A phthalazinone compound, a preparation method thereof, a pharmaceutical composition, and a use thereof

Abstract

A phthalazine ketone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and a medical use of the compound. The compound of the present application has a neuroprotective effect and can be used for treating / preventing cerebrovascular-related diseases.

Description

Technical Field

[0001] This invention relates to an phthalazinone compound or a pharmaceutically acceptable salt thereof, and its use in the preparation of medicaments for the prevention and / or treatment of cerebrovascular-related diseases. Background Technology

[0002] Cerebrovascular diseases are a group of diseases that occur in the blood vessels of the brain, causing brain tissue damage due to vascular dysfunction, such as stroke. Acute cerebrovascular diseases are generally divided into ischemic and hemorrhagic types. 62.4% of newly diagnosed stroke cases are ischemic strokes, and currently, there is a lack of drugs available for the clinical treatment of ischemic stroke. Although surgical thrombectomy allows for timely reperfusion of ischemic brain tissue, harmful substances such as inflammatory factors and excitatory amino acids produced during reperfusion can disrupt the blood-brain barrier and trigger excessive immune inflammatory responses, further aggravating pathological damage, causing ischemia-reperfusion injury, resulting in postoperative adverse reactions such as hemorrhagic transformation, cerebral edema, and neuroinflammation, and directly affecting post-stroke recovery. Therefore, developing safe and effective new drugs for the treatment of stroke has significant social implications. Summary of the Invention

[0003] This invention provides a phthalazinone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing such a compound, and the pharmaceutical uses of such a compound. The compounds of this invention have neuroprotective effects and can be used to treat / prevent cerebrovascular diseases.

[0004] This invention provides the following technical solution:

[0005] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] A is -(CH2)n, where n is an integer from 0 to 5;

[0009] R1 is selected from hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;

[0010] R2 is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl;

[0011] R3 is selected from C with optional substitution. 1-4 Straight-chain or branched alkyl groups.

[0012] Optionally, "optionally substituted" refers to unsubstituted or substituted with one or more substituents (preferably substituted with 1, 2, or 3 substituents), wherein "optionally substituted alkyl", "optionally substituted cycloalkyl", "optionally substituted aryl", "optionally substituted heterocycloalkyl", "optionally substituted heteroaryl", "optionally substituted C" 1-4 The substituents in "straight-chain or branched alkyl" are each independently selected from halogens, hydroxyl groups, amino groups, carboxyl groups, and alkyl groups;

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

[0014] Alternatively, when R1 and R2 are "optionally substituted alkyl groups", each of the alkyl groups is independently C1. 1-10 Straight-chain or branched alkyl groups, optionally C10, are used. 1-7 Straight-chain or branched alkyl groups, optionally C10, are used. 1-5 Straight-chain or branched alkyl groups, optionally C10, are used. 1-3 Straight-chain or branched alkyl groups, optionally 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 C3-C 10 Cycloalkyl groups with monocyclic, fused, spirocyclic, or polycyclic structures, optionally C3-C7 monocyclic cycloalkyl groups, 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 "heterocyclic alkyl" is a 3-10 membered non-aromatic heterocyclic group containing one, two, or three heteroatoms selected from N, O, and S on the ring; alternatively, the heterocycle is a 3-10 membered non-aromatic cyclic group containing one or two heteroatoms selected from N and O on the ring; alternatively, the heterocycle is a 3-6 membered non-aromatic cyclic group containing one or two heteroatoms selected from N and O on the ring; alternatively, the heterocycle is a 3-10 membered non-aromatic cyclic group containing one or two heteroatoms selected from N and S on the ring; alternatively, the heterocycle is a 3-6 membered non-aromatic cyclic group containing one or two 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, it is selected from pyridyl, pyrroloyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiopheneyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, imidazoleyl, triazolyl (1,2,4-triazolyl, 1,3,4-triazolyl, or 1,2,3-triazolyl). ), thiadiazole (1,3,4-thiadiazole, 1,2,5-thiadiazole, 1,2,3-thiadiazole or 1,2,4-thiadiazole) and oxadiazole (1,3,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole or 1,2,4-oxadiazole); 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.

