5-amino-1-alkyl-1h-1,2,3-triazole-4-carboxamides, their preparation and use

Abstract

The application discloses a kind of 5-amino-1-alkyl-1H-1, 2, 3-triazole-4-formamide compounds with the structure general formula shown in formula (1), its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereoisomer, tautomer.The application also discloses a pharmaceutical composition containing the compound of formula (1), and the application of the compound of formula (1), its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereoisomer, tautomer, or the pharmaceutical composition in preparing medicaments for treating diseases responsive to the regulation of ion channel function.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, and a preparation method and application thereof. Background Art

[0002] Ion channels are an important class of drug targets. Ion channels are transmembrane proteins that contain aqueous pores formed by multiple subunits and regulate the influx or efflux of various ions across the cell membrane in response to ligand binding or voltage changes. Ion channels function as fundamental excitatory or inhibitory units in the cell membranes of many tissues, including nerves, muscles, and glands. When the channels open, the influx or efflux of ions generates various electrical signals, promoting a wide range of cellular activities and fundamental physiological processes. Ion channels not only influence neurotransmitter release, muscle contraction, and glandular secretion but also play a key role in learning and memory, cell volume maintenance, and homeostasis. Ion channel dysfunction, or ion channelopathies, has been associated with impaired pain perception, inflammatory responses, diabetes, and tumor cell proliferation and migration. Furthermore, abnormal ion channels have been implicated in numerous neurological disorders and cardiac arrhythmias, including anxiety, insomnia, epilepsy, schizophrenia, Parkinson's disease, Alzheimer's disease, and long / short QT syndrome. Therefore, ion channels are an important class of drug targets.

[0003] In previous studies, the applicant reported two types of compounds that can be used to treat epilepsy. The patent specification with publication number CN113717133A discloses a class of 3-amido-N-arylbenzamide compounds and their use in the preparation of anti-epileptic therapeutic drugs. The patent specification with publication number CN114044757A discloses a class of triazole-4-(N-substituted carboxamide)-5-triazene compounds, their preparation method and their use in the preparation of anti-epileptic drugs. Neither of these two prior arts reports the drug effect in the lamotrigine resistance model and does not involve solving the drug resistance problem. In addition, the triazole-4-(N-substituted carboxamide)-5-triazene compounds disclosed in the patent specification with publication number CN114044757A contain a triazene group, which makes these compounds have biological toxicity and difficult to pass the test in terms of drug safety.

[0004] The present invention modifies the essential triazene-containing core structure of CN114044757A, discarding the potentially biotoxic triazene structure and replacing it with an amino group. This results in the design and synthesis of a class of non-biotoxic 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds. The unexpected discovery is that these novel compounds still possess significant electrophysiological activity, exhibiting inhibitory activity against sodium and other ion channels. In animal models of epilepsy, including the pentylenetetrazol acute seizure model (PTZ), the maximal electroshock seizure model (MES), and the lamotrigine-resistant model, some compounds exhibited more potent antiepileptic efficacy, significantly reducing seizure severity and increasing seizure latency. Furthermore, they maintained good antiepileptic efficacy in the lamotrigine-resistant model, demonstrating promising development prospects. Summary of the Invention

[0005] The present invention provides a class of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers thereof. The 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds have the general structural formula shown in the following formula (1):

[0006]

[0007] In formula (1):

[0008] R1 is a substituted or unsubstituted aromatic ring, wherein the aromatic ring is a benzene ring or an aromatic heterocycle, and the substituent on the aromatic ring contains a fluorine atom and is independently selected from halogen, nitro, amino, hydroxyl, cyano, alkoxy, thiol, carboxyl, ester, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Cycloalkyl, substituted or unsubstituted C 1-6 Heterocycloalkyl, substituted or unsubstituted C 4-10 Aryl, substituted or unsubstituted C 1-8 Heteroaryl, C 2-10 Alkenyl, C 2-10 one or more of alkynyl, alkyl monosubstituted amino, alkyl disubstituted amino, alkoxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, heteroarylcarbonyloxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, heteroarylcarbonylamino, aminocarbonyl, alkoxyformamido, alkylthiol, hydroxyalkoxy, sugar residue, sulfonic acid, phosphoric acid, polyhydroxyalkoxycarbonyl, carboxyalkoxy, and carboxyalkylformyloxy;

[0009] R2 and R3 are the same or different and are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, and the substituent on the C1-C4 alkyl is methoxyacyl or hydroxyl; or R2, R3 and the N connecting R2 and R3 form a six-membered ring, and the six-membered ring contains N, C and O.

[0010] The 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound may also have a general structural formula as shown in the following formula (2):

[0011]

[0012] In formula (2):

[0013] represents a benzene ring or a pyridine ring;

[0014] R1 represents one or more substituents on the benzene ring or pyridine ring, each independently selected from one or more of H, halogen, C1-C6 alkoxy, hydroxyl, cyano, amino, thienyl, pyrazolyl, and pyridinone;

[0015] R2 and R3 are independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl, and phenyl, and the substituent on the C1-C4 alkyl is one or more of phenyl, ester, and hydroxyl; or R2, R3 and the N connecting R2 and R3 form a substituted or unsubstituted six-membered ring, and the six-membered ring is composed of N and C or N, C and O, and the substituent on the six-membered ring is C1-C4 alkyl.

[0016] Furthermore, the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound can be selected from any one of the following compounds 1-32:

[0017]

[0018]

[0019]

[0020] The present invention also provides a method for preparing the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound.

[0021] The present invention can use reaction route I to synthesize compound 1-32;

[0022] Reaction Scheme I includes the following process:

[0023]

[0024] Ethyl cyanoacetate A reacts with benzyl azide compound B in DMF with NaH as base to generate substituted 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxylate compound C, which is then hydrolyzed and acidified under the action of NaOH to generate carboxylic acid compound D. Subsequently, under the promotion of condensation reagent HATU, it undergoes condensation reaction with amine compound E to generate target compound 1-32.

[0025] The at least one triazole compound, pharmaceutically acceptable salt thereof, or racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof prepared according to the above method can be purified by column chromatography, high performance liquid chromatography, crystallization, or other appropriate methods.

[0026] The present invention also provides a pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof.

[0027] A pharmaceutically acceptable carrier (i.e., a pharmaceutically acceptable carrier) refers to a carrier that is compatible with the active ingredient (5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof) in the composition (in some embodiments, can stabilize the active ingredient) and is harmless to the individual being treated. Excipients can be selected from one or more combinations of excipients, diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled-release matrices, colorants, flavorings, buffers, stabilizers, solubilizers, and the like.

[0028] The pharmaceutical compositions comprising the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds described herein, their pharmaceutically acceptable salts, or their racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, or tautomers can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation, or by implantation.

[0029] Depending on the purpose of treatment, the pharmaceutical composition can be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions).

[0030] To form the pharmaceutical composition into tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, and the like; disintegrants such as dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearate, starch, and lactose; disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated oil; adsorption promoters such as quaternary ammonium hydroxide and sodium lauryl sulfate; wetting agents such as glycerol and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder, and polyethylene glycol. Ordinary coating materials can be selected as needed to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets.

[0031] In order to shape the pharmaceutical composition into a pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder;

[0032] In order to shape the pharmaceutical composition into a suppository form, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like.

[0033] To prepare a pharmaceutical composition in the form of an injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose, or glycerol) and prepared into an injection with an osmotic pressure equal to that of blood. Any commonly used carrier in the art can be used in the preparation of the injection, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. In addition, conventional solvents, buffers, and analgesics can also be added.

[0034] In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. Various dosage forms can be selected for administration based on the patient's age, gender, and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules can be administered orally; injections can be administered alone or mixed with an injectable delivery fluid (such as a glucose solution or an amino acid solution) for intravenous injection; and suppositories are administered rectally.

[0035] On the other hand, the present invention also provides a method for regulating ion channel function, which comprises using an effective amount of a 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof.

[0036] On the other hand, the present invention also provides a method for regulating ion channel function, which comprises using an effective amount of a pharmaceutical composition to regulate ion channel function, wherein the pharmaceutical composition comprises at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer.

