(Z)-3-butenylphthalides 5 or 7 position derivatives, processes for their preparation, uses and pharmaceutical compositions

Abstract

The application belongs to the technical field of pharmacy, and relates to a (Z)-3-butenyl phthalide 5 or 7 derivative, a preparation method, application and a pharmaceutical composition thereof. A (Z)-3-butenyl phthalide 5 or 7 derivative, a preparation method and application of the compound in preparation of a medicament for treating a nerve cell injury related disease are disclosed. The compound has a structure shown in a general formula (I), and the preparation method comprises the following steps: (1) synthesizing valeryl hydrazine; (2) synthesizing an acylhydrazone compound; (3) synthesizing a valeryl benzoic acid compound; and (3) synthesizing a butenyl phthalide compound. The compound preparation method is simple and has a significant neuroprotective effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a class of (Z)-3-butenylphthalide 5- or 7-position derivatives thereof, their preparation methods, uses and pharmaceutical compositions. Background Technology

[0002] Nerve cells are the most basic structural and constituent units of the human nervous system, and the pathological basis of most nervous system diseases is due to nerve cell damage. Nerve cell damage can lead to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and ischemic stroke, placing a huge psychological and economic burden on patients' families.

[0003] The mechanisms of neurodegenerative diseases have long been a hot topic of research, with various hypotheses proposed, including amyloid-β-protein (Aβ) deposition, neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau protein, oxidative stress, and neuroinflammation. Aβ-induced chronic inflammation leads to neuronal damage, and oxidative stress, a stress-induced damage state caused by an imbalance between cellular oxidation and antioxidation, is also a mechanism leading to neuronal damage. Neuroinflammation also causes neuronal damage. Therefore, finding compounds with neuroprotective activity to reduce neuronal damage and inhibit neuronal death is an effective strategy for developing drugs to treat neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).

[0004] In addition to causing neurodegenerative diseases, studies have shown that neuronal cell damage caused by inflammatory responses induced by oxidative stress is also a possible pathological basis for central nervous system diseases such as epilepsy, depression, and eclampsia. Therefore, compounds with neuroprotective activity also hold promise for developing drugs to treat these diseases. Summary of the Invention

[0005] This patent designs and synthesizes a series of novel (Z)-3-butenylphthalide compounds, aiming to provide a new material basis for the treatment of diseases related to nerve cell damage.

[0006] The technical problem solved by the present invention is to provide compounds of various types as described in Formula I, and their pharmacodynamically acceptable salts; and to provide a method for preparing compounds of various types as described in Formula I; to provide a pharmaceutical composition comprising at least one compound of various types as described in Formula I, and its pharmacodynamically acceptable salt; and to provide the use of compounds of various types as described in Formula I, and their pharmacodynamically acceptable salts, in the manufacture of medicaments for treating neurodegenerative diseases.

[0007] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0008] The first aspect of the technical solution of the present invention is to provide the structure of the compound of the present invention as shown in general formula I:

[0009]

[0010] When R2 represents hydrogen, R1 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or OR. a ,in

[0011] The substituents on the phenyl or naphthyl group can be monosubstituted or polysubstituted, and the substituents can be selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0012] R a C indicates whether the linear or branched chain has been replaced or not. 1-10 Alkyl, -COR a1 ,in

[0013] The substituents are selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted aromatic heterogroups, wherein...

[0014] The substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0015] R a1 C can be self-substituted or unsubstituted straight or branched. 1-10 Alkyl, wherein

[0016] The substituents are selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted aromatic heterogroups, wherein...

[0017] The substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0018] When R1 represents hydrogen, R2 represents substituted or unsubstituted phenyl, OR b ,in

[0019] The substituents on the phenyl group can be monosubstituted or polysubstituted, and the substituents can be selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0020] R b C indicates whether the linear or branched chain has been replaced or not. 1-10 Alkyl, -COR b1 ,in

[0021] The substituents are selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted aromatic heterogroups, wherein...

[0022] The substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0023] R b1 C can be self-substituted or unsubstituted straight or branched. 1-10 Alkyl, wherein

[0024] The substituents are selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl groups, substituted or unsubstituted 3-7 membered heterocycloalkyl groups, substituted or unsubstituted phenyl groups, and substituted or unsubstituted aromatic heterogroups, wherein...

[0025] The substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C.1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0026] Preferably, the compounds of the present invention have the structure shown in general formula IA:

[0027]

[0028] Wherein, R1 represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or OR. a The substituents on the phenyl or naphthyl group can be monosubstituted or polysubstituted, and the substituents can be selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0029] R a C indicates whether the linear or branched chain has been replaced or not. 1-10 Alkyl, -COR a1 The substituent is selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heteroyl groups, wherein the substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0030] R a1 C can be self-substituted or unsubstituted straight or branched. 1-10 Alkyl group, wherein the substituent is selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heteroyl group, wherein the substituent may be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0031] According to the present invention, the preferred R1 group includes phenyl, 2,4-difluorophenyl, 4-fluorophenyl, naphthyl, methylenedioxyphenyl, and 4-cyanophenyl, but is not limited to the above groups; when R a C indicates that the straight chain or branched chain has not been replaced.1-10 When alkyl, R is preferred. a The radicals include ethyl, propyl, isopropyl, cyclopropylmethyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclohexylmethyl, etc., but are not limited to the above radicals.

[0032] According to the present invention, when R a C represents the replacement of straight or branched chains. 1-10 When alkyl, preferred general formulas include, but are not limited to, the groups represented by the following general formulas IAa, IAb, IAc, and IAd.

[0033]

[0034] Where n can be 1, 2, 3, 4 or 5, and m can be 0, 1, 2, 3 or 4.

[0035] Among them, each R a2 C atoms, selected independently from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched, are all C atoms. 1-6 alkyl,

[0036] -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkyl group.

[0037] Compounds are represented by the general formula IAa:

[0038]

[0039] Among them, R bl R b2 Each of the following can be represented independently: H, and C, either substituted or unsubstituted linear or branched chains. 1-10 Alkyl or -COR b3 The substituent is selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heteroyl groups, wherein the substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0040] R b3 C can be self-substituted or unsubstituted straight or branched. 1-10Alkyl group, substituted or unsubstituted phenyl group, wherein the substituent on the alkyl group can be monosubstituted or polysubstituted, and the substituent can be selected from -OH, -F, -Cl, -Br, -COOH, methylenedioxy, or -NH2; the substituent on the phenyl group can be monosubstituted or polysubstituted, and the substituent can be selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched C456. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0041] According to the present invention, when R bl R b2 C indicates that the straight chain or branched chain has not been replaced. 1-10 When alkyl, it is independently preferred from ethyl, propyl, isopropyl, cyclopropylmethyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, and cyclohexylmethyl, but is not limited to the above groups;

[0042] According to the present invention, when R b3 C can be self-substituted or unsubstituted straight or branched. 1-10 Alkyl groups, preferably ethyl, propyl, isopropyl, cyclopropylmethyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclohexylmethyl, but not limited to the above groups.

[0043] Preferably, the compounds of the present invention have the structure shown in general formula IB:

[0044]

[0045] Wherein, R2 represents substituted or unsubstituted phenyl, OR c The substituents on the benzene ring can be monosubstituted or polysubstituted, and the substituents can be selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched C. 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0046] R c C indicates whether the linear or branched chain has been replaced or not. 1-10 Alkyl, -COR c1 The substituent is selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heteroyl groups, wherein the substituent can be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C 1-6Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0047] R c1 C can be self-substituted or unsubstituted straight or branched. 1-10 Alkyl group, wherein the substituent is selected from -OH, -F, -Cl, -Br, -COOH, -SH, -NO2, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted aromatic heteroyl group, wherein the substituent may be selected from -F, -Cl, -Br, -COOH, straight-chain or branched C 1-6 Alkyl, methylenedioxy, -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkoxy;

[0048] According to the present invention, when R c C indicates that the straight chain or branched chain has not been replaced. 1-10 When alkyl, R is preferred. c The radicals include ethyl, propyl, isopropyl, cyclopropylmethyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, and cyclohexylmethyl, but are not limited to the above radicals.

[0049] According to the present invention, when R c C represents the replacement of straight or branched chains. 1-10 When alkyl, preferred general formulas include, but are not limited to, the groups represented by the following general formulas IBa, IBb, IBc, and IBd.

[0050]

[0051] Where n can be 1, 2, 3, 4 or 5, and m can be 0, 1, 2, 3 or 4.

[0052] Among them, each R c2 C atoms, selected independently from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched, are all C atoms. 1-6 alkyl,

[0053] -CHF2, -CF3, -CN, -NO2, -OCF3 or C 1-5 Alkyl group.

[0054] According to the present invention, preferred compounds include, but are not limited to, the following compounds:

[0055]

[0056]

[0057]

[0058] A second aspect of the present invention also provides a method for preparing the compound described in the first aspect, wherein the synthesis of the key intermediate includes the following steps:

[0059]

[0060] (1) Compound B was prepared by selective monosubstitution reaction using compound A as the starting material;

[0061] (2) Compound B reacts with o-hydroxybenzaldehyde, which is substituted at different positions, i.e., compound C, to obtain compound D;

[0062] (3) Compound D was converted into compound E by a transposition reaction catalyzed by lead tetraacetate;

[0063] (4) Compound E was synthesized by oxidation with sodium chlorite and hydrogen peroxide to obtain compound F and its hemiketal product F′;

[0064] (5) The mixture of compounds F and F′ was dehydrated and condensed under the catalysis of aluminum trichloride to obtain the key intermediate G.

[0065] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound as described in the cases of general formula (I) and a pharmaceutically acceptable carrier in an effective dose of the drug.

[0066] According to the present invention, the compounds of the present invention may exist in isomer form, and the term "compound of the present invention" generally includes isomers of the compound.

[0067] According to embodiments of the present invention, the compound further includes a pharmacodynamically acceptable salt, salt hydrate, or prodrug.

[0068] 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.

[0069] 3-7 membered cycloalkyl refers to a saturated monocyclic or polycyclic structure having 3 to 7 carbon ring atoms. Preferred groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, but are not limited to these groups.

[0070] 3-7 membered heterocyclic alkyl groups refer to saturated or partially unsaturated carbocyclic groups having 3 to 7 ring atoms, containing one or more heteroatoms selected from nitrogen, oxygen or sulfur (the number of heteroatoms is 1, 2 or 3), but the connection between heteroatoms in the ring does not include -OO-, -OS- or -SS-. Specific examples of 3-7 membered saturated heterocyclic alkyl groups include, but are not limited to: oxetane, azirane, azirane, oxetane, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, imidazoyl, pyrazolyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, 1,4-dioxetane, 1,3-dioxetane, piperidinyl, morpholinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiophenyl, etc.; preferred groups are oxetane, oxetane, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, etc.

[0071] Preferred alkoxy groups include methoxy, ethoxy, propoxy, cyclopropoxy, n-butoxy, or 3-methylbutoxy, but are not limited to these groups.

[0072] Aryl refers to an aromatic carbocyclic group, either monocyclic or bicyclic, which typically has 6-10 carbon atoms; for example, phenyl or naphthyl, preferably phenyl.

[0073] Aromatic heterocyclic groups refer to monocyclic 5- or 6-membered aromatic heterocyclic groups, including but not limited to: 5-membered heteroaryl groups: furanyl, thiophene, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazole, pyrazolyl, 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); 6-membered heteroaryl: pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, and bicyclic groups, such as benzofuranyl, benzothiopheneyl, indazoleyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphridinyl, quinazolinyl, indazinyl, indoleyl, isoindoleyl. Preferred heteroaryl groups are thiopheneyl, thiazolyl, pyridinyl, and pyrimidinyl, but are not limited to these groups.

[0074] A third aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of the compound of the present invention. In unit dosage forms, the content of the compound of the present invention is generally 0.1 to 100 mg, with preferred unit dosage forms containing 4 to 50 mg.

[0075] Pharmaceutical compositions of the compounds of the present invention can be prepared according to methods known in the art. For this purpose, if desired, the compounds of the present invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to formulate suitable administration or dosage forms for use as human or veterinary medicine.

[0076] The compounds of this invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum, or rectum.

[0077] The compounds of this invention or pharmaceutical compositions containing them can be administered via injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and acupoint injection, etc.

[0078] Dosage forms can be liquid or solid. Liquid dosage forms include true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and lyophilized powder injections.

[0079] The compounds of this invention can be formulated into conventional formulations, sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0080] For example, various carriers known in the art can be widely used to formulate unit-dose dosage forms into tablets. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and aluminum silicate; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, methylcellulose, and ethylcellulose; disintegration inhibitors such as sucrose, tristearate, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium salts and sodium dodecyl sulfate; and lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, and polyethylene glycol. 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.

[0081] For example, various carriers known in the art can be widely used to formulate the drug delivery unit into pills. Examples of carriers include diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0082] For example, to formulate the drug delivery unit into a capsule, the active ingredient, the compound of the present invention, is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or a soft capsule. Alternatively, the active ingredient, the compound of the present invention, can be formulated as a microcapsule, suspended in an aqueous medium to form a suspension, or filled into a hard capsule or formulated as an injectable preparation for use.

[0083] For example, the compounds of this invention can be formulated into injectable formulations, such as solutions, suspension solutions, emulsions, and lyophilized powders for injection. These formulations can be aqueous or non-aqueous and may contain one or more pharmacodynamically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. Diluents may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan esters, fatty acid esters, etc. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable formulations. In addition, conventional solubilizers, buffers, pH adjusters, etc., may also be added. These excipients are commonly used in the art.

[0084] In addition, colorants, preservatives, flavorings, tasters, sweeteners or other materials may be added to pharmaceutical preparations if necessary.

[0085] 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.

[0086] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the frequency of administration, and the therapeutic purpose. Therefore, the therapeutic dosage of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical components used in the present invention is well known to those skilled in the art. The actual amount of drug contained in the final formulation of the compound composition of the present invention can be appropriately adjusted to achieve the required therapeutic dose and fulfill the preventive or therapeutic purpose of the present invention. The suitable daily dosage range of the compound of the present invention is: 0.001–100 mg / kg body weight, preferably 0.1–60 mg / kg body weight, more preferably 1–30 mg / kg body weight, and most preferably 2–15 mg / kg body weight. For adult patients, the daily dosage of the compound of the present invention is 10–500 mg, preferably 20–100 mg, which can be taken once or divided into 2–3 doses; for children, the dosage is 5–30 mg / kg body weight, preferably 10–20 mg / kg body weight. The above dosage can be administered as a single dose or divided into several doses, such as two, three, or four doses, depending on the clinical experience of the attending physician and the dosing regimen of the treatment. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs.

