Tetrahydroisoquinoline compound as potassium channel modulator and preparation and application thereof

Abstract

A tetrahydroisoquinoline compound as a potassium channel modulator and preparation and application thereof. Specifically, the compound has the structure as shown in formula A. Formula (A)

Description

Tetrahydroisoquinoline compounds as potassium channel modulators and their preparation and use Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to tetrahydroisoquinoline compounds as potassium channel regulators and their preparation and application. Background Art

[0002] Kv7 potassium channels are a class of voltage-dependent potassium ion channels characterized by low-threshold activation, slow activation, and non-inactivation. The Kv7 potassium channel family consists of five members (Kv7.1-Kv7.5). All Kv7 potassium channel members share a similar topological structure: a functional channel composed of four subunits, each containing six transmembrane segments (S1-S6). S4 is the voltage-sensing region, important for sensing membrane potential changes and controlling conformational changes; SS-S6 are the primary components of the channel pore region, the primary assembly and active region of potassium channel openers. Kv7.1 potassium channels are a non-neuronal pathway distributed in peripheral tissues and expressed in the heart to mediate myocardial Iks. Mutations in these channels can lead to Long QT syndrome. Kv7.2-Kv7.5 potassium channels underlie neuronal M currents, are widely distributed throughout the nervous system, and possess diverse physiological activities. Mutations in the Kv7.2 and Kv7.3 potassium channel genes can lead to a variety of epilepsy phenotypes, such as benign familial neonatal convulsions (BFNC), highlighting the role of M currents in regulating neuronal excitability. Kv7.4 potassium channels are highly expressed in the outer hair cells of the cochlea and auditory nuclei of the brainstem, and mutations in these channels may cause hereditary deafness. Kv7.5 potassium channels are highly expressed in skeletal muscle and the brain, and mutations in these channels may lead to retinal diseases. Many diseases, such as epilepsy, anxiety, and deafness, share a common characteristic of membrane hyperexcitability. Kv7 potassium channels, as the molecular basis of M currents, can open by sensing changes in membrane potential, upregulating inhibitory potassium currents and thereby controlling membrane excitability. This makes Kv7 potassium channels important in pain and psychiatric disorders characterized by neural hyperexcitability.

[0003] Retigabine is a drug for the treatment of epilepsy and has been approved for marketing in the UK, Germany, and Denmark. Studies have confirmed that the effects of retigabine are related to voltage-gated potassium channels (KCNQs), with regulation of M-type potassium currents through KCNQ2 / 3 channels being its primary mechanism of action.

[0004] Retigabine (RTG), the first Kv7 potassium channel opener launched in 2011 for the adjunctive treatment of partial-onset epilepsy in adults, is a promising candidate for the treatment of anxiety, neuropathic pain, and neurodegenerative diseases. RTG effectively reduces or prevents epileptic seizures in various epilepsy models. RTG exhibits potent antiepileptic effects against both tonic seizures induced by maximal electroshock (MES) and clonic seizures induced by PTZ. Furthermore, RTG can prevent seizures induced by N-methyl-D-aspartate (NMDA), penicillin, picrotoxin, and kainic acid (KA). The kindling model is suitable for screening a variety of antiepileptic drugs, and RTG is more effective in this model than in other models. Due to its broad effects on all Kv7 potassium channel members and other channels, RTG has poor selectivity, which may lead to potential adverse effects. A large number of literature reports show 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. Other adverse reactions include kidney stones, urinary retention and other kidney and urinary system diseases, cardiac arrest, transient non-sustained ventricular tachycardia and other heart-related diseases, and can also lead to retinal discoloration, blue / purple pigmentation of the skin, nails, etc.

[0005] Summary of the Invention

[0006] The present invention aims to provide a compound represented by formula A, a preparation method thereof and use thereof as a potassium channel regulator.

[0007] The first aspect of the present invention provides a compound represented by formula A or a pharmaceutically acceptable salt thereof,

[0008]

[0009] in,

[0010] R1 is selected from the following group: substituted or unsubstituted: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR8R9, ethynyl;

[0011] R2 and R3 are independently selected from the following groups: hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0012] Or R2 and R3 and their respective connected C form C 3-10 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0013] R4 and R5 are independently selected from the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 alkoxy;

[0014] R6 is selected from the following group: substituted or unsubstituted: 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl;

[0015] n is selected from the following group: 1, 2, 3;

[0016] W is C-R7 or N;

[0017] R7 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0018] R8 and R9 are independently selected from the following groups: hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0019] Or R8 and R9 and the nitrogen to which they are attached form a 3-10 membered nitrogen heterocycloalkyl group.

[0020] In another preferred embodiment,

[0021] R1 is substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR8R9, ethynyl;

[0022] R2 and R3 are independently selected from the group consisting of hydrogen, deuterium;

[0023] R4 and R5 are methyl groups;

[0024] R6 is selected from the following group: substituted or unsubstituted: C 1-6 Alkyl, C 3-6 Cycloalkyl, the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0025] n is 1;

[0026] W is C-R7;

[0027] R7 is selected from the group consisting of hydrogen, halogen;

[0028] R8 and R9 are independently C 1-6 alkyl.

[0029] In another preferred embodiment,

[0030] R1 is substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR8R9, ethynyl;

[0031] R2 and R3 are independently selected from the group consisting of hydrogen, deuterium;

[0032] R4 and R5 are methyl groups;

[0033] R6 is selected from the following group: substituted or unsubstituted: C 1-6 Alkyl, C 3-6 Cycloalkyl, the substitution refers to being substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl;

[0034] n is 1;

[0035] W is C-R7;

[0036] R7 is selected from the group consisting of hydrogen, halogen;

[0037] R8 and R9 are independently C 1-6 alkyl.

[0038] In another preferred embodiment,

[0039] R1 is substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR8R9, ethynyl;

[0040] R2 and R3 are independently selected from the group consisting of hydrogen, deuterium;

[0041] R4 and R5 are methyl groups;

[0042] R6 is selected from the group consisting of:

[0043] n is 1;

[0044] W is C-R7;

[0045] R7 is selected from the group consisting of hydrogen, halogen;

[0046] R8 and R9 are independently C 1-6 alkyl.

[0047] In another preferred embodiment,

[0048] R1 is substituted or unsubstituted phenyl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NR8R9, ethynyl;

[0049] R2 and R3 are independently selected from the group consisting of hydrogen, deuterium;

[0050] R4 and R5 are methyl groups;

[0051] R6 is selected from the group consisting of:

[0052] n is 1;

[0053] W is C-R7;

[0054] R7 is selected from the group consisting of hydrogen, halogen;

[0055] R8 and R9 are independently C 1-6 alkyl.

[0056] In another preferred embodiment, R1 is a substituted or unsubstituted phenyl group, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NR8R9, ethynyl;

[0057] R2 and R3 are independently selected from the group consisting of hydrogen, deuterium;

[0058] R4 and R5 are methyl groups;

[0059] R6 is

[0060] n is 1;

[0061] W is C-R7;

[0062] R7 is selected from the group consisting of hydrogen, halogen;

[0063] R8 and R9 are independently C 1-6 alkyl.

[0064] In another preferred embodiment, the compound is selected from the following group:

[0065]

[0066] The second aspect of the present invention provides a method for preparing the compound or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, comprising the steps of:

[0067]

[0068] in:

[0069] X is selected from the group consisting of halogen, -B(OH)2, -OTf;

[0070] R1, R2, R3, R4, R5, R6, n, and W are as defined in the first aspect of the present invention.

[0071] The third 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 according to the first aspect of the present invention or pharmaceutically acceptable salts thereof.

[0072] The fourth aspect of the present invention provides a use of the compound or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention for preparing a medicament for preventing and / or treating diseases sensitive to potassium ion channels.

[0073] In another preferred embodiment, the disease sensitive to potassium ion channels is a central nervous system disease.

[0074] In another preferred embodiment, the central nervous system disease is selected from the group consisting of epilepsy, convulsions, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, cocaine abuse, nicotine withdrawal, alcohol withdrawal, and tinnitus.

[0075] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0076] After long and in-depth research, the inventors unexpectedly prepared a novel compound represented by Formula A through structural optimization, which has excellent potassium channel opening activity, pharmacokinetics (such as brain-to-blood ratio), in vivo efficacy and safety. Based on this, the inventors completed the present invention.

[0077] the term

[0078] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0079] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0080] In the present invention, "C1-C6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0081] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0082] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0083] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The terms "C3-C6 cycloalkyl" and "C3-C10 cycloalkyl" have similar meanings.

[0084] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0085] In the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic ring group with 6 to 10 carbon atoms and no heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C 6-10 "C6-C10 aryl" and "C6-C10 aryl" have the same meaning, and other similar terms also have similar identity.

[0086] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0087] In the present invention, the term "halo" means substituted with halogen.

[0088] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0089] In the present invention, the term "plurality" independently refers to 2, 3, 4, 5 or 6.

[0090] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.

[0091] Compound

[0092] The present invention provides a compound represented by formula A or a pharmaceutically acceptable salt thereof,

[0093]

[0094] R1, R2, R3, R4, R5, R6, n, and W are as defined above.

[0095] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, R5, R6, n, and W is a corresponding group in the specific compound.

[0096] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids 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, 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0097] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0098] Preparation method

[0099] The following describes in more detail the preparation methods of the compound of formula A of the present invention, but these specific methods do not limit the present invention in any way. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0100] Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0101]

[0102] in:

[0103] X is selected from the group consisting of halogen, -B(OH)2, -OTf;

[0104] R1, R2, R3, R4, R5, R6, n, and W are as defined above.

[0105] Pharmaceutical compositions and methods of administration

[0106] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-1000 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0107] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0108] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0109] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0110] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0111] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0112] 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 conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0113] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0114] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0115] 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 excipients include water, ethanol, polyols and suitable mixtures thereof.

[0116] Dosage forms for topical administration of the compounds 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 that may be required.

