A class of α,β-unsaturated amide compounds and preparation methods, pharmaceutical compositions and uses thereof

Abstract

The present invention provides a class of α, β-unsaturated amide compounds and preparation methods, pharmaceutical compositions and uses thereof. Specifically, the present invention provides a compound as shown in the following formula I, wherein the definitions of each group are as described in the specification. The compound can be used as a compound for improving cerebral blood flow and for preparing a pharmaceutical composition for treating neurodegenerative diseases such as Alzheimer's disease, vascular dementia and stroke.

Description

A class of α,β-unsaturated amide compounds and their preparation method, pharmaceutical composition and use Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and medicine, and in particular to a class of α,β-unsaturated amide compounds, a preparation method thereof, a pharmaceutical composition containing such compounds, and the use of such drugs for treating neurodegenerative diseases such as Alzheimer's disease and vascular dementia, as well as stroke. Background Art

[0002] Alzheimer's disease (AD) is a degenerative brain disorder that accounts for approximately two-thirds of dementia cases in the elderly. Its main symptoms include progressive memory loss, β-amyloid (Aβ) deposition, and neurofibrillary tangles (NFTs). The pathomechanism of AD is complex. Currently available drugs can only temporarily alleviate or control AD ​​symptoms, and effective therapies targeting the disease mechanism have yet to be discovered. Aging is the primary risk factor for AD. Over 95% of AD patients have late-onset disease, occurring in those over 65 years of age. Less than 5% of AD cases are early-onset, primarily due to genetic factors. Cardiovascular and cerebrovascular disease is also a major risk factor for AD. Vascular changes may contribute to the pathogenesis of AD, beyond the well-known vascular dementia caused by vascular disease. Capillaries, the most abundant and smallest vascular units in the brain, induce impairment of cerebral blood flow (CBF) or the blood-brain barrier (BBB), which is associated with memory loss in AD.

[0003] An increasing number of studies have found that reduced cerebral blood flow, impaired cerebrovascular reactivity, and impaired hemodynamic responses are present in the early stages of AD and in normal aging, including mild cognitive impairment (MCI). Early studies have shown that individuals with higher cerebral blood flow velocities, as measured by transcranial Doppler ultrasound of the middle cerebral artery, are less likely to develop dementia or hippocampal and amygdala atrophy. Arterial spin labeling MRI in patients with MCI or early AD demonstrates reduced cerebral blood flow in the posterior dentate gyrus and prefrontal cortex. In elderly individuals at high risk for AD, reduced or dysregulated cerebral blood flow precedes cognitive decline, brain atrophy, and β-amyloid accumulation. Apolipoprotein E (APOE) is a major genetic risk factor for AD and a susceptibility gene for vascular disease. In animal models, reduced cerebral blood flow and vascular dysfunction have also been observed in transgenic mice expressing human APOE4, specifically replacing murine apolipoprotein E4 (APOE) at positions 125-127. Furthermore, the vascular phenotype in APOE4-expressing mice has been shown to precede neuronal and synaptic dysfunction. Insufficient perfusion can induce or exacerbate Alzheimer's disease-like neuronal dysfunction and neuropathological changes. A chronic reduction of 50% in blood flow will lead to significant cognitive changes. A sustained reduction of more than 20% in human cerebral blood flow will lead to loss of attention, while a reduction of more than 30% in rat cerebral blood flow will impair spatial memory. Reduced cerebral blood flow will reduce Na + / K + The activity of the β-amyloid pump and all processes that depend on it, including maintenance of resting potential and glutamate uptake, also leads to the production of adenosine, which inhibits glutamate release, thereby affecting neuronal function. Bilateral carotid artery occlusion in rats causes memory impairment, neuronal dysfunction, synaptic changes, and the accumulation of β-amyloid, leading to the accumulation of neurotoxic β-amyloid oligomers. Cerebral ischemia, hypoxia, and Aβ deposition interact with each other. Hypoperfusion can trigger accelerated Aβ deposition. Aβ, in turn, impairs cerebrovascular function, increases arterial vasoconstriction, and reduces cerebral blood flow. In rodents, focal ischemia leads to the accumulation of hyperphosphorylated tau in neurons and the formation of fibrils similar to those seen in human neurodegenerative diseases and Alzheimer's disease. Hypoperfusion influences structural and functional changes in the brain and provides a promising potential biomarker for the identification and diagnosis of preclinical Alzheimer's disease.

[0004] Capillaries are the smallest blood vessels in the brain, branching out from arterioles to form a rich microvascular network. The maximum surface area of ​​capillaries per gram of brain is about 120 cm 2The capillary network is primarily composed of endothelial cells, basement membranes, pericytes, and astrocytes. Capillary disorganization has been observed in animal models as a precursor to dementia-related neurodegeneration. Capillary constriction in AD leads to hypoxia in neural tissue, which may also contribute to the decreased glucose metabolism seen in AD. Furthermore, ischemia and hypoxia have been shown to upregulate β-secretase (BACE1), the enzyme responsible for Aβ production. Capillary blood flow is primarily regulated by pericytes, and numerous studies have found that pericyte damage is closely associated with AD. In brain autopsies from some AD patients, pericyte levels can decrease by as much as 50%. Transgenic mice deficient in pericytes exhibit decreased blood flow, fewer microvessels, increased Aβ expression, and increased blood-brain barrier permeability. Numerous neuropathological studies have described morphological changes in brain capillaries and periventricular white matter lesions resembling ischemic infarction in AD. Autopsy studies of patients with advanced Alzheimer's disease have revealed extensive capillary endothelial cell loss, collapsed vessel walls, and decreased density in the brain. The delicate and specialized structure of capillaries increases their susceptibility to damage. Capillary degeneration is more frequent and prevalent than vascular amyloidosis, potentially suggesting that the long-term degeneration of the brain microvasculature in AD may be partially independent of amyloid toxicity. A growing body of research indicates that vascular factors are a major risk factor for AD, and damage to the neurovascular unit is associated with AD. Therefore, finding interventions to improve cerebral blood flow by intervening in capillaries may be important for the prevention and treatment of AD.

[0005] The present invention provides a class of target compounds that target capillaries to increase cerebral blood flow, thereby improving AD symptoms, and are used in the clinical treatment of neurodegenerative diseases such as Alzheimer's disease, vascular dementia, and stroke.

[0006] Summary of the Invention

[0007] One object of the present invention is to provide an α,β-unsaturated amide compound represented by general formula I or a pharmaceutically acceptable salt, racemate, R-isomer or S-isomer or a mixture thereof.

[0008] Another object of the present invention is to provide a method for preparing the α,β-unsaturated amide compound represented by the above general formula I.

[0009] Another object of the present invention is to provide a method for treating neurodegenerative diseases such as Alzheimer's disease, vascular dementia, and stroke related to cerebral blood flow, which comprises administering to a patient in need of such treatment one or more of the α,β-unsaturated amide compounds of the above-mentioned general formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers, or mixtures thereof.

[0010] In a first aspect of the present invention, there is provided an α,β-unsaturated amide compound having a structure as shown in Formula I below, or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof, or a mixture thereof:

[0011] in:

[0012] R 1 、R 2 、R 3 and R 4 can be independently selected from the following groups: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or (CHR 6 ) n R; wherein said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocyclic group, substituted or unsubstituted C3-C12 cycloalkyl or heterocondensed ring; or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a group selected from the group consisting of a carbonyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, or a substituted or unsubstituted 4-8 membered heterocyclyl group;

[0013] The ring is selected from the group consisting of a C6-C10 aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, a C3-C12 cycloalkyl group, or a hetero-fused ring;

[0014] R 5 For 1, 2, 3, 4 or 5 ring substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C3-C12 cycloalkyl;

[0015] or two adjacent R 5 and The atoms on the ring are connected end to end to form a substituted or unsubstituted 4-8 membered ring (i.e., forming a parallel ring structure with the A ring);

[0016] or Two R on the same atom in the ring 5 End to end The ring forms a substituted or unsubstituted 3-8 membered ring (i.e., forms a spiro ring structure with the A ring);

[0017] X is N(CH2) n R 6 , O, or S;

[0018] n is 0, 1, 2, or 3;

[0019] R 6 Independently selected from the following group: hydrogen, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C2~C10 acyl, substituted or unsubstituted C2~C10 ester, substituted or unsubstituted C1~C6 amide, -SO2R5, -COR5;

[0020] Wherein, unless otherwise specified, the heteroaromatic ring, heterocyclic ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the aromatic ring or heteroaromatic ring includes a monocyclic, fused or condensed ring; the carbocyclic ring or heterocyclic ring includes a monocyclic, fused, spiro or bridged ring;

[0021] Said substitution refers to substitution by one or more (preferably 1-3) substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, and 3-12 membered heterocyclyl;

[0022] The halogen is F, Cl, Br or I.

[0023] In another preferred embodiment, the The ring is selected from the following groups: C6-C10 aryl, C5-C12 heteroaryl.

[0024] In another preferred embodiment, the R 1 、R 2 、R 3 and R 4 are independently selected from the following groups: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or (CHR 6 ) n R; wherein said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl; n is 0, 1 or 2; R 6It is hydrogen, halogen, or substituted or unsubstituted C1-C6 alkyl.

[0025] In another preferred embodiment, the R 1 、R 2 、R 3 and R 4 are independently selected from the following groups: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, (CHR 6 ) n R; wherein, said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl.

[0026] In another preferred embodiment, the R 3 and R 4 Each is independently selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6 alkyl.

[0027] In another preferred embodiment, the R 1 is H or D, and R 2 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, (CHR 6 ) n R; wherein, the R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl; the substitution refers to substitution by one or more substituents selected from the following group: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl.

[0028] In another preferred embodiment, the R 3 and R 4 each independently deuterium.

[0029] In another preferred embodiment, the R 1 and R 2 each independently deuterium.

[0030] In another preferred embodiment, the compound of formula I is the compound described in each embodiment.

[0031] The second aspect of the present invention provides a method for preparing the compound of formula I according to the first aspect of the present invention, the method comprising the steps of:

[0032] In an inert solvent, the compound of formula II is reacted with the compound of formula III to obtain the compound of formula I.

[0033] In another preferred embodiment, the reaction is carried out in the presence of an organic amine and pivaloyl chloride.

[0034] In another preferred embodiment, the organic amine is triethylamine.

[0035] The third aspect of the present invention provides a pharmaceutical composition comprising (1) a compound as described in the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.

[0036] The fourth aspect of the present invention provides the use of the compound as described in the first aspect of the present invention or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition as described in claim 9, for preparing a pharmaceutical composition for preventing and / or treating neurodegenerative diseases or stroke.

[0037] In another preferred embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease and vascular dementia.

[0038] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG1 is a flow chart of a laser speckle test blood flow model in pharmacological activity experiment example 1;

[0040] FIG2 is a graph showing the blood flow improving effect of the compound of the present invention. DETAILED DESCRIPTION

[0041] After extensive and in-depth research, the inventors have developed an α,β-unsaturated amide compound that can be used to treat neurodegenerative diseases such as Alzheimer's disease. These compounds can effectively improve capillary cerebral blood flow. Based on these findings, the inventors completed the present invention.

[0042] the term

[0043] In the present invention, the halogen is F, Cl, Br or I.

[0044] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0045] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0046] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0047] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0048] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0049] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The terms "C3-C8 cycloalkyl," "C3-C7 cycloalkyl," and "C3-C6 cycloalkyl" have similar meanings.

[0050] In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecyl. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0051] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning. Preferably, "aryl group" is "C6-C12 aryl group" or "C6-C10 aryl group." The term "C6-C12 aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms and no heteroatoms in the ring, such as phenyl and naphthyl. The term "C6-C10 aryl group" has a similar meaning.

