CN115466260B - Imidazole and thiazole derivatives containing amino acid structure, and preparation method and application thereof - Google Patents

Imidazole and thiazole derivatives containing amino acid structure, and preparation method and application thereof Download PDF

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CN115466260B
CN115466260B CN202211083509.8A CN202211083509A CN115466260B CN 115466260 B CN115466260 B CN 115466260B CN 202211083509 A CN202211083509 A CN 202211083509A CN 115466260 B CN115466260 B CN 115466260B
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methylpyridin
pyridin
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triazol
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CN115466260A (en
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金成华
廉丽花
南极星
孟雨晴
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Yanbian University
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses imidazole and thiazole derivatives containing amino acid structures, two imidazole and thiazole compounds containing amino acid structures and having the structures shown in the following general formulas I and II, and pharmaceutically acceptable salts or hydrates thereof:in the general formula: r is R 1 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; r is R 2 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; x is O or S.

Description

Imidazole and thiazole derivatives containing amino acid structure, and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to imidazole and thiazole derivatives containing amino acid structures, and a preparation method and application thereof.
Background
Transforming growth factors (TGF-beta) are proteins with multiple functions and multi-directional regulation, belonging to a class of cytokine superfamily, including TGF-beta s (TGF-beta 1, TGF-beta 2, TGF-beta 3), activins (activins), inhibins (inhibins), and Bone Morphogenic Proteins (BMPs).
The signaling of TGF- β requires the passage through two types of single transmembrane serine/threonine (threonine) receptor kinases, type I and type II receptors (abbreviated as TβR-I and TβR-II), respectively. TGF-beta binds to the type II receptor first to form a dimer, followed by recruitment of two type I (or activin receptor-like kinase 5, ALK 5) receptors. The type II receptor activated by TGF- β hyperphosphorylates serine and threonine residues of ALK5 in the GS region, producing Smad proteins and activating ALK5. The activated ALK5 phosphorylates Smad2 and Smad3 proteins, thereby separating from the receptor, followed by conjugation to the co-regulator Smad4 to form a heteromer. The Smad complex is transferred into the nucleus, and combined with specific DNA to regulate the expression of gene transcription factors of extracellular matrix (Extracellular matrix, ECM), and promote the excessive generation and deposition of ECM. Activation of TGF- β signaling leads to the development of a variety of human diseases, such as breast cancer, hematologic malignancies, fibrosis, and the like. From this, it can be seen that a very effective method for inhibiting the binding of ALK5 to the substrates Smad2 and Smad3 or inhibiting the phosphorylation of Smad2 and Smad3 by ALK5, and thus blocking the TGF-beta signaling pathway, is provided.
Liver fibrosis (hepatic fibrosis) is a reversible pathophysiological process, and is also a compensatory response in liver injury and tissue repair processes after inflammation caused by various chronic pathogenic factors. Liver fibrosis is also an essential stage in the progression of chronic liver disease to cirrhosis, and is characterized by excessive and abnormal deposition of ECM components in the liver. (M Parola, M pinzani. Liver fibrology: pathogenicity, pathogenetic targets and clinical issues, mol. Asp. Med.2019,65,37-55.) according to the latest data, the number of deaths from liver cancer and cirrhosis is increasing worldwide, and mortality is high because liver cancer is usually diagnosed until late. In addition, china is a highly-developed country of viral hepatitis, and about 1.2 hundred million people infected with hepatitis B exist. Therefore, it is particularly important and urgent to treat liver fibrosis before it progresses to cirrhosis or even liver cancer.
Recent studies have shown that acute and chronic liver injury can both lead to liver fibrosis, further development can lead to cirrhosis, liver failure, portal hypertension or liver cancer, and ultimately death. Currently, only liver transplants are used to extend the life of patients with advanced liver Cancer (W Chen, R Zheng, PD Baade, et al Cancer statistics in China, CA Cancer J Clin.2016,66, 115-132.). But only a small percentage of people are available due to the limited number of donated organs.
In recent decades, research on anti-hepatic fibrosis drugs has been advanced to a certain extent, and currently, clinically multipurpose traditional Chinese medicines or Chinese patent medicines are used for treating the anti-hepatic fibrosis drugs, and the drugs have the defects of high toxicity, low selectivity, easiness in generating drug resistance and the like.
From the above, TGF- β plays an important role in tissue fibrosis, such as ECM synthesis, reactive oxygen species (Reactive oxygen species, ROS) generation, myofibroblast activation, and the like. Collagen (Collagen) and alpha-smooth muscle actin (alpha-SMA) secretion are major markers judging the extent of fibrosis, which regulate TGF-beta induced Smad activation and ROS signaling through fibrotic cytokines and their intracellular signaling pathways.
TGF- β1 is the most potent cytokine promoting liver fibrosis, which is caused by promoting the production and deposition of ECM in hepatic stellate cells, with TGF- β/Smad signaling pathway mediated ECM production being an important pathway for promoting collagen deposition in the liver.
There are a variety of amino acids in the human body, which are essential to the human body, and which are important parts of the constituent proteins. Therefore, the amino acid introduced into the designed compound structure can reduce toxicity and improve biological activity.
Since liver fibrosis is mainly characterized by excessive deposition of ECM components, mainly type I collagen, inhibition of type I collagen expression is one of the important strategies for current anti-fibrotic therapies. Therefore, the development of the medicine which has low toxicity and strong effect on inhibiting ALK5 kinase and collagen deposition has good application prospect in clinic.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide imidazole and thiazole derivatives containing amino acid structures, and a preparation method and application thereof.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
imidazole and thiazole derivatives containing amino acid structures, two imidazole and thiazole compounds containing amino acid structures and having structures shown in the following general formulas I and II, and pharmaceutically acceptable salts or hydrates thereof:
in the general formula: r is R 1 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; r is R 2 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; x is O or S.
The R is as follows 1 Is one of the following:
the R is as follows 2 Is one of the following:
the imidazole and thiazole derivatives include:
(S) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(R) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-aminopropionamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(S) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide;
(R) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-aminopropionamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide and pharmaceutically acceptable salts or hydrates thereof.