[0117] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0118] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0119] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0120] Compared with the prior art, the present invention has the following main advantages:

[0121] (1) The compound has better pharmacokinetic properties, such as better brain-to-blood ratio, half-life, exposure, metabolic stability, etc.;

[0122] (2) The compound has better potassium channel opening activity, better ion channel selectivity, better in vivo efficacy and better safety;

[0123] (3) The compounds are expected to be useful for treating and / or preventing diseases and conditions that are affected by the activity of potassium ion channels.

[0124] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0126] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0127] Example 1 Preparation of Compound A

[0128]

[0129] Step 1, Compound 2

[0130] Compound 1 (2 g, 8.05 mmol, 1.0 eq) was dissolved in a mixed solvent of dichloromethane (100 mL) and methanol (10 mL). BnMe3NBr3 (6.28 g, 16.1 mmol, 2.0 eq) and calcium carbonate (2.01 g, 20.1 mmol, 2.5 eq) were then added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain a residue which was purified by neutral alumina column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound 2 (2.9 g, 90% yield) as a white solid.

[0131] LCMS: [M+H] + =406.9.

[0132] Step 2: Compound 3

[0133] Compound 2 (1 g, 2.46 mmol, 1.0 eq) was dissolved in 1,4-dioxane (50 mL), followed by the addition of methylboric acid (589 mg, 9.84 mmol, 4.0 eq), potassium phosphate (2.089 g, 9.84 mmol, 4.0 eq), and Pd(dppf)Cl2 (0.1 g, 0.14 mmol, 0.06 eq). The reaction mixture was heated to 120°C under nitrogen and stirred for 4 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate diluted with water, and extracted with ethyl acetate (3 × 40 mL). The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 3 (504 mg, 74% yield) as a white solid.

[0134] LCMS: [M+H] + =277.2.

[0135] Step 3, Compound 5

[0136] Compound 3 (600 mg, 2.17 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), cooled to 0°C, and triethylamine (0.78 mL, 5.43 mmol, 2.5 eq) and compound 4 (438 mg, 3.26 mmol, 1.5 eq) were added. The reaction solution was warmed to room temperature and stirred for 0.5 hours. The reaction solution was diluted with water and then extracted with dichloromethane (3 × 10 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with a mixed solvent (petroleum ether / ethyl acetate = 30 mL / 3 mL) for half an hour and then filtered. The resulting solid was dried to give compound 5 (680 mg, yield 84%) as a white solid.

[0137] Step 4: Compound 6

[0138] Compound 5 (680 mg, 1.82 mmol, 1.0 eq) and methanolic hydrochloric acid (4 M, 13 mL) were added to a single-necked flask and stirred at room temperature for 0.5 hours. The reaction solution was concentrated and diluted with ethyl acetate (10 mL). The mixture was then washed with aqueous sodium carbonate (0.5 M, 20 mL). The separated aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic layer was concentrated, and the residue was dissolved in tetrahydrofuran and dried over anhydrous sodium sulfate. After concentration, compound 6 (370 mg, 74% yield) was obtained as a white solid.

[0139] LCMS: [M+H] + =275.2

[0140] Step 5: Compound A

[0141] Compound 6 (150 mg, 0.547 mmol, 1.5 eq) was dissolved in toluene (50 mL), followed by the addition of cesium carbonate (237 mg, 0.728 mmol, 2.0 eq), X-Phos (35 mg, 0.0728 mmol, 0.2 eq), compound 7 (81 mg, 0.364 mmol, 1.0 eq), and Pd2(dba)3 (34 mg, 0.0364 mmol, 0.1 eq). The reaction mixture was stirred at 90°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound A (6.0 mg, 3%) as a white solid.

[0142] LCMS: [M+H] + =369.2

[0143] 1 H NMR(400MHz,DMSO)δ9.10(s,1H),7.08-7.02(m,4H),6.90(s,1H),4.26(s,2H),3.49(s,2H),2.74-2.71(m,2H),2.21(s,2H),2.11(s,3H), 2.01(s,3H),1.06(s,9H).

[0144] Example 2 Preparation of Compound B

[0145]

[0146] Step 1: Compound B

[0147] Compound 1 (600 mg, 2.19 mmol, 1.0 eq), compound 2 (3.6 g, 27.3 mmol, 12.4 eq) and cesium carbonate (7.14 g, 21.9 mmol, 10 eq) were added to N-methylpyrrolidone (60 mL), and the reaction solution was heated to 180°C in a microwave reactor and stirred for 4 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (150 mL), then washed with saturated sodium chloride solution (80 mL x 4), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound B (83.9 mg, yield 10%) as a white solid.

[0148] LCMS: [M+H] + =387.1

[0149] 1 H NMR(400MHz,DMSO-d6)δ9.11(s,1H),7.21-7.15(m,1H),6.94-6.84(m,2H),6.80-6.69(m,1H),4.19 (s,2H),3.44-3.36(m,2H),2.76-2.71(m,2H),2.21(s,2H),2.10(s,3H),2.01(s,3H),1.05(s,9H).

[0150] Example 3 Preparation of Compound C

[0151]

[0152] Step 1: Compound C

[0153] Compound 1 (100 mg, 0.36 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (5 mL), followed by the addition of cesium carbonate (1.0 g, 3.1 mmol, 8.6 eq) and compound 2 (1.0 g, 6.67 mmol, 18.5 eq). The reaction mixture was heated to 200°C in a microwave reactor and stirred for 2 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with ethyl acetate (3 x 5 mL), and the filtrate was washed with saturated sodium chloride solution (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford compound C (15.5 mg, 10% yield) as a white solid.

[0154] LCMS: [M+H] + =405.1

[0155] 1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.58-7.46(m,1H),7.23-7.16(m,1H),6.86(s,1H),4.15(s ,2H),3.37-3.33(m,2H),2.79-2.72(m,2H),2.22(s,2H),2.11(s,3H),2.02(s,3H),1.07(s,9H).

[0156] Example 4 Preparation of Compound D

[0157]

[0158] Step 1, compound 3

[0159] Compound 1 (50 mg, 0.182 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), followed by the addition of compound 2 (164 mg, 0.547 mmol, 3.0 eq), Pd2(dba)3 (17 mg, 0.018 mmol, 0.1 eq), Dave-Phos (14 mg, 0.036 mmol, 0.2 eq), and LiHMDS (1 M, 1.8 mL, 1.8 mmol, 10 eq). The reaction mixture was stirred at 80°C under nitrogen for 2 hours, cooled to room temperature, diluted with ethyl acetate (150 mL), and then washed with saturated sodium chloride solution (80 mL x 4). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford compound 3 (46 mg, 28% yield) as a yellow solid.

[0160] LCMS: [M+H] + =447.2

[0161] Step 2: Compound D

[0162] Compound 3 (20 mg, 0.045 mmol, 1.0 eq) and potassium carbonate (62 mg, 0.447 mmol, 10 eq) were added to methanol (3 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated, and the resulting residue was dissolved in ethyl acetate (20 mL) and then washed with saturated sodium chloride solution (10 mL x 2). The resulting organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound D (4.2 mg, 7% yield) as a light red solid.

[0163] LCMS: [M+H] + =375.2

[0164] 1 H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 7.31 (d, J = 8.8Hz, 2H), 7.03-6.88 (m, 3H), 4.38 (s, 2H), 3. 90(s,1H),3.61(s,2H),2.75-2.72(m,2H),2.21(s,2H),2.10(s,3H),2.02(s,3H),1.06(s,9H).

[0165] Example 5 Preparation of Compound E

[0166]

[0167] Step 1, Compound E

[0168] Compound 1 (100 mg, 0.36 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (2 mL), followed by the addition of compound 2 (66 mg, 0.55 mmol, 1.5 eq) and potassium carbonate (151 mg, 1.09 mmol, 3.0 eq). The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to afford compound E (50.3 mg, 37% yield) as a white solid.

[0169] LCMS: [M+H] + =376.2

[0170] 1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.60-7.57(m,2H),7.08-7.05(m,2H),6.94(s,1H),4.49( s,2H),3.69(s,2H),2.77(t,J=5.6Hz,2H),2.21(s,2H),2.11(s,3H),2.03(s,3H),1.06(s,9H).

[0171] Example 6 Preparation of Compound F

[0172]

[0173] Step 1, Compound F

[0174] Compound 1 (120 mg, 0.44 mmol, 1.0 eq) was dissolved in acetonitrile (20 mL), and compound 2 (148 mg, 1.31 mmol, 3.0 eq) and diisopropylethylamine (339 mg, 2.63 mmol, 6.0 eq) were added. The mixture was heated to 160°C in a microwave reactor for 1 hour. The reaction solution was cooled to room temperature, concentrated, diluted with water, and then extracted with dichloromethane (3 x 100 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound F (40 mg, yield 26%) as a yellow solid.

[0175] LCMS: [M+H] + =352.2

[0176] Example 7 Preparation of Compound G

[0177]

[0178] Step 1, compound 3

[0179] Compound 1 (600 mg, 3.0 mmol, 1.0 eq) and compound 2 (780 mg, 3.9 mmol, 1.3 eq) were dissolved in a 1 M ammonia methanol solution (10.5 mL). The reaction mixture was heated to 90°C in a microwave reactor for half an hour. The reaction mixture was cooled to room temperature and concentrated. The mixture was extracted with ethyl acetate (50 mL x 3) and saturated sodium bicarbonate aqueous solution. The organic phases were combined and dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 15) to obtain compound 3 (350 mg, 42% yield) as a white solid.

[0180] Step 2: Compound 4

[0181] Compound 3 (350 mg, 1.25 mmol, 1.0 eq) and palladium on carbon (10%, 100 mg) were dissolved in methanol (30 mL) and stirred at room temperature under 1 atmosphere of hydrogen for 1 hour. The reaction mixture was filtered and the filtrate was concentrated to give compound 4 (300 mg, 96% yield) as a colorless oil.

[0182] LCMS: [M+H] + =250.1.