[0052] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0053] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, such as dioxolanyl. The term "3-7 membered heterocyclic group" has a similar meaning.

[0054] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, the two rings having a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, alkoxy, C1-10 sulfonyl, etc.

[0055] Compounds of formula I

[0056] The present invention provides an α,β-unsaturated amide compound having a structure as shown in Formula I below, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof:

[0057] in:

[0058] R 1 、R 2 、R 3 and R 4 can be independently selected from the following groups: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or (CHR 6 ) n R; wherein said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocyclic group, substituted or unsubstituted C3-C12 cycloalkyl or heterocondensed ring;

[0059] The ring is selected from the group consisting of a C6-C10 aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, a C3-C12 cycloalkyl group, or a hetero-fused ring;

[0060] R 5 For 1, 2, 3, 4 or 5 ring substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C3-C12 cycloalkyl;

[0061] or two adjacent R 5 and The atoms on the ring are connected end to end to form a substituted or unsubstituted 4-8 membered ring (i.e., forming a parallel ring structure with the A ring);

[0062] or Two R on the same atom in the ring 5 End to end The ring forms a substituted or unsubstituted 3-8 membered ring (i.e., forms a spiro ring structure with the A ring);

[0063] X is N(CH2) n R 6 , O, or S;

[0064] n is 0, 1, 2, or 3;

[0065] R 6 Independently selected from the following group: hydrogen, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C2~C10 acyl, substituted or unsubstituted C2~C10 ester, substituted or unsubstituted C1~C6 amide, -SO2R5, -COR5;

[0066] Wherein, unless otherwise specified, the heteroaromatic ring, heterocyclic ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the aromatic ring or heteroaromatic ring includes a monocyclic, fused or condensed ring; the carbocyclic ring or heterocyclic ring includes a monocyclic, fused, spiro or bridged ring;

[0067] Said substitution refers to substitution by one or more (preferably 1-3) substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, and 3-12 membered heterocyclyl;

[0068] The halogen is F, Cl, Br or I.

[0069] In a preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、 Ring, X, O, S or n are each independently a group corresponding to the compound in each embodiment.

[0070] Preparation method of compound of formula I

[0071] The present invention also provides a method for preparing the compound represented by general formula I, which is carried out according to the following scheme (example):

[0072] The compound of formula (I) can be prepared by the method shown in the following scheme 1

[0073] The structural formulae and R group designations used in the following schemes are used only in this section. Compounds of formula (II) and formula (III) are commercially available or can be synthesized using conventional techniques in the art.

[0074] Option 1:

[0075] Pharmaceutical composition

[0076] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds selected from the group consisting of the compounds of the above-mentioned general formula I, pharmaceutically acceptable salts, enantiomers, diastereomers, or racemates thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials, and / or diluents. The auxiliary materials may include, for example, flavoring agents, fragrances, sweeteners, and the like.

[0077] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in an amount of 1-99% by weight, preferably a compound of formula I as the active ingredient accounting for 65 wt% to 99 wt% of the total weight, with the remainder being a pharmaceutically acceptable carrier, diluent, solution or saline solution.

[0078] The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and can be present in suitable solid or liquid carriers or diluents and suitable sterile devices for injection or infusion.

[0079] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dosage of the formulation contains 1 mg-700 mg of the compound of formula I, preferably, the unit dosage of the formulation contains 25 mg-300 mg of the compound of formula I.

[0080] The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, and can be administered via the oral, nasal, dermal, pulmonary, or gastrointestinal routes. Oral administration is most preferred. The most preferred daily dose is 50-1400 mg / kg body weight taken as a single dose, or 25-700 mg / kg body weight taken in divided doses. Regardless of the route of administration, the optimal individual dose will depend on the specific treatment being used. Typically, a low dose is started and gradually increased until the most suitable dose is found.

[0081] Another aspect of the present invention provides a method for improving cerebral blood flow, comprising one or more compounds selected from the group consisting of the compounds represented by the above-mentioned general formula I, their pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0082] The compounds and compositions of the present invention are used to treat and prevent neurodegenerative diseases and stroke associated with cerebral blood flow, including, but not limited to, Alzheimer's disease, vascular dementia and stroke.

[0083] 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 invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0084] Example 1 (E)-3-(3-(o-tolyl)acryloyl)oxazolidin-2-one

[0085] Compound (E)-3-(o-Tolyl)acrylic acid 1a (400.0 mg, 2.47 mmol) and triethylamine (685.6 μL, 4.93 mmol) were dissolved in ultra-dry dichloromethane. Under argon protection, pivaloyl chloride (364.5 μL, 2.96 mmol) was added at -78°C. The mixture was stirred at room temperature for 1 hour. Oxazolidin-2-one (214.8 mg, 2.47 mmol) and lithium chloride (104.5 mg, 2.47 mmol) were then added at -78°C. The mixture was stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with water and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain the target product (E)-3-(3-(o-Tolyl)acryloyl)oxazolidin-2-one (490 mg, white solid) in a yield of 85.9%. 1 H NMR (400MHz, DMSO-d6) δ7.96(d,J=15.7Hz,1H),7.73(d,J=15.7Hz,1H),7.61(d,J=8.7Hz,1H),7.38–7.31(m ,1H),7.30(d,J=3.9Hz,2H),4.47–4.37(m,2H),4.06–3.97(m,2H),2.41(s,3H).LRMS(ESI):232.09[M+H]+.

[0086] Example 2 (E)-3-(3-(m-tolyl)acryloyl)oxazolidin-2-one

[0087] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(m-tolyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(m-tolyl)acryloyl)oxazolidin-2-one (yield 82.1%). 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=16.0Hz,1H),7.72(d,J=16.0Hz,1H),7.51-7.44(m,2H),7.36(dt,J=10.2,5.1Hz,1H), 7.28(d,J=7.8Hz,1H),4.42(td,J=8.1,2.4Hz,2H),4.00(td,J=8.1,2.6Hz,2H),2.34(s,3H).LRMS(ESI):232.09[M+H]+.

[0088] Example 3 (E)-3-(3-(p-Tolyl)acryloyl)oxazolidin-2-one

[0089] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(p-tolyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(p-tolyl)acryloyl)oxazolidin-2-one (yield 85.2%). 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=15.8Hz,1H),7.70(d,J=15.9Hz,1H),7.55(d,J=8.2Hz,2H),7.26(d,J=7. 9Hz, 2H), 4.39 (dd, J=8.6, 7.4Hz, 2H), 3.97 (dd, J=8.6, 7.4Hz, 2H), 2.32 (s, 3H). LRMS (ESI): 232.09 [M+H]+.

[0090] Example 4 (E)-3-(3-(2-methoxyphenyl)acryloyl)oxazolidin-2-one

[0091] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-methoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(2-methoxyphenyl)acryloyl)oxazolidin-2-one (yield 87.2%). 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=16.0Hz,1H),7.88(d,J=15.9Hz,1H),7.61(dd,J=7.7,1.6Hz,1H),7.45(ddd,J=8.5,7.3,1.6Hz,1H),7 .12(d,J=8.4Hz,1H),7.03(t,J=7.5Hz,1H),4.41(t,J=8.0Hz,2H),3.99(dd,J=8.5,7.4Hz,2H),3.88(s,3H).LRMS(ESI):248.08[M+H]+.

[0092] Example 5 (E)-3-(3-(3-methoxyphenyl)acryloyl)oxazolidin-2-one

[0093] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-methoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(3-methoxyphenyl)acryloyl)oxazolidin-2-one (yield 87.6%). 1H NMR (400MHz, DMSO-d6) δ7.81(d,J=15.8Hz,1H),7.73(d,J=15.8Hz,1H),7.39(t,J=7 .9Hz,1H),7.31–7.24(m,1H),7.21(t,J=2.0Hz,1H),7.08–7.02(m,1H),4.42(dd,J= 8.5,7.4Hz,2H),4.00(dd,J=8.6,7.3Hz,2H),3.80(s,3H).LRMS(ESI):248.08[M+H]+.

[0094] Example 6 (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one

[0095] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-methoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one (yield 82.7%). 1 H NMR (400MHz, DMSO-d6) δ7.77–7.66(m,2H),7.64(d,J=8.7Hz,2H),7.03(d,J=8.8Hz,2H),4.41 (dd,J=8.5,7.4Hz,2H),3.99(dd,J=8.5,7.4Hz,2H),3.81(s,3H).LRMS(ESI):248.08[M+H]+.

[0096] Example 7 (E)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0097] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 81.5%). 1 H NMR (400MHz, DMSO-d6) δ7.98–7.78(m,5H),7.68(t,J=7.6Hz,1H),4.43(dd,J=8.5,7.4Hz,2H),4.02(dd,J=8.5,7.4Hz,2H).LRMS(ESI):286.06[M+H]+.

[0098] Example 8 (E)-3-(3-(3-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0099] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-trifluoromethylphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(3-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 80.3%). 1 H NMR (400MHz, DMSO-d6) δ8.05–7.97(m,2H),7.94–7.83(m,2H),7.82(d,J=7.1Hz,1H),7.71(t,J= 7.8Hz, 1H), 4.43 (dd, J=8.5, 7.4Hz, 2H), 4.02 (dd, J=8.5, 7.4Hz, 2H). LRMS (ESI): 286.06 [M+H]+.

[0100] Example 9 (E)-3-(3-(4-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0101] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-trifluoromethylphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 85.6%). 1 H NMR (400MHz, DMSO-d6) δ7.95–7.87(m,3H),7.85–7.79(m,3H),4.43(dd,J=8.5,7.4Hz,2H),4.01(dd,J=8.6,7.4Hz,2H).LRMS(ESI):286.06[M+H]+.

[0102] Example 10 (E)-3-(3-(2-fluorophenyl)acryloyl)oxazolidin-2-one

[0103] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-fluorophenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(2-fluorophenyl)acryloyl)oxazolidin-2-one (yield 92.1%). 1 H NMR(400MHz,DMSO-d6)δ7.93(d,J=16.0Hz,1H),7.77(d,J=16.0Hz,1H),7.79–7.72(m,1H),7.5 8–7.47(m,1H),7.42–7.26(m,2H),4.50–4.37(m,2H),4.01(m,2H).LRMS(ESI):236.06[M+H]+.

[0104] Example 11 (E)-3-(3-(4-fluorophenyl)acryloyl)oxazolidin-2-one

[0105] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-fluorophenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-fluorophenyl)acryloyl)oxazolidin-2-one (yield 89.0%). 1 H NMR(400MHz,DMSO-d6)δ7.77(s,2H),7.77–7.73(m,2H),7.37–7.25(m,2H),4.42 (dd,J=8.6,7.3Hz,2H),4.00(dd,J=8.5,7.4Hz,2H).LRMS(ESI):236.06[M+H]+.

[0106] Example 12 (E)-3-(3-(4-chlorophenyl)acryloyl)oxazolidin-2-one

[0107] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-chlorophenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-chlorophenyl)acryloyl)oxazolidin-2-one (yield 91.1%). 1 H NMR(400MHz, DMSO-d6)δ7.82(d,J=15.9Hz,1H),7.75(d,J=15.9Hz,1H),7.73–7.68(m,2H),7.53 (dd,J=8.4,1.2Hz,2H),4.42(t,J=8.0Hz,2H),4.00(t,J=8.0Hz,2H).LRMS(ESI):252.03[M+H]+.

