Phenalide ring-opening derivative as well as preparation method and application thereof

Abstract

The invention provides a phthalide ring-opening derivative as shown in a formula (I-1) and a stereoisomer or pharmaceutically acceptable salt thereof and application thereof. Experimental results show that the compound disclosed by the invention has excellent pharmacokinetic properties, and the release of butylphthalide and dexcanthanol in vivo is superior to that of single drug butylphthalide and dexcanthanol and is also superior to that of a compound composition. The compound disclosed by the invention has an excellent brain protection effect and can greatly reduce the cerebral infarction area; the compound can be used for preventing and treating nerve injury, degenerative diseases and ischemic diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a class of phthalide ring-opening derivatives, 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 properties, and prevention / treatment of dementia (including Alzheimer's disease, vascular dementia, and 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 represented by formula (I) or formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0008]

[0009] in,

[0010] Each R1 is the same or different and is independently selected from H, halogen, amino, cyano, nitro, hydroxyl, thiol, or, unsubstituted or optionally substituted by one, two or more R a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-;

[0011] n is selected from 1, 2, 3 or 4;

[0012] R2 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl;

[0013] U is

[0014] R3 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R c Substituted C 1-6 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group;

[0015] X1 is selected from -C(O)-, -C(O)O-, * terminal indicates that it is connected to the O terminal, and # terminal indicates that it is connected to the X2 or X3 terminal;

[0016] R4 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R d Substituted C 1-6 Alkyl, or

[0017] X2 is independently selected from: a bond, -O-, -[(CHR5) p OC(O)] q -、-[(CHR5) p O] q -、-[(CHR5) p OC(O)O] q -、-[(CHR5) p C(O)O] q -[(CHR5) p O] m -、-[(CHR5) p C(O)O] q -

[0018] [(CHR5) p OC(O)O] m -、-[(CHR5) p C(O)O] q -[(CHR5) p OC(O)] m -、-[(CHR5) p OC(O)O] q -[(CHR5) p O] m -、-[(CHR5) p OC(O)O] q -[(CHR5) p OC(O)O] m -、-[(CHR5) p OC(O)O] q -

[0019] [(CHR5) p OC(O)] m -、-[(CHR5)p Oh] q -[(CHR5) p Oh] m -、-[(CHR5) p Oh] q -[(CHR5) p [OC(O)O] m -、-[(CHR5) p Oh] q -[(CHR5) p [OC(O)] m -、-[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p Oh] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p [OC(O)O] m -、

[0020] -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p [OC(O)] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p Oh] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p [OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p [OC(O)] m -、-[(CHR5) p C(O)O] q -[(CHR5) p N(R6)] m -、-[(CHR5) p Oh] m -[(CHR5) p OP(O)(OR6)O] q -、

[0021] -[(CHR5) p OC(O)O] m -[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p OC(O)] m -

[0022] [(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p OC(O)] m -[(CHR5)​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-[(CHR5) p C(O)O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p C(O)O] m -,

[0027] -[(CHR5) p O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -,

[0028] -[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -;

[0029] X3 each person independently selects: Key, -O-, -[(CHR5) p O] q -, -[(CHR5) p O.C.(O)O] q -,

[0030] -[(CHR5) p C(O)O] q -[(CHR5) p O] m -, -[(CHR5) p C(O)O] q -[(CHR5) p O.C.(O)O] m -,

[0031] -[(CHR5) p C(O)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p O] m -,

[0032] -[(CHR5) p O.C.(O)O] q -[(CHR5)p O.C.(O)O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p O] q -[(CHR5) p O] m -, -[(CHR5) p O] q -[(CHR5) p O.C.(O)O] m -, -[(CHR5) p O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p OP(O)(OR6)O] q -, -[(CHR5) p OP(O)(OR6)O] q -

[0033] [(CHR5) p O] m -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p O.C.(O)O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p O.C.(O)O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -;

[0034] pSelect 0, 1, 2, 3, 4 or 5;

[0035] q, m, t, r are selected from 1, 2, 3, 4 or 5;

[0036] Each R5 is the same or different and is independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, thiol, unsubstituted or optionally substituted by one, two or more R e Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0037] Each R6 is the same or different and is independently selected from hydrogen, unsubstituted or optionally substituted with one, two or more R f Substituted C 1-6 Alkyl, benzyl;

[0038] Every R a 、R b 、R c 、R d 、R e 、R f 、R g The same or different, independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 Alkyl, benzyl;

[0039] w is selected from 1, 2, 3, 4 or 5;

[0040] H in the compound of formula (I) or formula (II) is optionally replaced by D.

[0041] In some embodiments of the present invention, X1 is selected from -C(O)-, -C(O)O-, * terminal indicates that it is connected to the O terminal, and # terminal indicates that it is connected to the X2 or X3 terminal;

[0042] R4 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R d Substituted C 1-3 Alkyl, or

[0043] R d are independently selected from C 1-3 Alkyl, benzyl;

[0044] X3 is as defined above.

[0045] Preferably,

[0046] X1 is selected from -C(O)-, -C(O)O-, * terminal indicates that it is connected to the O terminal, and # terminal indicates that it is connected to the X2 or X3 terminal;

[0047] R4 is selected from hydrogen, methyl, or

[0048] R d are independently selected from methyl and benzyl;

[0049] X3 is as defined above.

[0050] More preferably,

[0051] X1 is selected from -C(O)-, -C(O)O-, * terminal indicates that it is connected to the O terminal, and # terminal indicates that it is connected to the X2 or X3 terminal;

[0052] R4 is selected from hydrogen or

[0053] X3 is as defined above.

[0054] In some embodiments of the present invention, the compound of formula (I) has the structure shown in the following formula (I-1), formula (I-2), and formula (I-3); the compound of formula (II) has the structure shown in the following formula (II-1), formula (II-2), formula (II-3), and formula (II-4):

[0055]

[0056]

[0057] R1, R2, R3, X2, X3, R g , n, w are defined as described above.