[0087] The fourth aspect of this invention is the use of the compound described in the first aspect in the preparation of a medicament for the prevention or treatment of diseases related to nerve cell damage, including neurodegenerative diseases or neuropsychiatric disorders. The neurodegenerative diseases include Alzheimer's disease, Huntington's disease, cognitive impairment, Parkinson's disease, and cerebral ischemia-reperfusion injury; the neuropsychiatric disorders include epilepsy, seizures, depression, and anxiety disorders. Attached Figure Description

[0088] Figure 1 Effects of compounds K16 and K46 on the step-down test (latency) of a scopolamine-induced ICR mouse dementia model.

[0089] Figure 2 Effects of compounds K16 and K46 on the step-down test in a scopolamine-induced ICR mouse dementia model (number of errors) Detailed Implementation

[0090] 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.

[0091] 1Recorded on the instrument during 500MHz H NMR spectroscopy. 1 1H NMR spectra were obtained in solution form (reported in ppm), using CDCl3 (7.26 ppm) or DMSO-d6 (2.50 ppm) as reference standards. 13 C10 NMR spectra were obtained in solution form (reported in ppm), using CDCl3 (77.16 ppm) or DMSO-d6 (39.52 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet), overlap. Coupling constants are given in Hertz (Hz).

[0092] In the following preparation methods and examples, "Me" refers to methyl, "Et" refers to ethyl, "Ph" refers to phenyl, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" refers to methanol, "EtOH" refers to ethanol, "DMF" refers to N,N-dimethylformamide, "Hexane" refers to n-hexane, "CDCl3" refers to deuterated chloroform, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "CD3OD-d4" refers to deuterated methanol, "DCM" refers to dichloromethane, "DCE" refers to 1,2-dichloroethane, "THF" refers to tetrahydrofuran, "HCl" refers to hydrochloric acid, "TsOH" refers to p-toluenesulfonic acid, "AlCl3" refers to aluminum trichloride, "TEA" refers to triethylamine, "DMAP" refers to N,N-dimethylaminopyridine, and "BINAP" refers to 1,1′-binaphthyl-2,2′- Bis(diphenylphosphine), "Pd(OAc)2" refers to palladium acetate, "Cs2CO3" refers to cesium carbonate, "NBS" refers to N-bromosuccinimide, "Na2SO4" refers to sodium sulfate, "K2CO3" refers to potassium carbonate, "PPh3" refers to triphenylphosphine, "Pd(PPh3)4" refers to tetratetraphenylphosphine palladium, "Ar" refers to argon, "M" refers to volumetric molar concentration, "rt" refers to room temperature, "min" refers to minutes, "h" refers to hours, "mL" refers to milliliters, "μL" refers to microliters, "N" refers to 1 mol / L, "mmol" refers to millimoles, "℃" refers to degrees Celsius, "calc.for" refers to the theoretical molecular weight of the compound, "found" refers to the molecular weight actually measured by high-resolution mass spectrometry, "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and "TLC" refers to thin-layer chromatography.

[0093] Example 1: Preparation of a general intermediate

[0094] Step 1: Preparation of valeryl hydrazide (B)

[0095]

[0096] A 250 mL solution of hydrazine hydrate (85%, 6640 mmol) was stirred at 80 °C. Methyl valerate (100 mL, 985 mmol) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with 100 mL of water, extracted with chloroform (150 mL × 4), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product (B) as a pure white solid (120 g, yield 98%), which was used directly in the next step of the reaction without purification.

[0097] 1 H NMR (500MHz, DMSO-d6) δ: 8.90 (s, 1H), 4.12 (s, 2H), 2.00 (t, J = 7.0Hz), 1.43-1.49 (m, 2H), 1.22-1.26 (m, 2H), 0.85 (t, J = 7.0Hz, 3H);

[0098] 13 C NMR (125MHz, DMSO-d6) δ: 171.68, 33.16, 27.33, 21.83, 13.66.

[0099] Step 2: Preparation of N′-(2-hydroxy-4-methoxybenzyl)valerate (D1)

[0100]

[0101] Compound 2-hydroxy-4-methoxybenzaldehyde (C1, 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. Compound B (21.6 g, 186 mmol) was dissolved in 150 mL of anhydrous ethanol and added to the reaction solution. The reaction mixture was stirred at 80 °C for 2 h. The reaction solution was concentrated to give a pale yellow solid product (D1, 44.0 g, yield 99%), which was used directly in the next reaction without purification.

[0102] The compound's NMR spectrum showed two sets of spectra. The two sets of spectra were assigned using HMBC spectroscopy (E:Z = 2.5:1).

[0103] Spectrum A (E style)

[0104] 1H NMR(500MHz,DMSO-d6)δ:11.53(s,1H),11.48(s,1H),8.25(s,1H),7.37(d,J=8.5Hz,1H),6.44-6.50 (m,2H),3.76(s,3H),2.19(t,J=7.0Hz,2H),1.52-1.58(m,2H),1.27-1.35(m,2H),0.87-0.90(m,3H);

[0105] 13 C NMR (125MHz, DMSO-d6) δ: 168.82, 162.49, 159.88, 147.57, 131.69, 112.32, 106.99, 101.74, 55.93, 34.26, 27.74, 22.46, 14.36.

[0106] Spectrum B (Z-type)

[0107] 1 H NMR (500MHz, DMSO-d6) δ: 11.09 (s, 0.4H), 10.35 (s, 0.4H), 8.15 (s, 0.4H), 7.48 (d, J = 8.5Hz, 0.4H), 6.44-6.50 (m ,0.8H),3.73(s,1.2H),2.53(t,J=7.0Hz,0.8H),1.52-1.58(m,0.8H),1.27-1.35(m,0.8H),0.87-0.90(m,1.2H);

[0108] 13 C NMR (125MHz, DMSO-d6) δ: 174.17, 162.26, 158.59, 142.19, 129.14, 113.53, 107.01, 101.59, 55.82, 32.33, 26.97, 22.46, 14.43.

[0109] Step 3: Preparation of 4-methoxy-2-pentanoylbenzaldehyde (E1)

[0110]

[0111] Compound D1 (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 product (E1) as a colorless oil (24.5 g, yield 63%).

[0112] 1 H NMR (500MHz, DMSO-d6) δ: 9.85 (s, 1H), 7.90 (d, J = 8.5Hz, 1H), 7.21 (dd, J = 8.5Hz, 2.5Hz, 1H), 7.17 (d, J = 2. 5Hz,1H),3.89(s,3H),2.85(t,J=7.0Hz,2H),1.56-1.62(m,2H),1.30-1.38(m,2H),0.88(t,J=7.5Hz,3H);

[0113] 13 C NMR (125MHz, DMSO-d6) δ: 204.77, 190.89, 163.31, 144.52, 133.46, 127.28, 115.34, 113.12, 55.95, 41.30, 25.61, 21.67, 13.89.

[0114] Step 4: Preparation of 4-methoxy-2-pentanoylbenzoic acid (F1) and 3-butyl-3-hydroxy-5-methoxyisobenzofuran-1(3H)one (F1′)

[0115]

[0116] Compound E1 (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). After extraction, the ethyl acetate fraction was evaporated to dryness. 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 obtain products (F1 and F1′) as colorless oils (16.4 g, yield 67%).

[0117] HRMS(ESI):calc.for C 13 H 17 O4,[M+H] + :237.1121,found:237.1115

[0118] Spectrum F1

[0119] 1 H NMR(500MHz,DMSO-d6)δ:7.84(d,J=8.5Hz,1H),7.05(dd,J=8.5Hz,2.5Hz,1H),6.86(d,J=2.5Hz,1H ),3.83(s,3H),2.70(t,J=7.0Hz,2H),1.54-1.59(m,2H),1.28-1.36(m,2H),0.87(t,J=7.5Hz,3H);

[0120] 13 C NMR (125MHz, DMSO-d6) δ: 205.61, 166.86, 162.27, 146.71, 132.18, 120.03, 114.28, 111.41, 55.79, 42.33, 25.67, 21.62, 13.93.

[0121] Spectrum F1′

[0122] 1H NMR(500MHz,DMSO-d6)δ:7.73(s,1H),7.69(d,J=8.5Hz,1H),7.17(d,J=2.5Hz,1H),7.13(dd,J=8.5Hz,2.5Hz,1H) ,3.88(s,3H),2.04-2.11(m,1H),1.95-2.00(m,1H),1.18-1.26(m,3H),0.92-1.00(m,1H),0.79(t,J=7.5Hz,3H);

[0123] 13 C NMR (125MHz, DMSO-d6) δ: 167.76, 164.68, 152.49, 126.19, 118.71, 117.36, 107.26, 106.83, 56.14, 38.08, 25.24, 22.03, 13.86.

[0124] Step 5: Preparation of (Z)-3-Butylene-5-methoxyisobenzofuran-1(3H)one (G1)

[0125]

[0126] Compounds F1 and F1′ (16.4 g, 69.5 mmol) were dissolved in 200 mL of chloroform solution with anhydrous calcium sulfate (18.9 g, 139 mmol). Thionyl chloride (25 mL) was slowly added to the solution, and the reaction was carried out at 60 °C for 5 h. The reaction was monitored by TLC until complete. The reaction solution was filtered to remove solid insoluble matter. The reaction was quenched with 200 mL of water and extracted with chloroform (100 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate (200 mL) and saturated brine (200 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 give product (G1) as a white solid (13.0 g, yield 90.8%).

[0127] 1 H NMR(500MHz,DMSO-d6)δ:7.74(d,J=8.5Hz,1H),7.51(d,J=2.5Hz,1H),7.09(dd,J=8.5Hz,2.5Hz,1H) ,5.97(t,J=7.0Hz,1H),3.89(s,3H),2.33(q,J=7.5Hz,2H),1.45-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0128] 13C NMR (125MHz, DMSO-d6) δ: 165.87, 164.92, 145.08, 141.85, 126.26, 118.44, 115.80, 109.38, 103.50, 56.14, 27.44, 22.00, 13.70.

[0129] Step 6: Preparation of (Z)-3-Butylene-5-hydroxyisobenzofuran-1(3H)one (H1)

[0130]

[0131] Compound G1 (13.0 g, 59.0 mmol) was dissolved in 200 mL of anhydrous dichloromethane. Under argon protection, the reaction mixture was stirred at -40 °C, and boron tribromide (10.8 mL, 118.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and reacted overnight (10 h). The reaction was monitored by TLC until complete. The reaction mixture was quenched in crushed ice, extracted with dichloromethane (100 mL × 2), and the combined organic layers were washed with saturated sodium bicarbonate (200 mL) and saturated brine (200 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 = 3:1, v / v) to give product (H1) as a white solid (9.0 g, yield 74.0%).

[0132] HRMS(ESI):calc.for C 12 H 13 O3, [M+H] + :205.0859,found:205.0859

[0133] 1 H NMR(500MHz,DMSO-d6)δ:10.84(s,1H),7.70(d,J=8.5Hz,1H),7.19(d,J=2.0Hz,1H),6.99(dd,J=8.5H z,2.0Hz,1H),5.86(t,J=7.0Hz,1H),2.32(q,J=7.5Hz,2H),1.45-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0134] 13 C NMR (125MHz, DMSO-d6) δ: 166.71, 164.39, 145.67, 142.43, 127.42, 119.14, 115.04, 109.40, 106.16, 27.98, 22.60, 14.35.

[0135] Step 7: Preparation of (Z)-3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1)

[0136]

[0137] Compound H1 (1.0 g, 4.9 mmol), DMAP (60 mg, 0.5 mmol), and TEA (1.36 mL, 10 mmol) were dissolved in 20 mL of dichloromethane. Trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol) was slowly added dropwise under argon protection at 0 °C. The reaction was allowed to proceed overnight (10 h) at room temperature, and TLC was used to monitor the reaction until complete. The reaction solution was quenched in crushed ice, extracted with dichloromethane (20 mL × 2), and the combined organic layers were washed with saturated sodium bicarbonate (20 mL) and saturated brine (20 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 = 5:1, v / v) to obtain product (I1) as a pale yellow solid (1.0 g, yield 70.0%).

[0138] 1 H NMR (500MHz, CDCl3) δ: 7.99 (d, J = 8.5Hz, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.39 (dd, J = 8.5Hz, 2.0Hz ,1H),5.75(t,J=7.0Hz,1H),2.48(q,J=7.0Hz,2H),1.53-1.61(m,2H),0.99(t,J=7.5Hz,3H);

[0139] 13 C NMR (125MHz, CDCl3) δ: 165.32, 153.71, 144.34, 141.59, 127.92, 124.19, 122.89, 118.78 (d, J = 320Hz), 113.14, 112.67, 28.09, 22.47, 13.97.

[0140] Step 8: Preparation of (Z)-5-amino-3-butylidene isobenzofuran-1(3H)one (J1)

[0141]

[0142] Compound I1 (336 mg, 1 mmol), Pd(OAc)2 (0.025 mmol, 5.6 mg), BINAP (0.025 mmol, 15.6 mg), and Cs2CO3 (489 mg, 1.5 mmol) were dissolved in 5 mL of toluene solution. Diphenylimino ketone (200 μl, 1.2 mmol) was added, and the mixture was refluxed at 100 °C for 10 h under argon protection. The reaction was monitored by TLC until it was complete. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. THF (5 mL) and 1N hydrochloric acid solution (5 mL) were added to the concentrate and stirred for 1 h. The mixture was extracted with ethyl acetate (20 mL × 2), and the combined organic layers were washed with saturated sodium bicarbonate (20 mL) and saturated brine (20 mL), respectively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, Hexane / EtOAc = 8:1 to 5:1 gradient elution, v / v) to obtain the product (J1) as a light brown solid (180 mg, yield 88.7%).

[0143] HRMS(ESI):calc.for C 12 H 14 O2N, [M+H] + :204.1019,found:204.1017

[0144] 1 H NMR(500MHz,DMSO-d6)δ:7.48(d,J=8.5Hz,1H),6.78(d,J=2.0Hz,1H),6.71(dd,J=8.5Hz,2.0Hz,1H) ,6.39(s,2H),5.62(t,J=8.0Hz,1H),2.28(q,J=7.0Hz,2H),1.43-1.51(m,2H),0.92(t,J=7.0Hz,3H);

[0145] 13 C NMR (125MHz, DMSO-d6) δ: 166.43, 155.33, 145.57, 141.81, 126.30, 116.21, 110.06, 106.95, 101.42, 27.30, 22.07, 13.75.

[0146] Step 9: Preparation of 2-hydroxy-6-methoxybenzaldehyde (C5)

[0147]

[0148] Aluminum trichloride (20.0 g, 150 mmol) was dissolved in 100 mL of anhydrous dichloromethane and stirred at -15 °C. 2,6-Dimethoxybenzaldehyde (16.6 g, 100 mmol) was dissolved in 100 mL of anhydrous dichloromethane and slowly added to the reaction mixture. After the addition was complete, the reaction mixture was slowly brought to room temperature and stirred overnight (10 h). The reaction was monitored by TLC until complete. The reaction mixture was cooled to -15 °C, and the reaction was quenched by slowly adding 1 N hydrochloric acid solution (200 mL). The mixture was extracted with dichloromethane (100 mL × 2), and the combined organic layers were washed with saturated brine (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography (silica gel, Hexane / EtOAc = 3:1, v / v) to obtain the product (C5) as a white solid (10.9 g, yield 72.0%).

