A selective sodium channel modulator and its preparation and application

Abstract

The present invention provides a compound as a selective sodium channel modulator and a method for synthesizing and using the compound. Specifically, the present invention provides a compound as shown in formula (I), a method for preparing the compound and a method for using the compound as a selective sodium channel modulator. The compound exhibits excellent activity as a sodium channel modulator.

Description

Technical Field

[0001] The present invention relates to a class of compounds as selective sodium channel modulators, and isomers, solvates and salts of the compounds and drugs using the compounds or their salts as active ingredients, and use of the compounds in drugs for treating and / or preventing sodium channel modulation-related target diseases, such as pain. Background Art

[0002] Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevents further damage to damaged tissue. Nevertheless, there are many situations in which pain persists beyond its usefulness or in which patients would benefit from suppressing pain.

[0003] Neuropathic pain is a form of chronic pain caused by sensory nerve damage, which can be divided into two categories, pain caused by metabolic damage to the nerves and pain caused by damage to the continuity of the nerves. Pain indications caused by metabolic damage include post-herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Pain indications caused by damage to the continuity of the nerves include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries such as neuropathic back pain.

[0004] Voltage-gated sodium channels (Nav's) are involved in pain signaling. Nav's are biological mediators of electrical signaling because they mediate the rapid upsurge of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes). Evidence from the role of these channels in normal physiology, pathological states caused by mutations in sodium channel genes, preclinical work in animal models, and clinical pharmacology of known sodium channel modulators all point to a central role for Nav's in pain sensation. Nav's mediate the rapid upsurge of action potentials in many excitable cell types (e.g., neurons, skeletal muscle cells, cardiomyocytes) and are therefore involved in the initiation of signaling in these cells. Due to the role of Nav's in the initiation and propagation of neuronal signals, antagonists that reduce Nav's currents can prevent or reduce neural signaling, and Nav's are considered possible targets for pain relief in cases where hyperexcitability is observed. Several clinically useful analgesics have been identified as inhibitors of Nav's. Local anesthetics such as lidocaine block pain by inhibiting Nav channels, and other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants have been shown to effectively reduce pain through sodium channel inhibition.

[0005] Nav's form a subfamily of the voltage-gated ion channel superfamily and contain nine isoforms, designated Nav1.1-Nav1.9. The tissue localization of the nine isoforms varies. Nav1.4 is the major sodium channel of skeletal muscle and Nav1.5 is the major sodium channel of cardiac myocytes. Nav's 1.7, 1.8 and 1.9 are mainly localized in the peripheral nervous system, while Nay's 1.1, 1.2, 1.3 and 1.6 are neural channels found in 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.

[0006] Nav1.8 channel is identified as a possible target of analgesia, which has been shown to act as a carrier of sodium current, maintain the action potential firing of neurons in small dorsal root ganglia, and also participate in the spontaneous electrical signal firing of damaged neurons, such as driving the generation of neuropathic pain, etc. The main disadvantage of some known Nav's inhibitors is that their therapeutic window is poor, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, there is still a need to develop new Nav1.8 selective inhibitors in this area. Summary of the invention

[0007] The purpose of the present invention is to provide a Nav1.8 selective inhibitor.

[0008] The first aspect of the present invention provides a compound represented by the following formula (I), and its isomers, solvates or pharmaceutically acceptable salts:

[0009]

[0010] L is selected from the following group: S(O) p , O, NR5, CO or C(R6)R7;

[0011] Cyc is selected from: 5-6 membered heteroaryl, wherein the heteroatoms of the heteroaryl are independently selected from O, N or S(O) p ;

[0012] R1 is selected from the following group: hydrogen, deuterium, =O, halogen, CHF2, CF3, CD3, OCF3, OCH3, OCD3, cyano, nitro, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NR5, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, wherein the heteroatoms are independently selected from O, N or S(O) p; or two adjacent R1 and the atoms to which they are connected form a substituted or unsubstituted 5-6-membered carbocyclic or heterocyclic ring;

[0013] R2 is selected from the following group: C3-C6 cycloalkyl substituted by 0-4 R1, C4-C6 heterocyclic group substituted by 0-4 R1, 6-10 membered aryl substituted by 0-4 R1, 5-10 membered heteroaryl substituted by 0-4 R1; wherein two adjacent R1 can form a 5-6 membered carbocyclic or heterocyclic ring together with the ring atoms connected to them;