[0058] In the compounds of formula (I), formula (I-1), formula (I-2), (I-3) and formula (II), formula (II-1), formula (II-2), formula (II-3), and formula (II-4):

[0059] In some embodiments, each R1 is the same or different and is independently selected from H, halogen, cyano, hydroxyl, or, unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-NH-;

[0060] n is selected from 1, 2, 3 or 4;

[0061] R a are independently selected from halogen, amino, cyano, hydroxyl, C 1-3 alkyl.

[0062] Preferably,

[0063] Each R1 is the same or different and is independently selected from H, F, Cl, Br, cyano, hydroxyl, or, unsubstituted or optionally substituted by one, two or more Ra Substituted following groups: methyl, CH3O-, CH3NH-;

[0064] n is selected from 1, 2, 3 or 4;

[0065] R a are independently selected from F, Cl, Br, amino, cyano, hydroxyl, and methyl.

[0066] More preferably,

[0067] Each R1 is the same or different and is independently selected from H, F, Cl, Br, hydroxyl, methyl, CH3O-, -CF3, and -CHF2.

[0068] More preferably, R1 is H.

[0069] In some embodiments, R2 is selected from unsubstituted or optionally substituted with one, two, or more R b Substituted C 1-6 alkyl;

[0070] R b are independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 alkyl.

[0071] Preferably,

[0072] R2 is selected from unsubstituted or optionally substituted with one, two or more R b substituted butyl;

[0073] R b are independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-3 alkyl.

[0074] More preferably,

[0075] R2 is selected from unsubstituted or optionally substituted with one, two or more R b substituted butyl;

[0076] R b Each is independently selected from F, Cl, Br, amino, cyano, nitro, hydroxyl, mercapto, and methyl.

[0077] More preferably, R2 is selected from butyl.

[0078] In some embodiments of the present invention, the compound of formula (I) has the structure shown in the following formula (I-4), (I-5), (I-6); the compound of formula (II) has the structure shown in the following formula (II-5), (II-6), (II-7), (II-8):

[0079]

[0080] R3, X2, X3, R g , w are defined as described above.

[0081] In the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6) and formula (II), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), and formula (II-8):

[0082] R3 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R c Substituted C 1-6 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group.

[0083] Preferably, R3 is selected from hydrogen, unsubstituted or optionally substituted with one, two or more R c Substituted C 1-4 Alkyl, C 5-6 Carbocyclic group, 5-6 membered heterocyclic group;

[0084] R c are independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-3 Alkyl, benzyl.

[0085] More preferably,

[0086] R3 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R c Substituted methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, cyclohexenyl,

[0087] R c are independently selected from halogen, amino, cyano, nitro, hydroxy, mercapto, methyl, and benzyl.

[0088] More preferably,

[0089] R3 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclohexenyl,

[0090] More preferably,

[0091] R3 is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl.

[0092] In the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), formula (I-6), and formula (II), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II-7), and formula (II-8):

[0093] In some embodiments, X2 is independently selected from the group consisting of: a bond, -O-, -[(CHR5) p OC(O)] q -、

[0094] -[(CHR5) p OC(O)O] q -、-[(CHR5) p C(O)O] q -、-[(CHR5) p C(O)O] q -[(CHR5) p O] m -、

[0095] -[(CHR5) p C(O)O] q -[(CHR5) p OC(O)O] m -、-[(CHR5) p C(O)O] q -[(CHR5) p OC(O)] m -、

[0096] -[(CHR5) p OC(O)O] q -[(CHR5) p O] m -、-[(CHR5) p OC(O)O] q -[(CHR5) p OC(O)O] m -、

[0097] -[(CHR5) p OC(O)O] q -[(CHR5) p OC(O)] m -、-[(CHR5) p O] q -[(CHR5) p O] m -、-[(CHR5) p O] q-[(CHR5) p [OC(O)O] m -、-[(CHR5) p Oh] q -[(CHR5) p [OC(O)] m -、-[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p Oh] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p OC(O)

[0098] Oh] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p [OC(O)] m -、-[(CR5=CR5) t C(O)O] q -

[0099] [(CHR5) p Oh] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p [OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p [OC(O)] m -、-[(CHR5) p Oh] m -[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p [OC(O)O] m -[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p [OC(O)] m -[(CHR5) p OP(O)(OR6)O] q -、

[0100] -[(CHR5) p C(O)O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p OC(O)O] q -[(CHR5) p C(O)O] m -、

[0101] -[(CHR5) p O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -、

[0102] -[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -;

[0103] p is 0, 1, 2, or 3;

[0104] q, m, t are 1 or 2; preferably 1;

[0105] Each R5 is the same or different and is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, unsubstituted or optionally substituted by one, two or more R e Substituted C 1-3 Alkyl, C 3-5 Cycloalkyl,

[0106] Each R6 is the same or different and is independently selected from hydrogen, unsubstituted or optionally substituted with one, two or more R f Substituted C 1-3 Alkyl, benzyl;

[0107] Every R e 、R f The same or different, independently selected from halogen, amino, hydroxyl, thiol, C 1-3 Alkyl, benzyl;

[0108] Preferably,

[0109] Each R6 is the same or different and is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, unsubstituted or optionally substituted by one, two or more R e substituted methyl, ethyl, isopropyl, cyclopropyl, cyclobutane;

[0110] Each R6 is the same or different and is independently selected from hydrogen, unsubstituted or optionally substituted with one, two or more R f substituted methyl, ethyl, isopropyl, benzyl;

[0111] Every R e 、R f the same or different, independently selected from F, Cl, Br, amino, hydroxy, mercapto, methyl, ethyl, benzyl;

[0112] More preferably,

[0113] Each R6 is the same or different and is independently selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropane; preferably hydrogen, methyl, amino;

[0114] Each R6 is the same or different and is independently selected from hydrogen, methyl, ethyl, isopropyl, benzyl; preferably hydrogen.