[0019] Optionally, R3 is "C 1-4 When "straight-chain or branched alkyl" is used, it may optionally be methyl, ethyl, propyl, isopropyl, n-butyl, or isobutyl.

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

[0021] Optionally, R1 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 with 1, 2, or 3 halogens, pyridyl, pyrroloyl, pyrazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, isothiazolyl, and imidazoleyl.

[0022] Optionally, R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthyl, or phenyl or naphthyl optionally substituted with 1, 2, or 3 halogens.

[0023] Optionally, R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

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

[0025]

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

[0027]

[0028] (1) Compound IA was prepared by condensation reaction using hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde as starting materials;

[0029] (2) Compound IA was converted into compound IB via a transposition reaction;

[0030] (3) Compound IB was prepared into compound IC by oxidation reaction;

[0031] (4) Compound IC was converted into compound ID via a condensation reaction;

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

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

[0034] (7) Compound (I) is prepared by reacting compound IF with the corresponding halide;

[0035] A third aspect of the present invention provides a pharmaceutical composition comprising at least one compound of 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 may be selected from liquid dosage forms, solid dosage forms, or semi-solid dosage forms.

[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 double emulsion), a suspension, an injection (including water injection, powder injection and infusion) and nasal drops, 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, microcapsules, droplets, suppositories, films, patches, lyophilized powder injections, etc.; the semi-solid dosage form can be ointment, gel, paste, etc.

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

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

[0042] A third aspect of the present invention provides the use of a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of cerebrovascular-related diseases;

[0043] Optionally, the cerebrovascular-related diseases are 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 medicament for the treatment / prevention of stroke and post-stroke neurological repair, the method comprising administering to a subject in need a preventive and / or therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.

[0045] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0046] "Optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally halogenated alkyl group" means that a halogen may but does not have to be present, and the description includes cases where the alkyl group is halogenated and cases where the alkyl group is not halogenated.

[0047] The compounds described in this invention include their pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt that is pharmaceutically acceptable and possesses the pharmacological activity required by the parent compound. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic bases, or inorganic and organic acids, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, bisulfites, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, acrylates, formates, oxalates, malonates, succinates, fumarates, maleates, benzoates, chlorobenzoates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolate, and tartrates.

[0048] The formulations of phthalazinone compounds or pharmaceutical compositions containing them of this invention are prepared according to methods well known to those skilled in the art. The excipients used in the manufacture of tablets, capsules, and coatings are conventionally used adjuvants, such as starch, gelatin, gum arabic, silica, and polyethylene glycol. Solvents used in liquid dosage forms include, for example, water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of this invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and colorants.

[0049] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0050] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0051] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants 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 compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure adjusters can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusters can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0053] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0054] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.01 to 500 mg / kg body weight, preferably 0.1 to 300 mg / kg body weight. The above doses can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0055] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation. Attached Figure Description

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

[0057] Figure 2 Effect of compound 17 on body weight in 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<0.05 vs. vehicle, **p<0.01 vs. vehicle). Detailed Implementation

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

[0059] Preparation method

[0060] The compounds described in this invention can be synthesized using the synthetic methods described herein and / or techniques well known in the art. For example, the compounds provided by this invention can be prepared according to the following general synthetic methods.

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

[0062]

[0063] Specifically, the phthalazinone derivatives of this invention can be prepared through a 6-7 step reaction in the method. For example, starting with hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde, compound IA is prepared by condensation reaction, followed by transposition reaction to obtain compound IB; IB is oxidized to obtain compound IC, and compound IC is condensed to obtain compound ID; the methyl group of compound ID is deprotected to obtain compound IE; compound IE reacts with the corresponding halogen to obtain compound IF; compound IF reacts with the corresponding halogen to obtain the phthalazinone compounds of this invention.

