WO2023143388A1 - 作为钾通道调节剂的酰胺类化合物及其制备和应用 - Google Patents

作为钾通道调节剂的酰胺类化合物及其制备和应用 Download PDF

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WO2023143388A1
WO2023143388A1 PCT/CN2023/073191 CN2023073191W WO2023143388A1 WO 2023143388 A1 WO2023143388 A1 WO 2023143388A1 CN 2023073191 W CN2023073191 W CN 2023073191W WO 2023143388 A1 WO2023143388 A1 WO 2023143388A1
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alkyl
cycloalkyl
halogen
compound
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French (fr)
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梁波
刘刚
江兆建
黄孟炜
陈焕明
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上海挚盟医药科技有限公司
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/08—Bridged systems

Definitions

  • the invention relates to the field of biomedicine, in particular to amide compounds as potassium channel modulators and their preparation and application.
  • Kv7 potassium channel is a kind of voltage-dependent potassium ion channel, which has the characteristics of low threshold activation, slow activation and non-inactivation.
  • the Kv7 potassium channel has five family members (Kv7.1-Kv7.5), and all Kv7 potassium channel members have a similar topology, that is, a functional channel consists of four subunits, each subunit contains six Transmembrane segment (S1-S6).
  • S4 is the voltage sensing region, which plays an important role in sensing membrane potential changes and controlling conformational changes
  • SS-S6 is the main component of the channel pore region, and is the main combination and action region of potassium channel openers.
  • KV7.1 potassium channel is a non-neuronal pathway distributed in peripheral tissues and expressed in the heart to mediate myocardial Iks, mutations of which 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.
  • Kv7.2 and Kv7.3 potassium channel gene mutations can lead to a variety of different epileptic phenotypes, such as benign familial neonatal convulsions (BFNC), which fully illustrate the role of M currents in regulating neuronal excitability role.
  • BFNC benign familial neonatal convulsions
  • the Kv7.4 potassium channel is highly expressed in the outer hair cells of the cochlea and auditory nuclei of the brainstem, and its mutation may cause hereditary deafness.
  • the Kv7.5 potassium channel is highly expressed in skeletal muscle and brain, and mutations in it may cause retinopathy.
  • Many diseases, such as epilepsy, anxiety, deafness, etc. have a common feature of high membrane excitability, and the Kv7 potassium channel, as the molecular basis of M current, can be opened by sensing the change of membrane potential to up-regulate the inhibitory potassium current, thereby controlling Membrane excitability makes the Kv7 potassium channel important in pain and psychiatric disorders represented by neural hyperexcitability.
  • Retigabine is a drug for the treatment of epilepsy, which has been approved for marketing in the UK, Germany, and Denmark. Studies have confirmed that the effect of retigabine is related to voltage-gated potassium ion channels (KCNQs), and the main mechanism of action is to regulate M-type potassium currents by acting on KCNQ2/3 channels.
  • KCNQs voltage-gated potassium ion channels
  • RTG Retigabine
  • MES maximal electroshock
  • NMDA N-methyl-D-aspartate
  • KA Kainic acid
  • Kindle model is suitable for the screening of various antiepileptic drugs, and RTG has a stronger effect on this model than other models.
  • RTG has the potential for adverse effects due to its broad action on all Kv7 potassium channel members and other channels, with poor selectivity.
  • a large number of literatures have reported that RTG has a high incidence of adverse events related to the central nervous system, which can lead to dizziness, fatigue, aphasia, speech disorders, balance disorders and other adverse reactions, including kidney stones, urinary retention and other kidney and urinary system diseases, cardiac arrest, etc.
  • Heart-related diseases such as cardiac arrest and transient non-sustained ventricular tachycardia can also cause retinal discoloration, blue/purple pigmentation of the skin, nails, etc.
  • the object of the present invention is to provide a compound represented by formula I, its preparation method and its use as a potassium channel modulator.
  • the first aspect of the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, in,
  • Ring A is selected from the group consisting of none, C 6-10 aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, saturated or unsaturated C 3-6 ring Hydrocarbyl, 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, halogen, cyano, -OH, -COOH, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, C 2-6 alkenyl, C 2-6 alkynyl, saturated or unsaturated C 3-6 ring Hydrocarbyl, 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5 -14 membered heteroaryl, C 6-12 aralkyl, -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 ',
  • n, r are independently selected from the following group: 0, 1, 2;
  • n is selected from the following group: 1, 2;
  • W 1 , W 2 are independently selected from the following group: None, C, N; and, W 1 and W 2 are not simultaneously None;
  • Ring B is selected from the group consisting of C 6-10 aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, saturated or unsaturated C 3-10 cycloalkyl, A 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, a 3-10 membered heterobridged ring group containing 1-3 heteroatoms selected from N, O or S;
  • V is selected from the group consisting of C, CR 8 , N;
  • R 8 is selected from the following group: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl; the above-mentioned alkyl and cycloalkyl are optionally selected One or more substituents from the following group are substituted: halogen, C 1-6 alkyl, C 3-6 cycloalkyl;
  • V' is selected from the group consisting of -(CH 2 ) p -, -C(CH 3 ) 2 -, -NH-, -(CH 2 ) p -NH-, -CF 2 -NH-, -C(CH 3 ) 2 -NH-,
  • p is selected from the group: 0, 1, 2;
  • X, Y are independently selected from the following group: N, CR 9 ;
  • R is selected from the group consisting of hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy; the above-mentioned amino, alkyl, cycloalkyl , Alkoxy is optionally substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl;
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, cyano, amino, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy; Base, cycloalkyl, alkoxy are optionally substituted by one or more substituents selected from the group: halogen, C 1-6 alkyl, C 3-6 cycloalkyl;
  • U is selected from the group consisting of O, S, N(R 10 );
  • Z is selected from the group consisting of O, -(CH 2 ) q -, -N(R 11 )-;
  • q is selected from the group: 0, 1, 2;
  • R 10 and R 11 are independently selected from the following group: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; the above-mentioned alkyl and cycloalkyl are optionally substituted by one or more selected from the following group Substitution: halogen, C 1-6 alkyl, C 3-6 cycloalkyl;
  • R 7 is selected from the following group: C 1-6 alkyl, C 3-6 cycloalkyl, C 5-8 bridged ring group, adamantyl, C 6-10 aryl, containing 1-3 selected from N, 3-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, 4-8 membered heterocycloalkyl, C 3-6 cycloalkenyl, C 2 -6 alkenyl, C 2-6 alkynyl, any of the above-mentioned alkyl, cycloalkyl, bridged ring, adamantyl, aryl, heteroaryl, heterocycloalkyl, cycloalkenyl, alkenyl, alkynyl Optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxyl, C 1-6 alkyl-CO-, C 1-6 alkyl, C 3- 6 cycloalkyl, C 6-10
  • Ring A is selected from the group consisting of none, C 6-10 aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; the substitution means selected Substituted by one or more substituents from the following group: halogen;
  • n and r are selected from the following group: 0, 1, 2;
  • W 1 and W 2 are independently selected from the following group: none, C, N, and W 1 and W 2 are not N at the same time;
  • Ring B is selected from the group consisting of C 6-10 aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, saturated or unsaturated C 3-10 cycloalkyl, A 3-10 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, a 3-10 membered heterobridged ring group containing 1-3 heteroatoms selected from N, O or S;
  • V is N
  • V' is selected from the group consisting of -(CH 2 ) p -, -NH-, -CH 2 -NH-;
  • p is selected from the group: 0, 1;
  • X and Y are CH;
  • R 5 and R 6 are independently selected from the following group: halogen, C 1-6 alkyl; the above-mentioned alkyl is optionally substituted by one or more substituents selected from the group: halogen;
  • Z is CH2 ;
  • R 7 is selected from the following group: C 3-6 cycloalkyl group, C 5-8 bridged ring group; the above-mentioned cycloalkyl group, bridged ring group is optionally substituted by one or more substituents selected from the group: hydrogen, Halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; the substitution means selected Substituted by one or more substituents from the following group: halogen;
  • n, r are independently selected from the group: 0, 1, 2.
