Spiro compound as well as preparation method and application thereof

Abstract

The invention provides a spiro compound as shown in a formula (I) or a tautomer, a stereoisomer or pharmaceutically acceptable salt thereof and application thereof. In-vivo and in-vitro experiment results show that the compound disclosed by the invention has an excellent protection effect on cerebral cortex neuronal cells, and particularly, the survival rate of the cerebral cortex neuronal cells can be remarkably improved under the condition of hypoxia and hypoglycemia; the pharmaceutical composition has excellent pharmacokinetic behavior and brain protection effect, and the cerebral infarction area can be greatly reduced; the compound can be used for preventing and treating nerve injury, degenerative diseases and ischemic diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a spirocyclic compound, a preparation method thereof, and pharmaceutical uses thereof. Background Art

[0002] Ischemic stroke is a brain injury caused by ischemia and hypoxia in the brain tissue. It leads to neuronal cell death and damage to the neurovascular unit, resulting in severe neuronal necrosis. Characterized by high morbidity and mortality, it has become a major threat to human health and life. Clinical studies have found that ischemic stroke is caused by temporary blockage of cerebral blood vessels and arteries supplying the brain, resulting in insufficient blood supply to localized brain tissue, occlusion of cerebral arteries, and slowed or stopped cerebral blood flow. It is a multifactorial, multi-linked, and malignant cascade process.

[0003] Currently, clinical treatment for ischemic stroke patients focuses on two main approaches. First, strategies such as thrombolysis and vasodilator therapy, specifically the use of thrombolytics, antiplatelet agents, anticoagulants, and fibrinolytics, aim to improve blood supply to the ischemic area. Restoration of cerebral blood flow after thrombolytic therapy may lead to ischemia-reperfusion (IR) injury. For example, recombinant tissue plasminogen activator (RTPA), a US Food and Drug Administration-approved drug for the treatment of acute ischemic stroke, has demonstrated some efficacy. However, due to RTPA-induced reperfusion injury, a narrow therapeutic window, and side effects such as hemorrhagic transformation and cell damage after restoration of cerebral blood flow, only 5% of stroke patients are currently eligible for RTPA. Second, the goal is to protect brain neuronal function by mitigating damage or apoptosis caused by a lack of blood supply. These drugs primarily include glutamate receptor antagonists, free radical scavengers, GABA receptor agonists, and calcium channel blockers. Currently, many drugs are available for the prevention and treatment of ischemic stroke, but these drugs have numerous limitations, such as limited therapeutic conditions and inability to meet clinical needs. Recently, researchers have discovered that protecting brain neurons after cerebral ischemia can significantly extend the time window for thrombolytic therapy. Therefore, the study of small molecule compounds with neuroprotective properties that improve blood circulation is of great significance.

[0004] Butylphthalide (3-n-butyphthalide, NBP, Formula A) is a benzofuranone compound extracted from celery seeds. Its chemical name is (R / S)-3-n-butyl-1(3H)-isobenzofuranone. Butylphthalide is a drug independently developed in my country for the treatment of ischemic stroke. It exhibits multiple biological activities, including antithrombotic and antiplatelet aggregation, and preventive / therapeutic effects in conditions including Alzheimer's disease, vascular dementia, Lewy body dementia, Parkinson's disease, concussion, amyotrophic lateral sclerosis (ALS), Meniere's disease, mitochondrial myopathy, cerebral palsy, spinal cord injury, peripheral neuropathy (including diabetes-induced and chemotherapy-induced peripheral neuropathy), and radiation-induced brain injury. Ischemic stroke is a major research focus. Although butylphthalide can alleviate multiple pathological conditions of cerebral ischemia, its oily nature limits its development in dosage forms. There are methods to modify and transform the structure of butylphthalide through chiral splitting, introduction of substituents on the benzene ring, and derivatization after ring opening of the ester, but no products have been successfully launched on the market.

[0005]

[0006] Therefore, research and development of new and highly effective drugs for preventing and treating cerebral ischemia is an important topic that medical scientists are currently paying attention to. Summary of the Invention

[0007] The first aspect of the present invention provides a compound as shown in formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof,

[0008]

[0009] in,

[0010] Y and Z are each independently selected from carbonyl, O or S, and when Y is carbonyl, Z is selected from O or S, or when Z is carbonyl, Y is selected from O or S;

[0011] W1, W2, W3 are each independently selected from C or N;

[0012] R1 is 1-4 (e.g., 1, 2, 3, 4), each selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OR 3 、-SR 3 、-NR 3 R 3 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 、-OC(O)R 3 、-S(O) 0-2R 3 、-S(O)2NR 3 R 3 、-N(R 3 )S(O)2R 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)NR 3 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with 0-6 identical or different cyano, amino, hydroxyl or halogen groups;

[0013] R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OR 5 、-SR 5 、-NR 5 R 5 、-C(O)R 5 、-C(O)OR 5 、-C(O)NR 5 R 5 、-OC(O)R 5 、-S(O) 0- 2R 5 、-S(O)2NR 5 R 5 、-N(R 5 )S(O)2R 5 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)NR 5 、-C 1-6 Alkyl R 5 、-N(R 5 )C 1-6 Alkyl R 5 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 0-6 identical or different cyano, amino, hydroxyl, halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) 0-2 R 5 、-NR 5 R 5 replace;

[0014] R 3 、R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl and 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 The aryl group and the 3-10 membered heterocyclyl group are each optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups;

[0015] Alternatively, R2 and the atoms to which it is attached form a ring to form C 3-8 Carbocyclyl, or 3-8 membered heterocyclyl, wherein the heteroatoms are selected from 1-3 N, S or O;

[0016] H in the compound represented by formula (I) is optionally replaced by D.

