Phthalazinone compound and preparation method therefor, pharmaceutical composition, and use

Abstract

A phthalazinone 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 invention has a neuroprotective effect and can be used for treating / preventing cerebrovascular-related diseases.

Description

A phthalazinone compound, preparation method thereof, pharmaceutical composition and use thereof 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, such as stroke, is a group of conditions that occur in the brain's blood vessels, causing damage to brain tissue due to dysfunction in these vessels. Acute cerebrovascular disease is generally divided into two categories: ischemic and hemorrhagic. Ischemic stroke accounts for 62.4% of new stroke cases, and currently, there is a shortage of clinical medications for the 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 an excessive immune inflammatory response, further exacerbating pathological damage and causing ischemia-reperfusion injury. This can lead to postoperative adverse reactions such as hemorrhagic transformation, cerebral edema, and neuroinflammation, directly impacting post-stroke recovery. Therefore, the development of new, safe and effective drugs for the treatment of stroke is of great social significance.

[0003] Summary of the Invention

[0004] 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.

[0005] The present invention provides the following technical solutions:

[0006] 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:

[0007] in:

[0008] A is -(CH2)n-, wherein 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 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-chain or branched-chain alkyl" are each independently selected from halogen, hydroxy, amino, carboxyl, alkyl;

[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", the alkyl groups are each independently C 1-10 Straight or branched chain alkyl, optionally C 1-7 Straight or branched chain alkyl, optionally C 1-5 Straight or branched chain alkyl, optionally C 1-3 Straight-chain or branched alkyl, 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 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;

[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] Alternatively, 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; alternatively, the heterocycle is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocycle is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and O on the ring; alternatively, the heterocycle is a 3-10 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring; alternatively, the heterocycle is a 3-6 membered non-aromatic ring group containing 1 or 2 heteroatoms selected from N and S on the ring;

[0018] Alternatively, the "heteroaryl" is a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S on the ring; Alternatively, the "heteroaryl" is a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S on the ring; Alternatively, it is 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, 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.

[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, pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl.

[0022] Alternatively, 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 with 1, 2 or 3 halogens.

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

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

[0025] 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:

[0026] (1) Using hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde as starting materials, compound IA was prepared through a condensation reaction;

[0027] (2) Compound IA is subjected to a transposition reaction to prepare compound IB;

[0028] (3) Compound IB is subjected to oxidation reaction to prepare Compound IC;

[0029] (4) Compound IC is subjected to condensation reaction to prepare Compound ID;

[0030] (5) Deprotecting the methyl group of compound ID to prepare compound IE;

[0031] (6) Compound IE reacts with the corresponding halide to prepare compound IF;

[0032] (7) Compound IF is reacted with a corresponding halide to prepare compound (I);

[0033] The third aspect of the technical solution of the present invention provides a pharmaceutical composition comprising at least one compound represented by formula (I) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and / or excipient;

[0034] Preferably, the pharmaceutical composition further comprises one or more pharmaceutically active ingredients other than the compound or a pharmaceutically acceptable salt thereof;

[0035] Preferably, the formulation of the pharmaceutical composition can be selected from a liquid dosage form, a solid dosage form or a semisolid dosage form.

[0036] Preferably, the liquid dosage form can be a solution (including true solution and colloidal solution), emulsion (including o / w type, w / o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion) and nasal drops, etc.;

[0037] 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, freeze-dried powder injections, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0038] It can be made into ordinary preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0039] Preferably, the other active pharmaceutical ingredients are active pharmaceutical ingredients for preventing and / or treating cerebrovascular-related diseases;

[0040] 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.

[0041] In another aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use in preventing and / or treating cerebrovascular-related diseases.

[0042] In another aspect, the present invention provides a drug for preventing and / or treating cerebrovascular-related diseases, comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0043] In another aspect, the present invention provides a method for treating cerebrovascular diseases, comprising administering an effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above to a subject in need thereof.

[0044] Optionally, the cerebrovascular-related disease is selected from ischemic stroke, hemorrhagic stroke, and post-stroke neurological recovery-related diseases.

