Patent Application
20250092050
The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound, and preparation therefor and use therefor.
The adenosine receptor is a kind of G protein-coupled receptor, which contains seven transmembrane α helices, including four subtypes of A1, A2A, A2B and A3 receptors. There is a large amount of extracellular adenosine in the tumor microenvironment. High concentration of extracellular adenosine interacts with G protein-coupled adenosine receptors on the surface of the immune cell membrane. Adenosine transmits immunosuppressive signals into immune cells, thereby inhibits the proliferation and maturation of immune cells such as T cells, NK cells, macrophages, and dendritic DC cells. Adenosine also inhibits the production of immune cytokines (IL-2, IFN-γ), resulting in immune injury to the body, causing the immune escape of tumor cells. Among the four G protein-coupled adenosine receptors, adenosine A2A is the most widely expressed subtype in T cells, NK cells and other immune cells, which produces immunosuppressive effects when combined with adenosine. Therefore, the development of adenosine receptor inhibitors is of great significance to improve the immune performance of the body.
At present, small molecule adenosine receptor inhibitors are being widely studied. They can improve the immune response of the body by blocking the transmission of immunosuppressive signals mediated by A2A receptors. At present, many small molecule A2A receptor inhibitors are in clinical research. These small molecule adenosine receptor inhibitors are often used in melanoma, lung squamous cell carcinoma, breast cancer, gastric cancer, ovarian cancer, prostate cancer and shows significant curative effect in these common tumor diseases.
However, the development of small molecule adenosine receptor inhibitors is still in infancy and requires more development. Therefore, there is an urgent need to develop more novel adenosine receptor inhibitors with anti-tumor activity.
In order to overcome the shortcomings of the prior art, the primary purpose of the present invention is to provide a kind of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound.
The second purpose of the present invention is to provide a method for preparation of the above-mentioned 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound.
The third purpose of the present invention is to provide the application of the above-mentioned 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound. The compound has good inhibition activities on adenosine A2A receptors and good subtype selectivity. They is expected to be used in tumor immunotherapy targeting adenosine A2A receptor.
The said first purpose of the present invention is achieved by the following technical solution:
Preferably, the said R1 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl; R2 is independently selected from n-pentyl, isopentyl, n-butyl, isobutyl, 2-methoxyethyl, 2,2-difluoroethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 2-substituted furyl, thienyl, 2-substituted thienyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, pyrazinvl, pyridazinyl, quinolyl, isoquinolyl, naphthyl, indolyl, substitute indolyl,
As a preferred embodiment of the present invention, the above-mentioned 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound is selected from any one of the following structural formulas:
The said second purpose of the present invention is achieved by the following technical solution:
When the R1 group in the compound shown in the formula I obtained by the preparation process needs to be modified. The modification can be performed by referring to a conventional group modification method. For example, when R2 is
and when R4 is substituted phenyl, the substituent is 4-hydroxy, the compound in which R4 is 4-methoxyphenyl can be subjected to conventional reaction to prepare the compound in which R4 is 4-hydroxyphenyl.
The compound of this present invention bas a novel structure and the chemical synthesis method is simple, the conditions are mild, the product yield and purity is high. It can be produced and prepared on a large industrial scale, which is convenient for promotion and application
Preferably, in step S1, the said acidic solvent includes acetic acid, propionic acid, and DMF (N, N-dimethylformamide). Specifically, the acidic solvent is acetic acid.
Preferably, in step S1, the molar mass ratio of the compound shown in the Formula 1 to the compound shown in the Formula 2 is 1:1.
Preferably, in step S2, the molar mass ratio of the compound shown in the Formula 3 to ammonia is 1:3-4.
More preferably, in step S2, the molar mass ratio of the compound shown in the Formula 3 to ammonia is 1:4;
Preferably, in step S3, the said alkaline substance added to the basic organic solvent comprises triethylamine, N,N-diisopropylethylamine, potassium carbonate and cesium carbonate; And the said organic solvent comprises acetonitrile, dichloromethane, DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide), NMP (N-methylpyrrolidone). Specifically, the said alkaline substance is N,N-diisopropylethylamine (DIPEA), and the said organic solvent is acetonitrile.
Preferably, in step S3, the molar mass ratio of the compound shown in the Formula 4 to the compound of Formula 5 is 1:1.
Preferably, in the step S4, the said ammonium salt includes ammonium acetate, ammonium sulfate and ammonium nitrate. And the said acid comprises acetic acid and glacial acetic acid. Specifically, the said ammonium salt is ammonium acetate and the said acid is acetic acid.
Preferably, in step S4, the molar mass ratio of the compound shown in the Formula 6 to the ammonium salt is 1:6, and the reaction temperature is 95° C.
Preferably, in step S5, the alkaline substance added to the alkaline organic solvent comprises triethylamine and N,N-diisopropylethylamine; The organic solvent comprises dichloromethane, tetrahydrofuran and 1,2-dichloroethane. Specifically, the said alkaline substance is triethylamine, and the said organic solvent is tetrahydrofuran.
Preferably, in step S5, the molar mass ratio of the compound shown in the Formula 7 to di-tert-butyl dicarbonate is 1:2.
Preferably, in step S6, the said alkaline substance comprises potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide; The said organic solvent is methanol, ethanol and acetonitrile. Specifically. the said alkaline substance is potassium carbonate, and the said organic solvent is methanol.