The invention provides a preparation method of imidazole and thiazole derivatives containing amino acid structures, which comprises the following steps:
S1, oxidizing a compound shown in a formula 1 with hydrobromic acid in dimethyl sulfoxide to obtain 1- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -2- (6-methylpyridin-2-yl) ethane-1, 2-dione (formula 2);
s2, carrying out cyclization reaction on the formula 2 and 2- (1, 3-dioxoisoindol-2-yl) acetaldehyde to obtain 2- ((4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) indoline-1, 3-dione (formula 4);
s3, carrying out deprotection reaction on the formula 4 and hydrazine hydrate to obtain 4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazole-2-yl) methylamine (formula 5);
s4, carrying out condensation reaction on the formula 5 and the formula 6 or the formula 7 in the presence of benzotriazole-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP) and Diisopropylethylamine (DIPEA) to obtain the imidazole compound containing the amide structure, wherein the structural formula of the imidazole compound is shown as the general formula I.
The invention provides a preparation method of imidazole and thiazole derivatives containing amino acid structures, which comprises the following steps:
s1, carrying out halogenation reaction on a compound shown in a formula 1 and bromine water to obtain 2-bromo-1- (6-methylpyridin-2-yl) -2- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) ethane-ketone (formula 8);
S2, carrying out cyclization reaction on the formula 8 and thiourea to obtain 4- (6-methylpyridine-2-yl) -5- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -thiazole-2 amine (formula 9);
s3, carrying out condensation reaction on the formula 9 and the formula 6 or the formula 7 in the presence of benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP) and Diisopropylethylamine (DIPEA) to obtain the thiazole compound containing the amide structure, wherein the structural formula of the thiazole compound is shown as the general formula II.
According to the technical scheme, the invention further provides an ALK5 kinase inhibitor, which comprises imidazole and thiazole compounds containing amino acid structures.
Further, the application of the ALK5 kinase inhibitor in the preparation of medicines for inhibiting hepatic fibrosis is provided.
The inventor discovers that the method for preparing the compound shown in the formula I by using the method provided by the embodiment of the invention is rapid and effective, short in synthetic route, environment-friendly, high in yield and purity of target products, easy in raw material acquisition, simple in operation and post-treatment, and suitable for industrial production. In the examples of the present invention, the synthetic route for the compounds of formula I-1 is:
the general procedure for the preparation of the compounds of formula I-1 employed in the examples of the present invention is described below:
Step (1): the compound is 1- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -2- (6-methylpyridin-2-yl) ethane-1, 2-dione (the compound shown in formula 2).
According to an embodiment of the present invention, in step (1), the 1- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -2- (6-methyl-2-pyridinyl) ethanone (compound 1 of formula 1) is reacted with the compound of formula 2 in dimethyl sulfoxide (DMSO), the dimethyl methylene peak containing HBr.
According to a specific example of the present invention, in step (1), the compound represented by formula 1 is contacted with HBr at 70 ℃ for 1.5 hours, whereby the reaction efficiency can be improved while the two are sufficiently reacted, thereby finally improving the yield of the compound represented by formula 2. According to a specific embodiment of the invention, in step (1), the molar ratio between the compound of formula 1 and 48% hbr is 1:2-5. According to a specific embodiment of the invention, it is preferably 1:3.4. Furthermore, the yield of the compound shown in the formula 2 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound represented by formula 2 may be carried out according to the following steps: the compound represented by formula 1 was dissolved in DMSO, 48% hbr was added dropwise thereto, and the mixture was reacted at 70 ℃ with stirring for 1.5 hours. After the reaction was completed, it was transferred to room temperature, cooled to room temperature, transferred to an ice bath, and neutralized with saturated sodium bicarbonate solution. The mixture was extracted several times with dichloromethane and the organic layers were combined. The organic layer was washed with distilled water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was a compound represented by formula 2.
Step (2): the compound is the preparation of 2- ((4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) indoline-1, 3-dione (the compound shown in formula 4).
According to an embodiment of the present invention, in step (2), the compound represented by formula 2 is reacted with 2- (1, 3-dioxoisoindol-2-yl) acetaldehyde (compound 3 represented by formula 3) in the presence of ammonium acetate in an organic solvent. According to a specific example of the present invention, the organic solvent may be at least one selected from methanol, ethanol, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether (MTBE). Mixed solvents of MTBE and methanol are preferred. Thus, a good reaction environment can be provided for the compound shown in the formula 2 and the compound shown in the formula 3, and the yield of the compound shown in the formula 4 is further improved.
According to a specific example of the present invention, the compound represented by formula 2 is contacted with the compound represented by formula 3 at 50 ℃. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 4 can be further improved. According to another specific example of the present invention, in the step (2), the molar ratio of the compound represented by formula 2, the compound represented by formula 3, and ammonium acetate may be 1:1 to 3:5 to 20. According to a specific embodiment of the invention, it is preferably 1:1.5:10. Furthermore, the yield of the compound shown in the formula 2 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound represented by formula 4 may be carried out specifically according to the following steps: the compound represented by formula 2 was dissolved in methanol at room temperature, and ammonium acetate, the compound represented by formula 3, and MTBE were sequentially added thereto. The mixture was heated at 50 ℃ for 10 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product which was a compound of formula 4.
Step (3): the compound is the preparation of 4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methylamine (the compound shown in formula 5).
According to a specific embodiment of the invention, in step (3), the formula 4 and hydrazine hydrate are reacted in the presence of an organic solvent. According to a specific example of the present invention, the organic solvent may be at least one selected from methanol, ethanol, propanol, butanol. Ethanol is preferred. Therefore, a good reaction environment can be provided for the formula 4 and the hydrazine hydrate, and the yield of the compound shown in the formula 5 is further improved.
According to a specific example of the present invention, the compound represented by formula 4 is reacted with hydrazine hydrate at the time of refluxing. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 5 can be further improved. According to another specific example of the present invention, in step (2), the molar ratio of the compound represented by formula 4 to hydrazine hydrate may be 1:20. According to a specific embodiment of the invention, it is preferably 1:10. Furthermore, the yield of the compound shown in the formula 5 can be improved, and the cost of raw materials can be saved.
