Fused heterocyclic compound, and pharmaceutical composition and application thereof

Abstract

The invention relates to a fused heterocyclic compound as well as a pharmaceutical composition and application thereof. Specifically, the invention provides a fused heterocycle compound as shown in a formula (I), and each group in the formula (I) is defined in the specification. The fused heterocycle compound provided by the invention can be used for preparing medicines, especially medicines for preventing and / or treating Kv1.3 channel mediated diseases or symptoms.

Description

Technical Field

[0001] This application belongs to the pharmaceutical field, specifically relating to a fused heterocyclic compound, its pharmaceutical composition and uses, which can be used as a Kv1.3 channel inhibitor. Background Technology

[0002] Kv1.3 channels are members of the Kv family, first discovered in human T lymphocytes, and are expressed in the immune system, nervous system, and vascular smooth muscle cells. Kv1.3 is one of the major potassium ion channels found in T cells, and its function is primarily manifested in the regulation of cell membrane potential. During antigen presentation, Kv1.3 channels accumulate at the synapses of immune cells and promote Ca2+ expression. 2+ Signal transmission.

[0003] Studies have shown that Kv1.3 is primarily involved in the activation of effector T cells, and therefore, different T cell subtypes exhibit varying degrees of sensitivity to Kv1.3 inhibitors. Selective inhibition of the Kv1.3 channel could potentially achieve selective inhibition of effector T cell activation, offering a new approach for the treatment of autoimmune diseases related to effector T cells. Kv1.3 has thus become a novel target protein for the treatment of autoimmune diseases such as multiple sclerosis, type 1 diabetes, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis.

[0004] Kv1.3 channels also play a role in gastrointestinal disorders, including inflammatory bowel diseases (“IBD”) such as ulcerative colitis (“UC”) and Crohn’s disease. UC is a chronic IBD characterized by excessive T-cell infiltration and cytokine production. UC can impair quality of life and can lead to life-threatening complications. High levels of Kv1.3 channels in CD4 and CD8-positive T cells in the inflamed mucosa of UC patients have been associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered a biomarker of disease activity, and pharmacological blockade may constitute a novel immunosuppressive strategy for UC.

[0005] Peptide toxins with Kv1.3 inhibitory activity have been isolated from scorpions and sea anemones. Dalazatide (ShK-186), derived from non-natural amino acids, showed some therapeutic effect in a phase Ib clinical trial for psoriasis. However, its application is limited by poor subtype selectivity and the inability to orally administer peptide molecules. Therefore, the development of highly selective, orally administered small-molecule Kv1.3 inhibitors has significant social and market value.

[0006] Currently, publicly disclosed patents related to Kv1.3 channel inhibitors (blockers) include WO2022076285A1, WO2022251561A2, WO2021071821A1, and WO2021071812A1. Summary of the Invention

[0007] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008]

[0009] in:

[0010] Z is OH;

[0011] X is C, Y is N; or X is N, Y is C;

[0012] It can be a single bond or a double bond;

[0013] G 1 G 2 and G 3 Whether the two are the same or different, and each is an independent CR 8 Or N;

[0014] R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl and C 3-6 Halogenated cycloalkyl groups;

[0015] R 5 Selected from H, halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, oxo, C 3-6The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0016] R 6 and R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, hydroxyl, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0017] Or, R 5 and R 6 R 5 and R 7 Any group of carbon atoms bonded to it forms C 3-8 cycloalkyl or 3-8 membered heterocyclic groups, wherein the C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0018] R 8 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups and The C mentioned 1-6 Alkyl, C 3-12 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally separated by one or more R groups. g replace;

[0019] R g Whether the same or different, each is independently selected from halogens, hydroxyl groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C(O)R p , cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0020] R 9 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano and C 3-6 cycloalkyl;

[0021] R 10 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, hydroxy, cyano, and amino;

[0022] R p Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, hydroxyl, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0023] n is 1 or 2;

[0024] m is 1 or 2;

[0025] The condition is that when R 5 When it is H, G 1 G 2 and G 3 At least one of them is CR 8 And at least one R 8 for

[0026] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from H, halogens, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Alkoxy, hydroxy, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups are optionally selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, cyano, amino, oxo, C 3-6 It is substituted by one or more substituents in cycloalkyl and 3-6 membered heterocyclic groups.

[0027] In some implementations, the C 1-6The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, methyl.

[0028] In some embodiments, the halogen is fluorine, chlorine, bromine, or iodine, such as chlorine.

[0029] In some implementations, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, for example, cyclopropyl.

