WO2018148863A1 - N-(5-吗啉代噻唑-2-基)甲酰胺类化合物及其制备方法和用途 - Google Patents

N-(5-吗啉代噻唑-2-基)甲酰胺类化合物及其制备方法和用途 Download PDF

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WO2018148863A1
WO2018148863A1 PCT/CN2017/073472 CN2017073472W WO2018148863A1 WO 2018148863 A1 WO2018148863 A1 WO 2018148863A1 CN 2017073472 W CN2017073472 W CN 2017073472W WO 2018148863 A1 WO2018148863 A1 WO 2018148863A1
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morpholinothiazol
compound
group
alkyl
substituted
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PCT/CN2017/073472
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French (fr)
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李剑
沈旭
蒋华良
朱进
邱晓霞
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华东理工大学
中国科学院上海药物研究所
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Priority to CN201780083160.9A priority Critical patent/CN110198937A/zh
Priority to PCT/CN2017/073472 priority patent/WO2018148863A1/zh
Publication of WO2018148863A1 publication Critical patent/WO2018148863A1/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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • 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
    • A61K31/427—Thiazoles 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to the field of medicinal chemistry and pharmacotherapy, in particular to a class of N-(5-morpholinothiazol-2-yl)carboxamides, a preparation method thereof and a pharmacological use thereof, which can be used as an anti-Alzhai Silent drugs.
  • AD Alzheimer's Disease
  • a ⁇ amyloid beta Protein precipitation
  • neurofibrillary tangles caused by hyperphosphorylation of Tau protein
  • neuronal apoptosis are the main markers.
  • the main clinical manifestations of AD are deteriorating cognitive and memory functions, progressive decline in daily living ability, and various neuropsychiatric and behavioral disorders. In the early stage, the main manifestations were recent memory loss and personality changes. The mid-term manifestations were irritability, panic, sleep disorders, and even hallucinations. In the late stage, the main manifestations were loss of logical thinking, bedridden, and self-care.
  • AD Alzheimer's Association
  • AD treatments are only acetylcholinesterase (AChE) inhibitors (tacrine, donepezil, lissamine, galantamine, and huperzine) and N-methyl-D-aspartate.
  • AChE acetylcholinesterase
  • NMDA N-methyl-D-aspartate
  • NMDA receptor antagonists are two major categories.
  • these drugs can partially alleviate the symptoms of AD and improve the cognitive dysfunction of patients to a certain extent, they cannot fully restore their daily behavioral ability, nor can they fundamentally treat the disease or terminate the progression of AD. Therefore, there is an urgent need for the discovery of novel anti-AD drugs that can block the pathological process of AD.
  • AD Alzheimer's disease
  • a ⁇ is one of the main components of senile plaques. It is produced by the amyloid precursor protein (APP) by ⁇ -secretase and ⁇ -secretase. It is excessively increased in the brain tissue and causes the nervous system to produce oxidation. Excitability, inflammatory response, etc. eventually lead to neuronal apoptosis and the occurrence of AD. Therefore, it is generally believed that reducing the content of A ⁇ in the whole brain by inhibiting the production of A ⁇ or promoting the clearance of A ⁇ will effectively prevent or treat AD, and this is one of the main research and development directions of new anti-AD drugs.
  • APP amyloid precursor protein
  • a ⁇ in the body is the result of the joint action of A ⁇ production and A ⁇ clearance. Under normal physiological conditions, both can maintain one. A state of equilibrium, and once A ⁇ is hyperactive or A ⁇ clearance is inhibited, A ⁇ is accumulated in the body.
  • autophagy is considered to be an important pathway in A ⁇ clearance and is regulated by a variety of upstream proteins. The study is more in-depth to demonstrate the negative regulation of AKT/mTOR pathway on autophagy and the AMPK/Raptor pathway pair. The positive regulation of autophagy.
  • AKT AKT protein kinase kinase
  • mTOR phosphorylation level of mTOR
  • ULK1 phosphorylation ULK1 phosphorylation
  • autophagy regulatory protein disorder has also appeared, such as excessive activation of AKT. Therefore, promoting autophagy by regulating multiple target proteins upstream of autophagy will be a new therapeutic strategy.
  • Neurofibrillary tangles are another characteristic pathological change in AD, and the number of neurofibrillary tangles is also considered to be a marker for determining the severity of AD, which is formed by the aggregation of hyperphosphorylated Tau protein. .
  • Neurofibrillary tangles eventually lead to neurotransmitter transmission damage, and neuronal apoptosis eventually leads to AD.
  • Tau protein is a microtubule-associated protein that promotes the assembly of tubulin into microtubules and maintains the structure of microtubules, is widely expressed in neural tissues, and is abnormally hyperphosphorylated in brain tissue of AD patients. Normally, phosphorylation and dephosphorylation of Tau protein are in a dynamic equilibrium, but in abnormal cases, Tau protein is hyperphosphorylated, losing the function of maintaining microtubule structure, leading to axonal transport disorders.
  • R is a substituted or unsubstituted C 1 -C 8 linear or branched alkyl group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, a substituted or unsubstituted C 6 -C 20 heteroaryl group,
  • R is perfluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl.
  • R is a substituted phenyl group and the substituent is selected from the group consisting of acetoxy, hydroxy, trifluoromethyl, fluoro, nitro, methyl, methoxy.
  • R is a substituted phenyl group and the substituent is an acetoxy group or a hydroxyl group, the case where the substituent is in the ortho position is not included.
  • R is a substituted or unsubstituted C 3 -C 6 heteroaryl group, said substitution being substituted with one or more substituents selected from the group consisting of halogen, nitro, hydroxy, C 1 to C 4 alkyl, halogenated C 1 -C 4 alkyl, C 1 -C 4 alkoxy.
  • R is a substituted or unsubstituted furyl or thienyl group, and said substitution is substituted with one or more substituents selected from the group consisting of fluorine, chlorine, hydroxyl, C 1 -C 4 An alkyl group, a halogenated C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxy group.
  • the compound is: N-(5-morpholinothiazol-2-yl)acetamide, N-(5-morpholinothiazol-2-yl)propanamide, N-( 5-morpholinothiazol-2-yl)butanamide, N-(5-morpholinothiazol-2-yl)hexanamide, 3-methyl-N-(5-morpholinothiazol-2-yl) Butyramide, N-(5-morpholinothiazol-2-yl)cyclopropanecarboxamide, N-(5-morpholinothiazol-2-yl)cyclobutanecarboxamide, N-(5-morpholino Thiazol-2-yl)cyclopentanecarboxamide, N-(5-morpholinothiazol-2-yl)cyclohexanecarboxamide, N-(5-morpholinothiazol-2-yl)cycloheptane Amide, 2,2,3,3,4,4,4-heptafluoro-N
  • R is as defined above, and A is a chlorine atom or a hydroxyl group.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • N-(5-morpholinothiazol-2-yl)carboxamide compound (a compound of formula I) or a pharmaceutically acceptable salt thereof, for use in the preparation of A drug for the treatment of neurodegenerative diseases associated with A ⁇ clearance and/or Tau protein phosphorylation.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), Parkinson's syndrome (PD), Creutzfeldt-Jakob disease, cerebellar atrophy, amyotrophic lateral sclerosis Huntington's disease (HD), or a combination thereof.
  • AD Alzheimer's disease
  • PD Parkinson's syndrome
  • HD amyotrophic lateral sclerosis Huntington's disease
  • N-(5-morpholinothiazol-2-yl)carboxamide compound (the compound of formula I) or a pharmaceutically acceptable salt thereof for the preparation of prophylaxis / or drugs for the treatment of Alzheimer's disease.
  • the compound of the present invention is an N-(5-morpholinothiazol-2-yl)carboxamide compound having a novel structure, which promotes A ⁇ scavenging and inhibits Tau protein hyperphosphorylation, and has an improved APP/PS1 transgene AD.
  • the microtubule-associated protein Tau protein can promote the assembly of tubulin into microtubules and maintain the stability of microtubules.
  • the abnormal hyperphosphorylation of Tau protein in the brain of AD patients loses the function of maintaining microtubule structure and leads to axonal transport disorders. Therefore, the compound of the present invention is expected to be developed as a novel anti-Alzheimer's disease drug.
  • Figure 1 is a graph showing the effects of the compounds I-19(A) and I-33(B) on the AKT/mTOR pathway and the effects of promoting autophagy in cells.
  • Figure 2 shows that Compound I-19 is capable of reducing the A ⁇ content in cells in a concentration-dependent manner.
  • Figure 3 is a graph showing the results of inhibition of Tau protein phosphorylation by compounds I-19(A) and I-33(B).
  • Figure 4 is a graph showing the results of the compound I-19 water maze experiment.
  • alkyl means a saturated linear or branched hydrocarbon moiety, such as -CH 3, - (CH 2) 4 CH 3, -CH (CH 3) 2.
  • alkoxy means -O- (alkyl) groups such as -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 CH 3.
  • cycloalkyl denotes a monocyclic or polycyclic cyclic hydrocarbon substituent, and non-limiting examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptane
  • the polycyclic cycloalkyl group includes a cycloalkyl group, a fused ring, and a bridged ring.
  • heterocycloalkyl denotes a cycloalkyl group containing at least one ring heteroatom (eg, N, O or S).
  • aryl denotes a hydrocarbon group containing one or more aromatic rings, and examples include phenyl (Ph), naphthyl, anthryl, fluorenyl and phenanthryl.
  • heteroaryl denotes an aromatic ring group containing one or more heteroatoms having at least one hetero atom (eg, N, O or S).
  • heteroaryl moiety include furyl, thiazolyl, pyrrolyl, oxazolyl, imidazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and anthracenyl.
  • amino means -NH 2 , -NH-(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 .
  • halogen means F, Cl, Br, I.
  • substitution in the present invention means a mono- or poly-substitution such as a di-, tri-, tetra-substituted or the like.
  • the substituent is F, it may be a partial F substitution or a full F substitution.
  • alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups described herein include both substituted and unsubstituted groups.
  • Possible substituents for alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups include, but are not limited to, C1-C10 alkyl, hydroxy, halogen, nitro, C2-C10 alkenyl , C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20, cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C10 alkoxy, C6-C10 aryl , aryloxy, C3-C10 heteroaryl, amino, C1-C10 alkylamino, C1-C20 dialkylamino.
  • N-(5-morpholinothiazol-2-yl)carboxamide compound of the present invention has a structure as shown in Formula I, and is also referred to as a compound of Formula I, a compound of Formula I, and an N-Formula of Formula I.
  • R is a substituted or unsubstituted C 1 -C 8 linear or branched alkyl group, a substituted or unsubstituted C 3 -C 20 cycloalkyl group, a substituted or unsubstituted C 6 -C 20 aryl group, a substituted or unsubstituted C 6 -C 20 heteroaryl group,
  • R is a C1 to C6 straight or branched alkyl group, a C3 to C7 cycloalkyl group, a C1 to C3 fluorine-substituted alkyl group, a bridged cycloalkyl group, an aralkyl group, a substituted or unsubstituted group.
  • substituent of the substituted six-membered aromatic ring group is selected from the group consisting of: acetoxy, hydroxy, C1-C3 straight or branched perfluoroalkyl, halogen (F, Cl, Br or I), nitro, A a C1-C4 linear or branched alkoxy group, the number of substituents being an integer from 1 to 4;
  • the substituted or unsubstituted heteroaryl ring group is selected from the group consisting of: furan, thiophene; wherein the substituent of the substituted heteroaryl ring group is selected from the group consisting of methyl, halogen (F, Cl, Br or I).
  • the C 1 -C 6 straight or branched alkyl group is selected from the group consisting of methyl, ethyl, propyl, pentyl, isobutyl.
  • the C 1 -C 3 fluorosubstituted alkyl group is selected from the group consisting of perfluoropropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl.
  • the bridged cycloalkyl group is adamantane.
  • the substituted or unsubstituted six-membered aromatic ring group is selected from a substituted or unsubstituted phenyl group, wherein the substituent of the substituted phenyl group is selected from the group consisting of an acetoxy group, a hydroxyl group, and a C 1 -C 3 linear chain. Or branched perfluoroalkyl, halogen (F, Cl, Br or I), nitro, methyl, C 1 -C 4 straight or branched alkoxy, the number of substituents is an integer from 1 to 4 .
  • the substituent of the substituted phenyl group is selected from the group consisting of acetoxy, hydroxy, trifluoromethyl, fluoro, nitro, methyl, methoxy.
  • R is a substituted phenyl group and the substituent is an acetoxy group or a hydroxyl group, the case where the substituent is in the ortho position is not included.