Preferably, in step S6, the molar mass ratio of the compound shown in the Formula 8 to the alkaline substance is 1:2.
Preferably, in step S7, the said oxidizing agent comprises Dess-Martin periodinane and pyridinium chlorochromate. Specifically, the said oxidizing agent is Dess-Martin periodinane.
More preferably, in step S7, the molar mass ratio of the compound shown in the Formula 9 to the oxidizing agent is 1:1.
Preferably, in step S8, the said oxidizing agent is sodium hypochlorite, and the said organic solvent comprises tetrahydrofuran and 2-methyltetrahydrofuran. Specifically, the said organic solvent is tetrahydrofuran.
Preferably, in step S8, the molar mass ratio of the compound shown in the Formula 10 to the oxidizing agent is 1:2.
Preferably, in step S9, the compound shown in the Formula 12 is selected from 2-aminomethylpyridine, n-pentylamine, isobutylamine, 2,2-difluoroethylamine, 2-methoxyethylamine, ethanolamine, isopropanolamine, DL-aminopropanol, 3-amino-1-propanol, substitues 2-aminomethylpyridine, aniline, p-toluidine, m-aminoanisole, p-chlorobenzeneamine, 2-aminopyridine, 3-aminopyridine, benzylamine, 3-chlorobenzylamine, 3-aminomethylpyridine, 4-aminomethylpyridine, 2-furylmethylamine, 1-(2-)Pyridine) ethylamine substitues 2-aminomethylpyridine, (quinoline-8-methyl) amine, 1-(8-quinoline) ethylamine, 2-(pyridin-2-yl) -2-propylamine, 2-(3-chlorophenyl)ethylamine and 2-(4-methoxyphenyl) ethylamine.
Preferably, in step S9, the said condensing agent comprises a mixture of DMAP (4-dimethylaminopyridine) and DCC (dicyclohexylcarbodiimide), a mixture of DMAP and EDCI (1-(3-dimethylpyridine)),Aminopropyl)-3-ethylcarbodiimide hydrochloride), HATU (2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and DIPEA (N,N-diisopropylethylamine), a mixture of HOBt (1-hydroxybenzotriazole) and DCC, a mixture of HOBt and EDCI. Specifically, the condensing agent is a mixture of HOBt and DCC, and the molar ratio of HOBt to DCC is 1:1.
Preferably, in step S9, the molar mass ratio of the compound shown in the Formula 11 to the compound shown in the Formula 12 is 1:1.
Preferably, in step S10, the said acidic substance comprises trifluoroacetic acid, formic acid, and concentrated hydrochloric acid. Specifically, the said acidic substance is trifluoroacetic acid.
Preferably, in step S10, the molar mass ratio of the compound shown in the Formula 13 to the acidic substance is 1:10.
The said third purpose of the presented invention is achieved by the following technical solution:
The application of the 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound in the preparation of adenosine receptor inhibitors or anti-tumor drugs.
Preferably, the said adenosine receptor is an adenosine A2A receptor, and the anti-tumor drug is a tumor immunotherapy drug targeting the A2A receptor.
The 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound of the invention has good inhibition effect on adenosine A2A receptor. Wherein, the compounds 14a to 14e, compound 14k, compound 14o, compound 14p, compounds 14r to 14u, compound 14w, compound 14x and compounds 14ac to 14ae, inhibit adenosine A2A receptor by more than 70%. Especially, the inhibitory rate of compounds 14a, 14r, 14s, 14u and 14ac are more than 80%, and show excellent inhibition effect on adenosine A2A receptors. These compounds can be prepared to be adenosine A2A receptor inhibitors or tumor immunotherapy drugs targeting the adenosine A2A receptor.
Specifically, the present invention provides an adenosine receptor inhibitor. The inhibitor uses the 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound according to any one of claims 1-3, as the main active ingredient.
Specifically, the present invention also provides an anti-tumor drug. The drug uses the 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compound according to any one of claims 1-3 as the main active ingredient.
Compared with the prior art, the present invention has the following beneficial effects:
The present invention discloses a series of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compounds with a novel structure and is an adenosine receptor inhibitor, has good inhibitory activity on adenosine A2A receptors, has good subtype selectivity, and can be used as a targeted adenosine A2A receptor inhibitor for immunotherapy. By means of inhibiting the activity of the adenosine A2A receptor, the function of removing tumor cells by the immune system is released, so that the effect of treating tumors is achieved. Furthermore, the method for preparing the compound of the present invention is simple, uses cheap and easily available compounds as raw materials, has mild reaction conditions and high total yield and purity, can achieve dozens of grams of scale production, and supports the research of the clinical candidate adenosine A2A receptor inhibitor in the later stage.
Specific solutions of the present invention are further illustrated below. It should be noted that the illustration of these embodiments is provided to assist in understanding the present invention, and does not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental methods in the following examples are all conventional methods unless otherwise specified, and the experimental materials used in the following examples, unless otherwise specified, can be purchased through conventional commercial channels.
