CN114805334A - QC and GSK-3 beta multi-target inhibitor and preparation method and application thereof - Google Patents

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

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CN114805334A
CN114805334A CN202210569047.4A CN202210569047A CN114805334A CN 114805334 A CN114805334 A CN 114805334A CN 202210569047 A CN202210569047 A CN 202210569047A CN 114805334 A CN114805334 A CN 114805334A
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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-target inhibitor and a preparation method and application thereof, wherein the chemical structural general formula of the QC and GSK-3 beta multi-target inhibitor is as follows:
Figure DDA0003659469640000011
the invention provides a preparation method of the novel inhibitor, which has the advantages of easily obtained raw materials and simple and feasible preparation method. The novel inhibitor provided by the invention obviously expands the 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-target inhibitor and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal 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, early symptoms include difficulty in recalling recent conversations, names, or events, and as the disease progresses, the patient has symptoms of impaired communication ability, disorganized thinking, altered behavior, 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 deaths is increased year by year, and the economic burden caused by AD is huge, which has become a worldwide health, economic and social problem. The pathological features of AD mainly include Amyloid plaques composed of A beta (Amyloid-beta), neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau protein, inflammation and the like. However, the pathogenesis of AD is still unclear, no specific drugs are clinically available, and the research and development of innovative anti-AD drugs are urgently needed.
Glutaminyl Cyclase (QC), an enzyme that catalyzes the formation of pyroglutamic acid (pE) from N-terminal glutamine/glutamic acid during post-translational modification of active peptides or proteins, catalyzes the formation of stable five-membered rings from primary amines on the alpha and delta carbon atoms of glutamine/glutamic acid, releases a molecule of NH 3 /H 2 O, may alter the chemical structure of the N-terminus of a peptide or protein, modulate its activity, enhance stability, etc. However, abnormal rise of QC activity plays a key role in regulation and control in the onset of a plurality of serious diseases such as AD and the like. In recent years, it has been found that compared with the normal senile A beta senile plaque of the brain of an elderly person, the AD patient has a pE-A beta obtained by intramolecular cyclization of an N-terminal glutamine residue of a variant A beta rather than A beta as a main component of the senile plaque of the brain 3-42 /pE-Aβ 3-40 (the content exceeds 50%). Compared with the Abeta, the pE-Abeta has stronger neurotoxicity, higher stability and enzymolysis resistance, higher aggregation speed, capability of further promoting Abeta aggregation and the like. Meanwhile, high-expression QC can induce systemic neuroinflammation and the like by catalyzing and generating factors such as pE-CCL2 and the like, and further accelerate the onset of AD. In the early stage of onset, QC (quaternary ammonium) of brains of AD patients shows specific high expression. 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 (GSK-3) is a kinase that regulates glycogen synthase activity through phosphorylation, and is closely related to apoptosis, differentiation, proliferation, maintenance of microtubule morphology, and the like. Two isoenzymes GSK-3 alpha and GSK-3 beta are found, and the GSK-3 beta has an important regulation and control effect on Tau phosphorylation. Tau protein is a microtubule-associated protein (MAP) that stabilizes microtubules by immobilizing a combination of tubulins, the function and affinity for microtubules being mainly dependent on the autophosphorylation status. In AD, Tau proteins are hyperphosphorylated and accumulate in the cytoplasm, leading to microtubule disassembly, loss of neuronal integrity, and finally the formation of NFTs. At the same time, GSK-3 β acts on APP, participates in a β production and subsequent deposition in the AD brain, inducing the appearance of a β pathology by disrupting the insulin signaling pathway. In addition, abnormally activated GSK-3 β can cause synaptic dysfunction leading to memory deficits, inhibiting adult hippocampal nerves; regulate biological reaction of microglia, promote the production of inflammatory factors, and cause the death of neurons. Therefore, GSK-3 beta can be used as another important target point for anti-AD drug research.
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 opens a new idea for researching innovative anti-AD drugs. However, only a few of such inhibitors have been reported.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a QC and GSK-3 beta multi-target inhibitor, a preparation method and application thereof, aims to act on a plurality of targets related to AD diseases, and enables an inhibitor drug to have better curative effect and produce fewer side effects due to the synergistic effect.