[0183] Step 3, Compound 5

[0184] Compound 4 (300 mg, 1.2 mmol, 1.0 eq), benzyltrimethylammonium tribromide (936 mg, 2.4 mmol, 2.0 eq), and calcium carbonate (300 mg, 3.0 mmol, 2.5 eq) were dissolved in a mixture of dichloromethane and methanol (10 / 1, 40 mL / 4 mL) and stirred at room temperature for half an hour. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 5 (160 mg, 33% yield) as a white solid.

[0185] LCMS: [M+Na] + =429.9.

[0186] Step 4: Compound 7

[0187] Compound 5 (160 mg, 0.4 mmol, 1.0 eq) was dissolved in 1,4-dioxane (15 mL), and methylboronic acid (96 mg, 1.6 mmol, 4.0 eq), Pd(dppf)Cl2 (58 mg, 0.08 mmol, 0.2 eq), and potassium phosphate (339 mg, 1.6 mmol, 4.0 eq) were added. The reaction mixture was heated to 120°C under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 65 / 35) to afford compound 7 (80 mg, 72% yield) as a white solid.

[0188] LCMS: [M+H] + =278.1

[0189] Step 5, compound 9

[0190] Compound 7 (80 mg, 0.3 mmol, 1.0 eq) and triethylamine (116 mg, 0.9 mmol, 3.0 eq) were dissolved in dichloromethane (15 mL). Compound 8 (60 mg, 0.45 mmol, 1.5 eq) was slowly added under a nitrogen atmosphere and stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (50 mL x 3) and saturated aqueous sodium bicarbonate solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 65 / 35) to afford compound 9 (80 mg, 71%) as a light yellow solid.

[0191] LCMS: [M+H] + =376.3

[0192] Step 6, Compound 10

[0193] Compound 9 (80 mg, 0.21 mmol, 1.0 eq) was dissolved in a 4 M solution of hydrogen chloride in methanol (4 mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 10 (70 mg, yield 96%) as a light yellow oil.

[0194] LCMS: [M+H] + =276.2

[0195] Step 7: Compound G

[0196] Compound 10 (30 mg, 0.11 mmol, 1.0 eq) and compound 11 (38 mg, 0.17 mmol, 1.5 eq) were dissolved in toluene (10 mL). Pd2(dba)3 (20 mg, 0.022 mmol, 0.2 eq), X-Phos (10 mg, 0.022 mmol, 0.2 eq), and cesium carbonate (90 mg, 0.275 mmol, 2.5 eq) were then added sequentially. The mixture was heated to 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound G (5.3 mg, 13% yield) as a white solid.

[0197] LCMS: [M+H] + =370.1

[0198] 1 H NMR (400MHz, CDCl3) δ7.02-6.94(m,4H),6.80(s,1H),4.35(s,2H),3.50(t,J=5.6H z,2H),2.84(t,J=5.6Hz,2H),2.48(s,3H),2.33(s,2H),2.15(s,3H),1.16(s,9H).

[0199] Example 8 Preparation of Compound H

[0200]

[0201] Step 1, compound 3

[0202] Compound 1 (5.0 g, 24.63 mmol, 1.0 eq) was dissolved in toluene (100 mL), and compound 2 (3.88 g, 36.945 mmol, 1.5 eq) was added. The reaction mixture was heated to 140°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated to obtain compound 3 (7 g, 98% yield) as a brown oil, which was used directly in the next reaction without purification.

[0203] Step 2: Compound 4

[0204] Compound 3 (3 g, 10.344 mmol, 1.0 eq) was dissolved in methanol (30 mL), cooled to 0°C, and sodium borohydride (0.27 g, 7.241 mmol, 0.7 eq) was added. The mixture was warmed to room temperature and stirred for 2 hours. Ice water was added to the reaction solution, which was concentrated to remove the methanol and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 4 (2.5 g, 82% yield) as a white solid.

[0205] LCMS: [M+H] + =292.0

[0206] Step 3, Compound 5

[0207] Compound 4 (7.45 g, 25.5 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL). 4-Dimethylaminopyridine (156 mg, 1.28 mmol, 0.05 eq) and triethylamine (5.16 g, 51.0 mmol, 2.0 eq) were added sequentially. The reaction mixture was cooled to 0°C under nitrogen, and p-toluenesulfonyl chloride (5.10 g, 26.8 mmol, 1.05 eq) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours before being quenched with ice water (200 mL). The aqueous phase was extracted with dichloromethane (200 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 5 (11.0 g, 96% yield).

[0208] LCMS: [M+Na] + =469.9

[0209] Step 4: Compound 6

[0210] Dichloromethane (300 mL) was added to a reaction flask containing aluminum chloride (22.0 g, 165 mmol, 6.7 eq). The mixture was cooled to 0°C under nitrogen and a solution of compound 5 (11.0 g, 24.65 mmol, 1.0 eq) in dichloromethane (100 v mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours before being quenched with ice water (100 mL). The pH of the solution was adjusted to 10 with aqueous ammonia, and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 6 (2.6 g, 47% yield).

[0211] LCMS: [M+H] + =225.9

[0212] Step 5, Compound 7

[0213] Compound 6 (2.6 g, 11.5 mmol, 1.0 eq) was dissolved in acetic acid (40 mL) and cooled to 0°C under nitrogen. Sodium borohydride (1.3 g, 34.5 mmol, 3.0 eq) was then added. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was diluted with water (200 mL), cooled to 0°C, and the pH of the solution was adjusted to 10 with sodium carbonate. The mixture was then extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to afford crude compound 7 (3.0 g), which was used directly in the next step without purification.

[0214] LCMS: [M+H] + =230.0

[0215] Step 6, Compound 8

[0216] Compound 7 (3.0 g, 11.5 mmol, 1.0 eq) was dissolved in tetrahydrofuran (40 mL), and diisopropylethylamine (743 mg, 5.75 mmol, 0.5 eq) and Boc2O (3.0 g, 13.8 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 8 (3.0 g, 79% yield over two steps).

[0217] LCMS: [M+Na] + =352.0

[0218] Step 7, Compound 10

[0219] Compound 8 (3.0 g, 9.09 mmol, 1.0 eq) and compound 9 (3.3 g, 18.7 mmol, 2.0 eq) were dissolved in toluene (100 mL). Cesium carbonate (8.88 g, 27.26 mmol, 3.0 eq), BINAP (1.13 g, 1.82 mmol, 0.2 eq), and Pd2(dba)3 (832 mg, 0.09 mmol, 0.1 eq) were then added under nitrogen. The reaction mixture was heated to 80°C and stirred for 20 hours, then heated to 100°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the solid was washed with ethyl acetate (200 mL). The combined filtrate was washed with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated to give crude compound 10 (6.0 g), which was used directly in the next step without purification.

[0220] LCMS: [M+H] + =431.1

[0221] Step 8, Compound 11

[0222] Compound 10 (crude product, 6.0 g, 9.09 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL), and aqueous hydrochloric acid (4 M, 100 mL) was added and stirred at room temperature for 2 hours. The reaction solution was separated, and the organic phase was washed with aqueous hydrochloric acid (4 M, 3 x 30 mL). The combined aqueous phase was adjusted to pH 8 with sodium carbonate to obtain an aqueous solution of compound 11 (approximately 200 mL).

[0223] LCMS: [M+H] + =167.1

[0224] Step 9, Compound 12

[0225] To an aqueous solution of compound 11 (approximately 200 mL) was added a solution of Boc2O (4.0 g, 18 mmol, 2.0 eq) in tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound 12 (3.0 g, 90% yield over three steps).

[0226] LCMS: [M+Na] + =389.1

[0227] Step 10, Compound 13

[0228] Compound 12 (2.8 g, 7.65 mmol, 1.0 eq) was dissolved in a 4 M solution of hydrogen chloride in methanol (40 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain compound 13 (2.0 g) as a white solid.

[0229] LCMS: [M+H] + =167.1

[0230] Step 11, Compound 14

[0231] Compound 13 (2.0 g) was dissolved in tetrahydrofuran (50 mL), the pH was adjusted to 8 with aqueous sodium carbonate solution, and Boc2O (1.5 g, 6.88 mmol, 0.9 eq) was added. The reaction solution was stirred at room temperature for 10 minutes and then extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 14 (0.85 g, 42% yield over two steps).

[0232] LCMS: [M+H] + =267.1

[0233] Step 12, compound 15

[0234] Compound 14 (0.8 g, 3.0 mmol, 1.0 eq) was dissolved in a mixed solvent of dichloromethane (100 mL) and methanol (10 mL), and calcium carbonate (2.1 g, 21.03 mmol, 7.0 eq) was added. The temperature was lowered to 0°C under nitrogen protection, and BnMe3NBr3 (4.5 g, 11.5 mmol, 4.0 eq) was slowly added to the reaction solution in batches. The reaction solution was warmed to room temperature and stirred for half an hour. The reaction solution was filtered and the solid was washed with dichloromethane (100 mL). The combined filtrate was washed with a mixed aqueous solution of sodium bicarbonate and sodium sulfite, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 15 (1.1 g, yield 80%) as a white solid.

[0235] LCMS: [M+Na] + =446.8

[0236] Step 13, Compound 17

[0237] Compound 17 (1.0 g, 2.36 mmol, 1.0 eq) was dissolved in 1,4-dioxane (100 mL), and methylboric acid (1.13 g, 18.86 mmol, 4.0 eq), potassium phosphate (2.5 g, 11.79 mmol, 5.0 eq), and Pd(dppf)Cl2 (289 mg, 0.35 mmol, 0.15 eq) were added. The mixture was heated to 120°C and stirred under nitrogen for 8 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and then dissolved in water and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain compound 17 (650 mg, 85% yield) as a white solid.

[0238] LCMS: [M+H] + =295.1

[0239] Step 14, Compound 19

[0240] Compound 17 (600 mg, 2.04 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL) and cooled to 0°C before adding triethylamine (515 mg, 5.10 mmol, 2.5 eq) and compound 18 (411 mg, 3.06 mmol, 1.5 eq). The reaction solution was warmed to room temperature and stirred for 0.5 hours. The reaction solution was diluted with water and then extracted with dichloromethane (3 × 50 mL). The combined organic phases were washed with water and dried over anhydrous sodium sulfate. The concentrated residue was slurried with a mixed solvent (petroleum ether / ethyl acetate = 40 / 1) for half an hour. The solid obtained after filtration was dried to obtain compound 19 (700 mg, yield 87%) as a white solid.

