Amide-based compounds as potassium channel modulators and their preparation and use

Abstract

The present invention relates to amide-based compounds and their preparation and use as potassium channel regulators. 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] JPEG2025504538000045.jpg59133

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine, specifically to amide-based compounds as potassium channel modulators and their preparation and use. [Background technology]

[0002] 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 [Problem to be solved by the invention]

[0005] 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. [Means for solving the problem]

[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]

[0007] (however, A ring: None, 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.

[0008] R1, R2, R3, and R4 are independently 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′, wherein the substitution is selected from the group consisting of halogen, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6Alkoxy group, C 3-6 Cycloalkyloxy group, C 1-6 Haloalkyl group, C 3-6 Halocycloalkyl groups, C 1-6 Haloalkoxy group, C 3-6 halocycloalkyloxy groups. n and r are independently selected from the group consisting of 0, 1 and 2.

[0009] R1' and R2' are 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.

[0010] m is selected from the group consisting of 1 and 2. W1 and W2 are independently selected from the group consisting of none, C, and N. W1 and W2 cannot be none at the same time. [ka] is selected from the group consisting of none, a single bond, and a double bond.

[0011] B 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 3-10 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 and S, and a 3-10 membered bridged heterocyclic group containing 1-3 heteroatoms selected from N, O and S. V is selected from the group consisting of C, CR8, and N.

[0012] R8 is hydrogen, 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.

[0013] V' is -(CH2) p -, -C(CH3)2-, [ka] -NH-, -(CH2) p -NH-, -CF2-NH-, -C(CH3)2-NH-, [ka] is selected from the group consisting of: p is selected from the group consisting of 0, 1, and 2. X and Y are independently selected from the group consisting of N and CR9.

[0014] R9 is hydrogen, halogen, cyano group, amino group, hydroxyl group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 The amino group, alkyl group, cycloalkyl group, and alkoxy group 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.

[0015] R5 and R6 are independently hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 The amino group, alkyl group, cycloalkyl group, and alkoxy group are optionally selected from the group consisting of halogen, C1-6 Alkyl group, C 3-6 It is substituted with one or more substituents selected from the group consisting of cycloalkyl groups.

[0016] U is O, S, N(R 10 ). Z is O, -(CH2) q -, -N(R 11 )-. q is selected from the group consisting of 0, 1, and 2.

[0017] R 10 , R 11 are independently hydrogen, C 1-6 Alkyl group, C 3-6 The alkyl group and the cycloalkyl group are 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.

[0018] R7 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, 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, 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 1-6Alkoxy 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.

[0019] In another preferred embodiment, A ring: None, C 6-10 aryl groups, and 4-7 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; R1, R2, R3, and R4 are independently substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; n and r are selected from the group consisting of 0, 1, and 2; W1 and W2 are independently selected from the group consisting of none, C, and N, and W1 and W2 are not N at the same time; B 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 3-10 selected from the group consisting of a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S, and a 3- to 10-membered bridged heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; V is N, V' is -(CH2) p -, -NH-, -CH2-NH-, p is selected from the group consisting of 0 and 1; X and Y are CH, R5 and R6 are independently halogen, C 1-6 alkyl groups, said alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is CH2, R7 is C 3-6 Cycloalkyl groups, C 5-8The cycloalkyl group and the bridged ring group are optionally selected from the group consisting of hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0020] In another preferred embodiment, In formula I [ka] teeth, [ka] Selected from the group consisting of: R1, R2, R3, and R4 are independently substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; n and r are independently selected from the group consisting of 0, 1 and 2.