According to one embodiment of the present invention, the preparation of the compound represented by formula 5 may be performed specifically according to the following steps: ethanol and hydrazine hydrate were added to the stirred compound of formula 5 at room temperature. After the mixture was heated under reflux for 5 hours, it was cooled to room temperature. The excessive hydrazine hydrate in the reaction mixture is quenched by acetone, and concentrated under reduced pressure, and the product is obtained by column chromatography separation, which is a compound shown in a formula 5.
Step (4): the compound is the preparation of N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) acetamide (formula I-1).
According to an embodiment of the present invention, in step (4), the compound represented by formula 5 is reacted with the compound represented by formula 6 or the compound represented by formula 7 in the presence of an organic solvent, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), diisopropylethylamine (DIPEA). According to a specific example of the present invention, the organic solvent may be at least one selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran, and dichloromethane. Dimethylformamide is preferred. Therefore, a good reaction environment can be provided for the formula 5 and the formula 6 or the formula 7, and the yield of the compound shown in the formula I-1 is further improved.
According to a specific example of the present invention, the compound represented by formula 5 is reacted with the compound represented by formula 6 or the compound represented by formula 7 at room temperature. By selecting a suitable reaction temperature, the yield of the compound of formula I-1 can be further increased. According to another specific example of the present invention, in the step (4), the compound represented by formula 5, the compound represented by formula 6, or the compound represented by formula 7, the mole ratio of PyBOP and DIPEA may be 1:1-3:1-3:1-3. According to a specific embodiment of the invention, it is preferably 1:1:1.1:2. Furthermore, the yield of the compound shown in the formula I-1 can be improved, and the cost of raw materials can be saved.
According to one embodiment of the present invention, the preparation of the compound of formula I-1 may be carried out according to the following steps: the compound represented by formula 5 was dissolved in dimethylformamide at room temperature, and the compound represented by formula 6 or the compound represented by formula 7, pyBOP and DIPEA were sequentially added thereto, followed by stirring for 6 hours after the addition. The reaction mixture was dissolved in ethyl acetate, washed with saturated sodium hydrogencarbonate, water and saturated brine in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give an intermediate containing Boc protection.
After the intermediate was dissolved in methylene chloride, trifluoroacetic acid was added dropwise thereto and stirred for 1 hour. The reaction mixture was concentrated and then neutralized with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic solvents were washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by I-1.
In the examples of the present invention, the synthetic route for the compound of formula II-1 is:
the general procedure for the preparation of the compounds of formula II-1 employed in the examples of the present invention is described below:
step (1): the compound is the preparation of 2-bromo-1- (6-methylpyridin-2-yl) -2- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) ethan-one (the compound shown in formula 8).
According to an embodiment of the present invention, in step (1), the compound represented by formula 1 is reacted with bromine water in 1, 4-dioxane. According to a specific example of the present invention, the organic solvent may be at least one selected from dimethylformamide, 1, 4-dioxane, tetrahydrofuran, diethyl ether. 1, 4-dioxane is preferred. This provides a good reaction environment for the compound of formula 1, and further improves the yield of the compound of formula 8.
According to a specific example of the present invention, in step (1), the compound represented by formula 1 is reacted with bromine water at normal temperature. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 8 can be further improved. According to another specific example of the present invention, in the step (1), the molar ratio of the compound represented by formula 1 to bromine water may be 1:0.9 to 1.3. According to a specific embodiment of the invention, it is preferably 1:1.1. Furthermore, the yield of the compound shown in the formula 8 can be improved, and the raw material cost can be saved.
According to an embodiment of the present invention, the preparation of the compound represented by formula 8 may be specifically performed according to the following steps: the compound represented by formula 1 was dissolved in 1, 4-dioxane, bromine water was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to give the compound of formula 8.
Step (2): the compound is the preparation of 4- (6-methylpyridin-2-yl) -5- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -thiazol-2-amine (the compound shown in formula 9).
According to an embodiment of the present invention, in step (2), the compound represented by formula 8 is reacted with thiourea in dimethylformamide. According to a specific example of the present cover, the organic solvent may be selected from one of dimethylformamide, dimethylsulfoxide, 1, 4-dioxane, and tetrahydrofuran. Dimethylformamide is preferred. This provides a good reaction environment for the compound represented by formula 8, and further improves the yield of the compound represented by formula 9.
According to a specific example of the present invention, in step (2), the compound represented by formula 8 is reacted with thiourea at 120 ℃. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 9 can be further improved. According to another specific example of the present invention, in the step (2), the molar ratio of the compound represented by formula 8 to thiourea may be 1:1 to 4. According to a specific embodiment of the invention, it is preferably 1:2.1. Furthermore, the yield of the compound shown in the formula 9 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound represented by formula 9 may be performed specifically according to the following steps: the compound represented by formula 8 was dissolved in dimethylformamide, thiourea was added thereto, and the mixture was stirred at 120℃for 2 hours. After the reaction solution was cooled to 0 ℃, ice water was added to the mixture, and solids were precipitated, filtered, and washed with water to obtain a reddish brown product, which was a compound represented by formula 9.
Step (3): the compound is the preparation of N- (5- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) thiazol-2-yl) acetamide (formula II-1). The preparation method of the compound is the same as that of the compound shown in the formula I-1.
In the examples of the present invention, the synthetic routes for the compounds of formulas I-2 and II-2 are:
step (1): the compound is the preparation of N- ((4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1-hydro-imidazol-2-yl) thioacetamide (the compound shown in the formula I-2).
According to an embodiment of the present invention, in step (1), tert-butyl ((1- (((4- ([ 1,2,4] triazol [1,5- α ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) amino) -1-oxopropan-2-yl) carbamate (formula 10) is reacted with a Lawsen reagent.
According to a specific example of the present invention, in step (1), the compound of formula 10 is reacted with a lawsonia reagent in a pressurized bottle at 85 ℃. By selecting a suitable reaction temperature, the yield of the compound represented by the formula I-2 can be further improved. According to another specific example of the present invention, in step (1), the molar ratio of the compound of formula 10 to the lawsen reagent may be 1:0.9-1.3. According to a specific embodiment of the invention, it is preferably 1:1. And further, the yield of the compound shown in the formula I-2 can be improved, and meanwhile, the cost of raw materials is saved.
