CN114805334B - QC and GSK-3 beta multi-targeting inhibitor and preparation method and application thereof - Google Patents

QC and GSK-3 beta multi-targeting inhibitor and preparation method and application thereof Download PDF

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CN114805334B
CN114805334B CN202210569047.4A CN202210569047A CN114805334B CN 114805334 B CN114805334 B CN 114805334B CN 202210569047 A CN202210569047 A CN 202210569047A CN 114805334 B CN114805334 B CN 114805334B
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吴海强
魏定钧
周晴晴
王亦男
蔡嘉欣
熊炜
李晨阳
许晨舒
秦菲霞
刘娇
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Abstract

The invention provides a QC and GSK-3 beta multi-targeting inhibitor, a preparation method and application thereof, wherein the chemical structural general formula of the QC and GSK-3 beta multi-targeting inhibitor is as follows:
Figure DDA0003659469640000011
the invention provides a preparation method of the novel inhibitor, which has the advantages of easily available raw materials and simple and feasible preparation method. The novel inhibitor provided by the invention remarkably expands molecular structure diversity of QC and GSK-3 beta multi-target inhibitors, and can be widely used for QC and/or GSK-3 beta specific high-expression related disease treatment drugs, diagnostic reagents and the like.

Description

QC and GSK-3 beta multi-targeting inhibitor and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a QC and GSK-3 beta multi-targeting inhibitor and a preparation method and application thereof.
Technical Field
Alzheimer's Disease (AD) is a neurodegenerative disease, and early symptoms include difficulty in recall of recent dialogues, names or events, and the like, and along with the development of the disease, patients have symptoms such as impaired communication ability, confusion of thinking, behavior change, poor judgment, and the like. With the rapid development of global aging, the incidence of AD and the number of patients are rapidly increased, the number of dead people is increased year by year, and the economic burden caused by AD is huge, which becomes a health, economic and social problem worldwide. AD pathological features mainly include Amyloid plaques composed of aβ (amylase- β), neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau protein, inflammation, etc. However, the pathogenesis of AD is not completely clear, no specific medicine exists clinically, and the development of innovative anti-AD medicines is urgent.
Glutaminyl cyclase (Glutaminyl Cyclase, QC) is an enzyme that catalyzes the formation of pyroglutamic acid (pE) from N-terminal glutamine/glutamate during post-translational modification of active peptides or proteins, which catalyzes the formation of stable five membered rings from primary amines on the alpha and delta carbon atoms of glutamine/glutamate, releasing one molecule of NH 3 /H 2 O can change the chemical structure of N end of peptide or protein, regulate its activity, raise stability, etc. However, abnormal elevation of QC activity plays a key regulatory role in the onset of a variety of major diseases such as AD. In recent years, it has been found that, compared with the normal senile brain Abeta senile plaque, the main component of the AD brain senile plaque is not Abeta, but mutated Abeta, in particular pE-Abeta formed by intramolecular cyclization of N-terminal glutamine residues of Abeta 3-42 /pE-Aβ 3-40 (content more than 50%). Compared with Abeta, pE-Abeta has stronger neurotoxicity, higher stability and enzymolysis resistanceForce, aggregation speed is faster and aβ aggregation can be further promoted, etc. Meanwhile, the high-expression QC can induce systemic neuritis and the like through catalyzing and generating factors such as pE-CCL2 and the like, so that the onset of AD is further accelerated. Early in onset, AD patients exhibited high expression of specificity in brain QC. Therefore, QC high expression is a key factor for the onset and development of AD, and is expected to become an important new target for developing innovative anti-AD drugs.
Glycogen synthase kinase-3 (glycogen synthase kinase-3, GSK-3) is a kinase that regulates glycogen synthase activity by phosphorylation, and is closely related to apoptosis, differentiation, proliferation, microtubule morphology maintenance, and the like. Two isoenzymes GSK-3 alpha and GSK-3 beta have been found, and GSK-3 beta has important regulation and control effects on Tau phosphorylation. Tau protein is a microtubule-associated protein (MAP) that stabilizes microtubules by immobilizing combinations of microtubules, whose function and affinity for microtubules is primarily dependent on autophosphorylation status. In AD, tau protein is hyperphosphorylated and accumulated in the cytoplasm, resulting in microtubule disintegration, loss of neuronal integrity, and ultimately formation of NFTs. At the same time, GSK-3 beta can act on APP, participating in the production of aβ and subsequent deposition in AD brain, inducing the appearance of aβ pathological features by disrupting insulin signaling pathways. In addition, abnormally activated GSK-3β may cause synaptic dysfunction leading to memory deficit, inhibiting adult hippocampal nerves; regulate biological reaction of microglial cells, promote the production of inflammatory factors, and cause neuronal death, etc. Therefore, GSK-3 beta can be used as another important target point for research of anti-AD drugs.