[0037] On the other hand, the present invention also provides a method for treating a disease in an individual that is responsive to modulation of ion channel function, comprising administering to an individual in need thereof an amount of a 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, or tautomer thereof that is effective in modulating ion channel function.

[0038] On the other hand, the present invention also provides a method for treating a disease in an individual that is responsive to modulation of ion channel function, comprising administering to an individual in need thereof a pharmaceutical composition in an amount effective to modulate ion channel function, the pharmaceutical composition comprising at least one of a pharmaceutically acceptable carrier and an excipient, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, a hydrate, a solvate, a prodrug, an enantiomer, a diastereomer, or a tautomer thereof.

[0039] The present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition in the preparation of ion channel blockers.

[0040] The present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or pharmaceutical composition in the preparation of a medicament for treating ion channel-related diseases.

[0041] The ion channel of the present invention may be a sodium ion channel.

[0042] The ion channel-related diseases include central nervous system diseases, inflammatory diseases, autoimmune diseases, cancer, infectious diseases, cardiovascular and cerebrovascular diseases, etc.

[0043] The central nervous system diseases include epilepsy, Parkinson's disease, Alzheimer's disease, anxiety, depression, schizophrenia, etc.

[0044] Inflammatory diseases refer to pathological conditions that result in an inflammatory response, particularly due to neutrophil chemotaxis. Examples of such diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including tissue reperfusion injury caused by surgery, myocardial ischemia such as myocardial infarction, cardiac arrest, postoperative reperfusion after cardiac surgery, and abnormal coronary vasoconstriction after percutaneous transluminal coronary angioplasty; tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; cerebral edema secondary to stroke; cranial trauma; hemorrhagic shock; ventricular asphyxia; adult respiratory distress syndrome; acute lung injury; Behçet's disease; dermatomyositis; polymyositis; multiple sclerosis; dermatitis; meningitis Inflammation; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis; Sjögren's syndrome; vasculitis; diseases involving leukocytic infiltration; inflammatory diseases of the central nervous system secondary to sepsis or trauma, multiple organ injury syndrome: alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis, sepsis, sarcoidosis; immunopathological reactions caused by tissue / organ transplantation; lung inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, and cystic fibrosis.

[0045] Autoimmune diseases are diseases or conditions caused by an immune response to self-antigens, resulting in damage to the body's own tissues or organs. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease, allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis, psoriasis, inflammatory bowel disease, asthma, idiopathic thrombocytopenic purpura, and myeloproliferative disorders such as myelofibrosis and polycythemia vera / essential thrombocythemia myelofibrosis.

[0046] The inflammatory diseases and autoimmune diseases include rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, lupus erythematosus, psoriasis and multiple sclerosis.

[0047] Includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels, including both primary and metastatic cancers.

[0048] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, head and neck squamous cell carcinoma; skin cancer, including, for example, malignant melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, for example, gliomas, anaplastic oligodendrogliomas, adult glioblastoma multiforme, and adult anaplastic astrocytomas; bone cancer; soft tissue sarcomas; and thyroid cancer.

[0049] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast crisis (CML-BP); acute lymphocytic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes, including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and refractory anemia with excess blasts combined with acute transformation; and myeloproliferative syndromes.

[0050] In some embodiments, typically, the cancer can be selected from leukemia, multiple myeloma (MM), lymphoma; the leukemia is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML); the lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B cell lymphoma, T cell lymphoma, diffuse large B cell lymphoma (DLBCL).

[0051] The infectious diseases include bacterial infection, fungal infection, viral infection, parasitic infection and the like.

[0052] The cardiovascular and cerebrovascular diseases include acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosclerosis, coronary heart disease, restenosis and vascular stenosis, as well as traumatic brain injury, stroke, ischemia-reperfusion injury, etc.

[0053] The present invention also provides the use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound, its pharmaceutically acceptable salt, or its racemic mixture, hydrate, solvate, prodrug, enantiomer, diastereomer, tautomer, or the pharmaceutical composition in the preparation of anesthetics.

[0054] In addition, the compounds of formula (1) and / or pharmaceutically acceptable salts thereof described herein can be used in combination with other active ingredients for the treatment of central nervous system diseases, inflammatory diseases, autoimmune diseases, cancer, infectious diseases or cardiovascular and cerebrovascular diseases, as well as for the preparation of anesthetics. The compounds of formula (1) and / or pharmaceutically acceptable salts thereof can be used separately from other active ingredients or prepared into compound preparations. Other active ingredients refer to those known to be effective ingredients for the treatment of diseases related to ion channel function.

[0055] definition

[0056] The following words, phrases and symbols used in this application have the meanings described below unless the context indicates otherwise.

[0057] A hyphen ("-") that is not between two letters or symbols indicates the point of attachment of a substituent. For example, -O(C 1-4 Alkyl) refers to a C 1-4 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0058] The term "alkyl" as used herein refers to a straight or branched chain saturated alkyl group containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, further such as 1 to 6 carbon atoms, further such as 1 to 4 carbon atoms. 1-6 "Alkyl" within the scope of "alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), and tert-butyl ("t-Bu").

[0059] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo, and "halogen" refers to fluorine, chlorine, bromine and iodine.

[0060] The term "haloalkyl" as used herein refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from one another. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are the same as one another. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl group as defined herein in which two or more hydrogen atoms, such as 2, 3, 4 or 5 hydrogen atoms, are replaced by halogen atoms, wherein the halogen atoms are different from one another. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, etc.

[0061] The term "alkoxy" as used herein refers to the group -O-alkyl, wherein alkyl is as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy, including their isomers.

[0062] As used herein, the term "aryl" refers to a carbocyclic hydrocarbon group consisting of one or more fused rings containing 6 to 14 ring carbon atoms, for example, 6 to 12 ring carbon atoms, wherein at least one ring is aromatic and the other rings are not heteroaryl as defined below, and the point of attachment can be on the aromatic ring or on another ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl.

[0063] As used herein, "aryl" or "aromatic" follows Huckel's rule, where the number of π electrons is equal to 4n+2, and n is zero or any positive integer up to 6.

[0064] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a 4- to 12-membered monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated ring selected from the group consisting of at least one, e.g., 1-4, further e.g., 1-3, or further e.g., 1 or 2, heteroatoms selected from O, S, and N, and at least one carbon atom. The point of attachment of the heteroaryl group can be on a heteroatom or on a carbon atom. "Heteroaryl" or "heteroaromatic" also refers to a monocyclic ring containing at least one heteroatom selected from O, S, and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S, and N and the other ring is not a heteroaryl or aryl group, the point of attachment of which can be on the heteroaryl group or on the other ring.

[0065] As used herein, the term "heteroaryl" refers to:

[0066] a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example having 6 ring atoms, which contains one or more, for example 1, 2 or 3, for example 1 or 2, ring heteroatoms independently selected from N, O and S in the ring, the remaining ring atoms being carbon atoms: and

[0067] Bicyclic aromatic hydrocarbon groups having 8 to 12 ring atoms, for example 9 or 10 ring atoms, which contain one or more, for example 1, 2, 3 or 4, for example 1 or 2, ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon atoms, wherein at least one ring is aromatic. For example, bicyclic heteroaryl groups include 5-6 membered heteroaryl rings fused to 5-6 membered cycloalkyl rings, heteroaryl rings or aryl rings, wherein the point of attachment can be on the heteroaryl ring or on the cycloalkyl ring / heteroaryl ring / aryl ring.

[0068] Heteroaryl groups also include those in which the N ring heteroatom is in the form of an N-oxide, for example N-oxidopyrimidinyl.

[0069] In some embodiments, the ring heteroatom in the above heteroaryl groups is an N atom, and such heteroaryl groups are referred to as “nitrogen-containing heteroaryl groups.” Nitrogen-containing heteroaryl groups also include those heteroaryl groups in which the N ring heteroatom is in the form of an N-oxide, such as N-oxidized pyridinyl.