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

[0046] "Optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with halogen" means that halogen may but need not be present, and that 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. A pharmaceutically acceptable salt is a salt that is pharmaceutically acceptable and has the desired pharmacological activity of 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 accordingly with certain inorganic or organic bases, or inorganic and organic acids, to form pharmaceutically acceptable salts. 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 phthalazinone compounds of the present invention or pharmaceutical compositions containing them are prepared according to methods well known to those skilled in the art. Conventional adjuvants used in the manufacture of tablets, capsules, and coatings include starch, gelatin, gum arabic, silica, and polyethylene glycol. Solvents used in liquid dosage forms include water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, and olive oil. Formulations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, and pigments.

[0049] In order to prepare the compound of the present invention into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropyl alcohol, etc.; binders can 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.; disintegrants can 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 lauryl sulfate, etc.; lubricants and glidants can 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] To prepare the dosing unit as 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 or soft capsule. Alternatively, the active ingredient compound of the present invention can be first mixed with a diluent, a binder, and a disintegrant to form granules or pellets, which are then placed in a hard or 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 compounds of the present invention as injections, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of solubilizers, cosolvents, pH adjusters, and osmotic pressure regulators commonly used in the art can be added. Examples of solubilizers or cosolvents include poloxamer, lecithin, and hydroxypropyl-β-cyclodextrin; pH adjusters include phosphates, acetates, hydrochloric acid, and sodium hydroxide; and osmotic pressure regulators include sodium chloride, mannitol, glucose, phosphates, and acetates. For lyophilized powder injections, mannitol, glucose, and the like can also be added as support agents.

[0053] 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 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 speaking, a suitable daily dosage 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 dosage can be administered as a single dosage unit or divided into several dosage units, depending on the clinician's clinical experience and the dosage regimen including the use of other therapeutic 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 in rats with ischemic stroke (n=12, *p<0.05 vs. vehicle);

[0058] Figure 3. Effect of compound 17 on cerebral infarct volume in rats with ischemic stroke (n=12, *p<0.05 vs. vehicle, **p<0.01 vs. vehicle). DETAILED DESCRIPTION

[0059] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the scope of protection 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 scope of protection of the present invention.

[0060] Preparation method

[0061] 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.

[0062] In a general synthetic method, the compound represented by formula (I) is prepared according to the method.

[0063] Specifically, the phthalazinone derivatives described herein can be prepared through a 6-7 reaction step. For example, starting from hydrazine valerate and 2-hydroxy-6-methoxybenzaldehyde, a condensation reaction is performed to prepare compound IA, which is then subjected to a transposition reaction to obtain compound IB; IB is oxidized to obtain compound IC, which is then subjected to a 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; and compound IF is reacted with a corresponding halide to obtain the phthalazinone compound described herein.

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

[0065] Dissolve 2-hydroxy-6-methoxybenzaldehyde (27.0 g, 178 mmol) in 150 mL of anhydrous ethanol and heat with stirring at 80°C until the compound is completely dissolved. Add valeryl hydrazide (21.6 g, 186 mmol) in 150 mL of anhydrous ethanol and stir at 80°C. The reaction mixture is stirred at 80°C for 2 hours. Concentrate the reaction mixture to obtain a pale yellow solid product (44.0 g, 99% yield), which can be used directly 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 portionwise at 0°C. After 5 h of reaction, the reaction was complete 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 product 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 give the product as a colorless oil (24.5 g, 63% yield).

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

[0069] 2-Methoxy-6-pentanoylbenzaldehyde (24.5 g, 111 mmol) was dissolved in a mixture of 200 mL of acetonitrile and 100 mL of tert-butanol. Sodium chlorite (24.8 g, 222 mmol) was dissolved in 50 mL of water and slowly added to the reaction mixture. Aqueous hydrogen peroxide (36%, 24.0 mL, 222 mmol) was then slowly added dropwise to the reaction mixture. The reaction was stirred at room temperature overnight (10 h). TLC confirmed the reaction was complete. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (200 mL). The ethyl acetate phase was then evaporated to dryness. The remaining aqueous layer was extracted with ethyl acetate (200 mL x 2). The combined organic layers were 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 afford a pair of isomers as colorless oils (16.4 g, 67% yield).