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

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

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

[0067] (E)-N'-(2-hydroxy-6-methoxybenzyl)valerate (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 5 h of reaction, the reaction was monitored by TLC to ensure complete reaction. The reaction solution was filtered to remove solid insoluble matter. The reaction was quenched with 200 mL of water. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated sodium bicarbonate (500 mL) and saturated brine (300 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography (silica gel, Hexane / EtOAc = 10:1, v / v) to obtain a colorless oily product (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-butanol. Sodium chlorite (24.8 g, 222 mmol) was dissolved in 50 mL water and slowly added to the reaction solution. Hydrogen peroxide aqueous solution (36%, 24.0 mL, 222 mmol) was then slowly added dropwise to the reaction solution. The mixture was stirred overnight (10 h) at room temperature. The reaction was monitored by TLC until complete. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (200 mL). The ethyl acetate phase was evaporated to dryness, and the remaining aqueous layer was extracted again with ethyl acetate (200 mL × 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography (silica gel, Hexane / EtOAc = 5:1, v / v) to give a pair of isomers as a colorless oil (16.4 g, yield 67%).

[0070] Step 4: Synthesis of 4-butyl-8-methoxy-phthalazine-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 flask, and 50 mL of ethanol was added. The reaction was carried out at 80 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution was concentrated to give a pale yellow solid product (2.8 g, yield 95%), which can be used directly in the next step of the reaction without purification.

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

[0073] 4-Butyl-8-methoxy-phthalazine-1(2H)-one (2.0 g, 8.6 mmol) was dissolved in 20 mL of toluene solution. AlCl3 (3.4 g, 25.8 mmol) was slowly added to the reaction solution at 0 °C. The reaction was carried out at 110 °C for 40 min. The reaction was monitored by TLC until complete. The toluene was removed by concentration. The reaction solution was diluted with 50 mL of water and extracted with dichloromethane (50 mL × 4). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a light brown solid (1.7 g, yield 92%). The product can be used directly in the next reaction without purification.

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

[0075] 0.3 mmol of 2-hydroxy-4-butylphthalazine-1(2H)-one and 0.5 mmol of the halogenated derivative were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.75 mmol of potassium carbonate were added. The reaction was carried out at 70 °C for 1 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain O-substituted phthalazinone derivatives.

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

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

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

[0079]

[0080] Following the method described in step 7 of Method I, 4-butyl-8-methoxy-phthalazine 1(2H)-one (0.3 mmol) was used as the starting material and bromoethane (0.5 mmol) was placed in a reaction flask. 3.0 mL of anhydrous DMF was added to dissolve the mixture. Sodium hydride (60%, 0.6 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain the title compound 2.

[0081] ESI-MS: m / z 261.5 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0083]

[0084] Following the method in step 7 of Method I, 4-butyl-8-methoxy-phthalazine-1(2H)-one (0.3 mmol) was used as the starting material and placed in a reaction flask with iodopropane (0.5 mmol). 3.0 mL of anhydrous DMF was added to dissolve the mixture. Sodium hydride (60%, 0.6 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-propyl-4-butyl-8-methoxy-phthalazine-1(2H)-one.

[0085] ESI-MS: m / z 275.3 [M+H] + .1H NMR (500MHz, Methanol-d4)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-d4)δ C: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-phthalazine-1(2H)-one

[0087]

[0088] Following the method described in step 7 of Method I, 4-butyl-8-methoxy-phthalazine-1(2H)-one (0.3 mmol) was used as the starting material and mixed with bromomethylcyclopropane (0.5 mmol) in a reaction flask. 3.0 mL of anhydrous DMF was added for dissolution. Sodium hydride (60%, 0.6 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(cyclopropylmethyl)-4-butyl-8-methoxy-phthalazine-1(2H)-one.

[0089] ESI-MS: m / z 287.6 [M+H] + . 1 H NMR (500MHz, Methanol-d4)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-d4)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-phthalazine-1(2H)-one

[0091]

[0092] Following the method in step 7 of Method I, 4-butyl-8-methoxy-phthalazine-1(2H)-one (0.3 mmol) was used as the starting material and bromomethylcyclopropane (0.5 mmol) was placed in a reaction flask. 3.0 mL of anhydrous DMF was added to dissolve the mixture. Sodium hydride (60%, 0.6 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-cyclopropylmethyl-4-butyl-8-methoxy-phthalazine-1(2H)-one.