[0021] In another preferred embodiment, R7 is C 3-6 Cycloalkyl groups, C 5-8 bridged ring groups. In another preferred embodiment, R7 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridging ring group are selected from the group consisting of hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0022] In another preferred embodiment, In formula I [ka] teeth, [ka] Selected from the group consisting of: R1, R2, R3, and R4 are independently substituted or unsubstituted hydrogen, halogen, C 1-6 Alkyl group, C 1-6 an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; n and r are independently selected from the group consisting of 0, 1 and 2; V' is -(CH2) p -, -NH-, -CH2-NH-, [ka] Selected from the group consisting of: p is selected from the group consisting of 0 and 1; X and Y are independently selected from the group consisting of N and CH; R5 and R6 are independently hydrogen, halogen, amino group, C 1-6 Alkyl group, C 1-6 alkoxy groups; U is O, Z is CH2, R7 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridged ring group are optionally selected from the group consisting of hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0023] In another preferred embodiment, R1, R2, R3, and R4 are independently substituted or unsubstituted hydrogen, halogen, C 1-6 alkyl groups, n is selected from the group consisting of 0, 1 and 2; V' is -(CH2) p -, -NH-, -CH2-NH-, p is selected from the group consisting of 0 and 1; X and Y are CH, R5 and R6 are independently halogen, C 1-6 alkyl groups, U is O, Z is CH2, R7 is C 3-6 Cycloalkyl groups, C 5-8 The cycloalkyl group and the bridged ring group are optionally selected from the group consisting of hydrogen, halogen, cyano group, C 1-6 Alkyl group, C 1-6 It is substituted with one or more substituents selected from the group consisting of haloalkyl groups.

[0024] In another preferred embodiment, the compound is selected from the following group: [ka] [ka] [ka]

[0025] In a second aspect of the invention, there is provided a pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a therapeutically effective amount of one or more compounds according to the first aspect of the invention, or a pharma- ceutically acceptable salt thereof.

[0026] 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.

[0027] 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

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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:

[0034] 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.

[0035] 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:

[0036] 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.

[0037] 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.

[0038] In the present invention, the term "C 6-12 An "aralkyl group" is an alkyl group substituted with an aryl group having a total of 6-10 carbon atoms and no heteroatoms. In the present invention, the term "halo" refers to substitution with halogen. In the present invention, the term "deuterated" means substituted with deuterium.

[0039] 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.

[0040] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have an analogous meaning. The term "multiple" 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.

[0041] 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).

[0042] In another preferred embodiment, in the compound, ring A, ring B, W1, W2, r, n, R1, R2, R3, R4, R5, R6, R7, V, V', X, Y, 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] "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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] Besides these inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. 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.

[0053] 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. 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] Example 1 Preparation of Compound 3001 [ka] Step 1. Compound 3001 Compound 1 (100 mg, 0.420 mmol, 1.0 eq) was dissolved in toluene (6 mL) and then compound 2 (149 mg, 0.50 mmol, 1.2 eq), potassium t-butoxide (142 mg, 1.26 mmol, 3.0 eq), Dave-Phos (17 mg, 0.042 mmol, 0.1 eq) and Pd2(dba)3 (19 mg, 0.021 mmol, 0.05 eq) were added. The reaction was heated to 90 °C under a nitrogen atmosphere and stirred for 16 h. After cooling to 25° C., the reaction mixture was diluted with ethyl acetate (30 mL), washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound 3001 (65.4 mg, 37%).

[0060] LCMS: [M+H] + = 417.2 1 H NMR (400 MHz DMSO-d6) δ 8.81 (s, 1H), 7.54-7.52 (m, 2H), 7.47-7.45 (m, 1H), 6.74 (s, 2H), 4.43 (s, 2H), 3.52 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.17 (s, 2H), 2.11 (s, 6H), 1.14 (s, 3H), 0.53 (q, J = 4.1 Hz, 2H), 0.31 (q, J = 4.1 Hz, 2H).

[0061] Example 2 Preparation of Compound 3002 [ka]

[0062] Step 1. Compound 3 Compound 1 (5.0 g, 20.0 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (50 mL), and compound 2 (6.65 g, 20.0 mmol, 1.0 eq) and Pd(PPh3)4 (700 mg, 0.6 mmol, 0.03 eq) were added in that order. The mixture was heated to 80°C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the residue after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 3 (3.5 g, 87%), which was a white solid. LCMS: [M+H] + = 202.2

[0063] Step 2. Compound 5 Compound 3 (1.5 g, 7.46 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), cooled to 0° C., and compound 4 (810 mg, 8.95 mmol, 1.2 eq) and triethylamine (2.3 g, 22.4 mmol, 3.0 eq) were added. The reaction solution was stirred at 25° C. for 1 hour under nitrogen gas protection, diluted with ethyl acetate (50 mL), washed with saturated saline, and the organic phase was 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 5 (1.5 g, 79%), which was a white solid. LCMS: [M+H] + =256.1