[0014] R4 is selected from the following group: hydrogen, deuterium, halogen, hydroxyl, amine, cyano, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NR5, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, wherein the heteroatoms are independently selected from O, N or S(O) p ;

[0015] n is selected from the following group: 0, 1, 2, 3 or 4;

[0016] p is selected from the following group: 0, 1 or 2;

[0017] R5 is selected from the following groups: hydrogen, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NH, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, wherein the heteroatoms are independently selected from O, N or S(O) p ;

[0018] R6 and R7 are independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NR5, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclic group, wherein the heteroatoms are independently selected from O, N or S(O) p ; or R6 and R7 and the atoms to which they are connected form a C3-C6 carbocycle or a C4-C6 heterocycle;

[0019] Unless otherwise specified, the "substituted" refers to replacement by one or more (e.g., 2, 3, 4, etc.) substituents selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxyl, amino, carboxyl, amide, sulfonamide, sulfone; unsubstituted or substituted by one or more substituents selected from the following group: C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O, halogenated 5-10 membered heterocyclyl having 1-3 heteroatoms selected from N, S and O, and the substituents are selected from the following group: halogen, C1-C6 alkyl, C1-C6 alkoxy, =O.

[0020] In another preferred embodiment, R4 is selected from the following group: hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl.

[0021] In another preferred embodiment, the R1 is selected from the following group: hydrogen, deuterium, halogen, CF3, CD3, OCF3, OCH3, OCD3, CN.

[0022] In another preferred embodiment, the R2 is selected from the following group: phenyl, pyridyl, pyrimidinyl, pyrazinyl; wherein the R2 can also be substituted by one or more R1.

[0023] In another preferred embodiment, the R5 is selected from the following group: hydrogen, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NH.

[0024] In another preferred embodiment, R6 and R7 are independently selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C4 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NR5, substituted or unsubstituted C3-C6 cycloalkyl.

[0025] In another preferred embodiment, the R8 is selected from: hydrogen, substituted or unsubstituted C1-C4 alkyl.

[0026] In another preferred embodiment, the compound of formula (I) has a structure as shown in the following formula (II):

[0027]

[0028] Where G is N or N + -O - ,

[0029] In another preferred embodiment, the compound of formula (I) has a structure as shown below:

[0030]

[0031] In another preferred embodiment, it is characterized in that the L is O.

[0032] In another preferred embodiment, the compound has a structure shown in the following formula (III):

[0033]

[0034] In another preferred embodiment, the compound of formula (I) has a structure as shown below:

[0035]

[0036] Wherein, Ra, Rb, Rc and Rd are each independently selected from the following group: hydrogen, deuterium, halogen, CHF2, CF3, CD3, OCF3, OCH3, OCD3, cyano, nitro, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, C1-C6 alkyl in which 1 or 2 non-adjacent carbon atoms are replaced by O or NR5, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C6 heterocyclyl, wherein the heteroatoms are independently selected from O, N or S(O) p .

[0037] In another preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the following group: hydrogen, deuterium, halogen, CF3, CD3, OCF3, OCH3, OCD3, CN.

[0038] In another preferred embodiment, the compound is selected from the following group:

[0039]

[0040]

[0041]

[0042] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to the first aspect of the present invention.

[0043] In another preferred embodiment, the pharmaceutical composition is used for treating, alleviating or preventing a disease or condition related to sodium channel regulation; preferably, the disease or condition is pain.

[0044] In another preferred embodiment, the pain or disease is selected from the group consisting 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 arrhythmia.

[0045] In another preferred embodiment, the treatment includes reducing the severity of pain in the patient.

[0046] In another preferred embodiment, the neuropathic pain includes postherpetic neuralgia.

[0047] In another preferred embodiment, the neuropathic pain includes idiopathic small fiber neuropathy.

[0048] In another preferred embodiment, the musculoskeletal pain includes osteoarthritis pain.

[0049] In another preferred embodiment, the acute pain includes acute postoperative pain.

[0050] In another preferred embodiment, the postoperative pain includes bunionectomy pain or abdominoplasty pain.