[0115] In some embodiments of the present invention, X2 is selected from: a bond, -O-, -CH2OC(O)O-, -CH2C(O)O-, -CH(CH3)OC(O)O-, -CH2OC(O)-, -CH(CH3)C(O)O-, -CH2O-, -CH(CH3)OC(O)-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2OP(O)(OH)O-CH(CH3)OC(O)-, -CH2OP(O)(OH)O-CH2OC(O)-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2C(O)O-, -CH2CH2C(O)O-CH(CH3)C(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)O-CH2OC(O)O-, -C(O)OCH2C(O)O-, -CH2CH(NH2)C(O)O-, -CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -CH2CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH2C(O)O-, -CH=CHC(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH(CH3)O-, -CH=CHC(O)O-CH2O-, -CH2OC(O)(CH2)3NHC(O)-, -CH2CH(CH3)OP(O)(OH)O-, -CH2OC(O)(cyclopropyl)OP(O)(OH)O-, -CH2OC(O)-(1,4-cyclohexyl)-OP(O)(OH)O-, -CH2OC(O)-CH(CH3)-OP(O)(OH)O-, -CH(isopropyl)OC(O)-CH(CH3)-OP(O)(OH)O-, -CH2OC(O)-CH(isopropyl)-OP(O)(OH)O-, -CH2OC(O)-(CH2) 3-4-OP(O)(OH)O-, -CH2OC(O)O-CH2CH(CH3)-OP(O)(OH)O-, -CH2OC(O)O-(CH2) 4-5 -OP(O)(OH)O-, -CH2OC(O)O-CH2CH(CH3)-OP(O)(OH)O-, -CH2OC(O)N(CH3)-(CH2) 2-3 -OP(O)(OH)O-, -CH2OC(O)CH2N(CH3)-(CH2)3-OP(O)(OH)O-, -CH2OC(O)CH2N(CH3)C(O)O-CH2-OP(O)(OH)O-, -CH2 OC(O)CH2N(CH3)C(O)CH(CH3)-OP(O)(OH)O-, -CH(isopropyl)OC(O)CH(isopropyl)NHC(O)OCH2-OP(O)(OH)O-, -CH2OC(O)(CH2) 2-4 NHC(O)CH(CH3)-OP(O)(OH)O-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2OP(O)(OH)O-CH2OC(O)-, -CH2OP(O)(OH)O-CH2OC(O)O-, -CH2CH2-, -CH2OC(O)-tetrahydropyrrolidinyl-CH2-;

[0116] Preferably,

[0117] X2 is selected from: a bond, -O-, -CH2OC(O)O-, -CH2C(O)O-, -CH(CH3)OC(O)O-, -CH2OC(O)-, -CH(CH3)C(O)O-, -CH2O-, -CH(CH3)OC(O)-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2OP(O)(OH)O-CH(CH3)OC(O)-, -CH2OP(O)(OH)O-CH2OC(O)-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2C(O)O-, -CH2CH2C(O)O-CH(CH3)C(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)O-CH2OC(O)O-, -C(O)OCH2C(O)O-, -CH2CH(NH2)C(O)O-, -CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2-CH2CH(NH2)C(O)O-, CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -CH2CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH2C(O)O-, -CH=CHC(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH(CH3)O-, -CH=CHC(O)O-CH2O-;

[0118] More preferably,

[0119] X2 is selected from a bond, -CH2OC(O)-, -CH(CH3)OC(O)-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2OP(O)(OH)O-CH(CH3)OC(O)-, -CH2OP(O)(OH)O-CH2OC(O)-;

[0120] Even more preferably, X2 is selected from a bond.

[0121] In some embodiments of the present invention, X3 is independently selected from the group consisting of: a bond, -O-, -[(CHR5) p O] q -、-[(CHR5) p OC(O)O] q -、-[(CHR5) p C(O)O] q -、-[(CHR5) p C(O)O] q -[(CHR5) p O] m -、

[0122] -[(CHR5) p C(O)O] q -[(CHR5) p OC(O)O] m -、-[(CHR5) p C(O)O] q -[(CHR5) p C(O)O] m -、

[0123] -[(CHR5) p OC(O)O] q -[(CHR5) p O] m -、-[(CHR5) p OC(O)O] q -[(CHR5) p OC(O)O] m -、

[0124] -[(CHR5) p OC(O)O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p O] q -[(CHR5) p O] m -、-[(CHR5) p O] q -[(CHR5) p OC(O)O] m -、-[(CHR5) p O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p OP(O)(OR6)O]q -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p O] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -;

[0125] P is 0, 1, 2, or 3;

[0126] q, m, t are 1 or 2; preferably 1;

[0127] Each R5 is the same or different and is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, unsubstituted or optionally substituted by one, two or more R e substituted methyl, ethyl, isopropyl, cyclopropyl, cyclobutane;

[0128] Each R6 is the same or different and is independently selected from hydrogen, unsubstituted or optionally substituted with one, two or more R f substituted methyl, ethyl, isopropyl, benzyl;

[0129] Every R e 、R f the same or different, independently selected from F, Cl, Br, amino, hydroxy, mercapto, methyl, ethyl, benzyl;

[0130] Preferably, each R5 is the same or different and is independently selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropane;

[0131] Preferably, each R6 is the same or different and is independently selected from hydrogen, methyl, ethyl, isopropyl, benzyl.

[0132] In some embodiments of the present invention, X3 is independently selected from the group consisting of: a bond, -O-, -CH2OC(O)O-, -CH2C(O)O-, -CH(CH3)OC(O)O-, -CH(CH3)C(O)O-, -CH2O-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3) OC(O)O-, -CH2CH2C(O)O-CH2C(O)O-, -CH2CH2C(O)O-CH(CH3)C(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)OCH 2OC(O)O-, -C(O)OCH2C(O)O-, -CH2CH(NH2)C(O)O, -CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH(NH2)C(O)O- CH2OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH2CH(N H2)C(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH2CH(NH2)C (O)O-CH(CH3)C(O)O-, -CH2CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -C H=CHC(O)O-CH2C(O)O-, -CH=CHC(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH(CH3)O-, -CH=CHC(O)O-CH2O-;

[0133] Preferably,

[0134] X3 are independently selected from: bond, -O-, -CH2OC(O)O-, -CH(CH3)OC(O)O-, -CH2O-, -CH2OP(O)(OH)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2 C(O)O-CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)OCH2OC(O)O-, -CH2CH(NH2)C(O)O-, -CH2CH(NH2)C(O)O-CH2C(O) O-, -CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2 CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2O-;

[0135] More preferably,

[0136] X3 are independently selected from the group consisting of: -CH2OC(O)O-, -CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3)OC(O)O-.