[0070] Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridyl N-oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; tetrazolyl; triazolyl; thienyl; furyl; pyranyl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; benzodioxaropentyl, for example, benzo[d][1,3]dioxaropentyl; benzoxazolyl, for example, benzo[d]oxazolyl; imidazopyridyl, for example, imidazo[1,2-a]pyridyl; triazolopyridyl, for example, [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridinyl; indazolyl; 2H-indazolyl; pyrrolopyrimidinyl, for example pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; pyrazolopyrimidinyl, for example pyrazolo[1,5-a]pyrimidinyl; tetrazolopyridinyl, for example tetrazolo[1,5-a]pyridinyl; benzothienyl; benzofuranyl; benzimidazolinyl; indolyl; indolinyl; purinyl, for example 9H-purinyl and 7H-purinyl; quinolyl; isoquinolyl; 1,2,3,4-tetrahydroquinolyl and 1,2,3,4-tetrahydroisoquinolyl.

[0071] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, pyrrolyl; pyrazolyl; imidazolyl; pyridinyl; pyrazinyl; pyrimidinyl, N-oxidized pyrimidinyl; pyridazinyl; pyrrolopyrimidinyl, such as pyrrolo[3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolyl; indolyl; and indazolyl.

[0072] As used herein, the term "hydroxyl" refers to an -OH group.

[0073] As used herein, the term "mercapto" refers to a -SH group.

[0074] As used herein, the term "carboxy" refers to a -C(O)-OH group.

[0075] The term "amino" as used herein refers to a -NH2 group.

[0076] As used herein, the term "cyano" refers to a -CN group.

[0077] If a structural formula herein contains an asterisk "*", the compound represented by the structural formula is a racemate.

[0078] As used herein, the term "substituted" or "substituted by" means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group, provided that the normal valence of the given atom is not exceeded.

[0079] As used herein, the term "substituted with one or more substituents" means that one or more hydrogen atoms on a given atom or group are independently replaced with one or more substituents selected from a given group. In some embodiments, "substituted with one or more substituents" means that a given atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from a given group.

[0080] It will be understood by those skilled in the art that some 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds may contain one or more chiral centers and therefore exist as two or more stereoisomers. Racemic mixtures of these isomers, individual isomers, and mixtures enriched in one enantiomer, as well as diastereomers and mixtures partially enriched in a specific diastereomer when there are two chiral centers, are all within the scope of the present invention. It will also be understood by those skilled in the art that the present invention includes all individual stereoisomers (e.g., enantiomers), racemic mixtures, or partially resolved mixtures of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, and, where appropriate, individual tautomers thereof.

[0081] The present invention also provides a pharmaceutically acceptable salt of a 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound. "Pharmaceutically acceptable salt" refers to a derivative of the disclosed compound wherein the parent compound is modified by converting an existing acid or base moiety into its salt form.

[0082] Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts of 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds bearing an acidic group formed with pharmaceutically acceptable cations. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two.

[0083] The term "solvate" is intended to include stoichiometric or non-stoichiometric solvent addition forms. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate.

[0084] The term "prodrug" refers to a compound that is an inactive precursor of a compound that is converted to its active form in vivo through normal metabolic pathways. For illustration, a prodrug can be converted to a pharmacologically active form by hydrolysis of, for example, an ester or amide bond, thereby introducing or exposing a functional group on the resulting product. Prodrugs can be designed to react with endogenous compounds to form water-soluble conjugates that further enhance the pharmacological properties of the compound, such as increasing the circulatory half-life. Alternatively, prodrugs can be designed to have functional groups covalently modified with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound. High molecular weight conjugates can also be excreted in the bile, cleaved by enzymes, and released back into the circulation, effectively increasing the biological half-life of the originally administered compound.

[0085] As used herein, the term "subject" refers to any animal, including mammals and non-mammals, preferably rats, mice, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0086] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0087] Compared with the prior art, the present invention has the following beneficial effects: the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures, hydrates, solvates, prodrugs, enantiomers, diastereomers, and tautomers thereof of the present invention have high pharmaceutical activity and are non-biotoxic, have good drug safety, and can overcome the drug resistance problem of existing drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 This is a graph showing the test results of the inhibitory activity of compounds 1, 2, 3, 7, 11, 14, 15, 22, and 26 on sodium ion channels.

[0089] Figure 2 The graph shows the results of the effect determination of the control drug and compounds 1 and 2 on the pentylenetetrazol acute epileptic seizure model (PTZ).

[0090] Figure 3 This is a graph showing the results of the effects of the control drug and compounds 1 and 2 on the maximum electric shock epileptic seizure model.

[0091] Figure 4 This is a graph showing the results of the anti-epileptic efficacy evaluation of the control drug and the compound of the present invention in the lamotrigine-resistant model.

[0092] Figure 5 This is the anti-epileptic efficacy result of the oral administration experiment of the control drug and compounds 1, 2, and 11 in the lamotrigine resistance model.

[0093] Figure 6 This is the safety evaluation result diagram of compounds 1 and 2. DETAILED DESCRIPTION

[0094] The present invention will be further described below with reference to the accompanying drawings and 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.

[0095] The 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds of the present invention are prepared by the following route:

[0096]

[0097] Preparation Example 1: Preparation of Compound 1

[0098]

[0099] Step 1: Place 600 mg of sodium hydride in a dry 100 mL two-necked flask, place it on a reflux line, and place it under argon. Add 20 mL of anhydrous DMF to the flask at 0°C and stir for 10 minutes. Dissolve 2.26 g of ethyl cyanoacetate A (20 mmol) in 10 mL of anhydrous DMF and add dropwise to the flask via syringe. Stir at 0°C for 15 minutes.

[0100] Step 2: Dissolve 1.7 g of 2,6-difluorobenzyl azide B (10 mmol) in 10 mL of anhydrous DMF and add dropwise to the two-necked flask at 0°C. The reaction system is then stirred at 65°C for 5 h. After completion of the reaction, the solvent is removed under reduced pressure. Column chromatography using silica gel as the stationary phase and dichloromethane / methanol as the eluent yields 1.7 g of intermediate C as a white solid in a 65% yield.

[0101] Step 3: Place 1.7 g of intermediate C (6.5 mmol) in a 100 mL beaker, add 20 mL of 5% sodium hydroxide aqueous solution, and stir at room temperature until clear. Subsequently, 10% hydrochloric acid is added dropwise to the beaker to adjust the pH to 2-3, and a large amount of white solid precipitates. The reaction solution is filtered and the filter residue is drained under reduced pressure. The filtrate is then extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a white solid, which is combined with the filter residue and drained. A total of 1.4 g of intermediate D is obtained, with a yield of 84% and a combined yield of 55% for the two steps.

[0102] Step 4: Place 1g of intermediate D (4.5mmol) and 2.85g of HATU (6.7mmol) in a 50mL dry two-necked flask, inject 25mL of DMF and 2.5mL of DIPEA (N,N-diisopropylethylamine, 14mmol) and 0.5mL of ammonia water, and stir at room temperature overnight. After the reaction is completed, 25mL of water is added to the reaction solution, and the mixture is extracted three times with dichloromethane. The organic phase is washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure. Column chromatography is performed using silica gel as the stationary phase and a dichloromethane / methanol system as the eluent to obtain 850mg of 5-amino-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid with a yield of 70%.

[0103] The physical properties and spectral data of the product are as follows: white solid; mp: 212.7℃; 1 H NMR (400MHz, DMSO-d6) δ7.49 (m, 1H), 7.41 (s, 1H), 7.15 (t, J = 8.0Hz, 2H), 7.08 (s, 1H), 6.44 (s, 2H), 5.39 (s, 2H); 13CNMR(101MHz,DMSO-d6)δ164.23,160.83(dd,J=249.0,7.7Hz),144.95,131. 21(t,J=10.4Hz),121.29,112.04–111.61(m),111.25(t,J=19.0Hz),36.93; 19 F NMR(376MHz,DMSO-d6)δ-114.35.

[0104] Preparation Example 2: Preparation of Compound 2

[0105]

[0106] The corresponding substrate was replaced and the preparation method was the same as that of Preparation Example 1. White solid 2 was obtained by column chromatography with a yield of 75%.