[0149] HRMS(ESI):calc.for C8H9O3,[M+H] + :153.0546,found:153.0545

[0150] 1 H NMR (500MHz, DMSO-d6) δ: 11.76 (s, 1H), 10.24 (s, 1H), 7.53 (t, J = 8.0Hz, 1H), 6.61 (d, J = 8.0Hz, 1H), 6.51 (d, J = 8.0Hz, 1H), 3.87 (s, 3H);

[0151] 13 C NMR (125MHz, DMSO-d6) δ: 193.96, 162.43, 162.24, 138.98, 110.40, 109.19, 102.17, 56.21.

[0152] Step 10: Preparation of (Z)-3-Butylene-7-hydroxyisobenzofuran-1(3H)one (H2)

[0153]

[0154] Compound H2 was synthesized from 2-hydroxy-6-methoxybenzaldehyde (C5) according to steps 2, 3, 4, 5, and 6 in the examples.

[0155] HRMS(ESI):calc.for C 12 H 13 O3, [M+H] + :205.0859,found:205.0858

[0156] 1H NMR(500MHz,DMSO-d6)δ:10.99(s,1H),7.55(t,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),6.91(d,J=8 .0Hz,1H),5.82(t,J=8.0Hz,1H),2.31(q,J=7.5Hz,2H),1.44-1.52(m,2H),0.90(t,J=7.5Hz,3H);

[0157] 13 C NMR (125MHz, DMSO-d6) δ: 165.02, 157.43, 145.69, 141.69, 137.30, 116.89, 111.17, 110.02, 108.74, 27.99, 22.66, 14.36.

[0158] Example 2: Preparation of (Z)-4-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)benzyl nitrile (K1)

[0159]

[0160] Intermediate (Z)-3-butylene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1, 67 mg, 0.2 mmol), 4-cyanophenylboronic acid (44 mg, 0.3 mmol), potassium phosphate (63 mg, 0.3 mmol), potassium bromide (36 mg, 0.3 mmol), and Pd(PPh3)4 (17 mg) were dissolved in 5 mL of dioxane. The mixture was heated at 90 °C for 10 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 10 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 60:1 to 10:1 gradient elution, v / v) to give compound K1 (40 mg, yield 70.0%).

[0161] HRMS(ESI):calc.for C 19 H 16 O2N, [M+H] + :290.1176,found:290.1176

[0162] 1H NMR(500MHz,DMSO-d6)δ:8.45(s,1H),8.01-8.05(m,4H),7.98(s,2H),6.17(t, J=8.0Hz,1H),2.40(q,J=7.0Hz,2H),1.51-1.56(m,2H),0.98(t,J=7.0Hz,3H);

[0163] 13 C NMR (125MHz, DMSO-d6) δ: 166.03, 145.06, 144.71, 143.05, 139.98, 133.04, 133.04, 128.94 ,,128.40,128.40,125.56,123.26,119.41,118.68,111.35,110.21,27.44,21.92,13.71.

[0164] Example 3: Preparation of (Z)-3-Butylene-5-phenylisobenzofuran-1(3H)one (K2)

[0165]

[0166] Compound K2 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and phenylboronic acid according to the method of Example 2.

[0167] HRMS(ESI):calc.for C 18 H 17 O3, [M+H] + :265.1223,found:265.1223

[0168] 1 H NMR(500MHz, CDCl3)δ:7.94(d,J=8.0Hz,1H),7.80(d,J=1.5Hz,1H),7.10(dd,J=8.0Hz,1.5Hz,1H),7.61-7.64(m,2H),7.4 8-7.52(m,2H),7.42-7.46(m,1H),5.70(t,J=7.0Hz,1H),2.48(q,J=7.0Hz,2H),1.53-1.61(m,2H),1.00(t,J=7.5Hz,3H);

[0169] 13C NMR (125MHz, CDCl3) δ: 167.28, 147.80, 145.92, 140.443, 139.87, 129.23, 129.23, 128 .95,128.80,,127.60,127.60,125.71,123.28,118.22,109.74,27.96,22.70,13.98.

[0170] Example 4: Preparation of (Z)-3-butylidene-5-(3,5-difluorophenyl)isobenzofuran-1(3H)(K3)one

[0171]

[0172] Compound K3 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and 3,5-difluorophenylboronic acid according to the method of Example 2.

[0173] HRMS(ESI):calc.for C 18 H 15 O2F2,[M+H] + :301.1035,found:301.1031

[0174] 1 H NMR(500MHz,DMSO-d6)δ:8.42(d,J=6.0Hz,1H),7.94(overlap,2H),7.61(t,J=6.0Hz,1H),7.35 (t,J=8.0Hz,1H),6.13(m,1H),2.38(q,J=7.5Hz,2H),1.48-1.56(m,2H),0.97(t,J=7.5Hz,3H);

[0175] 13 C NMR(125MHz, DMSO-d6)δ:165.97,163.00(dd,J=245.0,14.5Hz),145.04,143.79,142.04(t,J=10.0Hz),139.93,1 28.65, 125.42, 123.15, 119.12, 110.69 (dd, J = 20.0, 5.5Hz), 110.13, 104.15 (t, J = 25.5Hz), 27.42, 22.01, 13.70.

[0176] Example 5: Preparation of (Z)-5-(3-(benzyloxy)phenyl)-3-butylideneisobenzofuran-1(3H)one (K4)

[0177]

[0178] Compound K4 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and 3-(benzoxy)phenylboronic acid according to the method of Example 2.

[0179] HRMS(ESI):calc.for C 25 H 23 O3, [M+H] + :371.1642,found:371.1639

[0180] 1 H NMR (500MHz, DMSO-d6) δ: 8.34 (s, 1H), 7.92 (overlap, 2H), 7.39-7.51 (overlap, 7H), 7.34 (t, J=8.0Hz, 1H), 7.12 (dd, J= 8.0Hz,1.5Hz,1H),6.14(t,J=8.0Hz,1H),5.21(s,2H),2.38(q,J=7.5Hz,2H),1.48-1.56(m,2H),0.97(t,J=7.5Hz,3H);

[0181] 13 C NMR(125MHz,DMSO-d6)δ:166.19,158.99,146.48,145.21,140.06,139.93,136.98,130.30,128.68,128.51,128.5 1,127.99,127.87,127.87,125.34,122.35,119.90,118.72,115.18,113.86,109.83,69.44,27.32,22.08,13.64.

[0182] Example 6: Preparation of (Z)-3-butylidene-5-(2,3-dihydrobenzo[b][1,4]dioxane-6-yl)isobenzofuran-1(3H)one (K5)

[0183]

[0184] Compound K5 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and 2,3-dihydrobenzo[b][1,4]dioxane-6-ylphenylboronic acid according to the method of Example 2.

[0185] HRMS(ESI):calc.for C 20 H 19 O4,[M+H] + :323.1278,found:323.1276

[0186] 1 H NMR (500MHz, DMSO-d6) δ: 8.29 (s, 1H), 7.86 (overlap, 2H), 7.37 (s, 1H), 7.32 (dd, J = 8.0Hz, 1.5Hz, 1H), 7.00 (d, J =8.5Hz,1H),6.14(t,J=8.0Hz,1H),4.30(s,4H),2.38(q,J=7.5Hz,2H),1.48-1.56(m,2H),0.97(t,J=7.5Hz,3H);

[0187] 13 C NMR(125MHz,DMSO-d6)δ:166.69,146.52,145.65,144.77,144.30,140.45,132.08,128.39,1 25.67,122.03,120.80,118.38,118.15,116.39,110.09,64.74,64.57,27.86,22.46,14.16.

[0188] Example 7: Preparation of (Z)-5-(4-carboxyphenyl)-3-butylideneisobenzofuran-1(3H)one (K6)

[0189]

[0190] Compound K6 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and 4-carboxyphenylboronic acid according to the method of Example 2.

[0191] HRMS(ESI):calc.for C 19 H 15 O4,[M+H] + :307.0976,found:307.0976

[0192] 1H NMR (500MHz, DMSO-d6) δ: 13.10 (s, 1H), 8.42 (s, 1H), 8.07 (d, J = 8.0Hz, 2H), 7.97 (overlap, 4H),6.17(t,J=8.0Hz,1H),2.38(q,J=7.5Hz,2H),1.49-1.56(m,2H),0.97(t,J=7.5Hz,3H);

[0193] 13 C NMR(125MHz,DMSO-d6)δ:167.03,166.12,145.54,145.13,142.73,140.00,130.8 6,130.05,128.91,127.70,125.55,122.88,119.14,110.14,27.54,22.02,13.73.

[0194] Example 8: Preparation of (Z)-3-Butylidene-5-(naphth-2-yl)isobenzofuran-1(3H)one (K7)

[0195]

[0196] Compound K7 was prepared from intermediate (Z)-3-butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yltrifluoromethanesulfonate (I1) and 2-naphthoboronic acid according to the method of Example 2.

[0197] HRMS(ESI):calc.for C 22 H 19 O2, [M+H] + :315.1380,found:315.1376

[0198] 1 H NMR(500MHz,DMSO-d6)δ:8.51(s,1H),8.43(s,1H),8.04-8.09(overlap,3H),7.99-8.01(overlap,3H ),7.59(m,2H),6.20(t,J=8.0Hz,1H),2.40(q,J=7.5Hz,2H),1.51-1.59(m,2H),0.99(t,J=7.5Hz,3H);

[0199] 13C NMR(125MHz,DMSO-d6)δ:166.25,146.59,145.23,140.08,135.94,133.18,132.86,128.90,128.78,12 8.50,127.64,126.94,126.80,126.73,125.49,125.17,122.27,118.91,109.92,27.47,22.05,13.72.

[0200] Example 9: Preparation of (Z)-3-Butylene-5-((3-fluorobenzyl)oxy)isobenzofuran-1(3H)one (K8)

[0201]

[0202] Intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1, 80 mg, 0.39 mmol), potassium carbonate (138 mg, 1 mmol), and 3-fluorobenzyl bromide (74 μl, 0.6 mmol) were dissolved in DMF (5 mL) and reacted overnight (10 h) at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 60:1 to 10:1 gradient elution, v / v) to give compound K8 (116.0 mg, yield 95.0%).

[0203] HRMS(ESI):calc.for C 19 H 18 O3F,[M+H] + :313.1234,found:313.1231

[0204] 1 H NMR(500MHz,DMSO-d6)δ:7.80(d,J=8.5Hz,1H),7.67(brs,1H),7.44-7.49(m,1H),7.32-7.34(m,2H),7.18-7. 23(m,2H),5.99(t,J=7.5Hz,1H),5.28(s,2H),2.35(q,J=7.0Hz,2H),1.49-1.55(m,2H),0.96(t,J=7.0Hz,3H);

[0205] 13C NMR (125MHz, DMSO-d6) δ: 165.91, 163.78, 162.23 (d, J = 245.0Hz), 145.03, 141.79, 139.01 (d, J = 8.0Hz), 130.67 (d, J = 8.5Hz), 126.5 4,123.92(d,J=2.5Hz),118.86,116.16,115.02(d,J=20.0Hz),114.64(d,J=22.0Hz),109.49,104.59,69.22,27.23,22.09,13.67.

[0206] Example 10: Preparation of (Z)-3-butylidene-5-((naphthyl-2-yl)methoxy)isobenzofuran-1(3H)one (K9)

[0207]

[0208] Compound (K9) was synthesized from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 2-(bromomethyl)-naphthalene according to the method of Example 9.

[0209] HRMS(ESI):calc.for C 23 H 21 O3, [M+H] + :345.1485,found:345.1484

[0210] 1 H NMR(500MHz, CDCl3)δ:7.84-7.92(m,4H),7.80(d,J=8.0Hz,1H),7.48-7.55(m,3H),7.11-7.16(m,2H) ,5.58(t,J=7.0Hz,1H),5.33(s,2H),2.43(q,J=7.0Hz,2H),1.50-1.59(m,2H),0.98(t,J=7.0Hz,3H);

[0211] 13 C NMR(125MHz, CDCl3)δ:167.12,164.15,145.67,142.24,133.37,133.34,133.22,128.85,128.10,127.95 ,127.05,126.70,126.65,126.57,125.17,118.17,117.55,109.51,103.90,70.79,27.89,22.63,14.17.

[0212] Example 11: Preparation of (Z)-3-Butylene-5-((4-methylphenyl)methoxy)isobenzofuran-1(3H)one (K10)

[0213]

[0214] Compound K10 was synthesized from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 4-methylbenzyl bromide according to the method of Example 9.

[0215] HRMS(ESI):calc.for C 20 H 21 O3, [M+H] + :309.1485,found:309.1484

[0216] 1 H NMR(500MHz,DMSO-d6)δ:7.77(d,J=8.5Hz,1H),7.65(s,1H),7.37(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),7.17(d,J=8.5 Hz,1H),5.60(t,J=7.5Hz,1H),5.20(s,2H),2.36(q,J=7.0Hz,2H),2.31(s,3H),1.48-1.53(m,2H),0.96(t,J=7.0Hz,3H);

[0217] 13 C NMR(125MHz,DMSO-d6)δ:165.87,164.03,145.07,141.80,137.56,133.08,129.12,129.12,1 28.19,128.19,126.48,118.89,115.93,109.43,104.50,69.99,27.36,22.01,20.83,13.71.

[0218] Example 12: Preparation of (Z)-5-(benzyloxy)-3-butylideneisobenzofuran-1(3H)one (K11)

[0219]

[0220] Compound K11 was synthesized from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and benzyl bromide according to the method of Example 9.

[0221] HRMS(ESI):calc.for C 19 H 19O3, [M+H] + :295.1329,found:295.1326

[0222] 1 H NMR(500MHz, DMSO-d6)δ:7.79(d,J=8.5Hz,1H),7.68(d,J=2.0Hz,1H),7.47-7.50(m,2H),7.41-7.44(m,2H),7.35-7.38(m,1H),7 .20(dd,J=8.5Hz,2.0Hz,1H),6.00(t,J=7.0Hz,1H),5.23(s,3H),2.35(q,J=7.0Hz,2H),1.47-1.55(m,2H),0.95(t,J=7.5Hz,3H);

[0223] 13 C NMR(125MHz,DMSO-d6)δ:165.93,163.98,145.06,141.71,135.93,128.60,128.60,128.2 5,128.08,128.08,126.55,118.89,116.03,109.48,104.56,70.15,27.37,22.08,13.65.

[0224] Example 13: Preparation of (Z)-3-Butylene-5-((4-fluorobenzyl)oxy)isobenzofuran-1(3H)one (K12)

[0225]

[0226] Compound K12 was synthesized from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 4-fluorobenzyl bromide according to the method of Example 9.

