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, and in particular 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 characterized by low threshold activation, slow activation, and no inactivation. There are five Kv7 potassium channel family members (Kv7.1-Kv7.5). All Kv7 potassium channel members share a similar topology: four subunits form a functional channel, each containing six transmembrane segments (S1-S6). S4 is the voltage-sensing region, which plays an important role in sensing membrane potential changes and regulating conformational changes. S1-S6 constitute the main pore region and are the primary binding and action site for potassium channel openers. Kv7.1 potassium channels are non-neuronal, distributed in peripheral tissues, expressed in the heart, and mediate myocardial Iks. Mutations in Kv7.1 channels can lead to Long QT syndrome. Kv7.2-Kv7.5 potassium channels are the basis of neuronal M-currents, are widely distributed throughout the nervous system, and exhibit diverse 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), demonstrating the role of the M-current in regulating neuronal excitability. The Kv7.4 potassium channel is highly expressed in the outer hair cells of the cochlea and brainstem auditory nucleus, and its mutations can lead to hereditary hearing loss. The Kv7.5 potassium channel is highly expressed in skeletal muscle and the brain, and its mutations can lead to retinal pathology. Many disorders, such as epilepsy, anxiety, and hearing loss, share a common characteristic: high membrane excitability. The Kv7 potassium channel, which serves as the molecular basis for the M-current, opens upon sensing changes in membrane potential and suppresses membrane excitability by upregulating inhibitory potassium currents. Therefore, the Kv7 potassium channel is important for the treatment of pain and psychiatric disorders, which are characterized 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), and that its main mechanism of action is to act on KCNQ2 / 3 channels to modulate M-type potassium currents.

[0004] Retigabine (RTG), a Kv7 potassium channel opener, was first marketed in 2011 and is used as an adjunctive treatment for partial-onset epilepsy in adults. In addition to its antiepileptic properties, RTG can also be used to treat anxiety, neuralgia, and neurodegenerative disorders. RTG effectively reduces or prevents epileptic seizures in multiple epilepsy models. RTG exhibits effective antiepileptic effects against both tonic seizures induced by maximal electroshock (MES) and clonic seizures induced by PTZ. RTG can also prevent 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 stronger effects in this model than other models. RTG has a broad range of effects on all Kv7 potassium channel members and other channels, resulting in poor selectivity and potential adverse effects. As reported in a large body of literature, RTG is associated with a high incidence of central nervous system-related adverse events, including dizziness, fatigue, aphasia, speech disorders, and balance disorders. Other adverse reactions include kidney and urinary system disorders such as kidney stones and urinary retention, cardiac disorders such as sudden cardiac arrest and transient nonsustained ventricular tachycardia, and 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, 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 pharmaceutically acceptable salt thereof. [ka]

[0007] (however, A ring: None, C 6-10 aryl group, 4-7 membered heteroaryl group 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 group, saturated or unsaturated C 3-6 cyclic hydrocarbon groups, 3- to 10-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and 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' may be linked to an N atom to form a 3- to 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] The B ring is C 6-10 aryl group, 4-7 membered heteroaryl group 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 or S, and a 3-10 membered bridged heterocyclic group containing 1-3 heteroatoms selected from N, O or 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 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, hydroxy 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 group, amino group, hydroxy 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, 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 ) is selected from the group consisting of 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 may optionally be 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, C 3-6 Cycloalkenyl group, C 2-6 Alkenyl group, C 2-6 The alkyl group, cycloalkyl group, bridged ring group, adamantyl group, aryl group, heteroaryl group, heterocycloalkyl group, cycloalkenyl group, alkenyl group, and 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 groups, C 6-10 Aryl group, C 1-6 Haloalkyl group, C 1-6Alkoxy group, C 1-6 Alkylamino group, C 1-6 and 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 an aryl group, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; R1, R2, R3, and R4 are independently substituted or unsubstituted hydrogen, halogen, or C 1-6 Alkyl group, C 1-6 an alkoxy group, and the substitution is 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; The B ring is C 6-10 aryl group, 4-7 membered heteroaryl group 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 to 3 heteroatoms selected from N, O, or S, and a 3- to 10-membered bridged heterocyclic group containing 1 to 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, or C 1-6 Alkyl group, C 1-6 an alkoxy group, and the substitution is 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 The ring is selected from the group consisting of bridged ring groups. In another preferred embodiment, R7 is C 3-6 Cycloalkyl groups, 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 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, or C 1-6 Alkyl group, C 1-6 an alkoxy group, and the substitution is 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, or 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 group consisting of: [ka] [ka] [ka]