  • R 7 is selected from the following group: C 3-6 cycloalkyl, C 5-8 bridged ring group.
  • R is selected from the following group: C 3-6 cycloalkyl, C 5-8 bridged ring group; the above-mentioned cycloalkyl, bridged ring group is selected from one or more substituents of the following group Substitution: hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy; the substitution means selected Substituted by one or more substituents from the following group: halogen;
  • n, r are independently selected from the following group: 0, 1, 2;
  • V' is selected from the group consisting of -(CH 2 ) p -, -NH-, -CH 2 -NH-,
  • p is selected from the group: 0, 1;
  • X, Y are independently selected from the following group: N, CH;
  • R 5 and R 6 are independently selected from the following group: hydrogen, halogen, amino, C 1-6 alkyl, C 1-6 alkoxy;
  • Z is CH2 ;
  • R 7 is selected from the following group: C 3-6 cycloalkyl group, C 5-8 bridged ring group; the above-mentioned cycloalkyl group, bridged ring group is optionally substituted by one or more substituents selected from the group: hydrogen, Halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 1 , R 2 , R 3 , R 4 are independently selected from the following groups of substituted or unsubstituted groups: hydrogen, halogen, C 1-6 alkyl;
  • n is selected from the group: 0, 1, 2;
  • V' is selected from the group consisting of -(CH 2 ) p -, -NH-, -CH 2 -NH-;
  • p is selected from the group: 0, 1;
  • X and Y are CH;
  • R 5 and R 6 are independently selected from the following group: halogen, C 1-6 alkyl;
  • Z is CH2 ;
  • R 7 is selected from the following group: C 3-6 cycloalkyl group, C 5-8 bridged ring group; the above-mentioned cycloalkyl group, bridged ring group is optionally substituted by one or more substituents selected from the group: hydrogen, Halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition, comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of one or more compounds described in the first aspect of the present invention or its pharmaceutical composition acceptable salt.
  • the third aspect of the present invention provides a use of the compound described in the first aspect of the present invention or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for preventing and/or treating diseases sensitive to potassium ion channels .
  • the diseases sensitive to potassium ion channels are central nervous system diseases.
  • the inventors After long-term and in-depth research, the inventors have unexpectedly prepared a kind of potassium channel opening activity, pharmacokinetics (such as brain blood ratio performance, etc.), in vivo efficacy and safety and novel structure through structural optimization.
  • the compound shown in the formula I On this basis, the inventors have completed the present invention.
  • halogen refers to F, Cl, Br or I.
  • C 1-6 alkyl refers to a linear or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, tert-butyl, neopentyl, tertyl, or similar groups.
  • C 2-6 alkenyl refers to a straight-chain or branched alkenyl group with 2-6 carbon atoms containing a double bond, non-limitingly including vinyl, propenyl, butene base, isobutenyl, pentenyl and hexenyl, etc.
  • C 2-6 alkynyl refers to a straight chain or branched chain alkynyl group with 2-6 carbon atoms containing a triple bond, including without limitation ethynyl, propynyl, butynyl, Alkynyl, isobutynyl, pentynyl and hexynyl, etc.
  • C 3-6 cycloalkyl includes groups selected from the group consisting of C 3-6 cycloalkyl, C 3-6 cycloalkenyl, and C 3-6 cycloalkynyl.
  • C 3-6 cycloalkyl refers to a cyclic alkyl group with 3-6 carbon atoms on the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, etc.
  • C 5-8 bridged ring group refers to a cyclic alkyl group with a bridge and 5-8 carbon atoms, including without limitation wait.
  • C 1-6 alkoxy refers to a straight-chain or branched alkoxy group with 1-6 carbon atoms, including without limitation methoxy, ethoxy, propoxy , Isopropoxy and Butoxy, etc. It is preferably C 1-4 alkoxy.
  • heterocyclic group is a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, including (but not limited to) the following groups:
  • aromatic ring or “aryl” has the same meaning, preferably “C 6-10 aryl”.
  • C 6-10 aryl refers to an aromatic ring group having 6-10 carbon atoms that does not contain heteroatoms in the ring, such as phenyl, naphthyl and the like.
  • heteroaryl has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
  • C3-C10 heteroaryl refers to an aromatic heterocyclic ring 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.
  • heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the parent
  • the rings joined together by the structures are heteroaryl rings.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • C 6-12 aralkyl refers to an aryl-substituted alkyl group having a total of 6-10 carbon atoms without heteroatoms.
  • halo refers to substitution by halogen.
  • deuterated refers to substitution by deuterium.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a substituted group may have a 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.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the substituents are for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning.
  • the term “plurality” refers to 2-6, such as 2, 3, 4, 5 or 6.
  • the present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, Wherein, each group is as defined above.
  • the compound is preferably the compound prepared in each embodiment.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • 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; formic acid, acetic acid, trifluoroacetic acid, propionic 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 and other organic acids; Amino acids such as amino acid, phenylalanine, aspartic acid, and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid
  • salts of the compounds of the present invention with bases such as alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g.
  • lower alkanolammonium salts and other pharmaceutically acceptable amine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • methylamine salts such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butyl amine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salt
  • the compounds of the present invention can be prepared by the methods shown in the following examples, and can optionally be prepared by combining various synthetic methods described in this description or known in the art. Such a combination can be obtained from this It is easy for those skilled in the art to which the invention pertains.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid, magnesium stearate
  • calcium sulfate
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • the composition can also contain adjuvants such as wetting agents, emulsifying agents and suspending agents. agents, sweeteners, flavorings and spices.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention 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 which may be required, if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 5-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention has the following main advantages:
  • the compound has better pharmacokinetic properties, such as better brain-to-blood ratio, half-life, exposure, metabolic stability and other properties;
  • the compound has better potassium ion channel opening activity, better potassium ion channel activation rate, better ion channel selectivity, better drug efficacy in vivo and better safety;
  • the compound is expected to be used in the treatment and/or prevention of diseases and conditions affected by the activity of potassium ion channels.