[0030] In some embodiments, the heteroatoms in the 3-12 membered heterocyclic group, 3-8 membered heterocyclic group, and 3-6 membered heterocyclic group are N, O, or S, for example, N or O; the number of heteroatoms can be 1 or 2, and the 3-12 membered heterocyclic group is a 3-6 membered heterocyclic group, such as azirrobutyl, oxobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydrothiaranyl, piperidinyl, piperazineyl, morpholinyl, etc.

[0031] In some embodiments, the 3-12 membered heterocyclic group is a 3-8 membered heterocyclic group, for example...

[0032] In this invention, in the compound shown in formula (I), when When it is a double bond, the ring There will not be 3 or 4 double bonds in the structure at the same time, which is consistent with the understanding in this field.

[0033] In this invention, C 1-6 alkenyl is C 2-6 Alkenyl group.

[0034] In this invention, C 1-6 The alkynyl group is C 2-6 Alkyne group.

[0035] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II) or formula (III):

[0036]

[0037] in,

[0038] G 2 For CR 8a Or N;

[0039] R 8a Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups;

[0040] R 1 R 2 R3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Z, m, and n are as defined in compound (I); the condition is that when R 5 When it is H, R 8 for

[0041] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (II-1).

[0042]

[0043] in:

[0044] R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 , m and n are as defined in compound (I); the condition is that when R 5 When it is H, R 8 for

[0045] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl; or R 5 and R 6 R 5 and R 7 Any group of carbon atoms bonded to it forms C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 It is replaced by one or more substituents in the alkyl group.

[0046] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R5 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl; or R 5 and R 6 R 5 and R 7 Any group of carbon atoms bonded to it forms C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted; R 8 for R 9 R 10 , n and m are as defined in compound (I).

[0047] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 5 It is selected from methyl, hydroxymethyl, cyanomethyl and cyclopropyl.

[0048] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 5 and R 6 The carbon atom bonded to it forms a cyclopropyl group, wherein the cyclopropyl group is optionally selected from halogens, hydroxyl groups, and C. 1-6 It is replaced by one or more substituents in the alkyl group.

[0049] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 5 and R 7 The carbon atom bonded to it forms a cyclopropyl group, wherein the cyclopropyl group is optionally selected from halogens, hydroxyl groups, and C. 1-6 It is replaced by one or more substituents in the alkyl group.

[0050] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-1) or formula (III-2).

[0051]

[0052] in:

[0053] R 5 Selected from H, halogens, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl; or R 5 and R 6 R 5 and R 7 Any group of carbon atoms bonded to it forms C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0054] R 8a Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyl and cyano groups;

[0055] R 1 R 2 R 3 R 4 R 6 R 7 R 9 R 10 , n and m are as defined in compound (I).

[0056] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

[0057] R 5 For H;

[0058] R 1 and R 2 Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and cyano groups;

[0059] R 3 and R 4 Each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and cyano groups;

[0060] R 6 and R 7 Each is independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and cyano groups;

[0061] R 9 Selected from H, C 1-6 Alkyl, C1-6 Halogenated alkyl groups and cyano groups;

[0062] R 10 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyl and cyano groups;

[0063] n is 1 or 2;

[0064] m is 1 or 2.

[0065] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

[0066] R 5 For H;

[0067] R 1 and R 2 Each is independently represented by H;

[0068] R 3 and R 4 Each is an independent halogen;

[0069] R 6 and R 7 H independently;

[0070] R 9 Selected from H, C 1-6 Alkyl and cyano groups;

[0071] R 10 Selected from H, C 1-6 Alkyl, C 1-6 Cyanoalkyl and C 1-6 Hydroxyalkyl;

[0072] n is 1 or 2;

[0073] m is 1 or 2.

[0074] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

[0075] R 5 For H;

[0076] R 1 and R 2 Each is independently represented by H;

[0077] R 3 and R 4 Each is an independent halogen;

[0078] R 6 and R7 H independently;

[0079] R 9 For H or C 1-6 alkyl;

[0080] R 10 For H;

[0081] n is 1 or 2;

[0082] m is 1 or 2.

[0083] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein

[0084] R 5 For H;

[0085] R 1 and R 2 Each is independently represented by H;

[0086] R 3 and R 4 Each is an independent halogen;

[0087] R 6 and R 7 H independently;

[0088] R 9 For H;

[0089] R 10 For H;

[0090] n is 1 or 2;

[0091] m is 1 or 2.

[0092] In some embodiments, the compounds represented by formulas (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein R 5 Selected from H, methyl, hydroxymethyl, cyanomethyl and cyclopropyl.

[0093] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from: R 8 R 9 R 10 , n and m are as defined in compound (I).