[0017] In some embodiments, Y is selected from carbonyl and Z is selected from O.

[0018] In some embodiments, Y is selected from O and Z is selected from carbonyl.

[0019] In some embodiments, W1, W2, and W3 are selected from C.

[0020] In some embodiments, the compound of formula (I) has the structure shown in the following formula (I-1):

[0021]

[0022] R1 and R2 are defined as above;

[0023] H in the compound represented by formula (I-1) is optionally replaced by D.

[0024] In the compounds represented by formula (I) and formula (I-1),

[0025] In some embodiments, R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, thiol, -SF5, -COOH, -OR 3 、-SR 3 、-NR 3 R 3 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 、-OC(O)R 3 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl groups are optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups;

[0026] R 3 are independently selected from: hydrogen, C 1-6 alkyl.

[0027] In some embodiments, R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, thiol, -SF5, -COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl; wherein the C 1-6 The alkyl groups are optionally substituted by 0-6 identical or different cyano groups, amino groups, hydroxyl groups or halogen groups; 1-6 The alkyl group is preferably C 1-4 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and more preferably methyl.

[0028] In some embodiments, R1 is 1-4 (eg, 1, 2, 3, 4), each independently selected from hydrogen, halogen, or C1-6 Alkyl; the halogen is preferably F, Cl, Br; the C 1-6 The alkyl group is preferably C 1-4 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and more preferably methyl.

[0029] In some embodiments, R1 is 1-4 (eg, 1, 2, 3, 4), each independently selected from hydrogen, F, Cl, Br or methyl, preferably hydrogen, F or Br.

[0030] In some embodiments, R1 is 4 hydrogens, or R1 is 3 hydrogens and 1 F, or R1 is 3 hydrogens and 1 Br; preferably, the F or Br is in the ortho or meta position of the benzene ring, more preferably, the F or Br is in the ortho position of the benzene ring. In some embodiments, R2 is 1-6 (e.g., 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, -NR 5 R 5 、-S(O) 0-2 R 5 、-N(R 5 )S(O)2R 5 、-N(R 5 )C(O)R 5 、-C 1-6 Alkyl R 5 、-N(R 5 )C 1-6 Alkyl R 5 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl groups are optionally substituted with 0-6 identical or different cyano, amino, hydroxyl, halogen, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) 0-2 R 5 、-NR 5 R 5 replace,

[0031] Alternatively, R2 and the atom to which it is attached form a C 3-6 a carbocyclic group, or a 3-6 membered heterocyclic group, wherein the heteroatoms are selected from 1-3 N, S or O,

[0032] R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and 3-6 membered heterocyclic group, wherein the C1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 The aryl group and the 3-6 membered heterocyclyl group are each optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups.

[0033] In some embodiments, R2 is 1-6 (eg, 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogenated C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -C 1-6 Alkyl SO2C 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl Ph, -C 1-6 Alkyl NH C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10 membered heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, or the atom to which R2 is attached forms a C 3-6 Carbocyclic group, or 3-6 membered heterocyclic group, wherein the heteroatoms are selected from 1-3 N, S or O.

[0034] In some embodiments, R2 is 1-6 (eg, 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHC(O)C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -C 1-4 Alkyl SO2C 1-4 Alkyl, -N(C 1-4 Alkyl)C 1-4 Alkyl C 6-10 Aryl, -C 1-4 Alkyl NH C 6-10 Aryl, -C 1-4 Alkyl-C 6-10 Aryl, -C 1-4 Alkyl-5-10 membered heteroaryl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, or the atom to which R2 is attached forms cyclobutyl, oxetanyl, or azetidinyl.

[0035] In some embodiments, R2 is 1-6 (eg, 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHC(O)C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -C 1-4 Alkyl SO2C 1-4 Alkyl, -N(C 1-4 Alkyl)C 1-4 Alkyl Ph, -C 1-4 Alkyl NHPh, -C 1-4 Alkyl Ph, -C 1-4 Alkyl-pyridyl, -C 1-4 Alkyl-cyclopropyl, -CH2-benzofuranyl, or the atom to which R2 is attached forms a cyclobutyl, oxetanyl, or azetidinyl.

[0036] In some embodiments, R2 is 1-6 (e.g., 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, allyl, propenyl, -CF3, -CH2CF3, -N(CH3)2, -NHC(O)CH3, -NHSO2CH3, -CH2SO2CH3, -N(CH3)CH2Ph, -CH(CH3)NHPh, -CH2Ph, -CH2-pyridine, -CH2-cyclopropyl, -CH2-benzofuranyl, or R2 and the atoms to which it is connected form a cyclobutyl or oxetanyl.

[0037] In some embodiments, R2 is 1-6 (eg, 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups; 1-6 Alkyl, preferably C 1-4 The alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, more preferably methyl, ethyl, or n-propyl, further preferably methyl, ethyl, or n-propyl.

[0038] In some embodiments, R2 is 1-6 (eg, 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, methyl, ethyl, and n-propyl.

[0039] In some embodiments, R2 is 6 hydrogens, or R2 is 5 hydrogens and 1 methyl, or R2 is 5 hydrogens and 1 ethyl, or R2 is 5 hydrogens and 1 propyl; preferably, the methyl, ethyl or propyl is in the para position of the spirocycle.

[0040] In the above embodiments of the present invention, except for the defined groups, the definitions of other groups are the same as those in the present invention, and are not described one by one for the sake of space saving.

