Phthalazinone compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to a phthalazinone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and medical application of the compound. The compound disclosed by the invention has a neuroprotective effect and can be used for treating / preventing cerebrovascular related diseases.

Description

Technical Field

[0001] The present invention relates to a phthalazinone compound or a pharmaceutically acceptable salt thereof, and use thereof in preparing a medicament for preventing and / or treating cerebrovascular-related diseases. Background Art

[0002] Cerebrovascular disease is a group of diseases that occur in the blood vessels of the brain and cause damage to brain tissue due to disorders in vascular function, such as stroke. Acute cerebrovascular disease is generally divided into two categories: ischemic and hemorrhagic. Among new cases of stroke, 62.4% are ischemic strokes. Currently, there is a shortage of drugs for the clinical treatment of ischemic strokes. Although surgical thrombectomy allows timely reperfusion of ischemic brain tissue, inflammatory factors, excitatory amino acids and other harmful substances produced during the reperfusion process can cause damage to the blood-brain barrier and excessive immune inflammatory response, further aggravating its pathological damage, causing ischemia-reperfusion injury, and causing postoperative adverse reactions such as hemorrhagic transformation, cerebral edema, and neuroinflammation, and directly affecting post-stroke recovery. Therefore, the development of new safe and effective drugs for the treatment of stroke has great social significance. Summary of the invention

[0003] The present invention provides a phthalazinone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and the medical use of the compound. The compound of the present invention has a neuroprotective effect and can be used to treat / prevent cerebrovascular-related diseases.

[0004] The present invention provides the following technical solutions:

[0005] In a first aspect of the technical solution of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] A is -(CH 2 )n, wherein n is an integer from 0 to 5;

[0009] R 1 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;

[0010] R 2 is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;

[0011] R 3 Selected from optionally substituted C 1-4 Straight chain or branched chain alkyl.

[0012] Alternatively, the "optionally substituted" refers to being unsubstituted or substituted by one or more substituents (preferably substituted by 1, 2, or 3 substituents), wherein the "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted aryl", "optionally substituted heterocycloalkyl", "optionally substituted heteroaryl", "optionally substituted C 1-4 The substituents in the "straight or branched alkyl" are each independently selected from halogen, hydroxyl, amino, carboxyl, alkyl;

[0013] Optionally, the halogen atom in the "halogen" is selected from fluorine, chlorine, bromine and iodine;

[0014] Optionally, R 1 and R 2 When the alkyl group is an "optionally substituted alkyl group", each of the alkyl groups is independently C 1-10 A straight chain or branched chain alkyl group, optionally C 1-7 A straight chain or branched chain alkyl group, optionally C 1-5 A straight chain or branched chain alkyl group, optionally C 1-3 Straight-chain or branched alkyl, optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl;

[0015] Optionally, the "cycloalkyl" is C 3 -C 10 A cycloalkyl group of a monocyclic, fused, spirocyclic or polycyclic structure, optionally, is C 3 -C 7 Monocyclic cycloalkyl is, optionally, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

[0016] Optionally, the "aryl" is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl;

[0017] Optionally, the "heterocycloalkyl" is a 3-10 membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; optionally, the heterocyclic ring is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the heterocyclic ring is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the heterocyclic ring is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the heterocyclic ring is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring;

[0018] Optionally, the "heteroaryl" is a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S on the ring; Optionally, the "heteroaryl" is a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; Optionally, selected from pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl ), thiadiazolyl (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl); optionally, selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyrazine-2-yl, pyrazine-3-yl.

[0019] Optionally, R 3 For "C 1-4 When the term "straight-chain or branched-chain alkyl" is used, it may be methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

[0020] Optionally, n is 0, 1, 2, 3, 4 or 5.

[0021] Optionally, R 1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, phenyl or naphthyl optionally substituted by 1, 2 or 3 halogens, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and imidazolyl.

[0022] Optionally, R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, phenyl or naphthyl optionally substituted by 1, 2 or 3 halogens.

[0023] Optionally, where R 3 Selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

[0024] Optionally, the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0025]

[0026] The second aspect of the technical solution of the present invention provides a method for preparing the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0027]

[0028] (1) Using hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde as starting materials, compound IA was prepared through a condensation reaction;

[0029] (2) Compound IA is subjected to a transposition reaction to prepare compound IB;

[0030] (3) Compound IB is subjected to oxidation reaction to prepare Compound IC;

[0031] (4) Compound IC is subjected to condensation reaction to prepare Compound ID;

[0032] (5) Deprotecting the methyl group of compound ID to prepare compound IE;

[0033] (6) Compound IE reacts with a corresponding halide to prepare compound IF;

[0034] (7) preparing compound (I) by reacting compound IF with a corresponding halide;

[0035] The third aspect of the technical solution of the present invention provides a pharmaceutical composition, which comprises at least one compound represented by formula (I) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and / or excipient;

[0036] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients other than the compound or a pharmaceutically acceptable salt thereof;

[0037] Preferably, the formulation of the pharmaceutical composition can be selected from a liquid dosage form, a solid dosage form or a semisolid dosage form.