[0241] LCMS: [M+Na] + =415.2

[0242] Step 15, Compound 20

[0243] Compound 19 (700 mg, 1.78 mmol, 1.0 eq) and a 4 M methanolic hydrogen chloride solution (15 mL) were added to a single-necked flask and stirred at room temperature for 0.5 hours. The reaction mixture was spin-dried and diluted with ethyl acetate. The pH was adjusted to 8 with aqueous sodium carbonate solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to yield compound 20 (400 mg, 77%).

[0244] LCMS: [M+H] + =293.2

[0245] Step 16: Compound H

[0246] Compound 20 (180 mg, 0.61 mmol, 1.0 eq), compound 21 (1.08 g, 8.18 mmol, 13.0 eq), and cesium carbonate (2.0 g, 6.1 mmol, 10 eq) were added to N-methylpyrrolidone (10 mL) and heated to 180°C in a microwave reactor under nitrogen for 4 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (150 mL), followed by washing with saturated sodium chloride solution (80 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1 to 2 / 1) to afford compound H (4.2 mg, 17% yield) as a white solid.

[0247] LCMS: [M+Na] + =405.1

[0248] 1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),7.21-7.18(m,1H),7.00-6.96(m,1H),6.82-6.77(m,1H),4.23 (s,2H),3.44-3.36(m,2H),2.82-2.73(m,2H),2.24(s,2H),2.04(s,3H),2.01(s,3H),1.07(s,9H).

[0249] Example 9 Preparation of Compound I

[0250]

[0251] Step 1, compound 5

[0252] Compound 3 (1.2 g, 10.8 mmol, 1.5 eq) was dissolved in anhydrous dimethylformamide (5 mL), and compound 4 (2.0 g, 7.2 mmol, 1.0 eq), HATU (6.84 g, 18 mmol, 2.5 eq), and diisopropylethylamine (6 mL, 36 mmol, 5.0 eq) were added sequentially. The reaction solution was heated to 45°C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5 (2.5 g, yield 62%) as a white solid.

[0253] LCMS: [M+Na] + =395.2.

[0254] Step 2: Compound 6

[0255] Compound 5 (2.5 g, 6.7 mmol, 1.0 eq) and a methanolic solution of hydrogen chloride (4 M, 55 mL) were added sequentially to a single-necked flask and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was dissolved in a 10 / 1 dichloromethane / methanol mixture. The mixture was then washed with a 0.5 M aqueous sodium carbonate solution (50 mL), and the aqueous phase was extracted with a 10 / 1 dichloromethane / methanol mixture (3 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to yield compound 6 (1.6 g, 85% yield) as a gray solid.

[0256] LCMS: [M+H] + =273.2

[0257] Step 3: Compound I

[0258] Compound 6 (1.4 g, 5.1 mmol, 1.0 eq) was dissolved in toluene (200 mL), and cesium carbonate (3.3 g, 10.2 mmol, 2.0 eq), compound 7 (1.7 g, 7.7 mmol, 1.5 eq), X-Phos (486 mg, 1.02 mmol, 0.2 eq) and Pd2(dba)3 (467 mg, 0.51 mmol, 0.1 eq) were added in sequence. The temperature was raised to 100 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The concentrated residue was purified by neutral alumina column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound I. The crude compound I was further purified by Pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound I (377.0 mg, 20%) as a white solid.

[0259] LCMS: [M+H] + =367.2

[0260] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.06-7.03(m,4H),6.91(s,1H),4.26(s,2H),3.50(s,2H),2.74-2 .72(m,2H),2.21(s,2H),2.11(s,3H),2.01(s,3H),1.15(s,3H),0.56-0.53(m,2H),0.33-0.31(m,2H).

[0261] Example 10 Preparation of Compound J

[0262]

[0263] Step 1, Compound J

[0264] Compound 1 (600 mg, 2.20 mmol, 1.0 eq), compound 2 (3.6 g, 27.3 mmol, 12.4 eq), and cesium carbonate (7.19 g, 22.0 mmol, 10 eq) were added to N-methylpyrrolidone (60 mL), and the reaction mixture was heated to 180° C. in a microwave reactor and stirred for 4 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (80 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound J (56.0 mg, 0.146 mmol, 7% yield) as a white solid.

[0265] LCMS: [M+H] + =385.1

[0266] 1 H NMR(400MHz, DMSO-d6)δ9.01(s,1H),7.19-7.12(m,1H),6.92-6.82(m,2H),6.75-6.67(m,1H),4.16(s,2H),3.37(t,J=5.6 Hz,2H),2.71(t,J=5.6Hz,2H),2.18(s,2H),2.07(s,3H),1.97(s,3H),1.11(s,3H),0.52-0.50(m,2H),0.29-0.27(m,2H).

[0267] Example 11 Preparation of Compound K

[0268]

[0269] Step 1, compound 3

[0270] Compound 1 (200 mg, 0.724 mmol, 1.0 eq) was dissolved in dimethylformamide (5 ml), and compound 2 (128 mg, 1.086 mmol, 1.5 eq), HATU (412 mg, 1.086 mmol, 1.5 eq), and diisopropylethylamine (280 mg, 2.172 mmol, 3.0 eq) were added. The mixture was heated to 60°C and stirred for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 3 (220 mg, 83% yield) as a yellow solid.

[0271] LCMS: [M+H] + =377.2

[0272] Step 2: Compound 4

[0273] Compound 3 (280 mg, 0.745 mmol, 1.0 eq) was dissolved in a 4 M solution of hydrogen chloride in methanol (10 mL) and stirred at room temperature for 1 hour. After concentration, the residue was adjusted to pH 8-9 by adding saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to afford compound 4 (180 mg, 88% yield) as a yellow solid.

[0274] LCMS: [M+H]+ =277.2

[0275] Step 3: Compound K

[0276] Compound 4 (10 mg, 0.036 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (1 mL), and cesium carbonate (117 mg, 0.36 mmol, 10.0 eq) and compound 5 (58 mg, 0.446 mmol, 12.4 eq) were added. The mixture was heated to 120 ° C using a microwave reactor for 0.5 h. The reaction solution was cooled to room temperature and concentrated. The residue was purified by prep-HPLC to obtain compound K.

[0277] LCMS: [M+H] + =389.1

[0278] Example 12 Preparation of Compound L

[0279]

[0280] Step 1, compound 3

[0281] Compound 1 (100 mg, 0.54 mmol, 1.0 eq) was dissolved in dimethylformamide (3 mL), and compound 2 (81 mg, 0.81 mmol, 1.5 eq), HATU (314 mg, 0.81 mmol, 1.5 eq), and diisopropylethylamine (209 mg, 1.62 mmol, 3.0 eq) were added sequentially. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (50 mL x 3) and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to obtain compound 3 (130 mg, yield 67%) as a white solid.

[0282] LCMS: [M+Na] + =381.1.

[0283] Step 2: Compound 4

[0284] Compound 3 (130 mg, 0.36 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford compound 4 (80 mg, 86% yield) as a light yellow oil.

[0285] LCMS: [M+H] + =259.1

[0286] Step 3: Compound L

[0287] Compound 4 (80 mg, 0.31 mmol, 1.0 eq) and compound 5 (103 mg, 0.47 mmol, 1.5 eq) were dissolved in toluene (10 mL). Pd2(dba)3 (57 mg, 0.062 mmol, 0.2 eq), x-Phos (30 mg, 0.062 mmol, 0.2 eq), and cesium carbonate (253 mg, 0.78 mmol, 2.5 eq) were added. The reaction solution was heated to 100°C under nitrogen for 18 hours. The reaction solution was cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound L (8.8 mg, 8% yield) as a white solid.

[0288] LCMS: [M+H] + =353.1

[0289] 1 H NMR(400MHz, CDCl3)δ7.23(s,1H),7.02-6.93(m,4H),6.90(s,1H), 4.27(s,2H),3.50-3.47(m,2H),2.84-2.82(m,2H),2.39(d,J=7.6Hz,2H),2.23 (s,3H),2.13(s,3H),1.19-1.11(m,1H),0.77-0.67(m,2H),0.36-0.33(m,2H).

[0290] Example 13 Preparation of Compound M

[0291]

[0292] Step 1, compound 3

[0293] Compound 1 (6.0 g, 49.5 mmol, 1.0 eq) and diisopropylethylamine (12.8 g, 99.0 mmol, 2.0 eq) were added to dichloromethane (100 mL). The solution was cooled to 0°C under nitrogen. Compound 2 (5.83 g, 74.3 mmol, 1.5 eq) was slowly added dropwise to the reaction solution. The reaction solution was reacted at room temperature under nitrogen for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a white solid 3 (6.0 g, 74% yield).

[0294] LCMS: [M+H] + =164.1.

[0295] Step 2: Compound 5

[0296] Aluminum trichloride (9.6 g, 72.0 mmol, 3.0 eq) was added to dichloromethane (100 mL), and the reaction mixture was cooled to 0 ° C under nitrogen protection, and a dichloromethane (50 mL) solution of compound 3 (4.0 g, 24.0 mmol, 1.0 eq) and compound 4 (7.4 g, 36.6 mmol, 1.5 eq) was slowly added. The reaction solution was slowly warmed to room temperature and stirred for 16 hours, diluted with dichloromethane (100 mL), and then washed with ice water (5 x 200 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude compound 5 (6.0 g). The crude compound 5 was slurried with a mixed solvent of dichloromethane / petroleum ether (20 mL / 40 mL) and filtered to give compound 5 (4.0 g, yield 58%) as a white solid.