[0051] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, for preparing a pharmaceutical composition for treating, alleviating or preventing diseases related to sodium channel regulation; preferably, the disease or condition is pain.

[0052] In another preferred embodiment, the pain or disease is selected from the group consisting 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 arrhythmia.

[0053] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0054] After long and in-depth research, the inventors unexpectedly discovered a compound as shown in formula (I). The compound has unexpected activity in regulating cytokines and / or interferons, and can be used to treat diseases mediated by cytokines and / or interferons. The compound has unexpected activity against Nav 1.8 and has excellent selectivity for other Navs subtypes, and can be used to treat, alleviate or prevent diseases related to Nav 1.8. Based on the above findings, the inventors completed the present invention.

[0055] definition

[0056] As used herein, the term "alkyl" includes straight or branched alkyl groups. For example, C1-C4 alkyl groups represent straight or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0057] As used herein, the term "C3-C8 cycloalkyl" refers to a cycloalkyl group having 3-8 carbon atoms. It can be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a similar group. It can also be a bicyclic form, such as a bridged ring, a cyclocyclic ring, or a spirocyclic form.

[0058] As used herein, the term "C6-C 10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.

[0059] As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or a condensed ring. Specific examples may include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

[0060] Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention may be substituted by substituents selected from the following groups: halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0061] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0062] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0063] As used herein, the term "hydrate" refers to a complex formed by coordination of a compound of the present invention with water.

[0064] The compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0065] The solvents used in this application can be obtained commercially. The abbreviations used in this application are as follows: aq represents aqueous solution; HATU represents O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide Amide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, an amino protecting group; Boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3 represents sodium cyanoborohydride; rt represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; Boc2O represents di-tert-butyl dicarbonate; LDA represents lithium diisopropylamide.

[0066] Compounds are artificially or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0067] Pharmaceutical compositions and methods of administration

[0068] Since the compounds of the present invention have excellent activity as sodium channel modulators, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) sodium channel-related diseases or conditions, such as pain, etc.

[0069] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 1-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0070] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0071] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration or topical administration).

[0072] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0073] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0074] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0075] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0076] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0077] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0078] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0079] When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used simultaneously, separately or sequentially with the compound of the present invention to prevent and / or treat cytokine and / or interferon-mediated diseases.

[0080] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 1 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0081] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0082] Example

[0083] Example 1

[0084]

[0085]

[0086] first step

[0087] Under nitrogen protection, compound 1a (10.00 g, 38.90 mmol) and potassium carbonate (16.10 g, 116.72 mmol) were dissolved in N, N-dimethylformamide (100 mL), and then iodomethane (8.30 g, 58.35 mmol) was added and reacted at room temperature for 2 hours. After the reaction was completed, water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL) was added, and the liquid was separated. The aqueous phase was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1b (12.00 g), with a yield of 99%.

[0088] 1 H NMR (400MHz, DMSO-d6) δ7.66 (dd, J=8.7, 0.4Hz, 1H), 7.10 (d, J=2.6Hz, 1H), 6.91–6.84 (m, 1H), 3.85 (s, 3H).

[0089] Step 2

[0090] Under nitrogen protection at -78°C, n-butyl lithium tetrahydrofuran solution (2.5M, 20mL, 0.50mmol) was slowly added dropwise to a tetrahydrofuran (100mL) solution of compound 1b (12.00g, 44.28mmol). After the addition was completed, stirring was continued for 30 minutes. Triisopropyl borate (11.66g, 62.00mmol) was added dropwise to the above reaction solution at -78°C and reacted at this temperature for 2 hours. After the reaction was completed, 1N dilute hydrochloric acid (60mL) was used to adjust the pH to 4-5, and ethyl acetate (50mL) was added. The liquids were separated, and the aqueous phase was extracted with ethyl acetate (30mLx 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 1c (6.00g), with a yield of 42%.

[0091] 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 8.2Hz, 1H), 6.88 (d, J = 8.2Hz, 1H), 6.72 (s, 1H), 5.78 (s, 2H), 3.93 (s, 3H).