[0038] Preferably, the liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion) and a nasal drop, etc.;

[0039] Preferably, the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, lyophilized powder injections, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0040] It can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0041] Preferably, the other active pharmaceutical ingredients are active pharmaceutical ingredients for preventing and / or treating cerebrovascular-related diseases;

[0042] The third aspect of the technical solution of the present invention provides a use of the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating cerebrovascular-related diseases;

[0043] Optionally, the cerebrovascular-related disease is selected from ischemic stroke, hemorrhagic stroke, and post-stroke neurological recovery-related diseases.

[0044] In other words, the present invention provides a method for preparing a drug for treating / preventing stroke and post-stroke neural repair, which comprises administering a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need.

[0045] Some of the terms used in the present invention are defined below, and other undefined terms have meanings known to those skilled in the art.

[0046] "Optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with halogen" means that halogen may but need not be present, and the description includes instances where the alkyl is substituted with halogen and instances where the alkyl is not substituted with halogen.

[0047] The compounds of the present invention include pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts refer to salts that are pharmaceutically acceptable and have the pharmacological activity required by the parent compound. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups or both types of functional groups, and react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutically acceptable salts accordingly. Examples of pharmaceutically acceptable salts include sulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, hydroiodides, acetates, propionates, acrylates, formates, oxalates, malonates, succinates, fumarates, maleates, benzoates, chlorobenzoates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates and tartrates.

[0048] The preparation of the phthalazinone compound of the present invention or the pharmaceutical composition containing the same is prepared according to methods well known to those skilled in the art. The auxiliary materials used for making tablets, capsules, and coatings are conventional auxiliary agents, such as starch, gelatin, gum arabic, silica, and polyethylene glycol, and the solvents used for liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. The preparation containing the compound of the present invention may also contain other auxiliary agents, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, and the like.

[0049] In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0050] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0051] In order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0052] To prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of a solubilizer, cosolvent, pH adjuster, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a support agent.

[0053] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0054] The dosage of the pharmaceutical composition of the compound of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Generally speaking, the suitable daily dosage range of the compound of the present invention is 0.01 to 500 mg / kg body weight, preferably 0.1 to 300 mg / kg body weight. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the doctor's clinical experience and the dosage regimen including the use of other treatment means.

[0055] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 . Effect of compound 17 on the survival rate of rats with ischemic stroke;

[0057] Figure 2 . Effect of compound 17 on body weight of rats with ischemic stroke (n=12, *p<0.05 vs. vehicle); Figure 3 . Effect of compound 17 on cerebral infarction volume in rats with ischemic stroke (n=12, *p<0.05vs.vehicle, **p<0.01vs.vehicle). DETAILED DESCRIPTION

[0058] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0059] Preparation method

[0060] The compounds of the present invention can be synthesized according to the synthesis methods of the present invention and / or techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthesis methods.

[0061] In a general synthetic method, the compound represented by formula (I) is prepared according to the method.

[0062]

[0063] Specifically, in the method, the phthalazinone derivatives of the present invention can be prepared by 6-7 steps of reaction. For example, hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde are used as starting materials, and compound IA is prepared by condensation reaction, and compound IB is obtained by transposition reaction; IB is subjected to oxidation reaction to obtain compound IC, and compound IC is subjected to condensation reaction to obtain compound ID; the methyl group of compound ID is deprotected to obtain compound IE; compound IE is reacted with a corresponding halide to obtain compound IF; compound IF is reacted with a corresponding halide to obtain the phthalazinone compound of the present invention.

[0064] Step 1: Synthesis of (E)-N'-(2-hydroxy-6-methoxybenzylidene)valeryl hydrazide

[0065] 2-Hydroxy-6-methoxybenzaldehyde (27.0 g, 178 mmol) was dissolved in 150 mL of anhydrous ethanol, heated and stirred at 80°C until the compound was completely dissolved, valeryl hydrazide (21.6 g, 186 mmol) was dissolved in 150 mL of anhydrous ethanol and added to the reaction solution, and the reaction mixture was stirred at 80°C for 2 h. The reaction solution was concentrated to obtain a light yellow solid product (44.0 g, yield 99%), which can be directly used in the next step without purification.