[0041] The above embodiments of the present invention can be combined arbitrarily, and the embodiments obtained by the combination also belong to the embodiments of the present invention.

[0042] In the above technical solution, the compound of formula (I) does not include the following compounds:

[0043]

[0044] The following are example structures, including but not limited to compounds of the following structural formulas, their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof:

[0045]

[0046]

[0047]

[0048]

[0049] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound represented by the aforementioned formula (I) or formula (I-1), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.

[0050] The third aspect of the present invention is to provide the use of the compound represented by the aforementioned formula (I) or formula (I-1), its tautomers, stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of drugs, wherein the drugs are used as neuroprotective agents, platelet aggregation inhibitors, anti-inflammatory agents or antioxidants, etc.

[0051] In some embodiments of the present invention, the drug is used to prevent and treat neurodegenerative diseases, ischemic diseases or other diseases for which butylphthalide is applicable; preferably, the neurodegenerative diseases include, for example, Alzheimer's disease, vascular dementia, Lewy body dementia, and Parkinson's disease; the ischemic diseases include myocardial ischemia and ischemic stroke; the other diseases for which butylphthalide is applicable include, but are not limited to, platelet aggregation, concussion, amyotrophic lateral sclerosis (ALS), Meniere's disease, mitochondrial myopathy, cerebral palsy, spinal cord injury, peripheral neuropathy (including diabetes-induced peripheral neuropathy, chemotherapy-induced peripheral neuropathy), radiation-induced brain injury, etc.

[0052] In some embodiments of the present invention, the drug is used for preventing and treating myocardial ischemia and ischemic stroke, or for related treatment during the recovery period of ischemic stroke.

[0053] The present invention provides a drug comprising a compound represented by the aforementioned formula (I) or formula (I-1), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and the drug is used as a neuroprotectant, platelet aggregation inhibitor, anti-inflammatory agent or antioxidant, etc.

[0054] In some embodiments of the present invention, the drug is used to prevent and treat neurodegenerative diseases, ischemic diseases or other diseases for which butylphthalide is applicable; preferably, the neurodegenerative diseases include, for example, Alzheimer's disease, vascular dementia, Lewy body dementia, etc.), and Parkinson's disease, etc.; the ischemic diseases include myocardial ischemia and ischemic stroke, etc.; the other diseases for which butylphthalide is applicable include, but are not limited to, platelet aggregation, concussion, amyotrophic lateral sclerosis (ALS), Meniere's disease, mitochondrial myopathy, cerebral palsy, spinal cord injury, peripheral neuropathy (including diabetes-induced peripheral neuropathy, chemotherapy-induced peripheral neuropathy), radiation-induced brain injury, etc.

[0055] In some embodiments of the present invention, the drug is used for preventing and treating myocardial ischemia and ischemic stroke, or for related treatment during the recovery period of ischemic stroke.

[0056] The fourth aspect of the present invention provides a method for preparing a compound of formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof,

[0057] When Y is a carbonyl group and Z is selected from O or S, the preparation method comprises the following steps:

[0058]

[0059] The halobenzoic acid intermediate (INT-I) and the ketone intermediate (INT-II) undergo ring closure under base catalysis to obtain the compound of formula (I).

[0060] in:

[0061] X is halogen, preferably bromine or iodine;

[0062] The base is selected from alkyl lithium (such as n-butyl lithium) reagent, lithium amide reagent, etc.;

[0063] Or when Z is a carbonyl group and Y is selected from O or S, the preparation method comprises the following steps:

[0064]

[0065] The lactone intermediate (INT-III) and the intermediate containing a double leaving group (INT-IV) undergo ring closure under base catalysis to obtain the compound of formula (I).

[0066] in:

[0067] LG is a leaving group, preferably a halogen (such as bromine, iodine) or a sulfonate (such as methanesulfonate);

[0068] The base is selected from: metal hydrogen (such as sodium hydrogen) reagent, alkyl lithium (such as n-butyl lithium) reagent, lithium amide reagent, etc.;

[0069] Wherein, W1, W2, W3, R1 and R2 are defined as described in the present invention.

[0070] definition

[0071] Unless otherwise specified, D in the present invention represents deuterium ( 2 H).

[0072] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent.

[0073] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "solvates" thereof. The terms "solvate" and "solvate" refer to the physical association of a salt of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0074] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "hydrates" thereof. The term "hydrate" refers to a substance formed by water molecules binding to cations or anions in the compound by coordinate bonds or covalent bonds, or refers to a substance formed by water ions not directly binding to cations or anions but existing in a certain proportion at a certain position in the solid crystal lattice.

[0075] Unless otherwise specified, the compounds of the present invention also include their "prodrugs," which refers to drugs that are converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example, but not limited to, of a prodrug is any compound of the present invention administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0076] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0077] Unless otherwise specified, the term "geometric isomers (cis / trans) isomers" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher-order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents higher-order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers.

[0078] Unless otherwise specified, the term "tautomer" refers to structural isomers of different energies that are interconvertible through a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.

[0079] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0080] Unless otherwise specified, the term "carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group ("C 3-14 In some embodiments, the carbocyclyl group has 3-8 ring carbon atoms ("C 3-8 carbocyclyl”), or 3-6 ring carbon atoms (“C 3-6 carbocyclyl”), or 5 to 8 ring carbon atoms (“C 5-8 In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 Carbocyclyl”). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 5-8 Carbocyclyl groups include, but are not limited to, the aforementioned C 3-6Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. As illustrated in the above examples, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or a fused (fused cyclyl), bridged (bridged cyclyl) or spiro-fused (spirocyclyl) ring system, such as a bicyclic ring system ("bicyclic carbocyclyl") and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of members of the carbocyclyl ring system is the number of carbons in the carbocyclyl ring system after fusion. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 5-8 In certain embodiments, the carbocyclyl group is a substituted C 5-8 Carbocyclic group.