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

[0026] A third aspect of the present invention provides use of a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating a potassium ion channel-sensitive disease. 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-mentioned technical features of the present invention and the technical features specifically described below (e.g., 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 INVENTION

[0028] The present inventors have conducted extensive research and have, through structural optimization, unexpectedly prepared a compound of formula I having a novel structure and excellent potassium channel opening activity, pharmacokinetics (e.g., brain-to-plasma concentration ratio), in vivo efficacy, and safety. 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" refers to a straight or branched chain alkyl group having 1-6 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 a straight or branched chain alkenyl group 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 a straight or branched chain alkynyl group having 2-6 carbon atoms and containing one triple bond, including, but not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[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 include groups selected from the group consisting of cycloalkynyl groups. 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] Including, but not limited to, the following:

[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" or "aryl group" have the same meaning and are preferably used interchangeably with "C 6-10 The term "C" is an aryl group. 6-10 The term "aryl group" refers to an aromatic ring group containing no heteroatoms and having 6 to 10 carbon atoms, such as phenyl and naphthyl groups.

[0037] In the present invention, the terms "aromatic heterocycle" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "C3-C10 heteroaryl group" refers to 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, and the like. 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 containing no heteroatoms and having a total of 6-10 carbon atoms. In the present invention, the term "halo" means substituted with halogen. In the present invention, the term "deuterated" means to be substituted with deuterium.

[0039] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms in a specific group with a specific substituent. The specific substituents are the corresponding substituents described above or in each example. Unless otherwise specified, a substituted group may have one substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. As will be understood by those skilled in the art, the combinations of substituents contemplated by the present invention are stable or chemically feasible combinations. Examples of the substituents include, but are not limited to, halogen, hydroxy, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic, aryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, and C1-C10 sulfonyl.

[0040] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5, or 6. Other similar terms each independently have similar meanings. The term "plurality" refers to 2-6, for example, 2, 3, 4, 5, or 6. 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. The terms "selected from the group consisting of" and "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 pharmaceutically acceptable salt thereof: [ka] (wherein each group is as defined above).

[0042] In another preferred example, 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 "pharmaceutically acceptable salt" refers to a medicament-appropriate salt formed between a compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic and organic salts. One type of suitable salt is a salt formed between a compound of the present invention and an acid. 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, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0044] Another type of suitable salt is a salt formed by a compound of the present 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 pharmaceutically 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 shown 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 easily accomplished by one skilled in the art.

[0046] Drug Compositions and Methods of Application The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof in a safe and effective amount, and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing severe side effects. Typically, the pharmaceutical composition contains the compound of the present invention in an amount of 1-2000 mg / preparation, preferably 5-1000 mg / preparation. Preferably, the "preparation" 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 of sufficient purity and sufficiently low toxicity to be applicable to humans. "Compatible" refers to the ability of each component in the composition to be compatible with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. 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., tinctures, etc.), and the like. 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 an injection, capsule, tablet, pill, powder, or granule. The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, but typical modes of administration include, but are not limited to, oral administration, intratumoral administration, rectal administration, parenteral 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, alginate, gelatin, polyvinylpyrrolidone, sucrose, or gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant, such as agar, calcium carbonate, or the like. The pharmaceutical composition may be mixed with ingredients such as calcium, potato starch, tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retardants such as paraffin, (f) absorption promoters such as ammonium compounds, (g) wetting agents such as cetanol and 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 substance or compound may be delayed in a certain part of the digestive tract. Examples of encapsulating materials that can be used include polymeric substances and wax-based materials. If necessary, the active compound may also be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0051] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent 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, and sesame oil, or mixtures of these substances.