[0107] The physical properties and spectral data of the product are as follows: white solid; mp: 211.4℃; 1 H NMR (400MHz, DMSO-d6) δ7.98(q,J=4.7Hz,1H),7.48(m,1H),7.20-7.08(m,2H),6.40(s,2H),5.39(s,2H),2.71(d,J=4.7Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ162.58,160.81(dd,J=249.2,7.4Hz),144.54,131.20( t,J=10.4Hz),121.46,112.28–111.41(m),111.23(t,J=19.2Hz),36.93,25.10; 19 F NMR(376MHz,DMSO-d6)δ-114.36.

[0108] Preparation Example 3: Preparation of Compound 3

[0109]

[0110] The corresponding substrate was replaced and the preparation method was the same as that in Preparation Example 1. White solid 3 was obtained by column chromatography with a yield of 68%.

[0111] The physical properties and spectral data of the product are as follows: white solid; mp: 147.5℃; 1 H NMR (400MHz, DMSO-d6) δ7.49 (m, 1H), 7.16 (t, J = 8.0Hz, 2H), 6.62 (s, 2H), 5.39 (s, 2H), 3.47 (s, 3H), 2.94 (s, 3H); 13CNMR(101MHz,DMSO-d6)δ162.46,160.85(dd,J=248.5,7.7Hz),146.78,131.25(t,J=10.3 Hz),121.99,111.88(d,J=6.0Hz),111.70(d,J=5.4Hz),111.33–110.93(m),37.89,36.90; 19 F NMR(376MHz,DMSO-d6)δ-114.18.

[0112] Preparation Example 4: Preparation of Compound 4

[0113]

[0114] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 4 was obtained by column chromatography with a yield of 77%.

[0115] The physical properties and spectral data of the product are as follows: white solid; mp: 177.9℃; 1 H NMR (400MHz, DMSO-d6) δ7.49(m,1H),7.16(t,J=8.1Hz,2H),6.67(s,2H),5.40(s,2H),3.61(dt,J=8.3,6.6Hz,4H); 13 C NMR(101MHz,Chloroform-d)δ161.81,161.39(dd,J=250.3,7.5Hz),146.29,13 1.47(t,J=10.5Hz),123.65,112.64–111.10(m),110.01,67.14,42.59,37.52; 19 F NMR(376MHz,DMSO-d6)δ-114.15.

[0116] Preparation Example 5: Preparation of Compound 5

[0117]

[0118] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 5 was obtained by column chromatography with a yield of 74%.

[0119] The physical properties and spectral data of the product are as follows: white solid; mp: 144.3℃; 1H NMR (400MHz, DMSO-d6) δ7.49(m,1H),7.16(t,J=8.0Hz,2H),6.64(s,2H),5.40(s,2H),3.94(d,J=277.4Hz,4H),2.33(t,J=5.0Hz,4H),2.19(s,3H); 13 C NMR(101MHz,Chloroform-d)δ161.4(dd,J=249.8,8.0Hz),161.71,146.25,131.4 3(t,J=8.4Hz),123.80,112.19–111.76(m),110.11,55.58,46.05,42.14,37.50; 19 F NMR(376MHz,DMSO-d6)δ-114.17.

[0120] Preparation Example 6: Preparation of Compound 6

[0121]

[0122] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 6 was obtained by column chromatography with a yield of 72%.

[0123] The physical properties and spectral data of the product are as follows: white solid; mp: 156.7℃; 1 H NMR(400MHz,DMSO-d6)δ8.04(m,1H),7.48(m,1H),7.28–6.90(m,2H),6.40(s ,2H),5.39(s,2H),3.21(qd,J=7.0,3.8Hz,2H),1.06(dt,J=7.3,3.3Hz,3H); 13 C NMR (101MHz, DMSO-d6) δ161.90, 160.82 (dd, J = 249.7, 6.9Hz), 144.65, 131.22 (t, J = 10.5Hz), 121.43, 112.00–111.65 (m), 36.93, 32.75, 15.20; 19 F NMR(376MHz,DMSO-d6)δ-114.23.

[0124] Preparation Example 7: Preparation of Compound 7

[0125]

[0126] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 7 was obtained by column chromatography with a yield of 72%.

[0127] The physical properties and spectral data of the product are as follows: white solid; mp: 162.6℃; 1 H NMR (400MHz, DMSO-d6) δ8.64(t,J=6.4Hz,1H),7.51(m,1H),7.31(d,J=4.3Hz,4H),7.26–7.11(m,3H),6.47(s,2H),5.42(s,2H),4.41(d,J=6.3Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ162.08,160.39(dd,J=250.5,8.1Hz),144.81,140.17,131.22(t,J=10 .6Hz),128.15,127.25,126.57,121.20,111.92,111.68,111.22(t,J=19.1Hz),41.48,36.92; 19 F NMR(376MHz,DMSO-d6)δ-114.17.

[0128] Preparation Example 8: Preparation of Compound 8

[0129]

[0130] The corresponding substrate was replaced and the preparation method was the same as that in Preparation Example 1. White solid 8 was obtained by column chromatography with a yield of 69%.

[0131] The physical properties and spectral data of the product are as follows: white solid; mp: 152.4℃; 1 H NMR(400MHz, DMSO-d6)δ8.09(d,J=4.5Hz,1H),7.48(m,1H),7.15(t,J=8.1Hz, 2H),6.44(s,2H),5.39(s,2H),2.77(tq,J=8.5,4.2Hz,1H),0.71–0.47(m,4H); 13 C NMR(101MHz,DMSO-d6)δ163.79,161.29(dd,J=249.1,7.8Hz),145.18,131.69 (t,J=10.3Hz),112.49–112.10(m),111.75(t,J=19.2Hz),37.44,22.53,6.18; 19 F NMR(376MHz,DMSO-d6)δ-114.24.

[0132] Preparation Example 9: Preparation of Compound 9

[0133]

[0134] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. 9 was obtained by column chromatography with a yield of 67%.

[0135] The physical properties and spectral data of the product are as follows: white solid; mp: 180.2℃; 1 H NMR (400MHz, DMSO-d6) δ8.38(t,J=6.1Hz,1H),7.51(m,1H),7.19(t,2H),6.49(s,2H),5.42(s,2H),3.95(d,J=6.1Hz,2H),3.65(s,3H); 13 C NMR (101MHz, DMSO-d6) δ170.54, 162.36, 160.81 (dd, J = 251.5, 7.8Hz), 131.24 (t, J=10.4Hz),120.85,112.07–111.63(m),111.46–110.94(m),51.67,40.20,36.95; 19 F NMR(376MHz,DMSO-d6)δ-114.25.

[0136] Preparation Example 10: Preparation of Compound 10

[0137]

[0138] The corresponding substrate was replaced and the preparation method was the same as that of Preparation Example 1. White solid 10 was obtained by column chromatography with a yield of 73%.

[0139] The physical properties and spectral data of the product are as follows: white solid; mp: 223.3℃; 1 H NMR (400MHz, DMSO-d6) δ7.55–7.26 (m, 4H), 7.24–6.89 (m, 1H), 6.50 (s, 2H), 5.40 (d, J = 1.6Hz, 2H); 13 C NMR (101MHz, DMSO-d6) δ164.25, 161.33 (d, J = 250.0Hz), 145.06, 134.72 (d, J = 5.2Hz), 131.32 (d, J = 10 .0Hz), 125.69 (d, J = 3.4Hz), 121.19, 120.96 (d, J = 17.5Hz), 114.76 (d, J = 22.2Hz), 40.46 (d, J = 3.8Hz); 19 F NMR(376MHz,DMSO-d6)δ-112.68.

[0140] Preparation Example 11: Preparation of Compound 11

[0141]

[0142] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 11 was obtained by column chromatography with a yield of 71%.

[0143] The physical properties and spectral data of the product are as follows: white solid; mp: 201.9℃; 1 H NMR (400MHz, DMSO-d6) δ7.49(s,1H),7.33(m,1H),7.20–7.03(m,3H),6.45(s,2H),5.45(s,2H); 13 C NMR (101MHz, DMSO-d6) δ164.71,160.49(dd,J=248.9,12.5Hz),145.47,131.22(dd,J=9.9,5. 6Hz), 122.10, 119.85 (dd, J=15.3, 3.7Hz), 112.36–112.03 (m), 104.65 (t, J=25.7Hz), 42.88; 19 FNMR(376MHz,DMSO-d6)δ-110.22,-112.70.