In view of the important role of abnormal up-regulation of QC and GSK-3 beta activity in the pathogenesis of AD, the development of a multi-target inhibitor acting on QC and GSK-3 beta will open a new idea for innovative anti-AD drug research. However, there are only a few reports of such inhibitors.
Accordingly, the prior art is still in need of improvement and development.
Disclosure of Invention
In view of the shortcomings of the prior art, the invention aims to provide a QC and GSK-3 beta multi-targeting inhibitor, a preparation method and application thereof, which aim to act on a plurality of targets related to AD diseases, and the synergistic effect can enable the inhibitor drug to exert better curative effect and generate fewer side effects.
The technical scheme of the invention is as follows:
QC and GSK-3 beta multi-target inhibitor, wherein the structural general formula is as follows:
Figure GDA0004184765990000031
wherein the A unit is one of benzene ring, six-membered aromatic heterocycle, five-membered aromatic heterocycle, seven-membered aromatic ring, anthracene, naphthalene, anthraquinone and multiple aromatic ring system, R 1 Is one of hydrogen, alkyl, alkoxy, nitro, amino, halogen, sulfonic acid group and ester group, and R 1 Is monosubstituted or polysubstituted at different positions; the B unit is a five-membered heterocycle or a six-membered heterocycle system, and the carbon atom n=1-4 in the alkyl chain; the C unit is imidazole ring or triazole ring heterocyclic ring system, R 2 Is one of hydrogen, linear alkyl, branched alkyl, alkoxy and halogen, and R 2 Is monosubstituted or polysubstituted at different positions; the substitution positions of the A and C units on the B ring are meta positions.
A method for preparing a multi-targeted inhibitor of QC and GSK-3 beta, comprising the steps of:
to be used for
Figure GDA0004184765990000032
And thiourea or->
Figure GDA0004184765990000033
The raw materials undergo a cyclization or coupling reaction for a first preset time to prepare an intermediate +.>
Figure GDA0004184765990000034
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl;
in the form of intermediates
Figure GDA0004184765990000035
Preparing an intermediate containing amino protecting groups by amino protecting reaction for a second preset time as a raw material>
Figure GDA0004184765990000036
In the form of intermediates
Figure GDA0004184765990000037
Preparing intermediate containing alkyl chain at the end of the structure by ring opening or bromination reaction for a third preset time>
Figure GDA0004184765990000038
In the form of intermediates
Figure GDA0004184765990000041
And an imidazole ring or triazole ring heterocyclic ring system as raw materials, and performing SN2 reaction for a fourth preset time to prepare an intermediate containing the imidazole ring or the triazole ring ∈>
Figure GDA0004184765990000042
In the form of intermediates
Figure GDA0004184765990000043
The amino group-containing intermediate ++is prepared by the deprotection reaction of amino group for the fifth predetermined time as the raw material>
Figure GDA0004184765990000044
In the form of intermediates
Figure GDA0004184765990000045
The target product is prepared by taking the raw materials and coupling reaction for a sixth preset time>
Figure GDA0004184765990000046
Use of a multi-targeted inhibitor of QC and GSK-3 beta, wherein the glutaminyl cyclase inhibitor is used for the preparation of an anti-AD drug.
Use of a multi-targeted inhibitor of QC and GSK-3 beta, wherein the glutaminyl cyclase inhibitor is used for the preparation of a kit for diagnosing AD.
The application of a multi-target inhibitor of QC and GSK-3 beta, wherein the glutaminyl cyclase inhibitor is used for preparing a medicine for preventing and treating diseases related to QC and/or GSK-3 beta specific high expression.
The application of a multi-target inhibitor of QC and GSK-3 beta, wherein the glutaminyl cyclase inhibitor is used for preparing a diagnostic kit for diseases related to QC and/or GSK-3 beta specific high expression.