[0081] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl), more preferably containing 1-6 carbon atoms (ie C 1-6 Alkyl), such as "C 1-6 "Alkyl" means that the group is an alkyl group and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0082] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-8 carbon atoms (C 3-8 Cycloalkyl), 3-6 carbon atoms (C 3-6 Cycloalkyl), 5-6 carbon atoms (C 5-6Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0083] Unless otherwise specified, "cycloalkenyl" refers to a group consisting of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings, however, the system is unsaturated, i.e., there is at least one C—C double bond but no aromatic system. Preferably, it contains 3 to 12 carbon atoms (i.e., C 3-12 cycloalkenyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 cycloalkenyl).

[0084] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above, i.e., containing 1-20 carbon atoms, preferably, containing 1-10 carbon atoms, more preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0085] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include CCl3, CF3, CHF2, CH2F, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3 and the like.

[0086] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized, and wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). Preferably, it contains 3 to 10 ring atoms (3-10 membered heterocyclyl), more preferably 3 to 8 ring atoms (3-8 membered heterocyclyl), or 3 to 6 ring atoms (3-6 membered heterocyclyl), or 4 to 6 ring atoms (4-6 membered heterocyclyl), 5 to 8 ring atoms (5-8 membered heterocyclyl) or 5 to 6 ring atoms (5-6 membered heterocyclyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. A "heterocyclic group" may be monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused heterocyclic group"), bridged ("heterobridged heterocyclic group" or "bridged heterocyclic group"), or spiro-fused ("heterospirocyclic group" or "spiroheterocyclic group") ring system, such as a bicyclic ring system ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, or a cycloalkyl ring, as defined above, is fused to one or more heteroaryl groups, wherein the point of attachment is on the heterocyclyl or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the number of atoms in the ring system after fusion. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiolanyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexanyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazacyclohexanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0087] Unless otherwise specified, "heterocycloalkyl" refers to a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, with the ring atoms as defined above, i.e., containing 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), with 1 to 4 heteroatoms (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. One or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized, and one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). Preferably, the ring atoms are 3 to 12 ("3-12 membered heterocycloalkyl"), more preferably 3 to 10 ("3-10 membered heterocycloalkyl"), even more preferably 3 to 8 ("3-8 membered heterocycloalkyl"), and even more preferably 3 to 4 ("3-4 membered heterocycloalkyl"). In certain embodiments, each example of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). Some exemplary "heterocycloalkyl" groups are given above in the "heterocyclyl" or "heterocycle" section, and also include, but are not limited to, aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiolanyl, oxazolidinyl, dioxanyl, dithiolanyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, and the like.

[0088] Unless otherwise specified, "heterocyclenyl" refers to an unsaturated alicyclic (non-aromatic) ring radical, including monocyclic as well as bridged, spirocyclic and / or fused ring systems (which may consist of two or three rings; for example, a fused ring system consisting of two or three fused rings), wherein the ring radical contains one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized, wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group), and wherein the ring radical further contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated alicyclic ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1-4 and there is at least one carbon ring atom (which may be optionally oxidized) in the corresponding heteroatom-containing ring. "Heterocycloalkenyl" may, for example, refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1,2-dihydropyridinyl, or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl, or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl, or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1,2,3,4,5,6,7,8-octahydroisoquinolinyl).Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3- to 12-membered unsaturated alicyclic radical that is a monocyclic or fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring radical contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5- to 7-membered monocyclic unsaturated non-aromatic ring radical containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bonds between adjacent ring atoms.

[0089] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring group." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0090] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure, or preferably a 5-10 membered structure, or preferably a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzo pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0091] Unless otherwise specified, the term "treat," "treatment," "treatment," or "treating" encompasses any treatment of a disease, disorder, or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder, or condition, i.e., arresting its development; or (b) relieving the symptoms of the disease, disorder, or condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder, or condition or one or more symptoms associated with the disease.

[0092] The therapeutically effective amount of the present invention refers to the effective dosage considered pharmaceutically, that is, the amount of the active compound is sufficient to significantly improve the condition without causing serious side effects.

[0093] The beneficial effects of the present invention are:

[0094] The spirocyclic derivatives of the present invention have excellent protective effects on cerebral cortical neuronal cells, particularly under conditions of oxygen and glucose deprivation, significantly increasing their survival rate. Furthermore, the compounds of the present invention exhibit excellent pharmacokinetic behavior and brain protective effects, significantly reducing the size of cerebral infarction. Furthermore, the effects of the compounds of the present invention are significantly superior to those observed in the model group and even to those observed in the positive drug butylphthalide. Therefore, the compounds of the present invention can be used to prepare neuroprotective agents, free radical scavenging drugs, platelet aggregation inhibitors, anti-inflammatory drugs, and antioxidant drugs, and can prevent and treat nerve damage, degenerative diseases, and ischemic diseases.

[0095] The spiro derivatives of the present invention have a simple synthesis method and the raw materials are cheap and readily available, and are therefore suitable for industrial application. DETAILED DESCRIPTION

[0096] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0097] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker AVANCE III 600 MHz instrument, LC-MS using an LCMS WATERS ACQUITY UPLC H-Class PLUS or / and SQD2, and HPLC using a WATERSe 2695-2998 or / and an Agilent 1100.