[0066] Step 2: Synthesis of 2-methoxy-6-pentanoylbenzaldehyde

[0067] (E)-N'-(2-Hydroxy-6-methoxybenzylidene) valeryl hydrazide (44.0 g, 176 mmol) was dissolved in 500 mL of anhydrous THF. Lead tetraacetate (195 g, 440 mmol) was added in portions at 0°C. After reacting for 5 h, the reaction was completed as monitored by TLC. The reaction solution was filtered to remove solid insolubles, and 200 mL of water was added to quench the reaction. The mixture was extracted with ethyl acetate (300 mL×3). The combined organic layer was washed with saturated sodium bicarbonate (500 mL) and saturated brine (300 mL), respectively, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, Hexane / EtOAc=10:1, v / v) to obtain the product as a colorless oil (24.5 g, yield 63%).

[0068] Step 3: Synthesis of 2-methoxy-6-pentanoylbenzoic acid

[0069] 2-Methoxy-6-pentanoylbenzaldehyde (24.5 g, 111 mmol) was dissolved in a mixed solution of 200 mL acetonitrile and 100 mL tert-butyl alcohol, sodium chlorite (24.8 g, 222 mmol) was dissolved in 50 mL water and slowly added to the reaction solution. Then, aqueous hydrogen peroxide solution (36%, 24.0 mL, 222 mmol) was slowly added dropwise to the reaction solution, stirred at room temperature for overnight reaction (10 h), and the reaction was complete after TLC monitoring. 100 mL of water was added to dilute the reaction solution, and ethyl acetate (200 mL) was added for extraction. The ethyl acetate phase was spin-dried, and the remaining aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, Hexane / EtOAc=5:1, v / v) to obtain a pair of isomer products as colorless oil (16.4 g, yield 67%).

[0070] Step 4: Synthesis of 4-butyl-8-methoxy-phthalazin-1(2H)-one

[0071] 2-Methoxy-6-pentanoylbenzoic acid (3.0 g, 12.7 mmol) and hydrazine hydrate (19.1 mmol, 0.96 mL) were placed in a reaction bottle, 50 mL of ethanol was added, and the reaction was carried out at 80 ° C for 2 h. The reaction was completed after TLC monitoring. The reaction solution was concentrated to obtain a light yellow solid product (2.8 g, yield 95%), which can be directly used in the next step without purification.

[0072] Step 5: Synthesis of 4-butyl-8-hydroxy-phthalazin-1(2H)-one

[0073] Dissolve 4-butyl-8-methoxy-phthalazin-1(2H)-one (2.0 g, 8.6 mmol) in 20 mL of toluene solution and add AlCl 3 (3.4 g, 25.8 mmol) was slowly added to the reaction solution at 0°C, and the reaction was carried out at 110°C for 40 min. The reaction was completed by TLC monitoring, and the toluene was removed by concentration. The reaction solution was diluted with 50 mL of water, extracted with dichloromethane (50 mL×4), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product as a light brown solid (1.7 g, yield 92%). The product can be directly used in the next step without purification.

[0074] Step 6: Synthesis of O-substituted phthalazinone derivatives

[0075] 2-Hydroxy-4-butyl-phthalazin-1(2H)-one (0.3mmol) and halide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, potassium carbonate (0.75mmol) was added, and the mixture was reacted at 70°C for 1h. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain O-substituted phthalazinone derivatives.

[0076] Step 7: Synthesis of N,O-substituted phthalazinone derivatives

[0077] O-substituted phthalazinone derivatives (0.3mmol) and halogenated compounds (0.5mmol) were placed in a reaction flask, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was extracted (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain N,O-substituted phthalazinone derivatives.

[0078] Example 1: 2-Ethyl-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0079]

[0080] According to the method of step 7 of method I, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3mmol) was used as the raw material and ethyl bromide (0.5mmol) was placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain the title compound 2.

[0081] ESI-MS: m / z 261.5[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H:7.81(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),4.05(q,J=6.5Hz,2H),3.87(s,3H), 2.85(t,J=8.0Hz,2H),1.59-1.65(m,2H),1.33-1.41(m,2H),1.23(t,J=6.5Hz,3H),0.90(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.7,156.0,144.7,134.4,131.2,116.3,116.2,113.3,56.1,45.1,31.6,29.7,21.9,13.8,13.5.

[0082] Example 2: 2-propyl-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0083]

[0084] According to the method of step 7 of method I, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3mmol) was used as a raw material and iodopropane (0.5mmol) was placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-propyl-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0085] ESI-MS: m / z 275.3[M+H] + .1H NMR (500MHz, Methanol-d 4 )δ H :7.78(m,1H),7.42(t,J=7.6Hz,1H),7.30(dd,J=8.9,4.4Hz,1H),4.09(t,J=7.2Hz,2H),3.94(d,J=2 .8Hz,3H),2.88(q,J=7.7,6.6Hz,2H),1.81(m,2H),1.69(m,2H),1.42(m,2H),0.94(q,J=7.3Hz,6H). 13 C NMR (125MHz, Methanol-d 4 )δC :160.1,158.3,146.4,134.4,131.5,116.2,116.1,112.8,55.2,52.3,31.7,29.7,22.1,21.4,12.9,10.2.