The technical scheme of the invention is as follows:
a QC and GSK-3 beta multi-target inhibitor is disclosed, wherein the general structural formula is as follows:
Figure BDA0003659469620000031
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 polyaromatic ring system, and R is 1 Is one of hydrogen, alkyl, alkoxy, nitro, amido, halogen, sulfonic acid group and ester group, and R is 1 Is mono-substituted or poly-substituted in different positions; the unit B is a five-membered heterocyclic ring or a six-membered heterocyclic ring system, and a carbon atom n in an alkyl chain is 1-4; c unit is imidazole ring or triazole ring heterocyclic ring system, R 2 Is one of hydrogen, straight chain alkyl, branched chain alkyl, alkoxy and halogen, and R 2 Is monosubstituted or polysubstituted in different positions; the substitution positions of the A and C units on the B ring are meta.
A method for preparing multi-targeting inhibitors of QC and GSK-3 β, comprising the steps of:
to be provided with
Figure BDA0003659469620000032
And thiourea or
Figure BDA0003659469620000033
Raw materials are subjected to cyclization or coupling reaction for a first preset time to prepare an intermediate containing a B unit heterocycle
Figure BDA0003659469620000034
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl;
by intermediates
Figure BDA0003659469620000035
Preparing an intermediate containing an amino protecting group by a protection reaction of an amino for a second preset time
Figure BDA0003659469620000036
By intermediates
Figure BDA0003659469620000037
The intermediate with alkyl chain at the tail end of the structure is prepared by the ring-opening or bromination reaction for the third preset time as the raw material
Figure BDA0003659469620000038
By intermediates
Figure BDA0003659469620000041
Reacting with imidazole ring or triazole ring heterocyclic ring system serving as raw material for fourth preset time by SN2 to obtain intermediate containing imidazole ring or triazole ring
Figure BDA0003659469620000042
As raw material, the first step of deprotection reaction of aminoPreparing an intermediate containing amino groups within five predetermined time
Figure BDA0003659469620000043
By intermediates
Figure BDA0003659469620000044
The raw materials are subjected to coupling reaction for the sixth preset time to prepare a target product
Figure BDA0003659469620000045
Use of a multi-targeted inhibitor of QC and GSK-3 β wherein said glutaminyl cyclase inhibitor is used in the preparation of an anti-AD drug.
Use of a multi-targeted inhibitor of QC and GSK-3 β, wherein said glutaminyl cyclase inhibitor is used for the preparation of a kit for the diagnosis of AD.
The application of the multi-target inhibitor of QC and GSK-3 beta is to prepare a medicine for preventing and treating diseases related to high specific expression of QC and/or GSK-3 beta by using the glutaminyl cyclase inhibitor.
The application of the multi-target inhibitor of QC and GSK-3 beta is to prepare a diagnostic kit for diseases related to QC and/or GSK-3 beta specific high expression by using the glutaminyl cyclase inhibitor.
Has the advantages that: the general structural formula of the QC and GSK-3 beta multi-target inhibitor provided by the invention is as follows:
Figure BDA0003659469620000051
the new structural compound obviously expands the molecular structural diversity of QC and GSK-3 beta multi-target inhibitors, has easily obtained raw materials and simple and feasible preparation method, and can be widely used for the development of QC and/or GSK-3 beta specific high expression related disease treatment drugs, diagnostic reagents and the like, such as AD drugs and diagnostic reagents.
Drawings
FIG. 1 is a schematic diagram of the simulated docking of the multi-targeted inhibitor of the present invention with QC and GSK-3 β proteins.
Detailed Description
The invention provides a multi-target inhibitor of QC and GSK-3 beta, a preparation method and application thereof, and the invention is further detailed below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The invention provides a multi-target inhibitor of QC and GSK-3 beta, which has the following structural general formula:
Figure BDA0003659469620000052
comprises three structural units, wherein,
the A unit is benzene ring, six-membered aromatic heterocycle, five-membered aromatic heterocycle, seven-membered aromatic ring, anthracene, naphthalene, anthraquinone or polyaromatic ring system, R 1 Is one of hydrogen, alkyl, alkoxy, nitro, amido, halogen, sulfonic acid group or ester group, R 1 Is monosubstituted or polysubstituted in different positions;
the B unit is a five-membered heterocyclic ring or a six-membered heterocyclic ring system such as a thiazole ring, and a carbon atom n in an alkyl chain is 1-4;
the C unit is imidazole ring, triazole ring or other heterocyclic ring systems, R 2 Is one of hydrogen, straight chain alkyl, branched chain alkyl, alkoxy and halogen, R 2 Is monosubstituted or polysubstituted in different positions;
the substitution positions of the A and C units on the B ring are meta.