[0094] In some embodiments, the compound represented by formula (II) or formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from: R 8 R 9 R 10 , n and m are as defined in compound (I).

[0095] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 8 It is a 3-8 membered heterocyclic group or The 3-8 member heterocyclic group is optionally coupled with one or more R g Replaced; R g R 9 R 10 , n and m are as defined in compound (I).

[0096] In some embodiments, the compounds represented by formulas (I), (II), (II-1), and (III), or pharmaceutically acceptable salts thereof, wherein R 8 Selected from

[0097] In some embodiments, the compounds represented by formulas (I), (II), (II-1), (III), (III-1), and (III-2), or their pharmaceutically acceptable salts, wherein R 9 Selected from H, C 1-3 Alkyl and cyano groups; R 10 Selected from H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Cyanoalkyl and C 1-3 Hydroxyalkyl.

[0098] In some embodiments, the compounds represented by formulas (I), (II), (II-1), (III), (III-1), and (III-2), or their pharmaceutically acceptable salts, wherein Selected from

[0099] In some embodiments, the compounds represented by formulas (I), (II), (II-1), (III), (III-1), and (III-2), or their pharmaceutically acceptable salts, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogens, and C. 1-6 Alkyl; preferably, R 3 and R4 Both are Cl, R 1 and R 2 All are H.

[0100] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table A below: Table A

[0101]

[0102]

[0103] Exemplary specific compounds shown in this application include, but are not limited to, the structures in Table B below: Table B

[0104]

[0105]

[0106]

[0107]

[0108]

[0109] In another aspect, this application provides isotope labels for compounds shown in Formulas (I), (II), (II-1), (III), (III-1), and (III-2), as well as those shown in Table A or Table B, wherein the isotope labels are preferably deuterium (D or... 2 H) replaces hydrogen ( 1 H).

[0110] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0111] In another aspect, this application also provides the use of compounds of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), shown in Table A or Table B, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, in the preparation of medicaments for inhibiting the Kv1.3 channel.

[0112] In another aspect, this application also provides the use of compounds of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), shown in Table A or Table B, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, in the preparation of medicaments for blocking Kv1.3 channels.

[0113] In another aspect, this application also provides the use of compounds of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), shown in Table A or Table B, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising them, in the preparation of medicaments for the prevention and / or treatment of Kv1.3 channel-mediated diseases.

[0114] This application also provides the use of compounds of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of medicaments for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer, such as in the preparation of medicaments for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0115] This application also provides a method for inhibiting the Kv1.3 channel, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned.

[0116] This application also provides a method for blocking the Kv1.3 channel, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a pharmaceutical composition comprising the aforementioned.

[0117] This application also provides a method for preventing and / or treating Kv1.3 channel-mediated diseases or conditions, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a aforementioned isotopic label thereof, or a aforementioned pharmaceutical composition comprising the aforementioned.

[0118] This application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), and formula (III-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the aforementioned.

[0119] This application also provides a method for preventing and / or treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke, comprising administering to a desired patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0120] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, for use as a medicine.

[0121] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, which is used as a Kv1.3 channel inhibitor.

[0122] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, which is used as a Kv1.3 channel blocker.

[0123] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the above, for use as a medicament for the prevention and / or treatment of Kv1.3 channel-mediated diseases or conditions.

[0124] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for the prevention and / or treatment of autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0125] This application also provides a compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1) and formula (III-2), a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, for use as a medicament for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0126] The diseases mediated by the Kv1.3 channel described in this application are selected from autoimmune diseases, inflammatory diseases, metabolic diseases, cardiovascular diseases, kidney diseases, central nervous system diseases, or cancer.

[0127] The diseases mediated by the Kv1.3 channel described in this application are selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke.

[0128] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0129] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof.

[0130] In some embodiments, the pharmaceutical composition contains 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopic label thereof.

[0131] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable one or more excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable one or more excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable one or more excipients.

[0132] When administered as a medicine, the compounds of this application may be given in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration may be local (e.g., transdermal, skin, eye, and mucous membrane delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single large dose or via, for example, a continuous infusion pump.

[0133] In preparing the compositions of this application, the active ingredient is typically mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or soluble in liquid solvents), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0134] The term "excipients" as used in this application refers to components other than the active ingredient, such as diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0135] On the other hand, pharmaceutically acceptable salts of the compounds described in this application may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form inner salts.

[0136] On the other hand, the compounds of this application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this application.

[0137] In the chemical structure of the compound described in this application, the bond... This indicates that no configuration has been specified. or Indicates absolute configuration, that is, if chiral isomers exist in the chemical structure, the bonds... It can be or Or simultaneously include and Two configurations, This indicates the presence of axial chirality.