[0137] In some embodiments of the present invention, each R g The same or different, each independently selected from halogen, amino, hydroxyl, thiol, C 1-6 alkyl;

[0138] Preferably,

[0139] Every R g The same or different, each independently selected from halogen, amino, hydroxyl, thiol, C 1-3 alkyl;

[0140] More preferably,

[0141] Every R g the same or different, each independently selected from F, Cl, Br, amino, hydroxy, mercapto, methyl, ethyl, propyl, isopropyl;

[0142] More preferably,

[0143] Every R g The same or different, each independently selected from F, amino, hydroxy, methyl;

[0144] More preferably,

[0145] Every R g are the same or different, each independently selected from hydrogen, methyl;

[0146] w is selected from 1, 2 or 3.

[0147] 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.

[0148] 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.

[0149] The following are example structures, including but not limited to compounds of the following structural formulas, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0150]

[0151]

[0152] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound, its stereoisomers or pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.

[0153] The third aspect of the present invention provides the use of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a drug, wherein the drug is used as a neuroprotectant, platelet aggregation inhibitor, anti-inflammatory agent or antioxidant, etc.

[0154] 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 dementia (such as 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 brain injury, etc.

[0155] 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.

[0156] The present invention provides a drug comprising the aforementioned compound, its stereoisomers or pharmaceutically acceptable salts thereof, and the drug is used as a neuroprotectant, platelet aggregation inhibitor, anti-inflammatory agent or antioxidant, etc.

[0157] 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 dementia (such as 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 brain injury, etc.

[0158] 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.

[0159] Beneficial effects:

[0160] The compounds of the present invention have excellent pharmacokinetic properties, with in vivo release of butylphthalide and dextranol superior to that of single-agent butylphthalide and dextranol, as well as to that of a combined composition. The compounds of the present invention also exhibit excellent brain protection, significantly reducing the size of cerebral infarction. 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.

[0161] definition

[0162] Unless otherwise specified, D in the present invention represents deuterium ( 2 H).

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] Unless otherwise specified, the compounds of the present invention also include their "solvates". The terms "solvate" and "solvate" mean the physical association 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.

[0168] Unless otherwise specified, the compounds of the present invention also include their "hydrates". The term "hydrate" refers to a substance formed by water molecules binding to cations or anions in the compound through coordination 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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 3-6 Carbocyclyl 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 5-8In certain embodiments, the carbocyclyl group is a substituted C 5-8 Carbocyclic group.

[0174] 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.

[0175] 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 5-6 Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

[0176] 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).

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] Unless otherwise specified, the term "treatment" encompasses any treatment of a patient's disease, disorder, or condition, including:

[0185] (a) inhibit the symptoms of a disease, disorder, or condition, i.e., arrest their development; or (b) alleviate the symptoms of a disease, disorder, or condition, i.e., cause regression of the disease or symptoms; or (c) ameliorate or eliminate the disease, disorder, or condition, or one or more symptoms associated with the disease.

[0186] 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. DETAILED DESCRIPTION

[0187] 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.

[0188] 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.

[0189] 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.

[0190] The abbreviations used in the Preparation Examples, Examples, Test Examples and elsewhere herein are:

[0191] mg milligrams

[0192] mmol millimole

[0193] mL milliliters

[0194] g grams

[0195] h hour

[0196] ℃ degrees Celsius

[0197] Prep-TLC Preparative Thin Layer Chromatography

[0198] ESI-MS high-resolution mass spectrometry

[0199] NMR Nuclear Magnetic Resonance

[0200] CDCl3 deuterated chloroform

[0201] DCM dichloromethane

[0202] DMAP 4-dimethylaminopyridine

[0203] DMF N,N-dimethylformamide

[0204] EA Ethyl acetate

[0205] H2O water

[0206] Example 1: Preparation of Compound 1

[0207]

[0208] Step 1: Preparation of intermediate 1-1

[0209] Dextranol (200 mg, 1.30 mmol) was dissolved in DCM (10 mL), pyridine (154 mg, 1.95 mmol) was added, the temperature was lowered to 0 ° C, chloromethyl chloroformate (183 mg, 1.43 mmol) was slowly added, and the reaction temperature was raised to room temperature for 14 h. Water (10 mL) was added to the reaction solution, and then extracted three times with DCM (20 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 250 mg of the crude intermediate 1-1, which was directly used in the next reaction.

[0210] Step 2: Preparation of intermediate 1-2

[0211] Butylphthalide (1 g, 5.3 mmol) was dissolved in a mixture of ethanol and water (volume ratio 2:1, 30 mL). Potassium hydroxide (402 mg, 7.17 mmol) was added and the mixture was allowed to react at 80°C for 2 h. After completion of the reaction, the solution was concentrated and diluted with water. The pH was adjusted to 3-4 with dilute hydrochloric acid to precipitate a white solid. The solid was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate to obtain a solution of intermediate 1-2, which was used directly in the next reaction. ESI-MS (m / z): 207.1 [MH] - .

[0212] Step 3: Preparation of Intermediates 1-3

[0213] Succinic anhydride (0.58 g, 5.83 mmol) was added to an ethyl acetate solution of Intermediate 1-2. DMAP (60 mg, 0.53 mmol) was then added dropwise, followed by triethylamine (644 mg, 6.36 mmol). The reaction was allowed to react at room temperature for 14 h. After completion of the reaction, the mixture was extracted with saturated sodium bicarbonate solution, the aqueous phase was collected, the pH of the aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.3 g of crude Intermediate 1-3, which was used directly in the next step. ESI-MS (m / z): 331.1 [M+Na] + .

[0214] Step 4: Preparation of compound 1

[0215] The crude product of Intermediate 1-3 (130 mg) was dissolved in DMF (10 mL), and potassium carbonate (292 mg, 2.11 mmol) was added. The crude product of Intermediate 1-1 (312 mg) and potassium iodide (14 mg, 0.08 mmol) were added with stirring at room temperature, and the mixture was allowed to react at room temperature for 14 h. After the reaction, water was added and the mixture was extracted three times with ethyl acetate. The organic phase was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by Prep-TLC to obtain Compound 1 (70 mg). ESI-MS (m / z): 751.4 [M+Na] +.