[0108] Example 13 (E)-3-(3-(2-bromophenyl)acryloyl)oxazolidin-2-one

[0109] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-bromophenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(2-bromophenyl)acryloyl)oxazolidin-2-one (yield 93.4%). 1H NMR (400MHz, DMSO-d6) δ7.96 (dd, J=15.9, 1.7Hz, 1H), 7.84–7.73 (m, 3H), 7.50 (td, J=7.5, 1.4Hz, 1H), 7.39 (td, J=7 .7,1.8Hz,1H),4.43(td,J=7.9,1.7Hz,2H),4.01(ddd,J=8.7,7.2,1.7Hz,2H).LRMS(ESI):295.98,297.98[M+H]+.

[0110] Example 14 (E)-3-(3-(4-bromophenyl)acryloyl)oxazolidin-2-one

[0111] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-bromophenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-bromophenyl)acryloyl)oxazolidin-2-one (yield 91.1%). 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=15.9Hz,1H),7.73(d,J=15.9Hz,1H),7.67(d,J=8.7Hz,2H),7.63(d,J= 8.7Hz, 2H), 4.42 (dd, J=8.6, 7.4Hz, 2H), 4.00 (dd, J=8.5, 7.4Hz, 2H). LRMS (ESI): 295.98, 297.98 [M+H]+.

[0112] Example 15 (E)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one

[0113] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-phenoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one (yield 89.3%). 1H NMR (400MHz, DMSO-d6) δ7.99–7.88(m,2H),7.83–7.76(m,1H),7.50–7.44(m,1H),7.41(tq,J=7.4,1.2Hz,2H),7.27(td,J=7.6,1.5Hz,1H),7.17( tt,J=7.4,1.2Hz,1H),7.05–6.98(m,2H),6.96(dt,J=8.2,1.3Hz,1H),4. 40(td,J=8.0,1.4Hz,2H),4.01–3.91(m,2H).LRMS(ESI):310.10[M+H]+.

[0114] Example 16 (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one

[0115] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-phenoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one (yield 82.7%). 1 H NMR(400MHz,DMSO-d6)δ7.80–7.70(m,2H),7.49–7.39(m,4H),7.31(dd,J=2.9,1.4Hz,1H),7.22– 7.15(m,1H),7.10–7.00(m,3H),4.45–4.36(m,2H),4.03–3.94(m,2H).LRMS(ESI):310.10[M+H]+.

[0116] Example 17 (E)-3-(3-(4-phenoxyphenyl)acryloyl)oxazolidin-2-one

[0117] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-phenoxyphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-phenoxyphenyl)acryloyl)oxazolidin-2-one (yield 88.1%). 1H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.1Hz,1H),7.61–7.52(m,1H),7.54–7.45(m,2H),7.39(t,J=7.5Hz,2H),7.19–7. 10(m,1H),7.06(ddd,J=7.8,5.7,1.9Hz,4H),4.40(t,J=6.3Hz,2H),4.05(t,J=6.4Hz,2H).LRMS(ESI):310.10[M+H]+.

[0118] Example 18 (E)-3-(3-([1,1'-biphenyl]-2-yl)acryloyl)oxazolidin-2-one

[0119] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-2-yl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-2-yl)acryloyl)oxazolidin-2-one (yield 86.7%). 1 H NMR(400MHz,DMSO-d6)δ7.90–7.78(m,2H),7.64(dd,J=15.8,1.4Hz,1H),7.60–7.39(m,6H ),7.33(dt,J=7.8,1.5Hz,2H),4.47–4.36(m,2H),3.95(m,2H).LRMS(ESI):294.11[M+H]+.

[0120] Example 19 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one

[0121] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one (yield 88.3%). 1 H NMR(400MHz, DMSO-d6)δ7.94(s,1H),7.88(d,J=5.9Hz,2H),7.78–7.68(m,4H),7.57(t,J=7.7Hz,1H),7.51(t, J=7.6Hz,2H),7.42(t,J=7.3Hz,1H),4.43(t,J=8.0Hz,2H),4.02(t,J=7.9Hz,2H).LRMS(ESI):294.11[M+H]+.

[0122] Example 20 (E)-3-(3-(4-fluoro-2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0123] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-fluoro-2-trifluoromethylphenyl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(4-fluoro-2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 81.0%). 1 H NMR(400MHz,Chloroform-d)δ8.15(dq,J=15.6,2.3Hz,1H),7.91–7.78(m,2H),7.42(dd,J=8.8,2.7 Hz,1H),7.35–7.22(m,1H),4.49(t,J=8.0Hz,2H),4.16(t,J=8.0Hz,2H).LRMS(ESI):304.05[M+H]+.

[0124] Example 21 (E)-3-(3-(naphthalen-1-yl)acryloyl)oxazolidin-2-one

[0125] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(naphthalen-1-yl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(naphthalen-1-yl)acryloyl)oxazolidin-2-one (yield 87.1%). 1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=15.6Hz,1H),8.25(d,J=8.3Hz,1H),8.09–8.00(m,2H),7.95–7.86(m,2H ),7.69–7.58(m,3H),4.45(dd,J=8.6,7.3Hz,2H),4.05(dd,J=8.6,7.3Hz,2H).LRMS(ESI):268.09[M+H]+.

[0126] Example 22 (E)-3-(3-(Benzo[d][1,3]dioxolan-5-yl)acryloyl)oxazolidin-2-one

[0127] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[d][1,3]dioxolan-5-yl)acrylic acid, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain (E)-3-(3-(benzo[d][1,3]dioxolan-5-yl)acryloyl)oxazolidin-2-one (yield 89.2%). 1H NMR(400MHz,Chloroform-d)δ7.79(d,J=15.7Hz,1H),7.73(d,J=15.6Hz,1H),7.15(d,J=1.7Hz,1H),7.10(dd,J=8.0,1.8Hz ,1H),6.82(d,J=8.0Hz,1H),6.02(s,2H),4.45(dd,J=8.6,7.5Hz,2H),4.13(dd,J=8.5,7.4Hz,2H); LRMS(ESI):262.06[M+H] + .

[0128] Example 23 (E)-3-(3-(Thien-2-yl)acryloyl)oxazolidin-2-one

[0129] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(thiophen-2-yl)acrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-(thiophen-2-yl)acryloyl)oxazolidin-2-one (yield 87.4%). 1 H NMR (400MHz, DMSO-d6) δ8.03(dd,J=2.8,1.2Hz,1H),7.77(d,J=15.8Hz,1H),7.66(ddd,J=5.0,2.9,0.7Hz,1H),7.61(d,J=15 .7Hz,1H),7.42(dd,J=5.1,1.2Hz,1H),4.41(dd,J=8.5,7.4Hz,2H),3.99(dd,J=8.5,7.4Hz,2H).LRMS(ESI):224.03[M+H]+.

[0130] Example 24 (E)-3-(3-cyclohexylacryloyl)oxazolidin-2-one

[0131] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-cyclohexylacrylic acid. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-3-(3-cyclohexylacryloyl)oxazolidin-2-one (yield 85.1%). 1H NMR (400MHz, DMSO-d6) δ7.12(dd,J=15.6,1.3Hz,1H),6.95(dd,J=15.6,6.6Hz,1H),4.37(dd,J=8.5,7.5Hz,2H),3.92(dd,J=8.6,7.4Hz,2H),2.21(qd ,J=8.0,7.3,4.5Hz,1H),1.77–1.68(m,4H),1.63(d,J=12.5Hz,1H),1.36–1 .23(m,2H),1.14(pd,J=13.3,12.7,3.7Hz,3H).LRMS(ESI):224.12[M+H]+.

[0132] Example 26 (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0133] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by 4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 89.9%). 1 H NMR(400MHz, DMSO-d6)δ7.95(d,J=7.8Hz,1H),7.91–7.77(m,4H),7.68(t,J=7.7Hz,1H),7.46–7.33(m,5H), 5.59(dd,J=8.6,4.1Hz,1H),4.82(t,J=8.7Hz,1H),4.24(dd,J=8.7,4.1Hz,1H).LRMS(ESI):362.09[M+H]+.

[0134] Example 27 (S,E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0135] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 90.9%). 1H NMR(400MHz, DMSO-d6)δ7.95(d,J=7.8Hz,1H),7.91–7.77(m,4H),7.68(t,J=7.7Hz,1H),7.46–7.33(m,5H), 5.59(dd,J=8.6,4.1Hz,1H),4.82(t,J=8.7Hz,1H),4.24(dd,J=8.7,4.1Hz,1H).LRMS(ESI):362.09[M+H]+.

[0136] Example 28 (R,E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0137] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-3-(3-(2-trifluoromethylphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 90.4%). 1 H NMR(400MHz, DMSO-d6)δ7.95(d,J=7.8Hz,1H),7.91–7.77(m,4H),7.68(t,J=7.7Hz,1H),7.46–7.33(m,5H), 5.59(dd,J=8.6,4.1Hz,1H),4.82(t,J=8.7Hz,1H),4.24(dd,J=8.7,4.1Hz,1H).LRMS(ESI):362.09[M+H]+.

[0138] Example 29 (S,E)-4-phenyl-3-(3-(3-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one

[0139] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-(3-(trifluoromethoxy)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(3-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one. 1H NMR(400MHz,Chloroform-d)δ7.94(d,J=15.7Hz,1H),7.72(d,J=15.7Hz,1H),7.52(dt,J=7.8,1.3Hz,1H),7.45–7.32(m,7H),7.25(d dd,J=8.2,2.7,1.5Hz,1H),5.56(dd,J=8.7,3.9Hz,1H),4.75(t,J=8.8Hz,1H),4.33(dd,J=8.9,3.9Hz,1H); LRMS(ESI):378.09[M+H] + .

[0140] Example 30 (S,E)-4-phenyl-3-(3-(2-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one

[0141] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-(2-(trifluoromethoxy)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(2-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.05(d,J=15.8Hz,1H),7.97(d,J=15.9Hz,1H),7.84–7.75(m,1H),7.47–7.25(m ,8H),5.56(dd,J=8.8,3.9Hz,1H),4.76(t,J=8.8Hz,1H),4.34(dd,J=8.9,3.9Hz,1H); LRMS(ESI):378.09[M+H] + .

[0142] Example 31 (S,E)-4-phenyl-3-(3-(4-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one

[0143] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-(4-(trifluoromethoxy)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(4-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one. 1H NMR(400MHz,Methylene Chloride-d2)δ7.90(d,J=15.8Hz,1H),7.73(d,J=15.7Hz,1H),7.68–7.63(m,2H),7.44–7.32(m,5H),7.28–7.22 (m,2H),5.53(dd,J=8.7,4.1Hz,1H),4.74(t,J=8.8Hz,1H),4.29(dd,J=8.9,4.1Hz,1H); LRMS(ESI):378.09[M+H] + .

[0144] Example 32 (S,E)-3-(3-(2-phenoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0145] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(2-phenoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 90.1%). 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=15.9Hz,1H),7.84(d,J=16.0Hz,1H),7.80(dd,J=7. 9,1.7Hz,1H),7.47(ddd,J=8.3,7.3,1.7Hz,1H),7.43–7.36(m,4H),7.35–7.25(m,4H), 7.18–7.13(m,1H),7.03–6.97(m,2H),6.94(dd,J=8.2,1.1Hz,1H),5.55(dd,J=8.6,3.9 Hz,1H),4.79(t,J=8.7Hz,1H),4.20(dd,J=8.7,3.9Hz,1H).LRMS(ESI):386.13[M+H]+.

[0146] Example 33 (R,E)-3-(3-(2-phenoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0147] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-3-(3-(2-phenoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 90.5%). 1H NMR (400MHz, DMSO-d6) δ7.98(d,J=15.9Hz,1H),7.84(d,J=16.0Hz,1H),7.80(dd,J=7. 9,1.7Hz,1H),7.47(ddd,J=8.3,7.3,1.7Hz,1H),7.43–7.36(m,4H),7.35–7.25(m,4H), 7.18–7.13(m,1H),7.03–6.97(m,2H),6.94(dd,J=8.2,1.1Hz,1H),5.55(dd,J=8.6,3.9 Hz,1H),4.79(t,J=8.7Hz,1H),4.20(dd,J=8.7,3.9Hz,1H).LRMS(ESI):386.13[M+H]+.