[0138] key This indicates that the configuration is not specified, including cis (E) or trans (Z) configurations.

[0139] Furthermore, the compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactamimide isomerization. All tautomer forms of all compounds in this application are within the scope of this application. The name of a compound named in a single manner does not exclude any tautomer.

[0140] This application also includes compounds of this application with the same structure as described herein, but with one or more atoms replaced by isotopes of atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All isotopic variations of the compounds in this application, regardless of radioactivity, are included within the scope of this application.

[0141] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood as having a deuterium abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium doping). The natural abundance of deuterium in the example compounds can be at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or higher. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the deuterated form of the compound by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare compounds in their deuterated form, or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0142] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of a drug or pharmacologically active agent, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0143] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0144] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred.

[0145] Beneficial effects

[0146] This application provides a small molecule compound that can be used as a Kv1.3 channel inhibitor (blocker), and such compounds or pharmaceutical compositions can be used to effectively treat or prevent Kv1.3 channel-mediated diseases.

[0147] Terminology Definitions and Explanations

[0148] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0149] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted.

[0150] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0151] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group, which may contain 1-20 carbon atoms, preferably 1-12 carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), etc. The alkylene group may be substituted or unsubstituted.

[0152] The term "alkenyl" should be understood to preferably refer to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkenyl". "C" 2-10 "Alkenyl" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C...). 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C24, C34, C4 ... 2-3 Alkenyl). It should be understood that when the alkenyl group contains more than one double bond, the double bonds may be separable or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pentyl-1-enyl, (Z)-pentyl-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl 2-Methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group may be substituted or unsubstituted.

[0153] The term "alkynyl" should be understood to refer to a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably "C". 2-10 "Alkyne group". The term "C" 2-10 "Alkyne" should be understood to preferably represent a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., "C"). 2-6 The alkynyl group ("C") has 2 or 3 carbon atoms ("C") 2-3 The alkynyl group is, for example, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, pent-1-alkynyl, pent-2-alkynyl, pent-3-alkynyl, pent-4-alkynyl, hex-1-alkynyl, hex-2-alkynyl, hex-3-alkynyl, hex-4-alkynyl, hex-5-alkynyl, 1-methylprop-2-alkynyl, 2-methylbut-3-alkynyl, 1-methylbut-3-alkynyl, 1-methylbut-2-alkynyl, 3-methylbut-1-alkynyl, 1-ethylprop-2-alkynyl, 3-methylpent-4-alkynyl, 2-methylpent-4-alkynyl, 1-methylpent-4-alkynyl, 2-methyl The alkynyl group can be pentyl-3-ynyl, 1-methylpentyl-3-ynyl, 4-methylpentyl-2-ynyl, 1-methylpentyl-2-ynyl, 4-methylpentyl-1-ynyl, 3-methylpentyl-1-ynyl, 2-ethylbutyl-3-ynyl, 1-ethylbutyl-3-ynyl, 1-ethylbutyl-2-ynyl, 1-propylpropyl-2-ynyl, 1-isopropylpropyl-2-ynyl, 2,2-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-3-ynyl, 1,1-dimethylbutyl-2-ynyl, or 3,3-dimethylbutyl-1-ynyl. Specifically, the alkynyl group is ethynyl, propyl-1-ynyl, or propyl-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0154] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms, wherein the ring atoms may optionally be oxidized, and the oxidizing group (=O) on the ring is part of the ring. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0155] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

[0156]

[0157] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0158]

[0159] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0160]

[0161] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl ring as described herein, wherein the ring attached to the parent structure may be a cycloalkyl ring or an aryl ring, and non-limiting examples include... etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0162] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon, wherein the ring carbon atoms may optionally be oxidized, and the oxidized group (=O) on the ring is part of the ring. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0163] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each monocyclic ring in the system shares one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 5-membered, or 5- / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include:

[0164]

[0165] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0166]

[0167] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0168]

[0169] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described herein, wherein the ring connected to the parent structure may be a heterocyclic ring, or an aryl, heteroaryl, or cycloalkyl ring, and non-limiting examples include:

[0170] The heterocyclic group may be substituted or unsubstituted.

[0171] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl group can be substituted or unsubstituted.

[0172] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl ring as described herein, wherein the ring connected to the parent structure can be a heteroaryl ring or an aryl ring, non-limiting examples of which include:

[0173] Etc. Heteroaryl groups can be substituted or unsubstituted.

[0174] The terms “alkyl,” “alkoxy,” “cycloalkyl,” “heterocyclic,” “aryl,” and “heteroaryl” used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably independently selected independently from one or more of the same or different substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0175] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one H from a parent ring atom, or residues derived from removing two H from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene", and "heteroarylene".