[0086] Example 3: 2-(Cyclopropylmethyl)-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0087]

[0088] According to the method of step 7 of method I, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3mmol) was used as a raw material and bromomethylcyclopropane (0.5mmol) was placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(cyclopropylmethyl)-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0089] ESI-MS: m / z 287.6[M+H] + . 1 H NMR (500MHz, Methanol-d 4 )δ H :7.82(t,J=8.2Hz,1H),7.48(dd,J=8.1,0.9Hz,1H),7.35(d,J=8.3Hz,1H),4.02(d,J=7.1Hz,2H),3.97(s,3H),2.9 3(m,2H),1.74(m,2H),1.46(m,2H),0.98(t,J=7.4Hz,3H),0.87(dd,J=17.3,6.9Hz,1H),0.51(m,2H),0.44(m,2H). 13 C NMR (125MHz, Methanol-d 4 )δ C :161.5,159.7,147.7,135.8,133.1,117.6,117.5,114.2,56.8,56.5,33.1,31.1,23.5,14.3,11.3,3.9.

[0090] Example 4: 2-Cyclopropylmethyl-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0091]

[0092] According to the method of step 7 of method I, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3mmol) was used as a raw material and bromomethylcyclopropane (0.5mmol) was placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-cyclopropylmethyl-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0093] ESI-MS: m / z 329.3[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :7.84(td,J=8.2,1.5Hz,1H),7.49(dd,J=8.0,2.0Hz,1H),7.36(d,J=8.3Hz,1H),4.01(d,J=7.2Hz,2H),3.97(s,3H) ,2.94(m,2H),2.00(m,1H),1.74(m,4H),1.66(m,3H),1.45(m,2H),1.26(m,2H),0.98(t,J=7.4Hz,3H),0.98(m,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :161.6,160.0,147.6,135.9,132.9,117.6,117.5,114.3,57.8,56.6,38.5,33.1,31.8,31.1,27.6,27.0,23.4,14.3.

[0094] Example 5: 4-Butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0095]

[0096] According to the method of step 6 of method I, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3mmol) and (bromomethyl)cyclohexane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, potassium carbonate (0.75mmol) was added, and the mixture was reacted at 70°C for 1h. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one.

[0097] ESI-MS: m / z 315.7[M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :11.91(s,1H),7.78(t,J=7.0Hz,1H),7.42(d,J=7.0Hz,1H),7.31(d,J=7.0Hz,1H),3.89(d,J=7.5Hz,2H),2.83(t,J=7.0Hz,2H) ,1.91(m,2H),1.81(m,1H),1.72(m,2H),1.60-1.67(overlap,3H),1.39(m,2H),1.07-1.30(overlap,5H),0.92(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.3,157.8,144.8,134.5,131.7,116.7,116.2,114.0,73.8,36.9,31.5,29.4,29.0,26.0,25.3,21.8,14.0.

[0098] Example 6: 2-Ethyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0099]

[0100] According to the method of step 7 of method I, 4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one (0.3mmol) and ethyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-ethyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one.

[0101] ESI-MS: m / z 343.6[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :7.76(t,J=8.0Hz,1H),7.40(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),4.04(q,J=7.0Hz,2H),3.85(d,J=6.5Hz,2H),2.83(t,J=7.0Hz,2H),1.92(m, 2H),1.78(m,1H),1.71(m,2H),1.60-1.67(overlap,3H),1.37(m,2H),1.19-1.30(overlap,5H),1.15(m,1H),1.08(m,2H),0.90(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.3,156.1,144.7,134.3,131.2,116.3,116.1,114.1,73.8,45.0,37.2,31.6,29.7,29.2,26.1,25.4,21.9,13.8,13.6.

[0102] Example 7: 2-Benzyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0103]

[0104] According to the method of step 7 of method I, 4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one (0.3mmol) and benzyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-benzyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one.

[0105] ESI-MS: m / z 405.9[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :7.79(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.22-7.33(overlap,6H),5.22(s,2H),3.86(d,J=6.5Hz,2H),2.84(t,J=7.5Hz,2H),1.92 (m,2H),1.78(m,1H),1.70(m,2H),1.60-1.66(overlap,3H),1.36(m,2H),1.14-1.30(overlap,3H),1.06(m,2H),0.88(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.4,156.5,145.1,138.0,134.6,131.3,128.4,127.4,127.1,116.3,116.3,114.4,73.8,53.3,37.1,31.5,29.6,29.2,26.1,25.4,21.8,13.8.