[0052] Besides these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfumes. In addition to the active compound, suspensions may contain a suspending agent such as, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol or sorbitan esters, microcrystalline cellulose, aluminum methoxy or agar, or mixtures of these substances.

[0053] Compositions for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions and 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, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants, as required.

[0054] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. The treatment methods of the present invention may be administered alone or in combination with other treatment modalities or therapeutic agents.

[0055] When using pharmaceutical compositions, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, and the dosage is a pharmacologically effective dosage, for example, 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 take into account factors such as the mode of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[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 potassium channel activity.

[0057] The present invention will be further described below with reference to specific examples. These examples are used only to illustrate the present invention and should not be construed as limiting the scope of the present invention. Experimental methods for which specific conditions are not specified in the following examples generally follow conventional conditions, such as those described in Sambrook et al., "Molecular Cloning: A Laboratory Manual" (New York: Cold Spring Harbor Laboratory Press, 1989), or manufacturer recommendations. 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. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only. Unless otherwise specified, all experimental materials and reagents used in the following examples are commercially available products.

[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 tert-butoxide (142 mg, 1.26 mmol, 3.0 eq), Dave-Phos (17 mg, 0.042 mmol, 0.1 eq), and Pd(dba) were added in that order. 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 give 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), followed by compound 2 (6.65 g, 20.0 mmol, 1.0 eq) and Pd(PPh3)4 (700 mg, 0.6 mmol, 0.03 eq). The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), 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 give compound 3 (3.5 g, 87%) as 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) and cooled to 0 °C. 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 mixture was stirred at 25 °C under nitrogen gas protection for 1 hour, diluted with ethyl acetate (50 mL), washed with saturated brine, 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 give compound 5 (1.5 g, 79%) as 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 mixture was stirred at 25 °C for 16 h under nitrogen gas protection, then diluted with ethyl acetate (50 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 6 (900 mg, 67%) as 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 mixture was stirred overnight at 25° C. under a hydrogen gas atmosphere at 1 atmosphere 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 mixture 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 added with compound 9 (139 mg, 0.47 mmol, 1.0 eq), potassium tert-butoxide (158 mg, 1.41 mmol, 3.0 eq), X-Phos (45 mg, 0.094 mmol, 0.2 eq), and Pd(dba) (43 mg, 0.047 mmol, 0.1 eq). The mixture was heated to 99 °C and stirred for 16 h. After cooling to 25 °C, the reaction mixture was filtered and concentrated. The 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 mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted with ethyl acetate and filtered. The filtrate was washed with saturated brine, 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), concentrated hydrochloric acid (12 M, 3 mL) and palladium hydroxide (0.4 g) were added, and the resulting reaction mixture was reacted at room temperature for 16 hours under a 0.4 MPa hydrogen gas atmosphere. The pH of the reaction mixture was adjusted to 8 with saturated aqueous sodium bicarbonate, filtered, and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate, washed with saturated sodium chloride, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 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) and 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, 0.785 mmol, 1.5 eq) were added, followed by heating to 80 °C and stirring for 16 h. The reaction mixture 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 give 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. 