Specifically, QC is a single zinc ion metalloenzyme, and the C unit in the multi-target inhibitor of the invention can enter the active pocket of QC and Zn at the bottom of the activity of QC protein 2+ Chelation and subsequent inhibition of its activity; further, the multi-targeted inhibitor can also enter the active pocket of GSK-3 β, wherein the B unit and the C unit can be inserted into the entrance of the pocket, the N atom and the O atom of the urea segment 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 protein at the same time, so that the compound with the structure can be used as the multi-target inhibitor of QC and GSK-3 beta,and the inhibitory activity is remarkable.
In some embodiments, the species multi-targeted inhibitor of QC and GSK-3 β may have the chemical formula:
Figure BDA0003659469620000061
Figure BDA0003659469620000071
Figure BDA0003659469620000081
Figure BDA0003659469620000082
but is not limited thereto.
The QC and GSK-3 beta multi-target inhibitors provided by the invention are all compounds disclosed for the first time, and have extremely important scientific significance and research value for research of self-innovative anti-AD lead medicaments. The QC and GSK-3 beta multi-target inhibitor can be widely applied to the research of network-targeted anti-AD new drugs and drugs for treating QC and/or GSK-3 beta specific high-expression related diseases or the development of related diagnostic kits.
In some embodiments, there is also provided a method for preparing QC and GSK-3 β multi-targeted inhibitors, comprising the steps of:
to be provided with
Figure BDA0003659469620000083
And thiourea or
Figure BDA0003659469620000084
The raw materials are subjected to cyclization or coupling reaction for 8-24h to prepare an intermediate containing a B unit heterocycle
Figure BDA0003659469620000085
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl;
by intermediates
Figure BDA0003659469620000086
Taking the raw material, and carrying out amino protection reaction for 2-5h to prepare an intermediate containing amino protection groups
Figure BDA0003659469620000087
By intermediates
Figure BDA0003659469620000091
The intermediate with the structure end containing alkyl chain is prepared by ring-opening or bromination reaction for 2-5h as the raw material
Figure BDA0003659469620000092
By intermediates
Figure BDA0003659469620000093
Reacting with imidazole ring or triazole ring heterocyclic ring system serving as raw material for 8-12h by SN2 to obtain intermediate containing imidazole ring or triazole ring
Figure BDA0003659469620000094
By intermediates
Figure BDA0003659469620000095
Taking the raw material as a raw material, carrying out deprotection reaction on amino for 2-6h, and preparing an intermediate containing amino
Figure BDA0003659469620000096
By intermediates
Figure BDA0003659469620000097
And
Figure BDA0003659469620000098
the target product is prepared by coupling reaction for 12-16h as raw material
Figure BDA0003659469620000099
In some embodiments, there is also provided a use of a QC and GSK-3 β multi-targeted inhibitor, wherein the QC and GSK-3 β multi-targeted inhibitor is used in the preparation of an anti-AD drug.
In this embodiment, the drug may be a pharmaceutically acceptable salt, including lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, iron salt, copper salt, organic ammonium salt, hydrochloride salt, phosphate salt, acetate salt, propionate salt, oxalate salt, citrate salt, and the like.
In some embodiments, also provided is the use of a QC and GSK-3 β multi-targeting inhibitor for the preparation of a kit for the diagnosis of AD.
In some embodiments, the application of the QC and GSK-3 beta multi-target inhibitor is also provided, and the QC and GSK-3 beta multi-target inhibitor is used for preparing a medicine for preventing and treating diseases related to QC and/or GSK-3 beta specific high expression.
In some embodiments, the application of the QC and GSK-3 beta multi-target inhibitor is further provided, wherein the QC and GSK-3 beta multi-target inhibitor is used for preparing a diagnostic kit for diseases related to QC and/or GSK-3 beta specific high expression.