The beneficial effects are that: the structural general formula of the QC and GSK-3 beta multi-targeting inhibitor provided by the invention is as follows:
Figure GDA0004184765990000051
the novel structural compound remarkably expands molecular structure diversity of QC and GSK-3 beta multi-targeting inhibitors, has easily available raw materials, simple and feasible preparation method, and can be widely used for developing QC and/or GSK-3 beta specific high-expression related disease therapeutic drugs, diagnostic reagents and the like, for example, AD drugs and diagnostic reagents. />
Drawings
FIG. 1 is a schematic representation of the simulated docking of a multi-targeted inhibitor of the present invention with QC and GSK-3 beta proteins.
Detailed Description
The invention provides a multi-targeting inhibitor of QC and GSK-3 beta, a preparation method and application thereof, and the invention is further described in detail below for making the purposes, technical schemes and effects of the invention clearer and more definite. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The invention provides a multi-targeting inhibitor of QC and GSK-3 beta, which has the following structural general formula:
Figure GDA0004184765990000052
comprising three structural units, wherein,
the A unit being a benzene ring, a six-membered aromatic heterocycle, a five-membered aromatic heterocycle, a seven-membered aromatic ring, an anthracene, a naphthalene, an anthraquinone or a polyaromatic ring system，R 1 Is one of hydrogen, alkyl, alkoxy, nitro, amino, halogen, sulfonic acid or ester group, R 1 Is monosubstituted or polysubstituted at different positions;
the B unit is a five-membered heterocyclic ring or a six-membered heterocyclic ring system such as thiazole ring, and the carbon atom n=1-4 in the alkyl chain;
the C unit is a heterocyclic ring system such as imidazole ring, triazole ring and the like, R 2 Is one of hydrogen, linear alkyl, branched alkyl, alkoxy and halogen, R 2 Is monosubstituted or polysubstituted at different positions;
the substitution positions of the A and C units on the B ring are meta positions.
Specifically, QC is a single zinc ion metalloenzyme, and the C unit in the multi-targeting inhibitor can enter the active pocket of QC and the Zn at the active bottom of QC protein 2+ Chelation in turn inhibits its activity; further, the multi-targeted inhibitor can also enter an active pocket of GSK-3 beta, wherein a B unit and a C unit can be embedded in the pocket entrance, and N atoms and O atoms of urea fragments between the A unit and the B unit have hydrogen bond interactions with GLN-185 and the like. Based on the analysis, the multi-target inhibitor can be tightly combined with QC and GSK-3 beta proteins, so that the compound with the structure can be used as the multi-target inhibitor of QC and GSK-3 beta, and the inhibition activity is obvious.
In some embodiments, the multi-targeted inhibitors of species QC and GSK-3 beta may have the chemical formula:
Figure GDA0004184765990000061
/>
Figure GDA0004184765990000071
Figure GDA0004184765990000081
/>
Figure GDA0004184765990000082
but is not limited thereto.
The QC and GSK-3 beta multi-target inhibitor provided by the invention are compounds disclosed for the first time, and have very important scientific significance and research value for the research of autonomous innovative AD-resistant lead medicaments. The QC and GSK-3 beta multi-targeting inhibitor can be widely applied to research of novel network targeting anti-AD drugs and drugs for treating QC and/or GSK-3 beta specific high-expression related diseases or development of related diagnostic kits.
In some embodiments, a method of preparing a QC and GSK-3 beta multi-targeted inhibitor is also provided, comprising the specific steps of:
to be used for
Figure GDA0004184765990000083
And thiourea or->
Figure GDA0004184765990000084
The raw materials undergo cyclization or coupling reaction for 8-24h to prepare an intermediate containing B unit heterocycle +.>
Figure GDA0004184765990000085
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl;
in the form of intermediates
Figure GDA0004184765990000086
The intermediate containing amino protecting group is prepared by amino protecting reaction for 2-5h as raw material>
Figure GDA0004184765990000087
In the form of intermediates
Figure GDA0004184765990000091
The intermediate with the structure terminal containing alkyl chain is prepared by ring opening or bromination reaction for 2-5h as raw material>
Figure GDA0004184765990000092
In the form of intermediates
Figure GDA0004184765990000093
And an imidazole ring or triazole ring heterocyclic ring system as raw materials, and carrying out SN2 reaction for 8-12h to prepare an intermediate containing the imidazole ring or the triazole ring>
Figure GDA0004184765990000094
/>
In the form of intermediates
Figure GDA0004184765990000095
The amino intermediate is prepared by deprotection reaction of amino group for 2-6h>
Figure GDA0004184765990000096
In the form of intermediates
Figure GDA0004184765990000097
The target product is prepared by taking the raw materials as the raw materials and carrying out coupling reaction for 12-16h>
Figure GDA0004184765990000098
In some embodiments, there is also provided the use of a QC and GSK-3β multi-targeted inhibitor, wherein the QC and GSK-3β multi-targeted inhibitor is used in the manufacture of an anti-AD medicament.
