WO2024008166A1 - 一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途 - Google Patents

一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途 Download PDF

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WO2024008166A1
WO2024008166A1 PCT/CN2023/106181 CN2023106181W WO2024008166A1 WO 2024008166 A1 WO2024008166 A1 WO 2024008166A1 CN 2023106181 W CN2023106181 W CN 2023106181W WO 2024008166 A1 WO2024008166 A1 WO 2024008166A1
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substituted
unsubstituted
oxazolidin
acryloyl
acrylic acid
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PCT/CN2023/106181
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English (en)
French (fr)
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柳红
徐林
周宇
谭娅红
王一冰
李津南
黄河
周启心
程异浪
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中国科学院上海药物研究所
中国科学院昆明动物研究所
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Publication of WO2024008166A1 publication Critical patent/WO2024008166A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the fields of medicinal chemistry and medicine, and specifically relates to a class of ⁇ , ⁇ -unsaturated amide compounds, their preparation methods, and pharmaceutical compositions containing such compounds, which are used to treat neurological diseases such as Alzheimer's disease and vascular dementia. Use of drugs for degenerative diseases and stroke.
  • AD Alzheimer's disease
  • ⁇ -Amyloid ⁇ -amyloid deposition
  • NFT neurofibrillary tangles
  • the pathological mechanism of AD is very complex. Existing drugs on the market can only temporarily slow down or control the symptoms of AD, and effective treatments targeting the disease mechanism have not yet been found.
  • Aging is the main risk factor for AD. More than 95% of AD patients have late-onset disease, with onset age above 65 years old. Less than 5% of AD is early-onset, and the main cause is genetic factors.
  • Cardiovascular and cerebrovascular diseases are also major risk factors for AD, and vascular changes may contribute to the pathogenesis of AD, not just vascular dementia caused by known vascular lesions.
  • CBF Cerebral blood flow
  • BBB blood brain barrier
  • APOE is a major genetic risk factor for AD and a susceptibility gene for vascular disease.
  • reduced cerebral blood flow and vascular dysfunction were also found in transgenic mice with targeted replacement of murine apolipoprotein E4 (APOE) with human APOE4 gene 125-127, and vascular dysfunction in APOE4-expressing mice was also found.
  • Phenotype precedes neuronal and synaptic dysfunction. Hypoperfusion can induce or exacerbate Alzheimer's disease-like neuronal dysfunction and neuropathological changes. Chronic reductions in blood flow of 50% lead to significant cognitive changes, sustained reductions in cerebral blood flow of more than 20% in humans lead to loss of attention, and cerebral blood flow of more than 30% in rats impairs spatial memory.
  • Reduced cerebral blood flow reduces the activity of the Na + /K + pump and all processes that depend on it (including maintenance of the resting potential and glutamate uptake). It also leads to the production of adenosine, which inhibits glutamate uptake. released, thereby affecting the function of neurons.
  • Bilateral carotid artery occlusion in rats results in memory impairment, neuronal dysfunction, synaptic changes, and beta-amyloid, leading to the accumulation of neurotoxic beta-amyloid oligomers.
  • Cerebral ischemia, hypoxia and A ⁇ deposition influence each other. Hypoperfusion can trigger accelerated deposition of A ⁇ . A ⁇ , in turn, can damage cerebrovascular function, increase arterial vasoconstriction and reduce cerebral blood flow.
  • ischemia leads to the accumulation and formation of hyperphosphorylated tau in neurons similar to filaments seen in human neurodegenerative diseases and Alzheimer's disease. Hypoperfusion affects structural and functional changes in the brain and offers promising biomarkers that could potentially identify and diagnose Alzheimer's disease in its preclinical state.
  • Capillaries are the smallest blood vessels in the brain. They branch out from arterioles and form a rich microvascular network. The maximum surface area of capillaries per gram of brain is approximately 120cm 2 .
  • the capillary network is mainly composed of endothelial cells, basement membrane, perithelial cells, and astrocytes. Capillary disorders have been observed in animal models as a precursor to dementia-related neurodegenerative changes. Capillary constriction in AD leads to hypoxia in nervous tissue, which may also be the cause of decreased glucose metabolism in AD. And ischemia and hypoxia have been shown to upregulate beta-secretase (BACE1), the enzyme responsible for generating A ⁇ . Capillary blood flow is mainly regulated by pericytes.
  • Capillaries have increased susceptibility to injury due to their delicate and specialized structure, and capillary degeneration is more frequent and prevalent than vascular amyloidosis, potentially suggesting that the long-term degenerative process of brain microvasculature in AD may be partially independent of amyloid. toxicity. More and more studies have shown that vascular factors are the main risk factors for AD, and damage to the neurovascular unit is related to AD. Therefore, finding ways to intervene in capillaries to improve cerebral blood flow may be of great significance to the prevention and treatment of AD.
  • the present invention provides a class of target compounds that target capillaries to increase cerebral blood flow and thereby improve AD symptoms, and are used for the clinical treatment of neurodegenerative diseases such as Alzheimer's disease, vascular dementia, and stroke.
  • One object of the present invention is to provide an ⁇ , ⁇ -unsaturated amide compound represented by the general formula I or a pharmaceutically acceptable salt, racemate, R-isomer or S-isomer thereof or Their mixture.
  • Another object of the present invention is to provide a method for preparing the ⁇ , ⁇ -unsaturated amide compound represented by the above general formula I.
  • Another object of the present invention is to provide a method of treating neurodegenerative diseases such as Alzheimer's disease, vascular dementia and stroke related to cerebral blood flow, which includes administering selected drugs to patients in need of the treatment.
  • neurodegenerative diseases such as Alzheimer's disease, vascular dementia and stroke related to cerebral blood flow
  • the first aspect of the present invention provides an ⁇ , ⁇ -unsaturated amide compound having the structure shown in Formula I below, or its racemate, R-isomer, S-isomer, pharmaceutical Acceptable salts or mixtures thereof:
  • R 1 , R 2 , R 3 and R 4 may each be independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted Or unsubstituted C1 ⁇ C6 alkoxy group, or (CHR 6 ) n R; wherein, the R is selected from the following group: substituted or unsubstituted C6 ⁇ C10 aryl group, substituted or unsubstituted 5-7 yuan Heteroaryl, substituted or unsubstituted 5-7 membered heterocyclyl, substituted or unsubstituted C3 ⁇ C12 cycloalkyl or heterofused ring; or R 3 and R 4 and the attached carbon atom together form a group selected from Groups of the following group: carbonyl, substituted or unsubstituted 3-8 membered cycloalkyl, or substituted or unsubsti
  • the ring is selected from the following group: C6-C10 aryl, 5-12-membered heteroaryl, 5-12-membered heterocyclyl, C3-C12 cycloalkyl or heterofused ring;
  • R 5 is located at 1, 2, 3, 4 or 5 substituents on the ring are selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1 ⁇ C6 alkyl, Substituted or unsubstituted C1 ⁇ C6 alkoxy group, substituted or unsubstituted C6 ⁇ C10 aryl group, substituted or unsubstituted C6 ⁇ C10 aryloxy group, substituted or unsubstituted 5-7 membered heteroaryl group, substituted Or unsubstituted 5-7 membered heteroaryloxy group, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C3 ⁇ C12 cycloalkyl group;
  • the two R 5's on the same atom in the ring are connected end to end with 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(CH 2 ) n R 6 , O, or S;
  • n 0, 1, 2, or 3;
  • R 6 is 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 substituted or unsubstituted C2 ⁇ C10 acyl, substituted or unsubstituted 5-12 membered heteroatoms containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen C2 ⁇ C10 ester group, substituted or unsubstituted C1 ⁇ C6 amide group, -SO 2 R 5 , -COR 5 ;
  • 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 single ring , and the ring or condensed ring, the carbocyclic ring or heterocyclic ring includes a single ring, a ring, a spiro ring or a bridged ring;
  • substitution refers to being substituted by one or more (preferably 1-3) 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, 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.