[0106] Example 8: 4-Butyl-8-propoxy-phthalazin-1(2H)-one

[0107]

[0108] According to the method of step 6 of method I, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3mmol) and 1-bromopropane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, potassium carbonate (0.75mmol) was added, and the mixture was reacted at 70°C for 1h. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0109] ESI-MS: m / z 261.5[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :12.02(s,1H),7.75(t,J=7.5Hz,1H),7.37(d,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),4.00(t,J=6.5Hz,2H), 2.78(t,J=7.5Hz,2H),1.75(m,2H),1.59(m,2H),1.34(m,2H),1.02(t,J=7.5Hz,3H),0.87(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.2,157.9,144.9,134.4,131.7,116.8,116.3,114.3,70.1,31.5,29.5,22.0,22.0,13.8,10.5.

[0110] Example 9: 2-(Pyridin-4-methylene)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0111]

[0112] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and 4-(bromomethyl)-pyridine (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(pyridin-4-methylene)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0113] ESI-MS: m / z 352.7[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :8.49(d,J=6.0Hz,2H),7.83(t,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.36(d,J=8.0Hz,1H),7.20(d,J=6.0Hz,2H),5.24(s,2H),4 .03(t,J=6.5Hz,2H),2.83(t,J=7.5Hz,2H),1.76(m,2H),1.64(m,2H),1.35(m,2H),1.02(t,J=7.5Hz,3H),0.87(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.3,156.5,149.7,146.8,145.7,134.7,131.3,122.1,116.5,116.1,114.7,70.2,52.6,31.5,29.5,22.0,21.9,13.7,10.5.

[0114] Example 10: 2-(4-Fluorobenzyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0115]

[0116] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and 4-fluorobenzyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(4-fluorobenzyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0117] ESI-MS: m / z 369.7[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :7.79(t,J=7.5Hz,1H),7.43(d,J=7.5Hz,1H),7.32-7.35(overlap,3H,H-7),7.13(m,2H),5.18(s,2H),4.02(t,J=6. 5Hz,2H),2.84(t,J=7.5Hz,2H),1.77(m,2H),1.62(m,2H),1.32(m,2H),1.03(t,J=7.5Hz,3H),0.88(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :162.4,160.5,159.3,156.4,145.2,134.6,134.1,134.1,131.3,129.8,129.7,116.4,116.3,115.2,115.1,114.6,70.2,52.8,31.5,29.5,22.1,21.8,13.8,10.6.

[0118] Example 11: 2-propyl-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0119]

[0120] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and iodopropane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-propyl-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0121] ESI-MS: m / z 303.2[M+H] + . 1 H NMR (500MHz, Methanol-d 4 )δ H :7.81(dq,J=24.4,8.2,7.8Hz,1H),7.45(dt,J=22.2,8.1Hz,1H),7.34(dt,J=21.9,8.0 Hz,1H),4.06(m,2H),4.02(d,J=6.9Hz,1H),3.97(m,1H),3.37(dd,J=12.7,6.2Hz,1H),2 .86(q,J=10.2,7.6Hz,1H),1.82(m,2H),1.76(s,3H),1.76(m,1H),1.67(dt,J=24.4,7. 4Hz,2H),1.39(dd,J=15.5,8.1Hz,2H),1.10(m,1H),1.06(d,J=7.4Hz,1H),0.92(m,6H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.3,156.3,144.5,134.3,131.2,116.3,116.2,114.4,70.2,51.5,31.5,29.7,22.1,21.9,21.4,13.8,11.1,10.6.

[0122] Example 12: 2-(Cyclopropylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0123]

[0124] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and bromomethylcyclopropane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(cyclopropylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0125] ESI-MS: m / z 315.3[M+H] + . 1 H NMR (500 MHz, DMSO-d 6 )δ H :7.80(t,J=8.1Hz,1H),7.43(d,J=8.0Hz,1H),7.33(d,J=8.3Hz,1H),4.04(t,J=6.3Hz,2H),3.89(d,J=7.1Hz,2H),2.86(t,J=7.6H z,2H),1.80(m,2H),1.66(m,2H),1.40(m,2H),1.27(m,1H),1.06(t,J=7.4Hz,3H),0.92(t,J=7.4Hz,3H),0.45(m,2H),0.37(m,2H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.3,156.4,144.3,134.3,131.3,116.4,116.2,114.4,70.2,54.4,31.5,29.5,22.1,21.9,13.8,10.6,10.4,3.2.

