Aromatic fused heterocyclic compounds as potassium channel modulators and their preparation and use

Abstract

The present invention relates to aromatic fused heterocyclic compounds as potassium channel regulators and their preparation and use.Specifically, the compounds of the present invention have the structure represented by Formula I, in which the definitions of each group and substituent are as described in the specification.The present invention also discloses a method for preparing the compounds and their use as potassium channel regulators. [Formula 1] JPEG2025504539000029.jpg57132

Description

[Technical field]

[0001] Technical Field The present invention relates to the field of biomedicine, specifically to aromatic fused heterocyclic compounds as potassium channel modulators and their preparation and use. [Background technology]

[0002] Background technology Kv7 potassium channels are voltage-gated potassium ion channels that are characterized by low threshold activation, slow activation, and no inactivation. There are five Kv7 potassium channel family members (Kv7.1-Kv7.5), and all Kv7 potassium channel members have a similar topological structure, i.e., four subunits form a functional channel, and each subunit contains six transmembrane segments (S1-S6). Among them, S4 is the voltage-sensing region, which plays an important role in sensing membrane potential changes and controlling conformational changes, and S1-S6 are the main components of the channel pore region, which are the main combination and action region of potassium channel openers. KV7.1 potassium channels are non-neuronal pathways, distributed in peripheral tissues, expressed in the heart, mediating myocardial Iks, and their mutations can lead to Long Q-T syndrome. Kv7.2-Kv7.5 potassium channels are the basis of neuronal M currents, widely distributed in the nervous system, and have various physiological activities. Genetic mutations in Kv7.2 and Kv7.3 potassium channels can lead to various epilepsy phenotypes, such as benign familial neonatal convulsions (BFNC), which fully demonstrate the role of M-current in regulating neuronal excitability. Kv7.4 potassium channels are highly expressed in the outer hair cells of the cochlea and brainstem auditory nuclei, and their mutations can lead to hereditary hearing loss. Kv7.5 potassium channels are highly expressed in skeletal muscle and brain, and their mutations can lead to retinal pathology. Many diseases, such as epilepsy, anxiety, and hearing loss, share a common feature of high membrane excitability. Kv7 potassium channels, as the molecular basis of M-current, open by sensing changes in membrane potential and can suppress membrane excitability by upregulating inhibitory potassium currents, so Kv7 potassium channels are of great significance in pain and psychiatric disorders, which are typified by high neuronal excitability.

[0003] Retigabine is a drug used to treat epilepsy and has been approved for sale in the UK, Germany and Denmark. Studies have demonstrated that the action of retigabine is related to voltage-gated potassium ion channels (KCNQs), where its main mechanism of action is to act on KCNQ2 / 3 channels to modulate M-type potassium currents.

[0004] Retigabine (RTG) was first marketed in 2011 and is a Kv7 potassium channel opener used for the adjunctive treatment of partial-onset epilepsy in adults. In addition to its antiepileptic effects, RTG can also be used to treat anxiety, neuralgia, and neurodegenerative diseases. RTG can effectively reduce or prevent epilepsy in many epilepsy models. RTG has an effective antiepileptic effect on both tonic seizures induced by maximal electroshock (MES) model and clonic seizures induced by PTZ. RTG can also prevent epilepsy seizures induced by N-methyl-D-aspartate (NMDA), penicillin, picrotoxin, and kainic acid (KA). The kindling model is suitable for screening many antiepileptic drugs, but RTG has a stronger effect on this model than other models. RTG has potential adverse effects due to its poor selectivity due to its broad action on all Kv7 potassium channel members and other channels. As reported in a large literature, RTG is associated with a high incidence of CNS-related adverse events, including dizziness, fatigue, aphasia, speech disorders, and balance disorders, as well as other adverse reactions including kidney stones, urinary retention, and other kidney and urinary system disorders, sudden cardiac arrest, and transient nonsustained ventricular tachycardia, as well as retinitis pigmentosa, blue / purple pigmentation of the skin and nails. Summary of the Invention

[0005] Summary of the Invention It is an object of the present invention to provide compounds of formula I, as well as methods for their preparation and use as potassium channel modulators.