[0093] ESI-MS: m / z 329.3 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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)-phthalazine-1(2H)-one

[0095]

[0096] Following step 6 of Method I, 0.3 mmol of 4-butyl-8-hydroxy-phthalazine-1(2H)-one and 0.5 mmol of (bromomethyl)cyclohexane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.75 mmol of potassium carbonate were added. The reaction was carried out at 70 °C for 1 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 4-butyl-8-(cyclohexylmethoxy)-phthalazine-1(2H)-one.

[0097] ESI-MS: m / z 315.7 [M+H] + .1H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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)-phthalazine-1(2H)-one

[0099]

[0100] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-(cyclohexylmethoxy)-phthalazine-1(2H)-one and 0.5 mmol of bromoethane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-ethyl-4-butyl-8-(cyclohexylmethoxy)-phthalazine-1(2H)-one.

[0101] ESI-MS: m / z 343.6 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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)-phthalazine-1(2H)-one

[0103]

[0104] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-(cyclohexylmethoxy)-phthalazine-1(2H)-one and 0.5 mmol of benzyl bromide were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-benzyl-4-butyl-8-(cyclohexylmethoxy)-phthalazine-1(2H)-one.

[0105] ESI-MS: m / z 405.9 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0107]

[0108] Following step 6 of Method I, 0.3 mmol of 4-butyl-8-hydroxy-phthalazine-1(2H)-one and 0.5 mmol of 1-bromopropane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.75 mmol of potassium carbonate were added. The reaction was carried out at 70 °C for 1 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0109] ESI-MS: m / z 261.5 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0111]

[0112] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of 4-(bromomethyl)-pyridine were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(pyridin-4-methylene)-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0113] ESI-MS: m / z 352.7 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0115]

[0116] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of 4-fluorobenzyl bromide were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(4-fluorobenzyl)-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0117] ESI-MS: m / z 369.7 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0119]

[0120] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of iodopropane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-propyl-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0121] ESI-MS: m / z 303.2 [M+H] + . 1 H NMR (500MHz, Methanol-d4)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0123]

[0124] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of bromomethylcyclopropane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(cyclopropylmethyl)-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0125] ESI-MS: m / z 315.3 [M+H] + . 1 H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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-phthalazine-1(2H)-one

[0127]

[0128] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of bromomethylcyclohexane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(cyclohexylmethyl)-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0129] ESI-MS: m / z 357.4 [M+H] + . 1 H NMR (500MHz, Methanol-d4)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-d4)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-phthalazine-1(2H)-one

[0131]

[0132] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-propoxy-phthalazine-1(2H)-one and 0.5 mmol of bromomethylnaphthalene were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(naphthylmethyl)-4-butyl-8-propoxy-phthalazine-1(2H)-one.

[0133] ESI-MS: m / z 401.3 [M+H] + .1H NMR (500MHz, Methanol-d4)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-d4)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)-phthalazine-1(2H)-one.

[0135]

[0136] Following the procedure in step 6 of Method I, 0.3 mmol of 4-butyl-8-hydroxy-phthalazine-1(2H)-one and 0.5 mmol of (bromomethyl)cyclopropane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.75 mmol of potassium carbonate were added. The reaction was carried out at 70 °C for 1 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 4-butyl-8-(cyclopropylmethoxy)-phthalazine-1(2H)-one.

[0137] ESI-MS: m / z 273.5 [M+H] + .1H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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)-phthalazine-1(2H)-one

[0139]

[0140] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-(cyclopropylmethoxy)-phthalazine-1(2H)-one and 0.5 mmol of 4-fluorobenzyl bromide were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-(4-fluorobenzyl)-4-butyl-8-(cyclopropylmethoxy)-phthalazine-1(2H)-one.

[0141] ESI-MS: m / z 381.7 [M+H] + .1H NMR (500MHz, DMSO-d6)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-d6)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)-phthalazine-1(2H)-one

[0144]

[0145] Following step 7 of Method I, 0.3 mmol of 4-butyl-8-(cyclopropylmethoxy)-phthalazine-1(2H)-one and 0.5 mmol of bromoethane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and TLC was used to monitor the reaction until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-ethyl-4-butyl-8-(cyclopropylmethoxy)-phthalazine-1(2H)-one.