In this embodiment, the drug may be a pharmaceutically acceptable salt, including lithium, sodium, potassium, magnesium, calcium, iron, copper, organic ammonium, hydrochloride, phosphate, acetate, propionate, oxalate, citrate, and the like.
In some embodiments, there is also provided the use of a QC and GSK-3β multi-targeted inhibitor for the preparation of a kit for diagnosing AD.
In some embodiments, the application of the QC and GSK-3 beta multi-targeting inhibitor is also provided, and the QC and GSK-3 beta multi-targeting inhibitor is used for preparing medicines for preventing and treating diseases related to QC and/or GSK-3 beta specific high expression.
In some embodiments, there is also provided the use of a QC and GSK-3β multi-targeted inhibitor, wherein the QC and GSK-3β multi-targeted inhibitor is used to prepare a diagnostic kit for QC and/or GSK-3β specific high expression related diseases.
The invention is further illustrated by the following examples:
example 1
Preparation of 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (1H-pyrrolo [3,2-b ] pyridin-5-yl) urea:
a. methanol is taken as a solvent, 1 equivalent of thiourea is added, not less than 1.2 equivalent of 2-bromo-1-cyclopropylethanone is added, stirring is started, and reflux reaction is carried out at 65 ℃ for overnight. After the reaction is finished, after the system is cooled to room temperature, the reaction system is distilled under reduced pressure, the solvent is removed, a proper amount of methanol dissolved product is added, the reduced pressure distillation is repeated for 2 to 3 times, so that excessive 2-bromo-1-cyclopropylethane in the system is removed, and 4-cyclopropyl thiazole-2-amine is obtained, and the yield is: 82%;
b. 1 equivalent of 4-cyclopropyl thiazole-2-amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate is prepared by column chromatography, and the yield is: 65%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4-cyclopropyl-thiazol-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was added, stirring was turned on, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, yield: 32%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of imidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) carbamate, wherein the yield is: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the 4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-amine is prepared by column chromatography, and the yield is: 75%;
f. 1 equivalent of 4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-amine was added with N-N-dimethylformamide as solvent, followed by 1 equivalent of 5-isocyanato-1H-pyrrolo [3,2-b ]]Pyridine, stirring is started, and reflux reaction is carried out for 15h at 100 ℃. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (1H-pyrrolo [3, 2-b)]Pyridin-5-yl) urea having the chemical structural formula:
Figure GDA0004184765990000111
the total yield thereof was found to be 27%.
Example 2
Preparation of 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (4-methoxyphenyl) urea:
a. methanol is taken as a solvent, 1 equivalent of thiourea is added, not less than 1.2 equivalent of 2-bromo-1-cyclopropylethanone is added, stirring is started, and reflux reaction is carried out at 65 ℃ for overnight. After the reaction is finished, after the system is cooled to room temperature, the reaction system is distilled under reduced pressure, the solvent is removed, a proper amount of methanol dissolved product is added, the reduced pressure distillation is repeated for 2 to 3 times, so that excessive 2-bromo-1-cyclopropylethane in the system is removed, and 4-cyclopropyl thiazole-2-amine is obtained, and the yield is: 82%;
b. 1 equivalent of 4-cyclopropyl thiazole-2-amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate is prepared by column chromatography, and the yield is: 65%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4-cyclopropyl-thiazol-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was added, stirring was turned on, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, yield: 32%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of imidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) carbamate, wherein the yield is: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the 4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-amine is prepared by column chromatography, and the yield is: 75%;
f. 1 equivalent of 4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-amine is added by taking N-N-dimethylformamide as a solvent, 1 equivalent of 1-isocyanato-4-methoxybenzene is added, stirring is started, and reflux reaction is carried out for 15H at 100 ℃. After the reaction, the system was poured intoExtracting with ethyl acetate for three times, mixing organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (4-methoxyphenyl) urea, wherein the chemical structural formula is as follows:
Figure GDA0004184765990000131
the total yield thereof was found to be 21%.