[0297] LCMS: [M+H] + =284.0

[0298] Step 3, Compound 6

[0299] Compound 5 (2.0 g, 7.0 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), HSiEt3 (10 mL) was added, the reaction solution was cooled to 0 ° C under nitrogen protection, trifluoroacetic acid (10 mL) was slowly added, the mixture was slowly warmed to room temperature and stirred for 16 hours. The above reaction solution was concentrated, the residue was dissolved in tetrahydrofuran (30 mL), then cooled to 0 ° C under nitrogen protection, sodium borohydride (532 mg, 14 mmol, 2.0 eq) was slowly added, the mixture was warmed to room temperature and stirred for 0.5 hours. The above reaction solution was cooled to 0 ° C under nitrogen protection, methanol (10 mL) was slowly added dropwise, and the residue obtained after the reaction solution was concentrated was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound 6 (2.0 g, yield 100%) as a white solid.

[0300] LCMS: [M+H] + =270.0.

[0301] Step 4: Compound 8

[0302] Compound 6 (2.0 g, 7.0 mmol, 1.0 eq), compound 7 (1.65 g, 14.8 mmol, 2.1 eq), potassium iodide (1.23 g, 7.0 mmol, 1.0 eq), and potassium carbonate (2.35 g, 22 mmol, 3.0 eq) were added to dimethylformamide (10 mL) under nitrogen protection. The reaction solution was heated to 90°C and stirred for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 8 (1.0 g, yield 45%) as a white solid.

[0303] LCMS: [M+H] + =301.1

[0304] Step 5, Compound 10

[0305] Compound 8 (600 mg, 2.0 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and compound 9 (296 mg, 1.0 mmol, 0.5 eq) was added. The mixture was stirred at room temperature for 1 hour under nitrogen. The reaction mixture was cooled to 0°C, and aluminum chloride (800 mg, 6.0 mmol, 3.0 eq) was added. The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with ice water, and the organic phase was dried over anhydrous sodium sulfate. The residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 10 (200 mg, 30% yield) as a white solid.

[0306] LCMS: [M+H] + =327.1

[0307] Step 6: Compound 11

[0308] Compound 10 (190 mg, 0.6 mmol) was dissolved in concentrated hydrochloric acid (12 M, 15 mL), heated to 99°C under nitrogen, and stirred for 64 hours. After cooling to room temperature, the reaction solution was concentrated, and the resulting residue was azeotropically dehydrated with toluene and ethanol to obtain crude compound 11 (200 mg) as a white solid.

[0309] LCMS: [M+H] + =285.2

[0310] Step 7, Compound 12

[0311] Compound 11 (200 mg, 0.6 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0°C, and LiAlD4 (252 mg, 6.0 mmol, 10.0 eq) was slowly added. The mixture was then warmed to room temperature and stirred for 16 hours. The reaction solution was diluted with tetrahydrofuran (250 mL) and cooled to 0°C. Sodium sulfate decahydrate (10 g) was added and stirred for 0.5 hours. The reaction solution was filtered and concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford compound 12 (25 mg, 15% yield over two steps) as a yellow solid.

[0312] LCMS: [M+H] + =273.1

[0313] Step 8: Compound M

[0314] Compound 13 (21 mg, 0.183 mmol, 2.0 eq), HATU (70 mg, 0.183 mmol, 2.0 eq), and diisopropylethylamine (36 mg, 0.275 mmol, 3.0 eq) were dissolved in dimethylformamide (5 mL) and stirred at room temperature under nitrogen for 0.5 hours. Compound 12 (25 mg, 0.092 mmol, 1.0 eq) was added to the reaction mixture, and the temperature was raised to 45°C and stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. The residue was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford compound M (2.3 mg, 6.8% yield) as a white solid.

[0315] LCMS: [M+H] + =369.2

[0316] 1 H NMR (400MHz, CDCl3) δ7.18 (s, 1H), 7.01-6.86 (m, 5H), 3.47 (t, J = 5.6Hz, 2H), 2.81 (t, J=5.6Hz,2H),2.38(s,2H),2.22(s,3H),2.12(s,3H),1.28(s,3H),0.60-0.50(m,4H).

[0317] Example 14 Preparation of Compound N

[0318]

[0319] Step 1: Compound N

[0320] Compound 1 (30 mg, 0.11 mmol, 1.0 eq) was dissolved in toluene (13 mL), and cesium carbonate (384 mg, 0.33 mmol, 3.0 eq), compound 2 (37 mg, 0.17 mmol, 1.5 eq), x-Phos (11 mg, 0.02 mmol, 0.2 eq), and Pd2(dba)3 (11 mg, 0.01 mmol, 0.1 eq) were added sequentially. The mixture was heated to 90°C and stirred under nitrogen for 15 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The concentrated residue was purified by Pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound N (2 mg, 5% yield) as a white solid.

[0321] LCMS: [M+H] + =363.2

[0322] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.04-7.02(m,2H),6.93-6.91(m,3H),4.25(s,2H),3.49(s,2H),2.51-2.49 (m,2H),2.21(s,2H),2.20(s,3H),2.11(s,3H),2.01(s,3H),1.15(s,3H),0.56-0.53(m,2H),0.33-0.31(m,2H).

[0323] Example 15 Preparation of Compound O

[0324]

[0325] Step 1: Compound O

[0326] Compound 1 (50 mg, 0.183 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (5 mL), and compound 2 (33 mg, 0.275 mmol, 1.5 eq) and potassium carbonate (76 mg, 0.275 mmol, 1.5 eq) were added. The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was concentrated and purified by pre-HPLC (0.1% ammonia / acetonitrile / water) to obtain compound O (4.2 mg, 6% yield) as a white solid.

[0327] LCMS: [M+H] + =374.1

[0328] 1 H NMR (400MHz, DMSO-d6) δ9.02(s,1H),7.56(d,J=9.0Hz,2H),7.04(d,J=9.1Hz,2H),6.92(s,1H),4.47(s,2H),3.66(s,2H) ,2.74(t,J=5.7Hz,2H),2.18(s,2H),2.09(s,3H),2.00(s,3H),1.12(s,3H),0.51(q,J=4.2Hz,2H),0.29(q,J=4.1Hz,2H).

[0329] Example 16 Preparation of Compound P

[0330]

[0331] Step 1: Compound P

[0332] Compound 1 (30 mg, 0.110 mmol, 1.0 eq) was dissolved in toluene (5 mL), and compound 2 (45 mg, 0.165 mmol, 1.5 eq), potassium tert-butoxide (37 mg, 0.330 mmol, 3.0 eq), X-Phos (11 mg, 0.022 mmol, 0.2 eq), and Pd2(dba)3 (10 mg, 0.011 mmol, 0.1 eq) were added. The mixture was heated to 100°C and stirred under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (30 mL) and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the residue was concentrated and purified by Pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound P (6.3 mg, 13% yield) as a white solid.

[0333] LCMS: [M+H] + =417.1

[0334] 1 H NMR(400MHz, DMSO-d6)δ9.05(s,1H),7.51(d,J=8.7Hz,2H),7.12(d,J=8.7Hz,2H),6.96(s,1H),4.46(s,2H),3 .68(s,2H),2.77(s,2H),2.22(s,2H),2.12(s,3H),2.03(s,3H),1.15(s,3H),0.55(s,2H),0.33-0.31(m,2H).

[0335] Example 17 Preparation of Compound Q

[0336]

[0337] Step 1: Compound Q

[0338] Compound 1 (40 mg, 0.15 mmol, 1.0 eq) and compound 2 (51.6 mg, 0.22 mmol, 1.5 eq) were dissolved in toluene (5 mL). Pd2(dba)3 (14 mg, 0.015 mmol, 0.1 eq), Xant-Phos (14 mg, 0.03 mmol, 0.2 eq), and cesium carbonate (143 mg, 0.45 mmol, 3.0 eq) were added. The mixture was heated to 90°C under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was concentrated, and the resulting residue was purified by Pre-HPLC (0.1% formic acid / acetonitrile / water) to afford compound Q (9.7 mg, 18% yield) as a white solid.

[0339] LCMS: [M+H] + =379.2

[0340] 1 H NMR(400MHz, CDCl3)δ7.18(s,1H),6.98(d,J=8.8Hz,2H),6.92–6.83(m,3H),4.23(s,2H),3.78(s,3H),3.44(t ,J=5.6Hz,2H),2.83(t,J=5.6Hz,2H),2.40(s,2H),2.23(s,3H),2.13(s,3H),1.30(s,3H),0.61–0.54(m,4H).

[0341] Example 18 Preparation of Compound R

[0342]

[0343] Step 1: Compound R

[0344] Compound 1 (30 mg, 0.11 mmol, 1.0 eq), compound 2 (33 mg, 0.17 mmol, 1.5 eq), sodium tert-butoxide (32 mg, 0.33 mmol, 3.0 eq), Dave-Phos (17 mg, 0.044 mmol, 0.4 eq) and Pd2(dba)3 (20 mg, 0.022 mmol, 0.2 eq) were dissolved in 1,4-dioxane (4 mL) and tert-butanol (2 mL). The temperature was raised to 99°C under nitrogen protection and the reaction was carried out for 18 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound R (26 mg, yield 60%) as a yellow solid.

[0345] LCMS: [M+H] + =392.2

[0346] 1 H NMR(400MHz,MeOD)δ7.15(s,1H),7.01(d,J=7.6Hz,2H),6.93(d,J=8.0Hz,2H),4.50(s,2H),2.93-2.90(m,2H),2.85–2. 83(m,2H),2.81(s,3H),2.80(s,3H),2.23(s,2H),2.11(s,3H),2.02(s,3H),1.12(s,3H),0.53-0.50(m,2H),0.33-0.31 (m,2H).

[0347] Example 19 Preparation of Compound S

[0348]

[0349] Step 1, compound 3

[0350] Compound 1 (50 mg, 0.18 mmol, 1.0 eq) was dissolved in tetrahydrofuran (15 mL), and compound 2 (83 mg, 0.26 mmol, 1.5 eq), Pd2(dba)3 (17 mg, 0.018 mmol, 0.1 eq), Dave-Phos (14 mg, 0.036 mmol, 0.2 eq), and LiHMDS (1 M, 1.8 mL, 1.8 mmol, 10 eq) were added. The mixture was heated to 80°C and stirred under nitrogen for 4 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 3 (4 mg, yield 5%) as a yellow solid.