[0176] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined herein.

[0177] The term “heterocyclic oxy group” refers to a heterocyclic group -O-, wherein the heterocyclic group is as defined herein.

[0178] The term “halogenated alkyl” refers to an alkyl group that is substituted with one or more halogens, wherein the alkyl group and the halogen are as defined herein.

[0179] The term “haloalkoxy” refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group and the halogen are as defined herein.

[0180] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group and the hydroxyl group are as defined herein.

[0181] The term "cyanoalkyl" refers to an alkyl group that is substituted with one or more cyano groups, wherein the alkyl and cyano groups are as defined herein.

[0182] The term "aminoalkyl" refers to an alkyl group that is substituted with one or more amino groups, wherein the alkyl and amino groups are as defined herein.

[0183] The term "halogen" refers to F, Cl, Br, or I.

[0184] The term "hydroxyl group" refers to -OH.

[0185] The term "amino" refers to -NH2.

[0186] The term "cyano" refers to -CN.

[0187] The term "nitro" refers to -NO2.

[0188] The term "oxo" or "oxo" refers to "=O".

[0189] The term "carbonyl" refers to C=O.

[0190] The term "carboxyl group" refers to -C(O)OH.

[0191] The term “carboxylic acid ester group” refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

[0192] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes situations in which the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that an alkyl group may but does not have to be present, and the description includes cases where the heterocyclic alkyl group is substituted with an alkyl group and cases where the heterocyclic alkyl group is not substituted with an alkyl group.

[0193] "Substituted" means that one or more H atoms in the given structure are replaced by specific substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. Furthermore, when the group is replaced by more than one of the substituents, the substituents are independent of each other (i.e., the more than one substituent can be different or the same).

[0194] It should be understood that the singular form used in this disclosure, such as "a," includes plural references, unless otherwise specified. Furthermore, the term "comprising" is an expansive limitation and not a closed one, meaning it includes only what is specified in this disclosure but does not exclude other aspects. Detailed Implementation

[0195] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0196] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0197] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The measurements are given in units of ppm. NMR determinations were performed using Bruker Ascend. TM -400 NMR was used, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using an Agilent 6110, Agilent 1100, Agilent 6120, or Agilent G6125B liquid chromatography-mass spectrometry system.

[0198] HPLC determinations were performed using a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um column).

[0199] Chiral HPLC analysis was performed using THARSFC X5.

[0200] The silica gel plates used for thin-layer chromatography are GF254 silica gel plates from Yantai Qingdao. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0201] Column chromatography typically uses Qingdao marine silica gel 200-300 mesh as the carrier.

[0202] High-performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2545, and the innovative Hengtong LC3000 preparative chromatograph.

[0203] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0204] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0205] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0206] The microwave reaction uses a Biotage initiator+ type microwave reactor.

[0207] Unless otherwise specified in the experimental examples, the reactions were carried out under an argon or nitrogen atmosphere.

[0208] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of about 1 liter.

[0209] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1 liter.

[0210] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20℃ to 30℃.

[0211] Example 1 (Compound 15)

[0212]

[0213] Step 1: Synthesis of compound 15b

[0214] At room temperature, hydrazine hydrate (342.4 mg, 5.47 mmol) was added to a 3 mL solution of 15a (400 mg, 2.74 mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 6 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%–10%) to give compound 15b (300 mg). MS m / z (ESI): 146.8 [M+1] + .

[0215] Step 2: Synthesis of compound 15d

[0216] At room temperature, compound 15b (160.2 mg, 1.10 mmol) was added sequentially to a 2 mL solution of dimethyl sulfoxide (DMSO) of compound 15c (190 mg, 0.73 mmol, synthetic method referred to in the specification of patent CN117946111A, page 47, paragraphs 0252-0280, synthesis of intermediate 8). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was lyophilized to obtain compound 15d (400 mg, crude product). The product was used directly in the next reaction without further purification. MS m / z (ESI): 374.0 [M+1] + .

[0217] Step 3: Synthesis of compound 15e

[0218] Compound 15d (400 mg, 1.07 mmol) was added to a 10 mL solution of n-butanol at room temperature. The reaction mixture was microwave-controlled and stirred at 150 °C for 1 hour. After the reaction was complete, the crude product was purified using a Combi-Flash rapid reagent system (C18 reversed-phase column, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-70%) to obtain compound 15e (60 mg). MS m / z (ESI): 356.0 [M+1] + .