  • N-(5-morpholinothiazol-2-yl)carboxamide compound is a compound shown in the following table, or a pharmaceutically acceptable salt thereof:
  • the invention further provides a pharmaceutically acceptable salt (also referred to as a pharmaceutically acceptable salt) of a compound of formula I, in particular a compound of formula I, which is reacted with an inorganic or organic acid to form a conventional non-toxic salt .
  • a pharmaceutically acceptable salt also referred to as a pharmaceutically acceptable salt
  • conventional non-toxic salts can be prepared by reacting a compound of formula I with an inorganic or organic acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, and the like, and Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, and para Benzenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic ester Acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-amino
  • A is a chlorine atom or a hydroxyl group, and the meaning of R is the same as described above.
  • Method 2 Put the R-substituted carboxylic acid (R-COOH) in a round bottom flask, add the solvent (the solvent used is toluene or dichloromethane), add a catalytic amount of N, N'-dimethylformamide, and then Add appropriate amount of chlorinating agent (halogenating agent is thionyl chloride or oxalyl chloride), control the temperature at 0 °C-80 °C for 3 hours, distill off the solvent under reduced pressure to obtain crude R-substituted acid chloride reagent; dissolve intermediate II In tetrahydrofuran, an appropriate amount of triethylamine is added, and the R-substituted acid chloride reagent prepared above is dissolved in tetrahydrofuran, and added dropwise to the above reaction system, and reacted at room temperature for 5 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue remains. The compound was purified by silica gel column
  • the method for synthesizing a part of the compound of the formula I is as follows, and the compound I-X wherein the R substituent is a chain alkyl group having a carbonyl group is reduced by a raw material:
  • n is the same as described above.
  • the present inventors have found through experiments that the compound of the formula I or a pharmaceutically acceptable salt thereof has the effect of promoting A ⁇ clearance and/or inhibiting Tau protein hyperphosphorylation, and has a memory impairment in a transgenic AD model mouse with improved APP/PS1. It can be used to prepare drugs for treating Alzheimer's disease associated with A ⁇ clearance and/or Tau protein phosphorylation.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise an odorant, a fragrance, and the like.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermixing with the active ingredient of the present invention (a compound of formula I or a pharmaceutically acceptable salt thereof) and the like, without significantly reducing the active ingredient. The efficacy of the drug.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose
  • the compounds and pharmaceutical compositions of the present invention may be in various forms, and may be administered orally or in the form of an injection, such as a capsule, a tablet, a granule, a solution, a powder, a powder or a syrup, or the present invention.
  • the compounds and pharmaceutical compositions may be presented in a suitable solid or liquid vehicle and in a suitable sterilizing device for injection or drip.
  • the above formulations can be prepared by conventional pharmaceutical methods.
  • the compounds and pharmaceutical compositions of this invention are useful for clinical use in mammals, including humans and animals, and can be administered by the oral, nasal or gastrointestinal routes.
  • the most preferred route of administration is oral.
  • Example 2 The acetyl chloride in Example 2 was replaced with propionyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with butyryl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with hexanoyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with isovaleryl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with cyclopropanecarbonyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with cyclobutanecarbonyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a pale pink solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with cyclopentanecarbonyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride of Example 2 was replaced with cyclohexanecarbonyl chloride, and the remaining starting materials, reagents and preparations were the same as those of Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with heptafluorobutyryl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a yellow solid.
  • Example 13 The 3,3,3-trifluoropropionic acid of Example 13 was replaced with 4,4,4-trifluorobutyric acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 13 to obtain the title compound as a white solid.
  • the rate is 71%.
  • Example 2 The acetyl chloride in Example 2 was replaced with adamantyl-1-carbonyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with phenylacetyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride of Example 2 was replaced with the hydrogenated cinnamoyl chloride, and the remaining starting materials, reagents and preparations were the same as those of Example 1-2 to give the title compound as a white solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with benzoyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a yellow solid.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 4-acetoxybenzoic acid, and the other desired starting materials, reagents and preparations were the same as in Example 11 to give the title compound as a yellow solid.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 3-acetoxybenzoic acid, and the remaining material, reagents and preparations were obtained in the same manner as in Example 11.
  • Example 2 The acetyl chloride of Example 2 was replaced with 2-trifluoromethylbenzoyl chloride, and the remaining starting materials, reagents and preparations were obtained in the same manner as in Example 1-2.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-fluorobenzoyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-nitrobenzoyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-methylbenzoyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-methoxybenzoyl chloride, and the remaining starting materials, reagents and preparation methods were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 1-naphthoyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-naphthoyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-furoyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a pale yellow solid.
  • Example 2 The acetyl chloride in Example 2 was replaced with 2-thienyl chloride, and the remaining starting materials, reagents and preparations were the same as those in Example 1-2 to give the title compound as a yellow solid.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 3-furancarboxylic acid, and the remaining material, reagents and preparations were obtained in the same manner as in Example 11.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 3-thiophenecarboxylic acid, and the remaining material, reagents and preparations were obtained in the same manner as in Example 11.
  • Example 2 The acetyl chloride in Example 2 was replaced with 5-chloro-2-thiophenecarbonyl chloride, and the remaining starting materials, reagents and preparations were the same as in Example 1-2 to give the title compound as a yellow solid.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 5-methyl-2-thiophenecarboxylic acid, and the remaining starting materials, reagents and preparations were the same as in Example 11 to give the title compound as a pale yellow solid.
  • Example 11 The cycloheptanecarboxylic acid of Example 11 was replaced with 3-methyl-2-thiophenecarboxylic acid, and the remaining material, reagents and preparations were obtained in the same manner as in Example 11 to give the title compound as a pale yellow solid.
  • Example 13 The 3,3,3-trifluoropropionic acid of Example 13 was replaced with 2-cyclohexanonecarboxylic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 13 to give the title compound as a pale yellow solid. .
  • Example 13 The 3,3,3-trifluoropropionic acid of Example 13 was replaced with 3-oxobutanoic acid, and the remaining starting materials, reagents and preparation methods were the same as those in Example 13 to give the title compound as a pale yellow solid. .
  • test and activity results of the percent inhibition activity of the compound of the present invention on phosphorylation of P70S6K.
  • the present invention detects the phosphorylation-inhibiting activity of the compound on P70S6K by the ⁇ -screen method in the synthesized N-(5-morpholinothiazol-2-yl)carboxamide compound in SH-SY5Y cells.
  • the experimental method is as follows:
  • the compound was added for 30 minutes, and then washed with PBS. Once again, the PBS was aspirated, and the cell lysate in the ⁇ -screen kit (PerkinElmer) was added, lysed for 15-20 minutes, and transferred to a white 384-impermeable plate for detection using an ⁇ -screen kit.
  • ⁇ -screen kit PerkinElmer
  • the compounds of the invention pass the test of the ability of the blood brain barrier.
  • N-(5-morpholinothiazol-2-yl)carboxamides with a phosphorylation inhibitory activity of more than 70% of P70S6K were selected, and the permeabilized brain barrier was detected by parallel artificial membrane permeability test. ability.
  • V d dose of the administration tank
  • V a volume of the receiving tank
  • A surface area of the hydrophobic membrane
  • t time of action
  • [drug] acceptor absorbance of the compound in the receiving tank
  • [drug] equilibrium theoretically absorbance of the compound in the receiving tank.
  • CNS+ Can pass the blood-brain barrier
  • CNS+/- Uncertain
  • I-19 and I-33 which have inhibitory activity against phosphorylation of P70S6K and better permeabilized brain barrier, are also treated with Wortmainnin and Nitazoxanide (NTZ) as positive controls in BV2 cells.
  • NTZ Nitazoxanide
  • BV2 cells were seeded into 12-well plates, and compounds of different concentrations (the compounds were dissolved in DMSO and placed in a concentration of 20 mM in mother liquor and diluted to different concentrations in the medium) were incubated for 24 hours, then the medium was aspirated and the cells were washed twice with PBS. Thereafter, the cells were directly lysed by adding 2 ⁇ loading buffer of SDS-PAGE, and the cell lysate was collected and dried at 99 ° C for 15 minutes, centrifuged at 12,000 rpm for 1 minute at 4 ° C, and stored at -20 ° C until use.
  • the SDS-PAGE gel with different concentrations is selected, and the processed cell sample is taken up to the supernatant of the SDS-PAGE, and each well is loaded with 8 ⁇ L, and the loading buffer is used to run out of the gel.
  • the semi-dry method is used for film transfer. Usually, the film transfer time is 90 minutes. It can also be adjusted according to the molecular weight of the protein. The larger the molecular weight, the longer the film transfer time. After the transfer was completed, the band of the molecular weight of the target protein was cut out, blocked with 5% skim milk powder for 1 hour, and then the corresponding primary antibody was incubated at 4 ° C overnight.
  • the primary antibody was collected and washed 3 times with TBST buffer for 15 minutes each time.
  • the secondary antibody was then incubated for 2 hours at room temperature and then the membrane was still washed 3 times with TBST buffer.
  • HRP horseradish peroxidase
  • the compounds of the invention increase the A ⁇ clearance assay and experimental results.
  • the experimental method is as follows: the cells are seeded in a 12-well plate, and when the cells are grown to 80%, different concentrations of the compound (the compound is dissolved in DMSO and configured to a mother liquor of 20 mM concentration and diluted to a different concentration in the medium) are incubated for 24 hours. Then, 2 ⁇ g/mL of A ⁇ was added for further 3 hours, the medium was aspirated, and the cells were washed twice with PBS, and then 200 ⁇ L of 1% SDS lysate (containing 1% protease inhibitor) was added to each well to lyse the cells, and lysed at 37 ° C for 15 minutes. The supernatant was collected and centrifuged at 12,000 g for 15 minutes. The A ⁇ in the supernatant was determined by ELISA, and the intracellular protein concentration was determined by the BCA method. The measured A ⁇ content was further divided by the total protein concentration of each sample to exclude the cell density against A ⁇ . Content interference.
  • the supernatant of the cell lysis was diluted 80-fold with a standard dilution and then assayed according to the method provided by the A ⁇ kit (purchased from Invitrogen). That is, the diluted supernatant, A ⁇ antibody and 96-well plate of another antibody linked to A ⁇ were incubated together for 3 hours at room temperature, and then washed with the rinse solution provided in the kit for 4 times, and then added to the couplet.
  • the horseradish peroxidase secondary antibody was incubated at room temperature for 30 minutes, and then washed with a rinse solution five times, then added to the color developing solution for 30 minutes at room temperature, and finally the reaction stop solution was added.
  • the OD value was read at 450 nm using a Bio-Rad microplate reader.
  • the compounds of the invention inhibit Tau protein phosphorylation experiments and experimental results.
  • LiCl and NTZ were used as positive controls to detect the regulation of Tau protein phosphorylation by Western blot, and multiple phosphorylation sites of Tau protein were performed. Detection.
  • the experimental method is as follows: In the cell experiment, SH-SY5Y cells were cultured in a six-well plate, and different concentrations of the compound were added when the cell density was 70% (the compound was dissolved in DMSO to prepare a mother liquor of 20 mM concentration, and diluted with a medium to form Incubation for 24 hours, then aspirate the culture medium and wash it 3 times with PBS, then the cells were buffered with SDS-PAGE (25% SDS, 62.5 mM Tris, 25% glycerol, 0.1% bromfen blue, pH 6 .8) Collected in a 1.5 mL EP tube, heat-treated at 98 ° C for 15 minutes, and then centrifuged at 10,000 g for 10 minutes at 4 ° C.
  • the supernatant was subjected to SDS-PAGE electrophoresis, followed by electroporation using a semi-dry method for 90 minutes, followed by blocking the membrane in TBST blocking solution (TBS, 0.5% Tween 20, 5% skim milk powder) for 30 minutes.
  • TST blocking solution TBS, 0.5% Tween 20, 5% skim milk powder
  • the blocked membrane was incubated overnight at 4 °C.
  • the membrane was washed 3 times with TBST buffer (TBS, 0.5% Tween 20) (15 minutes each) and then incubated with the secondary antibody for 2 hours.
  • the membrane was then washed 3 times with TBST buffer (15 minutes each).
  • HRP horseradish peroxidase
  • APP/PS1 double transgenic AD model mice Taking compound I-19 as an example and using NTZ as a positive control, the compound of APP/PS1 double transgenic AD model mice was administered by intragastric administration, and then the effect of compound on memory impairment of transgenic AD model mice was determined by water maze test.
  • APP/PS1 double transgenic AD model mice (APPswe, PS1dE9) can highly express embedded and mouse/human Swedish mutations APP (Mo/HuAPP695swe) and humans deleted the presenilin (PS1-dE9) of the 9th exon. These transgenic mice will have more obvious A ⁇ deposition at 6 months and will At 7 months, there was damage to spatial memory.