[0148] Example 34 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one

[0149] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced by 4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one (yield 86.9%). 1 H NMR (400MHz, DMSO-d6) δ7.96–7.89(m,2H),7.81–7.67(m,5H),7.56(t,J=7.7Hz,1H),7.50(dd,J=8.2,6.9Hz,2H),7.44–7 .32(m,6H),5.61(dd,J=8.6,3.9Hz,1H),4.82(t,J=8.7Hz,1H),4.23(dd,J=8.6,3.9Hz,1H).LRMS(ESI,m / z):370.14[M+H] +

[0150] Example 35 (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one

[0151] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one (yield 89.6%). 1 H NMR (400MHz, DMSO-d6) δ8.00–7.88(m,2H),7.81–7.66(m,5H),7.56(t,J=7.7Hz,1H),7.53–7.47(m,2H),7.45 –7.33(m,6H),5.61(dd,J=8.6,3.9Hz,1H),4.87–4.78(m,1H),4.27–4.20(m,1H).LRMS(ESI):370.14[M+H]+.

[0152] Example 36 (R,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one

[0153] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one (yield 88.9%). 1 H NMR (400MHz, DMSO-d6) δ8.00–7.88(m,2H),7.81–7.66(m,5H),7.56(t,J=7.7Hz,1H),7.53–7.47(m,2H),7.45 –7.33(m,6H),5.61(dd,J=8.6,3.9Hz,1H),4.87–4.78(m,1H),4.27–4.20(m,1H).LRMS(ESI):370.14[M+H]+.

[0154] Example 37 (S,E)-3-(3-(4'-fluoro-[1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one

[0155] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(4'-fluoro-[1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(4'-fluoro-[1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one (yield 78.1%). 1 H NMR (400MHz, DMSO-d6) δ7.94–7.87(m,2H),7.80–7.70(m,4H),7.68(dt,J=7.9,1.3Hz,1H),7.55(t,J=7.7Hz,1H),7.43–7.39(m,1H),7.39 –7.36(m,2H),7.36–7.28(m,4H),5.61(dd,J=8.6,3.9Hz,1H),4.82(t,J=8.7Hz,1H),4.23(dd,J=8.6,3.9Hz,1H).LRMS(ESI):409.9[M+Na] + .

[0156] Example 38 (S,E)-4-phenyl-3-(3-(3-(pyridin-3-yl)phenyl)acryloyl)oxazolidin-2-one

[0157] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(3-(pyridin-3-yl)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(3-(pyridin-3-yl)phenyl)acryloyl)oxazolidin-2-one (yield 67.1%). 1 H NMR(400MHz,DMSO-d6)δ8.95(d,J=2.4Hz,1H),8.61(dd,J=4.8,1.6Hz,1H),8.13(dt,J =8.0,2.0Hz,1H),8.01(t,J=1.7Hz,1H),7.93(d,J=15.9Hz,1H),7.85–7.72(m,3H),7.6 1(t,J=7.8Hz,1H),7.52(dd,J=8.0,4.8Hz,1H),7.45–7.31(m,5H),5.61(dd,J=8.6,3. 9Hz,1H),4.82(t,J=8.6Hz,1H),4.23(dd,J=8.6,3.9Hz,1H).LRMS(ESI):393.01[M+Na] + .

[0158] Example 39 (S,E)-4-phenyl-3-(3-(3-(pyridin-4-yl)phenyl)acryloyl)oxazolidin-2-one

[0159] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(3-(pyridin-4-yl)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-4-phenyl-3-(3-(3-(pyridin-4-yl)phenyl)acryloyl)oxazolidin-2-one (yield 65.5%). 1 H NMR (400MHz, DMSO-d6) δ8.70–8.65(m,2H),8.07(s,1H),7.97–7.90(m,1H),7.89(d,J=7.4Hz,1H),7.82–7.73(m,4H),7.62(t,J=7.6H z,1H),7.45–7.31(m,5H),5.61(dd,J=8.6,3.9Hz,1H),4.82(t,J=8.6Hz,1H),4.23(dd,J=8.6,3.9Hz,1H).LRMS(ESI):392.92[M+Na] + .

[0160] Example 40 (S,E)-4-phenyl-3-(3-(3-(thiophen-2-yl)phenyl)acryloyl)oxazolidin-2-one

[0161] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-(thiophen-2-yl)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(3-(thiophen-2-yl)phenyl)acryloyl)oxazolidin-2-one (yield 87.8%). 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J=15.0Hz, 1H), 7.78–7.66 (m, 2H), 7.62 (q, J=1. 7Hz,1H),7.55(d,J=15.2Hz,1H),7.55–7.43(m,2H),7.45–7.35(m,3H),7.36–7.2 6(m,2H),7.29–7.19(m,1H),7.13(t,J=7.5Hz,1H),5.29(t,J=7.0Hz,1H),5.08( dd,J=11.5,7.0Hz,1H),4.80(dd,J=11.5,7.0Hz,1H).LRMS(ESI):376.09[M+H]+.

[0162] Example 41 (S,E)-4-phenyl-3-(3-(5-phenylthiophen-2-yl)acryloyl)oxazolidin-2-one

[0163] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(5-phenylthiophen-2-yl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(5-phenylthiophen-2-yl)acryloyl)oxazolidin-2-one (yield 91.3%). 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=7.6Hz,1H),7.87–7.77(m,3H),7.71(d,J =7.4Hz,1H),7.55(d,J=15.1Hz,1H),7.52–7.44(m,3H),7.47–7.38(m,2H), 7.31(t,J=7.3Hz,2H),7.29–7.19(m,1H),5.29(t,J=7.0Hz,1H),5.07(dd,J =11.5,7.0Hz,1H),4.81(dd,J=11.4,6.9Hz,1H).LRMS(ESI):376.09[M+H]+.

[0164] Example 42 (S,E)-4-phenyl-3-(3-(4-phenylthiophen-2-yl)acryloyl)oxazolidin-2-one

[0165] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-phenylthiophen-2-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(4-phenylthiophen-2-yl)acryloyl)oxazolidin-2-one (yield 92.1%). 1 H NMR (400MHz, DMSO-d6) δ7.86–7.77(m,3H),7.63–7.53(m,3H),7.42(dtdd,J=9.3,7.1,4.5,3.0Hz,5H),7.31(t,J=7.3Hz,2H),7 .29–7.19(m,1H),5.31(t,J=6.9Hz,1H),5.08(dd,J=11.4,6.9Hz,1H),4.81(dd,J=11.5,7.0Hz,1H).LRMS(ESI):376.09[M+H]+.

[0166] Example 43 (S,E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4-phenyloxazolidin-2-one

[0167] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-4-fluoro-2-(trifluoromethyl)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.08(d,J=15.4Hz,1H),7.95–7.80(m,2H),7.39(dt,J=15.8,7.4Hz,6H),7.32–7.22 (m,1H),5.55(dd,J=8.7,3.9Hz,1H),4.76(t,J=8.8Hz,1H),4.35(dd,J=8.9,3.9Hz,1H); LRMS(ESI):380.24[M+H] + .

[0168] Example 44 (S,E)-3-(3-(Benzo[d][1,3]dioxolan-5-yl)acryloyl)-4-phenyloxazolidin-2-one

[0169] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[d][1,3]dioxolan-5-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzo[d][1,3]dioxolan-5-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR (400MHz, Chloroform-d) δ7.84–7.64(m,2H),7.44–7.29(m,5H),7.13(d,J=1.7Hz,1H),7.05(dd,J=8.1,1.7Hz,1H),6.80(d,J= 8.0Hz,1H),6.01(s,2H),5.55(dd,J=8.7,3.9Hz,1H),4.73(t,J=8.8Hz,1H),4.31(dd,J=8.8,3.8Hz,1H); LRMS(ESI):338.10[M+H] + .

[0170] Example 45 (S,E)-3-(3-(2-chloroquinolin-4-yl)acryloyl)-4-phenyloxazolidin-2-one

[0171] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-chloroquinolin-4-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(2-chloroquinolin-4-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.38(dd,J=15.6,0.8Hz,1H),8.13–8.05(m,3H),7.77(ddd,J=8.4,6.9,1.4Hz,1H),7.64(s,1H), 7.63–7.58(m,1H),7.40(m,5H),5.59(dd,J=8.8,4.0Hz,1H),4.81(t,J=8.8Hz,1H),4.43–4.35(m,1H); LRMS(ESI):379.08[M+H] + .

[0172] Example 46 (S,E)-3-(3-(Benzofuran-2-yl)acryloyl)-4-phenyloxazolidin-2-one

[0173] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzofuran-2-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzofuran-2-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR(400MHz,Methylene Chloride-d2)δ7.95(d,J=15.4Hz,1H),7.67–7.58(m,2H),7.55(dt,J=8.4,1.0Hz,1H),7.45–7.32(m,6H),7.30–7.22(m,1H),7 .03(d,J=4.6Hz,1H),5.54(dd,J=8.8,4.1Hz,1H),4.75(t,J=8.8Hz,1H),4.29(dd,J=8.9,4.1Hz,1H); LRMS(ESI):334.10[M+H] + .

[0174] Example 47 (S,E)-3-(3-(Benzofuran-7-yl)acryloyl)-4-phenyloxazolidin-2-one

[0175] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzofuran-7-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzofuran-7-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ7.97(d,J=15.7Hz,1H),7.92(d,J=15.7Hz,1H),7.8 6(d,J=1.7Hz,1H),7.67(d,J=2.2Hz,1H),7.60(dd,J=8.6,1.8Hz,1H),7.52(d,J=8 .6Hz,1H),7.46–7.35(m,5H),6.82(dd,J=2.3,0.9Hz,1H),5.60(dd,J=8.7,3.9Hz ,1H),4.78(t,J=8.8Hz,1H),4.35(dd,J=8.8,3.9Hz,1H); LRMS(ESI):334.10[M+H] + .

[0176] Example 48 (S,E)-3-(3-(naphthalen-1-yl)acryloyl)-4-phenyloxazolidin-2-one

[0177] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(naphthalene-1-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(naphthalene-1-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J=15.5Hz,1H),8.20(d,J=8.1Hz,1H),8.05(dt,J=15.5,0.9Hz,1H),7.97–7.91(m,2H),7.91–7.86(m,1H), 7.60–7.50(m,3H),7.48–7.35(m,5H),5.63(dd,J=8.7,3.9Hz,1H),4.80(ddt,J=9.7,8.8,1.0Hz,1H),4.41–4.34(m,1H); LRMS(ESI):344.12[M+H] + .

[0178] Example 49 (S,E)-3-(3-(Benzo[b]thiophen-2-yl)acryloyl)-4-phenyloxazolidin-2-one

[0179] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[b]thiophen-2-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzothiophen-2-yl)acryloyl)-4-phenyloxazolidin-2-one. 1 H NMR (400MHz, DMSO-d6) δ8.05–7.95(m,2H),7.93–7.82(m,2H),7.69(d,J=15.5Hz,1H),7.39(dp,J=21.3,8.2,7.0 Hz,7H),5.59(dd,J=8.7,3.9Hz,1H),4.81(t,J=8.7Hz,1H),4.22(dd,J=8.7,3.9Hz,1H); LRMS(ESI):350.08[M+H] + .