  • reaction solution was diluted with ethyl acetate (10 mL), washed with water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated, and the residue was passed through Pre-HPLC (0.1% formic acid/acetonitrile/water) Purification afforded compound 3004 (15.2 mg, 15%) as a white solid.
  • CHO-KCNQ2 cells were cultured in a 175cm 2 culture flask, and when the cell density grew to 60-80%, the culture medium was removed, washed once with 7mL PBS (Phosphate Buffered Saline, phosphate buffer saline), and then added 3mL 0.25 % Trypsin digestion. After the digestion is complete, add 7 mL of culture medium (90% DMEM/F12+10% FBS+500 ⁇ g/mL G418) to neutralize, centrifuge at 800 rpm for 3 minutes, suck off the supernatant, add 5 mL of culture medium to resuspend, and count the cells.
  • PBS Phosphate Buffered Saline, phosphate buffer saline
  • Cell plating Adjust the density to 3x10 cells/well according to the cell counting results. After standing at room temperature for 30 minutes, place it in a 37°C CO 2 incubator for overnight culture. After 16-18 hours, the cell density reaches about 80%.
  • Fluorescent dye incubation Discard the cell culture medium, add 80 ⁇ L/well of loading buffer, and incubate at room temperature for 60 minutes in the dark.
  • Compound incubation Discard the loading buffer, add 80 ⁇ L/well of the prepared compound solution, and incubate at room temperature for 20 minutes in the dark.
  • Fluorescence data collection use FDSS/ ⁇ CELL instrument for real-time fluorescence signal recording, excitation wavelength 480nm, emission wavelength 540nm, record once per second, start adding 20 ⁇ L/well stimulation buffer after recording the baseline for 10 seconds, and then continue recording for 180 seconds Finish.
  • Loading buffer 10mL/plate, prepared as follows:
  • Test buffer sample 100mL/plate
  • the preparation method is as follows:
  • Stimulation buffer 5mL/plate, prepared as follows:
  • the above buffer solution comes from a commercially available kit, and the name of the kit is FluxOR potassium ion channel assay.
  • test concentration 100 ⁇ M, followed by 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, 0.045 ⁇ M, a total of 8 concentrations. Each concentration was replicated in 3 wells.
  • the DMSO content in the final test concentration was not more than 0.5%, and this concentration of DMSO had no effect on the KCNQ2 potassium channel.
  • the experimental data was analyzed by Excel 2007 and GraphPad Prism 5.0 software, and the ratio of 180 seconds was used to calculate the agonistic effect.
  • the agonistic effect of the compound is calculated by the following formula:
  • FluxORTM detection kit (Invitrogen, Cat#F0017)

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Abstract

提供作为钾通道调节剂的酰胺类化合物及其制备和应用。所述化合物具有式I所示结构，其中各基团和取代基的定义如说明书中所述。

Description

作为钾通道调节剂的酰胺类化合物及其制备和应用 技术领域
本发明涉及生物医药领域，具体地涉及作为钾通道调节剂的酰胺类化合物及其制备和应用。
背景技术
Kv7钾通道是一类电压依赖性钾离子通道，具有低阈值激活、慢激活和非失活的特点。Kv7钾通道具有五个家族成员(Kv7.1-Kv7.5)，所有的Kv7钾通道成员具有相似的拓扑学结构，即由四个亚基组成一个功能性通道，每个亚基包含六个跨膜片段(S1-S6)。其中S4是电压感受区，在感受膜电位变化和控制构象改变等方面具有重要作用；SS-S6是通道孔区的主要组成部分，是钾通道开放剂的主要组合和作用区域。KV7.1钾通道是一种非神经元通路，分布于外周组织，在心脏中表达，以介导心肌Iks，其突变可导致Long Q-T综合征。Kv7.2-Kv7.5钾通道是神经元M电流的基础，广泛分布于神经系统中，具有多种生理活性。Kv7.2和Kv7.3钾通道基因突变可导致多种不同的癫痫表型，如良性家族性新生儿惊厥(Benign familial neonatal convulsions，BFNC)，这些充分说明了M电流在调节神经元兴奋性中的作用。Kv7.4钾通道高度表达于耳蜗和脑干听觉核的外毛细胞，其突变可能导致遗传性耳聋。Kv7.5钾通道在骨骼肌和脑中高度表达，其突变可能导致视网膜病变。许多疾病如癫痫、焦虑、耳聋等，它们的共同特征是膜高度兴奋性，而Kv7钾通道作为M电流的分子基础，可通过感受膜电位的变化而开放，使抑制性钾电流上调，从而控制膜兴奋性，使得Kv7钾通道在以神经高度兴奋性为代表的疼痛和精神疾病中具有重要意义。
瑞替加滨(Retigabine)是治疗癫痫的药物，目前已经在英国、德国、丹麦获准上市。研究证实，瑞替加滨的作用与电压门控型钾离子通道(KCNQs)有关，其中作用于KCNQ2/3通道调节M型钾电流是其主要的作用机制。
瑞替加滨(RTG)是在2011年上市的首个用于辅助治疗成人部分发作性癫痫的Kv7钾通道开放剂。除具有抗癫痫作用外，RTG还可用于治疗焦虑症、神经痛、神经退行性疾病等。RTG在多种癫痫模型中均能有效地减少或阻止癫痫发作。RTG对最大电休克(MES)模型导致的强直性发作和PTZ诱发的阵挛性发作 均表现出有效的抗癫痫作用。此外，RTG还可阻止N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)、青霉素、印防己毒素、海人酸(Kainic acid,KA)等所致的癫痫发作。点燃模型适用于多种抗癫痫药物的筛选，RTG对该模型的效果要强于其它模型。由于RTG对所有的Kv7钾通道成员和其它通道的广泛作用，选择性较差，使得它具有潜在的不良作用。大量文献报道了RTG与中枢神经系统相关的不良事件发生率较高，可导致头晕、疲劳、失语、言语障碍、平衡障碍等其它不良反应包括肾结石、尿潴留等肾脏和泌尿系统疾病，心脏骤停、短暂的非持续性室性心动过速等心脏相关疾病，还可导致视网膜变色、皮肤、指甲等蓝/紫色色素沉着等。
发明内容
本发明的目的在于提供一种式I所示化合物及其制备方法和其作为钾通道调节剂的用途。
本发明的第一方面，提供了一种式I所示的化合物或其药学上可接受的盐，

其中，
A环选自下组：无、C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基；
R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、氘、卤素、氰基、-OH、-COOH、硝基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-14元杂芳基、C6-12芳烷基、-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’，所述取代指被 选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、卤代C1-6烷基、卤代C3-6环烷基、卤代C1-6烷氧基、卤代C3-6环烷基氧基；
n、r独立地选自下组：0、1、2；
R1’、R2’独立地选自下组：氢、C1-6烷基、C3-6环烷基或R1’、R2’与其共同连接的N原子形成饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基；上述烷基、环烷基、杂环基任选地被选自下组的一个或多个取代基取代：＝O、卤素、C1-6烷基、C3-6环烷基；
m选自下组：1、2；