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 mixture was diluted with tetrahydrofuran (200 mL), and sodium sulfate decahydrate (4.0 g) was added and stirred for 2 hours. After filtration, the filtrate was concentrated to give 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 then compound 7 (221 mg, 0.74 mmol, 1.0 eq), Pd(dba) (68 mg, 0.07 mmol, 0.1 eq), Davephos (59 mg, 0.15 mmol, 0.2 eq), and potassium tert-butoxide (251 mg, 2.24 mmol, 3.0 eq) were added. The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give 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 BocO (406 mg, 1.86 mmol, 1.0 eq) and NaOH (223 mg, 5.59 mmol, 3.0 eq). The reaction mixture was heated to 75 °C under nitrogen gas protection and stirred for 1 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with water and 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 give 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 and diluted with ethyl acetate (50 mL) and water (50 mL). The separated aqueous phase was extracted with ethyl acetate (3 × 50 mL), and the organic phases were combined. The resulting organic phase was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give 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), and NaH (60%, 180 mg, 4.52 mmol, 6.0 eq) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched by pouring it into ice water and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. 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 and then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 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) and then 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 Pd(dba) (21 mg, 0.02 mmol, 0.1 eq) were added. The mixture was heated to 99 °C under nitrogen gas protection and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (10 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give compound 3004 (15.2 mg, 15%) as 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) and then compound 2 (271 mg, 0.92 mmol, 1.2 eq), potassium tert-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) were added. The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated, and the 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) and then compound 2 (150 mg, 0.5068 mmol, 1.0 eq), Pd2(dba)3 (46 mg, 0.05068 mmol, 0.1 eq), Dove-phos (40 mg, 0.1014 mmol, 0.2 eq), and t-BuOK (170 mg, 1.5204 mmol, 3.0 eq) were added. The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 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) and then compound 2 (264 mg, 0.893 mmol, 1.2 eq), potassium tert-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) were added. The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture 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, and then concentrated. 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 then compound 2 (779 mg, 2.63 mmol, 1.1 eq), Pd2(dba)3 (218 mg, 0.239 mmol, 0.1 eq), Dove-phos (188 mg, 0.478 mmol, 0.2 eq), and t-BuOK (804 mg, 7.17 mmol, 3.0 eq) were added. The mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 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 and then compound 2 (211 mg, 0.72 mmol, 1.0 eq), XantPhos (165 mg, 0.286 mmol, 0.4 eq), potassium tert-butoxide (240 mg, 2.14 mmol, 3.0 eq), and Pd2(dba)3 (82 mg, 0.14 mmol, 0.2 eq) were added. The mixture was heated to 120 °C and stirred for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 3009 (97.8 mg, 36%) as 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 sequentially 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), as 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 a 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 NaBHCN (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)O (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, and the organic phase was separated. 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. 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 a 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), Pd(dba) (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 and heated to 80 °C under nitrogen gas protection and stirred for 16 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by pre-HPLC to give 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. NaH (60%, 2.9 g, 120 mmol) was added, the mixture was heated to 25 °C, and stirred for 16 h. The mixture was diluted with 200 mL of ice water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 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 LiAlH in tetrahydrofuran (1 M, 10.5 mL, 10.5 mmol) was added. 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. The filtrate obtained after filtration was concentrated to give compound 4 (1.1 g, 95% yield) as 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 Dove-phos (134 mg, 0.34 mmol) and PD2(dba)3 (156 mg, 0.17 mmol). The mixture was heated to 80 °C under nitrogen gas protection and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 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 When the cell density reached 60-80%, the culture medium was discarded, the cells were washed once with 7 mL of phosphate buffered saline (PBS), and then digested with 3 mL of 0.25% trypsin. After digestion was complete, the cells were neutralized with 7 mL of culture medium (90% DMEM / F12 + 10% FBS + 500 μg / mL G418) and centrifuged at 800 rpm for 3 minutes. The supernatant was aspirated, and the cells were resuspended in 5 mL of culture medium and counted.

[0106] Cell plating: Cell count results showed a density of 3 x 10 4 The cells were adjusted to a density of 10 cells / well, left to stand at room temperature for 30 minutes, and then cultured overnight in a CO 2 incubator at 37°C, and further cultured for 16-18 hours until the cell density reached approximately 80%. Incubation of fluorescent dye: The cell culture medium was discarded, and 80 μL / well of loading buffer was added, followed by incubation at room temperature for 60 minutes in the dark.