[0227] HRMS(ESI):calc.for C 19 H 18 O3F,[M+H] + :313.1234,found:313.1234

[0228] 1H NMR (500MHz, CDCl3) δ: 7.79 (d, J=8.0Hz, 1H), 7.42 (m, 2H), 7.09 (overlap, 4H), 5.57 (t, J= 7.0Hz,1H),5.13(s,2H),2.44(q,J=7.0Hz,2H),1.50-1.59(m,2H),0.99(t,J=7.5Hz,3H);

[0229] 13 C NMR (125MHz, CDCl3) δ: 166.99, 163.93, 162.88 (d, J = 245.0Hz), 145.68, 142.22, 131.55 (d, J = 2.5Hz), 129.6 2(d,J=8.5Hz),127.05,118.28,117.61,115.91(d,J=22.0Hz),109.48,103.77,70.11,27.91,22.67,13.98.

[0230] Example 14: Preparation of (Z)-5-([1,1′-diphenyl]-4-ylmethoxy)-3-butylideneisobenzofuran-1(3H)one (K13)

[0231]

[0232] Compound K13 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 4-(bromomethyl)-1,1′-diphenyl according to the method of Example 9.

[0233] HRMS(ESI):calc.for C 25 H 23 O3, [M+H] + :371.1612,found:371.1638

[0234] 1 H NMR (500MHz, CDCl3) δ: 7.80 (d, J = 8.5Hz, 1H), 7.65 (d, J = 6.5Hz, 2H), 7.61 (d, J = 6.5Hz, 2H), 7.51 (d, J = 6.5Hz, 2H), 7.45 (t, J = 6.5Hz, 2H), 7.3 8(t,J=6.5Hz,2H),7.13(overlap,2H),5.59(t,J=7.0Hz,1H),5.21(s,2H),2.44(q,J=7.0Hz,2H),1.50-1.59(m,2H),0.99(t,J=7.5Hz,3H);

[0235] 13 C NMR(125MHz, CDCl3)δ:167.04,164.12,145.71,142.23,141.58,140.72,134.72,128.99,128.99,128.19,128.19 ,127.70,127.68,127.68,127.26,127.26,127.02,118.37,117.47,109.53,103.84,70.52,27.91,22.67,13.98.

[0236] Example 15: Preparation of (Z)-3-butylidene-5-(pyridin-4-ylmethoxy)isobenzofuran-1(3H)one (K14)

[0237]

[0238] Compound K14 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 4-bromomethylpyridine according to the method of Example 9.

[0239] HRMS(ESI):calc.for C 18 H 18 O3N,[M+H] + :296.1281,found:296.1280

[0240] 1 H NMR(500MHz,DMSO-d6)δ:8.61(d,J=6.0Hz,2H),7.81(d,J=8.5Hz,1H),7.67(d,J=2.0Hz,1H),7.47(d,J=6.0Hz,2H),7.25(d d,J=8.5Hz,2.0Hz,1H),5.99(t,J=7.5Hz,1H),5.35(s,2H),2.35(q,J=7.0Hz,2H),1.46-1.54(m,2H),0.95(t,J=7.0Hz,3H);

[0241] 13 C NMR(125MHz,DMSO-d6)δ:165.87,163.62,149.88,149.88,145.21,144.94,141.78,1 26.56,121.97,121.97,118.82,116.35,109.62,104.62,68.21,27.37,22.05,13.72.

[0242] Example 16: Preparation of (Z)-3-butylidene-5-(pyridin-2-ylmethoxy)isobenzofuran-1(3H)one (K15)

[0243]

[0244] Compound K15 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 2-bromomethylpyridine according to the method of Example 9.

[0245] HRMS(ESI):calc.for C 18 H 18 O3N,[M+H] + :296.1281,found:296.1279

[0246] 1 H NMR(500MHz,DMSO-d6)δ:8.61(d,J=4.5Hz,1H),7.87(td,J=7.5Hz,1.5Hz,1H ),7.81(d,J=8.5Hz,1H),7.72(d,J=1.5Hz,1H),7.58(d,J=7.5Hz,1H),7.39(d d,J=7.5Hz,4.5Hz,1H),7.25(dd,J=8.5Hz,1.5Hz,1H),6.02(t,J=7.5Hz,1H), 5.34(s,2H),2.36(q,J=7.5Hz,2H),1.47-1.55(m,2H),0.96(t,J=7.5Hz,3H);

[0247] 13 C NMR(125MHz,DMSO-d6)δ:165.91,163.82,155.70,149.27,145.02,141.80,137.09,1 26.58,123.21,121.89,118.86,116.21,109.61,104.69,70.98,27.38,21.90,13.73.

[0248] Example 17: Preparation of (Z)-3-butylidene-5-(pyridin-3-ylmethoxy)isobenzofuran-1(3H)one (K16)

[0249]

[0250] Compound K16 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 3-bromomethylpyridine according to the method of Example 9.

[0251] HRMS(ESI):calc.for C 18 H 18 O3N,[M+H] + :296.1281,found:296.1278

[0252] 1 H NMR(500MHz, DMSO-d6)δ:8.73(s,1H),8.58(d,J=3.5Hz,1H),7.92(d,J=7.5Hz,1H),7.80(d,J=7.5Hz,1H),7.71(brs,1H),7.46(dd,J=7 5Hz,5.0Hz,1H),7.21(dd,J=7 5Hz,1.5Hz,1H),6.01(t,J=7.5Hz,1H),5.31(s,2H),2.35(q,J=7.5Hz,2H),1.47-1.55(m,2H),0.96(t,J=7.5Hz,3H);

[0253] 13 C NMR(125MHz,DMSO-d6)δ:165.91,163.78,149.54,149.34,145.04,141.81,136.09,1 31.78,126.58,123.78,118.89,116.20,109.58,104.62,67.84,27.37,22.01,13.72.

[0254] Example 18: Preparation of (Z)-3-Butylene-5-(cyclohexylmethoxy)isobenzofuran-1(3H)one (K17)

[0255]

[0256] Compound K17 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and bromomethylcyclohexane according to the method of Example 9.

[0257] HRMS(ESI):calc.for C 19 H 25 O3, [M+H] + :301.1798,found:301.1797

[0258] 1H NMR(500MHz, CDCl3)δ:7.50(d,J=8.0Hz,1H),7.00(brs,2H),5.57(t,J=7.5Hz,1H),3.84(d,J=6.0Hz,2H),2.43(q ,J=7.0Hz,2H),1.70-1.88(m,6H),1.50-1.58(m,2H),1.17-1.35(m,3H),1.04-1.11(m,2H),0.98(t,J=7.0Hz,3H);

[0259] 13 C NMR(125MHz, CDCl3)δ:167.19,164.72,145.75,142.25,126.72,118.20,117.08,109 .06,103.02,74.31,37.67,29.80,29.80,27.78,26.62,25.61,25.61,22.58,14.00.

[0260] Example 19: Preparation of (Z)-3-butylidene-5-((tetrahydro-3H-pyran-4-yl)oxy)isobenzofuran-1(3H)one (K18)

[0261]

[0262] Intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1, 100 mg, 0.5 mmol) and 4-iodotetrahydropyran (20 μL, 1 mmol) were dissolved in DMF (5 mL), and the reaction was heated at 60 °C for 10 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 20:1 to 10:1 gradient elution, v / v) to give compound K18 (72.0 mg, yield 50.0%).

[0263] HRMS(ESI):calc.for C 17 H 21 O4,[M+H] + :289.1434,found:289.1427

[0264] 1H NMR(500MHz, CDCl3)δ:7.78(d,J=8.0Hz,1H),7.01-7.04(m,2H),5.57(t,J=8.0Hz,1H),4.62-4.67(m,1H),3.97-4.02(m,2H ),3.60-3.65(m,2H),2.43(q,J=7.0Hz,2H),2.04-2.09(m,2H),1.80-1.87(m,2H),1.50-1.58(m,2H),0.98(t,J=7.0Hz,3H);

[0265] 13 C NMR (125MHz, CDCl3) δ: 166.89, 162.74, 145.65, 142.03, 127.14, 118.76, 117. 27,109.46,104.66,72.26,65.00,65.00,31.63,31.63,27.89,22.61,13.98.

[0266] Example 20: Preparation of (Z)-3-Butylene-5-(cyclopropylmethoxy)isobenzofuran-1(3H)one (K19)

[0267]

[0268] Compound K19 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and bromomethylcyclopropane according to the method of Example 9.

[0269] 1 H NMR (500MHz, CDCl3) δ: 7.75 (d, J = 8.5Hz, 1H), 7.02 (dd, J = 8.5Hz, 2.0Hz, 1H), 6.99 (d, J = 2.0Hz, 1H), 5.56 (t, J = 8.0Hz, 1H), 3 .89(d,J=8.0Hz,1H),2.42(q,J=7.0Hz,2H),1.49-1.57(m,2H),0.98(t,J=7.0Hz,3H),0.67-0.71(m,2H),0.36-0.39(m,2H);

[0270] 13 C NMR (125MHz, CDCl3) δ: 167.14, 164.49, 145.77, 142.23, 126.80, 118.26, 117.05, 109.28, 103.22, 73.58, 27.79, 22.71, 13.96, 10.13, 3.44, 3.44.

[0271] Example 21: Preparation of (Z)-3-Butylene-5-(cyclohexyloxy)isobenzofuran-1(3H)one (K20)

[0272]

[0273] Compound K20 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and bromocyclohexane according to the method of Example 9.

[0274] HRMS(ESI):calc.for C 18 H 23 O3, [M+H] + :287.1642,found:287.1642

[0275] 1 H NMR(500MHz, CDCl3)δ:7.75(d,J=9.0Hz,1H),6.98-7.01(m,2H),5.56(t,J=7.0Hz,1H),4.37-4.42(m,1H),2.43(q ,J=7.0Hz,2H),1.98-2.01(m,2H),1.81-1.85(m,2H),1.50-1.61(m,6H),1.35-1.44(m,2H),0.98(t,J=7.5Hz,3H);

[0276] 13 C NMR(125MHz, CDCl3)δ:167.18,153.39,145.66,141.86,126.89,118.85,116.90, 109.14,104.30,76.09,31.61,31.61,27.83,25.52,25.52,23.69,22.69,13.98.

[0277] Example 22: Preparation of (Z)-3-Butylene-5-(2-hydroxyethoxy)isobenzofuran-1(3H)one (K21)

[0278]

[0279] Compound K21 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 2-iodoethanol according to the method of Example 9.

[0280] 1H NMR (500MHz, CDCl3) δ: 7.77 (d, J=8.0Hz, 1H), 7.02-7.05 (m, 2H), 5.58 (t, J=7.5Hz, 1H), 4.19 (t, J= 4.5Hz,2H),4.02(t,J=4.5Hz,2H),2.43(q,J=7.0Hz,2H),1.50-1.58(m,2H),0.98(t,J=7.0Hz,3H);

[0281] 13 C NMR (125MHz, CDCl3) δ: 166.86, 164.01, 145.48, 142.26, 126.94, 118.11, 117.34, 109.64, 103.26, 70.00, 61.29, 27.92, 22.64, 13.90.

[0282] Example 23: Preparation of (Z)-3-Butylene-5-(2-Methoxyethoxy)isobenzofuran-1(3H)one (K22)

[0283]

[0284] Compound K22 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and 2-bromoethyl methyl ether according to the method of Example 9.

[0285] 1 H NMR (500MHz, CDCl3) δ: 7.76 (d, J = 8.5Hz, 1H), 7.04-7.06 (m, 2H), 5.56 (t, J = 8.0Hz, 1H), 4.21 (t, J = 4.5Hz, 2H),3.78(t,J=4.5Hz,2H),3.46(s,3H),2.42(q,J=7.0Hz,2H),1.50-1.57(m,2H),0.97(t,J=7.0Hz,3H);

[0286] 13 C NMR (125MHz, CDCl3) δ: 167.05, 164.29, 145.70, 142.16, 126.89, 118.23, 117.40, 109.50, 103.44, 70.77, 68.03, 59.45, 27.87, 22.64, 13.95.

[0287] Example 24: Preparation of (R,Z)-3-Butylene-5-(2,3-dihydroxypropoxy)isobenzofuran-1(3H)one (K23)

[0288]

[0289] Compound K23 was prepared from intermediates (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and (R)-3-chloro-1,2-propanediol according to the method of Example 9.

[0290] 1 H NMR (500MHz, CDCl3) δ: 7.73 (d, J = 8.5Hz, 1H), 7.03 (d, J = 2.0Hz, 1H), 7.01 (dd, J = 8.0Hz, 2.0Hz, 1H), 5.58 (t, J = 7.5Hz, 1H), 4.13-4.19 (over lap,3H),3.88(dd,J=11.0Hz,3.5Hz,1H),3.78(dd,J=11.0Hz,3.5Hz,1H),2.42(q,J=7.0Hz,2H),1.50-1.58(m,2H),0.98(t,J=7.0Hz,3H);

[0291] 13 C NMR (125MHz, CDCl3) δ: 167.14, 163.93, 145.63, 142.18, 126.95, 118.20, 117.55, 109.87, 103.32, 70.25, 69.69, 63.47, 27.89, 22.61, 13.94.

[0292] Example 25: Preparation of (Z)-3-Butylene-5-ethoxyisobenzofuran-1(3H)one (K24)

[0293]

[0294] Compound K24 was prepared from intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1) and iodoethane according to the method of Example 9.

[0295] HRMS(ESI):calc.for C 14 H 17 O3, [M+H] + :233.1172,found:233.1171

[0296] 1H NMR (500MHz, CDCl3) δ: 7.50 (d, J = 8.0Hz, 1H), 7.00 (brs, 2H), 5.56 (t, J = 7.5Hz, 1H), 4.13 (q, J = 7. 0Hz,2H),2.43(q,J=7.0Hz,2H),1.50-1.56(m,2H),1.46(t,J=7.0Hz,3H),0.98(t,J=7.0Hz,3H);

[0297] 13 C NMR (125MHz, CDCl3) δ: 167.32, 164.32, 145.66, 142.23, 126.84, 117.96, 116.90, 109.25, 103.21, 64.39, 27.80, 22.66, 14.69, 13.95.

[0298] Example 26: Preparation of (Z)-6-bromo-3-butylidene-5-methoxyisobenzofuran-1(3H)one (K25)

[0299]

[0300] 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) was dissolved in 100 mL of dichloromethane and stirred at -20 °C under argon protection. Liquid bromine (Br2, 2.6 mL, 50 mmol) was dissolved in 20 mL of dichloromethane and slowly added dropwise to the reaction solution. After the addition was complete, the mixture was allowed to rise to room temperature and reacted overnight (10 h). The reaction was quenched by adding saturated sodium sulfite solution, extracted with dichloromethane (100 mL × 2), dried over anhydrous sodium sulfate, and recrystallized from ethyl acetate to give product (Z)-6-bromo-2-hydroxy-5-methoxybenzaldehyde (6.7 g, 58.0%).

[0301] Compound K25 was synthesized from (Z)-6-bromo-2-hydroxy-5-methoxybenzaldehyde according to steps 2, 3, 4, and 5 in Example 1.