[0351] LCMS: [M+H] + =445.2

[0352] Step 2: Compound S

[0353] Compound 3 (4 mg, 0.009 mmol, 1.0 eq) and potassium carbonate (4 mg, 0.027 mmol, 3.0 eq) were added to methanol (5 mL) and stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to obtain compound S (3 mg, yield 90%) as a yellow solid.

[0354] LCMS: [M+H] + =373.2

[0355] Example 20 Preparation of Compound T

[0356]

[0357] Step 1, compound 3

[0358] Compound 1 (80 mg, 0.293 mmol, 1.0 eq) was dissolved in toluene (5 mL), and compound 2 (129 mg, 0.587 mmol, 2.0 eq), sodium tert-butoxide (56 mg, 0.587 mmol, 2.0 eq), BINAP (37 mg, 0.0587 mmol, 0.2 eq), and Pd2(dba)3 (27 mg, 0.0293 mmol, 0.1 eq) were added. The mixture was heated to 100°C and stirred under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (30 mL) and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 3 (30 mg, yield 25%) as a brown solid.

[0359] LCMS: [M+H]+=413.1

[0360] Step 2: Compound 4

[0361] Compound 3 (20 mg, 0.0484 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), and lithium aluminum tetrahydride (9 mg, 0.2424 mmol, 5.0 eq) was added. The mixture was stirred at room temperature under nitrogen for 10 minutes. Tetrahydrofuran (5 mL) was added to dilute the mixture, and the reaction solution was cooled to 0°C. Sodium sulfate decahydrate (0.3 g) was added and stirred at 0°C for 15 minutes. The reaction solution was filtered and concentrated to afford compound 4 (15 mg, 80% yield) as a brown solid.

[0362] LCMS: [M+H]+=385.1

[0363] Step 2: Compound T

[0364] Compound 4 (10 mg, 0.026 mmol, 1.0 eq) was dissolved in anhydrous ethanol (1 mL). Triethylsilane (3 mg, 0.026 mmol, 1.0 eq) and palladium chloride (2 mg, 0.013 mmol, 0.5 eq) were added. The mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was filtered and concentrated to yield compound T (8 mg, 83%) as a brown solid.

[0365] LCMS: [M+H]+=369.1

[0366] Example 21 Preparation of Compound U

[0367]

[0368] Step 1: Compound U

[0369] Compound 1 (120 mg, 0.4 mmol, 1.0 eq) was dissolved in toluene (40 mL), and compound 2 (143 mg, 0.6 mmol, 1.5 eq), cesium carbonate (428.1 mg, 1.31 mmol, 3.0 eq), X-Phos (41.7 mg, 0.08 mmol, 0.2 eq), and Pd2(dba)3 (40.1 mg, 0.04 mmol, 0.1 eq) were added. The mixture was heated to 90°C and stirred under nitrogen for 16 hours. After cooling to room temperature, the reaction solution was filtered, diluted with water (30 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by neutral alumina silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford compound U (42.3 mg, 26% yield) as a white solid.

[0370] LCMS: [M+H] + =365.2

[0371] 1 H NMR (400MHz, DMSO) δ9.09 (s, 1H), 7.03 (d, J = 8.0Hz, 2H), 6.93-6.90 (m,3H),4.24(s,2H),3.50-3.47(m,2H),2.72-2.66(m,2H),2.21(s,2H),2.19(s,3H),2.11(s,3H),2.00(s,3H),1.06(s,9H).

[0372] Example 22 Preparation of Compound V

[0373]

[0374] Referring to the synthetic method of compound N, compound V was obtained (yield 15%).

[0375] LCMS: [M+H] + =349.2

[0376] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.24-7.20(m,2H),7.02-7.00(m,2H),6.93(s,1H),6.78-6.73(m,1H),4.31(s,2H),3 .55(s,2H),2.75-2.72(m,2H),2.21(s,2H),2.12(s,3H),2.02(s,3H),1.15(s,3H),0.56-0.53(m,2H),0.33-0.31(m,2H).

[0377] Example 23 Preparation of Compound W

[0378]

[0379] Step 1: Compound W

[0380] Under nitrogen, compound 1 (50 mg, 0.183 mmol, 1.0 eq) was dissolved in toluene (5 mL). Compound 2 (44 mg, 0.183 mmol, 1.0 eq), Pd2(dba)3 (17 mg, 0.0183 mmol, 0.1 eq), X-phos (17 mg, 0.0366 mmol, 0.2 eq), and Cs2CO3 (119 mg, 0.366 mmol, 2.0 eq) were added sequentially. The reaction mixture was heated to 90°C and stirred for 16 hours. After cooling to 25°C, the reaction mixture was diluted with ethyl acetate (50 mL) and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to give compound W (3.2 mg, 5%) as a white solid.

[0381] LCMS: [M+H] + =383.1

[0382] 1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.25–7.21(m,2H),7.04–6.99(m,2H),6.92(s,1H),4.32(s,2H),3.55(s,2H ),2.73-2.71(m,2H),2.21(s,2H),2.11(s,3H),2.01(s,3H),1.15(s,3H),0.56-0.53(m,2H),0.33-0.31(m,2H).

[0383] Example 24 Preparation of Compound X

[0384]

[0385] Step 1: Compound X

[0386] Compound 1 (300 mg, 1.101 mmol, 1.0 eq) was dissolved in toluene (15 mL), followed by the addition of compound 2 (727 mg, 2.202 mmol, 2.0 eq), cesium carbonate (1.07 g, 3.304 mmol, 3.0 eq), X-PHOS (105 mg, 0.2202 mmol, 0.2 eq), and Pd2(dba)3 (101 mg, 0.1101 mmol, 0.1 eq). The reaction mixture was heated to 90°C under nitrogen and stirred for 6 hours. After cooling to 25°C, the reaction mixture was diluted with ethyl acetate (30 mL) and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to yield compound X (6.3 mg, 1%) as a solid.

[0387] LCMS: [M+H]+=475.0

[0388] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.49-7.46(m,2H),6.92(s,1H),6.86-6.84(m,2H),4.31(s,2H),3.55(s,2H) ,2.72(t,J=5.8Hz,2H),2.21(s,2H),2.11(s,3H),2.01(s,3H),1.14(s,3H),0.55-0.53(m,2H),0.33-0.30(m,2H).

[0389] Example 25 Preparation of Compound Y

[0390]

[0391] Step 1: Compound Y

[0392] Compound 1 (50 mg, 0.183 mmol, 1.0 eq) was dissolved in toluene (5 mL), and compound 2 (87 mg, 0.367 mmol, 2.0 eq), cesium carbonate (179 mg, 0.551 mmol, 3.0 eq), Pd2(dba)3 (17 mg, 0.018 mmol, 0.1 eq), and X-PHOS (17 mg, 0.036 mmol, 0.2 eq) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After cooling to 25°C, it was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was concentrated and purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to yield compound Y (4.1 mg, 5%) as a white solid.

[0393] LCMS: [M+H] + =427.1

[0394] 1 H NMR (400MHz, CDCl3) δ7.35–7.33(m,2H),7.18(s,1H),6.91(s,1H),6.84(d,J=8.9Hz,2H),4.31(s,2H),3.53(t,J=5.6Hz ,2H),2.83(t,J=5.6Hz,2H),2.39(s,2H),2.24(s,3H),2.14(s,3H),1.29(s,3H),0.61–0.59(m,2H),0.56–0.54(m,2H).

[0395] Example 26 Preparation of Compound Z

[0396]

[0397] Step 1: Compound Z

[0398] Compound 1 (20 mg, 0.074 mmol, 1.0 eq) was dissolved in toluene (5 mL), and compound 2 (24.5 mg, 0.11 mmol, 1.5 eq), potassium tert-butoxide (25 mg, 0.220 mmol, 3.0 eq), Dave-phos (6 mg, 0.015 mmol, 0.2 eq), and Pd2(dba)3 (7 mg, 0.0074 mmol, 0.1 eq) were added sequentially. The mixture was heated to 80°C and stirred under nitrogen for 16 hours. After cooling to 25°C, the reaction solution was diluted with ethyl acetate (30 mL) and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a residue which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford compound Z (5.0 mg, 19%) as a white solid.

[0399] LCMS: [M+H]+=367.2

[0400] 1H NMR (400MHz, CDCl3) δ7.23–7.17(m,2H),6.93(s,1H),6.72(d,J=8.4Hz,1H),6.63(d,J=12.8Hz,1H),6.49(t,J=8.0Hz,1H),4.3 5(s,2H),3.56(t,J=5.6Hz,2H),2.84(t,J=5.6Hz,2H),2.40(s,2H),2.24(s,3H),2.15(s,3H),1.30(s,3H),0.62–0.54(m,4H).

[0401] Example 27 Preparation of Compound A1

[0402]

[0403] Step 1, Compound A1

[0404] Compound 1 (200 mg, 0.734 mmol, 1.0 eq) was dissolved in toluene (50 mL), and compound 2 (1.63 g, 7.34 mmol, 10.0 eq), cesium carbonate (1.2 g, 3.67 mmol, 5.0 eq), X-Phos (140 mg, 0.294 mmol, 0.4 eq), and Pd2(dba)3 (134 mg, 0.147 mmol, 0.2 eq) were added sequentially. The reaction mixture was heated to 130°C under nitrogen and stirred for 2 hours. The reaction mixture was cooled to 25°C, diluted with ethyl acetate (20 mL), and washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound A1 (24.3 mg, 9%) as a white solid.

[0405] LCMS: [M+H] + =367.2

[0406] 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.19-7.06(m,3H),7.01–6.94(m,1H), 6.88(s,1H),4.17(s,2H),3.44-3.35(m,2H),2.79-2.70(m,2H),2.22(s,2H), 2.12(s,3H),2.02(s,3H),1.15(s,3H),0.56-0.54(m,2H),0.34-0.31(m,2H).