[0006] In a first aspect of the present invention there is provided a compound of formula I, or a pharma- ceutically acceptable salt thereof. [ka] (however, A ring is C 6-10 aryl groups, 4-7 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, saturated or unsaturated C 3-6 It is selected from the group consisting of a cyclic hydrocarbon group, and a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S. Each R1 and R2 is independently a substituted or unsubstituted hydrogen, deuterium, halogen, cyano group, -OH, -COOH, nitro group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups, saturated or unsaturated C 3-6 A cyclic hydrocarbon group, a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl groups, 5-14 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 6-12 Aralkyl groups, -N(R1')(R2'), -C(O)-R1', -C(O)-N(R1')(R2'), -C(O)-OR1', -N(R1')-C(O)-R2', -S(O) m -R1', -S(O) m -N(R1')(R2'), -S(O) m -OR1', -N(R1')-S(O) m -R2', the substitution being selected from the group consisting of halogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 1-6 Haloalkyl group, C 3-6 Halocycloalkyl groups, C 1-6 Haloalkoxy group, C 3-6halocycloalkyloxy groups. n is selected from the group consisting of 0, 1, and 2. n' is selected from the group consisting of 0, 1 and 2. Each R' and R' is independently hydrogen, C 1-6 Alkyl group, C 3-6 Alternatively, R1' and R2' are linked to each other to form a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, which may be saturated or unsaturated. The alkyl, cycloalkyl and heterocyclic groups may optionally be ═O, halogen, C 1-6 Alkyl group, C 3-6 It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. m is selected from the group consisting of 1 and 2. X is selected from the group consisting of C, CR8, and N. Each R8 is independently H, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkenyl group, C 2-6 The alkyl and cycloalkyl groups are optionally selected from the group consisting of halogen, C 1-6 Alkyl group, C 3-6 It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. V is -C(R9)(R 10 )-, -N(R8)-. n'' is selected from the group consisting of 0 and 1. R9, R 10 are independently hydrogen, halogen, C 1-6 alkyl groups, or R, R 10 is a C atom and C 3-6 It forms a cycloalkyl group. The B ring is saturated or unsaturated C 3-10 It is selected from the group consisting of a cyclic hydrocarbon group, a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, which may be saturated or unsaturated. R6 and R7 are independently hydrogen, deuterium, halogen, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Haloalkyl group, C 3-6 It is selected from the group consisting of halocycloalkyl groups. Y is selected from the group consisting of CR8 and N. W is for CR 11 , N. R 11 is hydrogen, deuterium, halogen, cyano group, amino group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 The alkyl, cycloalkyl and alkoxy groups are optionally selected from the group consisting of halogen, C 1-6 Alkyl group, C 3-6 It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. R4 and R5 are independently hydrogen, deuterium, halogen, cyano group, amino group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 The alkyl, cycloalkyl and alkoxy groups are optionally selected from the group consisting of halogen, C 1-6 Alkyl group, C 3-6 It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. U is selected from the group consisting of O, S, and N(R1'). Z is O, -(CH2) q -, -N(R1')-. q is selected from the group consisting of 0, 1, and 2. R3 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 5-8Bridged ring group, adamantyl group, C 6-10 an aryl group, a 3-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; 3-6 Cycloalkenyl group, C 2-6 Alkenyl group, C 2-6 The alkyl group, the cycloalkyl group, the bridged ring group, the adamantyl group, the aryl group, the heteroaryl group, the heterocycloalkyl group, the cycloalkenyl group, the alkenyl group, and the alkynyl group are optionally selected from the group consisting of hydrogen, halogen, cyano group, nitro group, amino group, hydroxyl group, C 1-6 Alkyl-CO- group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 Aryl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 Alkylamino group, C 1-6 and is substituted with one or more substituents selected from the group consisting of haloalkoxy groups. In another preferred embodiment, A ring is C 6-10 aryl groups, and 4-7 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; Each R1 and R2 is independently a substituted or unsubstituted hydrogen, deuterium, halogen, cyano group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 2-6 Alkenyl group, C 2-6 an alkynyl group, -N(R1')(R2'), and the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R1 and R2 is independently hydrogen, C 1-6 Alkyl group, C 3-6cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogens; X is C, V is CH2, n″ is selected from the group consisting of 0 and 1; Ring B is a 3- to 10-membered saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; R6 and R7 are independently selected from the group consisting of hydrogen and deuterium; Y is N, W is for CR 11 , N; R 11 is hydrogen, halogen, C 1-6 alkyl groups, said alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogens; R4 and R5 are independently hydrogen, halogen, cyano, amino, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 a cycloalkyloxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is selected from the group consisting of O, CH2; R3 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 5-8 Bridged ring group, C 2-6 The alkyl, cycloalkyl, bridged ring and alkynyl groups are optionally selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkoxy groups. In another preferred embodiment, A ring is C 6-10 An aryl group, Each R1 and R2 is independently a substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Alkoxy group, C 3-6 Cycloalkyloxy group, C 2-6 an alkynyl group, -N(R1')(R2'), and the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R' and R' is independently hydrogen, C 1-6 alkyl groups, X is C, V is CH2, n″ is selected from the group consisting of 0 and 1; Ring B is a 3- to 10-membered saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; R6 and R7 are independently selected from the group consisting of hydrogen and deuterium; Y is N, W is CH, R4 and R5 are independently halogen, C 1-6 Alkyl group, C 1-6 an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is CH2, R3 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0007] In another preferred embodiment, the B ring is [ka] is selected from the group consisting of:

[0008] In another preferred embodiment, R3 is C 3-6 Cycloalkyl groups, C 5-8 bridged ring groups. In another preferred embodiment, R3 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are selected from the group consisting of halogen, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0009] In another preferred embodiment, the compound does not include the following compounds: [ka]