Example 3
Preparation of 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (naphthalen-2-yl) urea:
a. methanol is taken as a solvent, 1 equivalent of thiourea is added, not less than 1.2 equivalent of 2-bromo-1-cyclopropylethanone is added, stirring is started, and reflux reaction is carried out at 65 ℃ for overnight. After the reaction is finished, after the system is cooled to room temperature, the reaction system is distilled under reduced pressure, the solvent is removed, a proper amount of methanol dissolved product is added, the reduced pressure distillation is repeated for 2 to 3 times, so that excessive 2-bromo-1-cyclopropylethane in the system is removed, and 4-cyclopropyl thiazole-2-amine is obtained, and the yield is: 82%;
b. 1 equivalent of 4-cyclopropyl thiazole-2-amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate is prepared by column chromatography, and the yield is: 65%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4-cyclopropyl-thiazol-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was added, stirring was turned on, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, yield: 32%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of imidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) carbamate, wherein the yield is: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the 4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-amine is prepared by column chromatography, and the yield is: 75%;
f. 1 equivalent of 4- (3- (1H-imidazol-1-yl) propyl) thiazole-2-amine is added by taking N-N-dimethylformamide as a solvent, and then 2-naphthalene isocyanate is added, stirring is started, and reflux reaction is carried out for 15H at 100 ℃. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (naphthalene-2-yl) urea, wherein the chemical structural formula is as follows:
Figure GDA0004184765990000141
the total yield thereof was found to be 19%.
Example 4
Preparation of 1- (4-methoxyphenyl) -3- (4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazol-2-yl) urea:
a. methanol is taken as a solvent, 1 equivalent of thiourea is added, not less than 1.2 equivalent of 2-bromo-1-cyclopropylethanone is added, stirring is started, and reflux reaction is carried out at 65 ℃ for overnight. After the reaction is finished, after the system is cooled to room temperature, the reaction system is distilled under reduced pressure, the solvent is removed, a proper amount of methanol dissolved product is added, the reduced pressure distillation is repeated for 2 to 3 times, so that excessive 2-bromo-1-cyclopropylethane in the system is removed, and 4-cyclopropyl thiazole-2-amine is obtained, and the yield is: 82%;
b. 1 equivalent of 4-cyclopropyl thiazole-2-amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate is prepared by column chromatography, and the yield is: 65%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4-cyclopropyl-thiazol-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was added, stirring was turned on, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, yield: 32%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of 4-methylimidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazol-2-yl) carbamate, wherein the yield is: 57%;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazole-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the 4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazole-2-amine is prepared by column chromatography, so that the yield is: 72%;
f. 1 equivalent of 4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazole-2-amine is added by taking N-N-dimethylformamide as a solvent, and then 1 equivalent of 1-isocyanato-4-methoxybenzene is added, stirring is started, and reflux reaction is carried out for 15 hours at 100 ℃. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, performing reduced pressure distillation, and performing column chromatography to obtain a target product1- (4-methoxyphenyl) -3- (4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazol-2-yl) urea having the chemical structural formula:
Figure GDA0004184765990000151
the total yield thereof was found to be 16%.