[0216] 1 H NMR (600MHz, CDCl3) δ7.98 (d, J=7.8Hz, 1H), 7.57–7.50 (m, 2H), 7.35–7.31 (m, 1H), 6.57 (dd, J=8.7, 3.9Hz, 1H),6.05(dd,J=5.7,2.7Hz,1H),5.92(dd,J=5.7,1.8Hz,1H),5.75-5.73(m,2H),4.84(ddd,J=10.9,9.9,6 .3Hz,2H),2.75–2.65(m,4H),2.43–2.33(m,2H),1.97–1.89(m,2H),1.88–1.71(m,4H),1.69(t,J=3.8Hz,2 H),1.36(dddd,J=22.3,13.3,12.8,6.1Hz,5H),1.29–1.22(m,3H),1.15–1.08(m,2H),0.91–0.86(m,21H).

[0217] Example 2: Preparation of Compound 2

[0218]

[0219] Referring to the preparation method of compound 1 in Example 1, compound 2 was prepared by replacing chloromethyl chloroformate in step 1 with 1-chloroethyl chloroformate.

[0220] ESI-MS (m / z): 779.4 [M+Na] + .

[0221] 1 H NMR (600MHz, CDCl3) δ7.97–7.91(m,1H),7.58–7.50(m,2H),7.37–7.31(m,1H),7.02(dq,J=10.9,5 .4Hz,1H),6.81–6.74(m,1H),6.62(dd,J=7.8,3.9Hz,0.5H),6.57–6.52(m,0.5H),4.93–4.82(m,2H ),2.72–2.60(m,4H),2.44–2.35(m,2H),1.98–1.87(m,2H),1.85–1.73(m,4H),1.72–1.67(m,5H),1 .51(t,J=5.3Hz,3H),1.40–1.31(m,5H),1.32–1.27(m,3H),1.16–1.09(m,2H),0.93–0.87(m,21H).

[0222] Example 3: Preparation of Compound 3

[0223]

[0224] Step 1: Preparation of intermediate 3-1

[0225] Referring to the preparation method of intermediate 1-1, the chloromethyl chloroformate in the synthesis step was replaced with 1-chloroethyl chloroformate to obtain intermediate 3-1.

[0226] Step 2: Preparation of intermediate 1-2

[0227] The preparation method of intermediate 1-2 was referred to in Example 1, except that the EA extraction in the post-treatment step was replaced with ether extraction.

[0228] Step 3: Preparation of intermediate 3-2

[0229] The ether solution of Intermediate 1-2 was diluted with DCM, and triethylamine (1.6 g, 15.8 mmol) and DMAP (385 mg, 3.2 mmol) were added. The temperature was cooled to -10°C, and acetyl chloride was slowly added dropwise to the reaction solution. The reaction was allowed to react at -10°C for 5 h. After completion of the reaction, water was added and the mixture was extracted three times with DCM. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain Intermediate 3-2 (740 mg). ESI-MS (m / z): 273.1 [M+Na] + .

[0230] Step 4: Preparation of compound 3

[0231] Intermediate 3-2 (60 mg, 0.24 mmol) was dissolved in DMF (10 mL), and potassium carbonate (82.9 mg, 0.6 mmol) was added. The crude intermediate 3-1 (75 mg) and potassium iodide (4 mg, 0.024 mmol) were added with stirring at room temperature, and the mixture was allowed to react at room temperature for 14 h. After the reaction, water was added and the mixture was extracted three times with ethyl acetate. The organic phase was collected, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by Prep-TLC to obtain compound 3 (45 mg).

[0232] ESI-MS (m / z): 497.3 [M+Na] + .

[0233] 1H NMR (600MHz, CDCl3) δ7.96–7.90(m,1H),7.54(d,J=4.7Hz,2H),7.34(tdd,J=6.5,5.1,2.0Hz,1H),7. 03(dq,J=10.9,5.4Hz,1H),6.62–6.57(m,0.5H),6.53–6.49(m,0.5H),4.92–4.86(m,1H),2.44–2.35 (m,1H),2.10–2.08(m,3H),2.00–1.94(m,1H),1.92–1.73(m,3H),1.73–1.68(m,4H),1.44(dd,J=12. 5,7.5Hz,1H),1.34–1.29(m,2H),1.19–1.11(m,1H),0.93–0.89(m,12H),0.87(dd,J=8.2,5.2Hz,3H).

[0234] Example 4: Preparation of Compound 4

[0235]

[0236] Step 1: Preparation of intermediate 4-1

[0237] Dissolve dibenzyl phosphate (3 g, 10.782 mmol) in DCM (60 mL), add DMF (0.042 mL, 0.539 mmol) and oxalyl chloride (10.78 mL, 21.564 mmol), and stir overnight at room temperature. After the reaction, concentrate the reaction solution and use it directly in the next step.

[0238] Step 2: Preparation of intermediate 4-2

[0239] Intermediate 1-1 (1.5 g, 6.10 mmol) and sodium iodide (915 mg, 6.10 mmol) were added to acetonitrile (15 mL) and stirred at 60°C for 3 h. NMR analysis indicated complete reaction. The reaction mixture was filtered through celite and the filtrate was dried to afford Intermediate 4-2 (1.8 g).

[0240] 1 H-NMR (400MHz, CDCl3) δ5.95(s,2H),4.89(ddd,J=10.0,3.2,2.1Hz,1H),2.47–2.33(m,1H),1.95–1.85(m,1H),1.73( dt,J=9.0,4.0Hz,2H),1.37–1.31(m,1H),1.29–1.23(m,1H),1.12(dd,J=14.0,3.4Hz,1H),0.91(s,3H),0.88(s,6H).

[0241] Step 3: Preparation of intermediate 1-2

[0242] The preparation method of intermediate 1-2 was referred to as in Example 1, except that the solution of intermediate 1-2 obtained in the post-treatment step was concentrated at low temperature and then used directly in the next step.