[0010] In another preferred embodiment, Ring A is a phenyl group. Each R1 and R2 is independently a substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 an alkynyl group, -N(R1')(R2'), and the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R' and R' is independently hydrogen, C 1-6 alkyl groups, X is C, n'' is 0, The B ring is [ka] Selected from the group consisting of: R6 and R7 are independently selected from the group consisting of hydrogen and deuterium; W is CH, R4 and R5 are independently halogen, C 1-6 Alkyl group, C 1-6 an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH2-, R3 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0011] In another preferred embodiment, Ring A is a phenyl group. Each R1 and R2 is independently a substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 an alkynyl group, -N(R1')(R2'), and the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R' and R' is independently hydrogen, C 1-6 alkyl groups, X is C, n'' is 0, The B ring is [ka] Selected from the group consisting of: R6 and R7 are independently selected from the group consisting of hydrogen and deuterium; W is CH, R4 and R5 are independently halogen, C 1-6 Alkyl group, C 1-6 an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH2-, R3 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups. In another preferred embodiment, The A ring is a phenyl group. Each R1 and R2 is independently a substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 2-6 an alkynyl group, -N(R1')(R2'), and the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R' and R' is independently hydrogen, C 1-6 alkyl groups, X is C, V is -CH2-, n'' is 1, The B ring is [ka] Selected from the group consisting of: R6 and R7 are independently selected from the group consisting of hydrogen and deuterium; W is CH, R4 and R5 are independently halogen, C 1-6 Alkyl group, C 1-6an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH2-, R3 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0012] In another preferred embodiment, the compound is selected from the following group: [ka] [ka] [ka]

[0013] In a second aspect of the invention, there is provided a pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a safe and effective amount of one or more compounds according to the first aspect of the invention, or a pharma- ceutically acceptable salt thereof.

[0014] A third aspect of the present invention provides the use of a compound according to the first aspect of the present invention or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating a disease sensitive to a potassium ion channel. In another preferred embodiment, the potassium ion channel-sensitive disease is a central nervous system disease.

[0015] Of course, it is understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (for example, in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be described here one by one due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Specific embodiments The present inventors have conducted in-depth research over a long period of time, and by optimizing the structure, have unexpectedly produced a compound represented by formula I, which has excellent potassium channel opening activity, pharmacokinetics (e.g., brain-to-plasma concentration ratio, etc.), in vivo efficacy and safety, and has a novel structure. Based on this, the present inventors have completed the present invention.

[0017] term In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art. In the present invention, the term "halogen" means F, Cl, Br or I. In the present invention, "C 1-6 "Alkyl group" means a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, neopentyl, t-pentyl, or the like.

[0018] In the present invention, the term "C 2-6 "Alkenyl" refers to straight or branched alkenyl groups having 2-6 carbon atoms and containing one double bond, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl. In the present invention, the term "C 2-6 "Alkynyl" refers to straight or branched chain alkynyl groups having 2-6 carbon atoms and containing a triple bond, including, but not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, and hexynyl.

[0019] In the present invention, the term "C 3-6 "Cyclic hydrocarbon group" is C 3-6 Cycloalkyl groups, C 3-6 Cycloalkenyl group, C 3-6 Cycloalkynyl groups are included. In the present invention, the term "C 3-6 "Cycloalkyl group" refers to a cyclic alkyl group having 3-6 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

[0020] In the present invention, the term "C 5-8 "Bridged ring group" refers to a cyclic alkyl group having a bridge and 5-8 carbon atoms. [ka] These include, but are not limited to: In the present invention, the term "C 1-6 The term "alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. 1-4 It is an alkoxy group.

[0021] In the present invention, the term "heterocyclic group" refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; [ka] This includes, but is not limited to, groups such as: In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning and are preferably used interchangeably with "C 6-10 The term "C 6-10 The term "aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as phenyl and naphthyl groups.

[0022] In the present invention, the terms "aromatic heterocycle" or "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "C3-C10 heteroaryl group" is an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen and 3-10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl group, a heterocyclic group or a cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0023] In the present invention, the term "halo" refers to substitution with halogen. In the present invention, the term "deuterated" means substituted with deuterium. In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms in a particular group with a particular substituent. The particular substituent is the corresponding substituent described above or in each example. Unless otherwise specified, a substituted group may have one substituent selected from a particular group at any substitutable position of the group, and the substituent may be the same or different at each position. As will be understood by those skilled in the art, the combination of substituents contemplated by the present invention is a stable combination or a chemically feasible combination. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic, aryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0024] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each have an analogous meaning independently. The term "plurality" refers to 2-6, for example, 2, 3, 4, 5 or 6. In addition, when a group is present at multiple different positions in a compound, the definition at each position is independent of each other and may be the same or different. In addition, the term "selected from the group consisting of" and the term "each of ~ is independently selected from the group consisting of" have the same meaning.