[0180] Example 50 (E)-4-(4'-Fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0181] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as those in Example 1 to obtain (E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 380.08 [M+H] + .

[0182] Example 51 (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0183] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 380.08 [M+H] + .

[0184] Example 52 (E)-4-(4'-Fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one

[0185] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as those in Example 1 to obtain (E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 396.08 [M+H] + .

[0186] Example 53 (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one

[0187] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 396.08 [M+H] + .

[0188] Example 54 (E)-4-(4'-Fluorophenyl)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one

[0189] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (E)-4-(4'-fluorophenyl)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 404.12 [M+H]. + .

[0190] Example 55 (S,E)-4-(4'-fluorophenyl)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one

[0191] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 404.12 [M+H]. + .

[0192] Example 56 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-(4'-fluorophenyl)oxazolidin-2-one

[0193] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with 4-(4'-fluorophenyl)oxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-(4'-fluorophenyl)oxazolidin-2-one. LRMS (ESI): 388.13 [M+H]. + .

[0194] Example 57 (E)-4-Benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0195] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by 4-benzyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-4-benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 86.9%). 1 H NMR(400MHz, DMSO-d6)δ7.91–7.82(m,2H),7.76(td,J=7.4,2.0Hz,1H),7.64(d,J=15.0Hz,1 H),7.49(td,J=7.5,2.1Hz,1H),7.33–7.23(m,3H),7.24–7.14(m,3H),4.64(p, J=7.0Hz,1H),4.56(dd,J=11.3,7.0Hz,1H),4.33(dd,J=11.3,6.8Hz,1H),3.17 (dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,6.9Hz,1H).LRMS(ESI):376.11[M+H] + .

[0196] Example 58 (S,E)-4-Benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0197] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-benzyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (S,E)-4-benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 86.9%). 1 H NMR (400MHz, DMSO-d6) δ7.91–7.82(m,2H),7.76(td,J=7.4,2.0Hz,1H),7.64(d,J= 15.0Hz,1H),7.49(td,J=7.5,2.1Hz,1H),7.33–7.23(m,3H),7.24–7.14(m,3H),4. 64(p,J=7.0Hz,1H),4.56(dd,J=11.3,7.0Hz,1H),4.33(dd,J=11.3,6.8Hz,1H),3. 17(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,6.9Hz,1H).LRMS(ESI):376.11[M+H] + .

[0198] Example 59 (R,E)-4-Benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one

[0199] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-benzyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-4-benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one (yield 86.4%). 1H NMR (400MHz, DMSO-d6) δ7.91–7.82(m,2H),7.76(td,J=7.4,2.0Hz,1H),7.64(d,J= 15.0Hz,1H),7.49(td,J=7.5,2.1Hz,1H),7.33–7.23(m,3H),7.24–7.14(m,3H),4. 64(p,J=7.0Hz,1H),4.56(dd,J=11.3,7.0Hz,1H),4.33(dd,J=11.3,6.8Hz,1H),3. 17(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,6.9Hz,1H).LRMS(ESI):376.11[M+H] + .

[0200] Example 60 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-benzyloxazolidin-2-one

[0201] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced by 4-benzyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-benzyloxazolidin-2-one (yield 79.0%). 1 H NMR (400MHz, DMSO-d6) δ7.95(s,1H),7.93(d,J=15.8Hz,1H),7.87(d,J=15.8Hz,1H),7.78–7.74(m ,1H),7.74–7.68(m,3H),7.57(t,J=7.7Hz,1H),7.50(dd,J=8.2,7.0Hz,2H),7.44–7.38(m,1H),7.3 6–7.30(m,2H),7.29–7.21(m,3H),4.79(td,J=7.7,3.8Hz,1H),4.40(t,J=8.5Hz,1H),4.24(dd,J=8 .7,2.9Hz,1H),3.11(dd,J=13.6,3.4Hz,1H),3.02(dd,J=13.6,7.5Hz,1H).LRMS(ESI):384.0[M+H] + .

[0202] Example 61 (S,E)-4-Isopropyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0203] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.22(dq,J=15.5,2.3Hz,1H),7.92(d,J=15.5Hz,1H),7.8 6(d,J=7.8Hz,1H),7.71(dd,J=7.8,1.3Hz,1H),7.58(td,J=7.8,1.5Hz,1H),7.49(tt,J= 7.6,1.0Hz,1H),4.60–4.54(m,1H),4.34(dd,J=9.2,8.3Hz,1H),4.27(dd,J=9.1,3.2Hz, 1H),2.49(pd,J=7.0,3.9Hz,1H),0.95(dd,J=15.0,7.0Hz,6H); LRMS(ESI):328.11[M+H] + .

[0204] Example 62 (S,E)-4-Isopropyl-3-(3-(4-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0205] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(4-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(4-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 328.11 [M+H] + .

[0206] Example 63 (S,E)-4-Isopropyl-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0207] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(3-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(3-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 328.11 [M+H] + .

[0208] Example 64 (S,E)-4-Isopropyl-3-(3-(3-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one

[0209] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(3-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J=15.7Hz,1H),7.80(d,J=15.7Hz,1H),7. 56(dt,J=7.8,1.2Hz,1H),7.47–7.40(m,2H),7.29–7.21(m,1H),4.57(ddd,J=8. 3,4.0,3.2Hz,1H),4.34(dd,J=9.1,8.3Hz,1H),4.27(dd,J=9.1,3.2Hz,1H),2.4 6(pt,J=7.0,3.5Hz,1H),0.94(dd,J=17.4,7.0Hz,6H); LRMS(ESI):344.10[M+H] + .

[0210] Example 65 (S,E)-4-isopropyl-3-(3-(2-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one

[0211] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(2-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one. 1H NMR(400MHz,Chloroform-d)δ8.11(d,J=15.9Hz,1H),7.99(d,J=15.8Hz,1H),7.81(dd,J =7.8,1.7Hz,1H),7.44(ddd,J=8.2,7.4,1.7Hz,1H),7.36–7.28(m,2H),4.57(ddd,J=8.2 ,3.9,3.1Hz,1H),4.34(dd,J=9.1,8.3Hz,1H),4.27(dd,J=9.1,3.1Hz,1H),2.48(heptd, J=7.0,3.9Hz,1H),0.97(d,J=7.0Hz,3H),0.93(d,J=7.0Hz,3H); LRMS(ESI):344.10[M+H] + .

[0212] Example 66 (S,E)-4-Isopropyl-3-(3-(4-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one

[0213] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-(4-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(4-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one. LRMS (ESI): 344.10 [M+H] + .

[0214] Example 67 (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-isopropyloxazolidin-2-one

[0215] (E)-3-(o-Tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents, and preparation method were the same as in Example 1 to obtain (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-isopropyloxazolidin-2-one. LRMS (ESI): 336.15 [M+H] + .

[0216] Example 68 (S,E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4-isopropyloxazolidin-2-one

[0217] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-fluoro-2-(trifluoromethyl)phenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4-isopropyloxazolidin-2-one. 1 H NMR(400MHz, Chloroform-d)δ8.14(d,J=15.5Hz,1H),7.88(d,J=14.7Hz,2H),7.60–7.36(m,1H),7.30(d,J=8.5Hz,1H),4.57(d d,J=8.0,3.9Hz,1H),4.40–4.18(m,2H),2.64–2.34(m,1H),0.95(dd,J=16.0,7.0Hz,8H); LRMS(ESI):346.10[M+H] + .

[0218] Example 69 (S,E)-3-(3-(Benzofuran-2-yl)acryloyl)-4-isopropyloxazolidin-2-one

[0219] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzofuran-2-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzofuran-2-yl)acryloyl)-4-isopropyloxazolidin-2-one. 1 H NMR(400MHz,Methylene Chloride-d2)δ7.96(dd,J=15.4,0.6Hz,1H),7.70(d,J=15.4Hz,1H),7.62(ddd,J=7.8,1.3,0 .7Hz,1H),7.54(dq,J=8.4,0.9Hz,1H),7.42–7.36(m,1H),7.26(ddd,J=8.1,7.2,1.0Hz,1H),7 .05(s,1H),4.55(ddd,J=8.2,4.0,3.2Hz,1H),4.33(dd,J=9.1,8.2Hz,1H),4.26(dd,J=9.1,3 .2Hz,1H),2.00(s,1H),0.95(d,J=7.0Hz,3H),0.91(d,J=6.9Hz,3H); LRMS(ESI):300.12[M+H] + .

[0220] Example 70 (S,E)-3-(3-(Benzo[b]thiophen-2-yl)acryloyl)-4-isopropyloxazolidin-2-one

[0221] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[b]thiophen-2-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents, and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzo[b]thiophen-2-yl)acryloyl)-4-isopropyloxazolidin-2-one. 1 H NMR (400MHz, DMSO-d6) δ8.09–8.03(m,1H),8.02–7.98(m,1H),7.92–7.87(m,2H),7.69(d,J=15.4Hz,1H),7.44(pd,J=7.1,1.4Hz ,2H),4.49(dt,J=7.4,3.7Hz,1H),4.41–4.33(m,2H),1.32–1.19(m,1H),0.86(dd,J=26.2,6.9Hz,6H); LRMS(ESI):316.09[M+H] + .

[0222] Example 71 (S,E)-4-Isopropyl-3-(3-(naphthalen-1-yl)acryloyl)oxazolidin-2-one

[0223] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(naphthalene-1-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-isopropyl-3-(3-(naphthalene-1-yl)acryloyl)oxazolidin-2-one. 1H NMR(400MHz,Chloroform-d)δ8.74(d,J=15.5Hz,1H),8.28(d,J=8.4Hz,1H),8.06(d,J=15.5Hz,1 H),7.95(dd,J=7.7,3.5Hz,2H),7.91(dd,J=7.7,1.3Hz,1H),7.61(ddd,J=8.5,6.8,1.5Hz,1H),7. 58–7.51(m,2H),4.63(dt,J=8.3,3.5Hz,1H),4.37(t,J=8.7Hz,1H),4.30(dd,J=9.1,3.1Hz,1H),2 .54(pd,J=7.0,4.0Hz,1H),1.01(d,J=7.0Hz,3H),0.98(d,J=6.9Hz,3H); LRMS(ESI):310.10[M+H] + .

[0224] Example 72 (S,E)-3-(3-(Benzo[d][1,3]dioxolan-5-yl)acryloyl)-4-isopropyloxazolidin-2-one

[0225] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[d][1,3]dioxolan-5-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(benzo[d][1,3]dioxolan-5-yl)acryloyl)-4-isopropyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=0.9Hz,2H),7.15(d,J=1.7Hz,1H),7.10(d d,J=8.0,1.7Hz,1H),6.82(d,J=8.0Hz,1H),6.02(s,2H),4.56(ddd,J=8.2,4.0,3. 1Hz,1H),4.31(dd,J=9.1,8.3Hz,1H),4.25(dd,J=9.0,3.2Hz,1H),2.46(pd,J=7.0 ,3.9Hz,1H),0.96(d,J=7.0Hz,3H),0.91(d,J=6.9Hz,3H); LRMS(ESI):304.11[M+H] + .

[0226] Example 73 (E)-3-(3-(Benzo[d][1,3]dioxolan-5-yl)acryloyl)-4,4-dimethyloxazolidin-2-one

[0227] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(benzo[d][1,3]dioxolan-5-yl)acrylic acid, and oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(benzo[d][1,3]dioxolan-5-yl)acryloyl)-4,4-dimethyloxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ7.71(d,J=15.6Hz,1H),7.56(d,J=15.5Hz,1H),7.12(d,J=1.7Hz,1H),7.07(d d,J=8.0,1.7Hz,1H),6.81(d,J=8.0Hz,1H),6.01(s,2H),4.05(s,2H),1.64(s,6H); LRMS(ESI):290.10[M+H] + .