The invention is further illustrated by the following specific 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. using methanol as a solvent, adding 1 equivalent of thiourea, then adding not less than 1.2 equivalents of 2-bromo-1-cyclopropylethane, starting stirring, and carrying out reflux reaction at 65 ℃ overnight. After the reaction is finished, cooling the system to room temperature, distilling the reaction system under reduced pressure, removing the solvent, adding a proper amount of methanol to dissolve the product, distilling under reduced pressure, repeating the operation for 2-3 times to remove the excessive 2-bromo-1-cyclopropylethane in the system, and obtaining 4-cyclopropylthiazole-2-amine with the yield: 82%;
b. using dichloromethane as solvent, adding 1 equivalent of 4-cyclopropyl thiazole-2-amine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 h. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, wherein the yield is as follows: 65 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, and the yield is as follows: 32 percent;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of imidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, carrying out reduced pressure distillation and column chromatography to obtain (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate, wherein the yield is as follows: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate is added, more than or equal to 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, distilling the reaction system under reduced pressure, removing the solvent, and carrying out column chromatography to obtain the 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine, wherein the yield is as follows: 75 percent;
f. taking N-N-dimethylformamide as a solvent, adding 1 equivalent of 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine, and then adding 1 equivalent of 5-isocyano-1H-pyrrolo [3,2-b ]]Pyridine, starting stirring, and carrying out reflux reaction at 100 ℃ for 15 h. 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, and decompressedDistilling and column chromatography to obtain the target product 1- (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) -3- (1H-pyrrolo [3, 2-b)]Pyridin-5-yl) urea having the chemical formula:
Figure BDA0003659469620000111
the overall yield was 27%.
Example 2
Preparation of 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (4-methoxyphenyl) urea:
a. using methanol as a solvent, adding 1 equivalent of thiourea, then adding not less than 1.2 equivalents of 2-bromo-1-cyclopropylethane, starting stirring, and carrying out reflux reaction at 65 ℃ overnight. After the reaction is finished, cooling the system to room temperature, distilling the reaction system under reduced pressure, removing the solvent, adding a proper amount of methanol to dissolve the product, distilling under reduced pressure, repeating the operation for 2-3 times to remove excessive 2-bromo-1-cyclopropylethane in the system, and obtaining 4-cyclopropylthiazole-2-amine, wherein the yield is as follows: 82%;
b. using dichloromethane as solvent, adding 1 equivalent of 4-cyclopropyl thiazole-2-amine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 h. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, wherein the yield is as follows: 65 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, and the yield is as follows: 32 percent;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of imidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, carrying out reduced pressure distillation and column chromatography to obtain (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate, wherein the yield is as follows: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate is added, more than or equal to 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 subjected to reduced pressure distillation, the solvent is removed, and column chromatography is carried out to obtain the 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine, wherein the yield is as follows: 75 percent;
f. adding 1 equivalent of 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine into N-N-dimethylformamide serving as a solvent, then adding 1 equivalent of 1-isocyano-4-methoxybenzene, starting stirring, and carrying out reflux reaction for 15 hours at 100 ℃. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, distilling the mixture under reduced pressure, and carrying out column chromatography to obtain a target product 1- (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) -3- (4-methoxyphenyl) urea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000131
the total yield thereof was 21%.
Example 3
Preparation of 1- (4- (3- (1H-imidazol-1-yl) propyl) thiazol-2-yl) -3- (naphthalen-2-yl) urea:
a. using methanol as a solvent, adding 1 equivalent of thiourea, then adding not less than 1.2 equivalents of 2-bromo-1-cyclopropylethane, starting stirring, and carrying out reflux reaction at 65 ℃ overnight. After the reaction is finished, cooling the system to room temperature, distilling the reaction system under reduced pressure, removing the solvent, adding a proper amount of methanol to dissolve the product, distilling under reduced pressure, repeating the operation for 2-3 times to remove the excessive 2-bromo-1-cyclopropylethane in the system, and obtaining 4-cyclopropylthiazole-2-amine with the yield: 82%;
b. using dichloromethane as solvent, adding 1 equivalent of 4-cyclopropyl thiazole-2-amine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 h. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, wherein the yield is as follows: 65 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, and the yield is as follows: 32 percent;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of imidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, carrying out reduced pressure distillation and column chromatography to obtain (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate, wherein the yield is as follows: 60 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate is added, more than or equal to 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 subjected to reduced pressure distillation, the solvent is removed, and column chromatography is carried out to obtain the 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine, wherein the yield is as follows: 75 percent;
f. adding 1 equivalent of 4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-amine into N-N-dimethylformamide serving as a solvent, then adding 2-naphthalene isocyanate, starting stirring, and carrying out reflux reaction for 15 hours at 100 ℃. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain a target product 1- (4- (3- (1H-imidazole-1-yl) propyl) thiazole-2-yl) -3- (naphthalene-2-yl) urea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000141
the overall yield was 19%.