  • the The ring is selected from the following group: C6-C10 aryl group, C5-C12 heteroaryl group.
  • the R 1 , R 2 , R 3 and R 4 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, or (CHR 6 ) n R; wherein, the R is selected from the following group: substituted or unsubstituted C6-C10 aryl group, substituted or unsubstituted 5-7 membered heteroaryl group; n is 0, 1 or 2; R 6 is hydrogen , halogen, or substituted or unsubstituted C1 ⁇ C6 alkyl.
  • the R 1 , R 2 , R 3 and R 4 are each independently selected from the following group: 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 group, substituted or unsubstituted 5-7 membered heteroaryl group.
  • R 3 and R 4 are each independently selected from the following group: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl.
  • the R 1 is H or D
  • R 2 is selected from the following group: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, (CHR 6 ) n R; wherein, the The above-mentioned R is selected from the following group: substituted or unsubstituted C6 ⁇ C10 aryl group, Substituted or unsubstituted 5-7 yuan heteroaryl; the substitution refers to being substituted by one or more substituents selected from the following group: halogen, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl , mercapto group, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkoxy, C1-C6 alkoxycarbonyl.
  • R 3 and R 4 are each independently deuterium.
  • R 1 and R 2 are each independently deuterium.
  • the compound of formula I is the compound described in each embodiment.
  • a second aspect of the present invention provides a method for preparing the compound of formula I as described in the first aspect of the present invention, the method comprising the steps:
  • reaction is carried out in the presence of organic amine and pivaloyl chloride.
  • the organic amine is triethylamine.
  • the third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising (1) the compound as described in the first aspect of the present invention or its stereoisomer or tautomer, or its Pharmaceutically acceptable salts, hydrates or solvates; (2) Pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides 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 as claimed in the rights
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease and vascular dementia.
  • Figure 1 is a flow chart of the laser speckle test blood flow model of Pharmacological Activity Experiment Example 1;
  • Figure 2 is a diagram showing the blood flow improving effect of the compound of the present invention.
  • the inventor After long-term and in-depth research, the inventor has provided an ⁇ , ⁇ -unsaturated amide compound that can be used for neurodegenerative diseases such as Alzheimer's disease.
  • the compounds described can effectively improve capillary cerebral blood flow. Based on the above findings, the inventor completed the present invention.
  • the halogen is F, Cl, Br or I.
  • C1-C6 alkyl refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, without limitation.
  • Preferred include 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.
  • C1-C6 alkoxy refers to a straight-chain or branched chain alkoxy group with 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc.
  • C2-C6 alkenyl refers to a straight-chain or branched alkenyl group containing one double bond with 2 to 6 carbon atoms, including without limitation vinyl, propenyl, butenyl , isobutenyl, pentenyl and hexenyl, etc.
  • C2-C6 alkynyl refers to a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms and containing a triple bond, including without limitation ethynyl, propynyl, butynyl base, isobutynyl, pentynyl and hexynyl, etc.
  • C3-C10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
  • C3-C8 cycloalkyl “C3-C7 cycloalkyl”
  • C3-C6 cycloalkyl have similar meanings.
  • C3-C10 cycloalkenyl refers to a cyclic alkenyl group with 3 to 10 carbon atoms in the ring, including without limitation cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecylene, etc.
  • C3-C7 cycloalkenyl has a similar meaning.
  • aromatic ring or “aryl” has the same meaning, and preferably "aryl” is “C6-C12 aryl” or “C6-C10 aryl”.
  • aryl is “C6-C12 aryl” or “C6-C10 aryl”.
  • C6-C12 aryl refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.
  • C6-C10 aryl has a similar meaning.
  • aromatic heterocycle or “heteroaryl” have the same meaning and refer to heteroaromatic groups containing one to more heteroatoms.
  • Heteroatoms referred to here include oxygen, sulfur and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • 3-12-membered heterocyclyl refers to a saturated or unsaturated 3-12-membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen on the ring, for example Dioxolyl etc.
  • 3-7 membered heterocyclyl has a similar meaning.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as heterocycloalkyl can be linked to another ring, such as cycloalkyl, to form a spirobicyclic system, for example, both rings having a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, Heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, alkoxy, C1-10 sulfonyl, etc.
  • the present invention provides an ⁇ , ⁇ -unsaturated amide compound having the structure shown in Formula I below, or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or Their mixture:
  • R 1 , R 2 , R 3 and R 4 may each be independently selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1-C6 alkyl, substituted Or unsubstituted C1 ⁇ C6 alkoxy group, or (CHR 6 ) n R; wherein, the R is selected from the following group: substituted or unsubstituted C6 ⁇ C10 aryl group, substituted or unsubstituted 5-7 yuan heteroaryl, substituted or unsubstituted 5-7 membered heterocyclyl, substituted or unsubstituted C3 ⁇ C12 cycloalkyl or heterofused ring;
  • the ring is selected from the following group: C6-C10 aryl, 5-12-membered heteroaryl, 5-12-membered heterocyclyl, C3-C12 cycloalkyl or heterofused ring;
  • R 5 is located at 1, 2, 3, 4 or 5 substituents on the ring are selected from the following group: hydrogen, deuterium, tritium, halogen, cyano, amino, hydroxyl, nitro, substituted or unsubstituted C1 ⁇ C6 alkyl, Substituted or unsubstituted C1 ⁇ C6 alkoxy group, substituted or unsubstituted C6 ⁇ C10 aryl group, substituted or unsubstituted C6 ⁇ C10 aryloxy group, substituted or unsubstituted 5-7 membered heteroaryl group, substituted Or unsubstituted 5-7 membered heteroaryloxy group, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C3 ⁇ C12 cycloalkyl group;
  • the two R 5's on the same atom in the ring are connected end to end with 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(CH 2 ) n R 6 , O, or S;
  • n 0, 1, 2, or 3;
  • R 6 is 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 substituted or unsubstituted C2 ⁇ C10 acyl, substituted or unsubstituted 5-12 membered heteroatoms containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen C2 ⁇ C10 ester group, substituted or unsubstituted C1 ⁇ C6 amide group, -SO 2 R 5 , -COR 5 ;
  • 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 single ring , and the ring or condensed ring, the carbocyclic ring or heterocyclic ring includes a single ring, a ring, a spiro ring or a bridged ring;
  • substitution refers to being substituted by one or more (preferably 1-3) 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, 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.
  • 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.
  • the present invention also provides a preparation method of the compound represented by general formula I.
  • the preparation method is carried out according to the following scheme (example):
  • Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of a compound selected from the above-mentioned general formula I, its pharmaceutically acceptable salts, enantiomers, diastereomers or exosomes.
  • a pharmaceutical composition which contains a therapeutically effective amount of a compound selected from the above-mentioned general formula I, its pharmaceutically acceptable salts, enantiomers, diastereomers or exosomes.