[0228] Example 74 (E)-4,4-dimethyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0229] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-4,4-dimethyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one. 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J=15.4Hz,1H),7.83(d,J=7.8Hz,1H),7.79–7.65( m,2H),7.53(dt,J=37.3,7.7Hz,2H),4.08(s,2H),1.66(s,6H); LRMS(ESI):314.09[M+H] + .

[0230] Example 75 (E)-4,4-dimethyl-3-(3-(3-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one

[0231] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-4,4-dimethyl-3-(3-(3-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one. 1 H NMR (400MHz, Chloroform-d) δ7.73 (s, 2H), 7.53 (dt, J = 7.7, 1.2Hz, 1H), 7.45–7. 38(m,2H),7.25–7.22(m,1H),4.08(s,2H),1.65(s,6H); LRMS(ESI):330.09[M+H] + .

[0232] Example 76 (E)-4,4-dimethyl-3-(3-(2-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one

[0233] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain (E)-4,4-dimethyl-3-(3-(2-(trifluoromethoxy)phenyl)acryloyl)oxazolidin-2-one. 1 H NMR (400MHz, Chloroform-d) δ8.04 (d, J=15.8Hz, 1H), 7.88–7.66 (m, 2H), 7.47–7. 38(m,1H),7.38–7.20(m,2H),4.08(s,2H),1.66(s,6H); LRMS(ESI):330.09[M+H] + .

[0234] Example 77 (E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4,4-dimethyloxazolidin-2-one

[0235] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-fluoro-2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(4-fluoro-2-(trifluoromethyl)phenyl)acryloyl)-4,4-dimethyloxazolidin-2-one. 1H NMR(400MHz,Chloroform-d)δ8.07(d,J=15.6Hz,1H),7.84(dd,J=8.8,5.4Hz,1H),7.67(d,J=15.5H z,1H),7.45–7.38(m,1H),7.27(d,J=6.5Hz,1H),4.08(s,2H),1.66(s,6H); LRMS(ESI):332.12[M+H] + .

[0236] Example 78 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)thiazolidin-2-one

[0237] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced by thiazolidin-2-one. The remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)thiazolidin-2-one (yield 89.0%). 1 H NMR(400MHz,DMSO-d6)δ7.81(d,J= 15.0Hz,1H),7.73(dd,J=7.5,2.0Hz,2H),7.66–7.44(m,7H),7.44–7.34(m,1 H),3.70(t,J=6.1Hz,2H),3.55(t,J=6.0Hz,2H).LRMS(ESI):310.08[M+H]+.

[0238] Example 79 (E)-3-(3-(2-phenoxyphenyl)acryloyl)thiazolidin-2-one

[0239] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by thiazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-3-(3-(2-phenoxyphenyl)acryloyl)thiazolidin-2-one (yield 89.6%). 1 H NMR(400MHz, DMSO-d6)δ7.94(dd,J=15.0,0.9Hz,1H),7.68–7.60(m,2H),7.46(td,J=7.5,2.0Hz,1H),7.44–7.34(m, 2H),7.23–7.09(m,2H),7.12–7.01(m,3H),3.70(t,J=6.1Hz,2H),3.55(t,J=6.0Hz,2H).LRMS(ESI):326.08[M+H]+.

[0240] Example 80 (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)thiazolidin-2-one

[0241] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by thiazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)thiazolidin-2-one (yield 90.6%). 1 H NMR(400MHz, DMSO-d6)δ7.86–7.79(m,1H),7.76(td,J=7.5,2.0Hz,1H),7.69–7.55(m,2H),7.47(td,J=7 .4,2.1Hz,1H),7.30–7.23(m,1H),3.70(t,J=6.2Hz,2H),3.55(t,J=6.2Hz,2H).LRMS(ESI):302.04[M+H] + .

[0242] Example 81 (E)-3-(3-(thiophen-2-yl)acryloyl)thiazolidin-2-one

[0243] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(thiophen-2-yl)acrylic acid, and oxazolidin-2-one was replaced with thiazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(thiophen-2-yl)acryloyl)thiazolidin-2-one (yield 85.1%). 1 H NMR(400MHz, DMSO-d6)δ7.86–7.75(m,2H),7.70(dd,J=7.4,1.6Hz,1H),7.60(d,J=15.0Hz,1H) ,7.20(t,J=7.4Hz,1H),3.70(t,J=6.1Hz,2H),3.55(t,J=6.0Hz,2H).LRMS(ESI):240.01[M+H] + .

[0244] Example 83 (S,E)-4-phenyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0245] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ7.94(d,J=7.8Hz,1H),7.89–7.77(m,4H),7.67(t,J=7.6Hz,1H),7.44–7.30(m,5H),5.57(s,1H).LRMS(ESI):364.11[M+H] + .

[0246] Example 84 (S,E)-4-phenyl-3-(3-(2-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0247] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(2-trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=15.0Hz,1H),7.70–7.60(m,2H),7.39–7.28(m,4 H),7.28–7.18(m,2H),7.02(t,J=7.1Hz,2H),5.50(s,1H).LRMS(ESI):380.11[M+H] + .

[0248] Example 85 (S,E)-4-phenyl-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0249] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(2-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR(400MHz,DMSO-d6)δ7.95(d,J=15.0Hz,1H),7.68–7.58(m,2H),7.46(td,J=7.4,2.0Hz,1H), 7.42–7.19(m,7H),7.19–7.09(m,1H),7.09–7.01(m,2H),5.50(s,1H).LRMS(ESI):388.14[M+H] + .

[0250] Example 86 (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one-5,5-d2

[0251] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-isopropyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-phenyloxazolidin-2-one-5,5-d2. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=15.0Hz,1H),7.73(dd,J=7.6,2.0Hz,3H),7.62(dt,J=7.6,2.1Hz,1H),7.54–7.47( m,3H),7.47–7.32(m,7H),7.32–7.25(m,1H),7.24(ddt,J=5.3,3.9,1.6Hz,1H),5.50(s,1H).LRMS(ESI):372.15[M+H] + .

[0252] Example 87 (S,E)-4-phenyl-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0253] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-phenyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-phenyl-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.1Hz,1H),7.44–7.29(m,9H),7.29–7.20(m,2H),7.14(tt,J=7.4,2. 0Hz,1H),7.05(dd,J=7.5,2.0Hz,2H),6.88(dp,J=4.1,2.1Hz,2H),5.50(s,1H).LRMS(ESI):388.14[M+H] + .

[0254] Example 88 (E)-4-phenyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0255] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4-phenyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-4-phenyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ7.94(d,J=7.8Hz,1H),7.89–7.77(m,4H),7.67(t,J=7.6Hz,1H),7.44–7.30(m,5H),5.57(s,1H).LRMS(ESI):364.11[M+H] + .

[0256] Example 89 (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0257] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-trifluoromethylphenyl)acrylic acid, oxazolidin-2-one was replaced by oxazolidin-2-one-4,4,5,5-d4, and the remaining required raw materials, reagents and preparation method were the same as in Example 1 to obtain (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1 H NMR(400MHz, DMSO-d6)δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=1 5.0Hz,1H),7.35(td,J=7.5,2.0Hz,1H),7.27–7.19(m,1H).LRMS(ESI):290.09[M+H] + .

[0258] Example 90 (E)-3-(3-(2-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0259] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-methoxyphenyl)acrylic acid, oxazolidin-2-one was replaced by oxazolidin-2-one-4,4,5,5-d4, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain (E)-3-(3-(2-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1 H NMR(400MHz,DMSO-d6)δ7.95(dd,J=15.0,1.0Hz,1H),7.70–7.60(m,2H),7.49( td,J=7.5,2.0Hz,1H),7.11–6.97(m,2H),3.91(s,3H).LRMS(ESI):252.11[M+H] + .

[0260] Example 91 (E)-3-(3-(3-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0261] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(3-methoxyphenyl)acrylic acid, oxazolidin-2-one was replaced by oxazolidin-2-one-4,4,5,5-d4, and the remaining required raw materials, reagents and preparation method were the same as in Example 1 to obtain (E)-3-(3-(3-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.0Hz,1H),7.41–7.27(m,3H),7.04(t,J=1.6Hz,1H),6.86–6.77(m,1H),3.73(s,3H).LRMS(ESI):252.11[M+H] + .

[0262] Example 92 (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0263] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(4-methoxyphenyl)acrylic acid, oxazolidin-2-one was replaced by oxazolidin-2-one-4,4,5,5-d4, and the remaining required raw materials, reagents and preparation method were the same as in Example 1 to obtain (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1H NMR(400MHz,DMSO-d6)δ7.81(d,J=15.0Hz,1H),7.72–7.64(m,2H),7.37(dt, J=15.2,1.0Hz,1H),7.10–7.02(m,2H),3.79(s,3H).LRMS(ESI):252.11[M+H] + .

[0264] Example 93 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0265] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-4,4,5,5-d4. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1 H NMR(400MHz,DMSO-d6)δ7.81(d,J=15.0Hz,1H),7.73(dd,J=7.6,2.0Hz,3H),7.62(d t,J=7.6,2.1Hz,1H),7.54–7.43(m,4H),7.43–7.32(m,2H).LRMS(ESI):298.13[M+H] + .

[0266] Example 94 (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4

[0267] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(3-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by oxazolidin-2-one-4,4,5,5-d4. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-4,4,5,5-d4. 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.1Hz,1H),7.44–7.31(m,4H),7.29(t,J=7.7Hz,1H),7.14( tt,J=7.5,2.0Hz,1H),7.09–7.01(m,2H),6.88(dp,J=4.1,2.1Hz,2H).LRMS(ESI):314.13[M+H] + .

[0268] Example 95 (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4-d2

[0269] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-4,4-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-4,4-d2. 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.0Hz,1H),7.72–7.64(m,2H),7.37(dt,J=15.2 ,1.0Hz,1H),7.10–7.02(m,2H),4.30(s,2H),3.79(s,3H).LRMS(ESI):250.10[M+H] + .

[0270] Example 96 (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0271] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(4-methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.0Hz,1H),7.72–7.64(m,2H),7.37(dt,J=15.1 ,1.0Hz,1H),7.10–7.02(m,2H),3.80(s,2H),3.79(s,3H).LRMS(ESI):250.10[M+H] + .

[0272] Example 97 (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-4,4-d2

[0273] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-4,4-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-4,4-d2. 1H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.1Hz,1H),7.44–7.31(m,4H),7.29(t,J=7.7Hz,1H),7.14(tt,J= 7.5,2.0Hz,1H),7.09–7.01(m,2H),6.88(dp,J=5.7,2.1Hz,2H),4.30(s,2H).LRMS(ESI):312.12[M+H] + .

[0274] Example 98 (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0275] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(3-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=15.1Hz,1H),7.44–7.31(m,4H),7.29(t,J=7.7Hz,1H),7.14(tt,J= 7.5,2.0Hz,1H),7.09–7.01(m,2H),6.88(dp,J=5.7,2.1Hz,2H),3.80(s,2H).LRMS(ESI):312.12[M+H] + .

[0276] Example 99 (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0277] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR (400MHz, DMSO-d6) δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=15.0Hz,1H),7. 35(td,J=7.5,2.0Hz,1H),7.23(ddd,J=7.6,2.1,1.0Hz,1H),3.80(s,2H).LRMS(ESI):288.07[M+H] + .

[0278] Example 100 (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one-5,5-d2

[0279] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=15.0Hz,1H),7.73(dq,J=8.3,2.1Hz,3H),7.62(dt,J=7.6,2.1 Hz,1H),7.54–7.43(m,4H),7.39(s,1H),7.44–7.32(m,1H),3.80(s,2H).LRMS(ESI):296.12[M+H] + .