According to one embodiment of the present invention, the preparation of the compound shown as I-2 can be carried out according to the following steps: the compound of formula 10 placed in a pressurized bottle was dissolved in 1, 2-dimethoxyethane at room temperature, a lawson reagent was added thereto, and the mixture was stirred at 85 ℃ for reaction for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting mixture was separated by column chromatography to give an intermediate containing Boc protection.
After the intermediate was dissolved in methylene chloride, trifluoroacetic acid was added dropwise thereto and stirred for 1 hour. The reaction mixture was concentrated and then neutralized with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic solvents were washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound represented by I-2.
Step (2): the compound is N- (((4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -thiazol-2-yl) thioacetamide (the compound shown in the formula II-2) and the preparation method of the compound is the same as that of the compound shown in the formula I-1.
The imidazole and thiazole derivatives containing amino acid structures have the inhibitory activity of transforming growth factor beta 1 receptor (ALK 5) kinase, can inhibit collagen deposition in hepatic stellate cells induced by TGF-beta, can be used for treating hepatic fibrosis, and has good medical prospect.
Drawings
FIG. 1 is a graph showing the effect of compound J-1149 on LX-2 cell viability at various concentrations by MTT assay.
FIG. 2 is a graph showing the effect of compound J-1155 on LX-2 cell viability at various concentrations by MTT assay.
FIG. 3 is a graph showing the effect of compound J-1156 on LX-2 cell viability at various concentrations by MTT assay.
FIG. 4 is an immunofluorescence observation of the effect of compound J-1149 on TGF- β induced expression of hepatic fibrosis marker α -SMA at various concentrations.
FIG. 5 is an immunofluorescence observation of the effect of compounds J-1155 and J-1156 on TGF-beta induced expression of hepatic fibrosis markers α -SMA at various concentrations.
Detailed Description
The following description of the present invention will further illustrate the present invention, and the following examples are provided on the premise of the present technical solution, and the detailed implementation and the specific operation procedure are given, but the protection scope of the present invention is not limited to the present examples.
The invention relates to imidazole and thiazole derivatives containing amino acid structures, two imidazole and thiazole compounds containing amino acid structures and having the structures shown in the following general formulas I and II, and pharmaceutically acceptable salts or hydrates thereof:
in the general formula: r is R 1 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; r is R 2 Is a 6-membered heterocyclic ring, C 2 Or C 5 Alkylamine, C 2 A phenylamine; x is O or S.
The R is as follows 1 Is one of the following:
the R is as follows 2 Is one of the following:
the imidazole and thiazole derivatives include:
(S) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(R) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-aminopropionamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(S) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide;
(R) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-aminopropionamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide and pharmaceutically acceptable salts or hydrates thereof.
Example 1: preparation of Compound 2
Compound 1 (6.00 g,23.80 mmol) was dissolved in dimethyl sulfoxide (216 mL), 48% HBr (13.7 mL) was added dropwise thereto, and the mixture was reacted at 70℃with stirring for 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and neutralized with saturated sodium bicarbonate solution in an ice bath. The mixture was extracted with dichloromethane (3X 250 mL) and the organic solvents were combined. The organic solvent was washed with water (2X 250 mL) and brine (250 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 2 (5.19 g) as a yellow solid.
Compound 2 1- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -2- (6-methylpyridin-2-yl) ethane-1, 2-dione
Yield: 82%; 1 H NMR(300MHz,CDCl 3 )δ9.14(s,1H),8.50(s,1H),8.16(dd,J＝9.0Hz,1H),8.06(d,J＝9.0Hz,1H),7.94–7.81(m,2H),7.44(d,J＝7.8Hz,1H),2.52(s,3H).
example 2: preparation of Compound 4
Compound 2 (5.99 g,22.50 mmol) and methanol (120 mL) were placed in a 500mL round bottom flask at room temperature, and ammonium acetate (17.16 g,222.63 mmol), compound 3 (6.27 g,33.16 mmol) and MTBE (120 mL) were added sequentially. The mixture was heated at 50 ℃ for 10 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2X 300 mL), and the combined organic layers were washed once with water (150 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to give crude product. This was subjected to column chromatography using methanol and methylene chloride (1:50) as eluent to give compound 4 (6.17 g) as a yellow solid.
2- ((4- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) indoline-1, 3-dione
The yield thereof was found to be 63%; 1 H NMR(300MHz,DMSO-d 6 )δ9.63(br s,1H),8.49(s,1H),7.95(d,J＝6.0Hz,2H),7.89(br s,2H),7.79(br s,2H),7.73–7.63(m,1H),7.50(s,1H),7.33(d,J＝7.8Hz,1H),7.20(d,J＝9.0Hz,1H),4.95(s,2H),2.51(s,3H).
example 3: preparation of Compound 5
Compound 4 (3.50 g,11.46 mmol) was dissolved in ethanol (210 mL) at room temperature, 90% hydrazine hydrate (114.6 mmol) was added and the mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, quenched with acetone (51 mL) to quench excess hydrazine hydrate, and concentrated under reduced pressure to give crude product. This was subjected to column chromatography using methanol, methylene chloride and aqueous ammonia (1:100:0.1) as an eluent to give compound 5 (1.57 g) as a yellow solid.
4- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methylamine
Yield: 64%; 1 H NMR(300MHz,DMSO-d 6 )δ9.54(br s,1H),8.51(s,1H),8.08(dd,J＝9.0,3.0Hz,2H),7.88(dd,J＝9.0,3.0Hz,2H),7.75–7.66(m,1H),7.53(s,1H),7.17(d,J＝9.0Hz,1H),3.96(s,2H),2.51(s,3H).
example 4: preparation of Compound 8
Compound 1 (8.54 g,25.8 mmol) was dissolved in 1, 4-dioxane (33 mL), to which was added dropwise bromine water (28.45 mmol,1.46 mL) and stirred for 1 hour. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2X 250 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. This was subjected to column chromatography using ethyl acetate and petroleum ether (1:2) as eluent to give compound 8 (7.49 g) as a brown solid. Because compound 8 is unstable, the synthesis of compound 9 is directly performed after drying.