Example 5
Preparation of 1- (4- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) thiazol-2-yl) -3-phenylurea
a. Methanol is taken as a solvent, 1 equivalent of thiourea is added, not less than 1.2 equivalent of 2-bromo-1-cyclopropylethanone is added, stirring is started, and reflux reaction is carried out at 65 ℃ for overnight. After the reaction is finished, after the system is cooled to room temperature, the reaction system is distilled under reduced pressure, the solvent is removed, a proper amount of methanol dissolved product is added, the reduced pressure distillation is repeated for 2 to 3 times, so that excessive 2-bromo-1-cyclopropylethane in the system is removed, and 4-cyclopropyl thiazole-2-amine is obtained, and the yield is: 82%;
b. 1 equivalent of 4-cyclopropyl thiazole-2-amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate is prepared by column chromatography, and the yield is: 65%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4-cyclopropyl-thiazol-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was added, stirring was turned on, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate, yield: 32%;
d. N-N-dimethylformamide is taken as a solvent, 2 equivalents of anhydrous potassium carbonate is added, 3 equivalents of 5-methyl-1H-1, 2, 4-triazole is added, stirring is started, stirring is carried out for 0.5H at room temperature, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3-bromopropyl) thiazol-2-yl) carbamate is added, the temperature is raised to 60 ℃, and reflux reaction is carried out overnight. After the reaction, the system was poured into water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (4- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) thiazol-2-yl) carbamate, yield: 62%;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the 4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-amine is prepared by column chromatography, and the yield is: 70% of the total weight of the steel sheet;
f. N-N-dimethylformamide is taken as a solvent, 1 equivalent of 4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-amine is added, 1 equivalent of benzene isocyanate is added, stirring is started, and reflux reaction is carried out at 100 ℃ for 15 hours. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazol-2-yl) -3-phenylurea, wherein the chemical structural formula is as follows:
Figure GDA0004184765990000171
the total yield thereof was found to be 15%.
Example 6
Preparation of 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3-phenylurea
a. With water and toluene (1:4, v/v) as solvents, 1 equivalent of 2-amino-6-bromopyridine was added, followed by 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate, stirring was turned on, followed by 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate, and reflux reaction was performed at 100℃for 24 hours. After the reaction is finished, after the system is cooled to room temperature, the system is poured into water, extracted three times by ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure, and the 6-cyclopropyl-2-pyridine amine is prepared by column chromatography, and the yield is: 50%;
b. 1 equivalent of 6-cyclopropyl-2-pyridine amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate is prepared by column chromatography, and the yield is: 64%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (6-cyclopropylpyridin-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was further added, and stirring was started to react at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate, yield: 33%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of imidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) carbamate, wherein the yield is: 59%;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (6- (3- (1H-imidazol-1-yl) propyl) pyridine-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the column chromatography is performed to prepare 6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-amine, and the yield is: 66%;
f. 1 equivalent of 6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-amine was added to N-N-dimethylformamide as a solvent, and 1 equivalent of benzene isocyanate was added thereto, followed by stirring and reflux reaction at 100℃for 15 hours. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3-phenylurea, wherein the target product is chemically boundThe structure is as follows:
Figure GDA0004184765990000181
the total yield thereof was found to be 23%.
Example 7
Preparation of 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3- (furan-3-yl) urea
a. With water and toluene (1:4, v/v) as solvents, 1 equivalent of 2-amino-6-bromopyridine was added, followed by 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate, stirring was turned on, followed by 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate, and reflux reaction was performed at 100℃for 24 hours. After the reaction is finished, after the system is cooled to room temperature, the system is poured into water, extracted three times by ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure, and the 6-cyclopropyl-2-pyridine amine is prepared by column chromatography, and the yield is: 50%;
b. 1 equivalent of 6-cyclopropyl-2-pyridine amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate is prepared by column chromatography, and the yield is: 64%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (6-cyclopropylpyridin-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was further added, and stirring was started to react at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate, yield: 33%;
d. taking N-N-dimethylformamide as a solvent, adding 2 equivalents of anhydrous potassium carbonate, adding 3 equivalents of imidazole, starting stirring, stirring at room temperature for 0.5H, adding 1 equivalent of (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate, heating to 60 ℃, and carrying out reflux reaction overnight. After the reaction, pouring the system into water, extracting with ethyl acetate three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to prepare (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) carbamate, wherein the yield is: 59%;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (6- (3- (1H-imidazol-1-yl) propyl) pyridine-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the column chromatography is performed to prepare 6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-amine, and the yield is: 66%;
f. 1 equivalent of 6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-amine was added to N-N-dimethylformamide as a solvent, and 1 equivalent of 3-isocyanate furan was added thereto, followed by stirring and reflux reaction at 100℃for 15 hours. After the reaction is finished, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3- (furan-3-yl) urea, wherein the chemical structural formula is as follows:
Figure GDA0004184765990000191
the total yield thereof was found to be 21%.