  • the experimental method is as follows:
  • the APP/PS1 double transgenic AD model mice were purchased from Jackson Laboratory in the United States and then propagated.
  • the transgenic type of the progeny mouse was identified by using the tail of the mouse and then PCR to identify the gene sequence of the APP/PS1 of the mouse.
  • Non-transgenic mice were used as negative control mice in the experiment. Mice were housed under standard conditions (12/12 hour light and dark cycle, sufficient water and food, 22 ° C constant temperature, 60% humidity).
  • AD model mice were administered: 40 mice were randomly divided into 4 groups at the age of 9 months (transgenic solvent group, transgenic NTZ group, transgenic I-19 10 mg/kg dose group, transgenic I-19) In the 30 mg/kg dose group, 10 non-transgenic mice served as a negative control group.
  • the compound was dissolved in physiological saline of 26% PEG400 and 15% HS15, and then continuous intragastric administration was started.
  • the solvent group was given 26% PEG400, 15% HS15 physiological saline, and 100 days later, behavioral test was performed (Morris water maze test). .
  • Morris water maze experiment Morris water maze instrument is a circular pool with a diameter of 1.5 meters and a depth of 60 cm. The water is dyed into white by injecting milk into the pool. The water temperature is kept at 25 °C during the experiment, and the digital connection with the computer is used. The camera records the swimming trajectory of the mouse.
  • the pool is divided into four quadrants, one of which has a platform of 10 cm in diameter at 1.5 cm below the surface of the pool.
  • the mice are trained to find and remember the location of the platform; the mice are trained three times a day for eight days. In three training sessions, the mice were placed in the water in the quadrant where the three platforms were placed, and then the mice were given 90 seconds to find the platform position. If the platform could not be found within 90 seconds, it would be small.
  • the mouse is placed on the platform; in either case, the mouse standing on the platform will let it sit on the platform for 15 seconds to help it remember the platform position; record the mouse's time to find the platform as a mouse
  • the evaluation index of memory was averaged by taking three trainings per day.
  • the linear pattern of the latency of each group of mice in 8 days is shown in Fig. 4 (A).
  • the mice were subjected to a platform-finding experiment; in this experiment, the submerged platform was removed, and the mice were allowed to stand in the pool for 90 seconds to find the platform.
  • the number of times the mouse crossed the platform was also used as an indicator for evaluating the memory of the mice.
  • the histogram of the number of times the mice were worn on the 8th day is shown in Fig. 4 (B).
  • NV represents a non-transgenic solvent group
  • TV represents a transgenic solvent group
  • NTZ-30 mg/Kg represents a transgenic NTZ 30 mg/Kg dose group
  • L-10 mg/Kg represents a transgenic I-19 10 mg/Kg dose group
  • H-30 mg. /Kg indicates the transgenic I-19 30 mg/Kg dose group.
  • CHO-hERG cells were cultured in a 175 cm 2 flask, and the cell density was increased to 60-80%. The culture solution was removed, washed once with 7 mL of PBS, and then digested with 3 mL of Detachin. After the digestion was completed, 7 mL of the culture solution was added for neutralization, and then centrifuged, the supernatant was aspirated, and 5 mL of the culture solution was resuspended to ensure a cell density of 2 to 5 ⁇ 10 6 /mL.
  • Solution configuration The composition of the intracellular fluid and the external fluid is shown in Table 3.
  • Electrophysiological recording process Single-cell high-impedance sealing and whole-cell pattern formation were all done automatically by the Qpatch instrument. After obtaining the whole-cell recording mode, the cells were clamped at -80 mV and given a 5 second +40 mV. Prior to depolarization stimulation, a 50-millisecond -50 mV preamplifier is applied, then repolarized to -50 mV for 5 seconds and back to -80 mV. The voltage stimulation was applied every 15 seconds, and the extracellular fluid was recorded for 1 minute after 2 minutes of recording. Then, the administration process was started. The concentration of the compound was started from the lowest test concentration, and each test concentration was given for 1 minute. After all the concentrations were continuously administered, the administration was given. Positive control compound 10 ⁇ M Cisapride. Test at least 3 cells (n ⁇ 3) for each concentration.
  • >40 ⁇ M means that the inhibitory effect of this compound is less than 50% at 40 ⁇ M
  • the compounds I-19 and I-33 of the present invention have a poor inhibitory activity against the potassium channel of hERG, indicating that the compound of the present invention is safe in heart.

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Abstract

一种N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，结构如式I所示，式中R如说明书中所定义。本发明所的化合物或其药学上可接受的盐，具有促进Aβ清除和抑制Tau蛋白过度磷酸化作用，并具有改善APP/PS1转基因AD模型小鼠的记忆力损伤的作用，有望开发为新型抗阿尔茨海默病药物。

Description

N-(5-吗啉代噻唑-2-基)甲酰胺类化合物及其制备方法和用途 技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及一类N-(5-吗啉代噻唑-2-基)甲酰胺类化合物及其制备方法和药理用途，该类化合物可作为抗阿尔茨海默病药物。
背景技术
阿尔茨海默病(Alzheimer's Disease，AD)是一种进行性认知障碍和记忆力损害为主的中枢神经系统退行性疾病，以β淀粉样蛋白(Amyloid beta，Aβ)聚集导致的神经外淀粉样蛋白沉淀，Tau蛋白过度磷酸化导致的神经纤维缠结以及神经元细胞凋亡等为其主要标志。AD的主要临床表现为认知和记忆功能不断恶化，日常生活能力进行性减退，并有各种神经精神症状和行为障碍。早期主要表现为近期记忆丢失，个性变化；中期主要表现为易怒，恐慌，睡眠失常，甚至幻觉产生；晚期则主要表现为逻辑思维丧失，卧床不起，生活不能自理等。随着人口老龄化，我国已进入老年化社会，AD也成为一个导致老年人生活质量下降并导致死亡的重要原因，目前我国AD病人数目已大于800万，寻找治疗AD有效药物已成当务之急。据美国阿尔茨海默病协会估计，目前全世界每年在对AD患者的照顾的费用达到三千多亿美元，且有持续增长的趋势。因而AD已经变成社会和家庭的重要负担，寻找对阿尔茨海默病有较好疗效的药物具有重要意义。
目前临床上使用的AD治疗药物仅有乙酰胆碱酯酶(AChE)抑制剂(他克林、多奈哌齐、利斯的明、加兰他敏和石杉碱)和N-甲基-D-天冬氨酸(NMDA)受体拮抗剂(美金刚)这两大类。但是这些药物虽然能够部分缓解AD的症状，在一定程度上改善患者的认知功能障碍，但是却不能完全恢复其日常行为能力，也无法从根本上治疗疾病或终止AD的进程。因此对能够阻断AD病理进程的新型抗AD药物的发现有着迫切的需求。
目前，针对AD的根本致病原因提出了以下多种假说：β淀粉样蛋白假说、微管相关蛋白Tau蛋白假说、胆碱能假说、线粒体假说、炎症假说、胰岛素假说等。随着对AD致病机制研究的不断深入，越来发现AD的发生和发展涉及多种基因和通路之间的相互关联，是中枢神经系统多重复杂的调控网络和调控因子共同作用的结果。因此，当前临床上许多候选药物，虽然能够在体外实验或动物实验中有效地减少老年斑沉积或神经纤维缠结等AD病理表现，却在实际治疗中因为不能改善受损的认知功能而以失败告终。究其原因可能是以往的药物分子通常都是针对单一靶点发挥特异性治疗作用，但这样的单靶点效应往往又会过于单一，在复杂的生理环境中并不能充分发挥治疗作用。近年来，人们逐渐发现多靶点的药物能够通过同时对多个致病靶点发挥调控作用，从而获得更好的治疗效果。
Aβ是老年斑的主要成分之一，由淀粉样前体蛋白(Amyloid precursor protein，APP)经β-分泌酶和γ-分泌酶依次剪切生成，它在大脑组织中过度增加导致神经系统产生氧化应激，炎症反应等最终导致神经元凋亡及AD的发生。因此普遍认为通过抑制Aβ的生成或促进Aβ的清除来减少整体脑中Aβ的含量将可以有效的预防或治疗AD，而这也是目前抗AD新型药物的主要研发方向之一。
体内Aβ的含量是Aβ生成和Aβ清除共同作用的结果，正常生理情况下两者能够保持一 个平衡状态，而一旦Aβ生成亢进或是Aβ清除抑制都会导致Aβ在体内积累。目前自噬被认为是Aβ清除中一种重要的途径，并受到多种上游蛋白的调控，其中研究比较深入的是证明了AKT/mTOR通路对自噬的负调控作用，以及AMPK/Raptor通路对自噬的正调控作用。AKT的活性能够直接或间接地正向调控mTOR的活性，而mTOR的磷酸化水平升高则会导致自噬启始子之一的ULK1磷酸化失活，导致自噬抑制；因此，减少AKT的磷酸化能够减少mTOR的磷酸化，从而增强自噬。而在AD患者体内也出现了自噬调控蛋白紊乱的现象，例如AKT的过度激活等，因此通过调节自噬上游的多种靶点蛋白，促进自噬将会是一种新的治疗策略。
神经纤维缠结是AD中另一特征性的病理改变，同时神经纤维缠结的数量也被认为是一个判定AD严重程度的标志，而这些神经纤维缠结是由过度磷酸化的Tau蛋白聚集形成。神经纤维缠结最终会导致神经元递质传递损伤，神经元的凋亡等最终导致AD发生。Tau蛋白是一种微管相关蛋白，可以促进微管蛋白组装成微管和维持微管的结构，在神经组织中广泛表达，并在AD患者脑组织中被异常过度磷酸化。正常情况下，Tau蛋白的磷酸化和去磷酸化处于动态平衡，但异常情况下，Tau蛋白会被过度磷酸化，失去维持微管结构的功能，导致轴突转运障碍。
因此，开发具有促进Aβ清除和抑制Tau蛋白过度磷酸化活性的化合物，对AD的治疗有重要的意义。
发明内容
本发明的目的在于提供一种具有促进Aβ清除及/或抑制Tau蛋白过度磷酸化作用的全新的N-(5-吗啉代噻唑-2-基)甲酰胺类结构。
本发明的第一方面，提供一种式I所示的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物或其药学上可接受的盐：
Figure PCTCN2017073472-appb-000001
式中，R为取代或未取代的C1～C8直链或支链烷基，取代或未取代的C3～C20环烷基，取代或未取代的C6～C20芳基、取代或未取代的C6～C20杂芳基，
所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷基、C6～C10芳基、＝O、-O-C(＝O)-C1～C6烷基。
在另一优选例中，R为取代或未取代的C1～C6直链或支链烷基，所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C6烷氧基、卤代C1～C6烷基、C6～C10芳基、＝O、-O-C(＝O)-C1～C6烷基。
在另一优选例中，R为取代或未取代的甲基、乙基、丙基、正丁基、戊基或异丁基，所述取代是指被选自下组的一个或多个取代基取代：氟、氯、C6～C10芳基、＝O、羟基。