[0025] compound The present invention provides a compound represented by formula I, or a pharma- ceutically acceptable salt thereof. [ka] (wherein each group is as defined above).

[0026] In another preferred embodiment, in the compound, R1, R2, R3, R4, R5, R6, R7, ring A, n, n', X, V, n'', Y, ring B, W, U, and Z are each independently the corresponding groups in the specific compound. In another preferred embodiment, the compound is preferably a compound prepared in each of the Examples.

[0027] As used herein, the term "pharmaceutical acceptable salt" refers to a salt formed by the compound of the present invention and an acid or base, which is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. One type of suitable salt is a salt formed by the compound of the present invention and an acid. The acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc., and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0028] Another type of suitable salt is a salt formed by a compound of the invention with a base, such as an alkali metal salt (e.g., sodium salt, potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., ammonium salts of lower alkanols and other pharma- ceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, t-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, trihydroxyethylamine, and the amine salts formed from morpholine, piperazine, and lysine, respectively.

[0029] Of course, the compounds of the present invention can be prepared by the methods illustrated in the following examples, or can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be readily accomplished by one of ordinary skill in the art.

[0030] Drug Compositions and Methods of Application The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharma- ceutical acceptable salt in a safe effective amount range and a pharma- ceutical acceptable excipient or carrier. Here, the "safe effective amount" refers to the amount of the compound that is sufficient to significantly improve the disease condition and does not cause severe side effects. Usually, the pharmaceutical composition contains the compound of the present invention in an amount of 1-2000 mg / formulation, preferably 5-1000 mg / formulation. Preferably, the "formulation" is a capsule or tablet.

[0031] "Pharmaceutically acceptable vehicle" refers to one or more compatible solid or liquid fillers or gel substances that must be applicable to humans and have sufficient purity and sufficiently low toxicity. "Compatible" refers to the ability of each component in the composition to be blended with and among the compounds of the present invention without significantly reducing the effectiveness of the compounds. Some examples of pharmaceutically acceptable vehicles include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tallow, glyceryl ... R ), humectants (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and pyrogen-free distilled water.

[0032] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder, or granule. The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, but representative modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral gastrointestinal administration (intravenous, intramuscular, or subcutaneous administration), and topical administration.

[0033] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is usually mixed with at least one inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or may contain (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (b) a binder, such as hydromethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; and (d) a disintegrant, such as agar, calcium carbonate, or the like. The pharmaceutical composition may be mixed with ingredients such as calcium, potato starch or tapioca starch, alginic acid, certain complex silicates or sodium carbonate, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol or glycerin monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0034] Solid dosage forms, such as tablets, pills, capsules, pills, and granules, can be prepared with coatings or shells, such as enteric coatings and other materials known in the art. Opacifying agents may be included, and in such compositions, the release of the active or compound may be delayed in a certain part of the digestive tract. Examples of embedding materials that can be used include polymeric and wax-based materials. If necessary, the active compound may also be formed into a microcapsule with one or more of the above excipients.

[0035] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, compatibilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil, or sesame oil, or mixtures of these substances. Besides these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes.

[0036] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxyl or agar, or mixtures of these substances. Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0037] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, poultices, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required. The compounds of the present invention may be administered alone or in combination with other pharma- ceutically acceptable compounds. The treatment methods of the present invention may be administered alone or in combination with other therapeutic procedures or agents.

[0038] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, and the dosage is a pharmacologically effective dosage, and for a human weighing 60 kg, the daily dosage is usually 1-2000 mg, preferably 5-1000 mg. Of course, the specific dosage should further consider factors such as the mode of administration and the health condition of the patient, all of which are within the skill of a skilled doctor.

[0039] Compared with existing technologies, the present invention has the following main advantages: (1) The compound has better pharmacokinetic properties, such as better brain-to-plasma concentration ratio, half-life, exposure, metabolic stability, and the like. (2) The compound has better potassium ion channel opening activity, better potassium ion channel excitation rate, better ion channel selectivity, better in vivo efficacy and better safety. (3) The compounds are expected to be used in the treatment and / or prevention of diseases and disorders affected by the activity of potassium channels.

[0040] The present invention will be further described below with reference to specific examples. It is understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. Experimental methods for which no specific conditions are given in the following examples are generally performed according to standard conditions, such as those described in Sambrook et al., "Molecular Cloning: A Laboratory Manual" (New York, Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommended conditions. Unless otherwise specified, percentages and parts are calculated by weight.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only. All experimental materials and reagents used in the following examples are commercially available unless otherwise specified. EXAMPLES

[0042] Example 1 Preparation of Compound 3001 [ka]

[0043] Step 1. Compound 2 Compound 1 (5.0 g, 37.3 mmol, 1.0 eq) was dissolved in nitromethane (45 mL), and ammonium acetate (3.4 g, 44.7 mmol, 1.2 eq) was added to the reaction solution at 25°C, and the mixture was heated to reflux for 4 hours. After the reaction was completed, the temperature was lowered to 25°C, the reaction solution was concentrated, and ethyl acetate (80 mL) was added. The organic phase was washed with water (50 mL), saturated sodium chloride solution (50 mL), and dried over anhydrous sodium sulfate. The residue after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain compound 2 (3.0 g, 46%), which was a yellow solid. LCMS: [M+H] + = 178.1