[0064] Step 3. Compound 6 Compound 5 (1.5 g, 5.9 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and Grubbs II catalyst (300 mg, 0.353 mmol, 0.06 eq) was added under nitrogen gas protection. The reaction solution was stirred at 25°C for 16 hours under nitrogen gas protection, then diluted with ethyl acetate (50 mL), washed with saturated saline, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 6 (900 mg, 67%), which was a white solid. LCMS: [M+H] + =228.1

[0065] Step 4. Compound 7 Compound 6 (900 mg, 3.961 mmol, 1.0 eq) was dissolved in ethanol (20 mL), Pd / C (10%, 90 mg) was added, and the reaction solution was stirred overnight at 25° C. under an atmosphere of hydrogen gas at 1 atmospheric pressure. After filtration, the filtrate was concentrated to give compound 7 (900 mg, 99%) as a colorless oil. LCMS: [M+H] + =230.1

[0066] Step 5. Compound 8 Compound 7 (400 mg, 1.75 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) and cooled to 0°C. A solution of borane in tetrahydrofuran (1 M, 35 mL, 35 mmol, 20.0 eq) was added, and the mixture was heated to 50°C and stirred for 2 hours. After cooling to 0°C, methanol (30 mL) was added and stirred for 0.5 hours. The reaction solution was concentrated to give compound 8 (400 mg, 99%) as a colorless oil. LCMS: [M+H] + = 216.2

[0067] Step 6. Compound 3002 Compound 8 (100 mg, 0.47 mmol, 1.0 eq) was dissolved in toluene (5 mL), and compound 9 (139 mg, 0.47 mmol, 1.0 eq), potassium t-butoxide (158 mg, 1.41 mmol, 3.0 eq), X-Phos (45 mg, 0.094 mmol, 0.2 eq) and Pd2(dba)3 (43 mg, 0.047 mmol, 0.1 eq) were added, and the mixture was heated to 99°C and stirred for 16 hours. After cooling to 25°C, the reaction solution was filtered and concentrated, and the resulting residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give compound 3002 (41.6 mg, 21%). LCMS: [M+H] + = 431.2

[0068] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.69 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.42 (s, 2H), 3.63 (s, 2H), 2.76 (s, 2H), 2.17 (s, 2H), 2.03 (s, 6H), 1.73 (s, 2H), 1.65 (s, 2H), 1.13 (s, 3H), 0.55-0.51 (m, 2H), 0.32-0.28 (m, 2H).

[0069] Example 3 Preparation of Compound 3003 [ka]

[0070] Step 1. Compound 2 Compound 1 (1.0 g, 5.26 mmol, 1.0 eq) was dissolved in ethanol (20 mL), and hydroxylamine hydrochloride (1.24 g, 17.9 mmol, 3.4 eq) and sodium acetate (1.73 g, 21.04 mmol, 4.0 eq) were added. The reaction solution was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature and then concentrated. The residue obtained was diluted with ethyl acetate and then filtered. The filtrate obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give compound 2 (1.2 g, 100%). LCMS: [M+H] + = 206.2

[0071] Step 2. Compound 3 Compound 2 (1.2 g, 5.26 mmol) was dissolved in ethanol (30 mL), and concentrated hydrochloric acid (12 M, 3 mL) and palladium hydroxide (0.4 g) were added. The resulting reaction solution was reacted at room temperature for 16 hours in a hydrogen gas atmosphere of 0.4 MPa. The pH value of the reaction solution was adjusted to 8 with a saturated aqueous solution of sodium bicarbonate, and then the filtrate was concentrated. The resulting residue was diluted with ethyl acetate, washed with a saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound 3 (1.0 g, 99%). LCMS: [M+H] + = 192.1

[0072] Step 3. Compound 5 Compound 3 (1.0 g, 5.23 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), potassium carbonate (2.89 g, 20.93 mmol, 4.0 eq), tetrabutylammonium bromide (0.169 g, 0.52 mmol, 0.1 eq) and chloroacetyl chloride (0.886 g, 0.7.85 mmol, 1.5 eq) were added in that order, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5 (0.8 g, 66%). LCMS: [M+H] + = 232.1