W1、W2独立地选自下组：无、C、N；并且，W1和W2不同时为无；
------选自下组：无、单键、双键；
B环选自下组：C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-10环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、含1-3个选自N、O或S的杂原子的3-10元杂桥环基；
V选自下组：C、CR8、N；
R8选自下组：氢、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基；上述烷基、环烷基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
V’选自下组：-(CH2)p-、-C(CH3)2-、-NH-、-(CH2)p-NH-、-CF2-NH-、-C(CH3)2-NH-、
p选自下组：0、1、2；
X、Y独立地选自下组：N、CR9；
R9选自下组：氢、卤素、氰基、氨基、羟基、C1-6烷基、C3-6环烷基、C1-6烷氧基；上述氨基、烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
R5、R6独立地选自下组：氢、卤素、氰基、氨基、羟基、C1-6烷基、C3-6环烷基、C1-6烷氧基；上述氨基、烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
U选自下组：O、S、N(R10)；
Z选自下组：O、-(CH2)q-、-N(R11)-；
q选自下组：0、1、2；
R10、R11独立地选自下组：氢、C1-6烷基、C3-6环烷基；上述烷基、环烷基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
R7选自下组：C1-6烷基、C3-6环烷基、C5-8桥环基、金刚烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的3-10元杂芳基、含1-3个选自N、O或S的杂原子的4-8元杂环烷基、C3-6环烯基、C2-6烯基、C2-6炔基，上述烷基、环烷基、桥环基、金刚烷基、芳基、杂芳基、杂环烷基、环烯基、烯基、炔基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、硝基、氨基、羟基、C1-6烷基-CO-、C1-6烷基、C3-6环烷基、C6-10芳基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基氨基、C1-6卤代烷氧基。
在另一优选例中，
A环选自下组：无、C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基；
R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
n、r选自下组：0、1、2；
W1、W2独立地选自下组：无、C、N，并且W1、W2不同时为N；
B环选自下组：C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-10环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、含1-3个选自N、O或S的杂原子的3-10元杂桥环基；
V为N；
V’选自下组：-(CH2)p-、-NH-、-CH2-NH-；
p选自下组：0、1；
X和Y为CH；
R5、R6独立地选自下组：卤素、C1-6烷基；上述烷基任选地被选自下组的一个或多个取代基取代：卤素；
U为O；
Z为CH2；
R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
在另一优选例中，
式I中的选自下组：
R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
n、r独立地选自下组：0、1、2。
在另一优选例中，
R7选自下组：C3-6环烷基、C5-8桥环基。
在另一优选例中，R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
在另一优选例中，
式I中的选自下组：
R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
n、r独立地选自下组：0、1、2；
V’选自下组：-(CH2)p-、-NH-、-CH2-NH-、
p选自下组：0、1；
X、Y独立地选自下组：N、CH；
R5、R6独立地选自下组：氢、卤素、氨基、C1-6烷基、C1-6烷氧基；
U为O；
Z为CH2；
R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
在另一优选例中，
R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基；
n选自下组：0、1、2；
V’选自下组：-(CH2)p-、-NH-、-CH2-NH-；
p选自下组：0、1；
X和Y为CH；
R5、R6独立地选自下组：卤素、C1-6烷基；
U为O；
Z为CH2；
R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
在另一优选例中，所述化合物选自下组：


本发明的第二方面，提供了一种药物组合物，包含一种或多种药学上可接受的载体和治疗有效量的一种或多种本发明第一方面所述的化合物或其药学上可接受的盐。
本发明的第三方面，提供了一种本发明第一方面所述的化合物或其药学上可接受的盐的用途，用于制备用于预防和/或治疗对钾离子通道敏感的疾病的药物。
在另一优选例中，所述对钾离子通道敏感的疾病为中枢神经系统疾病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，通过结构优化，意外地制备了一种具有优异的钾通道开放活性、药代动力学(如脑血比性能等)、体内药效和安全性且结构新颖的式I所示化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含 义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中，术语“C2-6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-6环烃基”包括选自下组的基团：C3-6环烷基、C3-6环烯基、C3-6环炔基。
在本发明中，术语“C3-6环烷基”是指在环上具有3-6个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基等。
在本发明中，术语“C5-8桥环基”是指具有桥且具有5-8个碳原子的环状烷基，非限制性地包括等。
在本发明中，术语“C1-6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-4烷氧基。
在本发明中，术语“杂环基”为含1、2或3个选自N、O、S的杂原子的4-8元杂环基，包括(但并不限于)如下基团：
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-10芳基”。术语“C6-10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体 结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“C6-12芳烷基”是指不含杂原子的共具有6-10个碳原子的芳基取代的烷基。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“氘代”是指被氘取代。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语1-6个指1、2、3、4、5或6个。其他类似术语各自独立地具有类似含义。术语“多个”指2-6个，如2、3、4、5或6个。
应理解，当某一基团同时存在于化合物的多个不同位置时，其在各位置的定义是相互独立的，可以相同也可以不同。亦即，术语“选自下组：”与术语“各独立地选自下组：”具有相同含义。
化合物
本发明提供了一种式I所示的化合物或其药学上可接受的盐，

其中，各基团如上文定义。
在另一优选例中，所述的化合物中，A环、B环、W1、W2、r、n、R1、R2、 R3、R4、R5、R6、R7、V、V’、X、Y、U和Z中任一个分别独立地为所述具体化合物中所对应的基团。
在另一优选例中，所述化合物优选为各实施例所制备的化合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
应理解，本发明化合物可采用如下实施例所示方法制备，还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物 (如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮 剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)所述化合物具有更优的药代动力学性能，如更优的脑血比、半衰期、暴露量、代谢稳定性等性能；
(2)所述化合物具有更好的钾离子通道开放活性、更优的钾离子通道激动率、更优的离子通道选择性、更优的体内药效以及更好的安全性；
(3)所述化合物有望用于治疗和/或预防受钾离子通道的活性影响的疾病和病症。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通 常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1化合物3001的制备
步骤一、化合物3001
将化合物1(100mg,0.420mmol,1.0eq)溶于甲苯(6mL)，依次加入化合物2(149mg,0.50mmol,1.2eq)、叔丁醇钾(142mg,1.26mmol,3.0eq)、Dave-Phos(17mg,0.042mmol,0.1eq)和Pd2(dba)3(19mg,0.021mmol,0.05eq)。反应在氮气氛围下升温至90℃并搅拌16小时。冷却至25℃后用乙酸乙酯(30mL)稀释反应液，然依次用水、饱和氯化钠溶液洗涤并用无水硫酸钠干燥，浓缩后得到的残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化，得到化合物3001(65.4mg,37％)。
LCMS:[M+H]+＝417.2
1H NMR(400MHz DMSO-d6)δ8.81(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＝5.8Hz,2H),2.99(t,J＝5.8Hz,2H),2.17(s,2H),2.11(s,6H),1.14(s,3H),0.53(q,J＝4.1Hz,2H),0.31(q,J＝4.1Hz,2H).