The specific preparation process is as follows:
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 1 (1,2-phenylenediamine, 3.2 g, 30 mmol) and 50 ml of acetic acid were added into a reaction flask. And the initial raw material, namely, the compound shown in Formula 1 (methyl 2,2,2-trichloroiminoacetate, 4 mL, 30 mmol) was slowly added after the reaction flask was cooled through ice bath, then stirred at room temperature for 2 hours. After TLC showed that the reaction was complete, the reactants were filtered, and the resulting filter cake was washed with water (3 times, 25 mL each time). Finally, the compound shown in Formula 3 (2-trichloromethyl-benzopyrimidine) (7.1 g, 93%) was obtained by vacuum drying.
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 3 (2-trichloromethylbenzopyrimidine, 5.9 g, 25 mmol) was cooled to 0° C. A solution of ammonia in 1,4-dioxane (0.40 M, 125 mL) was then added at 0° C. The flask was sealed and the mixture was stirred at room temperature for 2 hours. After TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure and subjected to column chromatography to afford the compound shown in Formula 4 (2-cyanobenzopyrimidine, 2.7 g, 76%).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, MeCN (40 mL), DIPEA (4.4 g, 34 mmol) and the compound shown in Formula 4 (2-cyanobenzopyrimidine, 2.6 g, 17 mmol) were added to a reaction flask and cooled to −15° C. At this temperature, the compound shown in Formula 5 (3-bromo-2-oxopropyl acetate, 3.3 g, 17mmol) was added and the mixture was stirred at −15° C. for 3 hours. After TLC showed that the reaction was complete, the mixture was diluted with 150 ml of water, and extracted by ethyl acetate, dried with anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to afford the compound shown in Formula 6 (1-(2-(4-methoxyphenyl)-2-oxaethyl)-1H-benzopyrimidine-2-cyanide, 3.5 g, 80%). The characterization information of the product is as follows:
1H NMR (400 MHz, Chloroform-d) δ 7.89-7.86 (m, 1H), 7.50-7.40 (m, 2H), 7.30-7.28 (m, 1H), 5.28 (s, 2H), 4.81 (s, 2H), 2.22 (s, 3H).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 6 (3-(2-cyano-1H-benzo[d]imidazol-1-yl)-2-oxopropyl acetate), 3.3 g, 13 mmol), ammonium acetate (5.1 g, 66 mmol), and 5 mL of acetic acid were added to a sealed tube and stirred at 95° C. for 1 hour. After TLC showed that the reaction was complete, saturated sodium bicarbonate solution was added to neutralize the reaction until no bubbles were generated. The mixture was then extracted with dichloromethane (3 times, 100 mL of dichloromethane each time). The organic phases were collected, dried with anhydrous sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to afford the compound shown in Formula 7 (methyl (1-aminobenzo[4,5]imidazo[1,2-a]pyrazin-3-yl)acetate, 2.8 g, 85%). The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 7.96-7.86 (m, 3H), 7.56-7.46 (m, 3H), 6.06 (s, 2H), 5.10 (s, 2H), 2.16 (s, 3H).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 7 (methyl (1-aminobenzo[4,5]imidazo[1,2-a]pyrazin-3-yl)acetate, 2.8 g, 11 mmol), DMAP (134 mg, 1.1 mmol), triethylamine (4.5 g, 44 mmol) were dissolved in 50 mL of tetrahydrofuran and cooled to 0° C., di-tert-butyl dicarbonate (6.0 g, 27.5 mmol) was then slowly added dropwise at 0° C. and stirred at room temperature for 4 hours. After TLC showed that the reaction was complete, 150 mL of water was added. The mixture was extracted with dichloromethane (3 times, 100 mL of dichloromethane each time), and the organic phases were combined, washed with 100 ml of saturated saline and dried with sodium sulfate, concentrated under reduced pressure and subjected to column chromatography to afford the compound shown in Formula 8 (methyl (1-(di(t-butoxycarbonyl)amino)benzo[4,5]imidazo[1,2-a]pyrazin-3-yl)acetate, 4.2 g, 84%). The characterization information of the product is as follows:
1H NMR (400 MHz, Chloroform-d) 8.46 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 5.29 (s, 2H), 2.16 (3H, s), 1.41 (s, 18H)
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, compound shown in Formula 8 (Methyl (1-(di(t-butoxycarbonyl)amino)benzo[4,5]imidazo[1,2-a]pyrazin-3-yl)acetate, 4.1 g, 9 mmol) were dissolved in 50 mL of methanol and cooled to 0° C. Potassium carbonate (3.7 g, 27 mmol) was slowly added at 0° C. and the mixture was stirred at room temperature for 4 hours. After TLC showed that the reaction was complete, 200 ml of water was added, and the mixture was extracted with dichloromethane (3 times, 100 mL of dichloromethane each time), and the organic phases were combined, washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to afford the compound shown in Formula 9 (tert-butyl (3-(hydroxymethyl)benzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate, 67%, 1.9 g). The characterization information of the product is as follows:
1H NMR (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.12 (s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.61-7.57 (m, 1H), 7.50-7.60 (m, 1H), 4.85 (s, 2H), 1.56 (s, 9H).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 9 (tert-butyl (3-(hydroxymethyl)benzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate, 1.9 g, 6 mmol) were dissolved in 50 mL of dichloromethane and cooled to 0° C., then Dess-Martin periodinane (3.6 g, 8.4 mmol) was added slowly at 0° C. and the mixture was stirred at room temperature for 4 hours. The mixture was filtered after TLC showed that the reaction was completed. Then saturated sodium bicarbonate solution was added until no bubbles were generated. The mixture was extracted with dichloromethane (3 times, 100 mL of dichloromethane each time) and the organic phases were combined, washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to afford the compound shown in Formula 10 (tert-butyl (3-formylbenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate, 1.5 g, 81%). The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 10.17 (s, 1H), 8.82 (s, 1H), 8.03-8.00 (m, 2H), 7.70-7.67 (m, 1H), 7.61-7.57 (m, 1H), 1.61 (s, 9H).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, compound shown in Formula 10 (tert-butyl (3-formylbenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate, 1.4 g, 4.5 mmol), sodium dihydrogen phosphate (2.2 g, 18 mmol), isopentene (1.6 g, 22 mmol) were dissolved in a mixed solution of 40 ml of tetrahydrofuran and 20 ml of water. and the mixture was cooled to 0° C. Sodium chlorite (1.6 g, 18 mmol) was added slowly at 0° C. and the mixture was stirred at 0° C. for 4 hours. After TLC showed that the reaction was completed, sodium thiosulfate (3.6 g, 22 mmol) aqueous solution was added at 0° C. to quench the reaction. The mixture was further extracted with dichloromethane (3 times, 100 mL of dichloromethane each time), and the organic phases were combined, washed with saturated saline (100 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with n-hexane to afford the compound shown in Formula 11 (1-((tert-butoxycarbonyl)amino)benzo[4,5]imidazo[1,2-a]pyrazine-3-carboxylic acid, 886 mg, 60%). The characterization information of the product is as follows:
1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.56 (s, 1H), 7.98-7.96 (m, 1H), 7.65-7.54 (m, 2H), 1.50 (s, 9H).
The chemical reaction formula of the preparation process is as follows:
According to the above reaction formula, the compound shown in Formula 11 (1-(((-butoxycarbonyl)amino)benzo[4,5]imidazo[1,2-a]pyrazine-3-carboxylic acid), 67 mg, 0.2 mmol), the compound shown in Formula 12 (2-aminomethylpyridine, 32 mg, 0.3 mmol), HOBt (41 mg, 0.3 mmol) were dissolved in 2 mL of dichloromethane and cooled to 0° C., then DCC (62 mg, 0.3 mmol) was added slowly at 0° C. The mixture was stirred at room temperature for 16 hours. After TLC showed that the reaction was complete, the mixture was filtered on silica gel and washed with a mixture of dichloromethane/methanol (dichloromethane: methanol=50:1). The filtrate was concentrated under reduced pressure to afford a crude product of the compound shown in Formula 13 (tert-butyl (3-((pyridin-2-ylmethyl)carbamoyl)benzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate). The characterization information of the product is as follows:
1H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.95-8.92 (m, 1H), 8.63 (d, J=4.8 Hz, 1H), 8.49 (s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.70-7.62 (m, 2H), 7.58-7.54 (m, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.22-7.19 (m, 1H), 4.85 (d, J=5.8 Hz, 2H), 1.60 (s, 9H).
The chemical reaction formula of the preparation process is as follows:
The crude product of the compound shown in Formula 13 (tert-butyl (3-((pyridin-2-ylmethyl)carbamoyl)benzo[4,5]imidazo[1,2-a]pyrazin-1-yl)carbamate) was dissolved in 2 mL of dichloromethane and cooled to 0° C. Then 0.2 mL of trifluoroacetic acid was slowly added at 0° C., and stirred at room temperature for 4 hours. After TLC showed that the reaction was complete. the saturated sodium bicarbonate aqueous solution was added until no bubbles were generated. The mixture was extracted with dichloromethane (3 times, 100 mL of dichloromethane each time), and the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. and subjected to column chromatography to afford the target compound 14a (1-amino-N-(pyridin-2-ylmethyl)benzo[4,5]imidazo[1,2-a]pyrazine-3-formamide, 45 mg, 70% (this yield is the yield of steps (9) and (10). The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.81 (t, J=6.0 Hz, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.45 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.56-7.46 (m, 4H), 7.39 (d, J=7.8 Hz, 1H), 7.30 (t, J=6.2 Hz, 1H), 4.68 (d, J=5.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.2, 158.2, 149.4, 143.6, 137.3, 136.3, 130.6, 130.2, 126.4, 123.6, 122.8, 121.9, 120.7, 113.6, 111.5, 44.6.
The preparation process of the compound 14b was the same as the preparation process of compound 14a in Example 1, except that: in step S9. the compound shown in Formula 13 was prepared by using n-pentylamine instead of 2-aminomethylpyridine to finally afford the compound 14b (46 mg, 70%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 7.94 (dd, J=17.1, 8.3 Hz, 2H), 7.77 (t, J=5.3 Hz, 1H), 7.59-7.56 (m, 1H), 7.51-7.47 (m, 1H), 5.88 (s, 2H), 3.48 (q, J=6.8 Hz, 2H), 1.64 (p, J=7.3 Hz, 2H), 1.43-1.38 (m, 2H), 1.36-1.32 (m, 3H), 0.91-0.89 (m, 3H). 13C NMR (126 MHz, Chloroform-d) δ 163.7, 148.1, 143.7, 135.7, 130.1, 129.7, 126.6, 123.8, 121.0, 111.7, 39.5, 31.5, 29.7. 26.7. 22.6, 14.0.