[0073] Step 4. Compound 6 Compound 5 (800 mg, 3.46 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) and cooled to 0°C. Then, lithium aluminum hydride in tetrahydrofuran (1 M, 13 mL, 13 mmol, 3.7 eq) was added, and the mixture was heated to 25°C and stirred for 2 hours. The reaction solution was diluted with tetrahydrofuran (200 mL), sodium sulfate decahydrate (4.0 g) was added, and the mixture was stirred for 2 hours. After filtration, the filtrate was concentrated to obtain compound 6 (600 mg, 80%). LCMS: [M+H] + = 218.1

[0074] Step 5. Compound 3003 Compound 6 (162 mg, 0.74 mmol, 1.0 eq) was dissolved in toluene (20 mL), and compound 7 (221 mg, 0.74 mmol, 1.0 eq), Pd2(dba)3 (68 mg, 0.07 mmol, 0.1 eq), Davephos (59 mg, 0.15 mmol, 0.2 eq) and potassium t-butoxide (251 mg, 2.24 mmol, 3.0 eq) were added in that order, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The residue obtained was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound 3003 (50.9 mg, 16%). LCMS: [M+H] + = 433.2

[0075] 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 6.58 (s, 2H), 4.69 (s, 2H), 4.24 - 4.10 (m, 2H), 3.94 - 3.80 (m, 2H), 2.13 (s, 2H), 2.03 (s, 6H),1.11 (s, 3H), 0.52-0.49 (m, 2H), 0.29-0.26 (m, 2H).

[0076] Example 4 Preparation of Compound 3004 [ka]

[0077] Step 1. Compound 2 Compound 1 (330 mg, 1.86 mmol, 1.0 eq) was dissolved in anhydrous THF (10 mL), followed by Boc2O (406 mg, 1.86 mmol, 1.0 eq) and NaOH (223 mg, 5.59 mmol, 3.0 eq), and the reaction mixture was heated to 75°C under nitrogen gas protection and stirred for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with water, 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 2 (330 mg, 64%) as a white solid. LCMS: [Mt-Bu+H] + = 222.1

[0078] Step 2. Compound 4 Compound 2 (250 mg, 0.90 mmol, 1.0 eq) was dissolved in acetone (5 mL), 1,3-dibromopropane (637 mg, 3.16 mmol, 3.5 eq) and potassium carbonate (1.0 g, 7.21 mmol, 8.0 eq) were added, and the reaction mixture was heated to 75° C. under nitrogen gas protection and stirred for 1 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with ethyl acetate (50 mL) and water (50 mL), and the separated aqueous phase was extracted with ethyl acetate (3× 50 mL) and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the residue after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate=6 / 1) to obtain compound 4 (250 mg, 70%) as a yellow oil. LCMS: [Mt-Bu+H] + = 342.0

[0079] Step 3. Compound 5 Compound 4 (300 mg, 0.75 mmol, 1.0 eq) was dissolved in anhydrous THF (20 mL), NaH (60%, 180 mg, 4.52 mmol, 6.0 eq) was added, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was poured into ice water to quench and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1) to give compound 5 (160 mg, 66%). LCMS: [Mt-Bu+H] + = 262.0

[0080] Step 4. Compound 6 Compound 5 (160 mg, 0.50 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was adjusted to pH 7-8 with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (3 x 50 mL), and the combined organic phase was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 6 (80 mg, 73%) as a white solid. LCMS: [M+H] + = 218.1

[0081] Step 5. Compound 3004 Compound 6 (50 mg, 0.23 mmol, 1.0 eq) was dissolved in toluene (10 mL), followed by compound 7 (75 mg, 0.25 mmol, 1.1 eq), t-BuoK (77 mg, 0.69 mmol, 3.0 eq), Xantphos (26 mg, 0.04 mmol, 0.2 eq) and Pd2(dba)3 (21 mg, 0.02 mmol, 0.1 eq), and the mixture was heated to 99°C under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (10 mL), washed with water and 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 obtain compound 3004 (15.2 mg, 15%), which was a white solid. LCMS: [M+H] + = 433.2

[0082] 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 7.24-7.21 (m, 2H), 7.11-7.09 (m, 1H), 6.76 (s, 2H), 4.17-4.14 (m, 2H), 3.91-3.88 (m, 2H), 2.19 (s, 2H), 2.07 (s, 6H), 2.00-1.97 (m, 2H), 1.14 (s, 3H), 0.54-0.53 (m, 2H), 0.33-0.30 (m, 2H).