实施例2化合物3002的制备
步骤一、化合物3
将化合物1(5.0g,20.0mmol,1.0eq)溶于N,N-二甲基甲酰胺(50mL)，依次加入化合物2(6.65g,20.0mmol,1.0eq)和Pd(PPh3)4(700mg,0.6mmol,0.03eq)，升温至80℃并搅拌16小时。反应液用乙酸乙酯(50mL)稀释，然后用饱和氯化钠溶液洗涤并无水硫酸钠干燥，浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物3(3.5g，87％)为白色固体
LCMS:[M+H]+＝202.2
步骤二、化合物5
将化合物3(1.5g，7.46mmol，1.0eq)溶于四氢呋喃(20mL)后冷却至0℃，加入化合物4(810mg，8.95mmol，1.2eq)和三乙胺(2.3g，22.4mmol，3.0eq)。反应液在氮气保护下于25℃搅拌1小时后用乙酸乙酯(50mL)稀释，然后用饱和食盐水洗涤，有机相用无水硫酸钠干燥后浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化得到化合物5(1.5g，79％)为白色固体。
LCMS:[M+H]+＝256.1
步骤三、化合物6
将化合物5(1.5g，5.9mmol，1.0eq)溶于二氯甲烷(1mL)，氮气保护下加入Grubbs II catalyst(300mg,0.353mmol,0.06eq)。反应液在氮气保护下于25℃搅拌16小时后用乙酸乙酯(50mL)稀释，然后用饱和食盐水洗涤，有机相用无水硫酸钠干燥后浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物6(900mg，67％)为白色固体。
LCMS:[M+H]+＝228.1
步骤四、化合物7
将化合物6(900mg,3.961mmol,1.0eq)溶于乙醇(20mL)，加入Pd/C(10％,90mg)，反应液在1个大气压的氢气气氛下于25℃搅拌过夜。过滤后将滤液浓缩，得到化合物7(900mg，99％)为无色油状物。
LCMS:[M+H]+＝230.1
步骤五、化合物8
将化合物7(400mg,1.75mmol,1.0eq)溶于四氢呋喃(30mL)并冷却至0℃，加入硼烷四氢呋喃溶液(1M,35mL,35mmol,20.0eq)，升温至50℃并搅拌2小时。冷却至0℃后加入甲醇(30mL)并搅拌0.5小时，将反应液浓缩后得到化合物8(400mg,99％)为无色油状物。
LCMS:[M+H]+＝216.2
步骤六、化合物3002
将化合物8(100mg,0.47mmol,1.0eq)溶于甲苯(5mL)，加入化合物9(139mg,0.47mmol,1.0eq)、叔丁醇钾(158mg,1.41mmol,3.0eq)、X-Phos(45mg,0.094mmol,0.2eq)和Pd2(dba)3(43mg,0.047mmol,0.1eq)，升温至99℃并搅拌16小时。冷却至25℃后将反应液过滤并浓缩，得到的残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物3002(41.6mg,21％)。
LCMS:[M+H]+＝431.2
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.69(s,1H),7.53(d,J＝8.0Hz,1H),7.22(d,J＝8.0Hz,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).
实施例3化合物3003的制备
步骤一、化合物2
将化合物1(1.0g,5.26mmol,1.0eq)溶于乙醇(20mL)，加入盐酸羟胺(1.24g,17.9mmol,3.4eq)和醋酸钠(1.73g，21.04mmol,4.0eq)，反应液升温至80℃并搅拌16小时。将反应液冷却到室温后浓缩，得到的残留物用乙酸乙酯稀释后过滤，所得滤液用饱和食盐水洗涤并用无水硫酸钠干燥，浓缩后得到化合物2(1.2g,100％)。
LCMS:[M+H]+＝206.2
步骤二、化合物3
将化合物2(1.2g,5.26mmol)溶于乙醇(30mL)，加入浓盐酸(12M,3mL)和氢氧化钯(0.4g)，所得反应液在0.4MPa的氢气气氛下室温反应16小时。用饱和碳酸氢钠水溶液将反应液的pH值调节为8后过滤并将滤液浓缩，得到的 残留物用乙酸乙酯稀释，然后用饱和氯化钠溶液洗涤，有机相用无水硫酸钠干燥后浓缩，得到化合物3(1.0g,99％)。
LCMS:[M+H]+＝192.1
步骤三、化合物5
将化合物3(1.0g,5.23mmol，l.0eq)溶于乙腈(50mL)，依次加入碳酸钾(2.89g,20.93mmol，4.0eq)、四丁基溴化铵(0.169g，0.52mmol，0.1eq)和氯乙酰氯(0.886g，0.7.85mmol，1.5eq)，升温至80℃并搅拌16小时。将反应液冷却至室温后过滤，滤液浓缩后得到的残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物5(0.8g,66％)。
LCMS:[M+H]+＝232.1
步骤四、化合物6
将化合物5(800mg,3.46mmo，l.0eq)溶于四氢呋喃(30mL)，冷却至0℃后加入四氢铝锂的四氢呋喃溶液(1M,13mL，13mmol，3.7eq)，升温至25℃并搅拌2小时。用四氢呋喃(200mL)将反应液稀释，加入十水硫酸钠(4.0g)并搅拌2小时。过滤后将滤液浓缩得化合物6(600mg,80％)。
LCMS:[M+H]+＝218.1
步骤五、化合物3003
将化合物6(162mg,0.74mmol，1.0eq)溶于甲苯(20mL)，依次加入化合物7(221mg,0.74mmol，1.0eq)、Pd2(dba)3(68mg,0.07mmol,0.1eq)、Davephos(59mg,0.15mmol,0.2eq)和叔丁醇钾(251mg，2.24mmol,3.0eq)，升温至80℃并搅拌16小时。反应液冷却至室温后过滤，滤液浓缩后得到的残留物通过pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物3003(50.9mg,16％)。
LCMS:[M+H]+＝433.2
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.75(d,J＝7.6Hz,1H),7.37(d,J＝8.0Hz,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).