The preparation process of compound 14c was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using isobutylamine instead of 2-aminomethylpyridine to finally afford the compound 14c (43 mg, 70%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.96 (dd, J=16.6, 8.3 Hz, 2H), 7.84 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 5.77 (s, 2H), 3.33 (t, J=6.6 Hz, 2H), 1.02 (d, J=6.7 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 149.3, 143.6, 136.2, 130.6, 130.3, 126.4, 123.5, 120.6, 113.6, 111.2, 46.5, 28.8, 20.5.
The preparation process of compound 14d was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2,2-difluoroethylamine instead of 2-aminomethylpyridine to finally afford the compound 3 (44 mg, 75%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.46-8.44 (m, 1H), 8.41 (t, J=6.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.58-7.55 (m, 1H), 7.52-7.47 (m, 3H), 6.32-6.01 (m, 1H), 3.80 (tt, J=15.8, 4.2 Hz, 2H). 19F NMR (471 MHz, DMSO-d6) δ −122.25.
The preparation process of compound 14e was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-methoxyethylamine instead of 2-aminomethylpyridine to finally afford the compound 14e (40 mg, 71%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.06 (s, 1H), 7.96 (dd, J=17.6, 8.2 Hz, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 5.79 (s, 2H), 3.69 (q, J=5.2 Hz, 2H), 3.61 (t, J=4.9 Hz, 2H), 3.43 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 164.0, 149.4, 143.6, 136.2, 130.6, 130.1, 126.4, 123.5, 120.6, 113.6, 111.3, 71.1, 58.4, 38.9.
The preparation process of compound 14f was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using ethanolamine instead of 2-aminomethylpyridine to finally afford the compound 5 (27 mg, 50%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.43 (d, J=8.2 Hz, 1H), 8.23 (t, J=5.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.57-7.46 (m, 4H), 4.92 (t, J=4.7 Hz, 1H), 3.56 (q, J=4.8 Hz, 2H), 3.14 (t, J=3.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.0, 149.4, 143.6, 136.2, 130.6, 130.2, 126.4, 123.6, 120.6, 113.6, 111.2, 60.3, 41.9.
The preparation process of compound 14g was the same as the preparation process of compound 14a in Example 1, except that in step S9, the compound shown in Formula 13 was prepared by using isopropanolamine instead of 2-aminomethylpyridine to finally afford the compound 14g (30 mg, 53%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.20-8.15 (m, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.58-7.55 (d, J=12.1 Hz, 3H), 7.48 (t, J=7.5 Hz, 1H), 4.94 (d, J=4.2 Hz, 1H), 3.84-3.75 (m, 1H), 3.21-3.15 (M, 1H), 1.10 (d, J=6.1 Hz, 3H). 3C NMR (126 MHz, DMSO-d6) δ 163.9, 149.4, 143.5, 136.2, 130.6, 130.2, 126.4, 123.5, 120.6, 113.6, 111.2, 65.6, 46.6, 21.6.
The preparation process of compound 14h was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using DL-aminopropanol instead of 2-aminomethylpyridine to finally afford the compound 14h (28 mg,51%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.43 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.58-7.54 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 4.97 (s, 1H), 4.07-4.04 (M, 1H), 3.50-3.47 (m, 2H), 1.18 (d, J=6.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 163.3, 149.4, 143.6, 136.2, 130.6, 130.3, 126.4, 123.5, 120.6, 113.6, 111.2, 64.6, 46.8, 17.9.
The preparation process of compound 14i was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 3-amino-1-propanol instead of 2-aminomethylpyridine to finally afford the compound 14i (32 mg,55%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=1.6 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.22 (t, J=6.0 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.56 (t, J=6.8 Hz, 1H), 7.49-7.46 (m, 3H), 4.58 (t, J=5.0 Hz, 1H), 3.51 (q, J=5.3 Hz, 2H), 3.42 (q, J=6.2, 5.6 Hz, 2H), 1.71 (p, J=6.6 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.0, 149.3, 143.6, 136.2, 130.6, 130.4, 126.4, 123.5, 120.6, 113.6, 111.2, 59.1, 36.6, 32.9.
The preparation process of compound 14j was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using aniline instead of 2-aminomethylpyridine to finally afford the compound 14j (47 mg, 78%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.08 (s, 1H), 8.49 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.81 (d, J=7.9 Hz, 2H), 7.62-7.57 (m, 3H), 7.51 (t, J=7.6 Hz, 1H), 7.41 (t, J=7.5 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 162.5, 149.3, 143.7, 138.6, 136.2, 130.6, 130.0, 129.5, 126.5, 124.3, 123.7, 120.7, 120.0, 113.7, 112.1.
The preparation process of compound 14k was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using p-toluidine instead of 2-aminomethylpyridine to finally afford compound 14k (48 mg, 76%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.05 (s, 1H), 8.49-8.47 (m, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.68-7.50 (m, 6H), 7.22-7.18 (d, J=7.6 Hz, 2H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.3, 149.3, 143.7, 136.2, 136.1, 133.3, 130.6, 130.1, 129.8, 126.5, 123.7, 120.7, 120.0, 113.7, 112.0, 21.0.