[0098] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0099] Explanation of terms or abbreviations:

[0100]

[0101] Example 1: Preparation of 3'-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 006)

[0102]

[0103] Methyl 2-iodobenzoate (500 mg, 1.9 mmol) was added to a three-necked flask. THF (10 mL) was added under N2 protection, and the temperature was cooled to -78°C. Isopropylmagnesium chloride-lithium chloride solution (1.8 mL, 2.3 mmol, 1.3 M in THF) was added dropwise. After stirring for 0.5 h, cyclobutanone (143 mg, 2.1 mmol) was added dropwise. The mixture was then allowed to react at -78°C for 1 h. Completion of the reaction was monitored by TLC. Water (2 mL) was added dropwise to the reaction solution at -20°C to quench it. The mixture was then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford Compound 006 (250 mg, 75% yield).

[0104] ESI-MS (m / z): 175.1 [M+H]+ . 1 H NMR(600MHz, CDCl3)δ7.85(d,J=7.7Hz,1H),7.75–7.68(m,3H),7.52(dd,J=10.9,3.8 Hz,1H),2.93–2.85(m,3H),2.59–2.52(m,3H),2.26–2.17(m,1H),2.12–2.04(m,1H).

[0105] Example 2: Preparation of 3-ethyl-3'-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 009)

[0106] Step 1: Preparation of 2,2-dichloro-3-ethylcyclobutan-1-one

[0107] Zinc powder (4.6 g, 0.07 mol) was added to a reaction flask. Under nitrogen, diethyl ether (240 mL) and butene-1 (2.0 g, 0.04 mol) were added. The reaction solution was placed in an ultrasonicator and the temperature was controlled at 0-10°C. 2,2,2-Trichloroacetyl chloride (9.6 g, 0.05 mol) was dissolved in diethyl ether (40 mL) and slowly added dropwise to the reaction solution over 2 h. The reaction was then allowed to react at 10°C for 1 h. TLC (PE:Et2O=95:5, Rf=0.1) indicated the reaction was complete. Water (5 mL) was slowly added dropwise to the reaction solution, which was then filtered and washed three times with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and used directly in the next step.

[0108] Step 2: Preparation of 3-ethylcyclobutan-1-one

[0109] Zinc powder (11.5 g, 179.44 mmol) was added to a reaction flask. Under nitrogen, glacial acetic acid (20 mL) was added. The reaction was cooled to 10°C and a solution of 2,2-dichloro-3-ethylcyclobutan-1-one (6 g, 28.04 mmol) in glacial acetic acid (10 mL) was added dropwise. The reaction was allowed to react at 80°C for 40 minutes. TLC (PE / EA = 100:1, Rf = 0.9) indicated the reaction was complete. The mixture was cooled to room temperature, water (4 mL) was added, and the mixture was stirred vigorously for 10 minutes. The mixture was filtered and extracted with water and ethyl acetate. The organic phase was washed three times each with water, aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 3-ethylcyclobutan-1-one (1 g, 36.4% yield).

[0110] 1H NMR (400MHz, CDCl3) δ3.12–2.99(m,2H),2.65–2.51(m,2H),2.29–2.14(m,1H),1.54(m,2H),0.94–0.84(m,3H).

[0111] Step 3: Preparation of 3-ethyl-3'-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one

[0112] o-Bromobenzoic acid (400 mg, 1.99 mmol) was added to the reaction flask, and THF (10 mL) was added under N2 protection. The reaction was cooled to -78°C, and n-butyllithium (1.6 mL, 3.98 mmol, 2.5 M in n-hexane) solution was added dropwise. The reaction was allowed to react for 0.5 h, followed by the addition of 3-ethylcyclobutane-1-one (195 mg, 1.99 mmol) and the reaction was allowed to react for 1 h. Then, a 4 M hydrochloric acid / dioxane solution (10 mL) was added and the reaction was allowed to react for 1 h. The mixture was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by Prep-HPLC to obtain compound 009 (80 mg, 8% yield).

[0113] ESI-MS (m / z): 203.1 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.84(d,J=7.6Hz,1H),7.73–7.67(m,1H),7.65(d,J=7.6Hz,1H),7.50(td,J=7.6 ,1.2Hz,1H),2.64–2.56(m,2H),2.55–2.46(m,2H),2.28(m,1H),1.67–1.61(m,2H),0.98–0.91(m,3H).

[0114] Example 3: Preparation of 3-ethyl-5'-fluoro-3'-H-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 017) and 3-ethyl-3'-fluoro-3'-H-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 018)

[0115]

[0116] Referring to the preparation method of Example 2, compounds 017 and 018 were prepared by replacing o-bromobenzoic acid in step 3 with 2-bromo-5-fluorobenzoic acid.

[0117] Compound 017: ESI-MS (m / z): 221.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.60(dd,J=8.4,4.2Hz,1H),7.46(dd,J=7.2,2.4Hz,1H),7.39(td,J=8.6,2.4Hz,1H),2.58(dd d,J=8.0,7.2,2.4Hz,2H),2.53–2.44(m,2H),2.29–2.16(m,1H),1.62(p,J=7.4Hz,2H),0.91(td,J=7.4,3.0Hz,3H).

[0118] Compound 018: ESI-MS (m / z): 221.1 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.64(d,J=7.6Hz,1H),7.48(td,J=7.8,4.4Hz,1H),7.35(t,J=8.8Hz,1H),2.8 7–2.72(m,2H),2.70–2.50(m,1H),2.50–2.46(m,2H),1.67–1.58(m,2H),0.90(td,J=7.4,4.4Hz,3H).