[0083] Example 5 Preparation of Compound 3005 [ka] Step 1. Compound 3005 Compound 1 (120 mg, 0.76 mmol, 1.0 eq) was dissolved in toluene (3 mL), followed by compound 2 (271 mg, 0.92 mmol, 1.2 eq), potassium t-butoxide (257 mg, 2.29 mmol, 3.0 eq), Dave-Phos (60 mg, 0.15 mmol, 0.2 eq) and Pd2(dba)3 (70 mg, 0.076 mmol, 0.1 eq), and the mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the resulting residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give compound 3005 (41.3 mg, 15%). LCMS: [M+H] + = 373.2

[0084] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 6.70 (s, 2H), 6.52 (d, J = 2.4 Hz, 1H), 4.10 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.76 (s, 2H), 2.17 (s, 2H), 2.09 (s, 6H), 1.14 (s, 3H), 0.55 - 0.52 (m, 2H), 0.32 - 0.29 (m, 2H).

[0085] Example 6 Preparation of Compound 3006 [ka] Step 1. Compound 3006 Compound 1 (74 mg, 0.6082 mmol, 1.2 eq) was dissolved in toluene (20 mL), followed by compound 2 (150 mg, 0.5068 mmol, 1.0 eq), Pd2(dba)3 (46 mg, 0.05068 mmol, 0.1 eq), Dave-phos (40 mg, 0.1014 mmol, 0.2 eq) and t-BuOK (170 mg, 1.5204 mmol, 3.0 eq), and the mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3006 (96 mg, 56%). LCMS: [M+H] + = 338.2

[0086] 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 6.72 (s, 2H), 6.65 - 6.64 (m, 1H), 6.01 - 6.00 (m, 1H), 5.84 - 5.82 (m, 1H), 4.32 (s, 2H), 4.03 - 4.00 (m, 2H), 3.61 - 3.59 (m, 2H), 2.17 (s, 2H), 2.10 (s, 6H), 1.14 (s, 3H), 0.55 - 0.52 (m, 2H), 0.32 - 0.30 (m, 2H).

[0087] Example 7 Preparation of Compound 3007 [ka] Step 1. Compound 3007 Compound 1 (120 mg, 0.744 mmol, 1.0 eq) was dissolved in toluene (10 mL), followed by compound 2 (264 mg, 0.893 mmol, 1.2 eq), potassium t-butoxide (252 mg, 2.232 mmol, 3.0 eq), Dave-Phos (60 mg, 0.149 mmol, 0.2 eq) and Pd2(dba)3 (72 mg, 0.074 mmol, 0.1 eq), and the mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was diluted with water and extracted with ethyl acetate (20 mL × 3). 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 3007 (53.2 mg, 19%) as a white solid. LCMS: [M+H] + = 377.3

[0088] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.13 (s, 1H), 7.06 - 7.04 (m, 1H), 6.99-6.97 (m, 1H), 6.22 (s, 2H), 3.56 (s, 2H), 2.55 - 2.52 (m, 2H), 2.30 (s, 3H), 2.15 (s, 2H), 1.99 (s, 6H), 1.78-1.70 (m, 2H), 1.64 - 1.56 (m, 2H), 1.12 (s, 3H), 0.53-0.51 (m, 2H) ), 0.31 - 0.28 (m, 2H).

[0089] Example 8 Preparation of Compound 3008 [ka] Step 1. Compound 3008 Compound 1 (400 mg, 2.39 mmol, 1.0 eq) was dissolved in toluene (45 mL), and compound 2 (779 mg, 2.63 mmol, 1.1 eq), Pd2(dba)3 (218 mg, 0.239 mmol, 0.1 eq), Dave-phos (188 mg, 0.478 mmol, 0.2 eq) and t-BuOK (804 mg, 7.17 mmol, 3.0 eq) were added in that order, and the mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride solution in that order, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3008 (500 mg, 55%). LCMS: [M+H] + = 383.1

[0090] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.54-7.50 (m, 1H), 6.86-8.82 (m, 1H), 6.78-6.75 (m, 1H), 6.56 (s, 2H), 4.58 (s, 2H), 4.13 - 4.11 (m, 2H), 3.84 - 3.82 (m, 2H), 2.13 (s, 2H), 2.03 (s, 6H), 1.11 (s, 3H), 0.52-0.49 (m, 2H), 0.30-0.28 (m, 2H).