The preparation process of compound 11 was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using m-aminoanisole instead of 2-aminomethylpyridine to finally afford the compound 11 (46 mg, 69%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.07 (s, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.61-7.51 (m, 6H), 7.36-7.31 (m, 2H), 6.72 (d, J=8.1 Hz, 1H), 3.79 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 162.5, 160.2, 149.3, 143.7, 139.8, 136.2, 130.6, 130.3, 130.0, 126.6, 123.7, 120.7, 113.7, 112.3, 112.2, 109.8, 105.8, 55.55.
The preparation process of compound 14m was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using p-chloroaniline instead of 2-aminomethylpyridine to afford the compound 14m (41 mg, 61%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.08 (s, 1H), 8.49 (d, J=7.0 Hz, 1H), 7.95-7.85 (m, 3H), 7.60-7.45 (m, 6H). 13C NMR (126 MHz, DMSO-d6) δ 162.7, 149.3, 143.7, 137.7, 136.2, 130.6, 129.9, 129.3, 127.9, 126.6, 123.7, 121.7, 120.7, 113.7, 112.3.
The preparation process of compound 14n was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-aminopyridine instead of 2-aminomethylpyridine to finally afford the compound 14n (43 mg, 70%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.14 (s, 1H), 8.51 (d, J=8.1 Hz, 1H), 8.39 (s, 1H), 8.33 (d, J=8.3 Hz, 1H), 7.96-7.91 (m, 2H), 7.81 (s, 2H), 7.59 (t, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.20 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 162.5, 151.3, 149.5, 148.9, 143.7, 139.1, 136.3, 130.7, 129.1, 126.6, 123.8, 120.7, 120.4, 113.7, 113.3, 112.5.
The preparation process of compound 14o was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 3-aminopyridine instead of 2-aminomethylpyridine to finally afford the compound 14o (35 mg, 59%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.11 (s, 1H), 8.99 (s, 1H), 8.49 (d, J=8.1 Hz, 1H), 8.35-8.27 (m, 2H), 7.95 (d, J=8.2 Hz, 1H), 7.60-7.43 (m, 5H). 13C NMR (126 MHz, DMSO-d6) δ 163.3, 149.4, 145.2, 143.7, 142.1, 136.2, 135.5, 130.6, 129.8, 127.3, 126.6, 124.2, 123.7, 120.7, 113.7, 112.6.
The preparation process of compound 14p was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using benzylamine instead of 2-aminomethylpyridine to finally afford the compound 14p (46 mg, 73%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.60 (s, 1H), 8.44 (d, J=7.3 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.59-7.52 (m, 1H), 7.47 (s, 3H), 7.36 (s, 4H), 7.27 (s, 1H), 4.56 (d, J=5.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.1, 149.4, 143.6, 139.8, 136.2, 130.6, 130.2, 128.9, 128.0, 127.5, 126.4, 123.5, 120.6, 113.6, 111.5, 42.8.
The preparation process of compound 14q was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 3-chlorobenzylamine instead of 2-aminomethylpyridine to finally afford the compound 14q (44 mg, 62%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.77 (t, J=6.5 Hz, 1H), 8.43 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.50-7.45 (m, 3H), 7.41-7.37 (m, 2H), 7.33-7.32 (m, 2H), 4.55 (d, J=6.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.3, 149.4, 143.6, 142.6, 136.2, 133.5, 130.8, 130.6, 130.1, 127.7, 127.3, 126.6, 126.5, 123.6, 120.7, 113.6, 111.6, 42.3.
The preparation process of compound 14r was the same as the preparation of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 3-aminomethylpyridine instead of 2-aminomethylpyridine to finally afford the compound 14r (50 mg, 79%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.74 (t, J=5.9 Hz, 1H), 8.60 (s, 1H), 8.48 (d, J=4.2 Hz, 1H), 8.45 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.52-7.42 (m, 3H), 7.41-7.35 (m, 1H), 4.59 (d, J=6.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.4, 149.5, 149.4, 148.7, 143.6, 136.2, 135.8, 135.4, 130.6, 130.2, 126.4, 124.0, 123.6, 120.6, 113.6, 111.6, 40.5.
The preparation process of compound 14s was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 4-aminomethylpyridine instead of 2-aminomethylpyridine to finally afford the compound 14s (41 mg, 65%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.80 (t, J=6.1 Hz, 1H), 8.52 (d, J=5.0 Hz, 2H), 8.44 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50-7.45 (m, 3H), 7.33 (d, J=4.9 Hz, 2H), 4.58 (d, J=6.2 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.6, 150.0, 149.4, 148.9, 143.6, 136.3, 130.6, 130.1, 126.4, 123.6, 122.7, 120.7, 113.6, 111.7, 41.9.
The preparation process of compound 14t was the same as the preparation process of compound 14a in example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-furylmethylamine instead of 2-aminomethylpyridine to finally afford the compound 14t (39 mg, 64%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J=1.4 Hz, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.42 (t, J=5.9 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.63-7.62 (m, 1H), 7.59-7.55 (m, 1H), 7.52-7.47 (m, 3H), 6.44-6.43 (m, 1H), 6.36-6.35 (m, 1H), 4.58 (d, J=6.0 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.8, 152.4, 149.4, 143.6, 142.9, 136.2, 130.6, 130.0, 126.4, 123.6, 120.7, 113.6, 111.5, 111.0, 107.7, 36.1.