2-bromo-1- (6-methylpyridin-2-yl) -2- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) ethan-one
Yield: 67%
Example 5: preparation of Compound 9
Compound 8 (5.73 g,17.30 mmol) was dissolved in dimethylformamide (46 mL), thiourea (2.76 g,36.30 mmol) was added thereto, and the mixture was stirred at 120℃for 2 hours. After the reaction mixture was cooled to 0 ℃, ice water was added to the mixture, and solids were precipitated, filtered, and washed with water to give a reddish brown solid compound 9 (5.08 g).
4- (6-methylpyridin-2-yl) -5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -thiazol-2-amine
Yield: 95%; 1 H NMR(300MHz,CDCl 3 /CD 3 OD)δ8.51(s,1H),8.29(s,1H),7.64(d,J＝9.0Hz,1H),7.51–7.47(m,2H),7.31(d,J＝9.0Hz,1H),7.06(d,J＝6.0Hz,1H),2.35(s,3H).
example 6: preparation of Compounds of formulas I-1 and II-1
The general synthesis of N- ((4- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) acetamide (formula I-1-1-I-1-7) and N- (5- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) thiazol-2-yl) acetamide (formula II-1-1-II-1-7) is described by way of example in formulas I-1 and II-1.
Compound 5 or 9 (0.24 mmol) was dissolved in dimethylformamide (3 mL), and to this was added the compound represented by the above formula 6 or 7 (0.24 mmol), pyBOP (0.14 g,0.27 mmol), DIPEA (0.49 mmol,0.09 mL) in this order, followed by stirring for 6 hours. After the reaction mixture was dissolved in ethyl acetate (30 mL), it was washed with saturated sodium bicarbonate (10 mL), water (5X 5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (dichloromethane: methanol=60:1) to give an intermediate containing Boc protection.
After the intermediate was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1.42 mmol,0.10 mL) was added dropwise thereto, and the mixture was stirred for 1 hour. The reaction mixture was concentrated and then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2X 10 mL), and the combined organic layers were washed with water (5 mL) and saturated brine (5 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound of formula I-1 or II-1.
(S) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide (Compound I-1-1)
Yellow solid, yield: 80%; 1 H NMR(300MHz,CDCl 3 )δ9.01(s,1H),8.30(s,1H),7.78(dd,J＝9.0,3.0Hz,1H),7.68(d,J＝9.0Hz,1H),7.47(t,J＝7.5Hz,1H),7.21(d,J＝6.0Hz,1H),7.02(d,J＝9.0Hz,1H),4.50(s,2H),3.26–3.23(m,1H),3.12–3.03(m,4H),2.52(s,3H),1.80–1.75(m,4H)；MS-ESI:m/z 417[M+1] + 。
(R) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide (Compound I-1-2)
Yellow solid, 82%; 1 H NMR(300MHz,CDCl 3 )δ9.02(s,1H),8.32(s,1H),8.04(s,1H),7.79(d,J＝9.2Hz,1H),7.67(d,J＝9.2Hz,1H),7.46(t,J＝7.5Hz,1H),7.23(d,J＝6.0Hz,1H),7.02(d,J＝9.0Hz,1H),4.55(s,2H),3.37–3.34(m,1H),3.17–3.05(m,4H),2.55(s,3H),1.82–1.79(m,4H)；MS-ESI:m/z 417[M+1] + 。
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-aminopropionamide (Compound I-1-3)
Yellow solid, yield: 79%; 1 H NMR(300MHz,CDCl 3 )δ8.99(s,1H),8.33(s,1H),8.27(s,1H),7.79(d,J＝9.0Hz,1H),7.70(d,J＝9.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.22(d,J＝9.0Hz,1H),7.02(d,J＝9.0Hz,1H),4.55(s,2H),3.58(q,J＝6.0Hz,1H),2.55(s,3H),1.37(d,J＝6.0Hz,3H)；MS-ESI:m/z 377[M+1] + 。
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide (Compound I-1-4)
Yellow solidBody, yield: 85%; 1 H NMR(300MHz,CDCl 3 )δ8.98(s,1H),8.31(s,1H),7.76(dd,J＝9.0,3.0Hz,1H),7.71(d,J＝9.0Hz,1H),7.49(t,J＝7.5Hz,1H),7.19(d,J＝9.0Hz,1H),7.04(d,J＝9.0Hz,1H),4.49(s,2H),3.61–3.56(m,1H),2.53(s,3H),1.66–1.59(m,2H),1.48–1.43(m,1H),0.92(d,J＝6.0Hz,3H),0.90(d,J＝6.0Hz,3H)；MS-ESI:m/z 419[M+1] + 。
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide (Compound I-1-5)
Yellow solid, yield: 89%; 1 H NMR(300MHz,CDCl 3 /CD 3 OD)δ9.06(s,1H),8.36(s,1H),7.84(d,J＝9.0Hz,1H),7.75(d,J＝9.0Hz,1H),7.57(t,J＝7.5Hz,1H),7.28(d,J＝6.0Hz,1H),7.11(d,J＝9.0Hz,1H),4.55(s,2H),3.47–3.42(m,1H),2.57(s,3H),1.86–1.80(m,2H),1.77–1.58(m,1H),0.96(d,J＝6.0Hz,3H),0.94(d,J＝6.0Hz,3H)；MS-ESI:m/z 419[M+1] + 。
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide (Compound I-1-6)
Yellow solid, yield: 62%; 1 H NMR(300MHz,CDCl 3 )δ8.99(s,1H),8.31(s,1H),7.74(d,J＝9.0Hz,1H),7.70(d,J＝9.0Hz,1H),7.49(t,J＝7.5Hz,1H),7.22–7.12(m,6H),7.05(d,J＝9.0Hz,1H),4.47(m,2H),4.01(t,J＝7.5Hz,1H),3.19–3.12(m,1H),2.99–2.92(m,1H),2.52(s,3H)；MS-ESI:m/z 453[M+1] + 。