在另一优选例中，R为全氟丙基，2,2,2-三氟乙基，3,3,3-三氟丙基。
在另一优选例中，R为取代或未取代的C3～C12环烷基，所述取代是指被选自下组的一个或多个取代基取代：C1～C6烷基、卤素、硝基、羟基、C1～C6烷氧基、卤代C1～C6烷基、＝O、-O-C(＝O)-C1～C6烷基。
在另一优选例中，R为取代或未取代的环丙基、环丁基、环戊基、环己基、环庚基或金刚烷基，所述取代是指被选自下组的一个或多个取代基取代：C1～C4烷基、氟、氯、硝基、羟基、C1～C4烷氧基、卤代C1～C4烷基、＝O。
在另一优选例中，R为取代或未取代的C6～C10芳基，所述取代是指被选自下组的一个或多个取代基取代：羟基、卤代C1～C4烷基、氟、氯、硝基、C1～C4烷基、C1～C4烷氧基、-O-C(＝O)-C1～C4烷基。
在另一优选例中，R为取代或未取代的苯基或萘基，所述取代是指被选自下组的一个或多个取代基取代：羟基、卤代C1～C4烷基、氟、氯、硝基、C1～C4烷基、C1～C4烷氧基、-O-C(＝O)-C1～C4烷基。
在另一优选例中，R为取代苯基，取代基选自：乙酰氧基，羟基，三氟甲基，氟，硝基，甲基，甲氧基。
在另一优选例中，当R为取代苯基且取代基为乙酰氧基或羟基时，不包括取代基在邻位的情况。
在另一优选例中，R为取代或未取代的C3～C6杂芳基，所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C4烷基、卤代C1～C4烷基、C1～C4烷氧基。
在另一优选例中，R为取代或未取代的呋喃基或噻吩基，所述取代是指被选自下组的一个或多个取代基取代：氟、氯、羟基、C1～C4烷基、卤代C1～C4烷基、C1～C4烷氧基。
在另一优选例中，所述的化合物是：N-(5-吗啉代噻唑-2-基)乙酰胺、N-(5-吗啉代噻唑-2-基)丙酰胺、N-(5-吗啉代噻唑-2-基)丁酰胺、N-(5-吗啉代噻唑-2-基)己酰胺、3-甲基-N-(5-吗啉代噻唑-2-基)丁酰胺、N-(5-吗啉代噻唑-2-基)环丙烷甲酰胺、N-(5-吗啉代噻唑-2-基)环丁烷甲酰胺、N-(5-吗啉代噻唑-2-基)环戊烷甲酰胺、N-(5-吗啉代噻唑-2-基)环己烷甲酰胺、N-(5-吗啉代噻唑-2-基)环庚烷甲酰胺、2,2,3,3,4,4,4-七氟-N-(5-吗啉代噻唑-2-基)丁酰胺、3,3,3-三氟-N-(5-吗啉代噻唑-2-基)丙酰胺、4,4,4-三氟-N-(5-吗啉代噻唑-2-基)丁酰胺、(3r,5r,7r)-N-(5-吗啉代噻唑-2-基)金刚烷-1-甲酰胺、N-(5-吗啉代噻唑-2-基)-2-苯基乙酰胺、N-(5-吗啉代噻唑-2-基)-3-苯基丙酰胺、N-(5-吗啉代噻唑-2-基)苯甲酰胺、4-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、3-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、4-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、3-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-2-(三氟甲基)苯甲酰胺、2-氟-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-2-硝基苯甲酰胺、2-甲基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、2-甲氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-1-萘甲酰胺、N-(5-吗啉代噻唑-2-基)-2-萘甲酰胺、N-(5-吗啉代噻唑-2-基)呋喃-2-甲酰胺、N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、N-(5-吗啉代噻唑-2-基)呋喃-3-甲酰胺、N-(5-吗啉代噻唑-2-基)噻吩-3-甲酰胺、5-氯-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、5-甲基-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、3-甲基-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、N-(5-吗啉代噻唑-2-基)-2-氧代环己烷甲酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代丁酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代戊酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代己酰胺或3-羟基-N-(5-吗啉代噻唑-2-基)戊酰胺。
本发明的第二方面，提供上述N-(5-吗啉代噻唑-2-基)甲酰胺类化合物(式I所示化合物)或其药学上可接受的盐的制备方法，所述制备方法包括以下步骤：
Figure PCTCN2017073472-appb-000002
式II化合物与式III化合物反应得到式I所示化合物，
式中，R的定义如前所述，A为氯原子或羟基。
本发明的第三方面，提供一种药物组合物，包括第一方面所述的化合物或其药学上可接受的盐；和药学上可接受的载体。
本发明的第四方面，提供上述N-(5-吗啉代噻唑-2-基)甲酰胺类化合物(式I所示化合物)或其药学上可接受的盐的用途，用于制备用于治疗与Aβ清除及/或Tau蛋白磷酸化相关的神经退行性疾病的药物。
在另一优选例中，神经退行性疾病选自下组：阿尔茨海默病(AD)、帕金森综合症(PD)、克雅二氏病、小脑萎缩症、肌肉萎缩性侧索硬化症、亨廷顿病(HD)、或其组合。
本发明的第五方面，提供上述N-(5-吗啉代噻唑-2-基)甲酰胺类化合物(式I所示化合物)或其药学上可接受的盐的用途，用于制备预防和/或治疗阿尔茨海默病的药物。
本发明的化合物，为具有全新结构的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，具有促进Aβ清除和抑制Tau蛋白过度磷酸化作用，并具有改善APP/PS1转基因AD模型小鼠的记忆力损伤的作用。AD患者脑中Aβ过度增加并沉积形成老年斑，产生神经毒性，通过抑制Aβ的生成或促进Aβ的清除来减少整体脑中Aβ的含量将可以有效的预防或治疗AD。微管相关蛋白Tau蛋白可以促进微管蛋白组装成微管和维持微管的稳定，AD患者脑中Tau蛋白异常过度磷酸化，失去维持微管结构的功能，导致轴突转运障碍。因此，本发明化合物有望开发为新型抗阿尔茨海默病药物。
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为化合物I-19(A)与I-33(B)对AKT/mTOR通路的作用及促进细胞内自噬作用实验结果图。
图2示出化合物I-19能够浓度依赖性减少细胞内的Aβ含量。
图3为化合物I-19(A)与I-33(B)抑制Tau蛋白磷酸化实验结果图。
图4为化合物I-19水迷宫实验结果图。
具体实施方式
本发明人经过广泛而深入的研究，首次研发出具有全新结构的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，具有促进Aβ清除及/或抑制Tau蛋白过度磷酸化作用，并具有改善APP/PS1的转基因AD模型小鼠的记忆力损伤的作用。在此基础上完成了本发明。
术语
术语“烷基”表示饱和的线性或支链烃部分，例如-CH3、-(CH2)4CH3、-CH(CH3)2。
术语“烷氧基”表示-O-(烷基)基团，例如-OCH3、-OCH2CH3、-OCH2CH2CH3。
术语“环烷基”表示单环或多环环状烃取代基，单环环烷基的非限制性实施例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环烷基”表示包含至少一个环杂原子(例如N、O或S)的环烷基。
术语“芳基”表示包含一个或多个芳环的烃基，例子包括苯基(Ph)、萘基、芘基、蒽基和菲基。
术语“杂芳基”表示包含一个或多个具有至少一个杂原子(例如N、O或S)的芳环基团。杂芳基部分的例子包括呋喃基、噻唑基、吡咯基、噁唑基、咪唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基和吲哚基。
术语“氨基”表示-NH2、-NH-(C1-6烷基)或-N(C1-6烷基)2。
术语“卤素”表示F、Cl、Br、I。
本发明中取代是指单取代或多取代，如二取代、三取代、四取代等。在取代基为F的情况下，可以为部分F取代或全F取代。
除非另外说明，本文所述的烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基同时包括取代的和未取代的基团。烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基可能的取代基包括，但不限于：C1-C10烷基、羟基、卤素、硝基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20、环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、C6-C10芳基、芳氧基、C3-C10杂芳基、氨基、C1-C10烷基氨基、C1-C20二烷基氨基。
式I化合物或其药学上可接受的盐
本发明的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，结构如式I所示，也称为式I所示的化合物、式I化合物、式I所示的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物：
Figure PCTCN2017073472-appb-000003
式中，R为取代或未取代的C1～C8直链或支链烷基，取代或未取代的C3～C20环烷基，取代或未取代的C6～C20芳基、取代或未取代的C6～C20杂芳基，
所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷基、C6～C10芳基、＝O、-O-C(＝O)-C1～C6烷基。
在另一优选例中，R为C1～C6直链或支链烷基，C3～C7环烷基，C1～C3含氟取代的烷基，桥环烷基，芳烷基，取代或非取代六元芳环基，取代或非取代杂芳环基，萘环基，
Figure PCTCN2017073472-appb-000004
Figure PCTCN2017073472-appb-000005
各n独立地为0-2的整数；
其中，所述取代六元芳环基的取代基选自：乙酰氧基，羟基，C1～C3直链或支链全氟烷基，卤素(F、Cl、Br或I)，硝基，甲基，C1～C4直链或支链烷氧基，取代基的个数为1-4的整数；
所述取代或非取代杂芳环基选自：呋喃，噻吩；其中，取代杂芳环基的取代基选自：甲基，卤素(F、Cl、Br或I)。
在另一优选例中，所述C1～C6直链或支链烷基选自：甲基，乙基，丙基，戊基，异丁基。
在另一优选例中，所述C1～C3氟取代烷基选自：全氟丙基，2,2,2-三氟乙基，3,3,3-三氟丙基。
在另一优选例中，所述桥环烷基为金刚烷。
在另一优选例中，所述取代或非取代六元芳环基选自取代或非取代苯基，其中取代苯基的取代基选自：乙酰氧基，羟基，C1～C3直链或支链全氟烷基，卤素(F、Cl、Br或I)，硝基，甲基，C1～C4直链或支链烷氧基，取代基的个数为1-4的整数。
在另一优选例中，所述取代苯基的取代基选自：乙酰氧基，羟基，三氟甲基，氟，硝基，甲基，甲氧基。
在另一优选例中，当R为取代苯基且取代基为乙酰氧基或羟基时，不包括取代基在邻位的情况。
在另一优选例中，N-(5-吗啉代噻唑-2-基)甲酰胺类化合物为下表所示化合物、或其在药学上可接受的盐：
Figure PCTCN2017073472-appb-000006
Figure PCTCN2017073472-appb-000007
Figure PCTCN2017073472-appb-000008
本发明还提供式I所示的化合物的药学上可接受的盐(也称为可药用的盐)，具体地为式I所示的化合物与无机酸或有机酸反应形成常规的无毒盐。例如，常规的无毒盐可通过式I所示的化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲 苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(I)化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(I)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
制备方法
本发明式I所示的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，及其中间体II的制备方法，具体合成策略分别如下：
Figure PCTCN2017073472-appb-000009
式中，A为氯原子或羟基，R的含义与前文所述相同。
1)将5-溴-2-氨基噻唑氢溴酸盐溶于N,N’-二甲基甲酰胺中，加入碳酸钾，再滴加吗啉，加热至60℃反应3小时，待其反应完全后，加入适量的水，并用乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，然后过滤，减压蒸除溶剂，残余固体加入甲基叔丁基醚洗涤，抽滤得中间体5-吗啉-2-氨基噻唑(中间体II)。
2)方法一：将中间体II溶于四氢呋喃中，加入适量三乙胺，再加入R取代酰氯类化合物(R-COCl)，室温反应5小时，反应结束后，减压蒸除溶剂，残余物经硅胶柱层析纯化得化合物I。方法二：将R取代羧酸(R-COOH)置于圆底烧瓶中，加入溶剂(使用的溶剂为甲苯或二氯甲烷)，加入催化量的N,N’-二甲基甲酰胺，再加入适量的氯化剂(卤化剂为氯化亚砜或草酰氯)，控制温度于0℃-80℃下反应3小时，减压蒸除溶剂得到R取代的酰氯试剂粗品；将中间体II溶于四氢呋喃中，加入适量三乙胺，再将上述制得的R取代的酰氯试剂溶于四氢呋喃中，并滴加入上述反应体系中，室温反应5小时，反应结束后，减压蒸除溶剂，残余物经硅胶柱层析纯化得化合物I。
部分式I化合物的合成方法如下，以R取代基为含有羰基的链状烷基的化合物I-X为原料还原而制得：
Figure PCTCN2017073472-appb-000010
式中，n的含义与前文所述相同。
3)将化合物I-X溶于甲醇中，控制温度为0℃，加入硼氢化钠，反应15分钟后，加水淬 灭反应，并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得化合物I。
当R为取代苯基，且取代基为羟基时，其合成方法如下：
Figure PCTCN2017073472-appb-000011
4)将化合物I-18或I-19溶于四氢呋喃中，加入适量水，再加入氢氧化锂，室温搅拌过夜，待反应完全后，加适量盐酸调PH至3，然后加入适量水，并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得化合物I-20或I-21。
根据上述制备方法的教导，本领域普通技术人员无需创造性劳动，即可获得式I所包含的所有化合物。
用途
本发明人通过实验发现式I化合物或其药学上可接受的盐，具有促进Aβ清除及/或抑制Tau蛋白过度磷酸化作用，并具有改善APP/PS1的转基因AD模型小鼠的记忆力损伤的作用，能够用于制备治疗与Aβ清除及/或Tau蛋白磷酸化相关的阿尔茨海默病的药物。
药物组合物
本发明的药物组合物含有治疗有效量的式I化合物或其药学上可接受的盐，以及含有一种或多种可药用的载体。该药用组合物还可以进一步包含气味剂、香味剂等。
“可药用的载体”或“药学上可用的载体”是指一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分(式I化合物或其药学上可接受的盐)以及它们之间相互掺和，而不明显降低活性成分的药效。可药用的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2017073472-appb-000012
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的化合物和药物组合物可以是多种形式，可以通过如胶囊、片剂、颗粒剂、溶液状、粉剂、散剂或糖浆等形式口服给药或以注射剂的形式非口服给药，本发明的化合物和药物组合物可以存在于适宜的固体或液体载体中和适宜的用于注射或滴注的消毒器具中。上述制剂可通过常规制药方法制备。
本发明的化合物和药物组合物可用于哺乳动物临床使用，包括人和动物，可以通过口、鼻或胃肠道等途径给药。最优选的给药途径为口服。
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，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。实施例中的所有参数以及其余的说明，除另有说明外，都是以质量(毫克)为单位。
实施例1
5-吗啉-2-氨基-噻唑(中间体II)的制备
Figure PCTCN2017073472-appb-000013
称取8.83克5-溴-2氨基噻唑氢溴酸盐溶于60毫升N,N’-二甲基甲酰胺中，加入7.049克碳酸钾，再向体系中滴加5.92毫升吗啉，加热至60℃反应3小时，反应结束后，加入适量水，并用乙酸乙酯萃取后，有机层干燥过滤，减压蒸除溶剂后，残余固体加入甲基叔丁基醚洗涤，抽滤得标题化合物，3.71克红棕色固体，收率59％。
1H NMR(400MHz,DMSO-d6)δ6.48(s,2H),6.28(s,1H),3.72–3.60(m,4H),2.85–2.75(m,4H).