Example 8
Preparation of 1- (1H-indol-5-yl) -3- (6- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) pyridin-2-yl) urea
a. With water and toluene (1:4, v/v) as solvents, 1 equivalent of 2-amino-6-bromopyridine was added, followed by 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate, stirring was turned on, followed by 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate, and reflux reaction was performed at 100℃for 24 hours. After the reaction is finished, after the system is cooled to room temperature, the system is poured into water, extracted three times by ethyl acetate, the organic phases are combined, dried by anhydrous sodium sulfate and distilled under reduced pressure, and the 6-cyclopropyl-2-pyridine amine is prepared by column chromatography, and the yield is: 50%;
b. 1 equivalent of 6-cyclopropyl-2-pyridine amine is added by taking methylene dichloride as a solvent, and not less than 1.5 equivalent of fluorenylmethoxycarbonyl succinimide is added, stirring is started, and the reaction is carried out for 3 hours at room temperature. After the reaction, the reaction system is distilled under reduced pressure, the solvent is removed, and the (9H-fluorene-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate is prepared by column chromatography, and the yield is: 64%;
c. with tert-butanol as solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (6-cyclopropylpyridin-2-yl) carbamate was added, 1.5 equivalent of boron tribromide was further added, and stirring was started to react at room temperature for 3 hours. After the reaction was completed, the reaction system was carefully poured into water to terminate the reaction, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate, yield: 33%;
d. N-N-dimethylformamide is taken as a solvent, 2 equivalents of anhydrous potassium carbonate is added, 3 equivalents of 5-methyl-1H-1, 2, 4-triazole is added, stirring is started, stirring is carried out for 0.5H at room temperature, 1 equivalent of (9H-fluorene-9-yl) methyl (6- (3-bromopropyl) pyridin-2-yl) carbamate is added, the temperature is raised to 60 ℃, and reflux reaction is carried out overnight. After the reaction, the system was poured into water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, and column chromatography was performed to prepare (9H-fluoren-9-yl) methyl (6- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) pyridin-2-yl) carbamate, yield: 54%;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluorene-9-yl) methyl (6- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) pyridine-2-yl) carbamate is added, no less than 2 equivalents of piperidine is added, stirring is started, and the reaction is carried out for 2 hours at room temperature. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and the 6- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) pyridine-2-amine is prepared by column chromatography, and the yield is: 61%;
f. N-N-dimethylformamide is taken as a solvent, 1 equivalent of 6- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) pyridine-2-amine is added, 1 equivalent of 5-isocyanato-1H-indole is added, stirring is started, and reflux reaction is carried out for 15 hours at 100 ℃. After the reaction, pouring the system into water, extracting with ethyl acetate for three times, combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure, and performing column chromatography to obtain a target product 1- (1H-indol-5-yl) -3- (6- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) pyridin-2-yl) urea, wherein the target product is chemically boundThe structure is as follows:
Figure GDA0004184765990000211
the total yield thereof was found to be 18%.
Example 9
Test for QC enzyme inhibition Activity Using the Compounds of Table 1
40. Mu.LQC, 10. Mu.L of 100. Mu.M compound/10. Mu.L of 100. Mu.MPBD-150 (positive control)/10. Mu.L of DMSO (negative control)/50. Mu.L of HEPES buffer (blank control) were added to 96-well plates and incubated at room temperature for 3min. mu.L of substrate Q-AMC was added to each well. Incubate at room temperature for 10min at 25℃and 200 rpm. 100. Mu.L PAP was added to each well. Incubation at room temperature for 60min at 200rpm at 25 ℃ uses a single wavelength scan EX/em=360 nm/445nm. Inhibition (%) = (DMSO-Cpd)/(DMSO-Blank) ×100%. DMSO: fluorescence values of DMSO group; cpd: fluorescence values of inhibitor groups; blank: fluorescence values of the enzyme group were not added. The results are shown in Table 1.