[0044] Step 2. Compound 3 Compound 2 (2.0 g, 11.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL), and the above solution was slowly added dropwise to a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 45 mL, 45 mmol, 4.0 eq). Upon completion, the reaction was heated to reflux for 16 hours. The reaction was cooled to 25°C and quenched with sodium sulfate decahydrate, filtered, washed with ethyl acetate, and the filtrate was concentrated to give compound 3 (1.6 g, 95%) as a yellow solid. LCMS: [M+H] + = 150.1

[0045] Step 3. Compound 4 Triphosgene (1.3 g, 4.3 mmol, 0.4 eq) was dissolved in dichloromethane (10 mL), and the above solution was slowly added dropwise to a solution of compound 3 (1.6 g, 10.7 mmol, 1.0 eq) in dichloromethane (10 mL), cooled to 0°C, and triethylamine (2.2 g, 21.5 mmol, 2.0 eq) was slowly added dropwise. The reaction solution was stirred at 25°C for 2 hours, filtered, the solid was washed with a small amount of dichloromethane, and the obtained filtrate was slowly added dropwise to a suspension of aluminum trichloride (5.7 g, 42.9 mmol, 4.0 eq) in dichloromethane (25 mL). After stirring for 16 hours, the mixture was quenched by adding water. After separation, the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate=2 / 1) to obtain compound 4 (0.6 g, 32%) as a yellow solid. LCMS: [M+H] + = 176.1

[0046] Step 4. Compound 5 Compound 4 (200 mg, 1.14 mmol, 1.0 eq) was dissolved in chloroform (2 mL) and cooled to 0° C., and a solution of potassium nitrate (127 mg, 1.26 mmol, 1.1 eq) in concentrated sulfuric acid (98%, 3 mL) was added dropwise. The reaction was stirred at 0° C. for 0.5 h, then quenched with crushed ice, filtered, and the resulting solid was purified by trituration with water to give compound 5 (213 mg, 85%) as a yellow solid. LCMS: [M+H] + = 221.1

[0047] Step 5. Compound 7 Compound 5 (280 mg, 1.27 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), followed by compound 6 (339 mg, 1.53 mmol, 1.2 eq), cuprous iodide (48 mg, 0.25 mmol, 0.2 eq) and potassium carbonate (352 mg, 2.54 mmol, 2.0 eq). The reaction mixture was heated to 140°C in a nitrogen gas atmosphere and stirred for 6 hours, cooled to 25°C and diluted with ethyl acetate (10 mL). The reaction mixture was filtered, the solid was showered with ethyl acetate, the filtrate was washed with water (10 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 7 (145 mg, 36%), which was a yellow solid. LCMS: [M+H] + = 315.1

[0048] Step 6. Compound 8 Compound 7 (530 mg, 1.69 mmol, 1.0 eq) was dissolved in tetrahydrofuran (70 mL), and the above solution was slowly added dropwise to a solution of lithium aluminum hydride in tetrahydrofuran (1M, 17 mL, 17 mmol, 10.0 eq). After completion of the addition, the temperature was raised and refluxed for 6 hours. After cooling to 25°C, the reaction was quenched with sodium sulfate decahydrate, filtered, washed with ethyl acetate, and the obtained filtrate was concentrated to obtain compound 8 (423 mg, 93%), which was a yellow solid. LCMS: [M+H] + = 271.1

[0049] Step 7. Compound 3001 Compound 8 (200 mg, 0.74 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (6 mL), and compound 9 (102 mg, 0.89 mmol, 1.2 eq), pyridine (1170 mg, 14.8 mmol, 20.0 eq) and 1-propylphosphonic anhydride (50% ethyl acetate solution, 4.8 g, 7.4 mmol, 10.0 eq) were added in that order, and the mixture was heated to 50°C and stirred for 16 hours. After cooling to 25°C, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution in that order, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 3001 (139.1 mg, 52%), which was a white solid. LCMS: [M+H] + = 367.1 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.08-7.06 (m, 4H), 6.88 (s, 1H), 4.16 (s, 2H), 3.42 (t, J = 5.6 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.22 (s, 2H), 2.11 (s, 3H), 2.07 (s, 3H), 1.16 (s, 3H), 0.56-0.54 (m, 2H), 0.34-0.31 (m, 2H).