Example 4
Preparation of 1- (4-methoxyphenyl) -3- (4- (3- (4-methyl-1H-imidazol-1-yl) propyl) thiazol-2-yl) urea:
a. using methanol as a solvent, adding 1 equivalent of thiourea, then adding not less than 1.2 equivalents of 2-bromo-1-cyclopropylethane, starting stirring, and carrying out reflux reaction at 65 ℃ overnight. After the reaction is finished, cooling the system to room temperature, distilling the reaction system under reduced pressure, removing the solvent, adding a proper amount of methanol to dissolve the product, distilling under reduced pressure, repeating the operation for 2-3 times to remove the excessive 2-bromo-1-cyclopropylethane in the system, and obtaining 4-cyclopropylthiazole-2-amine with the yield: 82%;
b. using dichloromethane as solvent, adding 1 equivalent of 4-cyclopropyl thiazole-2-amine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 h. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, wherein the yield is as follows: 65 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, and the yield is as follows: 32 percent;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of 4-methylimidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain (9H-fluoren-9-yl) methyl (4- (3- (4-methyl-1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate, wherein the yield is as follows: 57 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3- (4-methyl-1H-imidazole-1-yl) propyl) thiazole-2-yl) carbamate and not less than 2 equivalents of piperidine are 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 subjected to reduced pressure distillation, the solvent is removed, and column chromatography is carried out to obtain the 4- (3- (4-methyl-1H-imidazole-1-yl) propyl) thiazole-2-amine, wherein the yield is as follows: 72 percent;
f. adding 1 equivalent of 4- (3- (4-methyl-1H-imidazole-1-yl) propyl) thiazole-2-amine into N-N-dimethylformamide serving as a solvent, then adding 1 equivalent of 1-isocyano acid radical-4-methoxybenzene, starting stirring, and carrying out reflux reaction for 15 hours at 100 ℃. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain a target product 1- (4-methoxyphenyl) -3- (4- (3- (4-methyl-1H-imidazole-1-yl) propyl) thiazole-2-yl) urea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000151
the total yield was 16%.
Example 5
Preparation of 1- (4- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) thiazol-2-yl) -3-phenylurea
a. Using methanol as a solvent, adding 1 equivalent of thiourea, then adding not less than 1.2 equivalents of 2-bromo-1-cyclopropylethane, starting stirring, and carrying out reflux reaction at 65 ℃ overnight. After the reaction is finished, cooling the system to room temperature, distilling the reaction system under reduced pressure, removing the solvent, adding a proper amount of methanol to dissolve the product, distilling under reduced pressure, repeating the operation for 2-3 times to remove the excessive 2-bromo-1-cyclopropylethane in the system, and obtaining 4-cyclopropylthiazole-2-amine with the yield: 82%;
b. using dichloromethane as solvent, adding 1 equivalent of 4-cyclopropyl thiazole-2-amine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 h. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, wherein the yield is as follows: 65 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (4-cyclopropyl thiazole-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (4- (3-bromopropyl) thiazole-2-yl) carbamate, and the yield is as follows: 32 percent;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of 5-methyl-1H-1, 2, 4-triazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain (9H-fluoren-9-yl) methyl (4- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) thiazol-2-yl) carbamate, wherein the yield is as follows: 62 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-yl) carbamate and not less than 2 equivalents of piperidine are 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, wherein the yield is as follows: 70 percent;
f. adding 1 equivalent of 4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-amine into N-N-dimethylformamide serving as a solvent, then adding 1 equivalent of benzene isocyanate, starting stirring, and carrying out reflux reaction for 15 hours at 100 ℃. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain a target product 1- (4- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) thiazole-2-yl) -3-phenylurea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000171
the total yield was 15%.