[0146] ESI-MS: m / z 301.7 [M+H] + .1H NMR (500MHz, DMSO-d6)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-d6)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)-phthalazine-1(2H)-one

[0149]

[0150] Following step 6 of Method I, 0.3 mmol of 4-butyl-8-hydroxy-phthalazine-1(2H)-one and 0.5 mmol of 2-(bromomethyl)-naphthalene were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.75 mmol of potassium carbonate were added. The reaction was carried out at 70 °C for 1 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 4-butyl-8-(naphthalene-2-methoxy)-phthalazine-1(2H)-one.

[0151] ESI-MS: m / z 359.2 [M+H] + .1H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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)-phthalazine-1(2H)-one

[0153]

[0154] Following the method described in step 7 of Method I, 0.3 mmol of 4-butyl-8-(naphth-2-methoxy)-phthalazin-1(2H)-one and 0.5 mmol of bromoethane were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and 0.6 mmol of sodium hydride (60%) was added at 0 °C. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (50 mL × 3), and the combined organic layers were washed with 20 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography to obtain 2-ethyl-4-butyl-8-(naphth-2-methoxy)-phthalazin-1(2H)-one.

[0155] ESI-MS: m / z 387.6 [M+H] + .1H NMR (500MHz, DMSO-d6)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 (125MHz, DMSO-d6)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 test compound uses the hydrogen peroxide injury and glutamate injury models. PC-12 cells are inoculated into a 96-well culture plate at a density of 1.5×10 4 cells / mL, 100 μL per well. The experiment is divided into a blank group, a model group and a drug addition group. The hydrogen peroxide injury and glutamate injury models are stimulated with hydrogen peroxide at a final concentration of 120 μM and glutamate at 8 mM for 2 h respectively. Subsequently, the blank group is cultured with complete medium, and the drug addition group is added with 10 μM of the test compound. After incubation for 24 h in each group, 10 μL of CCK-8 is added to each well. After 60 min, the absorbance at 490 nm is measured using an enzyme label instrument, and the survival rate is statistically analyzed. The increased survival rate = (survival rate of the drug administration group - survival rate of the model group) / (survival rate of the model group). The results are shown in Table 1 and Table 2:

[0158] Table 1 Protective effects of phthalazinone compounds on hydrogen peroxide (120 μM)-induced nerve cell injury

[0159]

[0160]

[0161] Table 2 Protective effects of phthalazinone compounds on glutamate (8 mM)-induced nerve cell injury

[0162]

[0163] Example 21: In vivo anti-ischemic stroke activity study of compound 17

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

[0165] One hundred and twenty male SD rats (SPF grade) weighing 280–300 g were randomly divided into six groups: sham-operated group (Sham group), model group (Vehicle group), positive control group (butylphthalide, NBP group), and drug-treated groups (low, medium, and high doses), with twenty rats in each group. A modified middle cerebral artery suture occlusion method was used. The suture was slowly inserted from the right external carotid artery through the internal carotid artery into the proximal end of the anterior cerebral artery, blocking the blood supply to the contralateral side of the middle cerebral artery. In the sham-operated group, only anesthesia and vascular dissection were performed; no ligation of the blood vessel or insertion of the suture was performed. The drug-treated groups were administered compound 17 at doses of 10, 30, and 60 mg / kg by gavage; the positive control group was administered NBP at a dose of 200 mg / kg by gavage; and the model group was administered the same volume of physiological saline by gavage. Administered once daily for seven consecutive days.

[0166] Three hours after successful model establishment, a 5-point neurological functional assessment was performed using the Longa method: 0 points, no obvious neurological symptoms; 1 point, inability to fully extend the contralateral forelimb; 2 points, circling to the contralateral side; 3 points, leaning to the contralateral side while walking; 4 points, inability to walk independently. Rats scoring 2 or 3 points were included in the group, and the rest were excluded.