实施例2
N-(5-吗啉代噻唑-2-基)乙酰胺(化合物I-1)的制备
Figure PCTCN2017073472-appb-000014
将100毫克5-吗啉-2-氨基-噻唑(中间体II)溶于5毫升无水四氢呋喃中，加入225微升三乙胺，再加入46微升乙酰氯，室温搅拌5小时，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析纯化得40毫克白色固体标题化合物，收率39％。
mp 253-256℃；1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),6.65(s,1H),3.77–3.63(m,4H),3.05–2.88(m,4H),2.07(s,3H).EI-MS m/z 227.1(M+)；185(100％)；HRMS(EI)m/z calcd C9H13N3O2S(M+)227.0728,found 227.0730.
实施例3
N-(5-吗啉代噻唑-2-基)丙酰胺(化合物I-2)的制备
Figure PCTCN2017073472-appb-000015
将实施例2中的乙酰氯替换成丙酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率65％。
mp 198-200℃；1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),6.65(s,1H),3.79–3.63(m,4H),3.05–2.89(m,4H),2.37(q,J＝7.5Hz,2H),1.06(t,J＝7.5Hz,3H).EI-MS m/z 241.1(M+)；185(100％)；HRMS(EI)m/z calcd C10H15N3O2S(M+)241.0885,found 241.0884.
实施例4
N-(5-吗啉代噻唑-2-基)丁酰胺(化合物I-3)的制备
Figure PCTCN2017073472-appb-000016
将实施例2中的乙酰氯替换成丁酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率48％。
mp 140-142℃；1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),6.65(s,1H),3.75–3.66(m, 4H),3.01–2.92(m,4H),2.33(t,J＝7.3Hz,2H),1.65–1.53(m,2H),0.88(t,J＝7.4Hz,3H).EI-MS m/z 255.1(M+)；185(100％)；HRMS(EI)m/z calcd C11H17N3O2S(M+)255.1041,found255.1040.
实施例5
N-(5-吗啉代噻唑-2-基)己酰胺(化合物I-4)的制备
Figure PCTCN2017073472-appb-000017
将实施例2中的乙酰氯替换成己酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率43％。
mp 94-96℃；1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),6.65(s,1H),3.74–3.67(m,4H),3.01–2.93(m,4H),2.35(t,J＝7.4Hz,2H),1.62–1.51(m,2H),1.34–1.18(m,4H),0.86(t,J＝7.0Hz,3H).EI-MS m/z 283.1(M+)；185(100％)；HRMS(EI)m/z calcd C13H21N3O2S(M+)283.1354,found 283.1353.
实施例6
3-甲基-N-(5-吗啉代噻唑-2-基)丁酰胺(化合物I-5)的制备
Figure PCTCN2017073472-appb-000018
将实施例2中的乙酰氯替换成异戊酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率70％。
mp 153-155℃；1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),6.66(s,1H),3.77–3.65(m,4H),3.03–2.93(m,4H),2.24(d,J＝7.2Hz,2H),2.11–1.98(m,1H),0.90(d,J＝6.7Hz,6H).EI-MS m/z 269.1(M+)；185(100％)；HRMS(EI)m/z calcd C12H19N3O2S(M+)269.1198,found269.1199.
实施例7
N-(5-吗啉代噻唑-2-基)环丙烷甲酰胺(化合物I-6)的制备
Figure PCTCN2017073472-appb-000019
将实施例2中的乙酰氯替换成环丙烷甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率61％。
mp 196-198℃；1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),6.65(s,1H),3.75–3.65(m,4H),3.01–2.90(m,4H),1.92–1.83(m,1H),0.90–0.79(m,4H).EI-MS m/z 253.1(M+)；185(100％)；HRMS(EI)m/z calcd C11H15N3O2S(M+)253.0885,found 253.0886.
实施例8
N-(5-吗啉代噻唑-2-基)环丁烷甲酰胺(化合物I-7)的制备
Figure PCTCN2017073472-appb-000020
将实施例2中的乙酰氯替换成环丁烷甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅粉色固体标题化合物，收率46％。
mp 179-184℃；1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),6.65(s,1H),3.76–3.65(m,4H),3.32–3.23(m,1H),3.01–2.91(m,4H),2.26–2.03(m,4H),2.00–1.86(m,1H),1.85–1.74(m,1H).EI-MS m/z 267.1(M+)；185(100％)；HRMS(EI)m/z calcd C12H17N3O2S(M+)267.1041,found 267.1036.
实施例9
N-(5-吗啉代噻唑-2-基)环戊烷甲酰胺(化合物I-8)的制备
Figure PCTCN2017073472-appb-000021
将实施例2中的乙酰氯替换成环戊烷甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率64％。
mp 175-177℃；1H NMR(400MHz,DMSO-d6)δ11.71(s,1H),6.66(s,1H),3.80–3.61(m,4H),3.05–2.90(m,4H),2.89–2.77(m,1H),1.90–1.76(m,2H),1.74–1.60(m,4H),1.59–1.46(s,2H).EI-MS m/z 281.1(M+)；185(100％)；HRMS(EI)m/z calcd C13H19N3O2S(M+)281.1198,found 281.1197.
实施例10
N-(5-吗啉代噻唑-2-基)环己烷甲酰胺(化合物I-9)的制备
Figure PCTCN2017073472-appb-000022
将实施例2中的乙酰氯替换成环己烷甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率68％。
mp 180-182℃；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),6.65(s,1H),3.76–3.61(m,4H),3.02–2.88(m,4H),2.46–2.36(m,1H),1.74(t,J＝12.6Hz,4H),1.63(d,J＝8.4Hz,1H),1.45–1.31(m,2H),1.30–1.09(m,3H).EI-MS m/z 295.1(M+)；185(100％)；HRMS(EI)m/z calcd C14H21N3O2S(M+)295.1354,found 295.1353.
实施例11
N-(5-吗啉代噻唑-2-基)环庚烷甲酰胺(化合物I-10)的制备
Figure PCTCN2017073472-appb-000023
将230毫克环庚烷甲酸溶于1毫升甲苯中，加入10微升N,N’-二甲基甲酰胺，再加入1毫升氯化亚砜，80℃下反应3小时，减压蒸除溶剂，得粗品环庚烷甲酰氯。将100毫克5-吗啉-2-氨基噻唑溶于5毫升无水四氢呋喃中，加入225微升三乙胺，将上述制得的环庚烷甲酰氯溶于3毫升无水四氢呋喃中，并滴加至上述反应体系中，室温反应5小时，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析纯化得114毫克白色固体标题化合物，收率70％。
mp 169-171℃；1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),6.65(s,1H),3.79–3.63(m,4H),3.06–2.89(m,4H),2.66–2.55(m,1H),1.86–1.36(m,12H).EI-MS m/z 309.2(M+)；185 (100％)；HRMS(EI)m/z calcd C15H23N3O2S(M+)309.1511,found 309.1509.
实施例12
2,2,3,3,4,4,4-七氟-N-(5-吗啉代噻唑-2-基)丁酰胺(化合物I-11)的制备
Figure PCTCN2017073472-appb-000024
将实施例2中的乙酰氯替换成七氟丁酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率40％。
mp 134-136℃；1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),6.86(s,1H),3.84–3.61(m,4H),3.14–2.94(m,4H).EI-MS m/z 381.0(M+)；381(100％)；HRMS(EI)m/z calcd C11H10F7N3O2S(M+)381.0382,found 381.0380.
实施例13
3,3,3-三氟-N-(5-吗啉代噻唑-2-基)丙酰胺(化合物I-12)的制备
Figure PCTCN2017073472-appb-000025
将500毫克3,3,3-三氟丙酸溶于1毫升二氯甲烷中，加入10微升N,N’-二甲基甲酰胺，控制温度为0℃下，滴加397微升草酰氯，继续0℃下反应20分钟后，将反应体系移至室温，继续反应2小时，然后减压蒸除溶剂，得粗品3,3,3-三氟丙酰氯。将100毫克5-吗啉-2-氨基噻唑溶于5毫升无水四氢呋喃中，加入225微升三乙胺，将上述制得的3,3,3-三氟丙酰氯溶于3毫升无水四氢呋喃中，并滴加至上述反应体系中，室温反应5小时，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析纯化得101毫克白色固体标题化合物，收率63％。
mp 231-233℃；1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),6.71(s,1H),3.76–3.67(m,4H),3.60(q,J＝11.0Hz,2H),3.05–2.93(m,4H).EI-MS m/z 295.1(M+)；295(100％)；HRMS(EI)m/z calcd C10H12F3N3O2S(M+)295.0602,found 295.0605.
实施例14
4,4,4-三氟-N-(5-吗啉代噻唑-2-基)丁酰胺(化合物I-13)的制备
Figure PCTCN2017073472-appb-000026
将实施例13中的3,3,3-三氟丙酸替换成4,4,4-三氟丁酸，其余所需原料，试剂及制备方法同实施例13，得白色固体标题化合物，收率71％。
mp 199-201℃；1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),6.67(s,1H),3.76–3.66(m,4H),3.03–2.94(m,4H),2.71–2.54(m,4H).EI-MS m/z 309.1(M+)；185(100％)；HRMS(EI)m/z calcd C11H14F3N3O2S(M+)309.0759,found 309.0758.
实施例15
(3r,5r,7r)-N-(5-吗啉代噻唑-2-基)金刚烷-1-甲酰胺(化合物I-14)的制备
Figure PCTCN2017073472-appb-000027
将实施例2中的乙酰氯替换成金刚烷-1-甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率80％。
mp 190-194℃；1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),6.68(s,1H),3.77–3.65(m,4H),3.02–2.89(m,4H),2.03–1.94(m,3H),1.93–1.82(m,6H),1.73–1.61(m,6H).EI-MS m/z347.2(M+)；347(100％)；HRMS(EI)m/z calcd C18H25N3O2S(M+)347.1667,found 347.1668.
实施例16
N-(5-吗啉代噻唑-2-基)-2-苯基乙酰胺(化合物I-15)的制备
Figure PCTCN2017073472-appb-000028
将实施例2中的乙酰氯替换成苯乙酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率57％。
mp 175-179℃；1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),7.36–7.28(m,4H),7.28–7.21(m,1H),6.67(s,1H),3.77–3.64(m,6H),3.02–2.89(m,4H).EI-MS m/z 303.1(M+)；185(100％)；HRMS(EI)m/z calcd C15H17N3O2S(M+)303.1041,found 303.1042.
实施例17
N-(5-吗啉代噻唑-2-基)-3-苯基丙酰胺(化合物I-16)的制备
Figure PCTCN2017073472-appb-000029
将实施例2中的乙酰氯替换成氢化肉桂酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率72％。
mp 188-190℃；1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),7.32–7.15(m,5H),6.65(s,1H),3.76–3.65(m,4H),3.02–2.94(m,4H),2.89(t,J＝7.6Hz,2H),2.68(t,J＝7.7Hz,2H).EI-MS m/z 317.1(M+)；185(100％)；HRMS(EI)m/z calcd C16H19N3O2S(M+)317.1198,found317.1196.
实施例18
N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-17)的制备
Figure PCTCN2017073472-appb-000030
将实施例2中的乙酰氯替换成苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率68％。
mp 211-213℃；1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.05(d,J＝7.3Hz,2H),7.61(t,J＝7.3Hz,1H),7.53(t,J＝7.5Hz,2H),6.77(s,1H),3.81–3.67(m,4H),3.10–2.97(m,4H).EI-MS m/z 289.1(M+)；289(100％)；HRMS(EI)m/z calcd C14H15N3O2S(M+)289.0885,found 289.0887.