[0092] Step 3

[0093] At 0°C, potassium persulfate (18.17 g, 28.10 mmol) was added to a solution of compound 1c (6.00 g, 25.53 mmol), sodium hydroxide (1.50 g, 38.30 mmol), sodium bicarbonate (21.40 g, 255.32 mmol), acetone (100 mL) and ethylenediaminetetraacetic acid (745 mg, 2.60 mmol) in water (100 mL), and then the mixture was warmed to room temperature and stirred for 2 hours. After the reaction was completed, the pH was adjusted to acidic with 2N dilute hydrochloric acid (180 mL), ethyl acetate (100 mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 1d (2.30 g), with a yield of 43%.

[0094] 1 H NMR (400MHz, CDCl3) δ6.87 (d, J = 8.4Hz, 1H), 6.73 (d, J = 10.4Hz, 2H), 3.88 (d, J = 0.6Hz, 3H).

[0095] Step 4

[0096] Under nitrogen protection at -78°C, slowly add diisopropylamide lithium (2.0M, 15mL, 30.00mmol) tetrahydrofuran solution to a solution of compound 1e (5.00g, 27.31mmol) in anhydrous tetrahydrofuran (50mL), and continue stirring at -78°C for 30 minutes after the addition is complete. Slowly add chloroformic acid ethyl ester (3.84g, 35.38mmol) in anhydrous tetrahydrofuran solution (10mL) to the above reaction solution. After the addition is complete, stir the resulting reaction solution at -78°C for 40 minutes, naturally warm to room temperature and continue the reaction for 1 hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to give 1f (3.10 g), with a yield of 45%.

[0097] 1 H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 4.42 (d, J = 7.1Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0098] Step 5

[0099] Under nitrogen protection at 0°C, cesium carbonate (877 mg, 2.69 mmol) was added to a solution of 1f (340 mg, 1.35 mmol) and 1d (280 mg, 1.35 mmol) in N,N-dimethylformamide (10 mL). The mixture was reacted at 0°C for 1.5 hours and then naturally warmed to room temperature. After the reaction was completed, water (20 mL) and ethyl acetate (30 mL) were added, the liquids were separated, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 1g (300 mg), with a yield of 51%.

[0100] 1 H NMR(400MHz,CD3OD)δ7.94(s,1H),7.31(d,J=8.8Hz,1H),7.11(d,J=2.3Hz,1H),7.00 -6.93(m,1H),4.40(dt,J=8.6,6.4Hz,2H),3.79(s,3H),1.35(td,J=7.1,1.6Hz,3H).

[0101] Step 6

[0102] At 0°C and under nitrogen protection, sodium hydroxide (135 mg, 3.38 mmol) was added in batches to a mixed solution of 1 g (300 mg, 0.68 mmol) of tetrahydrofuran (15 mL) and water (15 mL). After the addition, the reaction system was warmed to room temperature and the reaction was continued for 2 hours. After the reaction was completed, the pH was adjusted to about 2 with 1N dilute hydrochloric acid, extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 1h (290 mg).

[0103] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.21 (d, J = 8.4Hz, 1H), 6.87 (s, 2H), 3.78 (s, 3H).

[0104] Step 7

[0105] 1h (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1i (30 mg, 0.24 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137 mg, 0.36 mmol), and N,N-diisopropylethylamine (93 mg, 0.72 mmol) were added, and then the nitrogen was replaced three times. The reaction was carried out at room temperature for 2 hours. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction system, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain 1 (10 mg), with a yield of 10%.

[0106] MS-ESI calculated value [M+1] + 508, measured value 508.

[0107] 1 H NMR (400MHz, DMSO-d6) δ10.79(s,1H),8.13(s,1H),7.89(s,1H),7.43(d,J=9.6Hz,1H),7.3 5(d,J=8.9Hz,1H),7.22(s,1H),6.99(d,J=8.1Hz,1H),6.38(d,J=9.4Hz,1H),3.77(s,3H).

[0108] Example 2

[0109]

[0110] first step

[0111] Compound 2a (200 mg, 1.56 mmol) was dissolved in toluene (5 mL), potassium hydroxide (263 mg, 4.68 mmol) and benzyl alcohol (336 mg, 3.12 mmol) were added to the reaction system, and then nitrogen was replaced three times, and the temperature was raised to 120°C for overnight reaction. After the system was cooled to room temperature, water (50 mL) was added to the reaction system, and extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 2b (212 mg), with a yield of 58%.