[0144] Preparation Example 12: Preparation of Compound 12

[0145]

[0146] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 12 was obtained by column chromatography with a yield of 70%.

[0147] The physical properties and spectral data of the product are as follows: white solid; mp: 197.6℃; 1 H NMR (400MHz, DMSO-d6) δ7.49(m,2H),7.29(m,1H),7.11(s,1H),7.03(t,J=8.2Hz,1H),6.44(s,2H),5.45(s,2H); 13 CNMR(101MHz,DMSO-d6)δ164.19,159.74(d,J=250.4Hz),145.05,133.44(d,J=10.3Hz),130.49 (d, J=4.9Hz), 124.93 (d, J=3.7Hz), 122.22 (d, J=15.2Hz), 121.61, 116.18 (d, J=24.5Hz), 42.44; 19 F NMR(376MHz,DMSO-d6)δ-114.18.

[0148] Preparation Example 13: Preparation of Compound 13

[0149]

[0150] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 13 was obtained by column chromatography with a yield of 72%.

[0151] The physical properties and spectral data of the product are as follows: white solid; mp: 164.3℃; 1 H NMR (400MHz, DMSO-d6) δ7.88(t,J=5.9Hz,1H),7.48(m,1H),7.15(t,J=8.0Hz,2H),6.43( s,2H),5.40(s,2H),4.72(t,J=5.4Hz,1H),3.46(q,J=5.9Hz,2H),3.28(q,J=6.2Hz,2H); 13 C NMR(101MHz,DMSO-d6)δ162.67,161.30(dd,J=249.1,7.6Hz),145.17,131.71(t,J =10.5Hz),121.77,112.47–112.10(m),111.75(t,J=19.0Hz),60.50,41.26,37.45; 19 F NMR(376MHz,DMSO-d6)δ-114.13.

[0152] Preparation Example 14: Preparation of Compound 14

[0153]

[0154] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. Column chromatography gave white solid 14 in a yield of 72%.

[0155] The physical properties and spectral data of the product are as follows: white solid; mp: 194.5℃; 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),7.81(d,J=8.6Hz,2H),7.52(m,1H),7.31(t,2H),7.19(t,2H),7.06(t,1H),6.67(s,2H),5.48(s,2H); 13C NMR(101MHz,DMSO-d6)δ161.31(dd,J=249.5,8.1Hz),161.21,146.04,139.45,131.7 0(d,J=10.2Hz),128.98,123.54,121.65,120.50,112.96–112.03(m),111.72,37.56; 19 F NMR(376MHz,DMSO-d6)δ-114.25.

[0156] Preparation Example 15: Preparation of Compound 15

[0157]

[0158] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 15 was obtained by column chromatography with a yield of 71%.

[0159] The physical properties and spectral data of the product are as follows: white solid; mp: 193.3℃; 1 H NMR (400MHz, DMSO-d6) δ8.34(m,1H),7.77(m,1H),7.46(dt,J=8.8,4.5Hz,2H),7.07(s,1H),6.33(s,2H),5.60(s,2H); 13 C NMR(101MHz,DMSO-d6)δ164.83,157.26(d,J=256.7Hz),146.21,145.70(d,J=5.3Hz ),143.18(d,J=14.7Hz),125.58(d,J=3.8Hz),124.09(d,J=17.9Hz),122.02,45.54; 19 F NMR(376MHz,DMSO-d6)δ-125.88.

[0160] Preparation Example 16: Preparation of Compound 16

[0161]

[0162] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 16 was obtained by column chromatography with a yield of 74%.

[0163] The physical properties and spectral data of the product are as follows: white solid; mp: 177.1℃; 1H NMR (400MHz, DMSO-d6) δ8.60(d,J=1.7Hz,1H),8.39(d,J=4.8Hz,1H),7.50(s,1H),7.14(s,1H),6.86(t,J=5.7Hz,1H),6.48(s,2H),5.58(s,2H); 13 C NMR (101MHz, DMSO-d6) δ164.64, 157.34 (d, J = 255.8Hz), 146.83 (d, J = 5.3Hz), 145.78, 138.14 (d, J = 22.6Hz), 132.34 (d, J = 12.3Hz), 123.26, 122.14, 42.80; 19 F NMR(376MHz,DMSO-d6)δ-125.67.

[0164] Preparation Example 17: Preparation of Compound 17

[0165]

[0166] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 17 was obtained by column chromatography with a yield of 72%.

[0167] The physical properties and spectral data of the product are as follows: white solid; mp: 172.1℃; 1 H NMR (400MHz, DMSO-d6) δ7.39(m,2H),7.04(s,1H),6.91(d,J=8.4Hz,1H),6.85(t,J=8.5Hz,1H),6.25(s,2H),5.24(s,2H),3.81(s,3H); 13 C NMR (101MHz, DMSO-d6) δ164.30, 161.25 (d, J=245.5Hz), 158.45 (d, J=7.7Hz), 144.85, 130.70 (d, J= 10.6Hz), 121.22, 110.70 (d, J = 17.1Hz), 107.71 (d, J = 22.0Hz), 107.41 (d, J = 2.5Hz), 56.32, 37.43; 19 F NMR(376MHz,DMSO-d6)δ-116.36.

[0168] Preparation Example 18: Preparation of Compound 18

[0169]

[0170] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 18 was obtained by column chromatography with a yield of 75%.

[0171] The physical properties and spectral data of the product are as follows: white solid; mp: 157.4℃; 1 H NMR (400MHz, DMSO-d6) δ7.52–7.43(m,1H),7.09(m,2H),6.88(dd,J=12.2,2. 5Hz,1H),6.79(dd,J=8.6,2.5Hz,1H),6.40(s,2H),5.37(s,2H),3.77(s,3H); 13 C NMR (101MHz, DMSO-d6) δ164.75, 161.08 (d, J = 245.9Hz), 161.01 (d, J = 11.0Hz), 145.33, 130.90 (d, J = 5.8H z), 122.08, 115.00 (d, J = 15.4Hz), 110.87 (d, J = 2.9Hz), 102.15 (d, J = 24.9Hz), 56.19, 42.91 (d, J = 2.9Hz); 19 F NMR(376MHz,DMSO-d6)δ-115.13.

[0172] Preparation Example 19: Preparation of Compound 19

[0173]

[0174] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 19 was obtained by column chromatography with a yield of 67%.

[0175] The physical properties and spectral data of the product are as follows: white solid; mp: 220.8℃; 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),7.42(s,1H),7.07(s,1H),6.95(t,J=8.6Hz,1H),6.58(d,J=10.3Hz,2H),6.34(s,2H),5.30(s,2H); 13 C NMR (101MHz, DMSO-d6) δ164.78, 161.05 (d, J = 245.0Hz), 159.37 (d, J = 11.5Hz), 145.29, 130.97 (d,J=5.9Hz),122.08,113.29(d,J=15.3Hz),112.45–111.32(m),103.11(d,J=23.4Hz),42.96; 19F NMR(376MHz,DMSO-d6)δ-116.08.

[0176] Preparation Example 20: Preparation of Compound 20

[0177]

[0178] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 20 was obtained by column chromatography with a yield of 69%.

[0179] The physical properties and spectral data of the product are as follows: white solid; mp: 222.2℃; 1 H NMR(400MHz,DMSO-d6)δ10.53(d,J=1.7Hz,1H),7.36(s,1H),7.20(m,1H),7.0 3(s,1H),6.72(d,J=8.2Hz,1H),6.70–6.63(m,1H),6.22(s,2H),5.21(s,2H); 13 C NMR(101MHz,DMSO-d6)δ164.77,162.28(d,J=245.5Hz),157.38(d,J=7.7Hz),145.16,13 0.77(d,J=10.7Hz),121.79,111.83,109.83(d,J=17.2Hz),106.40(d,J=21.8Hz),38.17; 19 F NMR(376MHz,DMSO-d6)δ-116.20.

[0180] Preparation Example 21: Preparation of Compound 21

[0181]

[0182] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 21 was obtained by column chromatography with a yield of 71%.