实施例19
4-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-18)的制备
Figure PCTCN2017073472-appb-000031
将实施例11中的环庚烷甲酸替换成4-乙酰氧基苯甲酸，其余所需原料，试剂及制备方法同实施例11，得黄色固体标题化合物，收率90％。
mp 212-215℃；1H NMR(400MHz,DMSO-d6)δ12.28(s,1H),8.09(d,J＝8.6Hz,2H),7.29(d,J＝8.6Hz,2H),6.77(s,1H),3.81–3.68(m,4H),3.09–2.97(m,4H),2.31(s,3H).EI-MS m/z347.1(M+)；121(100％)；HRMS(EI)m/z calcd C16H17N3O4S(M+)347.0940,found 347.0938.
实施例20
3-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-19)的制备
Figure PCTCN2017073472-appb-000032
将实施例11中的环庚烷甲酸替换成3-乙酰氧基苯甲酸，其余所需原料，试剂及制备方法同实施例11，得黄色固体标题化合物，收率95％。
mp 191-194℃；1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),7.96(d,J＝7.9Hz,1H),7.82(t,J＝1.9Hz,1H),7.57(t,J＝7.9Hz,1H),7.39(dd,J＝8.0,1.6Hz,1H),6.77(s,1H),3.79–3.67(m,4H),3.09–2.98(m,4H),2.31(s,3H).EI-MS m/z 347.1(M+)；347(100％)；HRMS(EI)m/z calcd C16H17N3O4S(M+)347.0940,found 347.0942.
实施例21
4-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-20)的制备
Figure PCTCN2017073472-appb-000033
将50毫克4-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-18)溶于5毫升四氢呋喃中，称取10毫克氢氧化锂溶于3毫升水中并加入上述反应液，室温搅拌反应过夜后，用稀盐酸调PH至3，然后加入适量水，并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得39毫克黄色固体标题化合物，收率90％。
mp 229-231℃；1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.25(s,1H),7.97–7.91(m,2H),6.88–6.82(m,2H),6.73(s,1H),3.78–3.68(m,4H),3.06–2.97(m,4H).EI-MS m/z 305.1(M+)；185(100％)；HRMS(EI)m/z calcd C14H15N3O3S(M+)305.0834,found 305.0833.
实施例22
3-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-21)的制备
Figure PCTCN2017073472-appb-000034
将实施例21中的4-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-18)替换成3-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-19)，其余所需原料，试剂及制备方法同实施例21，得黄色固体标题化合物，收率93％。
mp 228-232℃；1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.79(s,1H),7.49(d,J＝7.9Hz,1H),7.41–7.36(m,1H),7.30(t,J＝7.9Hz,1H),6.99(dd,J＝8.0,1.9Hz,1H),6.75(s,1H),3.78–3.69(m,4H),3.09–2.98(m,4H).EI-MS m/z 305.1(M+)；305(100％)；HRMS(EI)m/z calcd C14H15N3O3S(M+)305.0834,found 305.0835.
实施例23
N-(5-吗啉代噻唑-2-基)-2-(三氟甲基)苯甲酰胺(化合物I-22)的制备
Figure PCTCN2017073472-appb-000035
将实施例2中的乙酰氯替换成2-三氟甲基苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得白色固体标题化合物，收率43％。
mp 262-265℃；1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.00–7.55(m,4H),6.74(s,1H),3.89–3.57(m,4H),3.17–2.90(m,4H).EI-MS m/z 357.1(M+)；357(100％)；HRMS(EI)m/z calcd C15H14F3N3O2S(M+)357.0759,found 357.0760.
实施例24
2-氟-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-23)的制备
Figure PCTCN2017073472-appb-000036
将实施例2中的乙酰氯替换成2-氟苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率73％。
mp 204-207℃；1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),7.69(td,J＝7.6,1.5Hz,1H),7.65–7.56(m,1H),7.40–7.28(m,2H),6.75(s,1H),3.79–3.66(m,4H),3.09–2.97(m,4H).EI-MS m/z 307.1(M+)；307(100％)；HRMS(EI)m/z calcd C14H14FN3O2S(M+)307.0791,found307.0794.
实施例25
N-(5-吗啉代噻唑-2-基)-2-硝基苯甲酰胺(化合物I-24)的制备
Figure PCTCN2017073472-appb-000037
将实施例2中的乙酰氯替换成2-硝基苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率38％。
mp 245-248℃；1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.15(d,J＝8.2Hz,1H),7.86 (t,J＝7.4Hz,1H),7.81–7.73(m,2H),6.75(s,1H),3.82–3.65(m,4H),3.11–2.96(m,4H).EI-MS m/z 334.1(M+)；184(100％)；HRMS(EI)m/z calcd C14H14N4O4S(M+)334.0736,found334.0732.
实施例26
2-甲基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-25)的制备
Figure PCTCN2017073472-appb-000038
将实施例2中的乙酰氯替换成2-甲基苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率63％。
mp 223-226℃；1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),7.49(d,J＝7.4Hz,1H),7.45–7.37(m,1H),7.34–7.24(m,2H),6.73(s,1H),3.80–3.67(m,4H),3.09–2.96(m,4H),2.38(s,3H).EI-MS m/z 303.1(M+)；303(100％)；HRMS(EI)m/z calcd C15H17N3O3S(M+)303.1041,found 303.1043.
实施例27
2-甲氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺(化合物I-26)的制备
Figure PCTCN2017073472-appb-000039
将实施例2中的乙酰氯替换成2-甲氧基苯甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率33％。
mp 154-156℃；1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),7.71(dd,J＝7.6,1.7Hz,1H),7.59–7.52(m,1H),7.21(d,J＝8.4Hz,1H),7.09(t,J＝7.5Hz,1H),6.73(s,1H),3.92(s,3H),3.78–3.67(m,4H),3.07–2.96(m,4H).EI-MS m/z 319.1(M+)；135(100％)；HRMS(EI)m/z calcd C15H17N3O3S(M+)319.0991,found 319.0992.
实施例28
N-(5-吗啉代噻唑-2-基)-1-萘甲酰胺(化合物I-27)的制备
Figure PCTCN2017073472-appb-000040
将实施例2中的乙酰氯替换成1-萘甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率52％。
mp 248-250℃；1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.25–8.17(m,1H),8.11(d,J＝8.3Hz,1H),8.06–7.99(m,1H),7.85–7.77(m,1H),7.67–7.55(m,3H),6.78(s,1H),3.82–3.68(m,4H),3.13–2.98(m,4H).EI-MS m/z 339.1(M+)；155(100％)；HRMS(EI)m/z calcd C18H17N3O2S(M+)339.1041,found 339.1039.
实施例29
N-(5-吗啉代噻唑-2-基)-2-萘甲酰胺(化合物I-28)的制备
Figure PCTCN2017073472-appb-000041
将实施例2中的乙酰氯替换成2-萘甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率38％。
mp 221-225℃；1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.73(s,1H),8.13–7.97(m,4H),7.72–7.59(m,2H),6.79(s,1H),3.81–3.69(m,4H),3.12–2.99(m,4H).EI-MS m/z 339.1(M+)；155(100％)；HRMS(EI)m/z calcd C18H17N3O2S(M+)339.1041,found 339.1042.
实施例30
N-(5-吗啉代噻唑-2-基)呋喃-2-甲酰胺(化合物I-29)的制备
Figure PCTCN2017073472-appb-000042
将实施例2中的乙酰氯替换成2-呋喃甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得浅黄色固体标题化合物，收率63％。
mp 199-201℃；1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),7.98(s,1H),7.57(d,J＝3.1Hz,1H),6.75(s,1H),6.71(dd,J＝3.5,1.7Hz,1H),3.81–3.62(m,4H),3.12–2.92(m,4H).EI-MS m/z 279.1(M+)；279(100％)；HRMS(EI)m/z calcd C12H13N3O3S(M+)279.0678,found279.0679.
实施例31
N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺(化合物I-30)的制备
Figure PCTCN2017073472-appb-000043
将实施例2中的乙酰氯替换成2-噻吩甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率65％。
mp 202-205℃；1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.16(s,1H),7.92(d,J＝4.8Hz,1H),7.23(dd,J＝4.8,4.0Hz,1H),6.75(s,1H),3.78–3.68(m,4H),3.07–2.96(m,4H).EI-MS m/z 295.0(M+)；295(100％)；HRMS(EI)m/z calcd C12H13N3O2S2(M+)295.0449,found295.0452.
实施例32
N-(5-吗啉代噻唑-2-基)呋喃-3-甲酰胺(化合物I-31)的制备
Figure PCTCN2017073472-appb-000044
将实施例11中的环庚烷甲酸替换成3-呋喃甲酸，其余所需原料，试剂及制备方法同实施例11，得白色固体标题化合物，收率65％。
mp 232-235℃；1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),8.50(d,J＝0.5Hz,1H),7.81(t,J＝1.7Hz,1H),7.10–7.03(m,1H),6.74(s,1H),3.79–3.65(m,4H),3.08–2.94(m,4H). EI-MS m/z 279.1(M+)；279(100％)；HRMS(EI)m/z calcd C12H13N3O3S(M+)279.0678,found279.0677.
实施例33
N-(5-吗啉代噻唑-2-基)噻吩-3-甲酰胺(化合物I-32)的制备
Figure PCTCN2017073472-appb-000045
将实施例11中的环庚烷甲酸替换成3-噻吩甲酸，其余所需原料，试剂及制备方法同实施例11，得浅黄色固体标题化合物，收率63％。
mp 218-221℃；1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),8.53(d,J＝1.5Hz,1H),7.75–7.63(m,2H),6.75(s,1H),3.80–3.67(m,4H),3.08–2.96(m,4H).EI-MS m/z 295.1(M+)；295(100％)；HRMS(EI)m/z calcd C12H13N3O2S2(M+)295.0449,found 295.0450.
实施例34
5-氯-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺(化合物I-33)的制备
Figure PCTCN2017073472-appb-000046
将实施例2中的乙酰氯替换成5-氯-2-噻吩甲酰氯，其余所需原料，试剂及制备方法同实施例1-2，得黄色固体标题化合物，收率94％。
mp 222-225℃；1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),7.99(s,1H),7.26(d,J＝3.9Hz,1H),6.75(s,1H),3.82–3.65(m,4H),3.09–2.94(m,4H).EI-MS m/z 329.0(M+)；329(100％)；HRMS(EI)m/z calcd C12H12 35ClN3O2S2(M+)329.0059,found 329.0061,calcd C12H12 37ClN3O2S2(M+)331.0030,found 331.0031.
实施例35
5-甲基-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺(化合物I-34)的制备
Figure PCTCN2017073472-appb-000047
将实施例11中的环庚烷甲酸替换成5-甲基-2-噻吩甲酸，其余所需原料，试剂及制备方法同实施例11，得浅黄色固体标题化合物，收率89％。
mp 195-197℃；1H NMR(400MHz,Acetone-d6)δ10.89(s,1H),7.93(d,J＝3.5Hz,1H),6.92(d,J＝2.8Hz,1H),6.66(s,1H),3.86–3.69(m,4H),3.13–2.97(m,4H),2.55(s,3H).EI-MS m/z 309.1(M+)；125(100％)；HRMS(EI)m/z calcd C13H15N3O2S2(M+)309.0606,found309.0607.
实施例36
3-甲基-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺(化合物I-35)的制备
Figure PCTCN2017073472-appb-000048
将实施例11中的环庚烷甲酸替换成3-甲基-2-噻吩甲酸，其余所需原料，试剂及制备方法同实施例11，得浅黄色固体标题化合物，收率81％。
mp 160-162℃；1H NMR(400MHz,Acetone-d6)δ10.78(s,1H),7.62(d,J＝5.0Hz,1H),7.04(d,J＝5.0Hz,1H),6.62(s,1H),3.83–3.72(m,4H),3.11–3.01(m,4H),2.58(s,3H).EI-MS m/z 309.1(M+)；125(100％)；HRMS(EI)m/z calcd C13H15N3O2S2(M+)309.0606,found 309.0605.
实施例37
N-(5-吗啉代噻唑-2-基)-2-氧代环己烷甲酰胺(化合物I-36)的制备
Figure PCTCN2017073472-appb-000049
将1克2-环己酮甲酸乙酯溶于10毫升四氢呋喃中，称取705毫克氢氧化钠溶于5毫升水中，并加入上述反应液中，加热至60℃反应过夜，待反应完全后，冷却，用稀盐酸调PH至3左右，然后加入适量水并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得粗品2-环己酮甲酸，794毫克无色油，随后直接投下一步反应。将实施例13中的3,3,3-三氟丙酸替换成2-环己酮甲酸，其余所需原料，试剂及制备方法同实施例13，得浅黄色固体标题化合物，收率21％。
mp 175-178℃；1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),6.67(s,1H),3.78–3.67(m,4H),3.61(dd,J＝12.2,5.6Hz,1H),3.05–2.93(m,4H),2.45–2.23(m,2H),2.15–1.75(m,4H),1.73–1.56(m,2H).EI-MS m/z 309.1(M+)；185(100％)；HRMS(EI)m/z calcd C14H19N3O3S(M+)309.1147,found 309.1145.