[0302] HRMS(ESI):calc.for C 13 H 14 O3Br,[M+H] + :297.0121,found:297.0117

[0303] 1H NMR(500MHz,DMSO-d6)δ:8.07(s,1H),7.73(s,1H),6.11(t,J=8.0Hz,1H),4 .01(s,3H),2.35(q,J=7.0Hz,2H),1.47-1.54(m,2H),0.96(t,J=7.0Hz,3H);

[0304] 13 C NMR (125MHz, DMSO-d6) δ: 164.93, 160.66, 144.68, 140.86, 129.04, 116.86, 113.61, 110.54, 103.51, 57.40, 27.48, 21.93, 13.73.

[0305] Example 27: Preparation of (Z)-4-bromo-3-butylidene-5-methoxyisobenzofuran-1(3H)one (K26)

[0306]

[0307] 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) was dissolved in 100 mL of dichloromethane and stirred at -20 °C under argon protection. Aluminum trichloride (6.65 g, 50 mmol) was added in three portions, and the mixture was stirred for 15 min. Liquid bromine (Br2, 2.6 mL, 50 mmol) was dissolved in 20 mL of dichloromethane and slowly added dropwise to the reaction solution. After the addition was complete, the mixture was allowed to react at room temperature overnight (10 h). The reaction was quenched with saturated sodium sulfite solution, extracted with dichloromethane (100 mL × 2), dried over anhydrous sodium sulfate, and recrystallized from ethyl acetate to give product (Z)-6-bromo-2-hydroxy-5-methoxybenzaldehyde (7.4 g, 64.0%).

[0308] Compound K26 was synthesized from (Z)-6-bromo-2-hydroxy-5-methoxybenzaldehyde according to steps 2, 3, 4, and 5 in the examples.

[0309] HRMS(ESI):calc.for C 13 H 14 O3Br,[M+H] + :297.0121,found:297.0118

[0310] 1H NMR(500MHz, CDCl3)δ:7.85(d,J=8.5Hz,1H),7.03(d,J=8.5Hz,1H),6.60(t,J=8.0H z,1H),4.02(s,3H),2.49(q,J=7.0Hz,2H),1.53-1.61(m,2H),0.99(t,J=7.0Hz,3H);

[0311] 13 C NMR (125MHz, CDCl3) δ: 165.82, 161.17, 144.76, 138.80, 126.08, 119.59, 115.93, 112.50, 104.96, 57.29, 28.47, 22.63, 14.03.

[0312] Example 28: Preparation of (Z)-3-Butylene-5-(dimethylamino)isobenzofuran-1(3H)one (K27)

[0313]

[0314] Compound (Z)-5-amino-3-butylideneisobenzofuran-1(3H)one (J1, 60 mg, 0.28 mmol) was dissolved in DMF (5 mL). Triethylamine (0.5 mL) and methyl iodide (74 μl, 1.2 mmol) were added to the reaction solution, and the reaction was carried out at 60 °C for 5 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 60:1 to 10:1 gradient elution, v / v) to give compound K27 (39 mg, yield 60.0%).

[0315] HRMS(ESI):calc.for C 14 H 18 O2N, [M+H] + :232.1332,found:232.1330

[0316] 1 H NMR(500MHz, CDCl3)δ:7.66(d,J=8.5Hz,1H),6.76(dd,J=8.5Hz,2.0Hz,1H),6.69(d,J=2.0Hz,1H), 5.53(t,J=8.0Hz,1H),3.09(s,6H),2.41(q,J=7.0Hz,2H),1.48-1.56(m,2H),0.97(t,J=7.0Hz,3H);

[0317] 13 C NMR (125MHz, CDCl3) δ: 167.80, 154.56, 146.43, 142.19, 126.37, 113.79, 111.86, 107.69, 99.89, 40.65, 40.65, 27.74, 22.60, 13.97.

[0318] Example 29: Preparation of (Z)-N-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-fluoro-N-(4-fluorobenzoyl)benzamide (K28)

[0319]

[0320] The compound (Z)-5-amino-3-butylideneisobenzofuran-1(3H)one (J1, 50 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and 4-fluorobenzoyl chloride (120 μl, 1 mmol) and triethylamine (0.5 mL) were added. The reaction was carried out overnight (10 h) at room temperature, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 60:1 to 5:1 gradient elution, v / v) to give compound K28 (78 mg, yield 70.0%).

[0321] HRMS(ESI):calc.for C 26 H 20 O4NF2,[M+H] + :448.1355,found:448.1349

[0322] 1 H NMR(500MHz,DMSO-d6)δ:8.13(d,J=1.5Hz,1H),7.89(d,J=8.5Hz,1H),7.86(overlap,4H),7.57(dd,J=8.5Hz,1.5H z,1H),7.30(overlap,4H),6.01(t,J=8.0Hz,1H),2.33(q,J=7.0Hz,2H),1.44-1.52(m,2H),0.93(t,J=7.0Hz,3H);

[0323] 13C NMR (125MHz, DMSO-d6) δ: 171.54, 165.47, 164.53 (d, J = 250.0Hz), 145.98, 144.43, 140.25, 132.26 (d, J = 10.0H z), 130.67 (d, J = 2.5Hz), 130.04, 126.09, 122.29, 120.44, 115.99 (d, J = 22.0Hz), 110.94, 27.42, 21.90, 13.71.

[0324] Example 30: Preparation of (Z)-N-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclopropionamide (K29)

[0325]

[0326] The compound (Z)-5-amino-3-butylideneisobenzofuran-1(3H)one (J1, 50 mg, 0.25 mmol) was dissolved in dichloromethane (5 mL), and cyclopropionyl chloride (27 μl, 0.3 mmol) and triethylamine (0.5 mL) were added. The reaction was carried out overnight (10 h) at room temperature, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 5:1 to 3:1 gradient elution, v / v) to give compound K29 ​​(47 mg, yield 70.0%).

[0327] HRMS(ESI):calc.for C 16 H 18 O3N,[M+H] + :272.1281,found:272.1277

[0328] 1 H NMR(500MHz,DMSO-d6)δ:10.78(s,1H),8.28(d,J=1.5Hz,1H),7.82(d,J=8.0Hz,1H),7.58(dd,J=8.0Hz,1.5Hz,1H),5.81(t, J=7.0Hz,1H),2.33(q,J=7.0Hz,2H),1.81-1.87(m,1H),1.46-1.54(m,2H),0.93(t,J=7.0Hz,3H),0.85-0.88(overlap,4H);

[0329] 13C NMR (125MHz, DMSO-d6) δ: 172.80, 165.94, 145.18, 140.41, 126.06, 120.82, 117.59, 109.07, 108.72, 27.44, 21.93, 14.84, 13.76, 7.90, 7.90.

[0330] Example 31: Preparation of (Z)-N-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)acetamide (K30)

[0331]

[0332] According to the method of Example 30, compound K30 was synthesized from compound (Z)-5-amino-3-butylidene isobenzofuran and acetyl chloride.

[0333] HRMS(ESI):calc.for C 14 H 16 O3N,[M+H] + :246.1125,found:246.1122

[0334] 1 H NMR (500MHz, CDCl3) δ: 8.29 (s, 1H), 8.21 (s, 1H), 7.76 (d, J = 8.5Hz, 1H), 7.32 (dd, J = 8.5Hz, 2.0Hz, 1H) ,5.65(t,J=8.0Hz,1H),2.40(q,J=7.0Hz,2H),3.26(s,3H),1.47-1.55(m,2H),0.95(t,J=7.0Hz,3H);

[0335] 13 C NMR (125MHz, CDCl3) δ: 169.30, 167.30, 145.67, 144.01, 141.57, 126.10, 120.66, 119.52, 110.50, 109.60, 28.00, 24.95, 22.56, 13.86.

[0336] Example 32: Preparation of (Z)-N-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-fluorobenzamide (K31)

[0337]

[0338] According to the method of Example 30, compound K31 was synthesized from compound (Z)-5-amino-3-butylidene isobenzofuran and 4-fluorobenzoyl chloride.

[0339] HRMS(ESI):calc.for C 19 H 17 O3NF,[M+H] + :326.1187,found:326.1183

[0340] 1 H NMR(500MHz,DMSO-d6)δ:10.76(s,1H),8.43(s,1H),8.07(dd,J=8.5Hz,5.5Hz,2H),7.88(d,J=8.5Hz,1H),7.83(d,J=8.5Hz,1H), 7.40(overlap,2H),7.25(t,J=8.5Hz,1H),5.87(t,J=8.0Hz,1H),2.36(q,J=7.0Hz,2H),1.48-1.56(m,2H),0.95(t,J=7.0Hz,3H);

[0341] 13 C NMR (125MHz, DMSO-d6) δ: 169.05, 165.91, 164.40 (d, J = 250.0Hz), 145.17, 140.21, 130.74 (d, J = 10.0Hz), 128.65 (d ,J=2.5Hz),125.82,122.16,118.28,115.60(d,J=22.0Hz),115.47,115.30,110.17,109.20,27.48,21.96,13.76.

[0342] Example 33: Preparation of (Z)-N-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)butyramide (K32)

[0343]

[0344] According to the method of Example 30, compound K32 was synthesized from compound (Z)-5-amino-3-butylidene isobenzofuran and butyryl chloride.

[0345] HRMS(ESI):calc.for C 16 H 20 O3N,[M+H] + :274.1438,found:274.1433

[0346] 1H NMR(500MHz,DMSO-d6)δ:10.43(s,1H),8.30(brs,1H),7.81(d,J=8.5Hz,1H),7.58(brd,J=8.5Hz,1H) ,5.83(t,J=7.5Hz,1H),2.35(overlap,4H),1.61-1.65(m,2H),1.49-1.54(m,2H),0.93(overlap,6H);

[0347] 13 C NMR(125MHz,DMSO-d6)δ:172.13,165.99,145.28,145.16,140.38,125.94, 120.90,117.58,109.04,108.69,38.42,27.50,21.92,18.38,13.74,13.61.

[0348] Example 34: Preparation of (Z)-N-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)cinnamamide (K33)

[0349]

[0350] According to the method of Example 30, compound K33 was synthesized from compound (Z)-5-amino-3-butylidene isobenzofuran and cinnamoyl chloride.

[0351] HRMS(ESI):calc.for C 21 H 20 O3N,[M+H] + :344.1438,found:344.1433

[0352] 1 H NMR (500MHz, CDCl3) δ: 8.44 (s, 1H), 8.12 (s, 1H), 7.82 (d, J = 6.0Hz, 1H), 7.79 (s, 1H), 7.53 (overlap, 2H), 7.39 (overlap, 2H), 6.6 5(d,J=11.0Hz,1H),5.67(t,J=7.0Hz,1H),4.30(t,J=7.0Hz,1H),2.41(q,J=7.0Hz,2H),1.48-1.56(m,2H),0.97(t,J=7.0Hz,3H);

[0353] 13C NMR(500MHz, CDCl3)δ:167.05,164.67,145.64,144.02,141.54,134.32,131.14,130.55,129.06 ,129.06,128.89,128.27,128.27,120.82,120.14,119.75,110.47,109.88,27.96,22.65,13.94.

[0354] Example 35: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-fluorobenzoate (K34)

[0355]

[0356] Intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1, 60 mg, 0.3 mmol), DMAP (24 mg, 0.2 mmol), and 4-fluorobenzoyl chloride (70 μl, 0.6 mmol) were dissolved in dichloromethane (5 mL) and reacted at room temperature for 10 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 20:1 to 3:1 gradient elution, v / v) to give compound K34 (88.0 mg, yield 90.0%).

[0357] HRMS(ESI):calc.for C 19 H 16 O4F,[M+H] + :327.1027,found:327.1024.

[0358] 1 H NMR (500MHz, DMSO-d6) δ: 8.22 (overlap, 2H), 8.00 (overlap, 2H), 7.55 (d, J=8.5Hz, 1H), 7.46 (t, J= 7.5Hz,2H),6.02(t,J=7.5Hz,1H),2.36(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0359] 13C NMR(125MHz, DMSO-d6)δ:165.77(d,J=253.0Hz),165.55,163.28,155.73,144.55,140.77,133.04(d,J=10.0H z), 126.62, 124.98 (d, J = 2.5Hz), 124.45, 121.17, 116.35 (d, J = 22.0Hz), 114.29, 110.65, 27.43, 21.93, 13.66.

[0360] Example 36: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-aminobenzoate (K35)

[0361]

[0362] Intermediate (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one (H1, 200 mg, 1.0 mmol), EDCI (230 mg, 1.2 mmol), DMAP (146 mg, 1.2 mmol), and p-aminobenzoic acid (176 mg, 1.2 mmol) were dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL acetonitrile. The reaction was carried out at room temperature for 10 h, and the reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 3:1 to 1:1 gradient elution, v / v) to obtain K35 (260.0 mg, yield 80.0%).

[0363] HRMS(ESI):calc.for C 19 H 18 O4N,[M+H] + :324.1230,found:324.1229.

[0364] 1 H NMR(500MHz,DMSO-d6)δ:7.93(overlap,2H),7.82(d,J=9.0Hz,2H),7.43(d,J=8.5Hz,1H),6.65(d,J=9.0H z,2H),6.29(s,2H),6.04(t,J=7.5Hz,1H),2.35(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0365] 13C NMR(125MHz,DMSO-d6)δ:165.69,164.19,156.46,154.77,144.63,140.76,132.24,132.2 4, 126.39, 124.62, 120.55, 114.36, 113.53, 112.88, 112.88, 110.48, 27.44, 21.96, 13.68.

[0366] Example 37: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)cyclopropionate (K36)

[0367]

[0368] According to the method of Example 35, compound K36 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and cyclopropionyl chloride.

[0369] HRMS(ESI):calc.for C 16 H 17 O4,[M+H] + :273.1121,found:273.1121.

[0370] 1 H NMR(500MHz,DMSO-d6)δ:7.93(d,J=8.0Hz,1H),7.87(d,J=2.0Hz,1H),7.38(dd,J=8.0Hz,2.0Hz,1H),6.04(t,J=7.5Hz, 1H),2.35(q,J=7.5Hz,2H),1.96(m,1H),1.46-1.53(m,2H),1.09-1.14(m,2H),1.05-1.08(m,2H),0.95(t,J=7.5Hz,3H);

[0371] 13 C NMR(125MHz,DMSO-d6)δ:172.51,165.56,155.64,144.49,140.75,126.54 ,124.36,120.91,114.22,110.63,27.42,21.93,13.68,12.65,9.37,9.37.

[0372] Example 38: Preparation of (Z)-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-(N-acetylacetamide)benzoate (K37)

[0373]

[0374] According to the method of Example 29, compound K37 was synthesized from compound (Z)-(3-butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-aminobenzoate and acetyl chloride.

[0375] HRMS(ESI):calc.for C 23 H 22 O6N,[M+H] + :408.1442,found:408.1438.