[0219] Step 4: Synthesis of Compound 15

[0220] At room temperature, iodophenylacetic acid (67.8 mg, 0.21 mmol) and ammonium carbamate (19.7 mg, 0.25 mmol) were added sequentially to an ethanol (1 mL) solution of compound 15e (30 mg, 0.084 mmol). The reaction mixture was stirred openly at 50 °C for 3 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini-C18; 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 15 (14.4 mg, yield 43.5%). MS m / z (ESI): 386.8 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.40(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5.05–4.90(m,1H),4.30(t,J=9.8Hz ,1H),4.16–4.01(m,2H),3.96–3.72(m,1H),3.57–3.45(m,1H),3.27–2.98(m,5H),2.59–2.53(m,1H),2.40–2.18(m,1H).

[0221] Example 2 (Compounds 16, 17)

[0222]

[0223] Step 1: Synthesis of Compound 16b

[0224] At room temperature, hydrazine hydrate (1.25 g, 24.96 mmol) was added to a 10 mL ethanol solution of compound 16a (800 mg, 4.99 mmol), and the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 3 / 1) to give compound 16b (730 mg). MS m / z (ESI): 161.15 [M+1] + .

[0225] Step 2: Synthesis of compound 16e

[0226] Compound 16d (3.11 g, 21.00 mmol) was added to a solution of compound 16c (3 g, 10.50 mmol) in dichloromethane (30 mL) (synthetic method referred to patent CN117946111A, 2024-04-30, page 42, Example 0190, Synthesis of Compound 2-Pyrrolidinone, 4-[2,3-dichloro-6-(2-propen-1-yloxy)phenyl]-). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (200 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine (100 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-3 / 1) to give compound 16e (1.50 g). MS m / z(ESI): 300.10 [M+1] + .

[0227] Step 3: Synthesis of compound 16f

[0228] At room temperature, compound 16b (160 mg, 1.00 mmol) was added to a dimethyl sulfoxide (DMSO) solution of compound 16e (200 mg, 0.67 mmol) in 2 mL. The reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and lyophilized to obtain compound 16f (260 mg, crude product). The product was used directly in the next step without purification. MS m / z (ESI): 428.25 [M+1] + .

[0229] Step 4: Synthesis of 16g ​​of compound

[0230] A solution of compound 16f (260 mg, 0.61 mmol) in 10 mL of n-butanol was microwave-stirred at 150 °C for 6 hours at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1%–9%) to give compound 16 g (160 mg). MS m / z (ESI): 410.25 [M+1] + .

[0231] Step 5: Synthesis of compound 16h

[0232] Under nitrogen protection, 1,3-dimethylbarbituric acid (114.1 mg, 0.73 mmol) and tetrakis(triphenylphosphine)palladium (42.2 mg, 0.037 mmol) were added to a methanol (2 mL) solution of 16 g (150 mg, 0.37 mmol) of compound 16 h. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1%–10%) to give compound 16 h (90 mg). MS m / z (ESI): 370.00 [M+1] + .

[0233] Step 6: Synthesis of Compound 16

[0234] Iodophenylacetic acid (173.9 mg, 0.54 mmol) and ammonium carbamate (50.6 mg, 0.65 mmol) were added to a 2 mL ethanol solution of compound 16h (80 mg, 0.22 mmol). The reaction mixture was stirred openly at 50 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and purified directly by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18; 150*21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-55%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 16 (17.6 mg). MS m / z (ESI): 400.80 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ10.57(s,1H),7.40(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5.08–4.90(m,1H), 4.27(t,J=9.8Hz,1H),4.10–3.99(m,1H),3.62(d,J=49.2Hz,1H),3.21–2.99(m,7H),2.28–2.05(m,4H).

[0235] Step 7: Synthesis of Compound 17

[0236] Under nitrogen protection, triethylsilane (26.1 mg, 0.22 mmol) and trifluoroacetic acid (25.6 mg, 0.22 mmol) were added sequentially to a solution of compound 16 (30 mg, 0.075 mmol) and paraformaldehyde (20.2 mg, 0.22 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C18; 150*21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 17 (16.4 mg). MS m / z (ESI): 415.00 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),7.39(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),5.05–4.89(m,1H),4.27(t,J =9.8Hz,1H),4.12–3.97(m,1H),3.20–3.00(m,5H),2.63(d,J=10.8Hz,3H),2.55–2.52(m,2H),2.26–2.02(m,4H).

[0237] Biological Examples

[0238] 1. Inhibitory activity of the compound on potassium ion channel Kv1.3

[0239] Objective: To detect the inhibitory effect of the compound on the current in HEK-293 cell line stably expressing the human Kv1.3 (KCNA3: NM_002232) channel using automated patch-clamp technique.