[0407] Example 28 Preparation of Compound A2

[0408]

[0409] Step 1, Compound 2

[0410] Compound 1 (10.0 g, 82.5 mmol, 1.0 eq) was dissolved in dichloromethane (100 mL), and trifluoroacetic anhydride (26 g, 123.75 mmol, 1.5 eq) was added. The reaction mixture was heated to 50°C and stirred for 1.5 hours. After cooling to 25°C, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The pH was then adjusted to 8-9 with saturated aqueous sodium bicarbonate. The separated organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to yield compound 2 (16 g, 89%) as a white solid.

[0411] LCMS: [M+H] + =218.1

[0412] Step 2: Compound 4

[0413] Aluminum trichloride (12.9 g, 96.69 mmol, 3.0 eq) was dissolved in dichloromethane (100 mL) and cooled to 0°C. A mixed solution of compound 2 (7.0 g, 32.23 mmol, 1.0 eq) and compound 3 (6.14 g, 48.34 mmol, 1.5 eq) in dichloromethane (20 mL) was added. The reaction solution was returned to 25°C under nitrogen and stirred for 16 hours. Dichloromethane (1 L) was added to dilute the reaction solution, which was then poured into ice water (1.0 L). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 x 300 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 4 (3.2 g, 32%) as a white solid.

[0414] LCMS: [M+H] + =308.1

[0415] Step 3, Compound 5

[0416] Compound 4 (3.0 g, 9.75 mmol) was dissolved in trifluoroacetic acid (25 mL), and triethylsilyl hydrochloride (25 mL) was slowly added dropwise. After the addition was complete, the reaction solution was heated to 40°C and stirred overnight. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (300 mL), then washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the residue obtained after concentration was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 5 (0.8 g, 28%).

[0417] LCMS: [M+H] + =294.1

[0418] Step 4: Compound 7

[0419] Compound 5 (800 mg, 2.72 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), potassium iodide (452 ​​mg, 2.72 mmol, 1.0 eq) and compound 6 (600 mg, 5.45 mmol, 2.0 eq) were added, and the mixture was stirred at 25°C for 0.5 hour before sodium carbonate (1.15 g, 10.89 mmol, 4.0 eq) was added and stirring continued for 16 hours. The reaction solution was diluted with ethyl acetate (300 mL), washed sequentially with water and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 7 (900 mg, 90%).

[0420] LCMS: [M+H] + =369.1

[0421] Step 5, Compound 8

[0422] Compound 7 (800 mg, 1.09 mmol, 1.0 eq) was dissolved in concentrated hydrochloric acid (12 M, 25 mL) and stirred at 99° C. (oil bath temperature) overnight. The reaction solution was cooled to room temperature and used directly in the next reaction.

[0423] LCMS: [M+H] + =273.2

[0424] Step 6: Compound 9

[0425] Compound 8 from the previous step was added to aqueous formaldehyde (37%, 88 mg, 2.66 mmol, 2.4 eq) at 25°C, heated to 60°C, and stirred for 1 hour. The above solution was directly concentrated at 55°C, and then a mixed solvent of toluene / ethanol (1:1, 200 mL) was added and concentrated. This process was repeated twice to obtain crude compound 9 (400 mg) as a yellow solid.

[0426] LCMS: [M+H] + =285.2

[0427] Step 7: Compound A2

[0428] Compound 9 (crude product, 200 mg, 0.7 mmol, 1 eq) and compound 10 (241 mg, 2.11 mmol, 3.0 eq) were dissolved in N,N-dimethylformamide (10 mL). Pyridine (1.11 g, 14.07 mmol, 20.0 eq) and 1-propylphosphoric anhydride in ethyl acetate (50%, 4.48 g, 7.03 mmol, 10.0 eq) were added under nitrogen. The reaction solution was heated to 50°C and stirred for 3 hours under nitrogen. The reaction solution was diluted with ethyl acetate (300 mL) and then washed with saturated sodium chloride solution (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to obtain compound A2 (23.2 mg, 4.5% yield over three steps) as a white solid.

[0429] LCMS: [M+H] + =381.2

[0430] 1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),7.09(s,1H),6.93-6.85(m,2H),6.78-6.74(m,2H),4.53(s,2H),3.75-3.56(m,2H),2.9 2-2.90(m,2H),2.18(s,2H),2.07(s,3H),2.05(s,3H),1.82-1.66(m,2H),1.13(s,3H),0.59-0.47(m,2H),0.34-0.27(m,2H).

[0431] Example 29 Preparation of Compound A3

[0432]

[0433] The synthesis method was based on compound M to obtain compound A3 as a white solid.

[0434] LCMS: [M+H] + =419.3

[0435] 1 H NMR (400MHz, CD3OD) δ7.47(d,J=8.6Hz,2H),7.07(d,J=8.7Hz,2H),6.99(s,1H),3.70-3.67(m,2H),2.87 -2.84(m,2H),2.32(s,2H),2.21(s,3H),2.13(s,3H),1.23(s,3H),0.62-0.60(m,2H),0.43-0.40(m,2H).

[0436] Example 30 Preparation of Compound A4

[0437]

[0438] Step 1: Compound A4

[0439] Compound 1 (150 mg, 0.55 mmol, 1.0 eq) was dissolved in toluene (3 mL), and compound 2 (224 mg, 0.826 mmol, 1.5 eq), potassium tert-butoxide (185 mg, 1.65 mmol, 3.0 eq), X-phos (52 mg, 0.11 mmol, 0.2 eq), and Pd2(dba)3 (50 mg, 0.05 mmol, 0.1 eq) were added sequentially. The reaction solution was heated to 100°C and stirred for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to 25°C, diluted with ethyl acetate (50 mL), washed sequentially with water and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound A4 (36.5 mg, 16%) as a white solid.

[0440] LCMS: [M+H] + =417.2

[0441] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),7.42(t,J=8.0Hz,1H),7.30–7.27(m,1H),7.23(s,1H),7.02(d,J=7.6Hz,1H),6.97(s,1H),4.41( s,2H),3.63(s,2H),2.77(t,J=5.7Hz,2H),2.21(s,2H),2.12(s,3H),2.03(s,3H),1.15(s,3H),0.56–0.53(m,2H),0.33–0.31(m,2H).

[0442] Example 31 Preparation of Compound A5

[0443]

[0444] Step 1, Compound A5

[0445] Compound 1 (100 mg, 0.368 mmol, 1.0 eq) was dissolved in DMF (6 mL), and compound 2 (66 mg, 0.44 mmol, 1.2 eq), 1-propylphosphonic anhydride (50%, 1.17 g, 1.84 mmol, 5.0 eq), and pyridine (582 mg, 7.36 mmol, 20.0 eq) were added sequentially. The reaction mixture was heated to 50°C and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25°C and then diluted with ethyl acetate (50 mL). The resulting solution was washed sequentially with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to afford compound A5 (84.2 mg, 58%) as a white solid.

[0446] LCMS: [M+H] + =403.1

[0447] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),7.08–7.00(m,4H),6.91(s,1H),4.26(s,2H),3.49(s,2H),2.77–2.72(m ,4H),2.68–2.67(m,1H),2.46–2.44(m,1H),2.40–2.36(m,2H),2.33–2.30(m,1H),2.08(s,3H),1.98(s,3H).

[0448] Example 32 Preparation of Compound A6

[0449]

[0450] Step 1, Compound A6

[0451] Compound 1 (50 mg, 0.185 mmol, 1.0 eq) was dissolved in DMF (3 mL), followed by the addition of compound 2 (37 mg, 0.222 mmol, 1.2 eq), 1-propylphosphonic anhydride (50%, 2.4 g, 3.700 mmol, 20.0 eq), and pyridine (146 mg, 1.850 mmol, 10.0 eq). The reaction mixture was heated to 50°C and stirred for 2 hours. After cooling to 25°C, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 x 3). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was concentrated and purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to afford compound A6 (8.9 mg, 11%) as a white solid.

[0452] LCMS: [M+H]+ =421.2

[0453] 1 H NMR(400MHz,DMSO-d6)δ9.31(s,1H),7.08-7.00(m,4H),6.91(s,1H),4.26(s,2H),3.49(s,2 H),2.72(t,J=5.7Hz,2H),2.67(s,2H),2.08(s,3H),1.99(s,3H),1.01(s,2H),0.98(s,2H).

[0454] Example 33 Preparation of Compound A7

[0455]

[0456] Step 1, Compound A7

[0457] Compound 1 (50 mg, 0.18 mmol, 1.0 eq) was dissolved in DMF (2 mL), and compound 2 (21 mg, 0.18 mmol, 1.0 eq), 1-propylphosphonic anhydride (50%, 1.15 g, 1.8 mmol, 10.0 eq), and pyridine (284 mg, 1.8 mmol, 10.0 eq) were added sequentially. The mixture was heated to 50°C and stirred for 2 hours. After cooling to 25°C, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was concentrated and purified by pre-HPLC (0.1% formic acid / acetonitrile / water) to afford compound A7 (4.9 mg, 7%) as a white solid.

[0458] LCMS: [M+H] + =367.1

[0459] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),7.09–6.98(m,4H),6.90(s,1H),4.25(s,2H),3.49(s,2H),2.72(t,J=5.6Hz,2H),2.3 9(t,J=7.6Hz,2H),2.09(s,3H),1.99(s,3H),1.54–1.48(m,2H),0.78–0.71(m,1H),0.45–0.37(m,2H),0.11–0.04(m,2H).

[0460] Example 34 Potassium Channel Opener Activity Test (FDSS / μCELL Assay)

[0461] 1. Experimental methods:

[0462] 1.1 Experimental Procedure

[0463] Cell preparation: CHO-KCNQ2 cells were cultured in 175 cm 2 When the cell density in the culture flask reaches 60-80%, remove the culture medium, wash once with 7 mL of PBS (Phosphate Buffered Saline), and then add 3 mL of 0.25% Trypsin for digestion. After digestion is complete, add 7 mL of culture medium (90% DMEM / F12 + 10% FBS + 500 μg / mL G418) for neutralization. Centrifuge at 800 rpm for 3 minutes, aspirate the supernatant, resuspend in 5 mL of culture medium, and count the cells.