[0091] Example 9 Preparation of Compound 3009 [ka] Step 1. Compound 3009 Compound 1 (140 mg, 0.86 mmol, 1.2 eq) was dissolved in toluene, followed by compound 2 (211 mg, 0.72 mmol, 1.0 eq), XantPhos (165 mg, 0.286 mmol, 0.4 eq), potassium t-butoxide (240 mg, 2.14 mmol, 3.0 eq) and Pd2(dba)3 (82 mg, 0.14 mmol, 0.2 eq), and the mixture was heated to 120°C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 3009 (97.8 mg, 36%), which was a white solid. LCMS: [M+H] + = 379.3.

[0092] 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 6.96-6.94 (m, 1H), 6.83-6.79 (m, 2H), 6.49 (s, 2H), 3.99-3.96 (m, 2H), 3.79-3.76 (m, 2H), 2.25 (s, 3H), 2.16 (s, 2H), 2.02 (s, 6H), 1.99-1.96 (m, 2H), 1.13 (s, 3H), 0.52-0.51 (m, 2H), 0.31-0.29 (m, 2H).

[0093] Example 10 Preparation of Compound 3010 [ka]

[0094] Step 1. Compound 3 Compound 1 (2 g, 21 mmol), compound 2 (6.01 g, 25.2 mmol) and cesium carbonate (10.28 g, 31.5 mmol) were added in sequence to 30 mL of N,N-dimethylformamide, heated to 100 °C and stirred for 4 h. After cooling to room temperature, 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was separated, and the aqueous phase was subsequently extracted three times with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give compound 3 (6.2 g, 98% yield), which was a yellow liquid. LCMS: [M+Na] + = 275.1

[0095] Step 2. Compound 4 Compound 3 (2 g, 7.93 mmol) was added to 10 mL of hydrochloric acid-acetic acid solution and stirred for 3 hours at 25° C. 100 mL of ethyl acetate and 100 mL of water were added, and the aqueous phase was separated and concentrated to give compound 4 (1.2 g, crude product). LCMS: [M+H] + = 153.1

[0096] Step 3. Compound 5 Compound 4 (1.2 g, crude) and NaBH3CN (2.1 g, 33.6 mmol) were added to 20 mL of methanol and stirred at 0° C. for 2 h. The mixture was diluted with 20 mL of methanol, filtered, dried, and concentrated to give compound 5 (1.1 g, crude, yellow liquid). LCMS: [M+H] + = 137.2

[0097] Step 4. Compound 6 Compound 5 (1.05 g, crude), (Boc)2O (2.1 g, 9.6 mmol) and potassium carbonate (2.2 g, 15.9 mmol) were added to 20 mL of tetrahydrofuran and stirred at 25 °C for 1 h. 100 mL of ethyl acetate and 100 mL of water were added, the organic phase was separated, and the aqueous phase was subsequently extracted three times with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the residue after concentration was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give compound 6 (685 mg, 41% yield), a yellow liquid. LCMS: [M+H] + = 237.2

[0098] Step 5. Compound 7 Compound 6 (300 mg, 1.271 mmol) was added to 6 mL of hydrochloric acid-acetic acid solution and stirred for 3 hours at 25° C. The reaction solution was concentrated to obtain compound 7 (252 mg, yellow liquid). LCMS: [M+H] + = 137.2

[0099] Step 6. Compound 3010 Compound 7 (252 mg, 1.47 mmol), compound 8 (250 mg, 0.848 mmol), Pd2(dba)3 (78 mg, 0.085 mmol), Dave-phos (68 mg, 0.17 mmol) and potassium t-butoxide (284 mg, 2.5 mmol) were added to 10 mL of toluene, heated to 80° C. under nitrogen gas protection and stirred for 16 hours. After cooling to room temperature, the reaction solution was concentrated and the residue was purified by Pre-HPLC to obtain compound 3010 (115 mg, 23% yield). LCMS: [M+H] + = 352.2

[0100] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 6.56 - 6.54 (m, 1H), 6.52 (s, 2H), 6.02 (dd, J = 3.2, 1.6 Hz, 1H), 5.73 - 5.70 (m, 1H), 4.48 (s, 2H), 4.14 - 4.07 (m, 2H), 3.73 (s, 2H), 2.13 (s, 2H), 2.02 (s, 6H), 1.73 (d, J = 4.4 Hz, 2H), 1.11 (s, 3H), 0.51 (q, J = 4.4 Hz, 2H), 0.28 (q, J = 4.0 Hz, 2H).