[0243] Step 4: Preparation of intermediate 4-3

[0244] Intermediate 1-2 (5.5 g, 26.409 mmol) was dissolved in THF (100 mL), and n-BuLi (3383.52 mg, 52.818 mmol) was added dropwise at -78°C. After reacting at -78°C for 0.5 h, Intermediate 4-1 (1.2 g, 39.614 mmol) was dissolved in THF (20 mL) and slowly added dropwise to the reaction mixture. The mixture was reacted at -78°C for 1 h. After completion of the reaction, the reaction mixture was quenched by adding it to 200 mL of water, then extracted three times with EA (200 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield crude Intermediate 4-3 (11.2 g).

[0245] Step 5: Preparation of intermediate 4-4

[0246] Crude intermediate 4-3 (11.2 g), iodomethyl pivalate (5.8 g, 23.907 mmol), and potassium carbonate (9.9 g, 71.720 mmol) were dissolved in DMF (100 mL) and reacted at room temperature for 16 h. LCMS indicated the reaction was complete. The reaction mixture was added with water, extracted with EA, and washed with saturated brine. The organic phase was concentrated and purified by column chromatography to yield intermediate 4-4 (1.6 g).

[0247] Step 6: Preparation of Intermediate 4-5

[0248] Intermediate 4-4 (600 mg, 1.030 mmol) and 10% Pd / C (109.59 mg, 1.030 mmol) were dissolved in methanol (24 mL). The atmosphere was replaced with a hydrogen balloon three times and stirred under a hydrogen atmosphere for 10 min. The reaction mixture was filtered and a solution of sodium bicarbonate (173.06 mg, 2.060 mmol) dissolved in H₂O (4 mL) was added to the filtrate to adjust the pH to 7. The mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated to obtain a crude product of Intermediate 4-5 (600 mg). This was used directly in the next step.

[0249] Step 7: Preparation of Intermediates 4-6

[0250] Intermediate 4-5 was dissolved in H2O (8 mL). Silver nitrate (524.90 mg, 3.090 mmol) was added and stirred at room temperature for 3 h. After filtration, the filter cake was dried under vacuum to obtain the crude intermediate 4-5 (490 mg), which was used directly in the next step.

[0251] Step 8: Preparation of compound 4

[0252] The crude intermediate 4-5 (490 mg, 0.795 mmol) and intermediate 4-2 (591.7 mg, 1.750 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 16 h. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain compound 4 (240 mg).

[0253] ESI-MS (m / z): 845.4 [M+Na] + .

[0254] 1 H-NMR(400MHz, CDCl3)δ7.88(dd,J=7.9,1.4Hz,1H),7.68–7.61(m,1H),7.52(td,J=7.7,1.4Hz,1 H),7.29(td,J=7.6,1.3Hz,1H),6.32(q,J=6.9Hz,1H),5.96(d,J=5.5Hz,1H),5.85(d,J=5.5Hz,1 H),5.66–5.35(m,4H),4.84–4.71(m,2H),2.31(tq,J=14.0,4.6Hz,2H),1.92–1.58(m,8H),1.45– 1.18(m,8H),1.16(s,9H),1.03(ddt,J=11.9,6.2,3.0Hz,2H),0.81(ddd,J=7.0,5.9,1.8Hz,21H).

[0255] Example 5: Preparation of Compound 5

[0256]

[0257]

[0258] Step 1: Preparation of intermediate 5-1

[0259] Intermediate 3-2 (1 g, 3.995 mmol) was dissolved in DCM, and N,N'-dicyclohexylcarbodiimide (1.65 g, 7.991 mmol) and DMAP (48.81 mg, 0.400 mmol) were added. The mixture was reacted at room temperature for 0.5 h. Ethylene glycol (1.11 mL, 19.977 mmol) was then added and the mixture was reacted at room temperature for 16 h. The reaction solution was filtered, and water was added to the filtrate. The mixture was extracted three times with DCM, and the organic phase was collected and washed with saturated brine. The organic phase was concentrated and purified by column chromatography to obtain intermediate 5-1 (500 mg). ESI-MS (m / z): 317.1 [M+Na] + .

[0260] Step 2: Preparation of intermediate 5-2

[0261] Intermediate 5-1 (160 mg, 0.544 mmol) was dissolved in THF (6 mL), cooled to -78°C, and n-BuLi (0.442 mL, 0.707 mmol) was slowly added dropwise. After reacting at -78°C for 0.5 h, Intermediate 4-1 (322.54 mg, 1.087 mmol) was dissolved in THF (6 mL) and slowly added dropwise to the reaction solution. The reaction was continued at -78°C for 1 h. The reaction solution was quenched by adding water (30 mL) and extracted three times with EA. The organic phase was collected, washed with saturated brine, concentrated, and purified by column chromatography to obtain Intermediate 5-2 (100 mg). ESI-MS (m / z): 577.2 [M+Na] +

[0262] Step 3: Preparation of intermediate 5-3

[0263] Intermediate 5-2 (100 mg, 0.180 mmol) and 10% Pd / C (19.19 mg) were dissolved in methanol (4 mL), replaced with a hydrogen balloon three times, and stirred under a hydrogen atmosphere for 20 min. The reaction solution was filtered, and a solution of NaHCO₃ (30.30 mg, 0.361 mmol) dissolved in H₂O (1 mL) was added to the filtrate to adjust the pH to 7. The mixture was stirred at room temperature for 10 min. The reaction solution was concentrated to obtain a crude product of Intermediate 5-3 (100 mg). This was used directly in the next step.

[0264] Step 4: Preparation of intermediate 5-4

[0265] Intermediate 5-3 was dissolved in H2O (3 mL). Silver nitrate (91.89 mg, 0.541 mmol) was added and stirred at room temperature for 3 h. After filtration, the filter cake was dried under vacuum to obtain the crude intermediate 5-4 (90 mg), which was used directly in the next step.

[0266] Step 5: Preparation of compound 5

[0267] The crude intermediate 5-4 (90 mg) and intermediate 4-2 (113.87 mg, 0.337 mmol) were dissolved in acetonitrile (6 mL). The mixture was reacted at room temperature for 1 hour. The reaction solution was filtered and concentrated, and purified by column chromatography to obtain compound 5 (52 mg). ESI-MS (m / z): 817.4 [M+Na] + .