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide (Compound I-1-7,J-1149)
Yellow solid, yield: 50%; 1 H NMR(300MHz,CDCl 3 /CD 3 OD)δ8.98(s,1H),8.30(s,1H),7.75(dd,J＝9.0,3.0Hz,1H),7.69(d,J＝9.0Hz,1H),7.50(t,J＝9.0Hz,1H),7.21–7.12(m,6H),7.05(d,J＝9.0Hz,1H),4.44(s,2H),3.94(t,J＝7.5Hz,1H),3.15–3.08(m,1H),2.98–2.91(m,1H),2.52(s,3H)；MS-ESI:m/z 453[M+1] + 。
(S) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide (Compound II-1-1)
Yellow solid, yield: 22%; 1 H NMR(300MHz,CDCl 3 )δ8.89–8.81(m,1H),8.35(s,1H),7.70–7.51(m,4H),7.42(s,1H),7.07(d,J＝6.0Hz,1H),3.67–3.54(m,1H),3.06–3.02(m,1H),2.89–2.69(m,2H),2.43(s,3H),2.38–2.29(m,2H),2.03–1.98(s,2H),1.62–1.50(m,2H)；MS-ESI:m/z 420[M+1] + 。
(R) -N- (5- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) piperidine-2-carboxamide (Compound II-1-2)
Yellow solid, yield: 53%; 1 H NMR(300MHz,CDCl 3 )δ8.90–8.78(m,1H),8.35(s,1H),7.72–7.51(m,4H),7.36(d,J＝6.0Hz,1H),7.08(dd,J＝9.0,3.0Hz,1H),3.68–3.64(m,1H),3.13–3.08(m,1H),2.90–2.70(m,2H),2.46(s,3H),2.34–2.29(m,2H),2.07–1.96(m,2H),1.88–1.81(m,2H)；MS-ESI:m/z 420[M+1] + 。
(S) -N- (5- ([ 1,2,4] triazol [1, 5-alpha ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-aminopropionamide (compound II-1-3)
Yellow solid, yield: 42%; 1 H NMR(300MHz,CDCl 3 )δ8.81(s,1H),8.34(s,1H),7.67(d,J＝9.0Hz,1H),7.55(d,J＝9.0Hz,1H),7.44(d,J＝9.0Hz,1H),7.06(d,J＝9.0Hz,1H),3.77(br s,1H),2.41(s,3H),1.47(d,J＝6.0Hz,3H)；MS-ESI:m/z 380[M+1] + 。
(S) -N- (5- ([ 1,2,4] triazol [1, 5-alpha ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide (compound II-1-4,J-1155)
Yellow solid, yield: 37%; 1 H NMR(300MHz,CDCl 3 )δ 1 H NMR(300MHz,CDCl 3 )δ8.81(s,1H),8.34(s,1H),7.69(d,J＝9.0Hz,1H),7.55(d,J＝6.0Hz,2H),7.43(d,J＝6.0Hz),7.07(d,J＝9.0Hz,1H),3.69–3.66(m,1H),2.42(s,3H),1.86–1.78(m,2H),1.51–1.41(m,1H),0.99(br s,6H)；MS-ESI:m/z 422[M+1] + 。
(R) -N- (5- ([ 1,2,4] triazol [1,5- α ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide (compound II-1-5,J-1156)
Yellow solid, yield: 31%; 1 H NMR(300MHz,CDCl 3 )δ8.81(s,1H),8.34(s,1H),7.68(d,J＝9.0Hz,1H),7.55(d,J＝6.0Hz,1H),7.43(d,J＝6.0Hz,1H),7.06(d,J＝6.0Hz,1H),3.69–3.66(m,1H),2.42(s,3H),1.81(br s,2H),1.51–1.44(m,1H),0.98(br s,6H)；MS-ESI:m/z 422[M+1] + 。
(S) -N- (5- ([ 1,2,4] triazol [1, 5-alpha ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide (compound II-1-6)
Yellow solid, yield: 61%; 1 H NMR(300MHz,CDCl 3 )δ8.91–8.84(m,1H),8.36(s,1H),7.71–7.53(m,5H),7.35–7.25(m,4H),7.08(d,J＝9.0Hz,1H),3.92–3.89(m,1H),3.42–3.36(m,1H),2.92–2.87(m,1H),2.43(s,3H)；MS-ESI:m/z 456[M+1] + 。
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide (compound II-1-7)
Yellow solid, yield: 68%; 1 H NMR(300MHz,CDCl 3 )δ8.83(s,1H),8.35(s,1H),7.68(d,J＝9.0Hz,1H),7.58–7.51(m,2H),7.44(d,J＝9.0Hz,1H),7.33–7.21(m,5H),7.06(d,J＝9.0Hz,1H),3.91–3.87(m,1H),3.40–3.34(m,1H),2.91–2.86(m,1H),2.41(s,3H)；MS-ESI:m/z 456[M+1] + 。
example 7: preparation of Compounds of formulas I-2 and II-2
Synthesis of N- ((4- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) thioacetamide (formula I-2) and N- (5- ([ 1,2,4] triazolo [1,5- α ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) thiazol-2-yl) thioacetamide (formula II-2) compounds.
The compound of formula 10 or formula 11 (0.14 mmol) placed in a pressurized bottle was dissolved in 1, 2-dimethoxyethane (5 mL) at room temperature, L-Lawson's reagent (0.057 g,0.14 mmol) was added thereto, and the mixture was stirred at 85℃for 12 hours. After cooling to room temperature, concentration under reduced pressure, isolation by column chromatography (dichloromethane: methanol=20:1) gives an intermediate containing Boc protection.
After the intermediate was dissolved in methylene chloride (1 mL), trifluoroacetic acid (1.42 mmol,0.10 mL) was added dropwise thereto, and the mixture was stirred for 1 hour. The reaction mixture was concentrated and then neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (2X 20 mL), and the combined organic layers were washed with water (10 mL) and saturated brine (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound of formula I-2 or II-2.
