 10-20 minutes; In step (2), the molar ratio of intermediate C, a base and an azidation reagent is 1:0.1-0.5:1-1.5; the base is an organic base or an inorganic base; the azidation reagent is diphenyl phosphorazide; the solvent of the reaction is a mixture of an organic solvent and an inorganic solvent; the reaction condition is that, first, 0.5-1.5 hours of reaction is carried out at 10-40 DEG C, and then 0.5-1.5 hours of reaction is carried out at 60-100 DEG C; In step (3), the molar ratio of intermediate D, compound E, an alkylating reagent and a reducing agent is 1:5-7:4-6:8-10; the alkylating reagent is magnesium methoxide; the reducing agent is sodium borohydride; the solvent of the reaction is an organic solvent; the reaction condition is that, first, 2-4 hours of reaction is carried out at 50-60 DEG C, and then 20-40 minutes of reaction is carried out at 10-40 DEG C.

4. The method of claim 3, wherein, In step (1), the molar ratio of compound A, compound B, the nitrogen nucleophile, the base and the catalyst is 1:1:0.7:13:0.3; the base is potassium carbonate; the catalyst is cuprous iodide; the solvent of the reaction is N,N'-dimethylformamide; the temperature of the reaction is 200 DEG C, and the time is 15 minutes; In step (2), the molar ratio of intermediate C, a base and an azidation reagent is 1:0.3:1.1; the base is triethylamine; the solvent of the reaction is a mixture of tetrahydrofuran and water; the reaction condition is that, first, 1 hour of reaction is carried out at 20-30 DEG C, and then 1 hour of reaction is carried out at 80 DEG C; In step (3), the molar ratio of intermediate D, compound E, an alkylating reagent and a reducing agent is 1:6:5:9; the solvent of the reaction is methanol; the reaction condition is that, first, 3 hours of reaction is carried out at 55 DEG C, and then 30 minutes of reaction is carried out at 20-30 DEG C.

5. The method of claim 3, wherein, After the reaction in step (1) is completed, the following purification step is further included: diluting the reaction solution with ethyl acetate; washing the organic phase with water and 10% LiCl aqueous solution, drying, filtering, and concentrating to obtain intermediate C; In step (2), the feeding mode of the reaction is that intermediate C, azide reagent and base are added into tetrahydrofuran, and then the mixture is reacted at 20-30 DEG C for 1 hour, water is added, and then the mixture is reacted at 80 DEG C for 1 hour; In step (3), the feeding mode of the reaction is that intermediate D, compound E and alkylating reagent are added into methanol, and then the mixture is reacted at 55 DEG C for 3 hours, a reducing agent is added, and then the mixture is reacted at 20-30 DEG C for 30 minutes; After the reaction in step (3) is completed, the following purification step is further included: the pH value is adjusted to 7 by using concentrated hydrochloric acid, the solvent is removed, extraction is performed using ethyl acetate, hydrochloric acid aqueous solution and potassium hydroxide aqueous solution, drying is performed, concentration is performed, and a ketone derivative is obtained.

6. a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, use of the ketone derivative according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, for the manufacture of an analgesic medicament which is a Navl.8 inhibitor.

7. Use according to claim 6, characterized in that, The analgesic drug is a non-addictive analgesic drug, the non-addictive analgesic drug includes a chronic neuropathic pain drug and a chronic inflammatory pain drug, and the analgesic drug is a Nav1.8 inhibitor.

8. A pharmaceutical composition, characterized by, The pharmaceutical composition is a preparation prepared by adding a pharmaceutically acceptable excipient to the ketone derivative, the stereoisomer thereof or the pharmaceutically acceptable salt thereof as an active ingredient.

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