[0183] The physical properties and spectral data of the product are as follows: white solid; mp: 185.6℃; 1 H NMR (400MHz, DMSO-d6) δ7.46(s,1H),7.38(m,1H),7.27–7.14(m,2H),7.10(s,1H),7.00(td,J=7.7,1.8Hz,1H),6.42(s,2H),5.46(s,2H). 13C NMR (101MHz, DMSO-d6) δ164.25, 159.83 (d, J = 246.1Hz), 145.08, 130.00 (d, J = 8.1Hz), 129.20 (d, J = 3. 9Hz), 124.65 (d, J = 3.5Hz), 122.93 (d, J = 14.8Hz), 121.59, 115.46 (d, J = 20.7Hz), 42.80 (d, J = 4.4Hz); 19 F NMR(376MHz,DMSO-d6)δ-117.60.

[0184] Preparation Example 22: Preparation of Compound 22

[0185]

[0186] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 22 was obtained by column chromatography with a yield of 70%.

[0187] The physical properties and spectral data of the product are as follows: white solid; mp: 236.1℃; 1 H NMR (400MHz, DMSO-d6) δ7.83-7.77(m,1H),7.67–7.62(m,2H),7.41(s,1H),7.10(s,1H),6.53(s,2H),5.49(s,2H); 13 C NMR (101MHz, DMSO-d6) δ164.69, 160.82 (d, J = 249.6Hz), 145.75, 132.24 (d, J = 9.3Hz), 130.28 (d, J = 3.4Hz ), 126.09 (d, J = 18.0Hz), 121.79 (d, J = 6.6Hz), 121.60, 116.63 (d, J = 3.9Hz), 114.63 (d, J = 5.4Hz), 42.08; 19 F NMR(376MHz,DMSO-d6)δ-113.31.

[0188] Preparation Example 23: Preparation of Compound 23

[0189]

[0190] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 23 was obtained by column chromatography with a yield of 72%.

[0191] The physical properties and spectral data of the product are as follows: white solid; mp: 210.1℃; 1H NMR (400MHz, DMSO-d6) δ7.94(d,J=9.9Hz,1H),7.72(d,J=8.0Hz,1H),7.51(s,1H),7.15(s,1H),7.09(t,J=7.7Hz,1H),6.50(s,2H),5.59(s,2H); 13 C NMR(101MHz,DMSO-d6)δ164.64,159.73(d,J=249.3Hz),145.70,130.42(d,J=4.6Hz),129.82,129 .73–129.55(m),122.14,119.92(d,J=25.0Hz),117.98(d,J=2.6Hz),112.68(d,J=9.7Hz),43.34; 19 F NMR(376MHz,DMSO-d6)δ-114.32.

[0192] Preparation Example 24: Preparation of Compound 24

[0193]

[0194] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 24 was obtained by column chromatography with a yield of 65%.

[0195] The physical properties and spectral data of the product are as follows: white solid; mp: 214.8℃; 1 H NMR (400MHz, DMSO-d6) δ7.57 (d, J = 7.1Hz, 2H), 7.43 (s, 1H), 7.10 (s, 1H), 6.46 (s, 2H), 5.37 (s, 2H); 13 C NMR (101MHz, DMSO-d6) δ164.66, 161.25 (dd, J = 253.0, 8.7Hz), 145.45, 122.64 (t, J = 12.7Hz), 121.79, 116.72–115.34 (m), 111.62 (t, J = 19.4Hz), 37.30; 19 F NMR(376MHz,DMSO-d6)δ-112.08.

[0196] Preparation Example 25: Preparation of Compound 25

[0197]

[0198] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 25 was obtained by column chromatography with a yield of 67%.

[0199] The physical properties and spectral data of the product are as follows: white solid; mp: 217.5℃; 1 H NMR (400MHz, DMSO-d6) δ7.38 (s, 1H), 7.05 (s, 1H), 6.27 (s, 2H), 6.19 (d, J = 10.3Hz, 2H), 5.85 (s, 2H), 5.14 (s, 2H); 13 C NMR (101MHz, DMSO-d6) δ164.79,162.31(dd,J=243.5,11.5Hz),151.96(t,J=14.4Hz),145.07,121.86,97.30(t,J=20.5Hz),96.58–95.18(m),37.24; 19 F NMR(376MHz,DMSO-d6)δ-115.83.

[0200] Preparation Example 26: Preparation of Compound 26

[0201]

[0202] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. Column chromatography gave white solid 26 in a yield of 67%.

[0203] The physical properties and spectral data of the product are as follows: white solid; mp: 212.4℃; 1 H NMR (400MHz, DMSO-d6) δ7.90 (d, J = 6.8Hz, 2H), 7.44 (s, 1H), 7.12 (s, 1H), 6.51 (s, 2H), 5.49 (s, 2H); 164.64, 161.47 (d d,J=249.7,8.6Hz),145.70,130.44,124.66(t,J=12.7Hz),123.79,115.34-115.07(m),112.63(t,J=27.5Hz),43.33; 19 F NMR(376MHz,DMSO-d6)δ-114.52.

[0204] Preparation Example 27: Preparation of Compound 27

[0205]

[0206] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. Column chromatography gave white solid 27 in a yield of 76%.

[0207] The physical properties and spectral data of the product are as follows: white solid; mp: 260.8℃; 1H NMR(400MHz,DMSO-d6)δ7.73(d,J=3.6Hz,1H),7.69(d,J=5.0Hz,1H),7.60–7.45 (m,2H),7.43(s,1H),7.28–7.15(m,1H),7.10(s,1H),6.46(s,2H),5.41(s,2H); 13 C NMR(101MHz,DMSO-d6)δ164.71,161.64(dd,J=248.7,9.0Hz),145.43,140.82,137.2 5,129.27,128.26,126.69,121.82,110.32(t,J=19.6Hz),109.55–108.20(m),37.40; 19 F NMR(376MHz,DMSO-d6)δ-113.47.

[0208] Preparation Example 28: Preparation of Compound 28

[0209]

[0210] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 28 was obtained by column chromatography with a yield of 73%.

[0211] The physical properties and spectral data of the product are as follows: white solid; mp: 248.8℃; 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.37(s,1H),8.07(s,1H),7.51–7.36(m,3H),7.08(s,1H),6.42(s,2H),5.36(s,2H); 13 C NMR (101MHz, DMSO-d6) δ164.73 (s), 161.86 (dd, J = 248.5, 8.8Hz), 145.37, 137.39, 127.32, 125.38, 121.83, 119.73, 110.03–106.85 (m), 37.38; 19 F NMR(376MHz,DMSO-d6)δ-114.78.

[0212] Preparation Example 29: Preparation of Compound 29

[0213]

[0214] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. Column chromatography gave white solid 29 in a yield of 56%.

[0215] The physical properties and spectral data of the product are as follows: white solid; mp: 215.7℃; 1 H NMR (400MHz, DMSO-d6) δ7.70(m,1H),7.52(m,1H),7.45–7.35(m,3H),7.08(s,1H),6.51(s,1H),6.48(s,2H),6.34(t,J=6.7Hz,1H),5.45(s,2H); 13 C NMR(101MHz,DMSO-d6)δ164.68,161.26,160.86(dd,J=248.9,9.1Hz),145.51,142 .70,141.51,139.01,121.79,121.12,113.63–110.28(m),108.53,106.42,37.31; 19 F NMR(376MHz,DMSO-d6)δ-113.15.

[0216] Preparation Example 30: Preparation of Compound 30

[0217]

[0218] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 30 was obtained by column chromatography with a yield of 67%.

[0219] The physical properties and spectral data of the product are as follows: white solid; mp: 204.4℃; 1 H NMR (400MHz, DMSO-d6) δ7.36(s,1H),7.20(dd,J=9.0,1.8Hz,1H),7.14(s,1H),7.04(s,1H),6.27(s,2H),5.20(s,2H),3.83(s,3H); 13 C NMR(101MHz,DMSO-d6)δ164.77,161.61(d,J=249.6Hz),159.51(d,J=8.7Hz),145.40 ,122.96(d,J=13.4Hz),121.71,111.97,111.71,110.95(d,J=17.3Hz),57.36,37.71; 19 F NMR(376MHz,DMSO-d6)δ-112.08.