[0280] Example 101 (E)-4,4-dimethyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0281] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, oxazolidin-2-one was replaced with 4,4-dimethyloxazolidin-2-one-5,5-d2, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain (E)-4,4-dimethyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR(400MHz, DMSO-d6)δ8.00–7.89(m,2H),7.76(td,J=7.5,2.0Hz,1H),7.64(d,J=15.0Hz,1H),7. 35(td,J=7.5,2.1Hz,1H),7.23(ddd,J=7.5,2.1,1.0Hz,1H),1.29(s,6H).LRMS(ESI):316.12[M+H] + .

[0282] Example 102 (E)-4-(4'-Fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0283] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, oxazolidin-2-one was replaced with 4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2, and the remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain (E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=15.0Hz, 1H),7.35(td,J=7.5,2.1Hz,1H),7.27–7.12(m,5H),5.50(s,1H).LRMS(ESI):382.10[M+H] + .

[0284] Example 103 (S,E)-4-(4'-Fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0285] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR(400MHz, DMSO-d6)δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=15.0Hz, 1H),7.35(td,J=7.5,2.1Hz,1H),7.27–7.12(m,5H),5.50(s,1H).LRMS(ESI):382.10[M+H] + .

[0286] Example 104 (E)-4-Benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0287] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with 4-benzyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (E)-4-benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR (400MHz, DMSO-d6) δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=15.0Hz,1H),7.35(td,J=7.5,2.1Hz,1H),7 .33–7.14(m,6H),4.60(t,J=5.3Hz,1H),3.04(dd,J=12.4,5.3Hz,1H),2.78(dd,J=12.4,5.3Hz,1H).LRMS(ESI):378.12[M+H] + .

[0288] Example 105 (S,E)-4-Benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0289] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-benzyloxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-benzyl-3-(3-(2-trifluoromethylphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR (400MHz, DMSO-d6) δ8.00–7.89(m,2H),7.76(td,J=7.5,2.1Hz,1H),7.64(d,J=15.0Hz,1H),7.35(td,J=7.5,2.1Hz,1H),7 .33–7.14(m,6H),4.60(t,J=5.3Hz,1H),3.04(dd,J=12.4,5.3Hz,1H),2.78(dd,J=12.4,5.3Hz,1H).LRMS(ESI):378.12[M+H] + .

[0290] Example 106 (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0291] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(2-trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(trifluoromethoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1 H NMR(400MHz, DMSO-d6)δ7.95(dd,J=15.0,0.9Hz,1H),7.70–7.60(m,2H),7.28–7.12(m,5H),7.02(t,J=7.1Hz,2H),5.50(s,1H).LRMS(ESI):398.09[M+H] + .

[0292] Example 107 (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0293] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(2-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(2-(phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR(400MHz, DMSO-d6)δ7.95(dd,J=15.0,0.9Hz,1H),7.68–7.58(m,2H),7.46(td,J=7.4,2.0Hz,1H),7.44– 7.34(m,2H),7.31–7.18(m,3H),7.21–7.10(m,3H),7.14–7.01(m,3H),5.50(s,1H).LRMS(ESI):406.13[M+H] + .

[0294] Example 108 (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2

[0295] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-([1,1'-biphenyl]-3-yl)acrylic acid, and oxazolidin-2-one was replaced with (S)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-3-(3-([1,1'-biphenyl]-3-yl)acryloyl)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. 1 H NMR (400MHz, DMSO-d6) δ7.81 (d, J=15.0Hz, 1H), 7.73 (dd, J=7.5, 2.0Hz, 3H), 7.62 (dt, J=7.6, 2.1Hz, 1H),7.54–7.43(m,4H),7.44–7.33(m,2H),7.26–7.12(m,4H),5.50(s,1H).LRMS(ESI):390.13[M+H] + .

[0296] Example 109 (S,E)-4-(4'-fluorophenyl)-3-(3-(3-phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2

[0297] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(3-phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-4-(4'-fluorophenyl)oxazolidin-2-one-5,5-d2. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-4-(4'-fluorophenyl)-3-(3-(3-(phenoxyphenyl)acryloyl)oxazolidin-2-one-5,5-d2. 1H NMR (400MHz, DMSO-d6) δ7.81 (d, J = 15.1Hz, 1H), 7.44–7.09 (m, 11H), 7.09–7. 01(m,2H),6.88(dp,J=4.1,2.1Hz,2H),5.50(s,1H).LRMS(ESI):406.13[M+H] + .

[0298] Example 110 (R,E)-5,5-dimethyl-4-phenyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0299] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(o-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (R)-5,5-dimethyl-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (R,E)-5,5-dimethyl-4-phenyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one (yield 64.2%). 1 H NMR(500MHz,Chloroform-d)δ8.16(dq,J=15.5,2.3Hz,1H),8.00(d,J=15.6Hz,1H),7.89(d,J=7.8Hz,1H),7.69(d,J=7.8Hz,1H),7.59(t, J=7.6Hz,1H),7.51–7.47(m,1H),7.42–7.33(m,3H),7.22–7.19(m,2H),5.20(s,1H),1.65(s,3H),1.04(s,3H).HRMS(ESI):390.1315[M+H] + .

[0300] Example 111 (S,E)-5,5-dimethyl-4-phenyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one

[0301] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(o-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-5,5-dimethyl-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-5,5-dimethyl-4-phenyl-3-(3-(2-(trifluoromethyl)phenyl)acryloyl)oxazolidin-2-one (yield 71.5%). 1H NMR(500MHz,Chloroform-d)δ8.19(ddd,J=7.4,1.5,0.6Hz,1H),8.02(td,J=7.4,1.6Hz,1H),7.96(dd,J=7.5,1.6Hz,1H),7.90(td,J=7.5,1.6Hz,1H), 7.88–7.82(m,1H),7.62(d,J=15.0Hz,1H),7.36–7.24(m,5H),5.25–5.21(m ,1H),1.46(d,J=1.6Hz,3H),1.41(d,J=1.5Hz,3H).LRMS(ESI):390.20[M+H] + .

[0302] Example 112 (R,E)-7-phenyl-6-(3-(2-(trifluoromethyl)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptan-5-one

[0303] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(o-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-7-phenyl-6-(3-(2-(trifluoromethyl)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 49.2%). 1 H NMR(500MHz,Chloroform-d)δ8.18–8.13(m,1H),7.94(d,J=15.4Hz,1H),7.86(d,J=7.8Hz,1H),7.68(dd,J=7.9,1.3Hz,1H),7.58(t,J=7.7Hz,1H),7.48(t, J=7.6Hz,1H),7.43–7.32(m,5H),5.32(s,1H),1.40–1.33(m,1H),1.21–1.13( m,1H),0.98–0.89(m,1H),0.48(d,J=345.4Hz,1H).HRMS(ESI):388.1156[M+H] + .

[0304] Example 113 (S,E)-7-phenyl-6-(3-(2-(trifluoromethyl)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptan-5-one

[0305] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(o-trifluoromethylphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-7-phenyl-6-(3-(2-(trifluoromethyl)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 47.2%). 1 H NMR(500MHz,Chloroform-d)δ8.19(ddd,J=7.4,1.6,0.6Hz,1H),8.02(td,J=7.4,1.6Hz,1H),7.96(dd,J=7.5,1.6Hz,1H),7.90(td,J=7.5,1.6Hz,1H), 7.88–7.82(m,1H),7.62(d,J=15.0Hz,1H),7.37–7.24(m,5H),5.20(d,J=0. 7Hz,1H),1.66–1.55(m,2H),1.55–1.44(m,2H).LRMS(ESI):388.12[M+H]+.

[0306] Example 114 (E)-5-phenyl-1-(3-(2-(trifluoromethyl)phenyl)acryloyl)imidazolidine-2,4-dione

[0307] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(m-methoxyphenyl), and oxazolidin-2-one was replaced by 5-phenylimidazolidine-2,4-dione. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (E)-5-phenyl-1-(3-(2-(trifluoromethyl)phenyl)acryloyl)imidazolidine-2,4-dione (yield 62.8%). 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),7.99–7.92(m,2H),7.91–7.84(m,1H),7.82–7.76(m,2H),7.6 7–7.62(m,1H),7.41(d,J=4.3Hz,4H),7.39–7.34(m,1H),5.67(s,1H).HRMS(ESI):375.0952[M+H]+.

[0308] Example 115 (R,E)-6-(3-(3-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0309] (E)-3-(o-Tolyl)acrylic acid was replaced by (E)-3-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-6-(3-(3-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 43.2%). 1 H NMR(500MHz,Chloroform-d)δ7.93(d,J=15.7Hz,1H),7.75(d,J=15.8Hz,2H),7.40–7.25(m,8H),7.19(dt,J=7.8,1.4Hz,1H),7.09(dd,J=2.6,1. 6Hz,1H),6.97–6.91(m,2H),5.32(s,1H),1.41–1.32(m,1H),1.20–1.10( m,1H),0.96–0.87(m,1H),0.51–0.42(m,1H).HRMS(ESI):350.1384[M+H] + .

[0310] Example 116 (S,E)-6-(3-(3-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0311] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-6-(3-(3-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 48.2%). 1 H NMR(500MHz,Chloroform-d)δ7.77(d,J=15.0Hz,1H),7.72–7.65(m,1H),7.37–7.23(m,7H),7.15(t,J=1.5Hz,1H),7.06(ddt ,J=7.5,3.1,1.6Hz,2H),5.20(d,J=0.7Hz,1H),3.80(s,2H),1.66–1.55(m,2H),1.55–1.44(m,2H).LRMS(ESI):350.15[M+H] + .

[0312] Example 117 (R,E)-6-(3-(3-phenoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0313] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-6-(3-(3-phenoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 51.1%). 1 H NMR(500MHz,Chloroform-d)δ7.91(d,J=15.7Hz,1H),7.72(d,J=15.7Hz,1H),7.42–7 .30(m,9H),7.24–7.21(m,1H),7.13(t,J=7.4Hz,1H),7.04–6.99(m,3H),5.31(s,1H), 1.39–1.32(m,1H),1.19–1.11(m,1H),0.96–0.88(m,1H),0.52–0.42(m,1H).HRMS(ESI):421.1542[M+H]+.

[0314] Example 118 (S,E)-6-(3-(3-phenoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0315] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(phenoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-6-(3-(3-phenoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 48.1%). 1 H NMR(500MHz,Chloroform-d)δ7.77(d,J=15.0Hz,1H),7.72–7.65(m,1H),7.40–7.24(m,10H),7 .20–7.15(m,1H),7.18–7.00(m,6H),5.19(s,1H),1.66–1.44(m,5H).LRMS(ESI):421.10[M+H] + .

[0316] Example 119 (R,E)-7-phenyl-6-(3-(2-(trifluoromethoxy)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptane-5-one

[0317] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (R,E)-7-phenyl-6-(3-(2-(trifluoromethoxy)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 34.2%). 1 H NMR(500MHz,Chloroform-d)δ8.08–7.96(m,2H),7.80(dd,J=7.8,1.7Hz,1H),7.45–7.24(m,8H),5.32(s,1 H),1.41–1.32(m,1H),1.19–1.12(m,1H),0.97–0.90(m,1H),0.51–0.43(m,1H).HRMS(ESI):404.1105[M+H] + .