[0464] Cell plating: According to the cell counting results, adjust the density to 3x10 4 After standing at room temperature for 30 minutes, the cells were placed in a 37°C CO2 incubator for overnight culture. After culturing for 16-18 hours, the cell density reached about 80%.

[0465] Fluorescent dye incubation: Discard the cell culture medium, add 80 μL / well loading buffer, and incubate at room temperature in the dark for 60 minutes.

[0466] Compound incubation: Discard the loading buffer, add 80 μL / well of the prepared compound solution, and incubate at room temperature in the dark for 20 minutes.

[0467] Fluorescence data acquisition: Real-time fluorescence signal recording was performed using an FDSS / μCELL instrument with an excitation wavelength of 480 nm and an emission wavelength of 540 nm. Recording was performed once per second. After a 10-second baseline, 20 μL / well of stimulation buffer was added and recording continued for 180 seconds.

[0468] 1.2 Solution preparation

[0469] Loading buffer: 10 mL / plate, prepared as follows:

[0470] Ingredient Volume PowerLoad TM Concentrate, 100X (ingredient C) 100μL LuxOR TM Reagent, reconstituted in DMSO (step 1.2) 10 μL deionized water 8.8 mL FluxOR TM Assay buffer, 10X (Component B) 1 mL probenecid, reconstituted in deionized water (step 1.1) 100 μL total volume 10 mL

[0471] Test buffer sample: 100 mL / plate, prepared as follows:

[0472] Ingredients Volume Deionized water 8.9 mL FluxOR TM Assay buffer, 10X (Component B) 1 mL probenecid, reconstituted in deionized water (step 1.1) 100 μL total volume 10 mL

[0473] Stimulation buffer: 5 mL / plate, prepared as follows:

[0474]

[0475] The above buffer solution is derived from a commercially available kit called FluxOR potassium ion channel assay.

[0476] 1.3 Compound preparation

[0477] Prepare a 20mM DMSO stock solution of the compound, take 10μL of the 20mM stock solution of the compound to 20μL DMSO solution, and serially dilute 3-fold to 8 intermediate concentrations; then take each intermediate concentration of the compound into the test buffer, dilute 200-fold to obtain the final concentration to be tested, and take 80μL to add to the test plate.

[0478] The highest concentration tested was 100 μM, followed by 8 concentrations: 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, and 0.045 μM. Each concentration was tested in triplicate.

[0479] The DMSO content in the final test concentration does not exceed 0.5%, and this concentration of DMSO has no effect on KCNQ2 potassium channels.

[0480] 1.4 Data Analysis

[0481] The experimental data were analyzed using Excel 2007 and GraphPad Prism 5.0 software, and the agonist effect was calculated by statistically analyzing the ratio over 180 seconds. The agonist effect of the compound was calculated using the following formula:

[0482]

[0483] 1.5 Quality Control

[0484] Environment: Temperature ~25℃

[0485] Reagents: FluxOR™ Detection Kit (Invitrogen, Cat# F0017)

[0486] The experimental data in the report must meet the following criteria: Z'Factor>0.5

[0487] 2. Determination results: See Table 1 for details, where EC50 The smaller the value, the higher the activity of the corresponding compound.

[0488] Table 1. Test results of some compounds described in the present invention

[0489] Compound maximum agonist rate (%) EC 50 (uM)A37.970.44B37.50.16D29.510.45I38.30.44U52.30.33O29.430.78P38.220.034V45.76 0.34W33.20.18X28.940.072Y37.960.20Z48.650.094A135.840.73A244.530.13A336.160.21

[0490] A448.110.27A534.410.049A617.080.29A735.920.40

[0491] References for the above test methods:

[0492] Zhaobing Gao et al.Journal of Biological Chemistry.2010,285(36):28322-28332.

[0493] Example 35 Pharmacokinetic Study in Mice

[0494] 1) Research purpose: To obtain the pharmacokinetic characteristics and blood-brain barrier status of the test compound in male ICR mice

[0495] 2) Experimental content

[0496] Six healthy male ICR mice (weight range 18-22 g) were divided into two groups, 3 mice per group. After fasting overnight (oral administration group only), the test compound was administered intravenously at 0.5 mg / kg and orally at 10 mg / kg. Blood was collected by jugular vein puncture at time points 0.083 (IV only), 0.25, 0.5, 1, 2, 4, 6 (PO only), 8 and 24 h. At least 0.3 mL of whole blood was collected into EDTA-K2 anticoagulant tubes. Within half an hour, plasma was obtained by centrifugation (6000 rpm, 8 minutes, 4°C) and frozen at -20°C for later use.

[0497] For brain-to-blood ratio studies, six healthy male ICR mice (weight range 18-22 g) were divided into two groups of three mice each. After an overnight fast, the test compound (10 mg / kg) was orally administered. Blood was collected by cardiac puncture at time points 2 and 4 hours. At least 0.5 mL of whole blood was collected into EDTA-K2 anticoagulant tubes. Within half an hour, plasma was centrifuged (6000 rpm, 8 minutes, 4°C) and frozen at -20°C until further use. Brain tissue was simultaneously collected, rinsed with saline, blotted dry with absorbent paper, weighed, and frozen at -20°C until further use.

[0498] Experimental results: According to the obtained blood drug concentration data, The pharmacokinetic parameters after drug administration were calculated using the non-compartmental model using Pharsight 7.0 software (Pharsight, USA).

[0499] Table 2 PK parameters of single dose in male ICR mice

[0500]

[0501]

[0502] * Intravenous (IV) dose is 1 mg / kg

[0503] Table 3 Brain-to-blood ratio at different time points after single oral administration in male ICR mice

[0504]

[0505] The brain-to-blood ratio is very important for neurological drugs. As shown in Table 3, the compounds of the present invention all have excellent brain-to-blood ratios, which will bring better efficacy and excellent safety. By comparing the brain-to-blood ratios of compound A and compound I, and compound B and compound J, it can be seen that the tert-butyl group of compound A or compound B is replaced by After treatment, the brain-blood ratio of mice increased significantly (more than 2 times).

[0506] Example 36 Pharmacokinetic Study in Rats

[0507] 1) Study objective: To obtain the pharmacokinetic characteristics of the test compound in male SD rats.

[0508] 2) Experimental content

[0509] Pharmacokinetic study: Six healthy male SD rats (SPF grade) were divided into two groups, 3 rats per group, and after fasting overnight (oral administration group only), they were given compound A at 0.3 mg / kg intravenous and 5 mg / kg orally. Blood was collected by jugular vein puncture at time points 0.083 (IV only), 0.25, 0.5, 1, 2, 4, 6 (PO only), 8 and 24 h. At least 0.3 mL of whole blood was collected into EDTA-K2 anticoagulant tubes. Within half an hour, plasma was obtained by centrifugation (6000 rpm, 8 minutes, 4°C) and frozen at -20°C for later use.

[0510] Experimental results: According to the obtained blood drug concentration data, The pharmacokinetic parameters after drug administration were calculated using the non-compartmental model using Pharsight 7.0 software (Pharsight, USA).

[0511] Table 4 PK parameters of single dose in male SD rats

[0512]

[0513]

[0514] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula A or a pharmaceutically acceptable salt thereof, in, R 1 is selected from the following substituted or unsubstituted groups: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR 8 R 9 , ethynyl; R 2 and R 3 are independently selected from the following groups: hydrogen, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; or R 2 and R 3 and their respective connected C to form C 3-10 Cycloalkyl, the cycloalkyl is optionally substituted by 1-3 substituents selected from the group consisting of hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; R 4 and R 5 are independently selected from the following groups: hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 6 is selected from the following substituted or unsubstituted groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; n is selected from the following group: 1, 2, 3; W is CR 7 or N; R 7 Selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; R 8 and R 9 are independently selected from the following groups: hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; or R 8 and R 9 and their respective attached N form a 3-10 membered azacycloalkyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that R 1 is a substituted or unsubstituted phenyl group, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR 8 R 9 , ethynyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, deuterium; R 4 and R 5 is methyl; R 6 is selected from the following substituted or unsubstituted groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl; n is 1; W is CR 7 ; R 7 Selected from the group consisting of hydrogen, halogen; R 8 and R 9 C 1-6 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, It is characterized in that R 1 is a substituted or unsubstituted phenyl group, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, -NR 8 R 9 , ethynyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, deuterium; R 4 and R 5 is methyl; R 6 Select from the following group: n is 1; W is CR 7 ; R 7 Selected from the group consisting of hydrogen, halogen; R 8 and R 9 C 1-6 alkyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, It is characterized in that R 1 is a substituted or unsubstituted phenyl group, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NR 8 R 9 , ethynyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, deuterium; R 4 and R 5 is methyl; R 6 Select from the following group: n is 1; W is CR 7 ; R 7 Selected from the group consisting of hydrogen, halogen; R 8 and R 9 C 1-6 alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that R 1 is a substituted or unsubstituted phenyl group, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, -NR 8 R 9 , ethynyl; R 2 and R 3 are independently selected from the group consisting of hydrogen, deuterium; R 4 and R 5 is methyl; R 6 for n is 1; W is CR 7 ; R 7 Selected from the group consisting of hydrogen, halogen; R 8 and R 9 C 1-6 alkyl.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that The compound is selected from the group consisting of:

7. A method for preparing the compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that Includes steps: in: X is selected from the group consisting of halogen, -B(OH) 2 , -OTf; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n, W as defined in claim 1.

8. A pharmaceutical composition, It is characterized in that It comprises one or more pharmaceutically acceptable carriers and a therapeutically effective amount of one or more compounds according to claim 1 or pharmaceutically acceptable salts thereof.

9. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, It is characterized in that Used for preparing drugs for preventing and / or treating diseases sensitive to potassium ion channels.

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

11. The use according to claim 10, It is characterized in that The central nervous system disease is selected from the group consisting of epilepsy, convulsions, inflammatory pain, neuropathic pain, migraine, depression, anxiety disorders, stroke, Alzheimer's disease, neurodegenerative diseases, cocaine abuse, nicotine withdrawal, alcohol withdrawal, and tinnitus.