[0119] Example 4: Preparation of 3-propyl-3'-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 019)

[0120]

[0121] Referring to the preparation method of Example 2, 3-ethylcyclobutane-1-one in step 3 was replaced with 3-propylcyclobutane-1-one to prepare compound 019.

[0122] ESI-MS (m / z): 217.1 [M+H] + . 1H NMR(400MHz, CDCl3) δ7.76(d,J=7.6Hz,1H),7.67–7.54(m,2H),7.43(td,J=7.6,1.0Hz,1H),2.58–2.49(m ,2H),2.47–2.38(m,2H),2.33–2.18(m,1H),1.58–1.49(m,2H),1.33–1.21(m,2H),0.88(t,J=7.2Hz,3H).

[0123] Example 5: Preparation of 5'-bromo-3-ethyl-3'-H-spiro[cyclobutane-1,1'-isobenzofuran]-3'-one (Compound 020)

[0124]

[0125] Referring to the preparation method of Example 2, compound 020 was prepared by replacing o-bromobenzoic acid in step 3 with 2,5-dibromobenzoic acid.

[0126] ESI-MS (m / z): 281.1 / 283.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.81 (d, J = 7.6Hz, 1H), 7.48 (dd, J = 43.0, 7.7Hz, 1H), 2. 60(dq,J=19.3,10.2Hz,4H),2.31–2.17(m,1H),1.70–1.56(m,2H),0.93(t,J=6.4Hz,3H).

[0127] Referring to the preparation method of Example 2, the following compounds were prepared using the corresponding raw materials:

[0128]

[0129]

[0130]

[0131]

[0132]

[0133] Biological activity assay:

[0134] Test Example 1: In vitro neuroprotection test

[0135] PC12 cells (rat adrenal pheochromocytoma cells, from Nanjing Kebai Biotechnology Co., Ltd.) in the logarithmic growth phase were trypsinized, centrifuged, resuspended, counted, and diluted to 150,000 cells / mL in complete culture medium. After pipetting evenly, they were inoculated into a 96-well plate at 100 μL per well, and a corresponding zeroing well (100 μL complete culture medium) was set. After 24 hours of incubation in a CO2 incubator to allow adhesion, the compound was added. Six replicates were set for each compound. The compound detection wells were diluted with complete culture medium and added to the 96-well plate at a final concentration of 200 μM, with 100 μL per well. At the same time, 100 μL of complete culture medium was added to the zeroing well, blank control well, and model well. After 6 hours of compound incubation, 100 μM 6-OHDA was added to the model well and compound detection well at 5 μL per well. After incubation in the incubator for another 24 hours, add 20 μL of MTT working solution (5 mg / ml) to each well. Incubate at 37°C for 4 hours, discard the supernatant, and add 150 μL of DMSO. Mix thoroughly using a microporous shaker. Wipe the plate clean and measure the optical density (OD) at 550 nm on a microplate reader. Calculate the relative cell viability of the model and compound groups relative to the blank control group. Use a t-test to determine the cytoprotective effect of each compound group relative to the model group or the positive control group (NBP).

[0136] The compounds of the present invention were tested according to the above method and found to have a certain protective effect on PC12 cells at 200 μM, which was comparable to or even better than the positive control drug NBP. The activity data of exemplary compounds are shown in Table 1:

[0137] Table 1 Results of in vitro neuroprotective tests of the compounds of the present invention

[0138]

[0139] Note: Compared with the model group, * P<0.05, ** P<0.01, *** P<0.001; compared with the positive control group, # P<0.05, ### P<0.001

[0140] Test Example 2: Pharmacokinetics and brain tissue distribution test in rats

[0141] (1) Pharmacokinetic study in rats

[0142] SD rats (male, weighing 180-200 g, aged 6-7 weeks) were fasted overnight and then administered the compound intravenously at 5 mg / kg, with 3 rats in each group. At different time points after administration (0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 8 h, 24 h), approximately 0.2 mL of blood was collected from the rat orbit and placed in an EDTA anticoagulant tube. The rat plasma samples were separated by centrifugation at 3000 g for 10 min within 2 h. The drug concentration in the rat plasma after administration was determined by protein precipitation-LC / MS / MS. The drug-time curve was drawn and the pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in rats after administration was described by the non-compartmental statistical moment parameters.

[0143] (2) Rat venous brain distribution test

[0144] Male SD rats (180-200 g, 6-7 weeks old) were fasted overnight and then intravenously administered the compound at 5 mg / kg. Three rats per group were used. Plasma and brain tissue samples were collected 0.5 h after administration. Drug concentrations in plasma and brain homogenates were determined using protein precipitation-LC / MS / MS.

[0145] The compounds of the present invention were subjected to the above-mentioned pharmacokinetic and brain tissue distribution tests. The experimental results of exemplary compounds are shown in Table 2.