Example 6
Preparation of 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3-phenylurea
a. Water and toluene (1:4, v/v) are used as solvents, 1 equivalent of 2-amino-6-bromopyridine is added, 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate are added, stirring is started, 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate are added, and reflux reaction is carried out at 100 ℃ for 24 hours. After the reaction is finished, cooling the system to room temperature, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, carrying out reduced pressure distillation, and carrying out column chromatography to obtain the 6-cyclopropyl-2-pyridylamine, wherein the yield is as follows: 50 percent;
b. taking dichloromethane as a solvent, adding 1 equivalent of 6-cyclopropyl-2-pyridylamine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, wherein the yield is as follows: 64 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluoren-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridine-2-yl) carbamate, and the yield is as follows: 33%;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of imidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) carbamate, wherein the yield is as follows: 59 percent of water;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) carbamate is added, more than or equal to 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 subjected to reduced pressure distillation, the solvent is removed, and column chromatography is carried out to obtain the 6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-amine, wherein the yield is as follows: 66 percent;
f. taking N-N-dimethylformamide as a solvent, adding 1 equivalent of 6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-amine, adding 1 equivalent of benzene isocyanate, starting stirring, and carrying out reflux reaction at 100 ℃ for 15 hours. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, distilling the organic phases under reduced pressure and carrying out column chromatography to obtain a target product 1- (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) -3-phenylurea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000181
the overall yield was 23%.
Example 7
Preparation of 1- (6- (3- (1H-imidazol-1-yl) propyl) pyridin-2-yl) -3- (furan-3-yl) urea
a. Water and toluene (1:4, v/v) are used as solvents, 1 equivalent of 2-amino-6-bromopyridine is added, 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate are added, stirring is started, 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate are added, and reflux reaction is carried out at 100 ℃ for 24 hours. After the reaction is finished, cooling the system to room temperature, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, carrying out reduced pressure distillation, and carrying out column chromatography to obtain the 6-cyclopropyl-2-pyridylamine, wherein the yield is as follows: 50 percent;
b. taking dichloromethane as a solvent, adding 1 equivalent of 6-cyclopropyl-2-pyridylamine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, wherein the yield is as follows: 64 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridine-2-yl) carbamate, and the yield is as follows: 33%;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of imidazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) carbamate, wherein the yield is as follows: 59 percent of water;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-9-yl) methyl (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) carbamate is added, more than or equal to 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 subjected to reduced pressure distillation, the solvent is removed, and column chromatography is carried out to obtain the 6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-amine, wherein the yield is as follows: 66 percent;
f. taking N-N-dimethylformamide as a solvent, adding 1 equivalent of 6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-amine, adding 1 equivalent of 3-isocyanate furan, starting stirring, and carrying out reflux reaction at 100 ℃ for 15 hours. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the mixture by using anhydrous sodium sulfate, distilling the mixture under reduced pressure, and carrying out column chromatography to obtain a target product 1- (6- (3- (1H-imidazole-1-yl) propyl) pyridine-2-yl) -3- (furan-3-yl) urea, wherein the chemical structural formula of the target product is as follows:
Figure BDA0003659469620000191