[0318] Example 120 (S,E)-7-phenyl-6-(3-(2-(trifluoromethoxy)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptan-5-one

[0319] (E)-3-(o-tolyl)acrylic acid was replaced with (E)-3-(trifluoromethoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced with (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (S,E)-7-phenyl-6-(3-(2-(trifluoromethoxy)phenyl)acryloyl)-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 36.5%). 1 H NMR(500MHz,Chloroform-d)δ7.81–7.75(m,1H),7.63(d,J=15.2Hz,1H),7.56(ddd,J=7.5,1.5,0.6Hz,1H),7.38–7.26(m,6H),7.2 3(dd,J=7.5,1.6Hz,1H),6.99(td,J=7.5,1.6Hz,1H),5.19(s,1H),1.66–1.55(m,2H),1.55–1.44(m,2H).LRMS(ESI):404.13[M+H] + .

[0320] Example 121 (R,E)-6-(3-(4-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0321] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-4-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (R,E)-6-(3-(4-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 41.9%). 1 H NMR(600MHz,Chloroform-d)δ7.85–7.73(m,2H),7.54(d,J=8.5Hz,2H),7.40–7.30(m,5H),6.89(d,J=8.6Hz,2H),5.31(s ,1H),3.83(s,3H),1.39–1.31(m,1H),1.17–1.09(m,1H),0.95–0.86(m,1H),0.50–0.43(m,1H).LRMS(ESI):350.40[M+H] + .

[0322] Example 122 (S,E)-6-(3-(4-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0323] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-4-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-6-(3-(4-methoxyphenyl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 41.9%). 1 H NMR(600MHz,Chloroform-d)δ7.85–7.73(m,2H),7.54(d,J=8.5Hz,2H),7.40–7.30(m,5H),6.89(d,J=8.6Hz,2H),5.31(s ,1H),3.83(s,3H),1.39–1.31(m,1H),1.17–1.09(m,1H),0.95–0.86(m,1H),0.50–0.43(m,1H).LRMS(ESI):350.40[M+H] + .

[0324] Example 123 (R,E)-6-(3-([1,1'-biphenyl]-4-yl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0325] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-4-yl)acrylic acid, and oxazolidin-2-one was replaced by (R)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those required in Example 1 to obtain (R,E)-6-(3-([1,1'-biphenyl]-4-yl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 33.2%). 1 H NMR(500MHz,Chloroform-d)δ7.97(d,J=15.7Hz,1H),7.80(d,J=15.7Hz,1H),7.68–7.56(m,6H),7.47–7.28(m,8H), 5.30(s,1H),1.39–1.31(m,1H),1.18–1.09(m,1H),0.96–0.87(m,1H),0.50–0.42(m,1H).HRMS(ESI):396.1599[M+H] + .

[0326] Example 124 (S,E)-6-(3-([1,1'-biphenyl]-4-yl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one

[0327] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-([1,1'-biphenyl]-4-yl)acrylic acid, and oxazolidin-2-one was replaced by (S)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-6-(3-([1,1'-biphenyl]-4-yl)acryloyl)-7-phenyl-4-oxa-6-azaspiro[2.4]heptane-5-one (yield 33.2%). 1 H NMR(500MHz,Chloroform-d)δ7.97(d,J=15.7Hz,1H),7.80(d,J=15.7Hz,1H),7.68–7.56(m,6H),7.47–7.28(m,8H) ,5.30(s,1H),1.39–1.31(m,1H),1.18–1.09(m,1H),0.96–0.87(m,1H),0.50–0.42(m,1H).LRMS(ESI):396.16[M+H]+ .

[0328] Example 125 (S,E)-3-(3-(4-methoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0329] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-4-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain (S,E)-3-(3-(4-methoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 48.2%). 1 H NMR(600MHz,Chloroform-d)δ7.86–7.76(m,2H),7.59–7.56(m,2H),7.43–7.40(m,2H),7.39–7.34(m,3H),6.94–6.90(m,2H ),5.58(dd,J=8.7,3.9Hz,1H),4.75(t,J=8.8Hz,1H),4.32(dd,J=8.8,3.9Hz,1H),3.86(s,3H).HRMS(ESI):324.1232[M+H] + .

[0330] Example 126 (S,E)-3-(3-(3-methoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one

[0331] (E)-3-(o-tolyl)acrylic acid was replaced by (E)-3-(methoxyphenyl)acrylic acid, and oxazolidin-2-one was replaced by (R)-4-phenyloxazolidin-2-one. The remaining raw materials, reagents and preparation method were the same as those required in Example 1 to obtain (S,E)-3-(3-(3-methoxyphenyl)acryloyl)-4-phenyloxazolidin-2-one (yield 46.2%). 1 H NMR(600MHz,Chloroform-d)δ7.95(d,J=15.7Hz,1H),7.77(d,J=15.7Hz,1H),7.46–7.29(m,6H),7.21(d,J=7.6Hz,1H),7.12(s,1H) ,6.96(d,J=8.2Hz,1H),5.56(d,J=8.5Hz,1H),4.73(t,J=8.8Hz,1H),4.31(d,J=8.8Hz,1H),3.84(s,3H).HRMS(ESI):324.1233[M+H] + .

[0332] Pharmacological activity test examples

[0333] Example 1. Determination of the activity of the compounds of the present invention in improving blood flow

[0334] We used a laser speckle pattern blood flow model to test the compounds' ability to improve brain blood flow in mice. Laser speckle patterning measures changes in light intensity in flowing blood, reflecting real-time brain blood flow. Comparing changes in blood flow before and after administration can be used to assess the compound's ability to improve blood flow.

[0335] The experimental procedure is shown in Figure 1. After 30 seconds of air anesthesia, the experimental mouse was secured to a rack. After a 2-minute wait for the baseline light intensity data to stabilize, cerebral blood flow light intensity data were recorded for 10 minutes, while the mouse was not receiving the drug. The test compound was then injected intraperitoneally, and cerebral blood flow light intensity data were recorded for 60 minutes after administration. Comparing the changes in light intensity before and after administration revealed the extent of changes in cerebral blood flow.

[0336] Using the laser speckle model described above, we conducted preliminary tests on the Example compounds for their ability to improve cerebral blood flow in mice, using ferulic acid (FA) as a positive control. The blood flow-improving effects of the compounds are shown in Figure 2. Several compounds demonstrated significant improvements in cerebral blood flow in this model. At a 5 mg / kg dose, compound 9 increased cerebral blood flow in mice by approximately 10%, and compound 16 by approximately 20%. At a 20 mg / kg dose, compounds 30 and 59 increased cerebral blood flow in mice by approximately 10%. Compounds 5, 6, 26, 28, 29, 35, 43, and 58 all increased cerebral blood flow in mice by approximately 20%. Compounds 16, 57, and 86 increased cerebral blood flow in mice by approximately 30%. Compounds 27, 84, and 104 increased cerebral blood flow by approximately 40%. Compound 83 increased cerebral blood flow in mice by 50% to 60%. Overall, the compounds in this patent have promising development prospects.

[0337] Example 2. Determination of in vivo pharmacokinetic parameters of the compounds of the present invention

[0338] Male ICR (CD-1) mice were divided into 2 groups, 3 mice in each group, and each group was gavaged with 20 mg / kg of the test substance or injected intravenously with 5 mg / kg of the test substance. Blood was collected before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Plasma was immediately collected by centrifugation, and the drug concentration in plasma was determined by liquid chromatography-tandem mass spectrometry.

[0339] The pharmacokinetic parameters in mice are shown in the table below. In mice, the oral bioavailabilities of compounds 27 and 83 were 14.7% and 17.4%, respectively, indicating good pharmacokinetic properties.

[0340] Table 2. Pharmacokinetic parameters of compounds 27 and 83 in mice

[0341] In addition, by measuring the drug distribution of the compound in brain tissue, it was found that the compound has good blood-brain barrier permeability. As shown in Table 3, compound 27 has good brain tissue drug distribution after oral administration to mice, with a B / P of approximately 0.7.

[0342] Table 3. Drug concentration determination in brain tissue

[0343] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. An α,β-unsaturated amide compound having a structure as shown in Formula I below, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, or mixture thereof: in: R 1 、R 2 、R 3 and R 4 can be independently selected from the following groups: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or (CHR 6 ) n R; wherein said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heterocyclic group, substituted or unsubstituted C3-C12 cycloalkyl or heterocondensed ring; or R 3 and R 4 Together with the carbon atom to which it is attached, it forms a group selected from the group consisting of a carbonyl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, or a substituted or unsubstituted 4-8 membered heterocyclyl group; The ring is selected from the group consisting of a C6-C10 aryl group, a 5-12 membered heteroaryl group, a 5-12 membered heterocyclyl group, a C3-C12 cycloalkyl group, or a hetero-fused ring; R 5 For 1, 2, 3, 4 or 5 ring substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxy, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted 5-7 membered heteroaryloxy, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C3-C12 cycloalkyl; or two adjacent R 5 and The atoms on the ring are connected end to end to form a substituted or unsubstituted 4-8 membered ring (i.e., forming a parallel ring structure with the A ring); or Two R on the same atom in the ring 5 End to end The ring forms a substituted or unsubstituted 3-8 membered ring (i.e., forms a spiro ring structure with the A ring); X is N(CH2) n R 6 , O, or S; n is 0, 1, 2, or 3; R 6 Independently selected from the following group: hydrogen, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1~C6 alkyl, substituted or unsubstituted C1~C6 alkoxy, substituted or unsubstituted C6~C10 aryl, substituted or unsubstituted 5-12 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted C2~C10 acyl, substituted or unsubstituted C2~C10 ester, substituted or unsubstituted C1~C6 amide, -SO2R5, -COR5; Wherein, unless otherwise specified, the heteroaromatic ring, heterocyclic ring or heterocyclic group each independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the aromatic ring or heteroaromatic ring includes a monocyclic, fused or condensed ring; the carbocyclic ring or heterocyclic ring includes a monocyclic, fused, spiro or bridged ring; Said substitution refers to substitution by one or more (preferably 1-3) substituents selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl, and 3-12 membered heterocyclyl; The halogen is F, Cl, Br or I.

2. The α,β-unsaturated amide compound according to claim 1, characterized in that The The ring is selected from the following groups: C6-C10 aryl, C5-C12 heteroaryl.

3. The α,β-unsaturated amide compound according to claim 1, characterized in that: The R 1 、R 2 、R 3 and R 4 are independently selected from the following groups: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or (CHR 6 ) n R; wherein said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl; n is 0, 1 or 2; R 6 It is hydrogen, halogen, or substituted or unsubstituted C1-C6 alkyl.

4. The α,β-unsaturated amide compound according to claim 1 or 2, characterized in that The R 1 、R 2 、R 3 and R 4 are independently selected from the following groups: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, (CHR 6 ) n R; wherein, said R is selected from the following group: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl.

5. The α,β-unsaturated amide compound according to claim 1 or 2, characterized in that: The R 1 is H or D, and R 2 Selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, (CHR 6 ) n R; wherein, the R is selected from the following groups: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroaryl; the substitution refers to substitution by one or more substituents selected from the following groups: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl.

6. The α,β-unsaturated amide compound according to claim 1 or 2, characterized in that: The R 3 and R 4 each independently deuterium.

7. The α,β-unsaturated amide compound according to claim 1, characterized in that: The compound of formula I is selected from the following table:

8. The method for preparing the compound of formula I according to claim 1, wherein The method comprises the steps of: In an inert solvent, the compound of formula II is reacted with the compound of formula III to obtain the compound of formula I.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises (1) the compound according to claim 1 or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.

10. Use of the compound according to claim 1 or its stereoisomer or tautomer, or its pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition according to claim 9, characterized in that: Used for preparing a pharmaceutical composition for preventing and / or treating neurodegenerative diseases or stroke; preferably, the neurodegenerative disease is selected from the following group: Alzheimer's disease and vascular dementia.

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