实施例38
N-(5-吗啉代噻唑-2-基)-3-氧代丁酰胺(化合物I-37)的制备
Figure PCTCN2017073472-appb-000050
将1克3-氧代丁酸乙酯溶于10毫升四氢呋喃中，称取922毫克氢氧化钠溶于5毫升水中，并加入上述反应液中，加热至60℃反应过夜，待反应完全后，冷却，用稀盐酸调PH至3左右，然后加入适量水并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得粗品3-氧代丁酸，752毫克无色油，直接投下一步反应。将实施例13中的3,3,3-三氟丙酸替换成3-氧代丁酸，其余所需原料，试剂及制备方法同实施例13，得浅黄色固体标题化合物，收率25％。
mp 172-176℃；1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),6.68(s,1H),3.77–3.67(m,4H),3.63(s,2H),3.04–2.93(m,4H),2.18(s,3H).EI-MS m/z 269.1(M+)；185(100％)；HRMS(EI)m/z calcd C11H15N3O3S(M+)269.0834,found 269.0833.
实施例39
N-(5-吗啉代噻唑-2-基)-3-氧代戊酰胺(化合物I-38)的制备
Figure PCTCN2017073472-appb-000051
将1克3-氧代戊酸乙酯溶于10毫升四氢呋喃中，称取832毫克氢氧化钠溶于5毫升水中， 并加入上述反应液中，加热至60℃反应过夜，待反应完全后，冷却，用稀盐酸调PH至3左右，然后加入适量水并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得粗品3-氧代戊酸，765毫克无色油，直接投下一步反应。将实施例13中的3,3,3-三氟丙酸替换成3-氧代戊酸，其余所需原料，试剂及制备方法同实施例13，得白色固体标题化合物，收率53％。
mp 163-166℃；1H NMR(400MHz,DMSO-d6)δ11.79(s,1H),6.68(s,1H),3.77–3.67(m,4H),3.62(s,2H),3.04–2.93(m,4H),2.58–2.51(m,2H),0.94(t,J＝7.2Hz,3H).EI-MS m/z283.1(M+)；185(100％)；HRMS(EI)m/z calcd C12H17N3O3S(M+)283.0991,found 283.0992.
实施例40
N-(5-吗啉代噻唑-2-基)-3-氧代己酰胺(化合物I-39)的制备
Figure PCTCN2017073472-appb-000052
将1克3-氧代己酸乙酯溶于10毫升四氢呋喃中，称取759毫克氢氧化钠溶于5毫升水中，并加入上述反应液中，加热至60℃反应过夜，待反应完全后，冷却，用稀盐酸调PH至3左右，然后加入适量水并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂得粗品3-氧代己酸，789毫克无色油，直接投下一步反应。将实施例13中的3,3,3-三氟丙酸替换成3-氧代己酸，其余所需原料，试剂及制备方法同实施例13，得白色固体标题化合物，收率28％。
mp 173-176℃；1H NMR(400MHz,Acetone-d6)δ10.73(s,1H),6.64(s,1H),3.80–3.73(m,4H),3.06–2.99(m,4H),2.82(s,2H),2.60(t,J＝7.2Hz,2H),1.62–1.55(m,2H),0.90(t,J＝7.4Hz,2H).EI-MS m/z 297.1(M+)；185(100％)；HRMS(EI)m/z calcd C13H19N3O3S(M+)297.1147,found 297.1145.
实施例41
3-羟基-N-(5-吗啉代噻唑-2-基)戊酰胺(化合物I-40)的制备
Figure PCTCN2017073472-appb-000053
将50毫克N-(5-吗啉代噻唑-2-基)-3-氧代戊酰胺(化合物I-38)溶于5毫升甲醇中，控制温度0℃下，分批加入8毫克硼氢化钠，0℃下继续反应10分钟，待反应完全后，加入适量水并用乙酸乙酯萃取，有机层干燥过滤，减压蒸除溶剂后得44毫克白色固体标题化合物，收率88％。
mp 114-117℃；1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),6.66(s,1H),4.72(d,J＝5.4Hz,1H),3.89–3.78(m,1H),3.77–3.66(m,4H),3.04–2.91(m,4H),2.43(d,J＝6.5Hz,2H),1.47–1.29(m,2H),0.86(t,J＝7.4Hz,3H).EI-MS m/z 285.1(M+)；185(100％)；HRMS(EI)m/z calcd C12H19N3O3S(M+)285.1147,found 285.1144.
实施例42
本发明化合物对P70S6K的磷酸化百分抑制活性的测定实验及活性结果。
本发明对合成的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，在SH-SY5Y细胞中，通过α-screen法检测化合物对P70S6K的磷酸化百分抑制活性。实验方法如下：
细胞铺96孔板后，待密度长至80％左右后，加入化合物处理30分钟，然后用PBS清洗 一遍，吸去PBS，加入α-screen试剂盒(PerkinElmer公司)中的细胞裂解液，裂解15-20分钟，转移至白色384不透板用α-screen试剂盒进行检测。
实验结果如表1所示。
表1.N-(5-吗啉代噻唑-2-基)甲酰胺类化合物对P70S6K的磷酸化抑制活性
Figure PCTCN2017073472-appb-000054
由表1可看出，本发明的具有结构通式I的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物大部分对P70S6K的磷酸化具有较强的抑制作用，而P70S6K是mTOR的直接底物，P70S6K的磷酸化强度直接反应了mTOR的磷酸化强度，说明本发明化合物可抑制AKT/mTOR通路激活。
实施例43
本发明化合物通过血脑屏障能力的测试。
本实施例选取15个对P70S6K的磷酸化抑制活性大于70％的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，通过平行人造膜渗透性实验，检测其透血脑屏障能力。
实验方法：取4μL 2％猪脑组织提取物(20mg猪脑组织提取物PBL，1mL正十二烷)溶液加于MAIPs4550的96孔板的疏水膜上，定量吸取200μL待测样品液(100μg/ml，溶于2％DMSO缓冲盐溶液)加入到96孔板中的膜上方作为给药池，膜另一侧加入300μL缓冲盐(pH 7.4PBS：乙醇＝70:30)为接受池，注意保持接受液与膜的充分接触；室温静止10h后，小心移除给药池，用UV光谱仪测试接受池内化合物吸光度值(250-500nm)；吸取200μL待测样品液与300μl缓冲盐(pH 7.4PBS：乙醇＝70:30)充分混匀，作为理论平衡溶液，测试其吸光度值(250-500nm)，需要用acceptor板测试；
根据公式计算Pe值：
Figure PCTCN2017073472-appb-000055
Vd：给药池体积，Va：接受池体积，A：疏水膜表面积，t：作用时间，[drug]acceptor：接收池中化合物吸光度，[drug]equilibrium：理论上接收池中化合物吸光度。
实验结果如表2所示，结果表明N-(5-吗啉代噻唑-2-基)甲酰胺类化合物能透过血脑屏障或处于不确定状态，具有成药的可能性。
表2.化合物Pe值
序号 编号 Pe(10-6cm s-1) 序号 编号 Pe(10-6cm s-1)
1 I-16 10.50±1.13(CNS+) 9 I-29 6.16±0.50(CNS+)
2 I-17 12.62±1.22(CNS+) 10 I-30 10.41±1.25(CNS+)
3 I-18 4.92±0.31(CNS+) 11 I-31 6.82±0.50(CNS+)
4 I-19 6.02±0.27(CNS+) 12 I-32 9.24±0.47(CNS+)
5 I-20 0.09±0.01(CNS+/-) 13 I-33 10.62±0.10(CNS+)
6 I-21 0.45±0.03(CNS+/-) 14 I-34 9.89±0.37(CNS+)
7 I-27 5.76±0.55(CNS+) 15 I-35 9.88±0.75(CNS+)
8 I-28 3.42±0.07(CNS+)      
CNS+：能通过血脑屏障；CNS+/-：不确定
由表2可以看出，本发明的具有结构通式I的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物大部分能通过血脑屏障。
实施例44
本发明化合物对AKT/mTOR通路激活的抑制及促进细胞内自噬作用实验与实验结果。
以2个对P70S6K的磷酸化具有抑制活性及透血脑屏障较好的I-19、I-33为例，同时以Wortmainnin与硝唑尼特(Nitazoxanide,NTZ)为阳性对照，在BV2细胞中利用western blot检测化合物对AKT/mTOR通路的作用。
BV2细胞接种至12孔板中，加入不同浓度的化合物(化合物溶于DMSO中配置成20mM浓度的母液，并用培养基稀释成不同浓度)共孵育24小时，然后吸出培养基用PBS洗涤细胞2次后，直接加入SDS-PAGE的2×上样缓冲液(loading buffer)裂解细胞，收集细胞裂解液于99℃煮样15分钟后，4℃ 12000rpm离心1分钟，冻存于-20℃备用。根据所需要检测的蛋白的分子量选择浓度不同的SDS-PAGE胶，将处理好的细胞样品吸取上清装载于SDS-PAGE的上样孔，每孔上样8μL，待loading buffer跑出胶即采用半干法进行转膜，通常转膜时间为90分钟，也可根据蛋白分子量进行调整，蛋白分子量越大，转膜时间越长。转膜结束后，剪下目的蛋白分子量所在条带，用5％的脱脂奶粉封闭1个小时，然后孵育相应的一抗4℃过夜。孵育结束后收集一抗，用TBST缓冲液洗涤3次，每次15分钟。接着室温孵育二抗2小时，然后仍用TBST缓冲液洗膜3次。最后用辣根过氧化物酶(HRP)底物孵育5分钟后，利用美国通用的光信号收集仪器(ImageQuant LAS4000mini)收集信号。
实验结果如图1所示。由图1可看出，western blot检测显示化合物I-19(A)、I-33(B)降低了AKT、mTOR及其下游的P70S6K的磷酸化水平，说明本发明化合物能够抑制AKT/mTOR通路的激活。同时，由图1还可看出，化合物抑制了自噬起始因子ULK1的757位点磷酸化失活，降低了自噬负调控蛋白p62的蛋白水平，说明本发明化合物能增强自噬。
实施例45
本发明化合物增加Aβ清除实验与实验结果。
以化合物I-19为例，在BV2细胞中进行细胞对外源性Aβ清除的实验以检测化合物对Aβ清除的影响，本实验基于BV2细胞能够通过胞内吞等作用将外源性的Aβ转入细胞内，然后通过相关途径将外源性的Aβ降解。
实验方法如下：细胞接种于12孔板中，待细胞长至80％时，加入不同浓度的化合物(化合物溶于DMSO中配置成20mM浓度的母液，并用培养基稀释成不同浓度)共孵育24小时，然后加入2μg/mL的Aβ继续培养3小时，吸去培养基，PBS洗涤细胞2遍后，每孔加入200μL1％SDS裂解液(含有1％蛋白酶抑制剂)裂解细胞，于37℃裂解15分钟收集上清，然后12,000g离心15分钟，上清中的Aβ通过ELISA的方法测定，并用BCA法测定细胞内蛋白浓度，测得的Aβ含量再除以各样品总蛋白浓度，排除细胞密度对Aβ含量的干扰。
ELISA检测：将细胞裂解的上清用标准稀释液进行80倍稀释，然后按照Aβ试剂盒(购自invitrogen公司)所提供方法进行检测。即在室温下将稀释后的上清、Aβ抗体和藕联Aβ另一种抗体的96孔板共同孵育3小时，然后用试剂盒中提供的漂洗液进行洗板4次，再加入藕联有辣根过氧化物酶的二抗室温下孵育30分钟，再用漂洗液洗板五次，然后加入显色液于室温孵育30分钟，最后加入反应中止液。以Bio-Rad酶标仪在450nm处读取OD值。
实验结果如图2所示。由图2可看出，本发明化合物能够浓度依赖性减少BV2细胞内的Aβ含量，说明本发明化合物具有明显的浓度依赖性的增加Aβ清除的作用。
实施例46
本发明化合物抑制Tau蛋白磷酸化实验与实验结果。
以化合物I-19、I-33为例，以LiCl与NTZ为阳性对照，通过Western blot实验检测化合物对Tau蛋白磷酸化水平的调节作用，且对Tau蛋白的多个磷酸化位点都进行了检测。