[0112] MS-ESI calculated value [M+1] + 201, measured value: 201.

[0113] Step 2

[0114] 1h (600 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2b (300 mg, 1.45 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (827 mg, 2.17 mmol), and N,N-diisopropylethylamine (562 mg, 4.35 mmol) were added. The atmosphere was replaced with nitrogen three times. After reacting at room temperature for 2 hours, water (60 mL) and ethyl acetate (60 mL) were added to the reaction system. The liquids were separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain 2c (350 mg). The yield was 43%.

[0115] MS-ESI calculated value [M+1] + 598, measured value 598.

[0116] Step 3

[0117] 2c (300 mg, 0.50 mmol) was dissolved in tetrahydrofuran (15 mL), and then 10% wet palladium carbon (30 mg) was added. After replacing hydrogen (15 psi) three times, the reaction was allowed to react at room temperature for 2 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain 2 (150 mg), yield: 59%.

[0118] MS-ESI calculated value [M+1] + 508, measured value 508.

[0119] 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),11.05(s,1H),8.14(s,1H),7.35(dd,J=16.1,8.0Hz ,2H),7.23(s,1H),7.00(d,J=8.5Hz,1H),6.66(s,1H),6.29(d,J=7.0Hz,1H),3.77(s,3H).

[0120] Example 3

[0121]

[0122] first step

[0123] 1f (300 mg, 1.17 mmol) and 3a (148 mg, 1.17 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (767 mg, 2.35 mmol) was slowly added at 0°C, and the nitrogen was replaced, and the mixture was stirred at room temperature at 0°C for 2 hours. The reaction system was diluted with water (30 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 3b (380 mg), with a yield of 90%.

[0124] 1 H NMR (400MHz, CDCl3) δ7.85(s,1H),7.04–6.90(m,3H),4.48–4.41(m,2H),2.20(s,3H),1.42–1.36(m,3H).

[0125] Step 2

[0126] 3b (380 mg, 1.05 mmol) was dissolved in tetrahydrofuran (5 mL), 1N sodium hydroxide aqueous solution (5 mL) was added, and the nitrogen atmosphere was replaced and stirred at room temperature for 2 hours. 6N dilute hydrochloric acid was added to the reaction solution to adjust the pH to about 1, and water (40 mL) was added to dilute it and then extracted with ethyl acetate (30 mL x 3). After the organic phases were combined, they were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 3c (250 mg), with a yield of 95%.

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.02 (s, 1H), 7.32–7.18 (m, 2H), 7.11 (dd, J = 8.4, 3.1Hz, 1H), 2.15 (s, 3H).

[0128] Step 3

[0129] 3c (100 mg, 0.28 mmol) was dissolved in anhydrous dichloromethane (5 mL), two drops of N, N-dimethylformamide were added, and then oxalyl chloride (107 mg, 0.83 mmol) was added, and then nitrogen was replaced three times. After stirring at room temperature for 2 hours, the organic solvent was removed by concentrating under reduced pressure. Then it was dissolved in anhydrous dichloromethane (5 mL), compound 3c (56 mg, 0.45 mmol) and triethylamine (151 mg, 1.51 mmol) were added to the reaction system, warmed to room temperature, stirred for reaction for 2 hours, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain 3e (70 mg), with a yield of 53%.

[0130] MS-ESI calculated value [M+1] + 440, measured value 440.

[0131] Step 4

[0132] 3e (70 mg, 0.16 mmol) was dissolved in acetic acid (10 mL) and hydrobromic acid acetic acid solution (3 mL), and then replaced with nitrogen three times. After stirring at 100°C for 2 hours, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 3 (56 mg), with a yield of 82%.

[0133] MS-ESI calculated value [M+1] + 426, measured value 426.

[0134] 1 H NMR (400MHz, DMSO-d6) δ11.40(s,1H),11.09(s,1H),8.14(s,1H),7.37(d,J=7.2Hz,1H),7. 30–7.24(m,2H),7.14–7.12(m,1H),6.69(d,J=2.0Hz,1H),6.33–6.31(m,1H),2.19(s,3H).