实施例4化合物3004的制备
步骤一、化合物2
将化合物1(330mg,1.86mmol,1.0eq)溶于无水THF(10mL),依次加入Boc2O(406mg,1.86mmol,1.0eq)和NaOH(223mg,5.59mmol,3.0eq)，反应液在氮气保护下升温至75℃并搅拌1小时。将反应液倒入冰水中,并用乙酸乙酯(3×50mL)萃取，有机相依次用水、饱和氯化钠溶液洗涤并用无水硫酸钠干燥，浓缩后得到的残留物用硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到化合物2(330mg,64％)为白色固体。
LCMS:[M-t-Bu+H]+＝222.1
步骤二、化合物4
将化合物2(250mg,0.90mmol,1.0eq)溶于丙酮(5mL),加入1,3-二溴丙烷(637mg,3.16mmol,3.5eq)和碳酸钾(1.0g,7.21mmol,8.0eq)，反应液在氮气保护下升温至75℃并搅拌1小时。冷却至室温后将反应液浓缩，加入乙酸乙酯(50mL)和水(50mL)稀释，分离出的水相用乙酸乙酯(3×50mL)萃取并合并有机相。依次用水、饱和氯化钠溶液洗涤得到的有机相并用无水硫酸钠干燥，浓缩后的残留物通过硅胶柱层析(石油醚/乙酸乙酯＝6/1)纯化，得到化合物4(250mg,70％)为黄色油状物。
LCMS:[M-t-Bu+H]+＝342.0
步骤三、化合物5
化合物4(300mg,0.75mmol,1.0eq)溶于无水THF(20mL),加入NaH(60％,180mg,4.52mmol,6.0eq)，反应液在25℃搅拌1小时。将上述反应液倒入冰水中淬灭并用乙酸乙酯(3×50mL)萃取，合并后的有机相依次用水、饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，残留物通过硅胶柱层析(石油醚/乙酸乙酯＝50/1)纯化得到化合物5(160mg,66％)。
LCMS:[M-t-Bu+H]+＝262.0
步骤四、化合物6
将化合物5(160mg,0.50mmol,1.0eq)溶解于二氯甲烷(5mL)，加入三氟乙酸(3mL)，于25℃搅拌1小时。将反应液用饱和碳酸钠水溶液调节PH值至7～8后用乙酸乙酯(3×50mL)萃取，合并后的有机相依次用水、饱和氯化钠水溶液洗涤，用无水硫酸钠干燥后浓缩，残留物通过硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物6(80mg,73％)为白色固体。
LCMS:[M+H]+＝218.1
步骤五、化合物3004
将化合物6(50mg,0.23mmol,1.0eq)溶于甲苯(10mL)，依次加入化合物7(75mg,0.25mmol 1.1eq)、t-BuoK(77mg,0.69mmol,3.0eq),、Xantphos(26mg,0.04mmol,0.2eq)和Pd2(dba)3(21mg,0.02mmol,0.1eq)，在氮气保护下升温至99℃并搅拌过夜。冷却至室温后反应液用乙酸乙酯(10mL)稀释，然后依次用水、饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，残留物通过Pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物3004(15.2mg,15％)为白色固体。
LCMS:[M+H]+＝433.2
1H NMR(400MHz,DMSO-d6)δ8.85(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).
实施例5化合物3005的制备
步骤一、化合物3005
将化合物1(120mg,0.76mmol,1.0eq)溶于甲苯(3mL)，依次加入化合物2(271mg,0.92mmol,1.2eq)、叔丁醇钾(257mg,2.29mmol,3.0eq)、Dave-Phos(60mg,0.15mmol,0.2eq)和Pd2(dba)3(70mg,0.076mmol,0.1eq)，升温至80℃并搅拌16小时。冷却至室温后将反应液过滤，滤液浓缩后得到的残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物3005(41.3mg,15％)。
LCMS:[M+H]+＝373.2
1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),6.70(s,2H),6.52(d,J＝2.4Hz,1H),4.10(s,2H),3.55(t,J＝5.6Hz,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).
实施例6化合物3006的制备
步骤一、化合物3006
将化合物1(74mg，0.6082mmol，1.2eq)溶于甲苯(20mL)，依次加入化合物2(150mg，0.5068mmol，1.0eq)、Pd2(dba)3(46mg，0.05068mmol，0.1eq)、Dave-phos(40mg，0.1014mmol，0.2eq)和t-BuOK(170mg，1.5204mmol，3.0eq)，升温至80℃搅拌16小时。冷却至室温后反应液用乙酸乙酯(50mL)稀释，依次用水、饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物3006(96mg，56％)。
LCMS:[M+H]+＝338.2
1H NMR(400MHz,DMSO-d6)δ8.82(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).
实施例7化合物3007的制备
步骤一、化合物3007
将化合物1(120mg,0.744mmol,1.0eq)溶于甲苯(10mL)，依次加入化合物2(264mg,0.893mmol,1.2eq)、叔丁醇钾(252mg,2.232mmol,3.0eq)、Dave-Phos(60mg,0.149mmol,0.2eq)和Pd2(dba)3(72mg,0.074mmol,0.1eq)，升温至80℃搅拌16小时。冷却至室温后将反应液过滤，滤液用水稀释，然后用乙酸乙酯(20mL x 3)萃取。合并后的有机相用饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，残留物用pre-HPLC(0.1％甲酸/乙腈/水)纯化得到化合物3007(53.2mg,19％)为白色固体。
LCMS:[M+H]+＝377.3
1H NMR(400MHz,DMSO-d6)δ8.68(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).
实施例8化合物3008的制备
步骤一、化合物3008
将化合物1(400mg,2.39mmol,1.0eq)溶于甲苯(45mL)，依次加入化合物2(779mg，2.63mmol，1.1eq)、Pd2(dba)3(218mg，0.239mmol，0.1eq)、Dave-phos(188mg，0.478mmol，0.2eq)和t-BuOK(804mg，7.17mmol，3.0eq)，升温至80℃搅拌16小时。冷却至室温后将反应液用乙酸乙酯(50mL)稀释，然后依次用水、饱和氯化钠溶液洗涤，用无水硫酸钠干燥后浓缩，残留物用硅胶柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物3008(500mg，55％)。
LCMS:[M+H]+＝383.1
1H NMR(400MHz,DMSO-d6)δ8.68(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).
实施例9化合物3009的制备
步骤一、化合物3009
将化合物1(140mg,0.86mmol,1.2eq)溶于甲苯，依次加入化合物2(211mg,0.72mmol,1.0eq)、XantPhos(165mg,0.286mmol,0.4eq)、叔丁醇钾(240mg,2.14mmol,3.0eq)和Pd2(dba)3(82mg,0.14mmol,0.2eq)，升温至120℃搅拌4小时。冷却至室温后将反应液倒入水中，用乙酸乙酯(50mL×2)萃取，合并后的机相用饱和氯化钠溶液洗涤并用无水硫酸钠干燥，浓缩后的残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化得到化合物3009(97.8mg,36％)为白色固体。
LCMS:[M+H]+＝379.3.