[0268] 1 H-NMR (400MHz, CDCl3) δ7.98 (dt, J=7.8, 1.1Hz, 1H), 7.56–7.47 (m, 2H), 7.33 (ddd, J=9.3, 8.0, 4.3Hz ,1H),6.53(dd,J=8.4,4.4Hz,1H),5.74–5.59(m,4H),4.85(ddd,J=10.1,3.6,1.9Hz,2H),4.59(dt,J= 9.5,4.0Hz,1H),4.49(dd,J=4.2,1.9Hz,1H),4.47–4.41(m,2H),2.36(ddd,J=14.0,9.8,4.5Hz,2H), 2.06(s,3H),1.96–1.66(m,8H),1.39–1.20(m,8H),1.10(dt,J=13.9,3.9Hz,2H),0.94–0.80(m,21H).

[0269] Examples 6-10: Preparation of other compounds

[0270] Referring to the preparation method of Example 1, the following compound was prepared.

[0271]

[0272] Referring to the preparation method of Example 4, the following compound was prepared.

[0273]

[0274] Comparative Example 1:

[0275]

[0276] Prepared according to the synthesis method of patent CN114315585. ESI-MS (m / z): 603.1 [M+Na] + .

[0277] Biological activity assay:

[0278] 1. Pharmacokinetic Study in Rat

[0279] SD rats (male, weighing 180-200g, aged 6-7 weeks) were fasted overnight and then administered the compound intravenously, with 3 rats in each group. At different time points after administration (0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h), approximately 0.2mL of blood was collected from the rat orbit and placed in a sodium heparin anticoagulant tube. The rat plasma samples were separated by centrifugation at 3000g for 10min within 2h. The drug (prototype drug, butylphthalide and dextran) concentrations in the rat plasma after administration were determined by HPLC-MS / MS using methanol protein precipitation. The drug-time curve was plotted and the pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in rats after administration was described by non-compartmental statistical moment parameters.

[0280] The above-mentioned pharmacokinetic test was conducted on the compounds of the present invention. The results of the exemplary compounds are shown in Table 1. At equimolar doses, the exposure of butylphthalide converted from Compound 2 was significantly better than the exposure of butylphthalide when butylphthalide was used alone or in combination with borneol. The exposure of borneol converted from Compound 2 was significantly better than the exposure of borneol when borneol was used alone or in combination with butylphthalide.

[0281] Table 1 Pharmacokinetic test results of the compounds of the present invention in rats

[0282]

[0283] 2. Pharmacodynamics of the compound in the rat tMACO model

[0284] (1) Animal modeling

[0285] The middle cerebral artery occlusion (MCAO) model in SD rats was established by suture embolism to evaluate the neuroprotective effects of compounds on rat cerebral ischemia-reperfusion.

[0286] Sprague-Dawley rats (male, 250-280 g, 7-9 weeks old) were anesthetized with isoflurane and 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 common carotid bifurcation to the skull base were carefully removed. The external and internal carotid arteries were then isolated sequentially. A suture was inserted from the free 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 common carotid bifurcation. 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 administered 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, and reperfusion of the internal carotid artery was allowed. After the animals regained consciousness, they were divided into groups and administered medication based on their neurological function scores. Reperfusion was performed 2 hours after embolization. The endpoint of the study was 24 hours after the third dose. Specific dosing information is as follows:

[0287]

[0288] (2) Detection indicators

[0289] 1) Neurological function score

[0290] Table 2. Scoring criteria for neurological impairment in MCAO rats

[0291]

[0292] 2) Cerebral infarction determination

[0293] 24 h after the third administration (i.e., 72 h after the first administration), the scoring was completed and the animals were exsanguinated after isoflurane anesthesia. The brain was removed and frozen in a -20°C refrigerator. The brain tissue was sliced from front to back and evenly cut into 6 slices. The TTC staining method was used to determine the range of cerebral infarction, and the percentage of infarct area in the hemisphere of the brain was calculated.

[0294] Cerebral infarction area (%) = (area of the contralateral hemisphere to surgery - area of the non-infarcted part of the hemisphere to surgery) / area of the contralateral hemisphere to surgery × 100%.

[0295] 3) Data processing and statistical analysis

[0296] The experimental data were expressed as mean ± standard deviation (mean ± SD) and analyzed using SPSS Statistics 25.0 statistical software.

[0297] The compounds of the present invention were evaluated in vivo for their efficacy, and were found to significantly inhibit cerebral infarction area. The test results for exemplary compounds are shown in Table 3.

[0298] Table 3 Pharmacodynamic test results of the compounds of the present invention in rat tMACO model

[0299] Group Pre-dose scoring Score 24 hours after the first dose Score 72 hours after first administration Cerebral infarction area% Model Group 10.9±0.32 10.4±0.7 9.3±0.95 40.74±5.04 Compound 2 10.9±0.32 9.1±1.52* 7.9±1.45* 31.12±11.49*

[0300] Note: *P<0.05 compared with the model group.

Claims

1. A compound represented by formula (I-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, Each R1 is the same or different and is independently selected from H, halogen, amino, cyano, nitro, hydroxyl, thiol, or, unsubstituted or optionally substituted by one, two or more R a Substituted with the following groups: C 1-6 Alkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-NH-; n is selected from 1, 2, 3 or 4; R2 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl; X3 each person independently selects: Key, -O-, -[(CHR5) p O] q -, -[(CHR5) p O.C.(O)O] q -, -[(CHR5) p C(O)O] q -[(CHR5) p O] m -, -[(CHR5) p C(O)O] q -[(CHR5) p O.C.(O)O] m -, -[(CHR5) p C(O)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p O.C.(O)O] m -, -[(CHR5) p O.C.(O)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p O] q -[(CHR5) p O] m -, -[(CHR5) p O] q -[(CHR5) p O.C.(O)O] m -, -[(CHR5) p O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p OP(O)(OR6)O] q -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p O] m -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -, -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p O.C.(O)O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p O.C.(O)O] m -, -[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -pSelect 0, 1, 2, 3, 4 or 5; q, m, t are selected from 1, 2, 3, 4 or 5; R5 is selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, unsubstituted or optionally substituted by one, two or more R e Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl; R6 is selected from hydrogen, unsubstituted or optionally substituted by one, two or more R f Substituted C 1-6 Alkyl, benzyl; Every R a 、R b 、R e 、R f The same or different, independently selected from hydrogen, halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 Alkyl, benzyl; H in the compound of formula (I-1) is optionally replaced by D.