[0135] Example 4

[0136]

[0137] first step

[0138] Compound 4a (100 mg, 0.44 mmol) was dissolved in dichloromethane (10 mL), and then oxalyl chloride (113 mg, 0.88 mmol) and a catalytic amount of N,N-dimethylformamide were added. After replacing with nitrogen three times, the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain a residue, which was then dissolved in dichloromethane (20 mL), triethylamine (133 mg, 1.32 mmol) and compound 3d (82 mg, 0.66 mmol) were added, and after replacing with nitrogen three times, the mixture was stirred at room temperature for 12 hours, and water (20 mL) and dichloromethane (30 mL) were added for separation, and the aqueous phase was extracted with dichloromethane (30 mL x 3). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 4b (90 mg), with a yield of 62%.

[0139] Step 2

[0140] Compound 4b (90 mg, 0.27 mmol) and 3a (34 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (877 mg, 2.69 mmol) was added under ice bath. After nitrogen was replaced three times, the reaction system was stirred and reacted under ice bath for 1.5 hours, warmed to room temperature, water (20 mL) and ethyl acetate (30 mL) were added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 3). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 0-100%) to obtain 4c (70 mg), with a yield of 62%.

[0141] Step 3

[0142] 4c (70 mg, 0.16 mmol) was dissolved in acetic acid (10 mL) and hydrobromic acid acetic acid solution (3 mL), and then replaced with nitrogen three times. After stirring at 100° C. for 2 hours, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 4 (50 mg). Yield: 77%

[0143] MS-ESI calculated value [M+1] + 408, measured value 408.

[0144] 1 H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.78(s,1H),8.90(s,1H),7.33–7.27(m,3H ),7.18–7.16(m,1H),6.96(s,1H),6.78(s,1H),6.37(d,J=5.6Hz,1H),2.12(s,3H).

[0145] Example 5

[0146]

[0147] first step

[0148] Compound 5a (500 mg, 2.72 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (6.42 g, 54.40 mmol) was added under ice bath. The mixture was stirred at room temperature for 1 hour, then cooled to 0°C and ammonia (1 mL) was added. The reaction solution was quenched by adding water (30 mL), and ethyl acetate (50 mL) was added. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 5b (200 mg), with a yield of 40%.

[0149] Step 2

[0150] Compound 5b (200 mg, 1.10 mmol), iron powder (200 mg, 6.60 mmol) and ammonium chloride (200 mg, 2.20 mmol) were dissolved in a mixed solution of ethanol (20 mL) and water (4 mL), and the reaction system was heated to 90°C and stirred for 8 hours under nitrogen protection. After cooling to room temperature, the reaction solution was concentrated under reduced pressure to obtain a residue, which was added to a mixed solvent of water (10 mL) and ethyl acetate (50 mL), separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 5c (80 mg), with a yield of 48%.

[0151] Step 3

[0152] Compound 5c (50 mg, 0.33 mmol), 1h (136 mg, 0.33 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylenediamine (126 mg, 0.99 mmol) was added. The mixture was stirred at room temperature for 2 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 5 (14 mg) in a yield of 8%.

[0153] MS-ESI calculated value [M+1] + 551, measured value 551.

[0154] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.82(s,1H),8.60(s,1H),8.20(s,1H),7.42(d,J=8.5,1H),7.21(s,1H),6.97(d,J=8.4,1H),3.76(s,3H).

[0155] Example 6

[0156]

[0157]

[0158] first step

[0159] 2 (50 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and then 60% sodium hydride (10 mg, 0.30 mmol) was added in an ice bath, and the mixture was naturally warmed to room temperature for 30 minutes, and methanol (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 6 (38 mg), with a yield of 74%.

[0160] MS-ESI calculated value [M+1] + 520, measured value 520.

[0161] 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),11.04(s,1H),7.89(s,1H),7.34–7.32(m,2H),7.22 (s,1H),6.99–6.98(m,1H),6.74(s,1H),6.34(d,J=7.2Hz,1H),3.91(s,3H),3.78(s,3H).

[0162] Example 7

[0163]

[0164] first step

[0165] Potassium hydroxide (159 mg, 2.80 mmol) was added to a toluene (10 mL) solution of compound 7a (300 mg, 2.30 mmol) and benzyl alcohol (249 mg, 2.30 mmol), and the temperature was raised to 100°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was added to water (10 mL) and dichloromethane (20 mL), and the liquids were separated. The aqueous phase was extracted with dichloromethane (20 mL x 3). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 7b (320 mg), with a yield of 64%.