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide (Compound I-2-1)
Yellow solid, yield: 46%; 1 H NMR(300MHz,CDCl 3 )δ9.01(s,1H),8.36(s,1H),7.82(d,J＝9.0Hz,1H),7.77(d,J＝9.0Hz,1H),7.49(t,J＝7.5Hz,1H),7.26–7.20(m,6H),7.05(d,J＝6.0Hz,1H),5.03(s,2H),4.15(dd,J＝9.0,3.0Hz,1H),3.57(dd,J＝15.0,3.0Hz,1H),2.74(dd,J＝15.0,9.0Hz,1H),2.58(s,3H)；MS-ESI:m/z 469[M+1] + 。
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide (compound I-2-2)
Yellow solid, yield: 22%; 1 H NMR(300MHz,CDCl 3 )δ9.00(s,1H),8.36(s,1H),7.81(d,J＝9.0Hz,1H),7.75(d,J＝9.0Hz,1H),7.49(t,J＝7.5Hz,1H),7.26–7.19(m,6H),7.05(d,J＝9.0Hz,1H),5.02(s,2H),4.13(dd,J＝9.0,3.0Hz,1H),3.56(dd,J＝15.0,3.0Hz,1H),2.73(dd,J＝15.0,9.0Hz,1H),2.56(s,3H)；MS-ESI:m/z 469[M+1] + 。
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide (compound II-2-1)
Yellow solid, yield: 11%; 1 H NMR(300MHz,CDCl 3 )δ8.89–8.72(m,1H),8.39–8.29(m,1H),7.74–7.47(m,4H),7.12(d,J＝6.0Hz,1H),3.13(d,J＝6.0Hz,1H),2.44(s,3H),1.76–1.67(m,2H),1.53–1.25(m,1H),1.01–0.89(m,6H)；MS-ESI:m/z 438[M+1] + 。
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide (compound II-2-2)
Color solid, yield: 15%; 1 H NMR(300MHz,CDCl 3 )δ8.77(br s,1H),8.36(d,J＝6.0Hz,1H),7.69(br s,2H),7.51(br s,2H),7.10(br s,1H),4.34(br s,1H),2.53(s,3H),2.07(br s,2H),1.41(br s,1H),0.98(br s,6H)；MS-ESI:m/z 438[M+1] + 。
biological data
The biological activity of the compounds of the invention can be assessed using the following assay:
example 8: ALK5 kinase inhibition activity research of imidazole derivative containing indazole structure
ALK5 kinase phosphorylation inhibition activity determination method
The ALK5 protein is derived from a human recombinant GST-fusion protein expressed in Sf9 insect cells. Kinase assays used 96-well plates with a microwell volume of 50 microliters of perkin elmer. Sequentially add 20. Mu.L of assay buffer (standard buffer), 5. Mu.L of ATP solution (in H 2 O), 5 μl of test compound (dissolved in 10% dmso), 20 μl of enzyme/substrate to formulate a reaction mixture. Has been matched withThe reaction mixture thus prepared was incubated at 30℃for 60min and then placed in 50. Mu.l of 2% (V/V) H 3 PO 4 In the solution, the assay buffer was removed and washed 2 times with 200. Mu.l of 0.9% (W/V) sodium chloride solution. The adoption of the micro-plate scintillation counter establishes 33 Incorporation of Pi. Kinase Activity assay Using Beckman Coulter/SAGAN TM The Core system detects.
TABLE 1 ALK5 kinase inhibitory Activity of Compounds of formulas I and II
Compounds of formulas I and II ALK5 kinase half-inhibitory activity (IC 50 ) As shown in Table 1, 13 compounds (I-1-1, I-1-2, I-1-4, I-1-6, I-1-7, II-1-3, II-1-4, II-1-5, I-2-1, I-2-2, II-2-1 and II-2-2) among all the target compounds synthesized were far more active than the positive control compound LY-2157299 (phase III clinic), in which the inhibitory activities of the compounds I-1-7 and II-2-2 were the strongest.
In order to demonstrate the effectiveness of the compounds, representative compounds I-1-7 (J-1149), II-1-4 (J-1155) and II-1-5 (J-1156) were selected for cytotoxicity and anti-hepatic fibrosis activity.
Example 9: cell culture and treatment
Human hepatic stellate cell line LX-2 (RRID: CVCL-5792) cells were cultured at 37℃in an incubator containing 5% carbon dioxide and saturated humidity, after addition of DMEM medium containing 10% Fetal Bovine Serum (FBS), 100U/ml penicillin and 100g/ml streptomycin. Passaging the cells with trypsin every 3 days, removing the culture solution in the bottle, adding 1-2mL trypsin solution (0.25%), standing at 37 ℃ for 2-3 minutes, removing protease solution, adding the culture solution, repeatedly blowing the bottle wall cells, centrifuging, and preparing the cell sediment with the culture solution into cell suspension. Inoculating into a new culture bottle containing a proper amount of fresh culture solution for culturing. Experiments were performed until the 4 th to 7 th generation cells used at the time of passage to the in vitro experimental study. LX-2 cells were seeded in 6-well plates for 24 hours, replaced with fresh medium containing TGF- β (10 ng/mL) for 24 hours, and TGF- β inhibitor-LY-2157299 and representative compounds were added to LX-2 cells separately 1 hour prior to TGF- β stimulation.
Example 10: MTT assay
Collecting LX-2 cells in logarithmic phase, adjusting cell suspension concentration, and seeding in 96-well plate, 1×10 4 /well. The cells were allowed to adhere to the wall in a 5% carbon dioxide incubator at 37 ℃. LX-2 cells were incubated with indicated concentrations of representative compounds (0. Mu.M, 0.625. Mu.M, 1.25. Mu.M, 2.5. Mu.M, 3.125. Mu.M, 6.25. Mu.M, 12.5. Mu.M, 25. Mu.M, 50. Mu.M, 100. Mu.M) for 24 hours, the supernatant was aspirated, 180. Mu.L of fresh culture medium was added per well after gentle washing with PBS, and further 20. Mu.L of MTT solution (5 mg/mL) was added for further incubation for 4 hours. The culture was terminated and the in-well culture solution was carefully aspirated. 150 mu L of dimethyl sulfoxide is added into each hole, and the mixture is placed on a shaking table to shake for 10 minutes at a low speed, so that crystals are fully dissolved. Absorbance was measured by a microplate reader at 540nm wavelength.
As shown in FIG. 1, it was confirmed by MTT method that compound J-1149 showed no toxicity at other concentrations (0-50. Mu.M) than a certain toxicity at 100. Mu.M.
As shown in FIG. 2, it was confirmed by MTT method that Compound J-1155 showed no toxicity at 0-100. Mu.M.