  • the auxiliary materials are, for example, odorants, flavoring agents, sweeteners, etc.
  • the pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 1-99%.
  • the preferred ratio is that the compound of general formula I as the active ingredient accounts for 65wt%-99wt% of the total weight, and the remainder is pharmaceutically acceptable.
  • carrier, diluent or solution or salt solution is pharmaceutically acceptable.
  • 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, etc., and can be present in suitable solid or liquid carriers or diluents. Neutralize suitable for use in sterile equipment for injection or infusion.
  • the unit dosage of the preparation formula contains 1 mg-700 mg of the compound of general formula I.
  • the unit dosage of the preparation formula contains 25 mg-300 mg of the compound of general formula I.
  • the compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered through the oral, nasal, skin, lung or gastrointestinal tract. Oral administration is most preferred.
  • the most preferred daily dose is 50-1400 mg/kg body weight taken in one go, or 25-700 mg/kg body weight taken in divided doses. Regardless of the method of administration, the optimal dose for the individual will depend on the specific treatment. Usually, you start with a small dose and gradually increase the dose until you find the most suitable dose.
  • Another aspect of the present invention provides a method for improving cerebral blood flow, which includes a compound selected from the group consisting of the compound represented by the above general formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S- One or more of the isomers or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the compounds and compositions of the present invention are used for the treatment and prevention of neurodegenerative diseases and stroke related to cerebral blood flow, including, but not limited to, Alzheimer's disease, vascular dementia, and stroke.
  • Example 1 Determination of the activity of the compounds of the present invention on improving blood flow
  • the principle is to measure changes in light intensity of flowing blood through laser speckle technology, which reflects real-time cerebral blood flow; the effect of compounds on improving blood flow can be detected by comparing the changes in blood flow before and after administration to mice.
  • the experimental process is shown in Figure 1. After the experimental mouse was anesthetized for 30 seconds, it was fixed on the stand. After waiting for 2 minutes for the light intensity data baseline to stabilize, the brain blood flow light intensity data of the mouse was recorded for 10 minutes without medication. The test compound was then injected intraperitoneally, and the light intensity data of the mouse cerebral blood flow were recorded within 60 minutes after administration. Comparing the changes in light intensity before and after administration can determine the degree of changes in cerebral blood flow in mice.
  • Example 2 Determination of in vivo pharmacokinetic parameters of the compounds of the present invention
  • mice Male ICR (CD-1) mice were divided into 2 groups, with 3 mice in each group. Each group was administered 20 mg/kg test substance or intravenously injected 5 mg/kg test substance, respectively, before and after administration at 0.25 Blood was collected at h, 0.5h, 1h, 2h, 4h, 8h and 24h, and the plasma was immediately centrifuged, and the drug concentration in the plasma was determined by liquid chromatography-tandem mass spectrometry.
  • mice The pharmacokinetic parameters in mice are shown in the table below. In mice, the oral bioavailability of compounds 27 and 83 were 14.7% and 17.4%, respectively, indicating good pharmacokinetic properties.

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Abstract

本发明提供了一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途，具体地，本发明提供了一种如下式I所示的化合物，其中，各基团的定义如说明书中所述。所述的化合物可以作为改善脑血流的化合物，用于制备治疗阿尔茨海默病、血管性痴呆等神经退行性疾病以及脑卒中的药物组合物。

Description

一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途 技术领域
本发明涉及药物化学和医药领域，具体涉及一类α,β-不饱和酰胺类化合物、其制备方法、含此类化合物的药物组合物，用于治疗阿尔茨海默病、血管性痴呆等神经退行性疾病以及脑卒中的药物的用途。
背景技术
阿尔茨海默氏病(Alzheimer’s disease,AD)是一种退行性大脑疾病，约占老年人痴呆症中的2/3，主要症状为记忆进行性丧失、β-淀粉样蛋白沉积(β-Amyloid,Aβ)和神经纤维缠结(Neurofibrillary tangles，NFT)等。AD的病理机制十分复杂，现有上市药物仅能短暂减缓或控制AD症状，靶向疾病机理的治疗尚未发现有效的途径。衰老是AD的最主要风险因素，95％以上的AD患者都是晚发型的，发病年龄在65岁以上。只有不到5％的AD是早发型的，发病原因主要为遗传因素。心脑血管疾病也是AD的主要风险因素，血管改变可能贡献于AD的病理发生，而不仅仅是已知的血管病变导致的血管性痴呆。毛细血管作为大脑中最丰富和最小的血管单位，其诱导的脑血流量(Cerebral blood flow,CBF)或血脑屏障(Blood brain barrier,BBB)的损伤与AD的记忆衰退有关。
越来越多的研究发现在AD的早期以及正常衰老-轻度认知障碍(Mild cognitive impairment,MCI)中，存在脑血流量降低、脑血管反应性损伤和血液动力学反应受损。早期研究发现，大脑中动脉经颅多普勒测量显示，具有较高脑血流量速度的个体患痴呆症或海马和杏仁核萎缩的可能性较小。MCI或AD早期的病人动脉自旋标记(Arterial spinlabeling)MRI显示在后齿状回和前突中脑血流量降低。在患AD高风险的老年人中脑血流量降低或脑血流量失调发生于认知能力下降，脑萎缩和β-淀粉样蛋白积聚之前。APOE是AD主要的遗传风险因子，同时是血管病变的易感基因。在动物模型中在以人APOE4基因125-127靶向替代鼠载脂蛋白E4(APOE)的转基因小鼠中，也发现脑血流量降低和血管功能障碍，而且还发现表达APOE4的小鼠的血管表型先于神经元和突触功能障碍。灌注不足会诱发或加剧阿尔茨海默氏病样的神经元功能障碍和神经病理学改变。慢性血流量减少50％将导致显著的认知变化，人脑血流持续的减少超过20％就会导致注意力丧失，而大鼠脑血流超过30％就会损害空间记忆。脑血流量减少会降低Na+/K+泵的活性以及依赖于它的所有过程(包括维持静息电位和glutamate摄取)，它还会导致腺苷的产生，而腺苷会抑制谷氨酸的释放，进而影响神经元的功能。大鼠的双侧颈动脉阻塞会导致记忆障碍，神经元功能障碍，突触变化和β-淀粉样蛋白，从而导致神经毒性的β-淀粉样蛋白低聚物的积累。脑缺血、缺氧和Aβ沉积是相互影响的。灌注不足可触发Aβ加速沉积。Aβ反之会损伤脑血管功能，增加动脉血管收缩和降低脑血流量。在啮齿类动物，局部缺血导致神经元中高磷酸化Tau的积累和形成类似于人类神经退行性疾病和阿尔茨海默氏病中的纤维丝。灌注不足影响大脑的结构和功能变化，并提供了有希望的可能的生物标志物，可以潜在地识别诊断处于临床前状态的阿尔茨海默氏病。