the total yield thereof was 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. Water and toluene (1:4, v/v) are used as solvents, 1 equivalent of 2-amino-6-bromopyridine is added, 1.3 equivalents of cyclopropylboronic acid and 3.5 equivalents of potassium phosphate are added, stirring is started, 0.1 equivalent of tricyclohexylphosphine and 0.05 equivalent of palladium acetate are added, and reflux reaction is carried out at 100 ℃ for 24 hours. After the reaction is finished, cooling the system to room temperature, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, carrying out reduced pressure distillation, and carrying out column chromatography to obtain the 6-cyclopropyl-2-pyridylamine, wherein the yield is as follows: 50 percent;
b. taking dichloromethane as a solvent, adding 1 equivalent of 6-cyclopropyl-2-pyridylamine, then adding not less than 1.5 equivalents of fluorenylmethoxycarbonyl succinimide, starting stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is decompressed and distilled, the solvent is removed, and column chromatography is carried out to obtain (9H-fluoren-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, wherein the yield is as follows: 64 percent;
c. taking tert-butyl alcohol as a solvent, adding 1 equivalent of (9H-fluorene-9-yl) methyl (6-cyclopropyl pyridine-2-yl) carbamate, adding 1.5 equivalents of boron tribromide, stirring, and reacting at room temperature for 3 hours. After the reaction is finished, the reaction system is carefully poured into water to stop the reaction, ethyl acetate is used for extraction for three times, organic phases are combined, anhydrous sodium sulfate is dried, reduced pressure distillation and column chromatography are carried out to obtain (9H-fluoren-9-yl) methyl (6- (3-bromopropyl) pyridine-2-yl) carbamate, and the yield is as follows: 33%;
d. adding 2 equivalents of anhydrous potassium carbonate and 3 equivalents of 5-methyl-1H-1, 2, 4-triazole into N-N-dimethylformamide serving as a solvent, 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 is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain (9H-fluoren-9-yl) methyl (6- (3- (5-methyl-1H-1, 2, 4-triazol-1-yl) propyl) pyridine-2-yl) carbamate, wherein the yield is as follows: 54 percent;
e. methanol is taken as a solvent, 1 equivalent of (9H-fluoren-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, wherein the yield is as follows: 61%;
f. taking N-N-dimethylformamide as a solvent, adding 1 equivalent of 6- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) pyridine-2-amine, adding 1 equivalent of 5-isocyano radical-1H-indole, starting stirring, and carrying out reflux reaction at 100 ℃ for 15 hours. After the reaction is finished, pouring the system into water, extracting the system for three times by using ethyl acetate, combining organic phases, drying the system by using anhydrous sodium sulfate, distilling the mixture under reduced pressure and carrying out column chromatography to obtain a target product 1- (1H-indol-5-yl) -3- (6- (3- (5-methyl-1H-1, 2, 4-triazole-1-yl) propyl) pyridin-2-yl) urea, wherein the chemical structural formula of the urea is as follows:
Figure BDA0003659469620000211
the total yield was 18%.
Example 9
QC enzyme inhibitory Activity Using the Compounds in Table 1
mu.L QC, 10. mu.L 100. mu.M compound/10. mu.L 100. mu.MPBD-150 (positive control)/10. mu.L DMSO (negative control)/50. mu.L HEPES buffer (blank control) was added to 96-well plates and incubated at room temperature for 3 min. 50 μ L of substrate Q-AMC was added to each well. Incubation was carried out at 200rpm for 10min at 25 ℃. Add 100 μ L PAP to each well. Incubation at 200rpm for 60min at 25 ℃ at room temperature was performed using a single wavelength scan EX/EM of 360nm/445 nm. The inhibition ratio (%) - (DMSO-Cpd)/(DMSO-Blank) × 100%. DMSO, DMSO: fluorescence values for the DMSO group; cpd: fluorescence values of the inhibitor groups; blank: fluorescence values for the enzyme groups were not added. The measurement results are shown in Table 1.
Example 10
GSK-3 β enzyme inhibitory activity was tested using the compounds in table 1:
mu.L of the kinase reaction was added to 384 well plates: mu.l of 4. mu.M ATP/0.12. mu.g/. mu.l substrate mix was added to each well, the inhibitors were diluted to serial 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 enzyme solution was added to the 384 well plates. A control without enzyme was also set up and the enzyme was replaced with an equal volume of 1X Buffer A. Incubating at room temperature for 60 min; add 5. mu.L ADP-GloTM reagent per well; incubating at room temperature for 40 min; adding 10 mu L of kinase detection reagent into each hole; incubating at room temperature for 30 min; the fluorescence intensity was measured. The inhibition ratio (%) - (DMSO-Cpd)/(DMSO-Blank) × 100%. DMSO, DMSO: the luminescence value of the DMSO group; cpd: the luminescence values of the inhibitor groups; blank: luminescence values of the enzyme groups were not added. The measurement results are shown in Table 1.