[0166] 1 H NMR (400MHz, CDCl3) δ7.41(d,J=7.0,2H),7.36(d,J=8.0,2H),7.34–7.29(m,1H),5.84(s,1H),5.75(d,J=1.4,1H),5.26(s,2H),4.24(s,2H).

[0167] Step 2

[0168] To a solution of compound 7b (50 mg, 0.23 mmol) in tetrahydrofuran (5 mL) was added 10% wet palladium on carbon (5 mg). The reaction system was replaced with hydrogen and stirred at room temperature for 1 hour. The filtrate was filtered through celite and concentrated under reduced pressure to give crude product 7c (22 mg) with a yield of 75%.

[0169] Step 3

[0170] Phosphorus oxychloride (77 mg, 0.50 mmol) was added to a solution of compound 7c (22 mg, 0.17 mmol) and 1h (70 mg, 0.17 mmol) in pyridine (5 mL) at 0°C, and then the mixture was warmed to room temperature and stirred for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 7 (3 mg), yield: 4%.

[0171] MS-ESI calculated value [M+1] + 526, measured value 526.

[0172] 1 H NMR (400MHz, CD3OD) δ8.01(s,1H),7.32(d,J=8.8,1H),7.08(s,1H),6.95–6.89(m,1H),6.83(s,1H),6.75(s,1H),3.80(s,3H).

[0173] Example 8

[0174]

[0175]

[0176] first step

[0177] Compound 8a (173 mg, 1.00 mmol) was dissolved in ethanol (4 mL) and water (1 mL), and iron powder (280 mg, 5.00 mmol) and ammonium chloride (535 mg, 10.00 mmol) were added, and the mixture was reacted at 80°C for 2 hours after nitrogen was replaced. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product 8b (140 mg) with a yield of 98%.

[0178] Step 2

[0179] Compound 8b (140 mg, 0.98 mmol) and benzyl alcohol (216 mg, 2.00 mmol) were dissolved in toluene (10 mL), and potassium hydroxide (168 mg, 3.00 mmol) was added. The nitrogen was replaced and stirred at 120°C for 16 hours. The reaction system was diluted with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 8c (20 mg). Yield: 10%.

[0180] MS-ESI calculated value [M+1] + 215, measured value: 215.

[0181] Step 3

[0182] 8c (20 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 1h (37 mg, 0.09 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (76 mg, 0.20 mmol), and N,N-diisopropylethylamine (32 mg, 0.25 mol) were added, and then nitrogen was replaced three times. After stirring at room temperature for 2 hours, water (20 mL) and ethyl acetate (30 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 8d (15 mg). Yield: 27%.

[0183] MS-ESI calculated value [M+1] + 612, measured value: 612.

[0184] Step 4

[0185] 8d (15 mg, 0.02 mmol) was dissolved in tetrahydrofuran (3 mL), and 10% wet palladium on carbon (5 mg) was added. The mixture was replaced three times under hydrogen conditions. After stirring at room temperature for 1 hour, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 8 (4 mg). Yield: 33%.

[0186] MS-ESI calculated value [M+1] + 522, measured value: 522.

[0187] 1H NMR (400MHz, CD3OD) δ8.00(s,1H),7.32(d,J=8.8Hz,1H),7.09(s,1H),6.94(d,J=8.8Hz,1H),6.76(s,1H),6.45(s,1H),3.80(s,3H),2.27(s,3H).

[0188] Example 9

[0189]

[0190] first step

[0191] Compound 9a (500 mg, 2.90 mmol) was dissolved in a mixed solvent of ethanol (4 mL) and water (1 mL), and then iron powder (812 mg, 14.50 mmol) and ammonium chloride (1552 mg, 29.00 mmol) were added. After nitrogen replacement three times, the temperature was raised to 80°C and stirred for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was added to water (50 mL) and extracted with ethyl acetate (50 mL x 3). After the organic phases were combined, they were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 9b (380 mg), with a yield of 92%.

[0192] MS-ESI calculated value [M+1] + 143, measured value: 143.