实验方法如下：在细胞实验中，SH-SY5Y细胞培养于六孔板中，待细胞密度为70％时加入不同浓度的化合物(化合物溶于DMSO中配置成20mM浓度的母液，并用培养基稀释成不同浓度)，培养24小时，随后吸取培养液，并以PBS清洗3次，随后细胞用SDS-PAGE收样缓冲液(25％SDS，62.5mM Tris，25％甘油，0.1％溴芬蓝，pH6.8)收集于1.5mL的EP管中，于98℃加热处理15分钟，然后于4℃以10，000g离心10分钟。上清进行SDS-PAGE电泳，随后采用半干法电转转膜90分钟，接着将膜于TBST封闭液(TBS，0.5％吐温20，5％脱脂奶粉)中封闭30分钟。将封闭后的膜与相应于4℃孵育过夜。第二天用TBST缓冲液(TBS，0.5％吐温20)洗膜3次(每次15分钟)，然后与二抗进行孵育2小时。随后同样采用TBST缓冲液洗膜3次(每次15分钟)。最后与辣根过氧化物酶(HRP)底物孵育5分钟，然后采用美国通用的光信号收集仪器(ImageQuant LAS4000mini)收集信号。
实验结果如图3所示。由图3可以看出，western blot检测显示化合物I-19(A)、I-33(B)抑制了Tau蛋白多个位点的磷酸化，说明本发明化合物能够抑制Tau蛋白过度磷酸化。
实施例47
本发明化合物逆转阿尔茨海默病转基因模型小鼠记忆力损伤的作用实验与实验结果。
以化合物I-19为例，同时以NTZ为阳性对照，通过灌胃给药给予APP/PS1双转基因AD模型小鼠化合物，然后通过水迷宫实验测定化合物对转基因AD模型小鼠记忆力损伤改善作用。APP/PS1双转基因AD模型小鼠(APPswe，PS1dE9)能高表达嵌和鼠/人的瑞典突变 APP(Mo/HuAPP695swe)和人源删除第9个外显子的早老素1蛋白(presenilin，PS1-dE9)，这类转基因小鼠会在6个月的时候出现较明显的Aβ沉积并且会在7个月的时候出现空间记忆力的损害。实验方法如下：
APP/PS1双转基因AD模型小鼠购买于美国的Jackson Laboratory公司，然后繁殖。对子代小鼠的转基因型鉴定，通过采用对小鼠剪尾，然后PCR鉴定小鼠的APP/PS1的基因序列。以非转基因小鼠作为实验中的阴性对照小鼠。小鼠在标准条件下饲养(12/12小时明暗循环，足够水和食物，22℃的恒温，60％的湿度)。
AD模型小鼠给药：在小鼠9月大小时，40只转基因小鼠被随机均分为4组(转基因溶剂组，转基因NTZ组，转基因I-19 10mg/kg剂量组，转基因I-19 30mg/kg剂量组)，10只非转基因小鼠作为阴性对照组。化合物溶解于26％PEG400、15％HS15的生理盐水中，然后开始连续灌胃给药，溶剂组给予26％PEG400、15％HS15的生理盐水，100天后进行行为学实验检测(Morris水迷宫实验)。
Morris水迷宫实验：Morris水迷宫仪器为一个直径为1.5米，深60厘米的圆形水池，水池中注入牛奶将水染成白色，实验过程中水温保持25℃左右，用和电脑相连接的数码相机来记录小鼠的游泳轨迹。将水池分为四个象限，其中一个象限的水池液面下1.5厘米有一个直径为10厘米的平台，训练小鼠寻找并记忆平台所在位置；让小鼠每天进行三次训练，持续八天的时间；在三次训练中分别将小鼠面向池壁于三个除平台所在的象限中置于水中，然后给小鼠90秒钟时间去寻找平台位置，如果90秒钟内不能找到平台，会将小鼠置于平台之上；不管是哪种情况下站到平台之上的小鼠都会让它在平台上放置15秒钟时间以帮助它记忆平台位置；记录小鼠寻找到平台的时间作为小鼠记忆力的评价指标，每天取三次训练的结果取平均值，8天时间每组小鼠潜伏期的线形图见图4中(A)。在第八天，在三次训练之后，小鼠会进行平台寻找实验；在这次实验中，潜于水面下的平台被撤除，然后让小鼠在水池中持续90秒钟去寻找平台，记录小鼠穿越平台所在位置次数同样作为评价小鼠记忆力的指标，第8天三组小鼠穿台次数的柱状图见图4中(B)。
图4中，NV表示非转基因溶剂组，TV表示转基因溶剂组，NTZ-30mg/Kg表示转基因NTZ 30mg/Kg剂量组，L-10mg/Kg表示转基因I-19 10mg/Kg剂量组，H-30mg/Kg表示转基因I-19 30mg/Kg剂量组。
由图4中(A)可以看出，非转基因小鼠的潜伏期随着训练天数的增加而迅速缩短，而转基因AD小鼠的潜伏期缩短幅度则明显小于非转基因组的小鼠，但在30mg/kg/day给药处理后的转基因小鼠的潜伏期对比溶剂组明显的改善，且几乎与非转基因组小鼠相当，说明APP/PS1的转基因模型小鼠的记忆力出现明显的损伤，化合物I-19能够明显的逆转这种记忆力损伤。由图4中(B)可以看出，最后一天的平台寻找实验中，转基因小鼠穿越平台所在位置的次数明显少于非转基因小鼠，而化合物I-19给药的转基因小鼠的穿越平台所在位置的次数明显比溶剂处理的转基因小鼠多，进一步说明了APP/PS1的转基因模型小鼠的记忆力出现明显的损伤，而化合物I-19能够明显的逆转这种记忆力损伤。
实施例48
本发明化合物对hERG钾通道作用实验与实验结果。
以化合物I-19、I-33为例，通过全自动膜片钳QPatch检测化合物对hERG钾通道的作用。 实验方法如下：
细胞准备：CHO-hERG细胞培养于175cm2培养瓶中，待细胞密度生长到60～80％，移走培养液，用7mL PBS洗一遍，然后加入3mL Detachin消化。待消化完全后加入7mL培养液中和，然后离心，吸走上清液，再加入5mL培养液重悬，以确保细胞密度为2～5×106/mL。
溶液配置：细胞内液和外液的组成成分如表3所示。
表3.细胞内液和外液的组成成分
Figure PCTCN2017073472-appb-000056
电生理记录过程：单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch仪器自动完成，在获得全细胞记录模式后，细胞钳制在-80毫伏，在给予一个5秒的+40毫伏去极化刺激前，先给予一个50毫秒的-50毫伏前置电压，然后复极化到-50毫伏维持5秒，再回到-80毫伏。每15秒施加此电压刺激，记录2分钟后给予细胞外液记录1分钟，然后开始给药过程，化合物浓度从最低测试浓度开始，每个测试浓度给予1分钟，连续给完所有浓度后，给予阳性对照化合物10μM Cisapride。每个浓度至少测试3个细胞(n≥3)。
化合物准备：将20mM的化合物母液(溶于DMSO)用细胞外液进行稀释，取2μL 20mM的化合物母液加入998μL细胞外液，然后在含0.2％DMSO的细胞外液中依次进行5倍连续稀释得到需要测试的最终浓度。最高测试浓度为40μM，依次分别为40，8，1.6，0.32，0.064，0.0128μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。
实验数据由XLFit软件进行分析。实验结果如下：
表4.化合物对hERG钾通道的抑制活性数据(IC50,μM)
序号 编号 最大浓度抑制率(％) IC50(μM)
1 I-19 19.00 >40
2 I-33 0.85 >40
>40μM指该化合物抑制效应在40μM时小于50％
由表4可看出，本发明化合物I-19、I-33对hERG钾通道的抑制活性较差，说明本发明化合物心脏安全性较好。
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. 一种式I所示化合物，或其药学上可接受的盐：
    Figure PCTCN2017073472-appb-100001
    式中，R为取代或未取代的C1～C8直链或支链烷基，取代或未取代的C3～C20环烷基，取代或未取代的C6～C20芳基、取代或未取代的C3～C10杂芳基，
    所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷基、C6～C10芳基、＝O、-O-C(＝O)-C1～C6烷基。
  2. 如权利要求1所述的化合物，其特征在于，R为取代或未取代的C1～C6直链或支链烷基，所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C6烷氧基、卤代C1～C6烷基、C6～C10芳基、＝O、-O-C(＝O)-C1～C6烷基。
  3. 如权利要求1所述的化合物，其特征在于，R为取代或未取代的C3～C12环烷基，所述取代是指被选自下组的一个或多个取代基取代：C1～C6烷基、卤素、硝基、羟基、C1～C6烷氧基、卤代C1～C6烷基、＝O、-O-C(＝O)-C1～C6烷基。
  4. 如权利要求1所述的化合物，其特征在于，R为取代或未取代的C6～C10芳基，所述取代是指被选自下组的一个或多个取代基取代：羟基、卤代C1～C4烷基、氟、氯、硝基、C1～C4烷基、C1～C4烷氧基、-O-C(＝O)-C1～C4烷基。
  5. 如权利要求1所述的化合物，其特征在于，R为取代或未取代的C3～C6杂芳基，所述取代是指被选自下组的一个或多个取代基取代：卤素、硝基、羟基、C1～C4烷基、卤代C1～C4烷基、C1～C4烷氧基。
  6. 如权利要求1所述的N-(5-吗啉代噻唑-2-基)甲酰胺类化合物，其特征在于，所述的化合物是：N-(5-吗啉代噻唑-2-基)乙酰胺、N-(5-吗啉代噻唑-2-基)丙酰胺、N-(5-吗啉代噻唑-2-基)丁酰胺、N-(5-吗啉代噻唑-2-基)己酰胺、3-甲基-N-(5-吗啉代噻唑-2-基)丁酰胺、N-(5-吗啉代噻唑-2-基)环丙烷甲酰胺、N-(5-吗啉代噻唑-2-基)环丁烷甲酰胺、N-(5-吗啉代噻唑-2-基)环戊烷甲酰胺、N-(5-吗啉代噻唑-2-基)环己烷甲酰胺、N-(5-吗啉代噻唑-2-基)环庚烷甲酰胺、2,2,3,3,4,4,4-七氟-N-(5-吗啉代噻唑-2-基)丁酰胺、3,3,3-三氟-N-(5-吗啉代噻唑-2-基)丙酰胺、4,4,4-三氟-N-(5-吗啉代噻唑-2-基)丁酰胺、(3r,5r,7r)-N-(5-吗啉代噻唑-2-基)金刚烷-1-甲酰胺、N-(5-吗啉代噻唑-2-基)-2-苯基乙酰胺、N-(5-吗啉代噻唑-2-基)-3-苯基丙酰胺、N-(5-吗啉代噻唑-2-基)苯甲酰胺、4-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、3-乙酰氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、4-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、3-羟基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-2-(三氟甲基)苯甲酰胺、2-氟-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-2-硝基苯甲酰胺、2-甲基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、2-甲氧基-N-(5-吗啉代噻唑-2-基)苯甲酰胺、N-(5-吗啉代噻唑-2-基)-1-萘甲酰胺、N-(5-吗啉代噻唑-2-基)-2-萘甲酰胺、N-(5-吗啉代噻唑-2-基)呋喃-2-甲酰胺、N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、N-(5-吗啉代噻唑-2-基)呋喃-3-甲酰胺、N-(5-吗啉代噻唑-2-基)噻吩-3-甲酰胺、5-氯-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、5-甲基-N-(5-吗啉代噻唑-2-基)噻吩-2-甲酰胺、3-甲基-N-(5-吗啉 代噻唑-2-基)噻吩-2-甲酰胺、N-(5-吗啉代噻唑-2-基)-2-氧代环己烷甲酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代丁酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代戊酰胺、N-(5-吗啉代噻唑-2-基)-3-氧代己酰胺或3-羟基-N-(5-吗啉代噻唑-2-基)戊酰胺。
  7. 一种式I所示化合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    Figure PCTCN2017073472-appb-100002
    式II化合物与式III化合物反应得到式I所示化合物，
    式中，R的定义如权利要求1所述，
    A为氯原子或羟基。
  8. 一种药物组合物，其特征在于，所述药物组合物包括权利要求1-6任一项所述的化合物或其药学上可接受的盐；和药学上可接受的载体。
  9. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、或权利要求8所述的药物组合物的用途，其特征在于，用于制备用于治疗与Aβ清除及/或Tau蛋白磷酸化相关的神经退行性疾病的药物。
  10. 如权利要求1-6任一项所述的化合物或其药学上可接受的盐、或权利要求8所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗阿尔茨海默病的药物。
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