1H NMR(400MHz,DMSO-d6):δ8.74(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).
实施例10化合物3010的制备
步骤一、化合物3
将化合物1(2g,21mmol)、化合物2(6.01g，25.2mmol)和碳酸铯(10.28g，31.5mmol)依次加入30mL N,N-二甲基甲酰胺中，升温至100℃反应4小时。冷却至室温后加入100mL乙酸乙酯和100mL水，分离出有机相，水相用乙酸乙酯萃取三次。合并后的有机相用饱和食盐水洗涤并用无水硫酸钠干燥，浓缩后得到化合物3(6.2g，收率98％)为黄色液体。
LCMS:[M+Na]+＝275.1
步骤二、化合物4
将化合物3(2g,7.93mmol)加入到10mL的盐酸-乙醇溶液，在25℃搅拌3小时。加入100mL乙酸乙酯和100mL水，分离出水相，浓缩后得到化合物4(1.2g，粗品)。
LCMS:[M+H]+＝153.1
步骤三、化合物5
将化合物4(1.2g，粗品)和NaBH3CN(2.1g，33.6mmol)加入到20mL甲醇中，在0℃下搅拌2小时。加入20mL甲醇稀释，过滤并干燥，浓缩后得到化合物5(1.1g，粗品，黄色液体)。
LCMS:[M+H]+＝137.2
步骤四、化合物6
将化合物5(1.05g，粗品)、(Boc)2O(2.1g，9.6mmol)和碳酸钾(2.2g，15.9mmol)加入到20mL四氢呋喃中，在25℃搅拌1小时。加入100mL乙酸乙酯和100mL水，分离出有机相，水相用乙酸乙酯萃取三次。合并后的有机相用饱和氯化钠溶液洗涤并用无水硫酸钠干燥，浓缩后的残余物用柱层析纯化(石油醚:乙酸乙酯＝3:1)得到化合物6(685mg,收率41％)为黄色液体。
LCMS:[M+H]+＝237.2
步骤五、化合物7
将化合物6(300mg,1.271mmol)加入到6mL的盐酸-乙醇溶液，在25℃搅拌3小时。将以上反应液浓缩，得到化合物7(252mg，黄色液体)。
LCMS:[M+H]+＝137.2
步骤六、化合物3010
将化合物7(252mg,1.47mmol)、化合物8(250mg，0.848mmol)、Pd2(dba)3(78mg，0.085mmol)、Dave-phos(68mg，0.17mmol)和叔丁醇钾(284mg，2.5mmol)加入到10mL甲苯中，氮气保护下升温至80℃搅拌16小时。冷却至室温，将以上反应液浓缩，残余物用Pre-HPLC纯化得到化合物3010(115mg，收率23％)。
LCMS:[M+H]+＝352.2
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),6.56–6.54(m,1H),6.52(s,2H),6.02(dd,J＝3.2,1.6Hz,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＝4.4Hz,2H),1.11(s,3H),0.51(q,J＝4.4Hz,2H),0.28(q,J＝4.0Hz,2H).
实施例11化合物3011的制备
步骤一、化合物3
将化合物1(4.0g,23.8mmol)和化合物2(2.8g，24mmol)加入到40mL的混合溶剂中(N,N-二甲基甲酰胺/四氢呋喃＝1/1)，冷却至0℃后加入NaH(60％，2.9g，120mmol)，升温至25℃搅拌16小时。用200mL冰水稀释，用乙酸乙酯萃取三次，合并后的有机相用饱和氯化钠溶液洗涤、无水硫酸钠干燥。浓缩后的残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝4/1)得到化合物3(1.2g,收率30％)。
LCMS:[M+H]+＝180.1
步骤二、化合物4
将化合物3(1.2g,6.9mmol)溶于20mL四氢呋喃中，加入LiAlH4的四氢呋喃溶液(1M,10.5mL，10.5mmol)，升温至70℃搅拌18小时。冷却至室温后加入十水合硫酸钠淬灭反应，将过滤后得到的滤液浓缩，得到化合物4(1.1g，收率95％)为黄色油状物。
LCMS:[M+H]+＝166.1
步骤三、化合物3011
将化合物4(308mg,1.87mmol)、化合物5(500mg，1.7mmol)和叔丁醇钾(570mg，5.1mmol)加入到10mL的甲苯中，再依次加入Dave-phos(134mg，0.34mmol)和pd2(dba)3(156mg，0.17mmol)，在氮气保护下升温至80℃搅拌16小时。冷却至室温后过滤，将滤液浓缩，得到的残余物用硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)，得到化合物3011(475mg,收率58％)。
LCMS:[M+H]+＝381.1
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.60(dd,J＝7.6,1.2Hz,1H),7.45(dd,J＝7.6,1.2Hz,1H),7.22(td,J＝7.6,1.2Hz,1H),7.12(td,J＝7.6,1.2Hz,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＝1.2Hz,2H),0.28(d,J＝1.6Hz,2H).