毛细血管是大脑中最小的血管，从小动脉分支出来，形成了丰富的微血管网络，每克大脑的毛细血管最大表面积约为120cm2。毛细血管网络主要由内皮细胞，基底膜，周皮细胞，星形胶质细胞组成。在动物模型中已观察到毛细血管紊乱是痴呆症相关的神经退行性变化的先兆。AD的毛细血管收缩导致神经组织缺氧，这也可能是AD葡萄糖代谢下降的原因。而且缺血和缺氧已被证明可上调负责生成Aβ的酶β分泌酶(BACE1)。毛细血管血流主要通过周皮细胞调控，大量研究发现周皮细胞损伤与AD密切相关，在一些AD患者的大脑解剖样本中，周细胞的水平甚至会下降50％之多。周皮细胞缺陷转基因小鼠中，血流量降低，微血管减少，Aβ表达增加，血脑屏障通透性增加。许多神经病理学研究已经描述了在AD中脑毛细血管的形态改变以及类似于缺血性梗塞的脑室周围白质的病变。在晚期阿尔茨海默患者尸检研究显示脑内有大量毛细血管内皮细胞脱落，血管壁坍塌，密度减少。毛细血管由于其精细特殊的结构使其对损伤的易感性增加，毛细血管变性比血管淀粉样病变更频繁和普遍，潜在地表明AD脑微脉管系统的长期退化过程可能部分独立于淀粉样蛋白毒性。越来越多的研究表明血管因素是AD的主要危险因素，神经血管单元的损伤与AD相关。因此，寻找干预毛细血管提高脑血流可能对AD的预防及治疗有重要意义。
本发明提供一类靶向毛细血管提高脑血流，进而改善AD症状的目标化合物，用于临床阿尔茨海默病、血管性痴呆等神经退行性疾病以及脑卒中的治疗。
发明内容
本发明的一个目的在于提供一种通式I所示的α,β-不饱和酰胺类化合物或其药学上可接受的盐、外消旋体、R-异构体或S-异构体或它们的混合物。
本发明的另一个目的在于提供一种上述通式I所示的α,β-不饱和酰胺类化合物的制备方法。
本发明的又一个目的在于提供一种治疗与脑血流相关的阿尔茨海默病、血管性痴呆等神经退行性疾病以及脑卒中的药物的方法，其包括向需要该治疗的患者给药选自上述通式I的α,β-不饱和酰胺类化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种。
本发明的第一方面，提供了一种具有如下式I所示结构的α,β-不饱和酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
其中：
R1、R2、R3和R4可各自独立地选自下组：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、或(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂环基、取代或未取代的C3～C12环烷基或杂稠环；或R3和R4与相连的碳原子共同形成选自下组的基团：羰基、取代或未取代的3-8元环烷基，或取代或未取代的4-8元杂环基；
环选自下组：C6～C10芳基、5～12元的杂芳基、5～12元的杂环基、C3～C12环烷基或杂稠环；
R5为位于环上的1、2、3、4或5个选自下组的取代基：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的C6～C10芳氧基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂芳氧基、取代或未取代的5-7元的杂环、取代或未取代的C3～C12环烷基；
或两个相邻的R5与环上的原子首尾相连形成取代或未取代的4-8元环(即，与A环形成并环结构)；
或环上同一原子上的两个R5首尾相连与环形成取代或未取代的3-8元环(即，与A环形成螺环结构)；
X为N(CH2)nR6、O、或S；
n为0、1、2、或3；
R6独立地选自下组：氢、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的含有1～3个选自氧、硫和氮中的杂原子的5-12元的杂环取代或未取代的C2～C10酰基、取代或未取代的C2～C10酯基、取代或未取代的C1～C6酰胺基、-SO2R5、-COR5；
其中，除非特别说明，所述杂芳环、杂环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；所述的芳环或杂芳环包括单环、并环或稠环，所述的碳环或杂环包括单环、并环、螺环或桥环；
所述的取代指被一个或多个(优选地为1-3个)选自下组的取代基取代：卤素、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷氧基羰基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷基磺酰基、取代或未取代的C6-C10芳基、取代或未取代的5-7元的杂芳基、和3-12元杂环基；
所述的卤素为F、Cl、Br或I。
在另一优选例中，所述的环选自下组：C6～C10芳基、C5～C12的杂芳基。
在另一优选例中，所述的R1、R2、R3和R4各自独立地选自下组：氢、氘、取代或未取代的C1～C6烷基、或(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基；n为0、1或2；R6为氢、卤素，或取代或未取代的C1～C6烷基。
在另一优选例中，所述的R1、R2、R3和R4各自独立地选自下组：氢、氘、取代或未取代的C1～C6烷基、(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基。
在另一优选例中，所述的R3和R4各自独立地选自下组：氢、氘、取代或未取代的C1-C6烷基。
在另一优选例中，所述的R1为H或D，且R2选自下组：氢、氘、取代或未取代的C1～C6烷基、(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、 取代或未取代的5-7元的杂芳基；所述的取代指被一个或多个选自下组的取代基取代：卤素、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷氧基羰基。
在另一优选例中，所述的R3和R4各自独立地为氘。
在另一优选例中，所述的R1和R2各自独立地为氘。
在另一优选例中，所述的式I的化合物为各个实施例中所述的化合物。
本发明的第二方面，提供了一种如本发明第一方面所述的式I化合物的制备方法，所述方法包括步骤：
在惰性溶剂中，用式II化合物和式III化合物反应，得到式I化合物。
在另一优选例中，所述的反应在有机胺和特戊酰氯存在下进行。
在另一优选例中，所述的有机胺为三乙胺。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
本发明的第四方面，提供了如本发明第一方面所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如权利要求9所述的药物组合物的用途，其用于制备预防和/或治疗神经退行性疾病或脑卒中的药物组合物。
在另一优选例中，所述的神经退行性疾病选自下组：阿尔茨海默病、血管性痴呆。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为药理活性实验实施例1的激光散斑测试血流量模型流程图；
图2为本发明化合物的血流改善效果图。
具体实施方式
本发明人经过长期而深入的研究，提供了一种可以用于阿尔兹海莫病等神经退行性疾病的α,β-不饱和酰胺类化合物。所述的化合物可以有效改善毛细血管脑血流。基于上述发现，发明人完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限 制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中，术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基、烷氧基、C1-10磺酰基等。
式I化合物
本发明提供了一种具有如下式I所示结构的α,β-不饱和酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：

其中：
R1、R2、R3和R4可各自独立地选自下组：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、或(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂环基、取代或未取代的C3～C12环烷基或杂稠环；
环选自下组：C6～C10芳基、5～12元的杂芳基、5～12元的杂环基、C3～C12环烷基或杂稠环；
R5为位于环上的1、2、3、4或5个选自下组的取代基：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的C6～C10芳氧基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂芳氧基、取代或未取代的5-7元的杂环、取代或未取代的C3～C12环烷基；
或两个相邻的R5与环上的原子首尾相连形成取代或未取代的4-8元环(即，与A环形成并环结构)；
或环上同一原子上的两个R5首尾相连与环形成取代或未取代的3-8元环(即，与A环形成螺环结构)；
X为N(CH2)nR6、O、或S；
n为0、1、2、或3；
R6独立地选自下组：氢、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的含有1～3个选自氧、硫和氮中的杂原子的5-12元的杂环取代或未取代的C2～C10酰基、取代或未取代的C2～C10酯基、取代或未取代的C1～C6酰胺基、-SO2R5、-COR5；
其中，除非特别说明，所述杂芳环、杂环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；所述的芳环或杂芳环包括单环、并环或稠环，所述的碳环或杂环包括单环、并环、螺环或桥环；
所述的取代指被一个或多个(优选地为1-3个)选自下组的取代基取代：卤素、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷氧基羰基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C1-C6烷基磺酰基、取代或未取代的C6-C10芳基、取代或未取代的5-7元的杂芳基、和3-12元杂环基；
所述的卤素为F、Cl、Br或I。
在一个优选的实施方式下，R1、R2、R3、R4、R5、R6、环、X、O、S或n各自独立地为各实施例中化合物所对应的基团。
式I化合物的制备方法
本发明还提供了一种通式I表示的化合物的制备方法，该制备方法按照如下方案进行(示例)：
式(I)化合物可以通过以下方案1所示的方法制备
以下方案中使用的结构式和R基团标号仅在本部分使用。式(II)化合物和式(III)化合物可市场上获得或可使用本领域的常规技术合成。
方案一：
药物组合物
本发明的另一方面提供了一种药物组合物，其含有治疗有效量的选自上述通式I的化合物、其可药用的盐、对映异构体、非对映异构体或外消旋体中的一种或多种，以及任选地，一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。所述辅料例如为气味剂、香味剂、甜味剂等。
本发明所提供的药物组合物优选含有重量比为1-99％的活性成份，其优选的比例是，通式I化合物作为活性成分占总重量的65wt％～99wt％，其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含1mg-700mg通式I化合物，优选地，制剂配方的单位计量中包含25mg-300mg通式I化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为50-1400mg/kg体重，一次性服用，或25-700mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明的又一方面提供了一种旨在提高脑血流，其包含选自上述通式I所示的化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及任选地一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的化合物和组合物用于治疗和预防与脑血流相关的神经退行性疾病、脑卒中，所述疾病包括，但不限于，阿尔茨海默病、血管性痴呆和脑卒中等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1(E)-3-(3-(邻甲苯基)丙烯酰)噁唑烷-2-酮
将化合物(E)-3-(邻甲苯基)丙烯酸1a(400.0mg,2.47mmol)和三乙胺(685.6μL,4.93mmol)溶解于超干二氯甲烷中，氩气保护，于-78℃条件下加入特戊酰氯(364.5μL,2.96mmol)，移至室温搅拌1小时，再于-78℃条件下加入噁唑烷-2-酮(214.8mg,2.47mmol)和氯化锂(104.5mg,2.47mmol)，室温搅拌12小时，TLC监测反应完全后，加水淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得目标产物(E)-3-(3-(邻甲苯基)丙烯酰)噁唑烷-2-酮(490mg，白色固体)，产率85.9％。1H 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]+。
实施例2(E)-3-(3-(间甲苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(间甲苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(间甲苯基)丙烯酰)噁唑烷-2-酮(产率82.1％)。1H 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]+。