The preparation process of compound 14u was the same as the preparation process of 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 1-(2-pyridyl)ethylamine instead of 2-aminomethylpyridine to finally afford the compound 14u (44 mg, 66%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, Chloroform-d) δ 8.78-8.75 (m, 2H), 8.64 (d, J=4.2 Hz, 1H), 7.98-7.92 (m, 2H), 7.68 (td, J=7.6, 1.8 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.23-7.21 (m, 1H), 5.93 (s, 2H), 5.39 (p, J=7.0 Hz, 1H), 1.64 (d, J=6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 163.2, 161.2, 149.4, 148.3, 143.6, 136.9, 135.8, 130.1, 129.9, 126.6, 123.8. 122.4, 121.5, 121.0, 111.7, 50.1, 22.4.
The preparation process of 14v was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using (quinoline-8-methyl)amine instead of 2-aminomethylpyridine to finally afford the compound 14v (48 mg, 65%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 9.06-9.05 (m, 1H), 8.94 (s, 1H), 8.84 (t, J=6.3 Hz, 1H), 8.45-8.42 (m, 2H), 7.93 (t, J=9.1 Hz, 2H), 7.73 (d, J=7.0 Hz, 1H), 7.64-7.54 (m, 3H), 7.49-7.46 (m, 3H), 5.16 (d, J=6.3 Hz, 2H).
The preparation process of compound 14w was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 1-(8-quinolinyl)ethylamine instead of 2-aminomethylpyridine to finally afford the compound 14 w (52 mg, 68%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 9.47 (d, J=9.0 Hz, 1H), 9.14 (d, J=4.3 Hz, 1H), 8.88 (s, 1H), 8.44-8.41 (m, 2H), 7.94-7.91 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.64-7.45 (m, 6H), 6.05 (p, J=7.1 Hz, 1H), 1.69 (d, J=6.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 162.9, 150.4, 149.4, 145.7, 143.6, 141.3, 137.3, 136.3, 130.6, 130.4, 128.9, 127.9, 127.3, 126.9, 126.4, 123.5, 121.9, 120.6, 113.6, 111.3, 47.4, 23.6.
The preparation process of compound 14x was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-(pyridin-2-yl)-2-propylamine instead of 2-aminomethylpyridine to finally afford the compound 14x (48 mg, 70%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 8.72 (s, 1H), 8.61 (d, J=4.4 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.72 (td, J=7.9, 1.5 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50-7.45 (m, 2H), 7.21-7.18 (m, 1H), 6.12 (s, 2H), 1.91 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 164.6, 163.1, 148.3, 148.1, 143.7, 136.9, 135.8, 130.7, 130.1, 126.5, 123.7, 121.8, 121.0, 119.4, 111.6, 111.4, 57.0, 27.8.
The preparation process of compound 14y was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-(3-chlorophenyl)ethylamine instead of 2-aminomethylpyridine to finally afford the compound 14y (46 mg, 63%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.43 (d, J=8.0 Hz, 1H), 8.25 (d, J=6.5 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 7.49-7.45 (m, 3H), 7.35-7.32 (m, 2H), 7.28-7.23 (m, 2H), 3.60 (q, J=7.0 Hz, 2H), 2.89 (t, J=6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.0, 149.3, 143.6, 142.4, 136.2, 133.5, 130.7, 130.6, 130.2, 129.0, 127.9, 126.7, 126.4, 123.5, 120.6, 113.6, 111.3, 35.3.
The preparation process of 14z was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in the Formula 13 was prepared by using 2-(4-methoxyphenyl)ethylamine instead of 2-aminomethylpyridine to finally afford the compound 14z (51 mg, 72%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.44 (d, J=8.2 Hz, 1H), 8.19 (t, J=6.1 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.50-7.46 (m, 3H), 7.19 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 3.73 (s, 3H), 3.55 (q, J=6.9 Hz, 2H), 2.81 (t, J=7.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 158.2, 149.3, 143.6, 136.2, 131.6, 130.6, 130.3, 130.1, 126.4, 123.5, 120.6, 114.3, 113.6, 111.2, 55.5, 40.9, 34.9.
The first part of the preparation process of compound 14aa was the same as the preparation process of compound 14z in Example 26, then compound 14z was used as an intermediate and the reaction was carried out according to the following reaction formula, namely, methoxy group was converted to hydroxyl group by using boron tribromide. The specific steps were as follows: The compound shown in 14z (36 mg, 0.1 mmol) was dissolved in 1 mL of dichloromethane and cooled to 0° C., then a solution of boron tribromide in dichloromethane was added (0.2 mmol, 0.2 mL). The mixture was transferred to room temperature for reaction and then purified by column to finally afford the compound 14aa (31 mg, 88%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.91 (s, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.18 (t, J=5.4 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.50-7.48 (m, 3H), 7.07 (d, J=8.0 Hz, 2H), 6.72 (d, J=8.0 Hz, 2H), 3.53 (q, J=6.4 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 156.2, 149.3, 143.6, 136.2, 130.6, 130.3, 130.0, 129.8, 126.4, 123.5, 120.6, 115.7, 113.6, 111.2, 41.0, 35.0.