[0193] Step 2

[0194] Compound 9b (200 mg, 1.41 mmol) was dissolved in toluene (5 mL), and potassium hydroxide (482 mg, 282.00 mmol) and benzyl alcohol (238 mg, 4.23 mmol) were added. After nitrogen was replaced three times, the temperature was raised to 120°C and stirred overnight, water (50 mL) was added, and ethyl acetate (50 mL x 3) was used for extraction. After the organic phases were combined, they were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 9c (160 mg), with a yield of 53%.

[0195] MS-ESI calculated value [M+1] + 215, measured value: 215.

[0196] Step 3

[0197] 9c (300 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1h (160 mg, 0.75 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (428 mg, 1.13 mmol), and N,N-diisopropylethylamine (291 mg, 2.25 mmol) were added, and then nitrogen was replaced three times. After stirring at room temperature for 2 hours, water (60 mL) and ethyl acetate (60 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain 9d (40 mg). The yield: 10%.

[0198] MS-ESI calculated value [M+1] + 612, measured value 612.

[0199] Step 4

[0200] 9d (40 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL), and then 10% wet palladium carbon (10 mg) was added. After replacing the hydrogen, the reaction system was stirred at room temperature for 2 hours. The reaction solution was filtered and dried, and purified by column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 9 (13 mg), yield: 36%.

[0201] MS-ESI calculated value [M+1] + 522, measured value 522.

[0202] 1 H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.12(s,1H),8.09(s,1H),7.36(d,J=8.8Hz,1H), 7.25(s,1H),7.21(s,1H),7.01(d,J=8.0Hz,1H),6.87(s,1H),3.78(s,3H),1.94(s,3H).

[0203] Biological activity test

[0204] The in vitro inhibitory effect of compounds on Nav1.8 was tested in HEK293 cells stably expressing human Nav1.8 using a manual patch clamp assay. The compounds to be tested were dissolved in DMSO to prepare a 9mM stock solution, which was dissolved in the extracellular fluid at the desired concentration on the day of the test. The extracellular fluid contained (mM): NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). The cells were clamped at –80mV and then depolarized to 10mV with a 10ms square wave to obtain NaV1.8 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound (dissolved in the extracellular fluid at the desired concentration) was perfused. When the reaction stabilized, the intensity of the compound's blocking effect on Nav1.8 was calculated based on the current intensity before and after the compound was perfused. Data collection and analysis were performed using pCLAMP10 (Molecular Devices, Union City, CA). Current stability refers to the current changing within a limited range over time. The test results are shown in Table 1.

[0205] Table-1 Inhibitory activity of compounds against Nav 1.8

[0206] Compound No. <![CDATA[IC 50 (nM)]]> Example 1 2.7 Example 2 1.2

[0207] Table-2 The percentage blocking rate of Nav1.8 channel when the compound concentration is 0.8nM

[0208]

[0209] Table-3 The percentage blocking rate of Nav1.8 channel at a compound concentration of 4 nM

[0210]

[0211]

[0212] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by the following formula (III), and a pharmaceutically acceptable salt thereof: in, G is N; L is O; The attachment site is located at the meta or para position of NH; n is selected from the following group: 0 or 1; R4 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C1-C4 alkyl; The Ra is CF3, and the Rb is F; Rc and Rd are each independently selected from the group consisting of halogen, C1 alkyl, CHF2, CF3, CD3, OCF3, OCH3, OCD3.

2. The compound according to claim 1, characterized in that Said Rc and Rd are each independently selected from the following group: halogen, CF3, CD3, OCF3, OCH3, OCD3.

3. A compound selected from the group consisting of:

4. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is used for treating, alleviating or preventing diseases or conditions related to sodium channel regulation; the sodium channel regulator is a Nav1.8 regulator; and the disease or condition is pain.

6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that: Used to prepare a pharmaceutical composition for treating, alleviating or preventing diseases related to sodium channel regulation; the sodium channel regulator is a Nav1.8 regulator; and the disease or condition is pain.

7. The use according to claim 6, characterized in that The pain or disease is selected from the group consisting of chronic pain and acute pain.

8. The use according to claim 6, characterized in that The pain or disease is selected from the group consisting of neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain.

9. The use according to claim 6, characterized in that The pain or disease is intestinal pain.

Images