实施例3(E)-3-(3-(对甲苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(对甲苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(对甲苯基)丙烯酰)噁唑烷-2-酮(产率85.2％)。1H 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]+。
实施例4(E)-3-(3-(2-甲氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-甲氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-甲氧基苯基)丙烯酰)噁唑烷-2-酮(产率87.2％)。1H 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]+。
实施例5(E)-3-(3-(3-甲氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-甲氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-甲氧基苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例6(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-甲氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮(产率82.7％)。1H 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]+。
实施例7(E)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率81.5％)。1H 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]+。
实施例8(E)-3-(3-(3-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-三氟甲基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率80.3％)。1H 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]+。
实施例9(E)-3-(3-(4-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-三氟甲基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率85.6％)。1H 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]+。
实施例10(E)-3-(3-(2-氟苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-氟苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-氟苯基)丙烯酰)噁唑烷-2-酮(产率92.1％)。1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝16.0Hz,1H),7.77(d,J＝16.0Hz,1H),7.79–7.72(m,1H),7.58–7.47(m,1H),7.42–7.26(m,2H),4.50–4.37(m,2H),4.01(m,2H).LRMS(ESI):236.06[M+H]+。
实施例11(E)-3-(3-(4-氟苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-氟苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-氟苯基)丙烯酰)噁唑烷-2-酮(产率89.0％)。1H 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]+。
实施例12(E)-3-(3-(4-氯苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-氯苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-氯苯基)丙烯酰)噁唑烷-2-酮(产率91.1％)。1H 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]+。
实施例13(E)-3-(3-(2-溴苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-溴苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-溴苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例14(E)-3-(3-(4-溴苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-溴苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-溴苯基)丙烯酰)噁唑烷-2-酮(产率91.1％)。1H 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]+。
实施例15(E)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例16(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮(产率82.7％)。1H 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]+。
实施例17(E)-3-(3-(4-苯氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-苯氧基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-苯氧基苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例18(E)-3-(3-([1,1'-联苯基]-2-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-2-基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯基]-2-基)丙烯酰)噁唑烷-2-酮(产率86.7％)。1H 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]+。
实施例19(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮(产率88.3％)。1H 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]+。
实施例20(E)-3-(3-(4-氟-2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-氟-2-三氟甲基苯基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-氟-2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率81.0％)。1H NMR(400MHz,Chloroform-d)δ8.15(dq,J＝15.6,2.3Hz,1H),7.91–7.78(m,2H),7.42(dd,J＝8.8,2.7Hz,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]+。
实施例21(E)-3-(3-(萘-1-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(萘-1-基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(萘-1-基)丙烯酰)噁唑烷-2-酮(产率87.1％)。1H 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]+。
实施例22(E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰)噁唑烷-2-酮(产率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]+.
实施例23(E)-3-(3-(噻吩-2-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(噻吩-2-基)丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(噻吩-2-基)丙烯酰)噁唑烷-2-酮(产率87.4％)。1H 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]+。
实施例24(E)-3-(3-环己基丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-环己基丙烯酸，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-环己基丙烯酰)噁唑烷-2-酮(产率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]+。
实施例26(E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮(产率89.9％)。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]+。
实施例27(S,E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮(产率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]+。
实施例28(R,E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(R)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(R,E)-3-(3-(2-三氟甲基苯基)丙烯酰)-4-苯基噁唑烷-2-酮(产率90.4％)。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]+。
实施例29(S,E)-4-苯基-3-(3-(3-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-(3-(三氟甲氧基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(3-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮。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(ddd,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]+.
实施例30(S,E)-4-苯基-3-(3-(2-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-(2-(三氟甲氧基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(2-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮。1H 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]+.
实施例31(S,E)-4-苯基-3-(3-(4-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-(4-(三氟甲氧基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(4-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮。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]+.