[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 flask, and 50 mL of ethanol was added. The mixture was reacted at 80°C for 2 h. TLC confirmed the reaction was complete. The reaction solution was concentrated to obtain a pale yellow solid product (2.8 g, 95% yield). The product was used directly in the next reaction without purification.

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

[0073] 4-Butyl-8-methoxy-phthalazin-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 continued at 110°C for 40 min. The reaction was completed after monitoring by TLC. The product was concentrated to remove toluene, and the reaction solution was diluted with 50 mL of water. The product was 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 was used directly in the next reaction without purification.

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

[0075] 2-Hydroxy-4-butyl-phthalazin-1(2H)-one (0.3 mmol) and a halide (0.5 mmol) were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and potassium carbonate (0.75 mmol) was added. The mixture was reacted at 70°C for 1 h, and the reaction was monitored for completion by TLC. The reaction was quenched by the addition of 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain an O-substituted phthalazinone derivative.

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

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

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

[0079] According to the procedure of Method I, Step 7, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3 mmol) was placed in a reaction flask with bromoethane (0.5 mmol). 3.0 mL of anhydrous DMF was added for dissolution. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by the addition of 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to obtain the title compound 2.

[0080] ESI-MS: m / z 261.5[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0081] Example 2: 2-propyl-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0082] According to the procedure of Method I, Step 7, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3 mmol) was placed in a reaction flask with iodopropane (0.5 mmol). 3.0 mL of anhydrous DMF was added for dissolution. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-propyl-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0083] 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 (125 MHz, 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.

[0084] Example 3: 2-(Cyclopropylmethyl)-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0085] According to the procedure of Method I, Step 7, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3 mmol) and bromomethylcyclopropane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(cyclopropylmethyl)-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0086] ESI-MS: m / z 287.6[M+H] + . 1 H NMR (500 MHz, 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),2.93(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 (125 MHz, 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.

[0087] Example 4: 2-Cyclopropylmethyl-4-butyl-8-methoxy-phthalazin-1(2H)-one

[0088] According to the procedure of Method I, Step 7, 4-butyl-8-methoxy-phthalazin-1(2H)-one (0.3 mmol) and bromomethylcyclopropane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-cyclopropylmethyl-4-butyl-8-methoxy-phthalazin-1(2H)-one.

[0089] ESI-MS: m / z 329.3[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0090] Example 5: 4-Butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0091] According to the procedure of Method I, Step 6, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3 mmol) and (bromomethyl)cyclohexane (0.5 mmol) were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and potassium carbonate (0.75 mmol) was added. The reaction was allowed to react at 70°C for 1 h. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine (20 mL), 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.

[0092] ESI-MS: m / z 315.7[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0093] Example 6: 2-Ethyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0094] According to the procedure of Method I, Step 7, 4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one (0.3 mmol) and ethyl bromide (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-ethyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one.

[0095] ESI-MS: m / z 343.6[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0096] Example 7: 2-Benzyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one

[0097] According to the procedure of Method I, Step 7, 4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one (0.3 mmol) and benzyl bromide (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-benzyl-4-butyl-8-(cyclohexylmethoxy)-phthalazin-1(2H)-one.

[0098] ESI-MS: m / z 405.9[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0099] Example 8: 4-Butyl-8-propoxy-phthalazin-1(2H)-one

[0100] According to the procedure of Method I, Step 6, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3 mmol) and 1-bromopropane (0.5 mmol) were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and potassium carbonate (0.75 mmol) was added. The reaction was allowed to react at 70°C for 1 h. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine (20 mL), 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.

[0101] ESI-MS: m / z 261.5[M+H] + . 1 H NMR (500 MHz, 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). 13C NMR (125 MHz, 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.