The preparation process of compound 14ab was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in the Formula 13 was prepared by using 2-aminomethylpyridine instead of 2-aminomethylpyridine to finally afford the compound 14ab (52 mg, 69%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.44 (d, J=8.2 Hz, 1H), 8.17 (t, J=6. 1 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.49-7.45 (m, 3H), 6.86-6.83 (m, 2H), 6.72 (d, J=7.7 Hz, 1H), 5.98 (s, 2H), 3.55 (q, J=6.9 Hz, 2H), 2.80 (t, J=7.3 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 149.3, 147.7, 146.0, 143.6, 136.2, 133.5, 130.6, 130.3, 126.4, 123.5, 122.0, 120.6, 113.6, 111.2, 109.4, 108.7, 101.2, 40.8, 35.5.
The preparation process of compound 14ac was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 2-(2-aminoethyl)pyridine instead of 2-aminomethylpyridine to finally afford the compound 14ac (48 mg, 71%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.45-8.42 (m, 2H), 7.92 (d, J=8.1 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.49-7.46 (m, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.27-7.24 (m, 1H), 3.74 (q, J=6.7 Hz, 2H), 3.05 (t, J=7.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 159.6, 149.6, 149.3, 143.6, 137.1, 136.2, 130.6, 130.3, 126.4, 123.6, 123.5, 122.0, 120.6, 113.6, 111.2, 38.8, 37.6.
The preparation process of compound 14ad was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in the Formula 13 was prepared by using 3-(2-aminoethyl)pyridine instead of 2-aminomethylpyridine to finally afford the compound 14ad (46 mg, 69%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.49 (s, 1H), 8.44-8.43 (m, 2H), 8.26 (t, J=6.2 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.71-7.69 (m, 1H), 7.56 (t, J=6.7 Hz, 1H), 7.49-7.45 (m, 3H), 7.35-7.32 (m, 1H), 3.62 (q, J=6.8 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.1, 150.3, 149.3, 148.0, 143.6, 136.7, 136.2, 135.3, 130.6, 130.2, 126.4, 124.0, 123.5, 120.6, 113.6, 111.3, 40.0, 32.9.
The preparation process of compound 14ae was the same as the preparation process of compound 14a in Example 1, except that: in step S9, the compound shown in Formula 13 was prepared by using 4-(2-aminoethyl)pyridine instead of 2-aminomethylpyridine to finally afford the compound 14ae (39 mg, 59%). The chemical structural formula is as follows:
The characterization information of the product is as follows:
1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.49-8.48 (m, 2H), 8.43 (d, J=8.3 Hz, 1H), 8.25 (t, J=6.1 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.58-7.54 (m, 1H), 7.49-7.46 (m, 1H), 7.43 (s, 2H), 7.31-7.30 (m, 2H), 3.64 (q, J=6.9 Hz, 2H), 2.92 (t, J=7.2 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 164.1, 150.0, 149.3, 148.8, 143.6, 136.2, 130.6, 130.2, 126.4, 124.7, 123.5, 120.6, 113.6, 111.3, 39.8. 34.9.
Testing the binding of 1-aminobenzo[4,5]imidazo[1,2-a]pyrazine-3-formamide compounds in Examples 1-31 and the adenosine A2A receptor. The specific process was as follows: A membrane protein solution (60 μg/tube, containing ADA 2 mg/mL) and a radioligand 1 nM [3H]-ZM241385 were added to each tube. Different compounds with the concentration of 10−4 M were added into the compound tubes respectively, shaken to mix uniformly, incubated at 37° C. for 30 minutes and the reaction was terminated in a water bath. Free and bound ligands were separated by suction filtration under negative pressure using GF/C glass fiber filter paper, washed three times with precooled 50 mM Tris-HCl, about 4 mL each time. Film was removed and placed upside down on the tray (i.e., with the grid side facing up), and baked for 3 minutes until dried. Dried small circular filter membrane was put into the liquid scintillation tube in sequence, and 2 mL of scintillation solution was added. [3H] count was then performed in a Multifunction Liquid Scintillation Counter. Each junction point was provided with triple tubes. and the average value was taken. Finally. data analysis was carried out to calculate the inhibition rate of the compound on the adenosine AzA receptor:
Compound inhibition rate (1%)=(sum of compound cpm−compound cpm)/sum of compound cpm×100%.
The test results are shown in Table 1. It can be seen from Table 1 that compounds 14a-14ae have a good inhibitory effect on adenosine A2A receptors. Among them, the inhibition rate on adenosine A2A receptors of compounds 14a to 14e, compound 14k, compound 14o, compound 14p, compounds 14r to 14u, compound 14w, compound 14x and compounds 14ac to 14ae is more than 70%. In particular, the inhibition rate of compounds 14a, 14r, 14s, 14u and 14ac is more than 80%, and they show excellent inhibitory effect on adenosine A2A receptor. They can be used as targeted adenosine A2A receptor inhibitors for immunotherapy, by inhibiting the activity of adenosine A2A receptor, releasing the elimination function of the immune system on tumor cells, thereby achieving the effect of treating tumors.
The embodiments of the presented invention have been illustrated in detail above, but the presented invention is not limited to the described embodiments. For those skilled in the art, without departing from the principles and spirit of the present invention, various changes, modifications, substitutions, and variations made to these embodiments still falls within the protection scope of the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202210018141.0 | Jan 2022 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/104398 | 7/7/2022 | WO |