[0167] Infarct volume in rats was determined using the 2,3,5-triphenyltetrazolium chloride staining method. Seven days after administration of the drug, rats were deeply anesthetized, decapitated, and their brains were removed. A brain model was placed in the model, and 2 mm thick brain slices were cut along the coronal plane. The brain slices were then immersed in 2,3,5-triphenyltetrazolium chloride staining solution and stained in the dark for 15 min. After fixation overnight with 4% paraformaldehyde, the stained brain slices were scanned, and the infarct volume was calculated.

[0168] Experimental results are as follows Figure 1-3 As shown, 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, and reduce the volume of cerebral infarction in a dose-dependent manner, and are superior to the positive control drug butylphthalide (200 mg / kg).

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in: A is Where n is 0, 1, 2, 3, 4 or 5; R1 is selected from hydrogen, alkyl, cycloalkyl, halogen-substituted aryl, aryl, and heteroaryl groups; R2 is selected from hydrogen, alkyl, cycloalkyl, and aryl; R3 is selected from C 1-4 Straight-chain or branched alkyl groups; The halogen atom in the "halogen" is selected from fluorine, chlorine, bromine, and iodine; When R1 and R2 are "alkyl", each alkyl group is independently C1. 1-10 Straight-chain or branched alkyl groups; The "cycloalkyl" is a C3-C7 monocyclic cycloalkyl; The "aryl" group is a 6-10 member monocyclic or bicyclic fused aromatic ring group; The "heteroaryl" is selected from pyridyl, pyrroleyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, or imidazolyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When R1 and R2 are "alkyl", each alkyl group is independently C1. 1-7 Straight-chain or branched alkyl groups.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, When R1 and R2 are "alkyl", each alkyl group is independently C1. 1-5 Straight-chain or branched alkyl groups.

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, When R1 and R2 are "alkyl", each alkyl group is independently C1. 1-3 Straight-chain or branched alkyl groups.

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, When R1 and R2 are "alkyl", each alkyl group is independently 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, or n-decyl.

6. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The "cycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

7. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The "aryl" is either phenyl or naphthyl.

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, The "aryl" group is phenyl, 1-naphthyl, or 2-naphthyl.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The "heteroaryl" is 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, or pyrazin-3-yl.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, phenyl or naphthyl substituted with 1, 2 or 3 halogens, pyridyl, pyrroleyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or imidazolyl.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 。 14. The compound of formula (I) according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts include the following salts formed by the compounds of formula (I) with acids: sulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, acrylates, formates, oxalates, malonates, succinates, fumarates, maleates, benzoates, chlorobenzoates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolate, and tartrates.

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one compound of formula (I) according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15, characterized in that, The formulation of the pharmaceutical composition is selected from liquid dosage forms, solid dosage forms, or semi-solid dosage forms.

17. The pharmaceutical composition according to claim 16, characterized in that, The liquid dosage form is selected from solutions, emulsions, suspensions, injections, and nasal drops.

18. The pharmaceutical composition according to claim 17, characterized in that, The solution is a true solution or a colloidal solution.

19. The pharmaceutical composition according to claim 17, characterized in that, The emulsion is o / w type, w / o type, or double emulsion.

20. The pharmaceutical composition according to claim 17, characterized in that, The injection is a water-based injection, a powder injection, or an infusion solution.

21. The pharmaceutical composition according to claim 16, characterized in that, The solid dosage form is selected from tablets, capsules, granules, powders, microcapsules, droplets, suppositories, films, patches, and lyophilized powder injections.

22. The pharmaceutical composition according to claim 21, characterized in that, The tablets are ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, or orally disintegrating tablets.

23. The pharmaceutical composition according to claim 21, characterized in that, The capsules are hard capsules, soft capsules, or enteric-coated capsules.

24. The pharmaceutical composition according to claim 16, characterized in that, The semi-solid dosage form is selected from ointments, gels, and pastes.

25. The pharmaceutical composition according to any one of claims 15-24, characterized in that, The pharmaceutical composition further comprises one or more other pharmaceutically active ingredients besides the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

26. The use of the compound of formula (I) according to any one of claims 1-14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 15-25, in the preparation of a medicament for the prevention and / or treatment of cerebrovascular-related diseases; wherein the cerebrovascular-related diseases are selected from ischemic stroke and post-stroke neurological recovery-related diseases.

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