[0102] Example 9: 2-(Pyridin-4-methylene)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0103] According to the procedure of Method I, Step 7, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and 4-(bromomethyl)-pyridine (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(pyridin-4-methylene)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0104] ESI-MS: m / z 352.7[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0105] Example 10: 2-(4-Fluorobenzyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0106] According to the procedure in Step 7 of Method I, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and 4-fluorobenzyl bromide (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(4-fluorobenzyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0107] ESI-MS: m / z 369.7[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0108] Example 11: 2-propyl-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0109] According to the procedure of Method I, Step 7, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and iodopropane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-propyl-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0110] ESI-MS: m / z 303.2[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0111] Example 12: 2-(Cyclopropylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0112] According to the procedure of Method I, Step 7, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and bromomethylcyclopropane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(cyclopropylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0113] ESI-MS: m / z 315.3[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0114] Example 13: 2-(Cyclohexylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0115] According to the procedure of Method I, Step 7, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and bromomethylcyclohexane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(cyclohexylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0116] ESI-MS: m / z 357.4[M+H] + . 1 H NMR (500 MHz, 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=10.6,3.8 Hz,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 (125 MHz, 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.

[0117] Example 14: 2-(Naphthylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one

[0118] According to the procedure of Method I, Step 7, 4-butyl-8-propoxy-phthalazin-1(2H)-one (0.3 mmol) and bromomethylnaphthalene (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(naphthylmethyl)-4-butyl-8-propoxy-phthalazin-1(2H)-one.

[0119] 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 (125 MHz, 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.

[0120] Example 15: 4-Butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0121] According to the procedure of Method I, Step 6, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3 mmol) and (bromomethyl)cyclopropane (0.5 mmol) were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and potassium carbonate (0.75 mmol) was added. The mixture was reacted at 70°C for 1 h, and the reaction was monitored for completion by TLC. The reaction was quenched by the addition of 50 mL of water, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), 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.

[0122] ESI-MS: m / z 273.5[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0123] Example 16: 2-(4-Fluorobenzyl)-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one

[0124] According to the procedure of Method I, Step 7, 4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one (0.3 mmol) and 4-fluorobenzyl bromide (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-(4-fluorobenzyl)-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0125] ESI-MS: m / z 381.7[M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ H :7.77(t,J=8.0Hz,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 C NMR (125 MHz, 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.

[0126] Example 17: 2-Ethyl-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one

[0127] According to the procedure of Method I, Step 7, 4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one (0.3 mmol) and ethyl bromide (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-ethyl-4-butyl-8-(cyclopropylmethoxy)-phthalazin-1(2H)-one.

[0128] ESI-MS: m / z 301.7[M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ H:7.77(t,J=8.0Hz,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 C NMR (125 MHz, 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.

[0129] Example 18: 4-Butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one

[0130] According to the procedure of Method I, Step 6, 4-butyl-8-hydroxy-phthalazin-1(2H)-one (0.3 mmol) and 2-(bromomethyl)-naphthalene (0.5 mmol) were placed in a reaction flask, dissolved in 3.0 mL of anhydrous DMF, and potassium carbonate (0.75 mmol) was added. The mixture was reacted at 70°C for 1 h. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water, extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with saturated brine (20 mL), 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.

[0131] ESI-MS: m / z 359.2[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0132] Example 19: 2-Ethyl-4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one

[0133] According to the procedure of Method I, Step 7, 4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one (0.3 mmol) and bromoethane (0.5 mmol) were placed in a reaction flask and dissolved in 3.0 mL of anhydrous DMF. Sodium hydride (60%, 0.6 mmol) was added at 0°C and allowed to react for 3 h at room temperature. TLC monitored the reaction for completion. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to afford 2-ethyl-4-butyl-8-(naphthalene-2-methoxy)-phthalazin-1(2H)-one.

[0134] ESI-MS: m / z 387.6[M+H] + . 1 H NMR (500 MHz, 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 (125 MHz, 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.