[0240] Test method:

[0241] 1) Cell Culture: The Kv1.3-HEK293 cell line was cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% carbon dioxide. For cell passage, the old medium was first removed and the cells were washed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for 1 minute. When the cells detached from the bottom of the dish, 5 mL of preheated (37°C) complete medium was added. The cell suspension was gently pipetted to separate aggregated cells. The cell suspension was transferred to sterile centrifuge tubes and centrifuged at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, cells were seeded in 6 cm cell culture dishes at a density of 2.5 × 10⁶ cells per dish. 5 100 cells (final volume: 5 mL). Cells were subjected to TrypLE assay before automated patch-clamp detection. TM After separating the cells using Express culture medium to stop digestion, centrifuge, resuspend the cells, count them, and adjust the cell density to 2-3 × 10⁶ cells / year. 6 Cells / mL were collected, and then the cells were gently mixed on a balanced shaker for 15-20 minutes at room temperature before being analyzed.

[0242] 2) When performing electrophysiological assays using the fully automated patch-clamp QPatch 48X (Sophion) device, the prepared cells are first placed on the centrifuge of the Qpatch workbench. The cells are washed using multiple centrifugation / resuspension methods, and the cell culture medium is replaced with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. A QPlate chip is removed and placed in the QPlate source position. The robotic arm scans the barcodes on the MTP-96 plate and the QPlate chip and then picks them up and transfers them to the measurement station. Intracellular fluid (145mM KF, 10mM HEPES, 10mM EGTA, 2mM MgCl2·6H2O, pH adjusted to 7.2 with KOH) and extracellular fluid (140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH) were aspirated from the liquid pools and added to the intracellular fluid pool and cell and compound pool of the QPlate chip. At the measurement station, all measurement sites on the QPlate underwent initial quality control. The quality control process included aspirating cell suspension from the centrifuge cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal, forming a whole-cell recording mode. Once a stable baseline control current is obtained, a final concentration of 10 nM of the test substance is aspirated from the MTP-96 plate and applied to the cells in a 4-dose regimen over at least 5 minutes. Blank control solution and working solution of the test compound are applied to the cells sequentially. The current detected in each cell in the solution without the compound serves as its control group. All electrophysiological experiments are performed at room temperature.

[0243] 3) The voltage stimulation protocol for whole-cell patch-clamp recording of Kv1.3 potassium current is as follows: After whole-cell sealing is achieved, the cell membrane voltage is clamped at -80mV, stepped to +40mV, and maintained for 500ms. Data is collected repeatedly every 20s to observe the effect of the drug on the peak value of Kv1.3 current.

[0244] Data Analysis:

[0245] The last dose in a multiple-dose series was used for data analysis. For each drug concentration, the average of the last three data points before the next dose was taken to represent the current value after that concentration. This average represents the current value (Id) for each drug concentration. 化合物 ) and the reference current value (I) used as a blank control 对照 Normalize, then calculate the inhibition rate corresponding to each drug concentration, i.e., inhibition rate (%) = (1-I 化合物 / I 对照*100%. For each concentration, the inhibition rate was calculated as the mean (Mean), standard deviation (SD), and standard error (SE), expressed as Mean ± SE. Test results are shown in Table 1. Where A represents: inhibition rate (%) ≥ 40%; B represents: 20% ≤ inhibition rate (%) < 40%; C represents: 10% ≤ inhibition rate (%) < 20%; D represents: inhibition rate (%) < 10%.

[0246] Table 1

[0247] Example number Compound numbering Inhibition rate (%) / 10nM Inhibition rate (%) - 10 nM 1 15 A 44.37％±2.80％ 2 16 A 47.52％±3.50％ 2 17 B 34.97％±5.13％