[0220] Preparation Example 31: Preparation of Compound 31

[0221]

[0222] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 31 was obtained by column chromatography with a yield of 72%.

[0223] The physical properties and spectral data of the product are as follows: white solid; mp: 237.1℃; 1 H NMR (400MHz, DMSO-d6) δ7.53(m,1H),7.47(t,J=1.2Hz,1H),7.37(s,1H),7.06(s,1H),6.36(s,2H),5.29(s,2H),3.87(s,3H); 13 C NMR(101MHz,DMSO-d6)δ164.72,161.24(d,J=248.0Hz),159.36(d,J=8.4Hz),145.55,121.67,11 8.12, 117.19 (d, J = 16.8Hz), 113.29 (d, J = 13.3Hz), 112.66 (d, J = 27.0Hz), 112.15, 57.60, 37.82; 19 F NMR(376MHz,DMSO-d6)δ-113.61.

[0224] Preparation Example 32: Preparation of Compound 32

[0225]

[0226] The corresponding substrate was replaced and the preparation method was the same as in Preparation Example 1. White solid 32 was obtained by column chromatography with a yield of 70%.

[0227] The physical properties and spectral data of the product are as follows: white solid; mp: 226.7℃; 1 H NMR (400MHz, DMSO-d6) δ7.68–7.61(m,2H),7.37(s,1H),7.20–7.14(m,2H),7.12(s,1H),7.05(s,1H),6.28(s,2H),5.24(s,2H),3.90(s,3H); 13 C NMR (101MHz, DMSO-d6) δ164.81,162.02(d,J=245.0Hz),159.29(d,J=8.7Hz),145.37,142.25,136.81(d,J=1 1.7Hz),129.07,127.42,125.95,121.76,110.23(d,J=17.5Hz),105.30(d,J=24.2Hz),104.93,57.01,37.87; 19F NMR(376MHz,DMSO-d6)δ-113.47.

[0228] Biological Experiment Example: Sodium Ion Channel Bioactivity Assay

[0229] 1. Selection of experimental animals

[0230] This experiment mainly used 6-8 week old male C57BL / 6 wild type (WT) mice.

[0231] 2. Reagent Solution Preparation

[0232] Preparation of small molecule compound solutions: The small molecule compounds were dissolved in dimethyl sulfoxide (DMSO, Amresco) solution to prepare a 10 mM stock solution. The laboratory used cerebrospinal fluid to dilute and prepare gradient concentrations of 1 μM, 3 μM, 10 μM, 30 μM, 60 μM, and 100 μM.

[0233] Cerebrospinal fluid formula (unit mM): 125NaCl, 2.5KCl, 2CaCl2, 1.25NaH2PO4, 1MgCl2, 25NaHCO3, 10D-glucose, adjust the pH to 7.4 with HCl.

[0234] Electrode solution formula (unit: mM): 50CsCl, 10NaCl, 60CsF, 2MgCl, 3Mg-ATP, 20EGTA, 10HEPES, and 10TEA. The pH was adjusted to 7.2 with CsOH.

[0235] 3. Recording of Sodium Channel Currents in Glutamatergic Neurons

[0236] After the mice were anesthetized with isoflurane, they were quickly decapitated and the brains removed. The brain tissue was then sliced ​​and quickly placed in a slicing solution saturated with a mixture of 95% oxygen and carbon dioxide at 4°C. The brain tissue containing the hippocampus was then quickly cut into 300μm slices using a vibratome. The slices were then incubated in artificial cerebrospinal fluid at a constant temperature of 34°C and oxygenated for one hour before being used for subsequent experiments.

[0237] Electrophysiological recordings were performed in whole-cell voltage clamp mode using glass microelectrodes pulled by a microelectrode puller with an impedance of 6-8 MΩ. Glutamatergic neurons in the hippocampal CA1 were recorded. This experiment focused on observing the effects of a series of small molecule compounds on the maximum open current (I) of sodium channels in hippocampal glutamatergic neurons. Na-Max )Amplitude effect. Record I Na-MaxWhen the recording cell is held at -70mV for 300ms, the holding voltage is immediately stepped to -10mV for 15ms, and the sodium current of the sodium channel under the depolarization voltage change is recorded, which is I Na-Max The experiment first recorded the baseline state of hippocampal glutamatergic neurons I Na-Max , and then different gradient concentrations of compounds were perfused to investigate the effects of the compounds on I Na-Max Compounds that can effectively inhibit sodium current (inhibition rate greater than 20%) were subjected to a second round of IC 50 For the compounds that were effective in the first round of screening, concentration gradients of 1μM, 3μM, 10μM, 30μM, and 100μM were set to screen the IC values ​​for the sodium channel. 50 , according to the inhibitory efficiency of the compound at each concentration (before and after administration I Na-Max The amplitude difference is divided by the I Na-Max amplitude), draw the concentration-drug effect curve, and calculate the IC 50 value.

[0238] The results of the first round of screening are as follows:

[0239] Compound number Action rate (%) Compound number Action rate (%) 1 76.68310727 17 -6.126687435 2 62.3 18 0.733855186 3 29.77707006 19 2.19123506 4 6.66666667 20 4.6021093 5 -0.12254902 21 6.859688196 6 16.4 22 41.40006335 7 20.97026604 23 -28.59855678 8 6.297502714 24 -0.61500615 9 -40.4379562 25 -1.169230769 10 -0.988875155 26 42.20183486 11 33.08690013 27 10.69682152 12 -104.0555556 28 14.9235474 13 3.604314654 29 -70.88036117 14 50.0295683 30 -8.617974806 15 37.34115347 31 2.929292929 16 5.772994129 32 -1.03021978

[0240] On this basis, the IC values ​​of compounds 1, 2, 3, 7, 11, 14, 15, 22, and 26 for sodium channel inhibition were determined. 50 From the experimental results, these compounds have good inhibitory activity on sodium ion channels. Figure 1 and the table below.

[0241] Compound number <![CDATA[IC 50 (μM)]]> Compound number <![CDATA[IC 50 (μM)]]> 1 21.34 14 48.95 2 103.7 15 108.3 3 41.24 22 23.14 7 46.56 26 13.26 11 14.59

[0242] Animal Experiment Example 1: Pentylenetetrazol (PTZ) Acute Epilepsy Model

[0243] The effects of the preferred compounds 1 and 2 on the acute epileptic seizure model induced by pentylenetetrazol (PTZ) were determined: adult male ICR mice weighing 25-30 g were used. The mice were randomly divided into the following groups according to their body weight: solvent group, Rufinamide positive control group, VPA positive control group and different compound groups (Rufinamide and candidate compounds were 50 mg / kg, VPA was 300 mg / kg), with 5-6 ICR male mice in each group. During the experiment, the solvent or drug was gavage, and 1 hour later, 100 mg / kg PTZ was injected intraperitoneally. Immediately afterwards, the epileptic seizures of the mice were observed and recorded for 30 minutes. The behavioral evaluation grading standard is: Grade 0: no obvious reaction; Grade 1: unconsciousness and dullness, ear and face twitching; Grade 2: whole body twitching, no forelimb lifting; Grade 3: one or both forelimbs lifted; Grade 4: one side of the body fell to the side with convulsions; Grade 5: fell to the ground on the back, or whole body tonic-clonic seizure; Grade 6: death after tonic seizure. The grade of epileptic seizure of each mouse was recorded ( Figure 2 a) From the start of drug administration to the latency of Grade 2 seizure ( Figure 2 b) Level 4 seizure latency ( Figure 2 c) Level 6 seizure latency ( Figure 2 d) and the survival rate of mice ( Figure 2 e). From the experimental results, compounds 1 and 2 showed good anti-epileptic efficacy, which was better than Rufinamide.