Example 10
GSK-3 beta enzyme inhibition activity was tested using the compounds in table 1:
mu.L of kinase reaction system was added to 384 well plates: mu.l of 4. Mu.M ATP/0.12. Mu.g/. Mu.l of substrate mixture was added to each well, the inhibitor was diluted to a series of concentrations with 1 XBuffer A, 1. Mu.l of inhibitor/1. Mu.l of 1% DMSO was added, and finally 2. Mu.l of 5 ng/. Mu.l of enzyme solution was added to 384 well plates. A control without enzyme was also set up, and the enzyme was replaced with an equal volume of 1 Xbuffer A. Incubating for 60min at room temperature; mu.L of ADP-GloTM reagent was added to each well; incubating for 40min at room temperature; adding 10 mu L of kinase detection reagent into each well; incubating for 30min at room temperature; the fluorescence intensity was measured. Inhibition (%) = (DMSO-Cpd)/(DMSO-Blank) ×100%. DMSO: luminescence values of DMSO group; cpd: luminescence values of inhibitor groups; blank: the luminescence value of the enzyme group was not added. The results are shown in Table 1.
Results of QC and GSK-3 beta enzyme inhibitory Activity test of Compounds of Table 1
Figure GDA0004184765990000221
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Figure GDA0004184765990000231
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Figure GDA0004184765990000241
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Figure GDA0004184765990000251
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Figure GDA0004184765990000261
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Figure GDA0004184765990000271
In conclusion, the series of novel structural compounds of the invention remarkably expands molecular structure diversity of QC and GSK-3 beta multi-target inhibitors, has easily available raw materials, simple and feasible preparation method and remarkable inhibition activity on QC and GSK-3 beta, and has potential for further developing innovative drugs as lead compounds.
It is to be understood that the invention is not limited in its application to the examples described above, but is capable of modification and variation in light of the above teachings by those skilled in the art, and that all such modifications and variations are intended to be included within the scope of the appended claims.

Claims (7)

1. A QC and GSK-3 beta multi-targeted inhibitor, wherein the QC and GSK-3 beta multi-targeted inhibitor is one of the following chemical structural formulas:
Figure FDA0004169949000000011
/>
Figure FDA0004169949000000021
2. a method of preparing a multi-targeted inhibitor of QC and GSK-3 beta as claimed in claim 1 comprising the steps of:
to be used for
Figure FDA0004169949000000031
And thiourea or->
Figure FDA0004169949000000032
The raw materials undergo a cyclization or coupling reaction for a first preset time to prepare an intermediate +.>
Figure FDA0004169949000000033
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl; />
In the form of intermediates
Figure FDA0004169949000000034
Preparing an intermediate containing amino protecting groups by amino protecting reaction for a second preset time as a raw material>
Figure FDA0004169949000000035
In the form of intermediates
Figure FDA0004169949000000036
Preparing intermediate containing alkyl chain at the end of the structure by ring opening or bromination reaction for a third preset time>
Figure FDA0004169949000000037
In the form of intermediates
Figure FDA0004169949000000038
And imidazole ring or triazole ring heterocyclic ring system as raw material through SN2Reacting for a fourth predetermined time to obtain an intermediate +.>
Figure FDA0004169949000000039
In the form of intermediates
Figure FDA00041699490000000310
The amino group-containing intermediate ++is prepared by the deprotection reaction of amino group for the fifth predetermined time as the raw material>
Figure FDA00041699490000000311
In the form of intermediates
Figure FDA0004169949000000041
The target product is prepared by taking the raw materials and coupling reaction for a sixth preset time>
Figure FDA0004169949000000042
3. The method of preparing a multi-targeted inhibitor of QC and GSK-3 beta as claimed in claim 2 wherein the first predetermined time is 8 to 24 hours; and/or, the second preset time is 2-5h; the third preset time is 2-5h; and/or, the fourth predetermined time is 8-12 hours; and/or, the fifth predetermined time is 2-6 hours; and/or, the sixth preset time is 12-16h.
4. Use of a multi-targeted inhibitor of QC and GSK-3β according to claim 1 for the preparation of an anti-AD medicament.
5. Use of a multi-targeted inhibitor of QC and GSK-3β according to claim 1 for the preparation of a kit for diagnosing AD.
6. Use of a multi-targeted inhibitor of QC and GSK-3β according to claim 1 for the preparation of a medicament for the prevention and treatment of QC-and/or GSK-3β specific high expression related diseases.
7. Use of a multi-targeted inhibitor of QC and GSK-3β according to claim 1 for the preparation of a diagnostic kit for QC-and/or GSK-3β specific high expression related diseases.
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