[0248] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z is OH; X is C and Y is N; or X is N and Y is C; is a single or double bond; G 1 , G 2 , and G 3 are the same or different and each independently CR 8 or N; R 1 , R 2 , R 3 and R 4 are identical or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl and C 3-6 halocycloalkyl; R 5 selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 6 and R 7 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, C 3-8 cycloalkyl and 3-8 membered heterocyclyl; or R 5 and R 6 , R 5 and R 7 form, together with the carbon atom to which they are attached, a C 3-8 cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 cycloalkyl or 3-8 membered heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 8 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, and the C 1-6 alkyl, C 3-12 cycloalkyl, and 3-12 membered heterocyclyl are optionally substituted with one or more R g substituents; R g the same or different, each independently selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C(O)R p , cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 9 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano and C 3-6 cycloalkyl; R 10 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, cyano, and amino; R p selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, hydroxy, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; n is 1 or 2; m is 1 or 2; provided that when R 5 is H, G 1 , G 2 , and G 3 are each CR 8 , and at least one R 8 is 2. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula (I) satisfies one or more of the following conditions: (1) the C 1-6 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; for example methyl; (2) the halogen is fluorine, chlorine, bromine or iodine, for example chlorine; (3) said C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, for example cyclopropyl; (4) the heteroatoms in the 3-12 membered heterocyclyl, 3-8 membered heterocyclyl and 3-6 membered heterocyclyl are N, O or S, for example N or O; the number of heteroatoms can be 1 or 2, the 3-12 membered heterocyclyl is a 3-6 membered heterocyclyl, for example azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, 3. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (II) or Formula (III): wherein, G 2 CR 8a or N; R 8a selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Z, m and n are as defined in claim 1 or 2; provided that when R 5 is H, R 8 is 4. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the compound of Formula (I) is a compound of Formula (II-1), wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m and n are as defined in any one of claims 1 to 3; provided that when R 5 is H, R 8 is 5. The compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 3-8 cycloalkyl; or R 5 and R 6 R 5 and R 7 Any group of carbon atoms bonded to it forms C 3-6 cycloalkyl, the C 3-6 Cycloalkyl groups are optionally selected from halogens, hydroxyl groups, and C. 1-6 It is replaced by one or more substituents in the alkyl group.

6. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the compound of Formula (I) is a compound of Formula (III-1) or Formula (III-2), wherein: R 5 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl and C 3-8 cycloalkyl; or R 5 and R 6 , R 5 and R 7 form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl group, said C 3-6 cycloalkyl group being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C 1-6 alkyl; R 8a is selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 9 , R 10 , n and m are as defined in any one of claims 1-4; Preferably, the compound of Formula (III-1) is any one of the following: Scheme (1) R 5 is H; R 1 and R 2 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; R 3 and R 4 are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; R 6 and R 7 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; R 9 selected from H, C 1-6 alkyl, C 1-6 haloalkyl and cyano; R 10 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl and cyano; n is 1 or 2; m is 1 or 2; Scheme (2) R 5 is H; R 1 and R 2 each independently H; R 3 and R 4 each independently is halogen; R 6 and R 7 each independently H; R 9 selected from H, C 1-6 alkyl and cyano; R 10 selected from H, C 1-6 alkyl, C 1-6 cyanoalkyl and C 1-6 hydroxyalkyl; n is 1 or 2; m is 1 or 2; Scheme (3) R 5 is H; R 1 and R 2 each independently H; R 3 and R 4 each independently halogen; R 6 and R 7 each independently H; R 9 is H or C 1-6 alkyl; R 10 is H; n is 1 or 2; m is 1 or 2; Scheme (4) R 5 is H; R 1 and R 2 each independently H; R 3 and R 4 each independently halogen; R 6 and R 7 each independently H; R 9 is H; R 10 is H; n is 1 or 2; m is 1 or 2.

7. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein selected from the group consisting of: R 8 , R 9 , R 10 , n and m are as defined in any one of claims 1-5.

8. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 and 7, wherein, R 8 is 3-8 membered heterocyclyl or said 3-8 membered heterocyclyl is optionally substituted with one or more R g ; R g , R 9 , R 10 , n and m are as defined in any one of claims 1-5 and 7; preferably R 8 is selected from 9. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein, R 9 selected from H, C 1-3 alkyl and cyano; R 10 selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 cyanoalkyl and C 1-3 hydroxyalkyl.

10. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein selected from 11. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein, R 1 , R 2 , R 3 and R 4 are the same or different and each is independently selected from H, halogen and C 1-6 alkyl; preferably, R 3 and R 4 are both Cl, R 1 and R 2 are both H.

12. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein, The compound has any one of the following structures:

13. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein the compound of Formula (I) is selected from any one of the following compounds:

14. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13, and one or more pharmaceutically acceptable excipients.

15. Use of a compound or a pharmaceutical composition according to claim 14 for the manufacture of a medicament, characterized in that, The compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13; The drug is a drug for inhibiting Kv1.3 channel or a drug for preventing and / or treating Kv1.3 channel-mediated diseases.

16. Use according to claim 15, characterized in that, The Kv1.3 channel-mediated disease is an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease or a cancer; Preferably, the Kv1.3 channel-mediated disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, kidney fibrosis, inflammatory neuropathy or ischemic stroke.

17. Use of a compound or a pharmaceutical composition according to claim 14 for the manufacture of a medicament for the prevention and / or treatment of a disease, characterized in that, The compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-13; The disease is an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease or a cancer; For example rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, kidney fibrosis, inflammatory neuropathy, or ischemic stroke.

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