[0244] Animal Experiment Example 2: Maximum Electroshock Model (MES)

[0245] Effects of preferred compounds 1 and 2 on the maximum electric shock epileptic seizure model: Adult male ICR mice weighing 25-30 g were used. The mice were randomly divided into groups according to their body weight: solvent group, Rufinamide positive control group, VPA positive control group and different compound groups (Rufinamide and candidate compounds were 50 mg / kg, VPA was 300 mg / kg), with 5-6 ICR male mice in each group. During the experiment, the solvent or drug was administered orally. After 0.5 h, the stimulation clamp of the maximum electric shock instrument was soaked with physiological saline, and the auricles of the mice were clamped and electrically stimulated. The stimulation frequency was 50 Hz, the stimulation duration was 0.2 s, and the stimulation current intensity was 25 mA. The behavioral assessment level of mice: Level 1: running; Level 2: forelimb rigidity; Level 3: hindlimb rigidity. The maximum seizure level of the mice in this model was recorded ( Figure 3 a) Duration of tonic-clonic seizures ( Figure 3 b) and the survival rate of mice ( Figure 3 c) From the experimental results, compounds 1 and 2 showed good anti-epileptic efficacy, which was better than Rufinamide.

[0246] Animal Experiment Example 3: Lamotrigine Resistance Model (LTG)

[0247] 1. Establishment of Lamotrigine-Resistant Hippocampal Kindling Intractable Epilepsy Model:

[0248] Selection of experimental animals:

[0249] This experiment mainly used adult male C57BL / 6 wild-type (WT) mice aged 2 to 4 months.

[0250] 1.1. Surgery

[0251] Anesthesia

[0252] Mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital (60 mg / kg).

[0253] 1.1.2. Positioning

[0254] The mouse was mounted on a stereotaxic instrument. The hair on the head was shaved, and the scalp was cut after disinfection with iodine. The skull was exposed and wiped with a very small amount of 3% hydrogen peroxide. The anterior and posterior fontanelles were exposed and any residual hydrogen peroxide was wiped away with cotton. The stereotaxic instrument was adjusted to locate the height of the anterior and posterior fontanelles. The nose clip was adjusted to ensure that the two were on the same horizontal plane, with a height difference of no more than 0.2 mm. According to a mouse brain atlas, the target nucleus was located with the anterior fontanelle as the origin, and a dental drill was used to drill a hole in the skull at the corresponding location.

[0255] 1.1.3. Electrode implantation

[0256] Four screws were placed discretely on the skull surface to enhance skull adhesion. One screw was placed in the sensorimotor cortex to record cortical EEG, and one in the cerebellum to connect to a reference electrode. A single hole was drilled on each side of the skull, away from the sutures, for fixation purposes only. A double-helix electrode, used for electrical stimulation to induce epileptic seizures and EEG recording, was implanted in the right ventral hippocampal CA3 region. The double-helix electrode consisted of a double strand of polytetrafluoroethylene-coated stainless steel wire. The insulation was scraped off 0.5 mm from the distal end, and the maximum separation between the tops was no more than 0.5 mm. The electrode implantation speed should be moderate (50–100 μm / min). After implantation, the electrode was fixed with dental cement. Once the cement had completely dried, the spiral was unwound, and the outer insulation of the electrode was removed with tweezers.

[0257] The electrodes were connected to the micro sockets by soldering and fixed with medical dental cement.

[0258] 1.2. EEG recording and threshold determination

[0259] EEG was recorded using a Neuroscan system, and the stimulation current (unidirectional square wave pulses, 20 Hz, 1 ms / pulse, 2 s duration) was applied using an electrical stimulator, starting at 40 μA and increasing by 20 μA every 1 min until an afterdischarge duration (ADD) of at least 5 s was induced. The current intensity at this point was defined as the animal's ADT and used for grouping.

[0260] 1.3. Electrical Kindling Stimulation and Epilepsy Grade Evaluation Criteria

[0261] Parameters for rapid electrical kindling: 1ms square wave pulses, 20Hz stimulation frequency, 400μA suprathreshold stimulation intensity, 2s duration. Before kindling, a subconvulsive dose of 5mg / kg lamotrigine was intraperitoneally administered. After a 30-minute rest, an electrical stimulation was administered, followed by another electrical stimulation half an hour later. The above process was repeated three times a day, with six electrical stimulations per day, until complete kindling. Behavioral severity was assessed according to the Racine classification system: Grade 1: Facial twitching; Grade 2: Nodding; Grade 3: Unilateral forelimb clonic seizure; Grade 4: Bilateral forelimb clonic seizure; Grade 5: Bilateral forelimb clonic seizure with loss of balance and collapse. Seizures of Grades 1-3 are generally considered FS, while Grades 4-5 are considered GS. Animals with three consecutive Grade 5 seizures are considered fully kindled.

[0262] 2. Efficacy Evaluation of Lamotrigine Resistance Model

[0263] After the fully ignited animals rested for half an hour, acute therapeutic doses of lamotrigine, levetiracetam, valproic acid, and the preferred compound at different dose gradients were intraperitoneally administered. Half an hour after administration, electrical stimulation was performed, EEG was recorded, and behavioral severity was assessed. The efficacy test was performed three times. A reduction in the seizure level to level 3 or below after administration was defined as effective, and levels 4-5 were defined as ineffective. The effect of the preferred compound on the seizure level was also determined. The level inhibition rate was calculated as the seizure level before administration minus the seizure level after administration divided by the seizure level before administration. Figure 4 From the experimental results, compounds 1, 2, and 11 still showed good anti-epileptic efficacy in this drug-resistant model.

[0264] In addition, in the oral administration experiment of the lamotrigine-resistant model, compounds 1, 2, and 11 all showed good anti-epileptic efficacy; at a dose of 200 mg / kg, they could significantly reduce the severity of epileptic seizures and had a high therapeutic efficacy. Figure 5 shown.

[0265] Animal Experiment Example 4: Safety Evaluation

[0266] Safety evaluation of compounds: The safety of compounds 1 and 2 was evaluated using adult male ICR mice weighing 25-30 g. The mice were randomly divided into a treatment group and a blank group according to their weight, with 5-6 ICR male mice in each group. During the experiment, the solvent or drug was gavage-administered for three consecutive weeks at a dose of 100 mg / kg. The weight changes of the mice were observed ( Figure 6 a) Athletic ability Figure 6 b- Figure 6 e) and blood routine indicators ( Figure 6 f- Figure 6 k). The experimental results showed that compounds 1 and 2 had no effect on the weight gain and exercise capacity of mice when administered continuously at a dose of 100 mg / kg, and all blood test indicators were within the normal range, indicating that compounds 1 and 2 have good safety.

[0267] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may 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. 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds, pharmaceutically acceptable salts thereof, or racemic mixtures or isotope-labeled substances thereof, characterized in that: The 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound is selected from any one of the following compounds 2, 3, 6, 11-13, 17-20, 22-26, 30, and 31:

2. The method for preparing 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compounds according to claim 1, characterized in that: Use reaction route 1 to synthesize any one of compounds 2, 3, 6, 11-13, 17-20, 22-26, 30, and 31; Reaction Scheme I The following processes are included: Ethyl cyanoacetate A reacts with a benzyl azide compound B in DMF with NaH as a base to generate a substituted 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxylate compound C, which is then hydrolyzed and acidified under the action of NaOH to generate a carboxylic acid compound D. Subsequently, under the promotion of a condensation reagent HATU, a condensation reaction occurs with an amine compound E to generate the target compound 2, 3, 6, 11-13, 17-20, 22-26, 30, or 31. In reaction scheme I, R1, R2, and R3 represent the corresponding groups in any one of compounds 2, 3, 6, 11-13, 17-20, 22-26, 30, or 31, respectively.

3. A pharmaceutical composition, characterized in that The invention comprises pharmaceutically acceptable excipients, and the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound according to claim 1, a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, or an isotope-labeled substance thereof.

4. The pharmaceutical composition according to claim 3, characterized in that The auxiliary materials include carriers.

5. Use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound according to claim 1, its pharmaceutically acceptable salt, or its racemic mixture, isotope-labeled substance, or the pharmaceutical composition according to claim 3 or 4 in the preparation of a sodium channel blocker.

6. Use of the 5-amino-1-alkyl-1H-1,2,3-triazole-4-carboxamide compound according to claim 1, its pharmaceutically acceptable salt, or its racemic mixture, isotope-labeled substance, or the pharmaceutical composition according to claim 3 or 4 in the preparation of a medicament for treating epilepsy.

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