[0101] Example 11 Preparation of Compound 3011 [ka] Step 1. Compound 3 Compound 1 (4.0 g, 23.8 mmol) and compound 2 (2.8 g, 24 mmol) were added to 40 mL of a mixed solvent (N,N-dimethylformamide / tetrahydrofuran = 1 / 1) and cooled to 0 ° C., then NaH (60%, 2.9 g, 120 mmol) was added, and the mixture was heated to 25 ° C. and stirred for 16 hours. It was diluted with 200 mL of ice water and extracted three times with ethyl acetate, and the combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 3 (1.2 g, 30% yield). LCMS: [M+H] + = 180.1

[0102] Step 2. Compound 4 Compound 3 (1.2 g, 6.9 mmol) was dissolved in 20 mL of tetrahydrofuran, and a solution of LiAlH4 in tetrahydrofuran (1M, 10.5 mL, 10.5 mmol) was added, and the mixture was heated to 70°C and stirred for 18 hours. After cooling to room temperature, sodium sulfate decahydrate was added to quench the reaction, and the filtrate obtained by filtration was concentrated to obtain compound 4 (1.1 g, 95% yield), which was a yellow oil. LCMS: [M+H] + = 166.1

[0103] Step 3. Compound 3011 Compound 4 (308 mg, 1.87 mmol), compound 5 (500 mg, 1.7 mmol) and potassium t-butoxide (570 mg, 5.1 mmol) were added to 10 mL of toluene, followed by Dave-phos (134 mg, 0.34 mmol) and pd2(dba)3 (156 mg, 0.17 mmol) in that order, and the mixture was heated to 80° C. under nitrogen gas protection and stirred for 16 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3 / 1) to obtain compound 3011 (475 mg, 58% yield). LCMS: [M+H] += 381.1

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.60 (dd, J = 7.6, 1.2 Hz, 1H), 7.45 (dd, J = 7.6, 1.2 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.12 (td, J = 7.6, 1.2 Hz, 1H), 6.53 (s, 2H), 4.75 (s, 2H), 4.06 - 3.94 (m, 2H), 2.95 - 2.88 (m, 2H), 2.12 (s, 2H), 2.02 (s, 6H), 1.11 (s, 3H), 0.50 (d, J = 1.2 Hz, 2H), 0.28 (d, J = 1.6 Hz, 2H).

[0105] 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 2 The 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.

[0106] 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.

[0107] 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.

[0108] 1.2 Preparation of solutions Loading buffer: 10 mL / plate, preparation method is as follows: [Table 1]

[0109] Test Buffer: 100 mL / plate, method of preparation is as follows: [Table 2]

[0110] Stimulation buffer: 5 mL / plate, preparation method is as follows: [Table 3] The above buffers were from a commercially available kit called FluxOR potassium ion channel assay.

[0111] 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.

[0112] 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

[0113] 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.

[0114] 2. Measurement results: For details, see Table 1. Here, EC 50 The smaller the value, the higher the activity of the corresponding compound. [Table 4]

[0115] References for the above test methods: Zhaobing Gao et al. Journal of Biological Chemistry. 2010, 285(36): 28322-28332.