[0376] 1 H NMR(500MHz,DMSO-d6)δ:8.25(d,J=8.5Hz,2H),8.04(d,J=2.0Hz,1H),8.02(d,J=8.5Hz,1H),7.58-7.61(over lap,3H),6.04(t,J=7.5Hz,1H),2.38(q,J=7.5Hz,2H),2.22(s,6H),1.47-1.55(m,2H),0.95(t,J=7.5Hz,3H);

[0377] 13 C NMR(125MHz,DMSO-d6)δ:172.04,165.58,163.64,155.81,144.99,144.57,140.79,131.19,131.19,1 30.09,130.09,128.45,126.71,124.51,121.23,114.34,110.68,27.44,26.83,26.83,21.95,13.70.

[0378] Example 39: Preparation of (Z)-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-(4-fluoro-N-(4-fluorobenzoyl)benzoamide)benzoate (K38)

[0379]

[0380] According to the method of Example 29, compound K38 was synthesized from compound (Z)-(3-butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-aminobenzoate and 4-fluorobenzoyl chloride.

[0381] HRMS(ESI):calc.for C 33 H 24 O6NF2,[M+H] +:568.1566,found:568.1563.

[0382] 1 H NMR(500MHz,DMSO-d6)δ:8.15(d,J=8.5Hz,2H),7.99-8.01(overlap,2H),7.88-7.91(overlap,4H),7.59(d,J=8.5Hz,2H),7.56(dd ,J=8.0Hz,2.0Hz,1H),7.32(t,J=8.0Hz,4H),6.01(t,J=7.5Hz,1H),2.37(q,J=7.5Hz,2H),1.47-1.54(m,2H),0.95(t,J=7.5Hz,3H);

[0383] 13 C NMR (125MHz, DMSO-d6) δ: 172.33, 166.19, 165.04 (d, J = 250.0Hz), 164.09, 156.40, 145.65, 145.19, 141.37, 132.88 (d, J = 10.0Hz), 131.81, 1 31.81, 131.29 (d, J = 2.5Hz), 129.37, 129.37, 127.98, 127.27, 125, 11, 121.80, 116.57 (d, J = 22.0Hz), 114.94, 111.23, 28.04, 22.61, 14.30.

[0384] Example 40: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)acetate (K39)

[0385]

[0386] According to the method of Example 35, compound K39 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and acetyl chloride.

[0387] HRMS(ESI):calc.for C 14 H 15 O4,[M+H] + :247.0965,found:247.0963.

[0388] 1H NMR(500MHz,DMSO-d6)δ:7.94(d,J=8.5Hz,1H),7.83(d,J=1.5Hz,1H),7.38(dd,J=8.5Hz,1.5 Hz,1H),6.02(t,J=7.5Hz,1H),2.35(overlap,5H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0389] 13 C NMR (125MHz, DMSO-d6) δ: 168.90, 165.53, 155.66, 144.52, 140.76, 126.55, 124.43, 120.93, 114.13, 110.58, 27.46, 21.93, 20.89, 13.69.

[0390] Example 41: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-3,4-dimethoxybenzoate (K40)

[0391]

[0392] According to the method of Example 35, compound K40 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and 3,4-dimethoxybenzoyl chloride.

[0393] HRMS(ESI):calc.for C 21 H 21 O6,[M+H] + :369.1333,found:369.1329.

[0394] 1 H NMR(500MHz,DMSO-d6)δ:7.97(overlap,2H),7.80(dd,J=8.5Hz,2.0Hz,1H),7.59(brs,1H),7.51(dd,J=8.0Hz,1.5Hz,1H),7.17( d,J=8.5Hz,1H),6.03(t,J=8.0Hz,1H),3.88(s,3H),3.85(s,3H),2.36(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0395] 13C NMR(125MHz,DMSO-d6)δ:165.68,163.96,155.98,153.94,148.67,144.59,140.76,126.56,124. 54,124.45,120.97,120.18,114.35,112.15,111.36,110.64,55.90,55.68,27.45,21.96,13.69.

[0396] Example 42: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-(4-fluoro-N-(4-acetamide)benzoate (K41)

[0397]

[0398] According to the method of Example 30, compound K41 was synthesized from compound (Z)-(3-butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-4-aminobenzoate and acetyl chloride.

[0399] HRMS(ESI):calc.for C 21 H 20 O5N,[M+H] + :366.1336,found:366.1333.

[0400] 1 H NMR(500MHz,DMSO-d6)δ:10.42(s,1H),8.10(d,J=8.0Hz,2H),7.99(d,J=2.0Hz,1H),7.98(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,2H), 7.52(dd,J=8.0Hz,2.0Hz,1H),6.04(t,J=8.0Hz,1H),2.36(q,J=7.5Hz,2H),2.11(s,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H).

[0401] Example 43: Preparation of (Z)-(3-Butylidene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-methylpropionate (K42)

[0402]

[0403] According to the method of Example 35, compound K42 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and 2-methylpropionyl chloride.

[0404] HRMS(ESI):calc.for C 16 H 19 O4,[M+H] + :275.1278,found:275.1273.

[0405] 1 H NMR(500MHz,DMSO-d6)δ:7.92(d,J=2.0Hz,1H),7.82(d,J=8.0Hz,1H),7.34(dd,J=8.0Hz,2.0Hz,1H),6. 03(t,J=8.0Hz,1H),2.86(m,1H),2.34(q,J=7.5Hz,2H),1.48(m,2H),1.25(m,6H),0.93(t,J=7.5Hz,3H);

[0406] 13 C NMR(125MHz,DMSO-d6)δ:174.61,165.48,155.81,144.44,140.74,126.47, 124.25,120.90,114.06,110.57,33.41,27.41,21.92,18.55,18.55,13.62.

[0407] Example 44: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-ylcinnamate (K43))

[0408]

[0409] According to the method of Example 35, compound K43 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and cinnamoyl chloride.

[0410] HRMS(ESI):calc.for C 21 H 19 O4,[M+H] + :335.1278,found:335.1275.

[0411] 1H NMR(500MHz,DMSO-d6)δ:7.90-7.98(overlap,3H),7.81-7.85(overlap,2H),7.46-7.51(overlap,4H),7.9 6(d,J=16.0Hz,1H),6.06(t,J=8.0Hz,1H),2.36(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.95(t,J=7.5Hz,3H);

[0412] 13 C NMR(125MHz,DMSO-d6)δ:165.59,164.58,155.74,147.46,144.63,140.80,133.74,131.17,129.1 0,129.10,128.88,128.88,126.60,124.44,120.96,116.55,114.24,110.66,27.44,21.98,13.70.

[0413] Example 45: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)furan-2-carboxylic acid ester (K44)

[0414]

[0415] According to the method of Example 35, compound K44 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and furan-2-acyl chloride.

[0416] HRMS(ESI):calc.for C 17 H 15 O5,[M+H] + :299.0914,found:299.0912.

[0417] 1 H NMR(500MHz,DMSO-d6)δ:8.16(d,J=1.5Hz,1H),8.01(d,J=1.5Hz,1H),7.99(d,J=8.5Hz,1H),7.66(d,J=4.0Hz,1H),7.54(dd,J=8.0H z,1.5Hz,1H),6.84(dd,J=4.0Hz,1.5Hz,1H),6.05(t,J=7.5Hz,1H),2.36(q,J=7.5Hz,2H),1.46-1.54(m,2H),0.95(t,J=7.5Hz,3H);

[0418] 13 C NMR(125MHz,DMSO-d6)δ:165.53,155.82,155.07,149.25,144.53,142.47,140.8 1,126.70,124.39,121.25,121.06,114.28,113.03,110.76,27.44,21.93,13.69.

[0419] Example 46: Preparation of (Z)-(3-Butylene-1-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrole-2-carboxylic acid ester (K45)

[0420]

[0421] According to the method of Example 35, compound K45 was synthesized from compound (Z)-3-butylidene-5-hydroxyisobenzofuran-1(3H)one and 1H-pyrrole-2-acyl chloride.

[0422] HRMS(ESI):calc.for C 17 H 15 O4NNa,[M+Na] + :320.0893,found:320.0889.

[0423] 1 H NMR (500MHz, DMSO-d6) δ: 12.33 (s, 1H), 7.97 (overlap, 2H), 7.49 (dd, J = 7.5Hz, 2.0Hz, 1H), 7.21 (m, 1H), 7.09 (m,1H),6.30(m,1H),6.07(t,J=7.5Hz,1H),2.37(q,J=7.5Hz,2H),1.47-1.54(m,2H),0.95(t,J=7.5Hz,3H);

[0424] 13 C NMR(125MHz,DMSO-d6)δ:165.63,158.12,155.76,144.60,140.81,126.54,126.1 9,124.59,120.82,120.15,117.58,114.37,110.62,110.48,27.44,21.98,13.70.

[0425] Example 47: Preparation of (Z)-3-Butylene-7-propoxyisobenzofuran-1(3H)one (K46)

[0426]

[0427] Intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2, 40 mg, 0.2 mmol), potassium carbonate (70 mg, 0.5 mmol), potassium iodide (17 mg, 0.1 mmol), and bromopropane (37 mg, 0.3 mmol) were dissolved in DMF (5 mL) and reacted overnight (10 h) at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (10 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 (silica gel, Hexane / EtOAc = 60:1 to 10:1 gradient elution, v / v) to give compound K46 (44 mg, yield 90.0%).

[0428] HRMS(ESI):calc.for C 15 H 19 O3, [M+H] + :247.1329,found:247.1326

[0429] 1 H NMR(500MHz, DMSO-d6)δ:7.72(t,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,1H),5.90(t,J=7.5Hz,1H),4.10( t,J=7.0Hz,1H),2.33(q,J=7.5Hz,2H),1.74-1.80(m,2H),1.46-1.53(m,2H),1.00(t,J=7.5Hz,3H),0.94(t,J=7.5Hz,3H);

[0430] 13 C NMR (125MHz, DMSO-d6) δ: 164.47, 157.83, 145.42, 141.93, 137.75, 113.24, 112.45, 111.34, 109.54, 70.43, 28.05, 22.63, 22.45, 14.35, 10.87.

[0431] Example 48: Preparation of (Z)-7-cyclopropylmethoxy-3-butylideneisobenzofuran-1(3H)one (K47)

[0432]

[0433] Compound K47 was prepared from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and bromomethylcyclopropane according to the method of Example 47.

[0434] HRMS(ESI):calc.for C 16 H 19 O3, [M+H] + :259.1328,found:259.1325

[0435] 1 H NMR(500MHz,DMSO-d6)δ:7.69(t,J=7.5Hz,1H),7.45(d,J=7.5Hz,1H),7.10(d,J=7.5Hz,1H),5.89(t,J=7.5Hz,1H),4.01 (d,J=7.0Hz,2H),2.32(q,J=7.5Hz,2H),1.45-1.52(m,2H),1.26(m,1H),0.93(t,J=7.5Hz,3H),0.59(m,2H),0.37(m,2H);

[0436] 13 C NMR (125MHz, DMSO-d6) δ: 163.88, 157.23, 144.79, 141.30, 137.08, 112.82, 111.84, 110.70, 108.89, 72.73, 27.43, 22.01, 13.74, 9.86, 3.19, 3.19.

[0437] Example 49: Preparation of (Z)-7-([1,1′-diphenyl]-4-ylmethoxy)-3-butylideneisobenzofuran-1(3H)one (K48)

[0438]

[0439] Compound K48 was prepared from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and 4-(bromomethyl)-1,1′-diphenyl according to the method of Example 47.

[0440] HRMS(ESI):calc.for C 25 H 23 O3, [M+H] + :371.1642,found:371.1637

[0441] 1H NMR(500MHz,DMSO-d6)δ:7.67-7.75(overlap,5H),7.59(d,J=8.0Hz,1H),7.45-7.51(overlap,3H),7.37(t,J=7.5Hz,1H), 7.25(d,J=7.5Hz,1H),5.94(t,J=7.5Hz,1H),5.36(s,2H),2.34(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0442] 13 C NMR(125MHz,DMSO-d6)δ:163.91,156.76,144.77,141.37,139.84,139.78,137.13,135.48,129.00,129.00,128.0 3,128.03,127.58,126.85,126.85,126.73,126.73,113.21,112.32,111.08,109.23,69.51,27.43,22.00,13.75.

[0443] Example 50: Preparation of (Z)-7-(cyclohexylmethoxy)-3-butylideneisobenzofuran-1(3H)one (K49)

[0444]

[0445] Compound K49 was prepared from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and bromomethylcyclohexane according to the method of Example 47.

[0446] HRMS(ESI):calc.for C 19 H 25 O3, [M+H] + :301.1798,found:301.1794

[0447] 1H NMR(500MHz,DMSO-d6)δ:7.69(t,J=7.5Hz,1H),7.44(d,J=7.5Hz,1H),7.11(d, J=7.5Hz,1H),5.89(t,J=7.5Hz,1H),3.93(d,J=6.0Hz,2H),2.32(q,J=7.5Hz,2 H),1.77-1.85(overlap,3H),1.71(d,J=11.0Hz,2H),1.65(d,J=11.0Hz,1H),1 .44-1.54(m,2H),1.14-1.18(overlap,3H),1.05(m,2H),0.93(t,J=7.5Hz,3H);

[0448] 13 C NMR(125MHz,DMSO-d6)δ:163.84,157.38,144.73,141.27,137.09,112.60,111.78,11 0.74,108.89,73.50,36.73,28.99,28.99,27.42,26.05,25.24,25.24,21.95,13.66.

[0449] Example 51: Preparation of (Z)-3-Butylene-7-(naphth-2-ylmethoxy)isobenzofuran-1(3H)one (K50)

[0450]

[0451] According to the method of Example 47, compound K50 was synthesized from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and 2-bromomethylnaphthalene.

[0452] HRMS(ESI):calc.for C 23 H 21 O3, [M+H] + :345.1485,found:345.1481

[0453] 1H NMR(500MHz,DMSO-d6)δ:8.03(brs,1H),7.97(t,J=7.5Hz,1H),7.93(overlap,2H),7.72(t,J=8.0Hz,1H),7.63(dd,J=8.5Hz,1.5Hz,1H),7.52-7.56(over lap,2H),7.49(d,J=7.5Hz,1H),7.27(d,J=8.0Hz,1H),5.93(t,J=7.5Hz,1H), 5.48(s,1H),2.34(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0454] 13 C NMR(125MHz,DMSO-d6)δ:163.92,156.78,144.87,141.36,137.15,133.90,132.75,132.63,128.23,127.8 4,127.69,126.45,126.28,126.21,125.42,113.28,112.33,111.14,109.19,69.95,27.45,22.00,13.73.

[0455] Example 52: Preparation of (Z)-3-Butylene-7-(2-Methoxyethoxy)isobenzofuran-1(3H)one (K51)

[0456]

[0457] Compound K51 was synthesized from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and bromoethyl methyl ether, according to the method of Example 47.

[0458] HRMS(ESI):calc.for C 15 H 19 O4,[M+H] + :263.1278,found:263.1275.