[0146] Table 2 Pharmacokinetics and brain tissue distribution test results of the compounds of the present invention in rats

[0147]

[0148] Test Example 3: Pharmacodynamics of the compound in the rat tMCAO model

[0149] (1) Animal modeling

[0150] A middle cerebral artery occlusion (MCAO) model was established in SD rats (male, 250-280 g, 7-9 weeks old) using a suture method to evaluate the neuroprotective effects of compounds against cerebral ischemia-reperfusion. After isoflurane anesthesia, the rats were immobilized in the supine position. A skin incision was made along the midline of the neck to expose the right common carotid artery. The nerves and fascia surrounding the bifurcation of the common carotid artery to the skull base were carefully removed. The external and internal carotid arteries were then isolated. An MCAO suture was inserted from the free end of the external carotid artery. The suture was then introduced from the distal end of the external carotid artery into the internal carotid artery and inserted into the middle cerebral artery at the circle of Willis to effectively occlude the middle cerebral artery. The suture was inserted 18-20 mm from the bifurcation of the common carotid artery. The free end of the external carotid artery and the intraluminal suture were then ligated to prevent bleeding. The subcutaneous fascia and skin were sutured layer by layer, and penicillin was applied topically to prevent infection. In the sham-operated group, only the internal carotid artery was isolated. Two hours after the initiation of MCAO, the suture was carefully removed from the internal carotid artery lumen, allowing reperfusion of the artery. After recovery, the animals were divided into groups based on neurological function scores and administered the drug. Reperfusion was performed two hours after embolization, and the drug was administered immediately after reperfusion. The experimental endpoint was 24 hours after drug administration.

[0151] (2) Detection indicators

[0152] 1) Neurological function score

[0153] Observe the degree of behavioral disturbance in the animals and score them 24 hours after treatment. The scoring criteria are detailed in Table 3.

[0154] Table 3. Scoring criteria for neurological impairment in MCAO rats

[0155]

[0156] 2) Cerebral infarction determination

[0157] After 24 hours of scoring after administration, the animals were anesthetized with isoflurane and exsanguinated, and the brains were removed. The brain tissues were frozen in a -20°C refrigerator and then sliced ​​from front to back into 6 even slices. The range of cerebral infarction was determined by TTC staining, and the percentage of infarct area to the total brain area was calculated.

[0158] 3) Data processing and statistical analysis

[0159] The experimental data were expressed as mean ± standard deviation (mean ± SD) and analyzed using IBM SPSS Statistics 25.0 software. T-test was used, and P < 0.05 was considered statistically significant.

[0160] The experimental results show that the compound of the present invention can significantly reduce the area of ​​cerebral infarction, and the effect is comparable to that of the positive drug NBP, or even better than NBP.

Claims

1. A compound represented by formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof: in: Y and Z are each independently selected from carbonyl, O or S, and when Y is carbonyl, Z is selected from O or S, or when Z is carbonyl, Y is selected from O or S; W1, W2, W3 are each independently selected from C or N; R1 is 1-4 (e.g., 1, 2, 3, 4), each selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OR 3 、-SR 3 、-NR 3 R 3 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 、-OC(O)R 3 、-S(O) 0-2 R 3 、-S(O)2NR 3 R 3 、-N(R 3 )S(O)2R 3 、-N(R 3 )C(O)R 3 、-N(R 3 )C(O)NR 3 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with 0-6 identical or different cyano, amino, hydroxyl or halogen groups; R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OR 5 、-SR 5 、-NR 5 R 5 、-C(O)R 5 、-C(O)OR 5 、-C(O)NR 5 R 5 、-OC(O)R 5 、-S(O) 0-2 R 5 、-S(O)2NR 5 R 5 、-N(R 5 )S(O)2R 5 、-N(R 5 )C(O)R 5 、-N(R 5 )C(O)NR 5 、-C 1-6 Alkyl R 5 、-N(R 5 )C 1-6 Alkyl R 5 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted by 0-6 identical or different cyano, amino, hydroxyl, halogen, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) 0-2 R 5 、-NR 5 R 5 replace; R 3 、R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 Aryl and 3-10 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 6-10 The aryl group and the 3-10 membered heterocyclyl group are each optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups; Alternatively, R2 and the atoms to which it is attached form a ring to form C 3-8 Carbocyclyl, or 3-8 membered heterocyclyl, wherein the heteroatoms are selected from 1-3 N, S or O; H in the compound represented by formula (I) is optionally replaced by D; The compound of formula (I) does not include the following compounds:

2. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: Y is selected from carbonyl, and Z is selected from O; or, Y is selected from O, and Z is selected from carbonyl.

3. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein: W1, W2, and W3 are selected from C.

4. The compound according to any one of claims 1 to 3, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I) has the structure shown in the following formula (I-1):

5. The compound according to any one of claims 1 to 4, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OR 3 、-SR 3 、-NR 3 R 3 、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 、-OC(O)R 3 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 The alkynyl groups are optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups; R 3 are independently selected from: hydrogen, C 1-6 alkyl; or, R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxyl, mercapto, -SF5, -COOH, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl; wherein the C 1-6 The alkyl groups are optionally substituted by 0-6 identical or different cyano groups, amino groups, hydroxyl groups or halogen groups; 1-6 The alkyl group is preferably C 1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, more preferably methyl; or, R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, halogen or C 1-6 Alkyl; the halogen is preferably F, Cl, Br; the C 1-6 The alkyl group is preferably C 1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, more preferably methyl; or, R1 is 1-4 (e.g., 1, 2, 3, 4), each independently selected from hydrogen, F, Cl, Br or methyl, preferably hydrogen, F or Br; or, R1 is 4 hydrogen atoms, or R1 is 3 hydrogen atoms and 1 F, or R1 is 3 hydrogen atoms and 1 Br; preferably, the F or Br is in the ortho position or meta position of the benzene ring, more preferably, the F or Br is in the ortho position of the benzene ring.