[0126] Example 13: 2-(Cyclohexylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0127]

[0128] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and bromomethylcyclohexane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(cyclohexylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0129] ESI-MS: m / z 357.4 [M+H] + . 1 H NMR (500MHz, Methanol-d 4 )δ H :7.79(t,J=8.2Hz,1H),7.45(d,J=7.8Hz,1H),7.32(d,J=8.3Hz,1H),4.11( t,J=6.6Hz,2H),3.99(d,J=7.3Hz,2H),2.92(t,J=7.6Hz,2H),1.99(m,1H),1 .93(m,2H),1.73(m,4H),1.66(dd,J=10.6,3.8Hz,3H),1.44(m,2H),1.24(m, 2H),1.22(s,1H),1.12(s,1H),1.10(d,J=7.5Hz,4H),0.97(t,J=7.4Hz,3H). 13 C NMR (125MHz, Methanol-d 4 )δ C :161.2,159.9,147.5,135.7,132.9,117.7,117.4,115.4,72.1,57.9,38.4,33.1,31.8,31.1,27.6,27.0,23.4,23.3,14.3,10.9.

[0130] Example 14: 2-(Naphthylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0131]

[0132] According to the method of step 7 of method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3mmol) and bromomethylnaphthalene (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(naphthylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0133] ESI-MS: m / z 401.3[M+H] + .1H NMR (500MHz, Methanol-d 4 )δ H :7.78(m,5H),7.52(dd,J=8.5,1.8Hz,1H),7.41(m,3H),7.29(d,J=8.3Hz,1H),5.47(s,2H),4.08(t,J=6.7Hz,2 H),2.91(t,J=7.6Hz,2H),1.91(m,2H),1.71(m,2H),1.38(m,2H),1.08(t,J=7.4Hz,3H),0.91(t,J=7.4Hz,3H). 13 C NMR (125MHz, Methanol-d 4 )δ C :161.2,159.8,148.3,136.3,135.9,134.8,134.3,133.1,129.2,128.8,128.6,128.0,127.2,127.1,126.9,117.8,117.5,115.5,72.1,55.6,33.1,31.0,23.4,23.2,14.3,10.8.

[0134] Example 15: 4-Butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0135]

[0136] According to the method of step 6 of method I, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3mmol) and (bromomethyl)cyclopropane (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, potassium carbonate (0.75mmol) was added, and the mixture was reacted at 70°C for 1h. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0137] ESI-MS: m / z 273.5[M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :12.03(s,1H),7.77(t,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,1H),3.97(d,J=6.5Hz,2H),2. 81(t,J=7.0Hz,2H),1.61(m,2H),1.35(m,2H),1.26(m,1H),0.90(t,J=7.5Hz,3H),0.54(m,2H),0.40(m,2H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :159.1,157.9,145.0,134.4,131.7,117.0,116.6,115.1,73.0,31.5,29.6,22.0,13.8,10.1,3.2.

[0138] Example 16: 2-(4-Fluorobenzyl)-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one

[0139]

[0140] According to the method of step 7 of method I, 4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one (0.3mmol) and 4-fluorobenzyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-(4-fluorobenzyl)-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0141] ESI-MS: m / z 381.7[M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :7.77(t,J=8.0

[0142] Hz,1H),7.42(d,J=8.0Hz,1H),7.34(m,2H),7.30(d,J=8.0Hz,1H),7.13(m,2H),5.18(m,2H),3.95(d,J=7.5Hz,2H ),2.83(t,J=7.5Hz,2H),1.61(m,2H),1.31(m,2H),1.25(m,1H),0.87(t,J=7.5Hz,3H),0.56(m,2H),0.39(m,2H). 13 CNMR (125MHz, DMSO-d 6 )δ C :162.4,160.4,159.2,156.2,145.2,134.5,134.1,134.1,131.3,129.8,129.7,116.5,116.4,115.2,115.2,115.0,73.0,52.8,31.5,29.5,21.8,13.8,10.0,3.2.

[0143] Example 17: 2-Ethyl-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one

[0144]

[0145] According to the method of step 7 of method I, 4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one (0.3mmol) and ethyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added to dissolve, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out at room temperature for 3h. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-ethyl-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0146] ESI-MS: m / z 301.7 [M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :7.77(t,J=8.0

[0147] Hz,1H),7.44(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),4.05(q,J=7.0Hz,2H),3.97(d,J=6.0Hz,2H),2.85(t,J=7 .0Hz,2H),1.64(m,2H),1.38(m,2H),1.22-1.30(overlap,4H),0.91(t,J=7.5Hz,3H),0.56(m,2H),0.40(m,2H). 13 CNMR (125MHz, DMSO-d 6 )δ C :159.1,156.0,144.8,134.3,131.2,116.6,116.5,115.2,73.0,45.1,31.6,29.7,21.9,13.8,13.5,10.1,3.1.

[0148] Example 18: 4-Butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one

[0149]

[0150] According to the method of step 6 of method I, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3mmol) and 2-(bromomethyl)-naphthalene (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, potassium carbonate (0.75mmol) was added, and the mixture was reacted at 70°C for 1h. The reaction was monitored to be complete by TLC. 50mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one.