[0116] 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, A ring: None, 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. R １ , R ２ , R ３ , R ４ 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 and r are independently selected from the group consisting of 0, 1 and 2. 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 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. W １ , W ２ is independently selected from the group consisting of none, C, and N; and W １ and W. ２ and nothing at the same time. 【Chemistry 2】 is selected from the group consisting of none, a single bond, and a double bond. B 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 ３－１０ It is selected from the group consisting of a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S, and a 3- to 10-membered bridged heterocyclic group containing 1-3 heteroatoms selected from N, O, or S. V is C, CR ８ , N. R ８ is hydrogen, 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 -(CH ２ ) ｐ -, -C(CH ３ ) ２ --, 【Chemistry 3】 -NH-,-(CH ２ ) ｐ -NH-,-CF ２ -NH-,-C(CH ３ ) ２ -NH-、 【Chemistry 4】 is selected from the group consisting of: p is selected from the group consisting of 0, 1 and 2. X and Y are independently N or CR ９ is selected from the group consisting of: R ９ is a hydrogen atom, a halogen atom, a cyano group, an amino group, a hydroxyl group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ The alkoxy group is selected from the group consisting of alkoxy groups. The above amino group, alkyl group, cycloalkyl group and alkoxy group are optionally halogenated, 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 ５ , R ６ are independently hydrogen, halogen, a cyano group, an amino group, a hydroxyl group, １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ The alkoxy group is selected from the group consisting of alkoxy groups. The amino group, alkyl group, cycloalkyl group, and alkoxy group may be optionally halogenated, 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 １０ ) is selected from the group consisting of Z is O, -(CH ２ ) ｑ -, -N(R １１ )- is selected from the group consisting of q is selected from the group consisting of 0, 1, and 2. R １０ , R １１ are independently hydrogen, C １－６ Alkyl group, C ３－６ It is selected from the group consisting of cycloalkyl 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. R ７ 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. A ring: None, C ６－１０ aryl groups, and 4-7 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, or S; R １ , R ２ , R ３ , R ４ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; n and r are selected from the group consisting of 0, 1, and 2; W １ , W ２ are independently selected from the group consisting of none, C, and N, and W １ , W ２ is not simultaneously N, B 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 ３－１０ selected from the group consisting of a cyclic hydrocarbon group, a 3- to 10-membered heterocyclic group containing 1-3 heteroatoms selected from N, O, or S, and a 3- to 10-membered bridged heterocyclic group containing 1-3 heteroatoms selected from N, O, or S; V is N, V' is -(CH ２ ) ｐ -, -NH-, -CH ２ -NH-, p is selected from the group consisting of 0 and 1; X and Y are CH; R ５ , R ６ are independently halogen, C １－６ alkyl groups, said alkyl groups being optionally substituted with one or more substituents selected from the group consisting of halogens; U is O, Z is CH ２ in, R ７ is C ３－６ It is selected from the group consisting of a cycloalkyl group and a C5-8 bridged ring group. The cycloalkyl group and the bridged ring group are optionally selected from hydrogen, halogen, cyano, C １－６ Alkyl 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 haloalkyl groups.

3. In formula I 【Chemistry 5】 Below: 【Chemistry 6】 Selected from the group consisting of: R １ , R ２ , R ３ , R ４ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; 2. The compound according to claim 1, wherein n and r are independently selected from the group consisting of 0, 1 and 2, or a pharma- ceutically acceptable salt thereof.

4. R ７ is C ３－６ Cycloalkyl group, C ５－８ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of bridged ring groups.

5. In formula I 【Chemistry 7】 Below: 【Chemistry 8】 Selected from the group consisting of: R １ , R ２ , R ３ , R ４ are independently substituted or unsubstituted hydrogen, halogen, C １－６ Alkyl group, C １－６ an alkoxy group, the substitution being substituted with one or more substituents selected from the group consisting of halogen; n and r are independently selected from the group consisting of 0, 1 and 2; V'は、-(CH ２ ) ｐ -、-NH-、-CH ２ -NH-、 【Chemistry 9】 Selected from the group consisting of: p is selected from the group consisting of 0 and 1; X and Y are independently selected from the group consisting of N and CH; R ５ , R ６ are independently hydrogen, halogen, amino group, C １－６ Alkyl group, C １－６ alkoxy groups; U is O, Z is CH ２ in, R ７ is C ３－６ Cycloalkyl group, C ５－８ The cycloalkyl group and the bridged ring group are selected from the group consisting of hydrogen, halogen, cyano group, C １－６ Alkyl 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 haloalkyl groups.

6. R １ , R ２ , R ３ , R ４ are independently substituted or unsubstituted hydrogen, halogen, C １－６ alkyl groups, n is selected from the group consisting of 0, 1 and 2; V' is -(CH ２ ) ｐ -, -NH-, -CH ２ -NH-, p is selected from the group consisting of 0 and 1; X and Y are CH; R ５ , R ６ are independently halogen, C １－６ alkyl groups, U is O, Z is CH ２ in, R ７ is C ３－６ cycloalkyl group, and C5-8 bridged ring group, wherein the cycloalkyl group and bridged ring group are optionally selected from the group consisting of hydrogen, halogen, cyano group, C １－６ Alkyl group, C １－６ 6. The compound according to claim 5 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 compounds are of the following group: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. 13. A pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and a therapeutically 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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