[0459] 1H NMR(500MHz,DMSO-d6)δ:7.71(t,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.14(d,J=8.0Hz,1H),5.91(t,J=7.5Hz,1H),4.2 7(t,J=4.0Hz,1H),3.71(t,J=4.0Hz,1H),3.35(s,3H),2.32(q,J=7.5Hz,2H),1.45-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0460] 13 C NMR (125MHz, DMSO-d6) δ: 163.81, 157.07, 144.75, 141.33, 137.12, 112.75, 112.11, 110.76, 109.02, 70.06, 68.25, 58.50, 27.36, 22.01, 13.74.

[0461] Example 53: Preparation of (Z)-3-Butylene-7-phenylethoxyisobenzofuran-1(3H)one (K52)

[0462]

[0463] According to the method of Example 47, compound K52 was synthesized from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and phenethyl bromide.

[0464] HRMS(ESI):calc.for C 20 H 21 O3, [M+H] + :309.1485,found:309.1483.

[0465] 1 H NMR(500MHz, DMSO-d6)δ:7.69(t,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.40(d,J=8.0Hz,2H),7.29(t,J=7.5Hz,2H),7.22(t,J=7.5Hz,1H),7.14(d, J=8.0Hz,1H),5.90(t,J=7.5Hz,1H),4.33(t,J=7.0Hz,2H),3.08(t,J=7. 0Hz,2H),2.32(q,J=7.5Hz,2H),1.45-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0466] 13C NMR(125MHz,DMSO-d6)δ:163.83,156.95,144.76,141.29,138.08,137.19,129.32,129.32,, 128.28, 128.28, 126.42, 112.63, 112.01, 110.69, 109.02, 69.20, 34.71, 27.43, 21.94, 13.66.

[0467] Example 54: Preparation of (Z)-3-Butylene-7-(2-methylpropoxy)isobenzofuran-1(3H)one (K53)

[0468]

[0469] According to the method of Example 47, compound K53 was synthesized from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and 2-methylpropyl bromide.

[0470] HRMS(ESI):calc.for C 16 H 21 O3, [M+H] + :261.1485,found:261.1482.

[0471] 1 H NMR(500MHz,DMSO-d6)δ:7.69(t,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H),5.89(t,J=7.5Hz,1H),3.9 1(d,J=6.5Hz,2H),2.32(q,J=7.5Hz,2H),2.06(m,1H),1.45-1.52(m,2H),1.00(d,J=6.5Hz,6H),0.93(t,J=7.5Hz,3H);

[0472] 13 C NMR(125MHz,DMSO-d6)δ:163.80,157.27,144.82,141.27,137.16,112.63, 111.83,110.77,108.90,74.30,27.66,27.42,21.95,18.87,18.87,13.72.

[0473] Example 55: Preparation of (Z)-3-Butylidene-7-(3-methylbutoxy)isobenzofuran-1(3H)one (K54)

[0474]

[0475] According to the method of Example 47, compound K54 was synthesized from intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2) and 3-methylbutyl bromide.

[0476] HRMS(ESI):calc.for C 17 H 23 O3, [M+H] + :275.1642,found:275.1639.

[0477] 1 H NMR(500MHz,DMSO-d6)δ:7.01(t,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),5.90(t,J=7.5Hz,1H),4. 16(t,J=6.5Hz,2H),2.32(q,J=7.5Hz,2H),1.83(m,1H),1.65(q,J=7.5Hz,2H),1.45-1.52(m,2H),0.93(overlap,9H);

[0478] 13 C NMR(125MHz,DMSO-d6)δ:163.85,157.25,144.72,141.29,137.13,112.64,111 .83,110.70,108.92,66.97,37.08,27.43,24.54,22.44,22.44,22.01,13.74.

[0479] Example 56: Preparation of (Z)-3-Butylene-7-(2-(4-ethylpiperazin-1-yl)ethoxy)isobenzofuran-1(3H)one (K55)

[0480]

[0481] The intermediate (Z)-3-butylide-7-hydroxyisobenzofuran-1(3H)one (H2, 260 mg, 1.27 mmol), potassium iodide (50 mg, 0.3 mmol), and potassium carbonate (350 mg, 2.5 mmol) were dissolved in acetonitrile (10 mL). 1,2-Dibromoethane (280 μl, 3.3 mmol) was added to the reaction solution. The reaction was carried out at 80 °C for 5 h under argon protection, and the reaction was monitored by TLC until it was complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (20 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 (silica gel, Hexane / EtOAc = 10:1 to 3:1 gradient elution, v / v) to give a pale yellow solid product (Z)-3-butylidene-7-(2-bromoethoxy)isobenzofuran-1(3H)one (183 mg, yield 46.0%).

[0482] The (Z)-3-butylidene-7-(2-bromoethoxy)isobenzofuran-1(3H)one (60 mg, 0.2 mmol), N-ethylpiperazine (50 μl, 0.4 mmol), and potassium carbonate (67 mg, 0.5 mmol) synthesized in the previous step were dissolved in DMF (5 mL), and reacted at 80 °C for 2 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (20 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 (silica gel, Hexane / EtOAc = 10:1 to 5:1 gradient elution, v / v) to give compound K55 (41 mg, yield 60.0%).

[0483] HRMS(ESI):calc.for C 20 H 29 O3N2,[M+H] + :345.2173,found:345.2169.

[0484] 1 H NMR(500MHz,CD3OD-d4)δ:7.64(t,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.05(d,J=8.0Hz,1H),5.76(t,J=8.0Hz,1H),4.29(t,J =5.0Hz,2H),2.50-2.92(overlap,12H),2.37(q,J=7.5Hz,2H),1.49-1.58(m,2H),1.11(t,J=7.5Hz,3H),0.94(t,J=7.5Hz,3H);

[0485] 13 C NMR(125MHz,CD3OD-d4)δ:166.59,158.59,146.77,143.27,138.13,113.31,113.04,112. 82,110.47,68.66,57.39,54.01,53.32,53.32,53.22,53.22,28.83,23.43,14.15,11.37.

[0486] Example 57: Preparation of (Z)-3-Butylene-7-(2-morpholinoethoxy)isobenzofuran-1(3H)one (K56)

[0487]

[0488] According to the method of Example 56, compound K56 was synthesized from intermediate (Z)-3-butylidene-7-(2-bromoethoxy)isobenzofuran-1(3H)one and morpholine.

[0489] HRMS(ESI):calc.for C 18 H 24 O4N,[M+H] + :318.1700,found:318.1699.

[0490] 1 H NMR(500MHz, DMSO-d6)δ:7.72(t,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.16(d,J=8.0Hz,1H),5.92(t,J=8.0Hz,1H),4.28(t,J=5.5Hz, 2H),3.56(t,J=5.5Hz,4H),2.76(t,J=5.5Hz,2H),2.54(overlap,4H),2.33(q,J=7.5Hz,2H),1.46-1.53(m,2H),0.94(t,J=7.5Hz,3H);

[0491] 13 C NMR(125MHz,DMSO-d6)δ:163.88,156.99,144.76,141.29,137.18,112.80,112.0 8,110.80,109.04,67.07,66.22,66.22,56.56,5.80,53.80,27.43,22.00,13.74.

[0492] Example 58: Preparation of (Z)-3-Butylidene-7-((1-tert-butyrylpyrrolidone-3-yl)oxy)isobenzofuran-1(3H)one (K57)

[0493]

[0494] The intermediate (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one (H2, 90 mg, 0.44 mmol), 3-bromotert-butyrylpyrrolidine (200 mg, 0.8 mmol), tetratert-butylammonium bromide (14 mg), and potassium carbonate (138 mg, 1 mmol) were dissolved in acetonitrile (5 mL) and refluxed at 80 °C for 10 h. The reaction was monitored by TLC until complete. The reaction was quenched with 50 mL of water, extracted with ethyl acetate (20 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 (silica gel, Hexane / EtOAc = 10:1 to 3:1 gradient elution, v / v) to give compound K57 (110 mg, yield 70.0%).

[0495] HRMS(ESI):calc.for C 21 H 27 O5NNa,[M+Na] + :396.1781,found:396.1777.

[0496] 1 H NMR(500MHz,DMSO-d6)δ:7.72(t,J=7.5Hz,1H),7.50(d,J=7.5Hz,1H),7.17(d,J=7.5Hz,1H),5.92(t,J=7.5Hz,1H),5.21(s,1H),3.60(m,1H) ,3.37-3.47(overlap,3H),2.34(q,J=7.5Hz,2H),2.07-2.19(overlap,2H),1.44-1.51(m,2H),1.38(d,J=10.0Hz,9H),0.93(t,J=7.5Hz,3H);

[0497] 13 C NMR(125MHz,DMSO-d6)δ:167.00,163.75,155.48,144.67,141.56,137.00,114.03,112.50,1 11.41,109.13,78.56,65.06,43.92,43.72,30.49,28.15,28.15,28.15,27.43,22.00,13.71.

[0498] Example 59: Preparation of (Z)-(1-Butylene-3-oxo-1,3-dihydroisobenzofuran-4-yl)acetate (K58)

[0499]

[0500] According to the method of Example 35, compound K58 was synthesized from compound (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one and acetyl chloride.

[0501] HRMS(ESI):calc.for C 14 H 14 O4Na,[M+Na] + :269.0784,found:269.0782.

[0502] 1 H NMR(500MHz,DMSO-d6)δ:7.84-7.91(overlap,2H),7.33(dd,J=7.5Hz,1.0Hz,1H),6.0 9(t,J=8.0Hz,1H),2.33-2.38(overlap,5H),1.47-1.54(m,2H),0.95(t,J=7.5Hz,3H);

[0503] 13 C NMR (125MHz, DMSO-d6) δ: 168.48, 163.48, 147.60, 144.38, 140.75, 136.97, 123.07, 118.39, 115.74, 110.85, 27.75, 21.88, 20.44, 13.69.

[0504] Example 60: Preparation of (Z)-(1-Butylidene-3-oxo-1,3-dihydroisobenzofuran-4-yl)-2-methylpropionate (K59)

[0505]

[0506] According to the method of Example 35, compound K59 was synthesized from compound (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one and 2-methylpropionyl chloride.

[0507] HRMS(ESI):calc.for C 16 H 18 O4Na,[M+Na] + :297.1097,found:297.1095.

[0508] 1 H NMR(500MHz,DMSO-d6)δ:7.86(overlap,2H),7.32(d,J=8.0Hz,1H),6.07(t,J=8.0Hz,1H),2.89( m,1H),2.35(q,J=7.5Hz,2H),1.46-1.54(m,2H),1.28(s,3H),1.27(s,3H),0.94(t,J=7.5Hz,3H);

[0509] 13 C NMR(125MHz,DMSO-d6)δ:174.14,163.50,147.78,144.42,140.77,136.86, 123.08,118.26,115.74,110.75,33.26,27.50,21.91,18.60,18.60,13.70.

[0510] Example 61: Preparation of (Z)-(1-Butylidene-3-oxo-1,3-dihydroisobenzofuran-4-yl)-4-fluorobenzoate (K60)

[0511]

[0512] According to the method of Example 35, compound K60 was synthesized from compound (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one and 4-fluorobenzoyl chloride.

[0513] HRMS(ESI):calc.for C 19 H 15 O4FNa,[M+Na] + :349.0847,found:349.0842.

[0514] 1 H NMR(500MHz,DMSO-d6)δ:8.23(dd,J=9.0Hz,5.5Hz,2H),7.93(overlap,2H),7.52(d,J=7.5Hz,1H),7.48 (t,J=9.0Hz,2H),6.12(t,J=7.5Hz,1H),2.36(q,J=7.5Hz,2H),1.48-1.55(m,2H),0.95(t,J=7.5Hz,3H);

[0515] 13C NMR (125MHz, DMSO-d6) δ: 165.78 (d, J = 255.5Hz), 163.46, 162.94, 147.57, 144.41, 140.86, 137.02, 133.10 (d, J=10.0Hz), 124.78 (d, J=2.5Hz), 123.22, 118.60, 116.38 (d, J=22.0Hz), 115.74, 111.08, 27.54, 22.04, 13.64.

[0516] Example 62: Preparation of (Z)-(1-Butylidene-3-oxo-1,3-dihydroisobenzofuran-4-yl)-cyclopropionate (K61)

[0517]

[0518] According to the method of Example 35, compound K61 was synthesized from compound (Z)-3-butylidene-7-hydroxyisobenzofuran-1(3H)one and cyclopropionyl chloride.

[0519] HRMS(ESI):calc.for C 16 H 16 O4Na,[M+Na] + :295.0941,found:295.0937.

[0520] 1 H NMR(500MHz,DMSO-d6)δ:7.82-7.89(overlap,2H),7.34(d,J=7.5Hz,1H),6.07(t,J=8.0Hz,1H),2.3 5(q,J=7.5Hz,2H),1.96(m,1H),1.48-1.55(m,2H),1.07-1.13(overlap,2H),0.95(t,J=7.5Hz,3H);

[0521] 13 C NMR(125MHz,DMSO-d6)δ:172.01,163.39,147.60,144.40,140.73,136.85 ,123.09,118.19,115.80,110.75,27.50,21.84,13.71,12.53,9.26,9.26.

[0522] Pharmacodynamic studies:

[0523] I. In vitro activity experiments of compounds:

[0524] 1. Cell protective effect of the compound on a primary cultured glutamate-induced neuronal injury model in rat fetal mice.

[0525] 1.1 Experimental Methods: Establishment of a Glutamate Injury Model

[0526] Cortical neurons were harvested from Wistar rat embryos within 12 hours of birth, and the neurons were cultured. Pre-incubation was performed for 1 hour with PHPB (10 μmol / L) and a screening compound (10 μmol / L), followed by 1 hour of pre-incubation with PHPB (10 μmol / L) and the test compound (10 μmol / L). Each well was then treated with glutamate dilution to a final concentration of 300 μM and PHPB / compound to a final concentration of 10 μM. After co-culturing for 20 hours, cell viability was assessed using the MTT assay.

[0527] The improvement in cell survival rate is calculated based on the following formula:

[0528] Improved survival rate (%) = (Sample group survival rate - Model group survival rate) / Model group survival rate * 100%

[0529] 1.2 Experimental Grouping:

[0530] 1) Normal control group

[0531] 2) Model group: Glutamate group (final concentration: 300 μM) / OGD group

[0532] 3) Positive assay tool PHPB group (final concentration 10 μmol / L)

[0533] 4) Group of compounds to be tested

[0534] 1.3 Experimental Results

[0535] At least three concentrations were selected for each compound, and each concentration was measured at least three times. The positive experimental results are shown in Table 1.

[0536] Generally, a 10% increase in cell survival rate is significant, and the results above show that many compounds have reached this standard, some even reaching around 30%, indicating that these compounds have a strong anti-glutamate damage effect.

[0537] 2. The effect of the compound on the survival rate of SK-N-SH cell oxygen-glucose deprivation model using a three-gas apparatus.