[0151] ESI-MS: m / z 359.2[M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :12.15(s,1H),8.18(s,1H),7.88-7.95(overlap,3H),7.82(t,J=8.0Hz,1H),7.72(dd,J=7.5Hz,1.5Hz,1H),7 .52(m,2H),7.48(m,2H),5.46(m,2H),2.83(t,J=7.5Hz,2H),1.64(m,2H),1.39(m,2H),0.91(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :158.5,158.1,145.1,134.7,134.5,132.8,132.5,131.8,127.9,127.8,127.7,126.3,126.0,125.6,125.2,117.1,117.0,115.2,70.1,31.5,29.6,22.1,13.9.

[0152] Example 19: 2-Ethyl-4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one

[0153]

[0154] According to the method of step 7 of method I, 4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one (0.3mmol) and ethyl bromide (0.5mmol) were placed in a reaction bottle, 3.0mL of anhydrous DMF was added for dissolution, sodium hydride (60%, 0.6mmol) was added at 0°C, and the reaction was carried out for 3h at room temperature. TLC monitored the reaction to be complete. 50mL of water was added to quench the reaction, and ethyl acetate was used for extraction (50mL×3). The combined organic layer was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain 2-ethyl-4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one.

[0155] ESI-MS: m / z 387.6[M+H] + .1H NMR (500MHz, DMSO-d 6 )δ H :8.14(s,1H),7.95(d,J=7.5Hz,1H),7.91(m,2H),7.80(t,J=8.0Hz,1H),7.76(dd,J=7.5Hz,1.5Hz,1H),7.52(m,2H),7.46(m,2H), 5.43(s,2H),4.10(q,J=7.5Hz,2H),2.85(t,J=7.5Hz,2H),1.64(m,2H),1.39(m,2H),1.26(t,J=7.5Hz,3H),0.91(t,J=7.5Hz,3H). 13 C NMR (125 MHz, DMSO-d 6 )δ C :158.6,156.2,144.8,134.6,134.3,132.8,132.5,131.3,128.0,127.8,127.7 126.3,126.3,126.0,125.7,125.3,116.9,116.8,115.3,70.3,45.2,31.6,29.5,21.8,13.9,13.6.

[0156] Example 20: In vitro neuroprotective activity screening

[0157] The in vitro neuroprotective model of the tested compounds was hydrogen peroxide injury and glutamate injury model. PC-12 cells were cultured at 1.5×10 4 / mL density, 100μL per well was inoculated in a 96-well culture plate, and the experiment was divided into a blank group, a model group, and a drug-added group. The hydrogen peroxide injury and glutamate injury models were stimulated for 2 hours with a final concentration of 120μM hydrogen peroxide and 8mM glutamate, respectively. The blank group was then cultured with complete medium, and the drug-added group was added with 10μM of the test compound. After incubation for 24 hours in each group, 10μL CCK-8 was added to each well. After 60 minutes, the absorbance at 490nm was measured using an enzyme reader, and the survival rate was calculated. The survival rate = (survival rate of the drug group-survival rate of the model group) / (survival rate of the model group). The results are shown in Tables 1 and 2:

[0158] Table 1 Protective effect of phthalazinones on neuronal cell damage induced by hydrogen peroxide (120 μM)

[0159]

[0160]

[0161] Table 2 Protective effect of phthalazinones on glutamate (8 mM)-induced neuronal cell damage

[0162]

[0163] Example 21: Study on the anti-ischemic stroke activity of compound 17 in vivo

[0164] Male SD rats weighing 280-300 g, certificate number: No.11400700293705, purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., license number SYXK (Beijing) 2014-0023, were kept in the SPF animal room of the Institute of Materia Medica, Chinese Academy of Medical Sciences. They were fed with normal feed and had free access to water. An appropriate amount of compound 17 prepared in Example 16 was accurately weighed and dissolved in physiological saline to prepare a 6 mg / mL solution for use. In the same way, butylphthalide (NBP) was prepared into a 20 mg / mL solution for use.

[0165] 120 SD male rats (SPF grade) weighing 280-300g were randomly divided into 6 groups, namely sham group, model group, positive drug group (butylphthalide, NBP group) and drug administration group (low, medium and high dose), with 20 rats in each group. Using the improved middle cerebral artery occlusion method, the suture slowly entered the proximal end of the anterior cerebral artery from the right external carotid artery through the internal carotid artery to block the blood supply source on the opposite side of the middle cerebral artery. The sham group was only anesthetized and vascular stripped, without ligating the blood vessels and introducing the suture. The drug administration group was gavaged with 10, 30, and 60 mg / kg of compound 17, the positive drug group was gavaged with 200 mg / kg of NBP, and the model group was gavaged with the same volume of normal saline, once a day for 7 consecutive days.