6. The compound according to any one of claims 1 to 5, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, -NR 5 R 5 、-S(O) 0-2 R 5 、-N(R 5 )S(O)2R 5 、-N(R 5 )C(O)R 5 、-C 1-6 Alkyl R 5 、-N(R 5 )C 1-6 Alkyl R 5 , wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl groups are optionally substituted with 0-6 identical or different cyano, amino, hydroxy, halogen, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -S(O) 0-2 R 5 、-NR 5 R 5 replace, Alternatively, R2 and the atom to which it is attached form a C 3-6 a carbocyclic group, or a 3-6 membered heterocyclic group, wherein the heteroatoms are selected from 1-3 N, S or O, R 5 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl and 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 The aryl group and the 3-6 membered heterocyclyl group are optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, halogenated C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NHC(O)C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -C 1-6 Alkyl SO2C 1-6 Alkyl, -N(C 1-6 Alkyl)C 1-6 Alkyl Ph, -C 1-6 Alkyl NH C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, -C 1-6 Alkyl-5-10 membered heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, or the atom to which R2 is attached forms a C 3-6 Carbocyclyl, or 3-6 membered heterocyclyl, wherein the heteroatoms are selected from 1-3 N, S or O; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHC(O)C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -C 1-4 Alkyl SO2C 1-4 Alkyl, -N(C 1-4 Alkyl)C 1-4 Alkyl C 6-10 Aryl, -C 1-4 Alkyl NH C 6-10 Aryl, -C 1-4 Alkyl-C 6-10 Aryl, -C 1-4 Alkyl-5-10 membered heteroaryl, -C 1-4 Alkyl-C 3-6 Cycloalkyl, or R2 and the atom to which it is attached form cyclobutyl, oxetanyl, or azetidinyl; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, C 1-4 Alkyl, C 2-4 Alkenyl, halogenated C 1-4 Alkyl, -N(C 1-4 Alkyl)2, -NHC(O)C 1-4 Alkyl, -NHSO2C 1-4 Alkyl, -C 1-4 Alkyl SO2C 1-4 Alkyl, -N(C 1-4 Alkyl)C 1-4 Alkyl Ph, -C 1-4 Alkyl NHPh, -C 1-4 Alkyl Ph, -C 1-4 Alkyl-pyridyl, -C 1-4 Alkyl-cyclopropyl, -CH2-benzofuranyl, or R2 and the atom to which it is attached form a cyclobutyl, oxetanyl, or azetidinyl group; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, allyl, propenyl, -CF3, -CH2CF3, -N(CH3)2, -NHC(O)CH3, -NHSO2CH3, -CH2SO2CH3, -N(CH3)CH2Ph, -CH(CH3)NHPh, -CH2Ph, -CH2-pyridine, -CH2-cyclopropyl, -CH2-benzofuranyl, or R2 and the atoms to which it is connected form a cyclobutyl or oxetanyl group; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5 or 6), each independently selected from hydrogen, C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0-6 identical or different cyano groups, amino groups, hydroxy groups or halogen groups; 1-6 Alkyl, preferably C 1-4 Alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, more preferably methyl, ethyl or n-propyl, further preferably methyl, ethyl or n-propyl; or, R2 is 1-6 (e.g., 1, 2, 3, 4, 5, or 6), each independently selected from hydrogen, methyl, ethyl, and n-propyl; or, R2 is 6 hydrogen atoms, or R2 is 5 hydrogen atoms and 1 methyl group, or R2 is 5 hydrogen atoms and 1 ethyl group, or R2 is 5 hydrogen atoms and 1 propyl group; preferably, the methyl group, ethyl group or propyl group is in the para position of the spiro ring.

7. A compound of the following structural formula, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for use as a neuroprotectant, platelet aggregation inhibitor, anti-inflammatory agent or antioxidant.

10. The use according to claim 9, characterized in that The drug is used to prevent and treat neurodegenerative diseases, ischemic diseases or other diseases for which butylphthalide is suitable; Preferably, the neurodegenerative diseases include dementia (such as Alzheimer's disease, vascular dementia, Lewy body dementia), and Parkinson's disease; the ischemic diseases include myocardial ischemia and ischemic stroke; the other diseases for which butylphthalide is applicable include but are not limited to: platelet aggregation, concussion, amyotrophic lateral sclerosis, Meniere's disease, mitochondrial myopathy, cerebral palsy, spinal cord injury, peripheral neuropathy (including diabetes-induced peripheral neuropathy, chemotherapy-induced peripheral neuropathy), and radiation-induced brain injury.

11. The use according to claim 9 or 10, characterized in that The medicine is used for preventing and treating myocardial ischemia and ischemic stroke, or for treating the recovery period of ischemic stroke.

12. A drug comprising the compound according to any one of claims 1 to 7, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the drug is used as a neuroprotective agent, platelet aggregation inhibitor, anti-inflammatory agent or antioxidant; Preferably, the drug is used to prevent and treat neurodegenerative diseases, ischemic diseases or other diseases for which butylphthalide is suitable; More preferably, the neurodegenerative diseases include dementia (e.g., Alzheimer's disease, vascular dementia, Lewy body dementia), and Parkinson's disease; the ischemic diseases include myocardial ischemia and ischemic stroke; other diseases for which butylphthalide is applicable include, but are not limited to, platelet aggregation, concussion, amyotrophic lateral sclerosis, Meniere's disease, mitochondrial myopathy, cerebral palsy, spinal cord injury, peripheral neuropathy (including diabetes-induced peripheral neuropathy, chemotherapy-induced peripheral neuropathy), and radiation-induced brain injury; Further preferably, the drug is used to prevent and treat myocardial ischemia, ischemic stroke, or for the treatment of the recovery period of ischemic stroke.

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