[0050] Example 2 Preparation of Compound 3002 [ka]

[0051] Step 1. Compound 3 Compound 1 (500 mg, 2.27 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), followed by compound 2 (926 mg, 3.40 mmol, 1.5 eq), potassium carbonate (784 mg, 5.68 mmol, 2.5 eq) and copper(I) iodide (86 mg, 0.45 mmol, 0.2 eq), and the reaction solution was heated to 140°C and stirred for 4 hours. After cooling the reaction solution to 25°C, water (50 mL) was added and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 3 (400 mg, 48%), which was a white solid. LCMS: [M+H] + =365.1

[0052] Step 2. Compound 4 Compound 3 (200 mg, 0.548 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL), cooled to 0°C, and a solution of lithium aluminum hydride in tetrahydrofuran (1 M, 5.48 mL, 5.48 mmol, 10.0 eq) was added dropwise. After completion of the addition, the reaction solution was heated to 60°C and stirred for 1 hour. After cooling to 0°C, the reaction solution was quenched with sodium sulfate decahydrate. The filtrate after filtration was concentrated to obtain compound 4 (150 mg, 85%), which was a white solid. LCMS: [M+H] + =321.1

[0053] Step 3. Compound 3002 Compound 4 (150 mg, 0.468 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), followed by compound 5 (64 mg, 0.561 mmol, 1.2 eq), 1-propylphosphonic anhydride (50%, 3.5 g, 5.500 mmol, 11.7 eq) and pyridine (740 mg, 9.36 mmol, 20.0 eq). The reaction mixture was heated to 50°C and stirred for 2 h. It was then cooled to 25°C, after which water (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give compound 3002 (40 mg, 20%) as a white solid. LCMS: [M+H] + =417.3 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.91 (s, 1H), 4.35 (s, 2H), 3.60 (t, J = 5.5 Hz, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.23 (s, 2H), 2.11 (d, J = 4.6 Hz, 6H), 1.16 (s, 3H), 0.56-0.54 (m, 2H), 0.34-0.31 (m, 2H).

[0054] Example A1 Potassium Channel Opener Activity Test (FDSS / μCELL Detection) 1. Experimental Method: 1.1 Experimental procedure Cell preparation: CHO-KNCQ2 cells were cultured at 175 cm 2The cells were cultured in a culture flask, and when the cell density reached 60-80%, the culture medium was discarded, washed once with 7 mL of PBS (Phosphate Buffered Saline), and then digested with 3 mL of 0.25% trypsin. After digestion was complete, 7 mL of culture medium (90% DMEM / F12 + 10% FBS + 500 μg / mL G418) was added to neutralize the cells, and the cells were centrifuged at 800 rpm for 3 minutes. The supernatant was then aspirated, and 5 mL of culture medium was added to resuspend the cells, and the cells were counted.

[0055] Plate cells: Cell count results indicate a density of 3×10 4 The cells were adjusted to have a cell density of about 80% per well, and then allowed to stand at room temperature for 30 minutes. The cells were then cultured overnight in a CO2 incubator at 37°C, and further cultured for 16-18 hours until the cell density reached about 80%. Incubation of fluorescent dye: Discard the cell culture medium, add 80 μL / well of loading buffer, and incubate at room temperature for 60 minutes away from light. Incubation of compound: The loading buffer was discarded, and the prepared compound solution was added at 80 μL / well, and incubated at room temperature for 20 minutes in the dark. Fluorescence data collection: The fluorescence signal was recorded in real time by the FDSS / μCELL device, with an excitation wavelength of 480 nm and an emission wavelength of 540 nm, recorded once every second. After recording a 10-s baseline, 20 μL / well of stimulation buffer was added and recording continued for another 180 seconds.

[0056] 1.2 Preparation of solutions Loading buffer: 10 mL / plate, preparation method is as follows: [Table A]

[0057] Test Buffer: 100 mL / plate, method of preparation is as follows: [Table B]

[0058] Stimulation buffer: 5 mL / plate, preparation method is as follows: [Table C] The above buffers were from a commercially available kit called FluxOR potassium ion channel assay.

[0059] 1.3 Preparation of compounds A 20 mM DMSO compound stock solution was prepared, 10 μL of the 20 mM compound stock solution was taken and placed into 20 μL of DMSO solution, serially diluted 3-fold to give 8 intermediate concentrations, and each intermediate concentration of compound was then taken and placed into test buffer, diluted 200-fold to give the required final test concentration, and 80 μL was taken and placed into the test plate. The highest concentration tested was 100 μM, followed by eight concentrations: 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, and 0.045 μM, with three replicate wells for each concentration. The DMSO content in the final test concentration was less than 0.5%, which is a concentration that has no effect on the KCNQ2 potassium channel.

[0060] 1.4 Data Analysis The experimental data was analyzed using Excel 2007 and GraphPad Prism 5.0 software, and the ratios at 180 seconds were statistically used to calculate the excitation effect. The excitation effect of the compound was calculated using the following formula:

number

[0061] 1.5 Quality control Environment: Temperature ~25℃ Reagents: FluxORTM Detection Kit (Invitrogen, Cat #F0017) The experimental data in the report must meet the following criteria: Z' Factor>0.5.