[0166] Three hours after the model was successfully prepared, the neurological function score was scored according to the Longa method on a 5-point scale: 0 points, no obvious neurological symptoms; 1 point, unable to fully extend the contralateral forelimb; 2 points, turning in circles to the contralateral side; 3 points, falling to the contralateral side when walking; 4 points, unable to walk independently. Rats with a score of 2 or 3 were included in the group, and the rest were excluded.

[0167] The 2,3,5-triphenyltetrazolium chloride staining method was used to detect the infarction volume of rats. After 7 days of drug administration, the rats were deeply anesthetized, and the brains were removed by decapitation. After being placed in a brain mold, 2 mm thick brain slices were cut along the coronal plane of the brain, and the brain slices were immersed in 2,3,5-triphenyltetrazolium chloride staining solution and stained for 15 minutes in the dark. After being fixed overnight with 4% paraformaldehyde, the stained brain slices were scanned and the infarction volume was calculated.

[0168] The experimental results are as follows Figure 1-3 As shown, it can be seen that different oral administrations of compound 17 (10, 30, 60 mg / kg) can effectively improve the survival rate of rats with ischemia-reperfusion injury, reverse the trend of weight loss in rats, and reduce the volume of cerebral infarction in a dose-dependent manner, and are superior to the effect of the positive drug butylphthalide (200 mg / kg).

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in: A is -(CH2)n-, wherein n is an integer from 0 to 5; R1 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl; R2 is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl; R3 is selected from optionally substituted C 1-4 Straight chain or branched chain alkyl.

2. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The "optionally substituted" refers to being unsubstituted or substituted by one or more substituents (preferably substituted by 1, 2, or 3 substituents), wherein the "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted aryl", "optionally substituted heterocycloalkyl", "optionally substituted heteroaryl", "optionally substituted C 1-4 The substituents in the "straight or branched alkyl" are independently selected from halogen, hydroxy, amino, carboxyl, alkyl, cyano; Optionally, the halogen atom in the "halogen" is selected from fluorine, chlorine, bromine and iodine; Optionally, when R1 and R2 are "optionally substituted alkyl", the alkyl groups are each independently C 1-10 A straight or branched chain alkyl group, optionally C 1-7 A straight or branched chain alkyl group, optionally C 1-5 A straight or branched chain alkyl group, optionally C 1-3 Straight-chain or branched alkyl, optionally, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl; Optionally, the "cycloalkyl" is C3-C 10 A cycloalkyl group having a monocyclic, condensed, spirocyclic or polycyclic structure, optionally, a C3-C7 monocyclic cycloalkyl group, optionally, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; Optionally, the "aryl" is a 6-10 membered monocyclic or bicyclic fused aromatic ring group; optionally, it is phenyl or naphthyl; optionally, it is phenyl, 1-naphthyl, or 2-naphthyl; Optionally, the "heterocycloalkyl" is a 3-10 membered non-aromatic heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; optionally, the heterocyclic ring is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the heterocyclic ring is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; optionally, the heterocyclic ring is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring; optionally, the heterocyclic ring is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring; Optionally, the "heteroaryl" is a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S on the ring; Optionally, the "heteroaryl" is a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; Optionally, selected from pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl or 1,2,3-triazolyl ), thiadiazolyl (1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or 1,2,4-thiadiazolyl) and oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl); optionally, selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazin-3-yl; Optionally, R3 is "C 1-4 When the term "straight-chain or branched-chain alkyl" is used, it may be methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

3. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that: The n is 0, 1, 2, 3, 4 or 5.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: R1 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, phenyl or naphthyl optionally substituted by 1, 2 or 3 halogens, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and imidazolyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, phenyl or naphthyl optionally substituted by 1, 2 or 3 halogens.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: Wherein R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: Selected from the following compounds:

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The pharmaceutically acceptable salts include the following salts formed by the compound represented by formula (I) and an acid: sulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, acrylate, formate, oxalate, malonate, succinate, fumarate, maleate, benzoate, chlorobenzoate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate and tartrate.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises at least one compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or excipient: Preferably, the formulation of the pharmaceutical composition is selected from a liquid dosage form, a solid dosage form or a semisolid dosage form; Preferably, the liquid dosage form can be selected from solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions) and nasal drops; Preferably, the solid dosage form is selected from tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, and freeze-dried powder injections; Preferably, the semisolid dosage form is selected from ointments, gels, and pastes.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition further comprises one or more other active pharmaceutical ingredients in addition to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

11. Use of the compound represented by formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 or 10 in the preparation of a medicament for preventing and / or treating cerebrovascular-related diseases; Optionally, the cerebrovascular-related disease is selected from ischemic stroke, hemorrhagic stroke, and post-stroke neurological recovery-related diseases.

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