实施例32(S,E)-3-(3-(2-苯氧基苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(2-苯氧基苯基)丙烯酰)-4-苯基噁唑烷-2-酮(产率90.1％)。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＝8.6,3.9Hz,1H),4.79(t,J＝8.7Hz,1H),4.20(dd,J＝8.7,3.9Hz,1H).LRMS(ESI):386.13[M+H]+。
实施例33(R,E)-3-(3-(2-苯氧基苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(R)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(R,E)-3-(3-(2-苯氧基苯基)丙烯酰)-4-苯基噁唑烷-2-酮(产率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＝8.6,3.9Hz,1H),4.79(t,J＝8.7Hz,1H),4.20(dd,J＝8.7,3.9Hz,1H).LRMS(ESI):386.13[M+H]+。
实施例34(E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮(产率86.9％)。1H 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]+
实施例35(S,E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮(产率89.6％)。1H 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]+。
实施例36(R,E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为(R)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(R,E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮(产率88.9％)。1H 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]+。
实施例37(S,E)-3-(3-(4'-氟-[1,1'-联苯]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4'-氟-[1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(4'-氟-[1,1'-联苯]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮(产率78.1％)。1H 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]+。
实施例38(S,E)-4-苯基-3-(3-(3-(吡啶-3-基)苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-(吡啶-3-基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(3-(吡啶-3-基)苯基)丙烯酰)噁唑烷-2-酮(产率67.1％)。1H 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),7.61(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]+。
实施例39(S,E)-4-苯基-3-(3-(3-(吡啶-4-基)苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-(吡啶-4-基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(3-(吡啶-4-基)苯基)丙烯酰)噁唑烷-2-酮(产率65.5％)。1H 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＝7.6Hz,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]+。
实施例40(S,E)-4-苯基-3-(3-(3-(噻吩-2-基)苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-(噻吩-2-基)苯基)丙烯酸，将噁唑烷-2-酮替 换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(3-(噻吩-2-基)苯基)丙烯酰)噁唑烷-2-酮(产率87.8％)。1H 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),7.36–7.26(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]+。
实施例41(S,E)-4-苯基-3-(3-(5-苯基噻吩-2-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(5-苯基噻吩-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(5-苯基噻吩-2-基)丙烯酰)噁唑烷-2-酮(产率91.3％)。1H 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]+。
实施例42(S,E)-4-苯基-3-(3-(4-苯基噻吩-2-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-苯基噻吩-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(4-苯基噻吩-2-基)丙烯酰)噁唑烷-2-酮(产率92.1％)。1H 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]+。
实施例43(S,E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-4-氟-2-(三氟甲基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4-苯基噁唑烷-2-酮。1H 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]+.
实施例44(S,E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4-苯基噁唑烷-2-酮。1H 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]+.
实施例45(S,E)-3-(3-(2-氯喹啉-4-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-氯喹啉-4-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(2-氯喹啉-4-基)丙烯酰)-4-苯基噁唑烷-2-酮。1H 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]+.
实施例46(S,E)-3-(3-(苯并呋喃-2-基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并呋喃-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并呋喃-2-基)丙烯酰基)-4-苯基噁唑烷-2-酮。1H 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]+.
实施例47(S,E)-3-(3-(苯并呋喃-7-基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并呋喃-7-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并呋喃-7-基)丙烯酰基)-4-苯基噁唑烷-2-酮。1H NMR(400MHz,Chloroform-d)δ7.97(d,J＝15.7Hz,1H),7.92(d,J＝15.7Hz,1H),7.86(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]+.
实施例48(S,E)-3-(3-(萘-1-基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(萘-1-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(萘-1-基)丙烯酰基)-4-苯基噁唑烷-2-酮。1H 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]+.
实施例49(S,E)-3-(3-(苯并[b]噻吩-2-基)丙烯酰)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[b]噻吩-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并噻吩-2-基)丙烯酰)-4-苯基噁唑烷-2-酮。1H 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＝21.3,8.2,7.0Hz,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]+.
实施例50(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮 替换为4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):380.08[M+H]+.
实施例51(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):380.08[M+H]+.
实施例52(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):396.08[M+H]+.
实施例53(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):396.08[M+H]+.
实施例54(E)-4-(4’-氟苯基)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-(4’-氟苯基)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):404.12[M+H]+.
实施例55(S,E)-4-(4’-氟苯基)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮。LRMS(ESI):404.12[M+H]+.
实施例56(E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-(4’-氟苯基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为4-(4’-氟苯基)噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-(4’-氟苯基)噁唑烷-2-酮。LRMS(ESI):388.13[M+H]+.
实施例57(E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4-苄基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率86.9％)。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]+。
实施例58(S,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苄基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率86.9％)。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]+。
实施例59(R,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(R)-4-苄基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(R,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例60(E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-苄基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为4-苄基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-苄基噁唑烷-2-酮(产率79.0％)。1H 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),7.36–7.30(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]+。
实施例61(S,E)-4-异丙基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮。1H NMR(400MHz,Chloroform-d)δ8.22(dq,J＝15.5,2.3Hz,1H),7.92(d,J＝15.5Hz,1H),7.86(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]+.
实施例62(S,E)-4-异丙基-3-(3-(4-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(4-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮。LRMS(ESI):328.11[M+H]+.
实施例63(S,E)-4-异丙基-3-(3-(3-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(3-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮。LRMS(ESI):328.11[M+H]+.
实施例64(S,E)-4-异丙基-3-(3-(3-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(3-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮。1H 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),2.46(pt,J＝7.0,3.5Hz,1H),0.94(dd,J＝17.4,7.0Hz,6H)；LRMS(ESI):344.10[M+H]+.
实施例65(S,E)-4-异丙基-3-(3-(2-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(2-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮。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]+.
实施例66(S,E)-4-异丙基-3-(3-(4-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(4-三氟甲氧基苯基)丙烯酰基)噁唑烷-2-酮。LRMS(ESI):344.10[M+H]+.
实施例67(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-异丙基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-异丙基噁唑烷-2-酮。LRMS(ESI):336.15[M+H]+.
实施例68(S,E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4-异丙基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-氟-2-(三氟甲基)苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4-异丙基噁唑烷-2-酮。1H 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(dd,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]+.
实施例69(S,E)-3-(3-(苯并呋喃-2-基)丙烯酰基)-4-异丙基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并呋喃-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并呋喃-2-基)丙烯酰基)-4-异丙基噁唑烷-2-酮。1H 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]+.
实施例70(S,E)-3-(3-(苯并[b]噻吩-2-基)丙烯酰基)-4-异丙基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[b]噻吩-2-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并[b]噻吩-2-基)丙烯酰基)-4-异丙基噁唑烷-2-酮。1H 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]+.
实施例71(S,E)-4-异丙基-3-(3-(萘-1-基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(萘-1-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-异丙基-3-(3-(萘-1-基)丙烯酰)噁唑烷-2-酮。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,1H),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]+.
实施例72(S,E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4-异丙基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4-异丙基噁唑烷-2-酮。1H NMR(400MHz,Chloroform-d)δ7.77(d,J＝0.9Hz,2H),7.15(d,J＝1.7Hz,1H),7.10(dd,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]+.
实施例73(E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4,4-二甲基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(苯并[d][1,3]二氧杂环戊烷-5-基)丙烯酰基)-4,4-二甲基噁唑烷-2-酮。1H 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(dd,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]+.
实施例74(E)-4,4-二甲基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4,4-二甲基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮。1H 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]+.
实施例75(E)-4,4-二甲基-3-(3-(3-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4,4-二甲基-3-(3-(3-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮。1H 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]+.
实施例76(E)-4,4-二甲基-3-(3-(2-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-4,4-二甲基-3-(3-(2-(三氟甲氧基)苯基)丙烯酰基)噁唑烷-2-酮。1H 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]+.
实施例77(E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4,4-二甲基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-氟-2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-氟-2-(三氟甲基)苯基)丙烯酰)-4,4-二甲基噁唑烷-2-酮。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＝15.5Hz,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]+.