QC and GSK-3 beta enzyme inhibitory Activity assay results for the Compounds of Table 1
Figure BDA0003659469620000221
Figure BDA0003659469620000231
Figure BDA0003659469620000241
Figure BDA0003659469620000251
Figure BDA0003659469620000261
Figure BDA0003659469620000271
In conclusion, the series of novel structural compounds provided by the invention remarkably expand the molecular structure diversity of QC and GSK-3 beta multi-target inhibitors, the raw materials are easy to obtain, the preparation method is simple and feasible, the inhibitory activity on QC and GSK-3 beta is remarkable, and the series of novel structural compounds have the potential of further developing and innovating medicaments as lead compounds.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.

Claims (8)

1. A QC and GSK-3 beta multi-target inhibitor is characterized by comprising the following structural general formula:
Figure FDA0003659469610000011
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 polyaromatic ring system, and R is 1 Is one of hydrogen, alkyl, alkoxy, nitro, amido, halogen, sulfonic acid group and ester group, and R is 1 Is mono-substituted or poly-substituted in different positions; the unit B is a five-membered heterocyclic ring or a six-membered heterocyclic ring system, and a carbon atom n in an alkyl chain is 1-4; c unit is imidazole ring or triazole ring heterocyclic ring system, R 2 Is one of hydrogen, straight chain alkyl, branched chain alkyl, alkoxy and halogen, and R 2 Is monosubstituted or polysubstituted in different positions; the substitution positions of the A and C units on the B ring are meta.
2. The QC and GSK-3 β multi-targeted inhibitor according to claim 1, wherein the QC and GSK-3 β multi-targeted inhibitor is of one of the following chemical structural formulae:
Figure FDA0003659469610000012
Figure FDA0003659469610000021
Figure FDA0003659469610000031
3. a method for the preparation of a multi-targeted inhibitor of QC and GSK-3 β according to any one of claims 1 to 2, comprising the steps of:
to be provided with
Figure FDA0003659469610000032
And thiourea or
Figure FDA0003659469610000033
And
Figure FDA0003659469610000034
raw materials are subjected to cyclization or coupling reaction for a first preset time to prepare an intermediate containing a B unit heterocycle
Figure FDA0003659469610000035
Wherein X is methyl, ethyl, cyclopropyl or cyclobutyl;
by intermediates
Figure FDA0003659469610000036
Preparing an intermediate containing an amino protecting group by a protection reaction of an amino for a second preset time
Figure FDA0003659469610000037
By intermediates
Figure FDA0003659469610000038
The intermediate with the structure end containing alkyl chain is prepared and obtained by ring-opening or bromination reaction for the third preset time as the raw material
Figure FDA0003659469610000039
By intermediates
Figure FDA0003659469610000041
Reacting with imidazole ring or triazole ring heterocyclic ring system serving as raw material for fourth preset time by SN2 to obtain intermediate containing imidazole ring or triazole ring
Figure FDA0003659469610000042
By intermediates
Figure FDA0003659469610000043
Preparing an intermediate containing amino through deprotection reaction of the amino for fifth preset time
Figure FDA0003659469610000044
By intermediates
Figure FDA0003659469610000045
The raw materials are subjected to coupling reaction for the sixth preset time to prepare a target product
Figure FDA0003659469610000046
4. A method of preparing multi-targeted inhibitors of QC and GSK-3 β according to claim 3, wherein the first predetermined time is 8-24 h; and/or the second preset time is 2-5 h; the third preset time is 2-5 h; and/or the fourth preset time is 8-12 h; and/or the fifth preset time is 2-6 h; and/or the sixth preset time is 12-16 h.
5. Use of a multi-targeted inhibitor of QC and GSK-3 β according to any one of claims 1-2, wherein the glutaminyl cyclase inhibitor is used for the preparation of an anti-AD drug.
6. Use of multi-targeted inhibitors of QC and GSK-3 β according to any one of claims 1-2, wherein said glutaminyl cyclase inhibitors are used for the preparation of kits for the diagnosis of AD.
7. Use of multi-targeted inhibitors of QC and GSK-3 β according to any one of claims 1 to 2, wherein said glutaminyl cyclase inhibitors are used for the preparation of a medicament for the control of diseases associated with high specific expression of QC and/or GSK-3 β.
8. Use of multi-targeted inhibitors of QC and GSK-3 β according to any one of claims 1 to 2, wherein said glutaminyl cyclase inhibitors are used for the preparation of diagnostic kits for diseases associated with QC and/or GSK-3 β specific high expression.
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