[0062] 2. Measurement results: For details, see Table 1. Here, EC 50 The smaller the value, the higher the activity of the corresponding compound. Table 1. Test results of some compounds described in this invention [Table 1]

[0063] References for the above test methods: Zhaobing Gao et al. Journal of Biological Chemistry. 2010, 285(36): 28322-28332.

[0064] All documents related to the present invention are incorporated herein by reference as if each document were incorporated individually. After reading the above content of the present invention, it will be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalent forms thereof are within the scope of the claims of the present invention.

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (however, The A ring is C ６－１０ an aryl group, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a saturated or unsaturated C ３－６ It is selected from the group consisting of a cyclic hydrocarbon group, and a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S. Each R １ , R ２ are independently substituted or unsubstituted hydrogen, deuterium, halogen, cyano group, -OH, -COOH, nitro group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, saturated or unsaturated C ３－６ a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; ６－１０ an aryl group, a 5-14 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; ６－１２ Aralkyl groups, -N(R １ ')(R ２ '), -C(O)-R １ ', -C(O)-N(R １ ')(R ２ '), -C(O)-OR １ ', -N(R １ ')-C(O)-R ２ ', -S(O) ｍ -R １ ', -S(O) ｍ -N(R １ ')(R ２ '), -S(O) ｍ -OR １ ', -N(R １ ')-S(O) ｍ -R ２ ', the substitution being selected from the group consisting of halogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C １－６ Haloalkyl group, C ３－６ Halocycloalkyl group, C １－６ Haloalkoxy group, C ３－６ halocycloalkyloxy groups. n is selected from the group consisting of 0, 1, and 2. n' is selected from the group consisting of 0, 1 and 2; Each R １ ', R ２ ' are independently hydrogen, C １－６ Alkyl group, C ３－６ cycloalkyl groups or R １ ', R ２ ' and the N atom linked thereto form a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from saturated or unsaturated N, O or S. The alkyl group, cycloalkyl group and heterocyclic group may optionally include ═O, halogen, C １－６ Alkyl group, C ３－６ It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. m is selected from the group consisting of 1 and 2. X is C, CR ８ , N. Each R ８ are independently H, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkenyl group, C ２－６ alkynyl groups. The alkyl and cycloalkyl groups may optionally be halogen, C １－６ Alkyl group, C ３－６ It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. V is -C(R ９ )(R １０ )-, -N(R ８ )- is selected from the group consisting of n'' is selected from the group consisting of 0 and 1. R ９ , R １０ are independently hydrogen, halogen, C １－６ alkyl groups or R ９ , R １０ is a C atom and C ３－６ It forms a cycloalkyl group. The B ring is a saturated or unsaturated C ３－１０ It is selected from the group consisting of a cyclic hydrocarbon group, a 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, which may be saturated or unsaturated. R ６ , R ７ are independently hydrogen, deuterium, halogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Haloalkyl group, C ３－６ It is selected from the group consisting of halocycloalkyl groups. Y is CR ８ , N. W is CR １１ , N. R １１ is hydrogen, deuterium, halogen, cyano group, amino group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyloxy group, -N(R １ ')(R ２ ') is selected from the group consisting of. The alkyl, cycloalkyl and alkoxy groups may optionally be halogen, C １－６ Alkyl group, C ３－６ It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. R ４ , R ５ are independently hydrogen, deuterium, halogen, cyano group, amino group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C3-6 cycloalkyloxy group, -N(R １ ')(R ２ ') is selected from the group consisting of. The alkyl, cycloalkyl and alkoxy groups may optionally be halogen, C １－６ Alkyl group, C ３－６ It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups. U is O, S, N(R １ ') is selected from the group consisting of. Z is O, -(CH ２ ) ｑ -, -N(R １ ')--is selected from the group consisting of. q is selected from the group consisting of 0, 1, and 2. R ３ is C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ５－８ Bridged ring group, adamantyl group, C ６－１０ an aryl group, a 3-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; a 4-8 membered heterocycloalkyl group containing 1-3 heteroatoms selected from N, O or S; ３－６ Cycloalkenyl group, C ２－６ Alkenyl group, C ２－６ The alkyl group, the cycloalkyl group, the bridged ring group, the adamantyl group, the aryl group, the heteroaryl group, the heterocycloalkyl group, the cycloalkenyl group, the alkenyl group, and the alkynyl group are optionally selected from the group consisting of hydrogen, halogen, cyano group, nitro group, amino group, hydroxy group, C １－６ Alkyl-CO- group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ６－１０ Aryl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ Alkylamino group, C １－６ and is substituted with one or more substituents selected from the group consisting of haloalkoxy groups.