实施例78(E)-3-(3-([1,1’-联苯基]-3-基)丙烯酰)噻唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1’-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为噻唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1’-联苯基]-3-基)丙烯酰)噻唑烷-2-酮(产率89.0％)。1H 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,1H),3.70(t,J＝6.1Hz,2H),3.55(t,J＝6.0Hz,2H).LRMS(ESI):310.08[M+H]+。
实施例79(E)-3-(3-(2-苯氧基苯基)丙烯酰)噻唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噻唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-苯氧基苯基)丙烯酰)噻唑烷-2-酮(产率89.6％)。1H 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]+。
实施例80(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噻唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为噻唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噻唑烷-2-酮(产率90.6％)。1H 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]+。
实施例81(E)-3-(3-(噻吩-2-基)丙烯酰)噻唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(噻吩-2-基)丙烯酸，将噁唑烷-2-酮替换为噻唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(噻吩-2-基)丙烯酰)噻唑烷-2-酮(产率85.1％)。1H 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]+。
实施例83(S,E)-4-苯基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H 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]+。
实施例84(S,E)-4-苯基-3-(3-(2-三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(2-三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝15.0Hz,1H),7.70–7.60(m,2H),7.39–7.28(m,4H),7.28–7.18(m,2H),7.02(t,J＝7.1Hz,2H),5.50(s,1H).LRMS(ESI):380.11[M+H]+。
实施例85(S,E)-4-苯基-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为 (S)-4-苯基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(2-苯氧基苯基)丙烯酰)噁唑烷-2-酮-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]+。
实施例86(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-异丙基噁唑烷-2-酮，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-苯基噁唑烷-2-酮-5,5-d2。1H 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]+.
实施例87(S,E)-4-苯基-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苯基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苯基-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-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]+。
实施例88(E)-4-苯基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4-苯基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-苯基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H 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]+。
实施例89(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4。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),7.27–7.19(m,1H).LRMS(ESI):290.09[M+H]+。
实施例90(E)-3-(3-(2-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4。1H 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]+。
实施例91(E)-3-(3-(3-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4。1H 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]+。
实施例92(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-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]+。
实施例93(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4。1H 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),7.54–7.43(m,4H),7.43–7.32(m,2H).LRMS(ESI):298.13[M+H]+。
实施例94(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4,5,5-d4，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-4,4,5,5-d4。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＝4.1,2.1Hz,2H).LRMS(ESI):314.13[M+H]+。
实施例95(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-4,4-d2。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),4.30(s,2H),3.79(s,3H).LRMS(ESI):250.10[M+H]+。
实施例96(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(4-甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(4-甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H 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]+。
实施例97(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-4,4-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-4,4-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-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]+。
实施例98(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(3-苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-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),3.80(s,2H).LRMS(ESI):312.12[M+H]+。
实施例99(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-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]+。
实施例100(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯基]-3-基)丙烯酸，将噁唑烷-2-酮替换为噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-3-(3-([1,1'-联苯基]-3-基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝15.0Hz,1H),7.73(dq,J＝8.3,2.1Hz,3H),7.62(dt,J＝7.6,2.1Hz,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]+。
实施例101(E)-4,4-二甲基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4,4-二甲基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-4,4-二甲基-3-(3-(2-(三氟甲基)苯基)丙烯酰基)噁唑烷-2-酮-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]+。
实施例102(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例103(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例104(E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为4-苄基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例105(S,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-苄基噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-苄基-3-(3-(2-三氟甲基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例106(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-三氟甲氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-(三氟甲氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2。1H 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]+.
实施例107(S,E)-4-(4’-氟苯基)-3-(3-(2-(苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(2-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(2-(苯氧基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例108(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-3-基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-([1,1'-联苯]-3-基)丙烯酰)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2。1H 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]+.
实施例109(S,E)-4-(4’-氟苯基)-3-(3-(3-(苯氧基苯基)丙烯酰)噁唑烷-2-酮-5,5-d2
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(3-苯氧基苯基)丙烯酸，将噁唑烷-2-酮替换为(S)-4-(4’-氟苯基)噁唑烷-2-酮-5,5-d2，其余所需原料、试剂及制备方法同实施例1，得到(S,E)-4-(4’-氟苯基)-3-(3-(3-(苯氧基苯基)丙烯酰)噁唑烷-2-酮-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]+.
实施例110(R,E)-5,5-二甲基-4-苯基-3-(3-(2-(三氟甲基)苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(邻三氟甲基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-5,5-二甲基-4-苯基噁唑烷-2-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-5,5-二甲基-4-苯基-3-(3-(2-(三氟甲基)苯基)丙烯酰)噁唑烷-2-酮(产率64.2％)。1H 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]+。
实施例111(S,E)-5,5-二甲基-4-苯基-3-(3-(2-(三氟甲基)苯基)丙烯酰)噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(邻三氟甲基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-5,5-二甲基-4-苯基噁唑烷-2-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-5,5-二甲基-4-苯基-3-(3-(2-(三氟甲基)苯基)丙烯酰)噁唑烷-2-酮(产率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]+。
实施例112(R,E)-7-苯基-6-(3-(2-(三氟甲基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(邻三氟甲基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-7-苯基-6-(3-(2-(三氟甲基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率49.2％)。1H 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]+。