[0107] Compound incubation: The loading buffer was discarded, and the prepared compound solution was added at 80 μL / well, followed by incubation 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 per second. After recording a 10-second baseline, 20 μL / well of stimulation buffer was added and recording continued for another 180 seconds.

[0108] 1.2 Preparation of solutions Preparation method: 10 mL / plate. [Table 1]

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

[0110] Stimulation buffer: 5 mL / plate, prepared as follows: [Table 3] The 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, and 10 μL of the 20 mM compound stock solution was added to 20 μL of DMSO solution, followed by a 3-fold serial dilution to give eight intermediate concentrations. Each intermediate concentration of compound was then added to the test buffer, followed by a 200-fold dilution to give the required final test concentration, and 80 μL was then added to 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 0.5% or less, and this concentration of DMSO 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 over 180 seconds were statistically analyzed 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℃ Reagent: FluxOR™ Detection Kit (Invitrogen, Cat #F0017) The experimental data in the report must meet the criterion of Z' Factor > 0.5.

[0114] 2. Measurement results: For details, see Table 1. 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 individually incorporated by reference. After reading the above content of the present invention, it should be understood that those skilled in the art can make various changes and modifications to the present invention, and that equivalents thereof are within the scope of the claims of the present invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (However, in Formula I 【Chemistry 2】 teeth, 【Transformation 3】 is selected from the group consisting of R １ , R 2 are independently selected from the group consisting of substituted or unsubstituted hydrogen, deuterium, halogen, and C1 alkyl group, and the substitution means substitution with one or more substituents selected from the group consisting of halogen. n and r are independently selected from the group consisting of 0 and 1. 【Chemistry 4】 is selected from the group consisting of a single bond and a double bond. V' is -(CH ２ ) ｐ - is. p is 0. X and Y are independently CR ９ is. R ９ is hydrogen. R ５ , R ６ are independently １ It is an alkyl group. U is O. Z is -(CH ２ ) ｑ - is. q is 1. R ７ is a C3 cycloalkyl group, said cycloalkyl group being substituted with one or more C1 alkyl groups.

2. R1 and R2 are independently selected from the group consisting of substituted or unsubstituted hydrogen, halogen, and C1 alkyl group, and the substitution means substitution with one or more substituents selected from the group consisting of halogen, n and r are 1; V' is -(CH ２ ) ｐ - and p is 0, X and Y are CH; R ５ , R ６ are independently a C 1-6 alkyl group; U is O, Z is CH ２ in, R ７ is C ３－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is substituted with one or more C 1-6 alkyl groups.

3. In Formula I 【Transformation 5】 Below: 【Transformation 6】 selected from the group consisting of R １ R 2 is independently selected from the group consisting of substituted or unsubstituted hydrogen and halogen, and the substitution means substitution with one or more substituents selected from the group consisting of halogen; n and r are independently 1; V' is -(CH ２ ) ｐ - and p is 0, X and Y are CH; R ５ , R ６ are independently a C1 alkyl group; U is O, Z is CH ２ in, R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is a C3 cycloalkyl group, and the cycloalkyl group is substituted with one or more C1 alkyl groups.

4. R １ , R 2 is independently selected from the group consisting of hydrogen, C 1 alkyl groups, which may be substituted or unsubstituted; n is 1, V' is -(CH ２ ) ｐ - and p is 0, X and Y are CH; R ５ , R ６ are independently a C1 alkyl group; U is O, Z is CH ２ in, R ７ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: is a C3 cycloalkyl group, and the cycloalkyl group is substituted with one or more C1 alkyl groups.

5. The compound is selected from the group: 【Transformation 7】 The compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

6. 10. The pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of one or more compounds according to claim 1 or 5, or pharmaceutically acceptable salts thereof.

7. 10. Use of the compound or its pharmaceutically acceptable salt according to claim 1 or 5, characterized in that it is for the manufacture of a drug for preventing and / or treating a disease sensitive to potassium ion channels.

8. The use according to claim 7, characterized in that the potassium ion channel-sensitive disease is a central nervous system disease.

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