2. The A ring is C ６－１０ aryl groups, and 4-7 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; Each R １ , R ２ are independently substituted or unsubstituted hydrogen, deuterium, halogen, cyano group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -N(R １ ')(R ２ ') wherein the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R １ , R ２ are independently hydrogen, C １－６ Alkyl group, C ３－６ cycloalkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogens; X is C, V is CH ２ in, n″ is selected from the group consisting of 0 and 1; Ring B is a saturated or unsaturated 3- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, or S; R ６ , R ７ are independently selected from the group consisting of hydrogen and deuterium; Y is N, W is CR １１ , N; R １１ is hydrogen, halogen, C １－６ alkyl groups, said alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogens; R ４ , R ５ are independently hydrogen, halogen, a cyano group, an amino group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ cycloalkyloxy groups, wherein the alkyl, cycloalkyl, and alkoxy groups are optionally substituted with one or more substituents selected from the group consisting of halogen; U is O, Z is O, CH ２ Selected from the group consisting of: R ３ is C １－６ Alkyl group, C ３－６ Cycloalkyl group, C ５－８ Bridged ring group, C ２－６ The alkyl, cycloalkyl, bridged ring and alkynyl groups are optionally selected from the group consisting of hydrogen, halogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C １－６ 2. The compound according to claim 1 or a pharma- ceutically acceptable salt thereof, which is substituted with one or more substituents selected from the group consisting of haloalkoxy groups.

3. The A ring is C ６－１０ An aryl group, Each R １ , R ２ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Alkoxy group, C ３－６ Cycloalkyloxy group, C ２－６ Alkynyl group, -N(R １ ')(R ２ ') wherein the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R １ ', R ２ ' are independently hydrogen, C １－６ alkyl groups, X is C, V is CH ２ in, n″ is selected from the group consisting of 0 and 1; Ring B is a saturated or unsaturated 3- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, or S; R ６ , R ７ are independently selected from the group consisting of hydrogen and deuterium; Y is N, W is CH, R ４ , R ５ are independently halogen, C １－６ Alkyl group, C １－６ an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is CH ２ in, R ３ is C ３－６ Cycloalkyl group, C ５－８ The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C １－６ Alkyl group, C １－６ 3. The compound according to claim 2, or a pharma- ceutically acceptable salt thereof, which is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

4. Ring A is a phenyl group. Each R １ , R ２ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkynyl group, -N(R １ ')(R ２ ') wherein the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R １ ', R ２ ' are independently hydrogen, C １－６ alkyl groups, X is C, n″ is 0, The B ring is 【Chemistry 2】 【Chemistry 3】 Selected from the group consisting of: R ６ , R ７ are independently selected from the group consisting of hydrogen and deuterium; W is CH, R ４ , R ５ are independently halogen, C １－６ Alkyl group, C １－６ an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH ２ -in, R ３ is C ３－６ Cycloalkyl group, C ５－８ The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C １－６ Alkyl group, C １－６ The compound according to claim 3 or a pharma- ceutically acceptable salt thereof, which is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

5. Ring A is a phenyl group. Each R １ , R ２ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkynyl group, -N(R １ ')(R ２ ') wherein the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R １ ', R ２ ' are independently hydrogen, C １－６ alkyl groups, X is C, n″ is 0, The B ring is 【Chemistry 4】 Selected from the group consisting of: R ６ , R ７ are independently selected from the group consisting of hydrogen and deuterium; W is CH, R ４ , R ５ are independently halogen, C １－６ Alkyl group, C １－６ an alkyl group, an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH ２ -in, R ３ is C ３－６ Cycloalkyl group, C ５－８ The cycloalkyl group and the bridging ring group are selected from the group consisting of hydrogen, halogen, C １－６ Alkyl group, C １－６ 5. The compound according to claim 4, or a pharma- ceutically acceptable salt thereof, which is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

6. Ring A is a phenyl group. Each R １ , R ２ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ Alkoxy group, C ２－６ Alkynyl group, -N(R １ ')(R ２ ') wherein the substitution is substituted with one or more substituents selected from the group consisting of halogen; n is selected from the group consisting of 0, 1 and 2; n' is selected from the group consisting of 0, 1 and 2; Each R １ ', R ２ ' are independently hydrogen, C １－６ alkyl groups, X is C, V is -CH ２ -in, n″ is 1, The B ring is 【Chemistry 5】 Selected from the group consisting of: R ６ , R ７ are independently selected from the group consisting of hydrogen and deuterium; W is CH, R ４ , R ５ are independently halogen, C １－６ Alkyl group, C １－６ an alkyl group or an alkoxy group, each of which is optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is -CH ２ -in, R ３ is C ３－６ Cycloalkyl group, C ５－８ The cycloalkyl group and the bridging ring group are optionally selected from the group consisting of hydrogen, halogen, C １－６ Alkyl group, C １－６ The compound according to claim 3 or a pharma- ceutically acceptable salt thereof, which is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

7. The compound according to claim 1, characterized in that the compound is selected from the group consisting of: 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】

8. 13. A pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a safe and effective amount of one or more compounds according to claim 1 or a pharma- ceutically acceptable salt thereof.

9. 13. Use of the compound according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that the use is for the manufacture of a drug for preventing and / or treating a disease sensitive to potassium ion channels.

10. The use according to claim 9, characterized in that the potassium ion channel sensitive disease is a central nervous system disease.

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