实施例113(S,E)-7-苯基-6-(3-(2-(三氟甲基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4] 庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(邻三氟甲基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-7-苯基-6-(3-(2-(三氟甲基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率47.2％)。1H 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]+。
实施例114(E)-5-苯基-1-(3-(2-(三氟甲基)苯基)丙烯酰基)咪唑烷-2,4-二酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(间甲氧苯基)，噁唑烷-2-酮替换为5-苯基咪唑烷-2,4-二酮其余所需原料、试剂及制备方法同实施例1，得到(E)-5-苯基-1-(3-(2-(三氟甲基)苯基)丙烯酰基)咪唑烷-2,4-二酮(产率62.8％)。1H 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),7.67–7.62(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]+。
实施例115(R,E)-6-(3-(3-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-6-(3-(3-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率43.2％)。1H 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]+。
实施例116(S,E)-6-(3-(3-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-6-(3-(3-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率48.2％)。1H 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]+。
实施例117(R,E)-6-(3-(3-苯氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-6-(3-(3-苯氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率51.1％)。1H 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]+。
实施例118(S,E)-6-(3-(3-苯氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(苯氧基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-6-(3-(3-苯氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率48.1％)。1H 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]+。
实施例119(R,E)-7-苯基-6-(3-(2-(三氟甲氧基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(三氟甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-7-苯基-6-(3-(2-(三氟甲氧基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率34.2％)。1H 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,1H),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]+。
实施例120(S,E)-7-苯基-6-(3-(2-(三氟甲氧基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(三氟甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-7-苯基-6-(3-(2-(三氟甲氧基)苯基)丙烯酰基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率36.5％)。1H 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),7.23(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]+。
实施例121(R,E)-6-(3-(4-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-4-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-6-(3-(4-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率41.9％)。1H 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]+。
实施例122(S,E)-6-(3-(4-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-4-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-6-(3-(4-甲氧基苯基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率41.9％)。1H 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]+。
实施例123(R,E)-6-(3-([1,1'-联苯]-4-基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-4-基)丙烯酸，噁唑烷-2-酮替换为(R)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(R,E)-6-(3-([1,1'-联苯]-4-基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率33.2％)。1H 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]+。
实施例124(S,E)-6-(3-([1,1'-联苯]-4-基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-([1,1'-联苯]-4-基)丙烯酸，噁唑烷-2-酮替换为(S)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-6-(3-([1,1'-联苯]-4-基)丙烯酰基)-7-苯基-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(产率33.2％)。1H 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]+。
实施例125(S,E)-3-(3-(4-甲氧基苯基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-4-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-4-苯基噁唑烷-2-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(4-甲氧基苯基)丙烯酰基)-4-苯基噁唑烷-2-酮(产率48.2％)。1H 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]+。
实施例126(S,E)-3-(3-(3-甲氧基苯基)丙烯酰基)-4-苯基噁唑烷-2-酮
将(E)-3-(邻甲苯基)丙烯酸替换为(E)-3-(甲氧基苯基)丙烯酸，噁唑烷-2-酮替换为(R)-4-苯基噁唑烷-2-酮其余所需原料、试剂及制备方法同实施例1，得到(S,E)-3-(3-(3-甲氧基苯基)丙烯酰基)-4-苯基噁唑烷-2-酮(产率46.2％)。1H 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]+。
药理活性试验实施例
实施例1.本发明化合物对血流改善的活性测定
我们采用激光散斑测试血流量模型对化合物进行小鼠脑部血流改善的活性测试。其原理是通过激光散斑技术测量流动血液的光强变化，反映实时脑血流量；通过比较小鼠给药前后血流量变化程度可以检测化合物改善血流效果。
实验过程如图1中所示，将实验小鼠气麻30s后固定到架上，等待2分钟光强数据基线稳定，开始记录10分钟小鼠未给药时脑血流量光强度数据。随后通过腹腔注射测试化合物，并记录给药后60分钟内小鼠脑血流量光强度数据。比较给药前后光强度变化可以获知小鼠脑血流量变化程度。
通过上述激光散斑模型，我们对实施例化合物进行了初步的小鼠脑部血流改善活性的测试，在本试验中采用阿魏酸(FA)作为阳性对照。化合物的血流改善效果见附图2，多个化合物在此模型中表现出对脑血流的明显改善作用，在5mg/kg剂量下，化合物9可使小鼠脑血流量提升约10％，化合物16可提升约20％。在20mg/kg剂量下，化合物30和59可使小鼠脑血流量提升约10％，化合物5、6、26、28、29、35、43和58均可使小鼠脑血流量提升约20％，化合物16、57和86可使小鼠脑血流量提升约30％，化合物27、84和104可提升约40％，化合物83可使小鼠脑血流量提升50％～60％。总体而言，本专利化合物具有良好的发展前景。
实施例2.本发明化合物体内药动学参数的测定
雄性ICR(CD-1)小鼠分为2组，每组3只，各组分别灌胃20mg/kg受试物或静脉注射5mg/kg受试物，分别在给药前、给药后0.25h、0.5h、1h、2h、4h、8h及24h取血，立即离心取血浆，以液相色谱-串联质谱法测定血浆中的药物浓度。
小鼠体内的药动学参数如下表所示。在小鼠体内，化合物27和83的口服生物利用度分别为14.7％和17.4％，具有良好的药代性质。
表2.化合物27和83在小鼠体内的药动学参数
另外，通过测定该化合物在脑组织的药物，发现该化合物具有良好的血脑屏障通透性，如表3所示，化合物27经小鼠口服后具有良好的脑组织药物分布，B/P约为0.7。
表3.脑组织的药物浓度测定
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种具有如下式I所示结构的α,β-不饱和酰胺类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
    其中：
    R1、R2、R3和R4可各自独立地选自下组：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、或(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂环基、取代或未取代的C3～C12环烷基或杂稠环；或R3和R4与相连的碳原子共同形成选自下组的基团：羰基、取代或未取代的3-8元环烷基，或取代或未取代的4-8元杂环基；
    环选自下组：C6～C10芳基、5～12元的杂芳基、5～12元的杂环基、C3～C12环烷基或杂稠环；
    R5为位于环上的1、2、3、4或5个选自下组的取代基：氢、氘、氚、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的C6～C10芳氧基、取代或未取代的5-7元的杂芳基、取代或未取代的5-7元的杂芳氧基、取代或未取代的5-7元的杂环、取代或未取代的C3～C12环烷基；
    或两个相邻的R5与环上的原子首尾相连形成取代或未取代的4-8元环(即，与A环形成并环结构)；
    或环上同一原子上的两个R5首尾相连与环形成取代或未取代的3-8元环(即，与A环形成螺环结构)；
    X为N(CH2)nR6、O、或S；
    n为0、1、2、或3；
    R6独立地选自下组：氢、卤素、氰基、氨基、羟基、硝基、取代或未取代的C1～C6烷基、取代或未取代的C1～C6烷氧基、取代或未取代的C6～C10芳基、取代或未取代的含有1～3个选自氧、硫和氮中的杂原子的5-12元的杂环取代或未取代的C2～C10酰基、取代或未取代的C2～C10酯基、取代或未取代的C1～C6酰胺基、-SO2R5、-COR5；
    其中，除非特别说明，所述杂芳环、杂环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；所述的芳环或杂芳环包括单环、并环或稠环，所述的碳环或杂环包括单环、并环、螺环或桥环；
    所述的取代指被一个或多个(优选地为1-3个)选自下组的取代基取代：卤素、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷氧基羰基、C2-C6烯基、C2-C6炔基、 C3-C8环烷基、C1-C6烷基磺酰基、取代或未取代的C6-C10芳基、取代或未取代的5-7元的杂芳基、和3-12元杂环基；
    所述的卤素为F、Cl、Br或I。
  2. 如权利要求1所述的α,β-不饱和酰胺类化合物，其特征在于，所述的环选自下组：C6～C10芳基、C5～C12的杂芳基。
  3. 如权利要求1所述的α,β-不饱和酰胺类化合物，其特征在于，所述的R1、R2、R3和R4各自独立地选自下组：氢、氘、取代或未取代的C1～C6烷基、或(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基；n为0、1或2；R6为氢、卤素，或取代或未取代的C1～C6烷基。
  4. 如权利要求1或2所述的α,β-不饱和酰胺类化合物，其特征在于，所述的R1、R2、R3和R4各自独立地选自下组：氢、氘、取代或未取代的C1～C6烷基、(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基。
  5. 如权利要求1或2所述的α,β-不饱和酰胺类化合物，其特征在于，所述的R1为H或D，且R2选自下组：氢、氘、取代或未取代的C1～C6烷基、(CHR6)nR；其中，所述的R选自下组：取代或未取代的C6～C10芳基、取代或未取代的5-7元的杂芳基；所述的取代指被一个或多个选自下组的取代基取代：卤素、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C1-C6烷氧基羰基。
  6. 如权利要求1或2所述的α,β-不饱和酰胺类化合物，其特征在于，所述的R3和R4各自独立地为氘。
  7. 如权利要求1所述的α,β-不饱和酰胺类化合物，其特征在于，所述的式I的化合物选自下表：











  8. 如权利要求1所述的式I化合物的制备方法，其特征在于，所述方法包括步骤：
    在惰性溶剂中，用式II化合物和式III化合物反应，得到式I化合物。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括(1)如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物；(2)药学上可接受的载体。
  10. 如权利要求1所述的化合物或其立体异构体或互变异构体，或其药学上可接受的盐、水合物或溶剂化物，或如权利要求9所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗神经退行性疾病或脑卒中的药物组合物；较佳地，所述的神经退行性疾病选自下组：阿尔茨海默病、血管性痴呆。
PCT/CN2023/106181 2022-07-06 2023-07-06 一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途 WO2024008166A1 (zh)

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