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: Each R1 is the same or different and is independently selected from H, halogen, cyano, hydroxyl, or, unsubstituted or optionally substituted by one, two or more R a Substituted with the following groups: C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-NH-; R a are independently selected from halogen, amino, cyano, hydroxyl, C 1-3 alkyl; or, Each R1 is the same or different and is independently selected from H, F, Cl, Br, cyano, hydroxyl, or, unsubstituted or optionally substituted by one, two or more R a Substituted groups: methyl, CH3O-, CH3NH-; R a are independently selected from F, Cl, Br, amino, cyano, hydroxyl, and methyl; or, Each R1 is the same or different and is independently selected from H, F, Cl, Br, hydroxyl, methyl, CH3O-, -CF3, -CHF2; Alternatively, R1 is H.

3. The compound according to any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted C 1-6 Alkyl; R b are independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-6 alkyl; or, R2 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted butyl; R b are independently selected from halogen, amino, cyano, nitro, hydroxyl, mercapto, C 1-3 alkyl; or, R2 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted butyl; R b are independently selected from F, Cl, Br, amino, cyano, nitro, hydroxyl, mercapto, and methyl; Alternatively, R2 is selected from butyl.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound of formula (I-1) has the structure shown in the following formula (I-4): X3 is defined as in claim 1.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: X3 are independently selected from: a bond, -O-, -[(CHR5) p O] q -、-[(CHR5) p OC(O)O] q -、-[(CHR5) p C(O)O] q -、-[(CHR5) p C(O)O] q -[(CHR5) p O] m -、 -[(CHR5) p C(O)O] q -[(CHR5) p [OC(O)O] m -、-[(CHR5) p C(O)O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p [OC(O)O] q -[(CHR5) p About m -、-[(CHR5) p [OC(O)O] q -[(CHR5) p [OC(O)O] m -、-[(CHR5) p [OC(O)O] q -[(CHR5) p C(O)O] m -、-[(CHR5) p About q -[(CHR5) p About m -、-[(CHR5) p About q -[(CHR5) p [OC(O)O] m -、-[(CHR5) p About q -[(CHR5) p C(O)O] m -、-[(CHR5) p OP(O)(OR6)O] q -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p About m -、-[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p C(O)O] m -、 -[(CHR5) p OP(O)(OR6)O] q -[(CHR5) p [OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p Oh] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p [OC(O)O] m -、-[(CR5=CR5) t C(O)O] q -[(CHR5) p C(O)O] m -; P is 0, 1, 2, or 3; q, m, t are 1 or 2; preferably 1; Each R5 is the same or different and is independently selected from hydrogen, halogen, amino, hydroxyl, thiol, unsubstituted or optionally substituted by one, two or more R e substituted methyl, ethyl, isopropyl, cyclopropyl, cyclobutane; Each R6 is the same or different and is independently selected from hydrogen, unsubstituted or optionally substituted with one, two or more R f substituted methyl, ethyl, isopropyl, benzyl; Every R e 、R f the same or different, independently selected from F, Cl, Br, amino, hydroxy, mercapto, methyl, ethyl, benzyl; Preferably, each R5 is the same or different and is independently selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropane; Preferably, each R6 is the same or different and is independently selected from hydrogen, methyl, ethyl, isopropyl, benzyl; or, X3 is independently selected from the group consisting of a bond, -O-, -CH2OC(O)O-, -CH2C(O)O-, -CH(CH3)OC(O)O-, -CH(CH3)C(O)O-, -CH2O-, -CH2OP(O)(OH)O-, -CH(CH3)OP(O)(OH)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3)OC(O)O-, -C H2CH2C(O)O-CH2C(O)O-, -CH2CH2C(O)O-CH(CH3)C(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)OCH2OC(O)O-, -C(O)OCH2C(O)O-, -CH2CH(NH2)C(O)O-, -CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH(NH2)C(O)O-CH2OC( O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH2CH(NH2)C (O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH2CH(NH2)C(O )O-CH(CH3)C(O)O-, -CH2CH2CH(NH2)C(O)O-CH2C(O)O-, -CH2CH2CH(NH2)C(O)O-CH(CH3)C(O)O-, -CH =CHC(O)O-CH2C(O)O-, -CH=CHC(O)O-CH(CH3)C(O)O-, -CH=CHC(O)O-CH(CH3)O-, -CH=CHC(O)O-CH2O; or, X3 are independently selected from: bond, -O-, -CH2OC(O)O-, -CH(CH3)OC(O)O-, -CH2O-, -CH2OP(O)(OH)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2 C(O)O-CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2O-, -C(O)OCH2OC(O)O-, -CH2CH(NH2)C(O)O-, -CH2CH(NH2)C(O)O-CH2C(O) O-, -CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH2CH2CH(NH2)C(O)O-CH2OC(O)O-, -CH2 CH2CH(NH2)C(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2OC(O)O-, -CH=CHC(O)O-CH(CH3)OC(O)O-, -CH=CHC(O)O-CH2O-; or, X3 are independently selected from the group consisting of: -CH2OC(O)O-, -CH(CH3)OC(O)O-, -CH2CH2C(O)O-CH2OC(O)O-, -CH2CH2C(O)O-CH(CH3)OC(O)O-.

6. The compound of the following structural formula, its stereoisomer or its pharmaceutically acceptable salt:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for use as a neuroprotectant, 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 for preventing and treating myocardial ischemia and ischemic stroke, or for treating the recovery period of ischemic stroke.

9. A medicament comprising the compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the medicament is used as a neuroprotective agent, a platelet aggregation inhibitor, an anti-inflammatory agent or an 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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