[0538] 2.1 Experimental Methods: Establishment of a Three-Gas Apparatus Oxygen-Glucose Deprivation Model

[0539] SK-N-SH cells were plated and cultured. The positive control drug PHPB (10 μmol / L) and the test compound (10 μmol / L) were co-incubated with SK-N-SH cells for 1 hour, respectively. The cells were then cultured in a three-gas incubator under hypoxia and hypoglycemia for 5 hours, followed by reoxygenation for 20 hours. Cell viability was detected by MTT assay.

[0540] The improvement in cell survival rate is calculated based on the following formula:

[0541] Improved survival rate (%) = (Sample group survival rate - Model group survival rate) / Model group survival rate * 100%

[0542] 2.2 Experimental Grouping:

[0543] 1) Normal control group

[0544] 2) Model group: Glutamate group (final concentration: 300 μM) / OGD group

[0545] 3) Positive assay tool PHPB group (final concentration 10 μmol / L)

[0546] 4) Screening compound groups

[0547] 2.3 Experimental Results

[0548] At least three concentrations were selected for each compound, and each concentration was measured at least three times. The experimental results that yielded positive results are shown in Table 2.

[0549] Generally, a 10% increase in cell survival rate is significant, and the results above show that many compounds have reached this standard, some even reaching around 40-50%, indicating that these compounds have a strong anti-hypoxic damage effect.

[0550] II. In vivo pharmacodynamic experiments in whole animals:

[0551] Effect of compound 1 on maximum electrical shock episode (MES) in mice:

[0552] 1.1 Experimental Methods and Reagents: Compound K22, a white lumpy substance with poor water solubility, was ground in 0.3% Tween 80 and dissolved in physiological saline to form a suspension.

[0553] Compound K25 is a white powder with poor water solubility. It can be dissolved in physiological saline in 0.3% Tween 80 solution after grinding.

[0554] Compound K47 is a waxy solid with moderate water solubility. When ground with 0.3% Tween 80, it can be dissolved in physiological saline to form a suspension.

[0555] Compound K50 is a white powder with poor water solubility. It can be dissolved in physiological saline to form a suspension after being ground with 0.3% Tween 80.

[0556] Carbamazepine, store at -20℃ in a sealed container protected from light. Dissolve in physiological saline to form a suspension using 0.3% Tween 80 grinding solution.

[0557] Instrument: YLS-9A Physiological Pharmacological Electronic Stimulator.

[0558] Animals: Male ICR mice, 23-25g, were housed at the GLP Animal Experiment Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences, with free access to food and water, and light exposure every 12 hours.

[0559] Experimental Methods: The positive drug was administered once half an hour before electrical stimulation. During the experiment, a suitable amount of physiological saline was applied to both ears of the animal, and the ear electrodes were clamped to the tips of both ears to apply the current. Observation and recording of electroconvulsive events in mice (the occurrence of rigidity in the hind limbs was used as the criterion for convulsion): number of convulsions and deaths, and duration of convulsions.

[0560] Data processing: The number of mice experiencing seizures and deaths in each group was statistically analyzed. The chi-square test was used to compare the drug-treated group with the model group; a p-value < 0.05 was considered statistically significant. The duration of seizures was assessed using the TTest test, comparing the drug-treated group with the model group; a p-value < 0.05 was considered statistically significant.

[0561] 1.2 Experimental Results

[0562] The results are shown in Tables 3 and 4, indicating that compounds K22 and K47 have certain anticonvulsant effects.

[0563] 2. Effects of the compound on decapitation tolerance in mice:

[0564] 2.1 Experimental Methods and Reagents: Compound K22, a white lumpy substance with poor water solubility, was ground in 0.3% Tween 80 and dissolved in physiological saline to form a suspension.

[0565] Compound K25 is a white powder with poor water solubility. It can be dissolved in physiological saline in 0.3% Tween 80 solution after grinding.

[0566] Compound K47 is a waxy solid with moderate water solubility. When ground with 0.3% Tween 80, it forms a suspension in physiological saline.

[0567] Compound K50 is a white powder with poor water solubility. It can be dissolved in physiological saline after grinding with 0.3% Tween 80 to form a suspension. Nimodipine white tablets, 30 mg / tablet, are supplied by Tianjin Central Pharmaceutical Co., Ltd. Batch number 161206, prepared as a 12 mg / mL suspension with distilled water.

[0568] Animals: Male ICR mice, 20-23g, provided by Vital River, were housed at the GLP Animal Experiment Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences, with free access to food and water, and light exposure every 12 hours.

[0569] Experimental Methods: Animals were randomly divided into 10 groups: a control group, a nimodipine oral administration group (120 mg / kg), and groups receiving intraperitoneal injections of compounds K22, K25, K47, and K50 (30 mg / kg and 100 mg / kg, respectively). The nimodipine oral administration group underwent decapitation 60 minutes after administration, while the other groups underwent decapitation 30 minutes after administration. Survival time and mouth opening frequency after decapitation were recorded. 2.2 Experimental Results:

[0570] The experimental results are shown in Table 5. It can be seen that compounds K22, K47 and K50 have certain anti-decapitation hypoxia effects.

[0571] 3. Effects of the compound on hypoxia tolerance in mice under suffocation

[0572] 3.1 Experimental Methods and Reagents: Compound K22, a white lumpy substance with poor water solubility, was ground in 0.3% Tween 80 and dissolved in physiological saline to form a suspension.

[0573] Compound K25 is a white powder with poor water solubility. It can be dissolved in physiological saline in 0.3% Tween 80 solution after grinding.

[0574] Compound K47 is a waxy solid with moderate water solubility. When ground with 0.3% Tween 80, it can be dissolved in physiological saline to form a suspension.

[0575] Compound K50 is a white powder with poor water solubility. It can be dissolved in physiological saline to form a suspension after being ground with 0.3% Tween 80.

[0576] Atenolol white tablets, 12.5 mg / tablet, supplied by Tianjin Central Pharmaceutical Co., Ltd. Batch number 170510, prepared as a 50 mg / mL suspension with distilled water.

[0577] Animals: Male ICR mice, 20-23g, provided by Vital River, were housed at the GLP Animal Experiment Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences, with free access to food and water, and light exposure every 12 hours.

[0578] Experimental methods: Animals were randomly divided into 10 groups: a control group, a nimodipine oral administration group (120 mg / kg), and groups receiving intraperitoneal injections of compounds K22, K25, K47, and K50 (30 mg / kg and 100 mg / kg, respectively). Atenolol oral administration groups were subjected to cupping 30 minutes after administration, while the other groups were subjected to cupping 20 minutes after administration. Survival time after cupping was recorded.

[0579] 3.2 Experimental Results:

[0580] The results are shown in Table 6, indicating that compound K50 has a significant anti-brain hypoxia effect.

[0581] 4. Scopolamine-induced dementia model in mice

[0582] 4.1. Experimental Objective:

[0583] The effects of the tested compounds on the mouse dementia model were investigated using an ICR mouse scopolamine dementia model.

[0584] 4.2. Experimental reagents:

[0585] Test compounds: Compound K16 (gray powder) and Compound K46 (oil). After grinding with 0.3% Tween 80, they were prepared with physiological saline and administered at a volume of 10 mg / kg via intraperitoneal injection.

[0586] Butylphthalide (NBP): Prepare by mixing with 0.1% Tween 80 and then adding pure water. Dosage volume: 10 mg / kg, administration method: oral gavage.

[0587] Donepezil Hydrochloride Tablets (Aricept) 10mg / tablet, after being ground and dissolved in water to form a suspension, is manufactured by Eisai (China) Pharmaceutical Co., Ltd., with National Drug Approval Number H20070181. Dosage volume: 10mg / kg, administration method: oral gavage.

[0588] Scopolamine: White powder, readily soluble in water, purchased from Sigma, catalog number: S1875-1G. Dosage volume: 10 mg / kg, administration method: intraperitoneal injection.

[0589] Laboratory animals:

[0590] ICR male mice, 22-24g, provided by Vitalisk.

[0591] Experimental Groups:

[0592] Animals were randomly divided into 8 groups: normal control group (sham), model control group (model), Don-3mg / kg, NBP-200mg / kg, K16-10mg / kg, K16-50mg / kg, K46-10mg / kg, and K46-50mg / kg.

[0593] Experimental methods:

[0594] The platform diving experiment lasted three days, with each treatment group receiving the drug once daily. The normal control group and the model control group received the corresponding volume of pure water.

[0595] Diving platform test method: The diving platform test was conducted continuously for 3 days. On the first day, animals were acclimatized to the environment without electrical stimulation for 5 minutes. On the second day, they were subjected to electrical stimulation for 3 minutes. On the third day, the test was conducted for 3 minutes, and the latency to exit the platform and the number of exits were recorded. On the second and third days, animals were orally administered pure water, Don, and NBP 60 minutes before the diving platform test. 50 minutes before the test, animals were intraperitoneally injected with compounds K16 and K46. 30 minutes before the diving platform test, all groups of animals were intraperitoneally injected with scopolamine 1 mg / kg (except for the normal control group).

[0596] 4.3. Experimental Results:

[0597] The results are shown in Table 7. Figure 1 and Figure 2 It is evident that compound K16 has a significant effect against scopolamine-induced dementia, and compound K46 also shows a certain trend.

[0598] summary:

[0599] The experimental results showed that on the third day of testing, the latency period in the normal control group was 169±11s, and in the model control group it was 111±24s, which was significantly different from the normal control group, indicating successful model establishment. The donepezil 3mg / kg group showed some improvement compared to the model group, but considering the possibly low N value, no significant difference was observed. The K16-50mg / kg group showed a statistically significant difference in latency compared to the model group.

[0600] Pharmacodynamic conclusions:

[0601] 1. In the maximum electroshock test in mice, compared with the model group, NBP-50mg / kg and K47-50mg / kg showed significant statistical differences or a certain trend, suggesting that these compounds have anti-epileptic and anticonvulsant effects.

[0602] 2. The above compounds have a protective effect against neuronal damage caused by excitatory amino acids and can be used for neuroprotection.

[0603] 3. The above-mentioned compounds have a protective effect against neuronal damage caused by oxygen-glucose deprivation and can be used for neuroprotection.

[0604] 4. In the decapitation antihyperxia experiment in mice, the duration of decapitation effects was significantly different between the nimodipine 120 mg / kg group, the K22-100 mg / kg group, and the K47-100 mg / kg group and the control group. Regarding the number of mouth openings, the nimodipine group showed an improved trend compared to the solvent control group, indicating that these compounds have anti-cerebral ischemia and hypoxia effects.

[0605] 5. In the mouse hypoxia-resistant suffocation experiment, the survival time of the control group was 37.0±1.2 minutes. The survival time of the atenolol 50mg / kg group and the K50-30mg / kg group was significantly different from that of the control group, indicating that these compounds have a protective effect against cerebral hypoxia.

[0606] 6. The mouse step-down experiment demonstrated that this type of compound can improve learning and memory impairment caused by scopolamine and enhance learning and memory abilities.

[0607] Table 1. Effects of the tested compounds on the survival rate of primary neuronal glutamate model cells.

[0608]

[0609] Table 2. Improvement of cell survival rate in the oxygen-glucose deprivation model of some compounds SK-N-SH.

[0610]

[0611] Table 3. Statistics on the number of cases and duration of seizures in the maximal electroshock seizure (MES) experiment with compounds K22 and K50 (mean ± SEM).

[0612]

[0613] Compared with the model group, and compared with the control group of 0.3% Tween 80 solvent, the positive drug group showed *P<0.05, **P<0.01.

[0614] Table 4. Statistics on the number of cases and duration of seizures in the maximal electroshock seizure (MES) experiment of compounds K25 and K47 (mean ± SEM).

[0615]

[0616] Compared with the model group: *P<0.05, **P<0.01.

[0617] Table 5. Effects of intraperitoneal injection of NBP derivatives on the efficacy of decapitation experiment in ICR mice (X±SEM)

[0618]

[0619] **Compared with the control group, P<0.01

[0620] Table 6. Efficacy of intraperitoneal injection in ICR mice (sealing experiment) X±SEM

[0621]

[0622] *P<0.05 compared with the control group.

[0623] Table 7. Effects of compounds K16 and K46 on the step-down test in a scopolamine-induced ICR mouse dementia model (X±SEM)

[0624]

Claims

1. Compounds represented by general formula I and their pharmaceutically acceptable salts: Its features are, The compound represented by general formula I is Z Configuration, When R2 represents hydrogen, R1 represents a substituted or unsubstituted phenyl group or OR. a ,in, The substituent on the phenyl group is monosubstituted, and the substituent is selected from -CN; R a C represents the replacement of straight or branched chains. 1-10 Alkyl, wherein, The substituents are selected from substituted or unsubstituted phenyl groups, and unsubstituted pyridyl groups, wherein, The phenyl substituent is selected from -F, -Cl, -Br or C. 1-5 Alkoxy; When R1 represents hydrogen, R2 represents OR. b ,in, R b C represents the replacement of straight or branched chains. 1-10 Alkyl, -COR b1 ,in, The substituents are selected from unsubstituted 3-7 membered cycloalkyl groups. R b1 C selected from unsubstituted straight or branched chains 1-10 alkyl.

2. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compounds are those represented by general formula IA and their pharmaceutically acceptable salts: Wherein, R1 represents a substituted or unsubstituted phenyl group or an OR group. a ,in The substituent on the phenyl group is monosubstituted, and the substituent is selected from -CN; R a C represents the replacement of straight or branched chains. 1-10 Alkyl, wherein, The substituents are selected from substituted or unsubstituted phenyl groups, and unsubstituted pyridyl groups, wherein, The phenyl substituent is selected from -F, -Cl, -Br or C. 1-5 Alkyl group.

3. The compound according to claim 1 and its pharmaceutically acceptable salt, characterized in that, The compounds are those represented by the general formula IB, and their pharmaceutically acceptable salts: Where R2 represents OR b ,in, R b C represents the replacement of straight or branched chains. 1-10 Alkyl, -COR b1 ,in, The substituents are selected from unsubstituted 3-7 membered cycloalkyl groups. R b1 C selected from unsubstituted straight or branched chains 1-10 alkyl.

4. The following compounds and their pharmaceutically acceptable salts, characterized in that, The following compounds are Z-configured. The compounds mentioned therein are selected from: 。 5. A pharmaceutical composition, characterized in that, Contains an effective dose of any compound as described in any one of claims 1-4 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, or controlled-release preparations.

7. The use of the compound of any one of claims 1-4 and its pharmaceutically acceptable salt in the preparation of a medicament for diseases related to nerve cell damage.

8. The application as described in claim 7, characterized in that, The diseases related to nerve cell damage mentioned above are neurodegenerative diseases or neuropsychiatric diseases.

9. The application according to claim 8, characterized in that, The neurodegenerative diseases mentioned are Alzheimer's disease, Huntington's disease, cognitive impairment, Parkinson's disease, and cerebral ischemic injury; the neuropsychiatric diseases mentioned are epilepsy, seizures, depression, and anxiety disorders.

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