[0135] Example 20: In vitro neuroprotective activity screening

[0136] The in vitro neuroprotective models of the tested compounds were hydrogen peroxide injury and glutamate injury models. PC-12 cells were cultured at 1.5×10 4 The density of cells / mL was set, and 100 μL was inoculated into a 96-well culture plate. 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 120 μM hydrogen peroxide and 8 mM glutamate, respectively. The blank group was then cultured with complete medium, and the drug-added group was added with 10 μM of the test compound. After incubation for 24 hours, 10 μL CCK-8 was added to each well. After 60 minutes, the absorbance at 490 nm was measured using a microplate reader, and the survival rate was calculated. The survival rate was calculated as follows: (survival rate of the drug-treated group - survival rate of the model group) / (survival rate of the model group). The results are shown in Tables 1 and 2:

[0137] Table 1 Protective effects of phthalazinones on neuronal cell damage induced by hydrogen peroxide (120 μM)

[0138] Table 2 Protective effects of phthalazinones on glutamate (8 mM)-induced neuronal damage

[0139] Example 21: Study on the anti-ischemic stroke activity of compound 17 in vivo

[0140] Male SD rats, weighing 280-300 g, were purchased from Spectrum Biotechnology (Beijing) Co., Ltd. (certification number: 11400700293705) under license number SYXK(Beijing)2014-0023 and housed in an SPF-grade animal facility at the Institute of Materia Medica, Chinese Academy of Medical Sciences. They were maintained on a normal diet with free access to water. An appropriate amount of compound 17 prepared in Example 16 was accurately weighed and dissolved in normal saline to a 6 mg / mL solution, which was then used. Similarly, butylphthalide (NBP) was prepared into a 20 mg / mL solution, which was then used.

[0141] 120 SD male rats (SPF grade) weighing 280-300g were randomly divided into 6 groups, namely sham group (Sham group), model group (Vehicle group), positive drug group (butylphthalide, NBP group) and drug group (low, medium and high doses), with 20 rats in each group. Using the improved middle cerebral artery occlusion method, the suture was slowly introduced from the right external carotid artery through the internal carotid artery into the proximal anterior cerebral artery to block the blood supply source on the contralateral side of the middle cerebral artery. The sham group was only anesthetized and vascular stripped without ligating the blood vessels or introducing the suture. The drug group was gavage-administered with 10, 30, and 60 mg / kg of compound 17, the positive drug group was gavage-administered with 200 mg / kg of NBP, and the model group was gavage-administered with the same volume of normal saline. The drugs were administered once a day for 7 consecutive days.

[0142] Three hours after successful model establishment, a 5-point neurological function score was performed according to the Longa method: 0, no obvious neurological symptoms; 1, inability to fully extend the contralateral forelimb; 2, turning in circles toward the contralateral side; 3, falling toward the contralateral side while walking; 4, inability to walk independently. Rats with a score of 2 or 3 were included in the group, and the rest were excluded.

[0143] The rat brain infarct volume was measured using 2,3,5-triphenyltetrazolium chloride staining. Seven days after administration, the rats were deeply anesthetized, decapitated, and the brains removed. After placement in a brain mold, 2 mm thick brain slices were cut along the coronal plane. The slices were immersed in 2,3,5-triphenyltetrazolium chloride staining solution and stained for 15 minutes in the dark. After overnight fixation with 4% paraformaldehyde, the stained brain slices were scanned and the infarct volume was calculated.

[0144] The experimental results are shown in Figures 1-3. 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 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; 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.

12. The compound of 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, 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.

13. A drug for preventing and / or treating cerebrovascular-related diseases, comprising a compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 or 10, Optionally, the cerebrovascular-related disease is selected from ischemic stroke, hemorrhagic stroke, and post-stroke neurological recovery-related diseases.

14. A method for treating cerebrovascular-related diseases, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 or 10. Optionally, the cerebrovascular-related disease is selected from ischemic stroke, hemorrhagic stroke, and post-stroke neurological recovery-related diseases.

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