实施例A1钾离子通道开放剂活性测试(FDSS/μCELL检测)
1.实验方法：
1.1实验流程
细胞准备：CHO-KCNQ2细胞培养于175cm2培养瓶中，待细胞密度生长到60～80％，移走培养液，用7mL PBS(Phosphate Buffered Saline，磷酸盐缓冲液)洗一遍，然后加入3mL 0.25％Trypsin消化。待消化完全后加入7mL培养液(90％DMEM/F12+10％FBS+500μg/mL G418)中和，800rpm离心3分钟，吸走上清液，再加入5mL培养液重悬，细胞计数。
细胞铺板：根据细胞计数结果，调整密度至3x104个/孔，室温静置30分钟后，放置于37℃ CO2培养箱培养过夜，培养16-18小时，细胞密度达到约80％。
荧光染料孵育：弃去细胞培养液，加入80μL/孔的上样缓冲液，室温避光孵育60分钟。
化合物孵育：弃去上样缓冲液，加入配制好的化合物溶液80μL/孔，室温避光孵育20分钟。
荧光数据采集：采用FDSS/μCELL仪器进行实时荧光信号记录，激发波长480nm、发射波长540nm，每秒记录1次，记录10秒基线后开始加入20μL/孔的刺激缓冲液，再持续记录至180秒结束。
1.2溶液配制
上样缓冲液：10mL/板，配制方式如下：
测试缓冲样：100mL/板，配制方式如下：
刺激缓冲液：5mL/板，配制方式如下：
上述缓冲液来源于市售的试剂盒，试剂盒名称为FluxOR potassium ion channel assay。
1.3化合物准备
配制20mM的DMSO化合物母液，取10μL 20mM的化合物母液至20μL DMSO溶液中，3倍连续稀释成8个中间浓度；再分别取中间浓度的化合物至测试缓冲液中，200倍稀释得到需要测试的最终浓度，取80μL加入至检测板中。
最高测试浓度为100μM，依次分别为100，33.33，11.11，3.70，1.23，0.41，0.137，0.045μM共8个浓度。每个浓度3复孔。
最终测试浓度中的DMSO含量不超过0.5％，此浓度的DMSO对KCNQ2钾通道没有影响。
1.4数据分析
实验数据由Excel 2007、GraphPad Prism 5.0软件进行分析，统计180秒的比值计算激动效应。化合物激动效应由如下公式计算：
1.5质量控制
环境：温度～25℃
试剂：FluxORTM检测试剂盒(Invitrogen,Cat#F0017)
报告中的实验数据必须满足以下标准：Z’Factor>0.5
2.测定结果：详见表1，其中EC50越小，表示相应化合物的活性越高。
表1.本发明所述的部分化合物测试结果

上述测试方法的参考文献：
Zhaobing Gao等人.Journal of Biological Chemistry.2010,285(36):28322-28332.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示的化合物或其药学上可接受的盐，
    其中，
    A环选自下组：无、C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基；
    R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、氘、卤素、氰基、-OH、-COOH、硝基、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、C2-6烯基、C2-6炔基、饱和或不饱和的C3-6环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、C6-10芳基、含1-3个选自N、O或S的杂原子的5-14元杂芳基、C6-12芳烷基、-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’，所述取代指被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基、C1-6烷氧基、C3-6环烷基氧基、卤代C1-6烷基、卤代C3-6环烷基、卤代C1-6烷氧基、卤代C3-6环烷基氧基；
    n、r独立地选自下组：0、1、2；
    R1’、R2’独立地选自下组：氢、C1-6烷基、C3-6环烷基或R1’、R2’与其共同连接的N原子形成饱和或不饱和的含1-3个选自N、O或S的杂原子的3-10元杂环基；上述烷基、环烷基、杂环基任选地被选自下组的一个或多个取代基取代：＝O、卤素、C1-6烷基、C3-6环烷基；
    m选自下组：1、2；
    W1、W2独立地选自下组：无、C、N；并且，W1和W2不同时为无；
    选自下组：无、单键、双键；
    B环选自下组：C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-10环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、含1-3个选自N、O或S的杂原子的3-10元杂桥环基；
    V选自下组：C、CR8、N；
    R8选自下组：氢、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基；上述烷基、环烷基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
    V’选自下组：-(CH2)p-、-C(CH3)2-、-NH-、-(CH2)p-NH-、-CF2-NH-、-C(CH3)2-NH-、
    p选自下组：0、1、2；
    X、Y独立地选自下组：N、CR9；
    R9选自下组：氢、卤素、氰基、氨基、羟基、C1-6烷基、C3-6环烷基、C1-6烷氧基；上述氨基、烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
    R5、R6独立地选自下组：氢、卤素、氰基、氨基、羟基、C1-6烷基、C3-6环烷基、C1-6烷氧基；上述氨基、烷基、环烷基、烷氧基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
    U选自下组：O、S、N(R10)；
    Z选自下组：O、-(CH2)q-、-N(R11)-；
    q选自下组：0、1、2；
    R10、R11独立地选自下组：氢、C1-6烷基、C3-6环烷基；上述烷基、环烷基任选地被选自下组的一个或多个取代基取代：卤素、C1-6烷基、C3-6环烷基；
    R7选自下组：C1-6烷基、C3-6环烷基、C5-8桥环基、金刚烷基、C6-10芳基、含1-3个选自N、O或S的杂原子的3-10元杂芳基、含1-3个选自N、O或S的杂原子的4-8元杂环烷基、C3-6环烯基、C2-6烯基、C2-6炔基，上述烷基、环烷基、桥环基、金刚烷基、芳基、杂芳基、杂环烷基、环烯基、烯基、炔基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、硝基、氨基、羟基、C1-6烷基-CO-、C1-6烷基、C3-6环烷基、C6-10芳基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基氨基、C1-6卤代烷氧基。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    A环选自下组：无、C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基；
    R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
    n、r选自下组：0、1、2；
    W1、W2独立地选自下组：无、C、N，并且W1、W2不同时为N；
    B环选自下组：C6-10芳基、含1-3个选自N、O或S的杂原子的4-7元杂芳基、饱和或不饱和的C3-10环烃基、含1-3个选自N、O或S的杂原子的3-10元杂环基、含1-3个选自N、O或S的杂原子的3-10元杂桥环基；
    V为N；
    V’选自下组：-(CH2)p-、-NH-、-CH2-NH-；
    p选自下组：0、1；
    X和Y为CH；
    R5、R6独立地选自下组：卤素、C1-6烷基；上述烷基任选地被选自下组的一个或多个取代基取代：卤素；
    U为O；
    Z为CH2；
    R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    式I中的选自下组：
    R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
    n、r独立地选自下组：0、1、2。
  4. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    R7选自下组：C3-6环烷基、C5-8桥环基。
  5. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，
    式I中的选自下组：
    R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基、C1-6烷氧基；所述取代指被选自下组的一个或多个取代基取代：卤素；
    n、r独立地选自下组：0、1、2；
    V’选自下组：-(CH2)p-、-NH-、-CH2-NH-、
    p选自下组：0、1；
    X、Y独立地选自下组：N、CH；
    R5、R6独立地选自下组：氢、卤素、氨基、C1-6烷基、C1-6烷氧基；
    U为O；
    Z为CH2；
    R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
  6. 如权利要求5所述的化合物或其药学上可接受的盐，其特征在于，
    R1、R2、R3、R4独立地选自取代或未取代的下组基团：氢、卤素、C1-6烷基；
    n选自下组：0、1、2；
    V’选自下组：-(CH2)p-、-NH-、-CH2-NH-；
    p选自下组：0、1；
    X和Y为CH；
    R5、R6独立地选自下组：卤素、C1-6烷基；
    U为O；
    Z为CH2；
    R7选自下组：C3-6环烷基、C5-8桥环基；上述环烷基、桥环基任选地被选自下组的一个或多个取代基取代：氢、卤素、氰基、C1-6烷基、C1-6卤代烷基。
  7. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述化合物选自下组：


  8. 一种药物组合物，其特征在于，包含一种或多种药学上可接受的载体和治疗有效量的一种或多种权利要求1所述的化合物或其药学上可接受的盐。
  9. 一种权利要求1所述的化合物或其药学上可接受的盐的用途，其特征在于，用于制备用于预防和/或治疗对钾离子通道敏感的疾病的药物。
  10. 如权利要求9所述的用途，其特征在于，所述对钾离子通道敏感的疾病为中枢神经系统疾病。
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