As shown in FIG. 3, it was confirmed by MTT method that compound J-1156 showed little or no toxicity at other concentrations (0-50. Mu.M) than a certain toxicity at 100. Mu.M.
Example 11: immunofluorescence staining method
Fluorescent staining of cells
Absorbing and removing fluorescent dish cell supernatant; PBS rinse (3 times, 5 min); paraformaldehyde (4% for 30 min) was added at room temperature; PBS (3 times, 5 min), and Trion-x (0.1% for 15 min) at room temperature; PBS rinse (3 times, 5 min); dropwise adding the coat Serum (10% for 1 h); dripping first antibody for incubation (4 ℃ for 12 h); taking out and standing at room temperature (30 min); PBS rinse (3 times, 5 min); dripping secondary antibody for incubation (1 h); PBS rinse (10 times, 5 min); dripping DAPI-containing anti-fluorescence quenching sealing tablet; care was taken to avoid light. The picture information was collected by fluorescence microscopy.
Fluorescent staining of tissue
Frozen sections (5 μm) were removed in a refrigerator at-80 ℃; drying at room temperature (20 min); immersing into acetone: methanol (1:1, 10 min); airing at room temperature (20 min); soaking in PBS (2 times, 5 min); incubating goat serum (5%, 30 min); dripping first antibody for incubation (4 ℃ for 12 h); taking out and standing at room temperature (30 min); PBS rinse (3 times, 5 min); dripping secondary antibody for incubation (1 h); PBS rinse (10 times, 5 min); dripping DAPI-containing anti-fluorescence quenching sealing tablet; care was taken to avoid light. The picture information was collected by fluorescence microscopy.
As shown in FIG. 4, compound J-1149 was confirmed to significantly inhibit TGF- β -induced expression of α -SMA with increasing concentration by immunofluorescent staining.
As shown in FIG. 5, immunofluorescent staining confirmed that compounds J-1155 and J-1156 significantly inhibited TGF- β -induced α -SMA expression with increasing concentration
Various modifications and variations of the present invention will be apparent to those skilled in the art in light of the foregoing teachings and are intended to be included within the scope of the following claims.

Claims (4)

1. Imidazole and thiazole derivatives containing an amino acid structure, wherein the imidazole and thiazole derivatives are selected from the group consisting of:
(S) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(R) -N- ((4- ([ 1,2,4] triazolo [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) piperidine-2-carboxamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-4-methylpentanamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropionamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-aminopropionamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-3-phenylpropionamide;
(S) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(R) -N- ((4- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) -2-amino-3-phenylpropanamide;
(S) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide;
(R) -N- (5- ([ 1,2,4] triazol [1, 5-a ] pyridin-6-yl) -4- (6-methylpyridin-2-yl) -thiazol-2-yl) -2-amino-4-methylpentanesulfonamide and pharmaceutically acceptable salts thereof.
2. A process for the preparation of imidazole and thiazole derivatives containing an amino acid structure according to claim 1, wherein the process for the preparation of imidazole derivatives comprises the steps of:
S1, oxidizing a compound shown in a formula 1 with hydrobromic acid in dimethyl sulfoxide to obtain 1- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -2- (6-methylpyridin-2-yl) ethane-1, 2-dione (formula 2);
；
s2, carrying out cyclization reaction on the formula 2 and 2- (1, 3-dioxoisoindol-2-yl) acetaldehyde to obtain 2- ((4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazol-2-yl) methyl) indoline-1, 3-dione (formula 4);
s3, carrying out deprotection reaction on the formula 4 and hydrazine hydrate to obtain 4- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -5- (6-methylpyridin-2-yl) -1H-imidazole-2-yl) methylamine (formula 5);
s4, carrying out condensation reaction on the formula 5 and the formula 6 or the formula 7 in the presence of benzotriazol-1-yl-oxy-tripyrrolidinylphosphine PyBOP hexafluorophosphate and diisopropylethylamine DIPEA to obtain the imidazole compound containing the amide structure as shown in claim 1;
6, & gt>Formula 7, wherein the substituent R' is shown as the corresponding structure of the compound in claim 1.
3. A method for preparing imidazole and thiazole derivatives containing an amino acid structure according to claim 1, wherein the method for preparing the thiazole derivatives comprises the following steps:
s1, carrying out halogenation reaction on a compound shown in a formula 1 and bromine water to obtain 2-bromo-1- (6-methylpyridin-2-yl) -2- ([ 1,2,4] triazolo [1, 5-alpha ] pyridin-6-yl) ethane-ketone (formula 8);
；
S2, carrying out cyclization reaction on the formula 8 and thiourea to obtain 4- (6-methylpyridine-2-yl) -5- ([ 1,2,4] triazolo [1, 5-alpha ] pyridine-6-yl) -thiazole-2 amine (formula 9);
s3, carrying out condensation reaction on the formula 9 and the formula 6 or the formula 7 in the presence of benzotriazol-1-yl-oxy-tripyrrolidinylphosphine PyBOP hexafluorophosphate and diisopropylethylamine DIPEA to obtain the thiazole compound containing the amide structure as shown in claim 1;
6, & gt>Formula 7, wherein the substituent R' is shown as the corresponding structure of the compound in claim 1.
4. An ALK5 kinase inhibitor, which comprises an imidazole and thiazole compound having an amino acid structure according to claim 1.
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CN1404478A (en) * 2000-02-21 2003-03-19 史密斯克莱·比奇曼公司 Pyridinylimidazoles
CN1681805A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel imidazole compounds as transforming growth factor (TGF) inhibitors
CN1681810A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors
WO2019195278A1 (en) * 2018-04-02 2019-10-10 Silverback Therapeutics, Inc. Alk5 inhibitors, conjugates, and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1404478A (en) * 2000-02-21 2003-03-19 史密斯克莱·比奇曼公司 Pyridinylimidazoles
CN1681805A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel imidazole compounds as transforming growth factor (TGF) inhibitors
CN1681810A (en) * 2002-09-18 2005-10-12 辉瑞产品公司 Novel oxazole and thiazole compounds as transforming growth factor (TGF) inhibitors
WO2019195278A1 (en) * 2018-04-02 2019-10-10 Silverback Therapeutics, Inc. Alk5 inhibitors, conjugates, and uses thereof

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